Adrenal insufficiency and hormonal active tumors of adrenal glands
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Adrenal glands
Adrenals are a pair of triangular structures located on top of the kidney and weighting approximately 5 g each. Vascularization: a. renalis superior (from a. phrenica inferior), a. suprarenalis media (from aorta abdominalis), a suprarenalis inferior (from a. renalis). Innervation: n. splanchnicus major (through plexus celiacus and plexus renalis), fibrae n. vagus and n. phrenicus).
The adrenals are divided into an outer area, the cortex, which accounts for about four fifth of the gland, and inner area or medulla. The cortex originates from mesodermal tissue and the medulla from the ectodermal tissue.
Adrenal cortex include three zones: - Glomerular (glomerulosa) (produces mineralocorticoids (e.g., aldosterone));
- fascicular (fasciculata) (produces glucocorticoids (e.g., cortisol (hydrocortisone)));
reticular (reticularis) (produces cortisol and androgens (dehydroisoandrosterone (dehydroepiandrosterone)), which exert their chief physiologic activity after conversion to testosterone and dihydrotestosterone).
- A fetal zone, unique to primates, produces dehydroepiandrosterone, a precursor of both androgens and estrogens. This zone involutes within the first few months of postnatal life
Action of mineralocorticoids:
- regulation of electrolyte balance in the organism (increasing the level of sodium (by sodium retention in distal nephron, colon, salivary gland) and decreasing the level of potassium (by excretion)).
Action of glucocorticoids:
- increasing of glycogen synthesis in liver and decreasing of glucose utilization by peripheral tissues, increasing gluconeogenesis;
- increasing of protein synthesis in liver and decreasing of its synthesis in muscles and increasing of protein destruction in muscles;
- increasing of lipolisis;
- anti-inflammatory function and immunomodulation;
- cardiovascular regulation (increasing of blood pressure).
- Cortisol secretion is regulated by ACTH, which, in turn, is regulated by CRH from the hypothalamus. Serum cortisol inhibits secretion of CRH and ACTH, thus preventing excessive secretion of cortisol from the adrenal glands. Adrenal androgen secretion is regulated partially by ACTH but also by other unknown factors. ACTH not only stimulates cortisol secretion, it also promotes growth of the adrenal cortex in conjunction with growth factors such as insulinlike growth factor (IGF)-1 and IGF-2.
Adrenal medulla produces catecholamines. (Catecholamines are produced from the tyrosine (organism takes it from the meal or from the phenilalanine in the liver) → dioxyphenilalanine (DOPHA) → dopamine (it goes into blood only from some neurons of the central nervous system) → norepinephrine (noradrenaline) (it goes into blood only from sympathetic teleneurons) → epinephrine (adrenaline) (it goes into blood only from adrenal medulla). The principle urinary metabolic products of epinephrine and norepinephrine are the metanephrines and vanillylmandalic acid (VMA).
Action of catecholamines:
- modulate vascular tone;
- increase heart rate;
- antagonize insulin action.
Regulation of secretion of catecholamines:
- mineralocorticoids’ secretion is regulated by the renin – angiotensin system, the level of Na+, K+ in blood, and to a lesser extent of ACTH.
CHRONIC ADRENOCORTICAL INSUFFICIENCY
It is an insidious and usually progressive disease resulting from adrenocortical hypofunction.
Frequency:
The calculated incidence is approximately 5-6 cases per million persons per year.
Mortality/Morbidity:
Adrenal insufficiency is a potentially fatal disease if unrecognized and untreated. Death usually results from hypotension or cardiac arrhythmia secondary to hyperkalemia.
Race: Adrenal insufficiency exhibits no racial predilection.
Sex:
- Autoimmune adrenal insufficiency is more common in females than males.
- Adrenal insufficiency due to adrenoleukodystrophy is limited to males because it is X-linked, as is a form of congenital adrenal hypoplasia, termed adrenal hypoplasia congenita (AHC). Both conditions are relatively rare.
- Secondary adrenal insufficiency due to a deficiency of ACTH or CRH, or to a lack of ACTH receptors, is equally common among males and females.
Age: Autoimmune adrenal insufficiency is more common in adults than in children. Congenital causes, such as congenital adrenal hyperplasia (CAH), congenital adrenal hypoplasia, and defects in the ACTH receptor, are more commonly recognized in childhood.
Classification.
1. Primary adrenocortical insufficiency (Addison’s disease).
2. Secondary adrenocortical insufficiency .
Primary adrenal insufficiency occurs when the adrenal gland itself is dysfunctional. Secondary adrenal insufficiency, also termed central adrenal insufficiency, occurs when lack of corticotropin-releasing hormone (CRH) secretion from the hypothalamus or adrenocorticotropic hormone (ACTH) secretion from the pituitary is responsible for hypofunction of the adrenal cortex. Adrenal insufficiency can be classified further as congenital or acquired.
Etiology of
primary adrenocortical insufficiency:
1. In developed countries, the most common cause is autoimmune destruction (50 – 65 %) of the adrenal cortex. This disorder may exist in isolation or may be part of a polyglandular autoimmune disorder
- Type 1 autoimmune polyglandular disease presents in the first decade of life and is transmitted as an autosomal recessive disorder with all or some of the following:
o Adrenal failure
o Hypoparathyroidism
o Hypothyroidism
o Gonadal failure
o Diabetes mellitus type 1
o Vitiligo
o Pernicious anemia
o Chronic mucocutaneous candidiasis
- Type 2 autoimmune polyglandular disease consists of type 1 diabetes mellitus, autoimmune thyroid disease, and adrenal failure. This condition presents in the second and third decades of life and is transmitted as an autosomal disorder with variable penetrance.
2. Less common causes of adrenal failure include the following:
1) Tuberculosis;
2) neoplasm, metastatic carcinoma;
3) inflammatory necrosis;
4) amyloidosis;
5) bilateral adrenal hemorrhage or infarction, intra – adrenal hemorrhage (Waterhouse – Friedrichsen syndrome following meningococcal septicemia);
6) heamochromatosis (may cause either primary or secondary adrenal insufficiency. Iron deposition in the pituitary and/or adrenal glands in multiply transfused patients with thalassemia patients also may cause adrenal insufficiency);
7) bilateral adrenalectomy;
3. Congenital primary adrenal insufficiency
o Congenital disease may occur from adrenal hypoplasia or hyperplasia.
o Adrenal hypoplasia congenita (AHC), inherited as an X-linked disorder, is caused by deletion of the DAX1 gene on chromosome X and often is part of a contiguous gene deletion that involves glycerol kinase deficiency, Duchenne muscular dystrophy, and hypogonadotropic hypogonadism. An alternate form, also X-linked, has been described characterized by intrauterine growth retardation and skeletal and genital anomalies. A third form of AHC is autosomal recessive.
o CAH results from a deficiency of 1 of several enzymes required for adrenal synthesis of cortisol. Adrenal insufficiency most often develops with combined deficiencies of cortisol and aldosterone. The most prevalent form of CAH is caused by a steroid 21-hydroxylase deficiency.
o Lipoid adrenal hyperplasia is another rare form of adrenal insufficiency caused either by a mutation in the steroid acute regulatory protein or a mutation in the cholesterol side chain cleavage gen. This disease causes a defective synthesis of all adrenocortical hormones and, in its complete form, is lethal.
o Mutations or deletions of P450 oxidoreductase, a flavoprotein that provides electrons to various enzyme systems, results in combined deficiencies of 17 hydroxylase, 21 hydroxylase, and 17-20 lyase activities resulting in adrenal insufficiency often accompanied by primary hypogonadism.
Etiology of
secondary adrenocortical insufficiency:
1) Most cases are iatrogenic, caused by long-term administration of glucocorticoids. A mere 2 weeks' exposure to pharmacological doses of glucocorticoids can cause CRH-ACTH-adrenal axis suppression. Suppression can be so great that acute withdrawal or stress may prevent the axis from responding with sufficient cortisol production to prevent an acute adrenal crisis. Recently, treatment with megesterol acetate, an orixegenic agent, has resulted in iatrogenic adrenal suppression, presumably through glucocorticoid properties of megesterol acetate.
2) hypothalamic or pituitary disease (primary injury of these organs leads to insufficiency of ACTH secretion that cause the two – side atrophy of adrenal glands).
Pathogenesis.
Cortisol deficiency contributes to the hypotension and produces in carbohydrate, fat, and protein metabolism, and severe insulin sensitivity. In the absence of cortisol, insufficient carbohydrate is formed from protein; hypoglycemia and diminished liver glycogen result. Weakness, due in part to deficient neuromuscular function follows. Resistance to infection, trauma, and other stress is diminished because of reduced adrenal output. Cardiac output is reduced and circulatory failure can occur. Reduced cortisol blood levels result in increased pituitary ACTH production and an increase in beta – lipotropin, which has melanocyte – stimulating activity and produces the hyperpigmentation of skin and mucous membranes characteristic of Addison’s disease.
There is increased excretion of Na and decreased excretion of K chiefly in the urine, but also in the sweat, saliva, and gastrointestinal tract. Low blood concentrations of Na and Cl and high serum K result. These changes in electrolyte balance produce increased water excretion with severe dehydration, increased plasma concentration, decreased circulatory volume, hypotension, and circulatory collapse.
Symptoms and signs.
Presentation may be acute and chronic. Frequently clinical signs of the primary chronic adrenocortical insufficiency are manifested in that time when adrenocortical tissue is destroyed on 70-90 %.
The most common complaints are: weakness, malaise, weight loss, anorexia, depression.
Objective examination:
1. Increased pigmentation (in patients with primary adrenal insufficiency) is characterized by diffuse tanning of both exposed and nonexposed portions of the body, especially on pressure points (bony prominences), skin folds, scars, and extensor surfaces, black freckles over the forehead, face, neck, and shoulders; bluish – black discoloration of the areolas and the mucous membranes of the lips, mouth, rectum and vagina are common. After compensation hyperpigmentation will decrease. Patients in 15 – 20 % of cases may have areas of vitiligo (depigmentation) as the sign of autoimmune process.
2. Hypotension or postural hypotension (88 – 90 %) with syncopal attacks can occur.
3. Tachycardia.
4. Weight loss (due to dyspeptic syndrome, true muscle tissue catabolism, dehydration).
5. Anorexia, nausea, vomiting, abdominal pain, diarrhea are often. Gastritis, ulcer disease can occur.
6. Decreased cold tolerance, with hypometabolism may be noted.
7. Sexual disorders.
8. Neurologic and psychiatric disorders: decreasing of the memory, mental activity, concentration of attention, depressions, hallucinations can occur due to chronic hypoglycemia which leads to changes of metabolism in brain tissue.
9. Hypoglycemia.
There are three stages of severity: mild, moderate and severe.
Laboratory findings.
- Clinical suspicion is important because presentation of the disorder may be insidious and subtle. When adrenal insufficiency is suspected, the following laboratory studies help establish the diagnosis:
- Electrolytes
- Fasting blood sugar
- Serum ACTH
- Plasma renin activity
- Serum cortisol
- Serum aldosterone
1. A low serum Na level and a high serum P level together with a characteristic clinical picture suggest the possibility of Addison’s disease.
2. Adrenal insufficiency can be specifically diagnosed by:
- low levels of plasma glucocorticoids and mineralocorticoids, or urinary 17 – hydroxycorticosteroid (17 – OHCS) or 17 – ketogenic steroid (17 – KGS);
- demonstrating failure to increase plasma cortisol levels, or urinary 17 – OHCS or 17 – KGS excretion, upon administration of ACTH (in patients with primary adrenal insufficiency).
3. To distinguish between primary and secondary adrenal insufficiency, me have to find the level of plasma ACTH: primary shows increased, and secondary shows decreased level: when plasma ACTH determination is not available, 0.25 mg of cosyntropin or depo-senacten(a synthetic ACTH that has fewer side effects than the natural preparations) may be infused IV (after dilution with dextrose or sodium chloride solution) over a period of 8 h daily for 2 days. Patients with primary adrenocortical insufficiency will show a little or no increase in plasma cortisol or 24 - h urinary corticosteroid levels. Those with secondary adrenocortical insufficiency will have a significant increase in plasma cortisol or 24 - h urinary corticosteroid levels.
- So, when hyponatremia or hyperkalemia is found, conduct a spot urine or 24-hour urine test for sodium, potassium, and creatinine, along with a simultaneous serum creatinine test to determine whether inappropriate natriuresis is occurring.
- Interpret random serum cortisol concentrations within the context from which they were obtained. (For example, adrenal insufficiency is unlikely in an otherwise healthy individual with an 8:00 am serum cortisol concentration more than 10 mcg/dL. Yet a serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient highly suggests adrenal insufficiency.)
- A diagnosis of adrenal insufficiency is confirmed by a serum cortisol concentration less than 18 mcg/dL in the presence of an elevated serum ACTH concentration and plasma renin activity, or a concentration lower than that level obtained 60 minutes following cosyntropin administration.
- Diagnosis also is confirmed when serum cortisol concentrations fail to increase to more than 18-20 mcg/dL by 60 minutes following cosyntropin administration.
- Note that these guidelines do not apply to premature and low birth weight infants, who have much lower cortisol secretion.
- If serum cortisol is low with elevated ACTH, measure antiadrenal antibodies. Antibodies to 1 or more steroidogenic enzymes, particularly 21-hydroxylase, often are found in autoimmune adrenal disease.
- Cosyntropin administration is controversial because whether the best dose is the standard 250 mcg, the 1 mcg, or the low 0.5 mcg/m2 is unresolved, particularly in the pediatric age group. The standard dose, therefore, is suggested. The common preparation of cosyntropin makes it cumbersome to deliver 1 mcg or less, and both doses seem supraphysiological.
- When serum cortisol response to cosyntropin is subnormal, but serum ACTH is not elevated, confirm the possibility of central adrenal insufficiency. In this context, a 6-hour or 3-day treatment with ACTH can produce a normal cortisol response, confirming that initial low cortisol response to cosyntropin was related to chronic ACTH deficiency. The dose of ACTH for the 6-hour test is 25 IU administered IV over the 6 hours. If the 3-day test is chosen, administer 25 mg/m2 of ACTH gel IM every 12 hours for the 3 days. Plasma cortisol should increase to more than 40 mcg/dL in response to either of these tests. Alternatively, 24-hour urinary 17-hydroxysteroid concentrations should increase 5-10 fold in response to the 3-day ACTH stimulation test.
- If the patient has recent onset (ie, <10 d) of central adrenal insufficiency (as in a recent surgery in the hypothalamus or pituitary regions), resorting to a more cumbersome and risk-bearing insulin tolerance test or metyrapone stimulation test may be preferable. These conditions are the only real indication for performing these tests in a patient with adrenal insufficiency
- An insulin tolerance test requires IV administration of insulin (usually 0.05-0.15 units regular insulin/kg) to induce a 50% drop in blood sugar. Measure cortisol and glucose concentrations every 15 minutes for 60 minutes. The test is considered adequate if the blood sugar drops by at least 50%. In response to this hypoglycemic stimulus, serum or plasma cortisol concentrations should rise to more than 20 mcg/dL. This test involves some risk of hypoglycemic seizure; therefore, closely monitor the patient and reverse the hypoglycemia if the patient becomes overly symptomatic.
- Standard metyrapone stimulation tests involve administering 300 mg/m2 metyrapone in 6 divided doses over 24 hours. Because metyrapone inhibits 11-hydroxylase, the last enzyme step in cortisol synthesis, the cortisol precursor 11-deoxycortisol increases in the plasma. A normal response is a rise in 11-deoxycortisol concentrations to more than 10.5 mcg/dL 4 hours following the last dose of metyrapone or a 2- to 3-fold increase in 24-hour urinary 17-hydroxycorticosteroid concentrations (which include tetrahydro compound S [urinary metabolite of 11-deoxycortisol]), on the day or day following metyrapone administration. This test is cumbersome and carries some risk of inducing an adrenal crisis.
- When primary adrenal insufficiency is confirmed, antiadrenal antibodies can confirm an autoimmune cause for the disorder. If the test results for antiadrenal antibodies are negative, search for another etiology such as TB, adrenal hemorrhage, or adrenoleukodystrophy.
- The standard ovine or human CRH stimulation test is reliable in the diagnosis and differential diagnosis of adrenal insufficiency.
- Patients with glucocorticoid deficiency of any etiology have subnormal cortisol responses.
- Patients with primary glucocorticoid deficiency have elevated ACTH concentrations basally and after CRH administration.
- Patients with secondary glucocorticoid deficiency have low ACTH levels throughout the test if they suffer from a primary pituitary deficiency, or these patients have exaggerated responses if their problem is tertiary.
Imaging Studies:
1. The ECG may decreased voltage and prolonged P – R and Q – T intervals.
2. The EEG shows alized slowing of the α – rhythm.
3. CT is the imaging study of choice and helps identify adrenal hemorrhage, calcifications, or infiltrative disease. MRI is not as useful as CT.
4. Abdominal radiographs may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, TB, or Wolman disease.
5. Ultrasonography is a poor imaging modality for investigation of the adrenal glands.
6. Iodocholesterol scanning is not particularly useful.
Procedures:
- CT-guided fine-needle aspiration sometimes helps diagnose the etiology of infiltrative adrenal diseases.
Histologic Findings:
Findings depend on the underlying cause. In cases of autoimmune adrenal failure, the adrenal gland is destroyed by lymphocytic infiltration. Granulomatous changes within the adrenal glands indicate tuberculous adrenal insufficiency. Neoplastic infiltrations are caused by metastatic tumors. Hemorrhagic adrenal insufficiency shows hemorrhagic destruction of adrenals. Fungal disease produces typical pictures.
Differential diagnosis.
- primary and secondary adrenocortical insufficiency (patients with secondary adrenal insufficiency are not hyperpigmented, they have relatively normal electrolyte values; those with panhypopituitarism have depressed thyroid and gonadal function; tests to differentiate primary and secondary adrenal insufficiency were discussed earlier);
- hyperpigmetation due to bronchogenic carcinoma, ingestion of heavy metals such as iron or silver, chronic skin conditions or hemochromatosis; Peutz – Jeghers syndrome (pigmentation of the buccal and rectal mucosa);
- hyperinsulinism;
- neuropsychiatric weakness;
- anorexia nervosa:
- diseases of the gastrointestinal tract.
Treatment.
I. Etiologic: appropriate treatment of complicating infections (e.g., tuberculosis).
II. Pathogenic:
1. Diet (enough quantity of proteins, vitamins, salt and water).
2. Glucocorticoids (normally, glucocorticoids are secreted maximally in the early morning hours, little being secreted at night).
Average dosage is:
- cortisol: 20 – 25 mg daily;
- prednisolone 5 – 7.5 mg daily;
- hydrocortisone 30 – 40 mg orally daily.
2/3 of the dose can be given in the morning and 1/3 in the afternoon. Night doses should be avoided, as they may produce insomnia.
3. Mineraloocorticoids.
DOCSA 5 mg orally daily should be used in patients with severe and moderate duration or fludrocortisone 0.1 – 0.2 mg orally once a day is recommended (this mineralocorticoid replaces aldosterone, some times it is necessary to reduce the dose to 0.05 mg every 2nd day on initial institution of therapy because of ankle edema, but the patient usually adjusts and can then take the larger doses)
4. Intercurrent illnesses (e.g., infections) should be regarded as potentially serious and the patient should double his dosage until he is well.
5. If nausea or vomiting preclude oral therapy, medical attention should be sought immediately andparental therapy started.
ADRENAL CRISIS -
is a medical emergency caused by sudden marked insufficiency of adrenocortical hormones.
Precipitating factors.
1) stress (infection (especially with septicemia, trauma, surgery, prolonged fasting, salt loss due to excessive sweating during hot weather);
2) sudden withdrawal of adrenocortical hormone therapy in patients with chronic insufficiency.
Clinical features.
An adrenal crisis is characterized by:
- profound asthenia,
- severe pains in the abdomen, lower back or legs;
- nausea, vomiting diarrhea;
- peripheral vascular collapse;
- renal shutdown with azotemia.
- Body temperature may be subnormal, through severe hyperthermia due to infection is often seen.
-
Treatment.
Therapy should be instituted immediately once a provisional diagnosis of adrenocortical failure has been made.
1) hydrocortisone 100 – 150 mg as a water – soluble ester (usually the succinate or phosphate) is injected IV over 30 seconds, followed by infusion of 1 L of 5 % glucose – in – saline solution containing 100 mg hydrocortisone ester given over 2 h. Additional saline is given until dehydration and hyponatremia have been corrected. Hydrocortisone therapy is given continuously to a total dosage in 24 h of 400 – 600 – 800 mg. Mineralocorticoids are not required when high – dose hydrocortisone is given. Restoration of BP and general improvement may be expected within 1h or less after the initial dose of hydrocortisone. Vasopressors may be needed until the full effect of hydrocortisone is apparent (a delay in instituting corticosteroid therapy may result in the patient’s death, particularly if hypoglycemia and hypotension are present). A total dose of hydrocortisone 150 mg is usually given over the second 24-h period if the patient is markedly improved, and 75 mg is given on the third day. Maintenance oral doses of hydrocortisone (30 mg) and fludrocortisone acetate (0.1 mg) are given daily there – after. Recovery depends upon treatment of the underlying cause and adequate hydrocortisone therapy.
2) Treatment of complications (hyperpyrexia, psychotic reactions).
3)
Prognosis.
With a substitution therapy, the prognosis is excellent and a patient with Addison’s disease should be able to lead a full life.
Types of cancer which occur in the adrenal glands
Carcinomas may arise in the adrenal cortex (adrenocortical carcinomas) or the adrenal medulla (malignant pheochromocytomas). They also may metastasize to the adrenals from other primary sites.
Approximately 50-70% adrenocortical carcinomas secrete steroid hormones, whereas 30-50% are nonfunctioning.
Functioning adrenocortical carcinomas secrete aldosterone, cortisol, or androgens-alone or in combination. Excessive aldosterone (Conn's syndrome) causes hypertension and hypokalemia.Cortisol overproduction results in Cushing's syndrome. Excessive androgen secretion causes hirsutism and virilization in women and precocious puberty in children but is often asymptomatic in men.
Nonfunctioning adrenocortical carcinomas present clinically as abdominal or flank pain or as an adrenal mass discovered incidentally during an imaging procedure.
Malignancy is strongly suggested by tumor size > 6 cm, evidence of locally invasive ormetastatic disease to the liver or lungs, and elevated urinary 17-ketosteroid excretion. The diagnosis of malignancy is often not suspected, however, until histologic examination after tumor removal.
Treatment for an adrenocortical carcinoma
The treatment of choice is surgery.
Mitotane, an adrenal cytotoxic agent, has produced partial or complete tumor regression, reduced production of adrenal hormones, and improved survival in nonrandomized, noncontrolled trials.
The combination of mitotane with etoposide, cisplatin, and doxorubicin has shown some promise, but responses to chemotherapy have, in general, been disappointing.
Radiation therapy has not been shown to be effective with these tumors.
What tumors metastasize to the adrenal glands?
The vascular adrenal glands are a frequent site of bilateral metastatic spread from cancers of the lung, breast, stomach, pancreas, colon, and kidney, and from melanomas and lymphomas.
Incidental adrenal masses should be assessed for evidence of malignancy and excess hormone secretion. Size is the best predictor of cancer; 25% of masses > 6 cm in size are malignant whereas < 2% of those that are < 4 cm in size are malignant. The most common hormonal disorder is subclinical Cushing's syndrome; the most risky is pheochromocytoma. Accordingly, the recommended hormone evaluation is a 1-mg overnight dexamethasone suppression test and plasma-free metanephrine measurement; patients with hypertension should also have plasma aldosterone and renin levels measured. Surgery is indicated for tumors > 6 cm in size, for those 4-6 cm in size with other radiologic features suggesting cancer or rapid growth on follow-up, for pheochromocytomas and for other overt hormonal syndromes.
Nonfunctioning masses > 6 cm and all hormone-secreting tumors should be removed surgically. Some experts recommend a size cutoff of 4.5 cm for surgery. Smaller masses should be reassessed in 3-6 months, then annually, and removed if growth occurs or if excess hormone secretion develops.
PHEOCHROMOCYTOMA
It is a tumor of chromaffin cells that secrete catecholamines.
Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells. Tumors that arise outside the adrenal gland are termed extra-adrenal pheochromocytomas or paragangliomas. Because of excessive catecholamine secretion, pheochromocytomas may precipitate life-threatening hypertension or cardiac arrhythmias. If the diagnosis of a pheochromocytoma is overlooked, the consequences could be disastrous, even fatal; however, if a pheochromocytoma is found, it is potentially curable.
The term pheochromocytoma (phios means dusky, chroma means color, and cytoma means tumor) refers to the color the tumor cells acquire when stained with chromium salts.
Etiology is unknown.
In about 80 – 90 % of cases, pheochromocytomas are found in the adrenal medulla, but may also be found in other tissues derived from neural crest cells (e.g., tumors may be found in the paraganglia of the sympathetic chain, retroperitoneally along the course of the aorta, in the carotid body, in the organ of Zuckerkandl (at the aortic bifurcation) in the GU system, in the brain, and in the dermoid cysts.
- Pheochromocytomas are known to occur in certain familial syndromes. These include MEN 2A and 2B, neurofibromatosis (von Recklinghausen disease), and VHL disease. The MEN 2A and 2B syndromes, which are autosomally inherited, have been found to have germline mutations in the ret proto-oncogene. The ret proto-oncogene, located on chromosome 10, encodes a tyrosine kinase receptor involved in the regulation of cell growth and differentiation. Pheochromocytomas occur bilaterally in the MEN syndromes in as many as 70% of cases. Pheochromocytomas occur in 1% of neurofibromatosis cases. VHL syndrome is associated with pheochromocytomas, cerebellar hemangioblastomas, and renal cell carcinoma.
- MEN 2A (Sipple syndrome) is characterized by medullary thyroid carcinoma, hyperparathyroidism, pheochromocytomas, and Hirschsprung disease. Over 95% of cases of MEN 2A are associated with mutations in the ret proto-oncogene affecting 1 of 5 codons in exon 10 (codons 609, 611, 618, 620) or exon 11 (codon 634).
- Medullary thyroid carcinoma, pheochromocytoma, mucosal neurofibromatosis, intestinal ganglioneuromatosis, Hirschsprung disease, and a marfanoid body habitus characterize MEN 2B. A germline missense mutation in the tyrosine kinase domain of the ret proto-oncogene (exon 16, codon 918) has been reported to be present in 95% of patients with MEN 2B.
- Pheochromocytoma, cerebellar hemangioblastoma, renal cell carcinoma, renal and pancreatic cysts, and epididymal cystadenomas are associated with VHL disease. One study found that this syndrome was present in nearly 19% of patients with pheochromocytomas (Neumann, 1993). More than 75 germline mutations have been identified in a VHL suppressor gene located on chromosome 3.
- Congenital anomalies (often benign tumors) of the skin, nervous system, bones, and endocrine glands characterize neurofibromatosis, or von Recklinghausen disease. Only 1% of patients with neurofibromatosis have been found to have pheochromocytomas, but as many as 5% of patients with pheochromocytomas have been found to have neurofibromatosis.
- Other neuroectodermal disorders associated with pheochromocytomas include tuberous sclerosis (Bourneville disease, epiloia) and Sturge-Weber syndrome.
- Pheochromocytomas may produce calcitonin, opioid peptides, somatostatin, corticotropin, and vasoactive intestinal peptide. Corticotropin hypersecretion has caused Cushing syndrome, and vasoactive intestinal peptide overproduction causes watery diarrhea.
Classification.
1. Paroxysmal form (45 %).
2. Permanent form (50 %):
- with crisis;
- without crises.
3. Latent or silent form (nonsymptomatic).
Clinical features
is due to secretion of one or more of the catecholamine hormones or precursors: norepinephrine (noradrenaline), epinephrine (adrenaline), dopamine.
- Clinical signs
- The most prominent feature is hypertension (paroxysmal in 50% of cases)
- Postural hypotension: This results from volume contraction.
- Hypertensive retinopathy
- Hypertrophy of left ventricle
- Weight loss
- Pallor
- Fever
- Tremor
- Neurofibromas
- Café au lait spots: These are patches of cutaneous pigmentation, which vary from 1-10 mmand occur any place on the body. Characteristic locations include the axillae and intertriginous areas (groin). They vary from light to dark brown, hence the name café au lait.
- Tachyarrhythmias
- Pulmonary edema
- Cardiomyopathy
- cold and clammy skin, severe headache, angina, palpitation,
- visual disturbances,
- dyspnea, parasthesias,
- nausea, vomiting, epigastric pain, constipation or diarrhea and a sense of impending doom are common; some or all of these symptoms and signs may occur in any patient.
Duration of hypertensive crisis is variable, lasting from a seconds or few minutes to a days., but 50 % of the paroxysms last less than 15 min. Permanent form of the disease’s duration looks like malignant hypertension. Nonsymptomatic form of the disease is rare.
The severity of the retinopathy and cardiomegaly is often less extensive than might be expected for the degree of hypertension present.
Laboratory features and investigations.1. Hyperglycemia2. Hypercalcemia3. Erythrocytosis4. An increased 3-h (24-h) urinary excretion of epinephrine, norepinephrine and their metabolic products (VMA or metanephrines).5. Increased plasma epinephrine, norepinephrine. Imaging StudiesCT scanning or MRI of the abdomen for the localization of the adrenal and extra – adrenal tumors is useful.Over 90 % of pheochromocytomas are located within the adrenal glands, and 98 % are within the abdomen. Extra-adrenal pheochromocytomas develop in the paraganglion chromaffin tissue of the sympathetic nervous system. They may occur anywhere from the base of the brain to the urinary bladder. Common locations for extra-adrenal pheochromocytomas include the organ of Zuckerkandl (close to origin of the inferior mesenteric artery), bladder wall, heart, mediastinum, and carotid and glomus jugulare bodies.Only perform imaging studies after biochemical studies have confirmed the diagnosis of a pheochromocytoma. MRI is preferred over CT scanning. MRI has a reported sensitivity of up to 100% in detecting adrenal pheochromocytomas , does not require contrast, and does not expose the patient to ionizing radiation. MRI is also superior to CT scanning for detecting extra-adrenal pheochromocytomas. Typically, (approximately 70% of cases), pheochromocytomas appear hyperintense on T2-weighted images because of their high water content.CT scanning of the abdomen has an accuracy of 85-95% for detecting adrenal masses with a spatial resolution of 1 cm or greater. CT scanning is less accurate for lesions smaller than 1 cm. Diferentiating an adenoma from a pheochromocytoma is more difficult using CT scanning. While most pheochromocytomas have CT attenuation greater than 10 Hounsfield units (HU), they rarely contain sufficient intracellular fat to have an attenuation of less than 10 HU. In addition, most pheochromocytomas have enhancement loss that is similar to that of adrenal metastases and significantly less than that of adrenal adenomas. However, in patients in whom pheochromocytomas are strongly suspected, adrenal pheochromocytomas cannot be entirely excluded from the list of differential diagnoses of adrenal neoplasms with less than 10-HU attenuation value and greater than 60% washout on delayed scanning.A scan with iodine I 131–labeled metaiodobenzylguanidine (MIBG) is reserved for cases in which a pheochromocytoma is confirmed biochemically but CT scanning or MRI do not show a tumor. The molecular structure of iodine I 123 MIBG resembles norepinephrine and concentrates within adrenal or extra-adrenal pheochromocytomas. This isotope has a short half-life and is expensive. It frequently is used in cases of familial pheochromocytoma syndromes, recurrent pheochromocytoma, or malignant pheochromocytoma. In the United States, only 131I-labeled MIBG is available, whereas 123I MIBG is used in Europe and Japan.A somatostatin receptor analog indium In 111 pentetreotide is less sensitive than MIBG and may be used to visualize pheochromocytomas that do not concentrate MIBG.Positron emission tomography (PET) scanning has been used as an imaging modality and has shown promising results. PET of 18F-fluorodeoxyglucose, which is selectively concentrated as part of the abnormal metabolism of many neoplasms, has been demonstrated to detect occult pheochromocytomas. Pheochromocytomas usually show increased uptake on PET scanning, as do adrenal metastases. The most impressive results to date have been with 6-[18F] fluorodopamine PET scanning and carbon 11 hydroxyephedrine PET scanning. Results of these studies suggest that PET scanning performed with both of these radioisotopes is extremely useful in the detection and localization of pheochromocytomas. Further study results with these agents are eagerly awaited.Histologic Findings:can help in differentiation of benign and malignant tumors.Differential diagnosis: hypertensive disease, symptomatic hypertension. Treatment.Surgical resection of the tumor is the treatment of choice and usually results in cure of the hypertension. Careful treatment with alpha- and beta-blockers is required preoperatively to control blood pressure and prevent intraoperative hypertensive crises.Start alpha blockade with phenoxybenzamine 7-10 days preoperatively to allow for expansion of blood volume.The patient should undergo volume expansion with isotonic sodium chloride solution. Encourage liberal salt intake.Initiate a beta-blocker only after adequate alpha blockade. If beta blockade is started prematurely, unopposed alpha stimulation could precipitate a hypertensive crisis.Administer the last doses of oral alpha- and beta-blockers on the morning of surgery.Surgical CareBoth an experienced anesthesiologist and an experienced surgeon are crucial to the success of the operation. Surgical mortality rates are less than 2-3% with an experienced anesthesiologist and surgeon.Administer stress-dose steroids if bilateral resection is planned. An anterior midline abdominal approach was used in the past; however, in current practice, laparoscopic adrenalectomy is the preferred procedure for lesions smaller than 8 cm.If the pheochromocytoma is intra-adrenal, remove the entire adrenal gland. In the case of a malignant pheochromocytoma, resect as much of the tumor as possible. Medical therapy is used for preoperative preparation prior to surgical resection, acute hypertensive crises, and primary therapy for patients with metastatic pheochromocytomas. Preoperative preparation requires combined alpha and beta blockade to control blood pressure and to prevent an intraoperative hypertensive crisis. Alpha-adrenergic blockade, in particular, is required to control blood pressure and prevent a hypertensive crisis. High circulating catecholamine levels stimulate alpha-receptors on blood vessels and cause vasoconstriction.Phenoxybenzamine (Dibenzyline) is the preferred alpha-blocker in preparation for surgery. After effective alpha blockade, administer a beta-blocker. Beta-blockers are needed to control the tachycardia associated with high circulating catecholamine levels and alpha blockade. Beta-adrenergic blockers are used if significant tachycardia occurs after alpha blockade. Only administer beta-adrenergic blockers after adequate alpha blockade because unopposed alpha-adrenergic receptor stimulation can precipitate a hypertensive crisis. Noncardioselective beta-blockers, such as propranolol (Inderal) or nadolol (Corgard), are often used; however, cardioselective agents, such as atenolol (Tenormin) and metoprolol (Lopressor), also may be used.Labetalol (Trandate, Normodyne) is a noncardioselective beta-adrenergic blocker and selective alpha-adrenergic blocker that has been shown to be effective in controlling hypertension associated with pheochromocytoma. It has also been associated with paradoxic episodes of hypertension thought to be secondary to incomplete alpha blockade. Thus, its use in the preoperative treatment of patients with pheochromocytoma is controversial. During surgery, intravenous phentolamine, a rapid-acting alpha-adrenergic antagonist, is used to control blood pressure. Rapid-acting intravenous beta-blockers, such as esmolol, are also used to normalize blood pressure. Selective alpha1-blocking agents, such as prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura), have more favorable adverse effect profiles and are used when long-term therapy is required (metastatic pheochromocytoma). These medications are not used to prepare patients for surgery because of their incomplete alpha blockade. During crisis a combination of α- and β- adrenergic blocking agents (phentolamine (tropaphen) 2 - 4 mg every 5 - 10 min till stopping of the crisis, phenoxybenzamine 10 – 20 mg 3 – 4 times daily, propranolol 30 – 60 mg/day) and infusion of sodium nitroprusside. Primary aldosteronismis a generic term for a group of disorders, in which excessive production of aldosterone by the zona glomerulosa of the adrenal cortex occurs independently of normal renin-angiotensin stimulation.These primary disorders of the adrenal system are distinct from forms of secondary hyperaldosteronism due to excessive renin, such as renal artery stenosis.The five clinical entities comprising primary aldosteronism includ:- solitary aldosterone-producing adenoma (APA),- bilateral hyperplasia of the zona glomerulosa (also known as idiopathic hyperaldosteronism [IHA]),- primary adrenal hyperplasia (PAH),- adrenal carcinoma, and- glucocorticoid-remediable aldosteronism.The most common manifestation of hyperaldosteronism is hypertension. It is estimated that 0.05-12% of the hypertensive population may have primary aldosteronism. Primary aldosteronism affects more women than men and occurs most commonly in the third through fifth decades of life.The common clinical manifestations of primary aldosteronismAldosterone normally acts at the renal distal convoluted tubule to stimulate reabsorption of sodium ions (Na+), as well as secretion of potassium (K+) and hydrogen ions (H+), and at the cortical and medullary collecting ducts to cause direct secretion of H+.Excess secretion of aldosterone in primary aldosteronism results in hypertension, hypokalemia, and metabolic alkalosis; hypomagnesemia may occur.Spontaneous hypokalemia (K < 3.5 mEq/L) occurs in 80% of cases of primary aldosteronism; the remaining patients develop hypokalemia within 3-5 days of initiation of liberal sodium intake (150 mEq/day).Most symptoms are manifestations of hypokalemia: weakness, muscle cramping, paresthesias, headaches, palpitations, polyuria, and polydipsia. Hyperglycemia due to insulinopenia occurs in approximately 25% of patients.Unfortunately, there is no single specific and sensitive screening test. One method of screening the hypertensive, hypokalemic patient is to obtain concomitant PA and PRA values. A PA/PRA ratio (PA in ng/dL; PRA in ng/mL/h) that exceeds 20 raises the possibility of primary aldosteronism. Most antihypertensive agents do not affect the PA/PRA ratio; spironolactone, however, must be discontinued for 6 weeks before screening. A 24-hour urine collection for aldosterone should also be collected. Because 12% of patients may have PA/PRA ratios lower than 20, review of the urinary aldosterone value is helpful. Urinary excretion of aldosterone (18-monogluconide) that exceeds 12 mg/day is also suggestive of primary aldosteronism.It is important to differentiate APA from IHAAPA is amenable to surgical resection of the involved adrenal gland, whereas IHA is usually treated medicallyAPAs produce greater amounts of aldosterone and can be stimulated by ACTH.Patients with APA, therefore, have greater PA levels at 8:00 AM, and these levels decrease over the ensuing 4 hours as normal secretion of ACTH diminishes. Patients with IHA, on the other hand, have somewhat lower levels of PA at 8:00 AM, and they experience an increase with upright ambulation. Finally, APAs produce large amounts of 18-OHB; levels > 100 ng/dL occur only in APA and PAH.Computed tomography (CT) or magnetic resonance imaging (MRI). To a limited extent, both localizing procedures may aid in identifying the cause of primary aldosteronism. A large APA may be discernible on high-resolution CT, which at some institutions can identify adenomas as small as 5 mm. MRI at present performs, as well as CT, in identifying APA but involves higher cost and longer scan time. The diagnostic accuracy of MRI or CT in preoperatively localizing an APA is approximately 70-85%. Neither modality is able to differentiate IHA from a small APA. Adrenal carcinoma, a rare cause of excessive aldosterone, is easily identified with either modality.TreatmentAfter the APA is localized, unilateral adrenalectomy is performed. Laparoscopic resection is now widely available and is preferable to the "standard" posterior approach. One year postoperatively, 70% of patients are normotensive. By the fifth postoperative year, only 53% remain normotensive. Normal potassium balance tends to be permanent.Pharmacologic therapy of IHAis quite effective.1) The agent of choice is spironolactone (50-200 mg b.i.d.), a competitive inhibitor of aldosterone. Hypokalemia corrects dramatically, whereas hypertension responds after 4-8 weeks. Unfortunately, spironolactone also inhibits synthesis of testosterone and peripheral action of androgens, causing decreased libido, impotence, and gynecomastia in men. Eplerenone (50 mg b.i.d.) is a recently developed aldosterone antagonist without many of the side effects of spironolactone.2) In patients intolerant of spironolactone, amiloride (5-15 mg b.i.d.) corrects hypokalemia within several days. A concomitant antihypertensive agent is usually necessary to reduce blood pressure. Success also has been reported in cases of IHA treated with calcium channel blockers (calcium is involved in the final common pathway for production of aldosterone) and angiotensin-converting enzyme (ACE) inhibitors (IHA appears to be sensitive to low concentrations of angiotensin II).Management of a patient with PAH. During evaluation, these rare cases appear to be APA. Screening and confirmatory tests, seemingly indicate an APA. Levels of 18-OHB exceed 100 mg/dL. Localizing tests are consistent with APA, and patients usually undergo surgical resection of a nodular hyperplastic gland. The diagnosis is made retrospectively, but surgery is curative.A patient with glucocorticoid-remediable aldosteronism have to be managed with low doses of dexamethasone (0.75 mg/day) or any of the agents used for therapy of IHA (see above) may be effective.Sources and references
A. Main
The Merck Manual of Diagnosis and Therapy (fourteenth Edition)/ Robert Berkow and others. – published by Merck Sharp & Dohme Research Laboratories, 1982. – P. 1014 – 1019,1025 – 1028, 1021 – 1024.
Short Textbook of Medical Diagnosis and Management (Third Edition). Mohammad Inam Danish. –Pakistan, 2002. – P.459 – 462, 504 – 505.
Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New York: WC Graw-Hill Book, 1985. - P. 38 – 42, 144 –164, 198 – 205.
B. Additional
1. Manual of Endocrinology and Metabolism (Second Edition)/ Norman Lavin. – Little, Brown and Company.- Boston-New York-Toronto-London, 1994. - P. 111 – 142, 173 - 180.
2. Endocrine secrets/ (fourth Edition)Michael T. Mc Dermott/ P. 240 – 272.
Contribtors
Congenital adrenal hyperplasia (CAH)
is a family of inherited disorders that result from a decrease in the activity of one of the various enzymes required for the biosynthesis of cortisol. These defects are inherited as autosomal recessive traits and are manifested during both prenatal and postnatal life.
Defects in any of the enzymes required for the synthesis of cortisol from cholesterol can lead to CAH, including steroidogenic acute regulatory (StAR) protein, which is essential in transporting cholesterol to the mitochondria; 3 β-hydroxysteroid dehydrogenase, which is responsible for cholesterol side-chain cleavage; and three hydroxylases, CYP 17 (17 α-hydroxylase), CYP21A2 (21-hydroxylase), and CYP11B1 (11 β-hydroxylase).
All of the enzyme defects leading to CAH are autosomal recessive disorders, that is, both copies of the involved gene must be abnormal for the condition to occur.
The process of adrenal hyperplasia begins in utero. Reduced production of cortisol in the fetus, due to decreased activity of one of the enzymes needed for cortisol synthesis, results in lowered levels of serum cortisol. Cortisol normally acts through a negative feedback loop to inhibit the secretion of ACTH by the pituitary gland and corticotropin-releasing hormone (CRH) by the hypothalamus. Thus, the low serum cortisol levels that occur in a person with CAH increase the secretion of ACTH and CRH in an attempt to stimulate the adrenal glands to overcome the enzyme block and to return the serum cortisol level to normal. As this process continues over time, the elevated levels of serum ACTH stimulate growth of the adrenal glands, leading to hyperplasia.
Adrenal crisis in the newborn period is the most serious consequence of CAH. It usually occurs with genetic defects that result in severe reductions in enzyme activity. It is especially insidious in genetic males who do not have ambiguous genitalia as a clue to the diagnosis. Overall, about two-thirds of patients with 21-hydroxylase deficiency have the salt-wasting form. These patients have decreased production of DOC and aldosterone, which results in hypotension, volume depletion, hyponatremia, hyperkalemia, and increased renin activity. The degree of residual activity of the defective enzyme varies greatly from one affected family to another, depending on the specific genetic alteration
Clinical consequences of CAH in females
Many of the precursors and metabolites that build up behind the blocked enzymes 21-hydroxylase, 11 β-hydroxylase, or 3β-hydroxysteroid dehydrogenase are androgens. They may cause the following:
- Masculinization of the external genitalia of a genetic female fetus, leading to ambiguous genitalia at birth (female pseudohermaphroditism).
- Behaviors more typical of boys during childhood in terms of toy preference, rough play, and aggressiveness. (However, most females are heterosexual and their sexual identity is invariably female.)
- Rapid growth during early childhood with ultimate short stature as an adult due to early closure of epiphyses.
Children with nonclassic CAH (also called late-onset CAH) usually are asymptomatic and have normal external genitalia but later present with the following:
- Premature puberty
- Severe cystic acne
- Hirsutism
- Oligomenorrhea
- Infertility
Newborn males with CAHdue to deficiency of 21-hydroxylase or 11 β-hydroxylase do not have ambiguous genitalia. Due to typical normal physical appearance, it is often difficult to detect an affected male, especially when symptoms of salt-wasting occur after the first week of life. Later in childhood or early adulthood, males can present with the following:
- Premature puberty
- Advanced height in early childhood with ultimate short stature
- Acne
- Testicular enlargement due to adrenal rests
- Infertility (rare)
How is the diagnosis of CAH confirmed?
Because one does not know which enzyme is deficient in a newborn with suspected CAH (unless the family has a documented history of a particular enzyme defect), serum levels of all steroids that may be in the affected biosynthetic pathway can be measured before and after the administration of 250 μg of ACTH. Urinary measurement of these steroids by gas chromatography/mass spectroscopy has recently become economically feasible. Plasma renin activity and aldosterone levels should also be measured to assess the adequacy of aldosterone synthesis. Determination of which steroid levels are supranormal and which are low facilitates localization of the exact enzyme block.
KEY POINTS: CAH
1. CAH, the most common inherited disease, is a group of autosomal recessive disorders, the most frequent of which is 21-hydroxylase deficiency.
2. The most serious consequences of CAH are ambiguous genitalia at birth, neonatal salt-wasting, short stature, and premature puberty.
3. CAH is diagnosed through measurement of cortisol precursors before and 1 hour after the intravenous administration of 250 μg of synthetic ACTH.
4. Predicted adult height can be achieved through early diagnosis, lower doses of corticosteroids in the first year of life, and the use of fludrocortisone even in those who are salt-wasters genetically but not clinically.
5. CAH is a rare cause of ambiguous genitalia in a genetic male.
Treatment
The most important goal of treatment is to prevent salt loss and adrenal crisis in the newborn period. This goal requires the prompt administration of glucocorticoids and, in many cases, mineralocorticoids, as well as careful monitoring of salt intake. This treatment not only replaces the deficient hormones but also suppresses elevated serum ACTH levels, thereby reducing adrenal production of androgenic precursors and metabolites. Such treatment may be given presumptively while awaiting the results of definitive laboratory tests and then discontinued if the tests are not confirmatory.
Surgical correction of ambiguous genitalia, such as repair of labioscrotal fusion, usually is carried out at a later time. Single-stage surgery is now implemented between 2 and 6 months of life.
The preferred glucocorticoid for chronic replacement is hydrocortisone because of its short half-life, which minimizes growth suppression in children. It is sometimes extremely difficult or impossible to find a dosage of glucocorticoid that normalizes production of androgen without impairing growth. In such situations, mineralocorticoids (fludrocortisone) and/or spironolactone/flutamide (androgen receptor blockers that prevent virilization) in combination with the aromatase inhibitor testolactone (which prevents estrogen-induced epiphyseal fusion) may be useful adjunctive therapy in combination with nonsuppressive replacement doses of glucocorticoids. Rarely, adrenalectomy has been used for difficult-to-control patients since treatment of adrenal insufficiency is relatively much simpler.
In adolescents and adults: prednisone or dexamethasone may be used once growth has been completed.
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In medicine (endocrinology), hypoparathyroidism is decreased function of the parathyroid glands, leading to decreased levels of parathyroid hormone (PTH). The consequence, hypocalcaemia, is a serious medical condition.Signs and symptoms
Tingling lips, fingers, and toes
Muscle cramps
Pain in the face, legs, and feet
Abdominal pain
Dry hair
Brittle nails
Dry, scaly skin
Cataracts
Weakened tooth enamel (in children)
Muscle spasms called tetany (can lead to spasms of the larynx, causing breathing difficulties)
Convulsions (seizures)
Tetanic contractions
Additional symptoms that may be associated with this disease include:
Painful menstruation
Hand or foot spasms
Decreased consciousness
Delayed or absent tooth formation
Calcification of the basal ganglia due to increased phosphorus levels driving calcium into the brain tissue.[1]
In contrast to hyperparathyroidism (hyperfunction of the parathyroids), hypoparathyroidism has been shown to result in increased calcium deposition into bones, accompanied by increased bone density, but at the same time, a higher fragility status, believed to result from faulty bone remodeling in the absence of parathyroid hormone activity. Some reports have described a high occurrence, as high as 50%, of vetebral deformities amongst patients with hypoparathyroidism.
Diagnosis
Diagnosis is by measurement of calcium, serum albumin (for correction) and PTH in blood. PTH degrades rapidly at ambient temperatures and the blood sample therefore has to be transported to the laboratory on ice.
If necessary, measuring cAMP (cyclic AMP) in the urine after an intravenous dose of PTH can help in the distinction between hypoparathyroidism and other causes.
Differential diagnoses are:
Pseudohypoparathyroidism (normal PTH levels but tissue insensitivity to the hormone, associated with mental retardation and skeletal deformities) and pseudopseudohypoparathyroidism (sic).
Vitamin D deficiency or hereditary insensitivity to this vitamin (X-linked dominant).
Malabsorption
Kidney disease
Medication: steroids, diuretics, some antiepileptics.
Other tests include ECG for abnormal heart rhythms, and measurement of blood magnesium levels.
[edit]Causes
Hypoparathyroidism can have a number of divergent causes:
Removal of or trauma to the parathyroid glands in thyroid surgery (thyroidectomy) or other neck surgeries is a recognized cause. It is now uncommon, as surgeons generally can spare them during procedures after identifying them. In a small percentage of cases, however, they can become traumatized during surgery and/or their blood supply can be compromised. When this happens the parathyroids may cease functioning for a while or stop altogether.
Autoimmune invasion and destruction is the most common non-surgical cause. It can occur as part of autoimmune polyendocrine syndromes.
Hemochromatosis can lead to iron accumulation and consequent dysfunction of a number of endocrine organs, including the parathyroids.
Absence or dysfunction of the parathyroid glands is one of the components of chromosome 22q11 microdeletion syndrome (other names: DiGeorge syndrome, Schprintzen syndrome, velocardiofacial syndrome).
Magnesium deficiency
DiGeorge syndrome, a disease in which hypoparathyroidism can occur due to a total absence of the parathyroid glands at birth. Familial hypoparathyroidism occurs with other endocrine diseases, such as adrenal insufficiency, in a syndrome called type I polyglandular autoimmune syndrome (PGA I).
Some very rare diseases
Idiopathic (of unknown cause), occasionally familial
[edit]Treatment
Severe hypocalcemia, a potentially life-threatening condition, is treated as soon as possible with intravenous calcium (e.g. as calcium gluconate). Generally, a central venous catheter is recommended, as the calcium can irritate peripheral veins and cause phlebitis.
Long-term treatment of hypoparathyroidism is with calcium and vitamin D3 supplementation (D1 is ineffective in the absence of renal conversion). Teriparatide, a synthetic form of PTH (presently registered for osteoporosis) might become the treatment of choice for PTH supplementation, although further studies are awaited.
In the event of a life-threatening attack of low calcium levels or tetany (prolonged muscle contractions), calcium is administered by intravenous (IV) infusion. Precautions are taken to prevent seizures or larynx spasms. The heart is monitored for abnormal rhythms until the person is stable. When the life-threatening attack has been controlled, treatment continues with medicine taken by mouth as often as four times a day.
[edit]Possible Complications
Tetany can lead to a blocked airway, requiring a tracheotomy.
Stunted growth, malformed teeth, and slow mental development can occur if hypoparathyroidism develops in childhood.
Overtreatment with vitamin D and calcium can cause hypercalcemia (high blood calcium) and sometimes interfere with kidney function.
There is an increased risk of pernicious anemia, Addison's disease, cataract development, and Parkinson's disease.
Hypoparathyroidism is a condition in which your body secretes abnormally low levels of parathyroid hormone (parathormone). This hormone plays a key role in regulating and maintaining a balance of your body's levels of two minerals — calcium and phosphorus.
The low production of parathyroid hormone in hypoparathyroidism leads to abnormally low calcium levels in your blood and bones and to an increased amount of phosphorus.
Treatment for hypoparathyroidism consists of taking supplements to normalize your levels of calcium and phosphorus. Because hypoparathyroidism is a chronic condition, treatment is generally lifelong.
Signs and symptoms of hypoparathyroidism can include:
Tingling or burning (paresthesias) in your fingertips, toes and lips
Muscle aches or cramps affecting your legs, feet, abdomen or face
Twitching or spasms of your muscles, particularly around your mouth, but also in your hands, arms and throat
Fatigue or weakness
Painful menstruation
Patchy hair loss, such as thinning of your eyebrows
Dry, coarse skin
Brittle nails
Anxiety or nervousness
Headaches
Depression, mood swings
Memory problems
When to see a doctor
If you have any of the signs and symptoms associated with hypoparathyroidism, make an appointment with your doctor for an evaluation. Once you've been diagnosed, contact your doctor immediately if you have a seizure or have difficulty breathing, both of which can be complications of hypoparathyroidism.
Hypoparathyroidism occurs when your parathyroid glands don't secrete enough parathyroid hormone. You have four parathyroid glands — each about the size of a grain of rice — located in your neck, adjacent to your thyroid gland.
The low production of parathyroid hormone leads to abnormally reduced calcium levels (hypocalcemia) in your blood and bones and to increased amount of phosphorus (hyperphosphatemia).
Factors that can cause hypoparathyroidism include:
Acquired hypoparathyroidism. This is the most common cause of hypoparathyroidism, and it develops after accidental damage to or removal of the parathyroid glands during surgery. This surgery may be a treatment for diseases of the nearby thyroid gland, or for throat cancer or neck cancer. The loss of function may be temporary, though it can also be permanent. Today, surgeons are aware of and more careful to avoid injuring the parathyroid glands in the course of surgery.
Hereditary hypoparathyroidism. In this form, either the parathyroid glands aren't present at birth or they don't work properly.
Autoimmune disease. In this condition, your immune system creates antibodies against the parathyroid tissues, trying to reject them as if they were foreign bodies. In the process, the parathyroid glands stop manufacturing their hormone.
Extensive cancer radiation treatment of your face or neck, which can result in destruction of your parathyroid glands, or occasionally because of radioactive iodine treatment for hyperthyroidism.
Low levels of magnesium in your blood, which can affect the function of your parathyroid glands. Normal magnesium levels are required for optimum secretion of parathyroid hormone.
Factors that may increase your risk of developing hypoparathyroidism include:
Recent neck surgery, particularly if the thyroid was involved
A family history of hypoparathyroidism
Having certain autoimmune or endocrine conditions, such as Addison's disease — a condition characterized by a deficit in hormone production by the adrenal glands
Hypoparathyroidism may result in any of a number of complications. The following complications are due to low calcium levels, and most may improve with adequate treatment:
Tetany, which refers to cramp-like spasms of your hands and fingers, which may be prolonged and painful; muscle discomfort; and twitches or spasms of the muscles of your face, throat or arms. When these spasms occur in your throat, they could interfere with breathing, creating a possible emergency.
Paresthesias, which are characterized by sensory symptoms consisting of odd, tingling sensations or pins and needles feelings of your lips, tongue, fingers and feet.
Loss of consciousness, with convulsions (grand mal seizures).
Malformation of the shape and size of the teeth.
Impaired kidney function.
Heart arrhythmias and fainting, even heart failure.
Other complications are associated with hypoparathyroidism, but will not improve with calcium and vitamin D treatment:
Stunted growth (short stature)
Slow mental development (or mental retardation) in children
Calcium deposits in the brain
Cataracts
You're likely to start by first seeing your family doctor or a general practitioner. However, you may then be referred to a doctor who specializes in treating hormone disorders (endocrinologist).
Because appointments can be brief, and there's often a lot of ground to cover, it's a good idea to be well prepared. Here's some information to help you get ready for your appointment, and what to expect from your doctor.
What you can do
Write down any symptoms you're experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment.
Write down key personal information, including any major stresses or recent life changes.
Make a list of all medications, vitamins and supplements that you're taking.
Ask a family member or friend to join you, if possible. Sometimes it can be difficult to soak up all the information provided to you during an appointment. Someone who accompanies you may remember something that you missed or forgot.
Write down questions to ask your doctor.
Your time with your doctor is limited, so preparing a list of questions may help you make the most of your time together. List your questions from most important to least important in case time runs out. For hypoparathyroidism, some basic questions to ask your doctor include:
What is likely causing my symptoms or condition?
Other than the most likely cause, what are other possible causes for my symptoms or condition?
What kinds of tests do I need?
Is my condition likely temporary or chronic?
What treatments are available and which do you recommend?
What are the alternatives to the primary approach that you're suggesting?
I have these other health conditions. How can I best manage them together?
Are there any dietary restrictions that I need to follow?
Are there any brochures or other printed material that I can take home with me? What Web sites do you recommend visiting?
In addition to the questions that you've prepared to ask your doctor, don't hesitate to ask questions during your appointment at any time that you don't understand something.
What to expect from your doctor
Your doctor is likely to ask you a number of questions. Being ready to answer them may reserve time to go over any points you want to spend more time on. Your doctor may ask:
When did you first begin experiencing symptoms?
Have you had any recent surgeries involving your neck?
Has anyone else in your family had similar symptoms?
Have your symptoms been continuous, or occasional?
How severe are your symptoms?
What, if anything, seems to improve your symptoms?
What, if anything, appears to worsen your symptoms?
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Medical history
A doctor who suspects hypoparathyroidism begins the diagnostic process by taking a medical history and asking about your symptoms, such as muscle cramps or tingling of the extremities. He or she will also want to know whether you've had any recent surgeries, particularly operations involving the thyroid or neck.
Physical exam
Next, your doctor will conduct a physical examination, looking for signs that suggest hypoparathyroidism, such as facial muscle twitching.
Blood tests
You'll also undergo blood tests, and the following findings may indicate hypoparathyroidism:
A low blood-calcium level
A low parathyroid hormone level
A high blood-phosphorus level
A low blood-magnesium level
Your doctor may also order these additional tests:
Electrocardiogram (ECG). This test involves taking electrical readings of your heart's activity. It can detect arrhythmias associated with hypocalcemia and, in turn, hypoparathyroidism.
Urine test. Evaluation of a sample of your urine can show whether your body is excreting too much calcium.
X-rays and bone density tests. These can determine whether abnormal calcium levels have affected the strength of your bones.
In diagnosing children, doctors check to see whether tooth development is normal and whether they have met developmental milestones.
In considering treatment for hypoparathyroidism, doctors take into account your symptoms, including their severity, and your overall health. The goal of treatment is to normalize the levels of calcium and phosphorus in your body. A treatment regimen typically includes:
Oral calcium carbonate tablets.
Vitamin D, which can help your body absorb calcium and eliminate phosphorus. The forms of vitamin D called ergocalciferol, dihydrotachysterol or calcitriol are recommended most often, because they have a longer duration of action or are more potent than are other forms of this vitamin. Often, the required doses of vitamin D are much higher than are those used for a typical daily vitamin supplement.
At high doses, calcium supplements can cause gastrointestinal side effects, such as constipation, in some people. For that reason, take these pills only under the guidance of your doctor.
Dietary steps
Your doctor may also recommend that you consult a dietitian, who is likely to advise a diet that is:
Rich in calcium. This includes dairy products, green leafy vegetables, broccoli, kale, and fortified orange juice and breakfast cereals.
Low in phosphorus-rich items. This means avoiding carbonated soft drinks, which contain phosphorus in the form of phosphoric acid. Eggs and meats also tend to be high in phosphorus.
Intravenous infusion
In some cases, when you need immediate relief of symptoms, your doctor may recommend hospitalization in order to administer calcium by intravenous (IV) infusion. These IV infusions may be important if you're having severe spasms associated with tetany. After hospital discharge, you can continue to take calcium and vitamin D as an oral supplement.
Regular monitoring
Your doctor will regularly check your blood to monitor levels of calcium and phosphorus. Initially, these tests will be weekly to monthly. Eventually, you'll need blood tests just twice a year.
Because hypoparathyroidism is a long-lasting (chronic) disorder, treatment strategies are generally recommended for the rest of your life, along with regular blood tests to determine whether calcium in particular is at normal levels. Your doctor will adjust your dose of supplemental calcium if your blood-calcium levels rise or fall.
If calcium in your blood remains low, despite treatment, your doctor may add a prescription diuretic medication — specifically, a thiazide diuretic such as hydrochlorothiazide or metolazone. While some other types of diuretics (loop diuretics) decrease calcium levels in your bloodstream, the thiazides can increase blood-calcium levels.
Most people who are treated for hypoparathyroidism can keep their symptoms under good control if they continue to receive treatment long term. This is particularly true with an early diagnosis, because some of the complications of hypoparathyroidism are permanent.
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There are no specific actions that you can take to prevent hypoparathyroidism. However, if you're scheduled to undergo thyroid or neck surgery, talk to your surgeon for assurance that steps will be taken to avoid damage to your parathyroid glands during the procedure.
If you've had surgery involving your thyroid or neck, be alert for signs and symptoms that could indicate hypoparathyroidism, such as a tingling or burning sensation in your fingers, toes or lips, or muscle twitching or cramping. When they occur, your doctor may recommend prompt treatment with calcium and vitamin D to minimize the seriousness of the disorder.
The parathyroid glands help control calcium use and removal by the body. They do this by producing parathyroid hormone, or PTH. PTH helps control calcium, phosphorus, and vitamin D levels within the blood and bone.
Hypoparathyroidism occurs when the glands produce too little PTH. Blood calcium levels fall, and phosphorus levels rise.
The most common cause of hypoparathyroidism is injury to the parathyroid glands during head and neck surgery. Rarely, hypoparathyroidism is a side effect of radioactive iodine treatment for hyperthyroidism.
Hypoparathyroidism may also be caused by
Low blood magnesium levels
Metabolic alkalosis
DiGeorge syndrome is a childhood disease in which hypoparathyroidism occurs because all the parathyroid glands are missing at birth. Familial hypoparathyroidism occurs with other endocrine diseases, such as adrenal insufficiency, in a syndrome called type I polyglandular autoimmune syndrome (PGA I).
The risk factors for hypoparathyroidism include recent thyroid or neck surgery, a family history of parathyroid disorder, or certain autoimmune diseases such as Addison's disease.
Symptoms
Abdominal pain
Brittle nails
Cataracts
Dry hair
Dry, scaly skin
Muscle cramps
Muscle spasms called tetany (can affect the larynx, causing breathing difficulties)
Pain in the face, legs, and feet
Seizures
Tingling lips, fingers, and toes
Weakened tooth enamel (in children)
Additional symptoms may include:
Decreased consciousness
Delayed or absent tooth formation
Hand or foot spasms
Painful menstruation
Exams and Tests
Blood tests will be done to check calcium, phosphorus, magnesium, and PTH levels. An ECG may show abnormal heart rhythms.
A urine test may be done to determine how much calcium is being removed from the body.
Treatment
The goal of treatment is to restore the calcium and mineral balance in the body.
Treatment involves calcium carbonate and vitamin D supplements, which usually must be taken for life. Blood levels are measured regularly to make sure that the dose is correct. A high-calcium, low-phosphorous diet is recommended.
Persons who have life-threatening attacks of low calcium levels or prolonged muscle contractions are given calcium through a vein (IV). Precautions are taken to prevent seizures or larynx spasms. The heart is monitored for abnormal rhythms until the person is stable. When the life-threatening attack has been controlled, treatment continues with medicine taken by mouth.
Outlook (Prognosis)
The outcome is likely to be good if the diagnosis is made early. However, changes in the teeth, the development of cataracts, and brain calcifications are irreversible.
Possible Complications
Hypoparathyroidism in children may lead to stunted growth, malformed teeth, and slow mental development.
Overtreatment with vitamin D and calcium can cause hypercalcemia (high blood calcium) and may sometimes interfere with kidney function.
Hypoparathyroidism increases your risk of pernicious anemia, Addison's disease, cataracts, and Parkinson's disease.
When to Contact a Medical Professional
Call your health care provider if you develop any symptoms of hypoparathyroidism.
Seizures or breathing problems are an emergency. Call 911 or your local emergency number immediately.
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Hypoparathyroidism is the combination of symptoms due to inadequate parathyroid hormone production. This is a very rare condition, and most commonly occurs because of damage to or removal of parathyroid glands at the time of parathyroid or thyroid surgery.
Hypoparathyroidism is the state of decreased secretion or activity of parathyroid hormone (PTH). This leads to decreased blood levels of calcium (hypocalcemia) and increased levels of blood phosphorus (hyperphosphatemia).
Symptoms can range from quite mild (tingling in the hands, fingers, and around the mouth) to more severe forms of muscle cramps leading. The most severe symptoms are tetany (severe muscle cramping of the entire body) and convulsions (this is very rare).
Parathyroid gland insufficiency is quite rare, but it can occur in several well-defined ways. The most common cause of hypoparathyroidism is the loss of active parathyroid tissue following thyroid or parathyroid surgery. More rare is a defect present at birth (congenital), where a person is born without parathyroid glands. Occasionally, the specific cause of hypoparathyroidism cannot be determined.
Two Categories of Hypoparathyroidism
Deficient parathyroid hormone secretion
Inability of the kidneys and bones to respond to PTH
Deficient Parathyroid Hormone Secretion
This type of hypoparathyroidism is the easiest to understand. A patient afflicted with this condition simply has too little (or a complete absence of) parathyroid tissue; therefore, inadequate PTH is produced.
There are 2 major causes of this problem:
Post-surgical Hypoparathyroidism: The first (and by far most common) cause of inadequate parathyroid hormone production is the removal of parathyroid glands during surgery. The operations that are typically associated with this problem are operations designed to remove parathyroid glands for hyperparathyroidism. The goal of this operation is to remove those parathyroid glands that are overproducing PTH. But occasionally, too much parathyroid tissue is removed.
The second operation associated with post-operative hypoparathyroidism is a total thyroidectomy. This operation is performed for a number of reasons, but because of the close relationship that the thyroid and parathyroid have to one another (including sharing the same blood supply), the parathyroid glands can be injured or removed. This is very rare. In many patients, the inadequate secretion of PTH is transient following surgery on the thyroid or parathyroid glands, so this diagnosis cannot be made immediately following surgery.
Idiopathic Hypoparathyroidsim: Deficient parathyroid hormone (PTH) secretion without a defined cause is termed Idiopathic hypoparathyroidism. This disease is rare and can be congenital or acquired later in life.
Congenital Hypoparathyroidism: Patients in this category are born without parathyroid tissues. Most patients with congenital hypoparathyroidism have no family history of the disease. Those who do may have any one of a number of congenital causes.
The inherited forms tend to arise from abnormal genes may: 1) encode abnormal forms of PTH or its receptor, 2) prevent normal conduction of cell signals from the PTH receptor to the nucleus, or 3) prevent normal gland development before birth.
Hypoparathyroidism with onset during the first few months of life can be permanent or temporary. The cause is usually unknown if spontaneous resolution occurs. If it does not, it will usually manifest by 24 months of age. Finally, mothers who have overactive parathyroid glands may have high calcium levels. The excess ionized calcium can enter the baby and suppress the baby’s parathyroid gland function. If suppression of the gland is not released quickly enough after birth, low calcium levels can be a temporary problem for the baby. This will not result in permanent parathyroid gland dysfunction in the child.
Acquired Hypoparathyroidism: The acquired form of this disease typically arises because the immune system has developed antibodies against parathyroid tissues in an attempt to reject what is sees as a foreign tissue. This disease can affect the parathyroid glands in isolation or can be part of a syndrome that involves many organs.
An antibody that binds to the calcium sensor in the parathyroid gland has been discovered in the blood of patients with autoimmune hypoparathyroidism. It has been proposed that such binding "tricks" the parathyroid gland into believing that the blood level of ionized calcium is high. Responding to this signal, the parathyroid stops making PTH.
Hypomagnesemia
The element magnesium is closely related to calcium in the body. When magnesium levels are too low, calcium levels may also fall. It appears that magnesium is important for parathyroid cells to make PTH normally. Once recognized, this is usually very easy to fix. Chronic alcoholism is a frequent cause of low calcium and magnesium levels.
Resistance to Parathyroid Hormone (Pseudo-hypoparathyroidism)
This disease is also very rare. Like hypoparathyroidism, this disease is characterized by hypocalcemia (too low calcium levels) and hyperphosphatemia (too high phosphorus levels), but patients with pseudo-hypoparathyroidism (or reistance to PTH) are distinguished by the fact that they produce PTH, but their bones and kidneys do not respond to it. Even if PTH is given to them in their veins, they do not respond to it. Therefore, these rare individuals have plenty of PTH, but their organs do not behave appropriately to it. They appear to have hypoparathyroidism, but they do not—thus the name pseudo-hypoparathyroid.
Treatment of Hypoparathyroidism
Vitamin D and calcium supplements are the primary treatments for hypoparathyroidism, regardless of the cause. The only exception is when the inactivity of PTH is due to hypomagnesemia, which is readily treated with magnesium supplementation.
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Hypoparathyroidism describes a condition in which there are low circulating levels of parathyroid hormone (PTH) or insensitivity to its action.1 The causes of hypoparathyroidism vary; however, they all share a common feature of hypocalcemia. The presentation of hypoparathyroidism also varies depending on the chronicity of the resultant hypocalcemia. Muscle spasms/tetany, paresthesias, and seizures may occur in an acute onset, whereas chronic hypoparathyroidism may only be evidenced by visual impairment due to cataract formation.
See Hypocalcemia for more information.
Pathophysiology
Many underlying pathologic etiologies of hypoparathyroidism exist.
The most common causes are neck surgery and autoimmune processes. Hypoparathyroidism resulting from thyroid or parathyroid surgery can become clinically apparent 1-2 days after the procedure or follow the operation by many years. The incidence of permanent hypoparathyroidism varies with the extent of the procedure, the surgeon’s experience, and the underlying disease process being treated. Rarely, hypoparathyroidism can be a complication of radioactive iodine treatment of external localized radiotherapy.2
Autoimmune insult to the parathyroid gland can be isolated or associated with a variety of polyglandular syndromes. Antibodies to the parathyroids have been detected in up to 30% of patients with isolated hypoparathyroidism and 40% of patients with polyglandular disease.3 The calcium sensor-receptor is another target of autoantibodies in hypoparathyroidism. In patients with polyglandular autoimmune syndrome type 1, more than 50% will have this antibody. See Polyglandular Autoimmune Syndrome, Type I.
Maternal hyperparathyroidism can result in transient neonatal hypoparathyroidism.4,5,6 Maternal PTH suppresses neonatal parathyroid activity; however, this resolves rapidly after birth and removal from excessive maternal PTH.
Both hypermagnesemia and hypomagnesemia can result in decreased PTH secretion. In the case of hypermagnesemia, elevated magnesium levels result in stimulation of a calcium-sensing receptor on the pituitary. This, in turn, attenuates PTH secretion. In the case of chronic alcoholics with hypomagnesemia, there is diminution of PTH secretion levels and a resistance to hormone activity.7 See Hypermagnesemia and Hypomagnesemia.
This condition is characterized by thymus and parathyroid dysgenesis, cardiac malformation, and facial dysmorphogenesis.8 Other complex syndromes associated with hypoparathyroidism have been described and include Sanjat-Sakati syndrome, HDR syndrome, Kenny-Caffey syndrome, Kearns-Sayre syndrome, and Pearson marrow-pancreas syndrome.9 See DiGeorge Syndrome and Kearns-Sayre Syndrome.
Infiltration of the parathyroid gland can lead to clinically significant hypoparathyroidism. Causes include metastatic carcinoma, hemochromatosis, transfusion-related iron overload, Wilson disease10 , and sarcoidosis11 . See Hemochromatosis, Wilson Disease, and Sarcoidosis.
PTH functions to maintain plasma calcium levels by withdrawing calcium from bone tissue, glomerular filtrate reabsorption, and indirectly through increased intestinal absorption of calcium by activation of vitamin D-1,25. Insufficient production of PTH is known as true hypoparathyroidism, while decreased action on target tissues iscalled pseudohypoparathyroidism.3 See Pseudohypoparathyroidism.
Frequency
United States
Primary hypoparathyroidism is rare. Familial cases occur with autosomal dominant, autosomal recessive, and X-linked transmission.
Mortality/Morbidity
Acute hypocalcemia can be treated with good outcome. The mortality rate of hypoparathyroidism depends on the underlying cause.
Sex
With the exception of X-linked transmitted syndromes, no sex predilection exists.
Age
Maternal hyperparathyroidism resulting in newborn hypoparathyroidism usually manifests by the third week of life;4,5 however, cases have been reported as late as 2 months of age.6
Patients with DiGeorge syndrome present for clinical evaluation between birth and 3 months of age with a variety of symptoms.
Patients with polyglandular autoimmune syndrome type I present early in life. These patients typically have candidiasis by age 5 years and hypoparathyroidism by age 10 years.
For other forms of hypoparathyroidism, no age predilection is noted.
Clinical
History
A full surgical and family history is essential in cases of suspected hypoparathyroidism.
Neuromuscular irritability, arising from hypocalcemia, is the hallmark of the condition. These features can range from mild-to-moderate paresthesias of the extremities or lips to painful muscle cramps. In severe cases, tetany can result in carpopedal spasm, laryngospasm,12 or generalized seizures. Recurrent laryngospasm should prompt an investigation of underlying hypoparathyroidism.13
Additionally, severe hypocalcemia can result in neuropsychiatric and cardiovascular abnormalities. Neuropsychiatric manifestations include irritability, anxiety, psychosis, dementia, hallucinations, depression, and confusion. The cardiovascular effects of hypocalcemia are usually bradydysrhythmias or prolongation of the QT interval. Severe hypocalcemia can rarely mimic myocardial infarction.14
Gastrointestinal complaints may result from hypocalcemia as well. Smooth muscle spasms can result in intestinal and biliary cramping. Several cases of dysphagia have been described in the setting of hypocalcemia.15
Symptoms are rare unless the ionized calcium level drops below 2.8 mg/dL.3
Physical
The clinical manifestation of hypoparathyroidism is due to hypocalcemia.
Head, ears, eyes, nose, and throat signs
Surgical/traumatic scars
Mucocutaneous candidiasis (in the setting of polyglandular failure type 116 )
Neurologic signs
Hyperreflexia
Tetany
Chvostek sign - Chvostek sign has low sensitivity and specificity. Twenty-five percent of healthy persons will have a positive result; 29% of hypocalcemic patients will have a negative result.3
Trousseau sign (carpal spasm caused by occluding the brachial artery) - Trousseau sign is more reliable. Only 1-4% of healthy persons will have a positive sign; 94% of hypocalcemic persons will have a positive sign.3
Seizures
Altered mental status
Cardiovascular signs
Heart failure17,18
Bradycardia19
Hypotension not responsive to fluids or pressors20
Ophthalmologic signs - Cataracts21
Signs in infants
Vomiting
Abdominal distention
Apneic spells
Intermittent cyanosis
Twitching, tremors, and seizures
Causes
Hypoparathyroidism has multiple etiologies:
Postsurgical
Autoimmune
Sporadic22
Polyglandular syndromes
Activating antibodies to the calcium-sensing receptor23,24
Infiltration
Parathyroid destruction
Copper10
Malignancy
Granulomatous disease11
Mitochondrial neuropathies
Inactivating mutations of the PTH gene22
DiGeorge syndrome8
Impaired secretion and/or action of PTH
Hypomagnesemia25
Pseudohypoparathyroidism
Hemochromatosis26
Infarction27
Hypermagnesemia28
Medication induced (aluminum,29 doxorubicin,25 aminoglycoside,30 cimetidine,31 alendronate32 , omeprazole33 )
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Differential Diagnoses
Candidiasis
Hypomagnesemia
Hypermagnesemia
Hypoparathyroidism
Hyperphosphatemia
Renal Failure, Acute
Hyperventilation Syndrome
Renal Failure, Chronic and Dialysis Complications
Hypocalcemia
Other Problems to Be Considered
Increased protein binding of calcium
Pseudohypoparathyroidism
Vitamin D deficiency
Rickets and osteomalacia
Addison disease
Pernicious anemia
Workup
Laboratory Studies
The diagnosis of hypoparathyroidism is supported by hypocalcemia, hyperphosphatemia, and low parathyroid hormone levels in the absence of renal failure or intestinal malabsorption.
Both total and ionized calcium are decreased. Normal total serum calcium levels range from 9-10.5 mg/dL (2.2-2.6 mmol/L). Normal ionized calcium levels are 4.5-5.6 mg/dL (1.1-1.4 mmol/L).
Serum magnesium level can be low, high, or normal.
Transient symptomatic hypocalcemia can occur immediately after thyroid surgery; normal PTH levels 3 hours after surgery and a normal serum calcium level on the postoperative day one rules out persistent hypoparathyroidism.34
Imaging Studies
Radiography: Bone density is increased35 ; tooth enamel and root abnormalities have been described.36 Ossification of the paravertebral ligaments is frequently observed.37
CT scan: Calcification of subcortical nuclei, dentate nucleus,38 and basal ganglia39 can occur.
Other Tests
ECG may show prolonged QT interval40 , bradycardia, or rarely ST-segment elevations.14
For D-xylose absorption test, the results are usually normal.41
Procedures
Slit lamp examination for cataracts21
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Prehospital Care
Address and stabilize ABCs.
Obtain intravenous access.
Control seizures with benzodiazepines.
Emergency Department Care
Acute, symptomatic hypocalcemia is a medical emergency. The main goal of treatment is to restore serum calcium levels to alleviate symptoms of acute hypocalcemia. In the setting of severe symptoms, calcium therapy should be given even if serum levels are only mildly reduced.
Care to prevent long-term complications from hypocalcemia or hypercalcemia42 should be coordinated with an endocrinologist.
Intravenous calcium: 100-300 mg elemental calcium diluted in 150 mL D5W over 10 minutes (10-30 mL of 10% calcium gluconate [9.3 mg/mL elemental calcium])
This solution raises ionized calcium level by 0.5-1.5 mmol. Calcium chloride may be used if infused through a central line, as it can be harmful when given in a peripheral vein.
Initial rate of infusion is 0.3-2 mg elemental calcium/kg/h. This scale is not exact; base subsequent adjustments on serial calcium measurements every 2-4 hours.
Infuse children with 2 mg/kg elemental calcium, or about 0.2 mL of 10% calcium gluconate/kg, IV.
Oral therapy: Calcium carbonate, 1-2 grams or more per day, in 3-4 divided doses.
May be appropriate for patients with mildly lowered calcium levels and mild or no symptoms.
Consultations
Consult an endocrinologist.
Medication
Hypoparathyroidism is treated primarily with vitamin D. Dietary supplementation with Ca2+ may be necessary.
Electrolyte supplements
Hypoparathyroidism manifests as hypocalcemia. As a result, calcium supplementation may be indicated.
Calcium gluconate (Kalcinate)
Can be given IV initially, then maintained as high-calcium diet. Some patients require calcium supplementation. The 10% IV solution provides 100 mg/mL of calcium gluconate that equals 9 mg/mL (0.46 mEq/mL) of elemental calcium. One 10-mL ampule contains 93 mg of elemental calcium.
Adult
100-300 mg elemental calcium IV (10-30 mL of 10% calcium gluconate) diluted in 150 mL D5W over 10 min; initial rate of infusion is 0.3-2 mg of elemental calcium/kg/h
Pediatric
2 mg/kg IV of elemental calcium (about 20 mg/kg of calcium gluconate 10%)
May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; when administered IV, antagonizes effects of calcium channel blockers; large intake of dietary fiber may decrease absorption and levels
contraindication- Renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
precaution- Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution when administering to digitalized patients or to those with respiratory failure or acidosis or severe hyperphosphatemia; closely monitor IV calcium supplementation because it can cause cardiac dysrhythmias
Vitamin D Analog
Vitamin D enhances absorption of calcium and maintains calcium homeostasis.
Calcitriol (Calcijex, Rocaltrol)
Stimulates absorption of calcium and phosphate from small intestine and promotes release of calcium from bone into blood.
dosing
Adult
0.2-2 mg PO qd, in divided doses
Pediatric
0.04-0.08 mg/kg PO qd, in divided doses
Colestipol, mineral oil, and cholestyramine may decrease absorption from small intestine; thiazide diuretics may increase effects of vitamin D; corticosteroids may
decrease the effectiveness of vitamin D analogs; vitamin D requirements are increased by phenytoin and other hydantoin anticonvulsants, sucralfate, barbiturates, and primidone; concurrent use of magnesium-containing antacids may lead to hypermagnesemia
contraindication
Documented hypersensitivity; hypercalcemia or malabsorption syndrome; patients receiving digitalis glycosides
precaution
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in impaired renal function, renal stones, heart disease, or arteriosclerosis
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Further Inpatient Care
Effects of 1 bolus of intravenous calcium will wane after 2 hours; therefore, subsequent continuous infusion is required to control hypocalcemia.
Cardiac monitoring is indicated for patients with hypoparathyroidism.
Further Outpatient Care
High-calcium diet
Calcium supplementation
Calcitriol
Complications
Complications of hypoparathyroidism may include the following:
Neuromuscular symptoms
Cataracts21
Intracranial calcifications38,39
Growth stunting (with HDR syndrome)43
Tooth malformation36
Mental retardation (with HDR syndrome)43
Hypothyroidism
Cardiomyopathy42
Parkinsonian symptoms44
Ossification of paravertebral ligaments37
Adhesive capsulitis45
Prognosis
Prognosis is determined by the underlying cause of hypoparathyroidism.
Patient Education
Educate patients concerning regulation and effects of calcium on the body.
Educate patients about the importance of periodic blood chemistry evaluation.
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What is hypoparathyroidism?
Hypoparathyroidism is a condition in which the body doesn't make enough parathyroid hormone (PTH).
This hormone regulates the amount of calcium and phosphorus in your body's bones and blood. Decreased levels of PTH lead to low levels of calcium and high levels of phosphorus in the blood. This imbalance can lead to problems with bones, muscles, skin, and nerve endings.
What causes hypoparathyroidism?
The most common cause of hypoparathyroidism is injury to the parathyroid glands, such as during head and neck surgery. Parathyroid glands are small endocrine glands that are located in the neck behind the thyroid gland.
It other cases, hypoparathyroidism is present at birth or may be associated with an autoimmune disease that affects the parathyroids along with other glands in the body, such as the thyroid, ovaries, or adrenal glands.
Hypoparathyroidism is very rare. It is different from hyperparathyroidism, a much more common condition in which the body makes too much PTH.
What are the symptoms of hypoparathyroidism?
Symptoms of hypoparathyroidism may include:
Tingling in the lips, fingers, and toes
Dry hair, brittle nails, and dry, coarse skin
Muscle cramps and pain in the face, hands, legs, and feet
Cataracts on the eyes
Malformations of the teeth, including weakened tooth enamel and misshapen roots of the teeth
Loss of memory
Headaches
Severe muscle spasms (also called tetany) and convulsions
from
Hypoparathyroidism is a rare condition that occurs when the parathyroid glands, located in your neck, do not make enough parathyroid hormone. Parathyroid hormone helps regulate the levels of calcium and phosphorus in your blood. If you have hypoparathyroidism, your body has too little calcium and too much phosphorus. Hypoparathyroidism may be either inherited or acquired (from injury to the glands or, more rarely, from surgery on the thyroid gland).
Signs and Symptoms:
Most symptoms of hypoparathyroidism are a result of the following signs of having too little calcium in the blood:
Muscle spasm or cramping, typically in hands or feet (tetany)
Hair loss
Dry skin or malformed nails
Numbness, tingling, or burning, especially around the mouth and fingers
Candidiasis (yeast infection)
Seizures
The following signs and symptoms often appear in children with hypoparathyroidism:
Poor tooth development
Vomiting
Headaches
Mental deficiency
What Causes It?:
There are a number of causes of hypoparathyroidism:
Underdeveloped or missing parathyroid glands at birth
Medical treatment (radiation to thyroid gland, drug treatment, thyroid or parathyroid surgery)
An underlying medical condition such as cancer, neck trauma, Wilson's disease, too much iron in tissues, low levels of magnesium
Who's Most At Risk?:
People with the following conditions or characteristics are at risk for developing hypoparathyroidism:
Family history of parathyroid disorder
Thyroid or neck surgery
Taking medications that suppress the parathyroid gland
Surgery or removal of the parathyroid gland
What to Expect at Your Provider's Office:
Your health care provider will check for muscle spasms, twitching, and seizures. Your health care provider will examine the skin for problems, such as dry skin, thinning hair, and fungal infections. In children, the health care provider will ask about and check for tooth formation and developmental progress. Blood tests can check levels of calcium, phosphate, magnesium, and parathyroid hormone.
Treatment Options:
Prevention
There is no way to prevent inherited hypoparathyroidism. Thyroid and parathyroid surgery once resulted in damage to parathyroid glands, often causing hypoparathyroidism. Today's surgical techniques, however, make this much less likely.
Treatment Plan
The main treatment for hypothyroidism is aimed at restoring the levels of calcium in the body. If you have hypoparathyroidism, you will probably have to take calcium and vitamin D (which is required for the body to absorb calcium) supplements for the rest of your life. To treat tetany (muscle spasms), calcium will be given intravenously (IV). You may also be prescribed diuretics (water pills) to prevent losing too much calcium in the urine and to reduce the amount of calcium and vitamin D needed.
It is important to get regular checkups so your doctor can monitor the levels of calcium and phosphorus in your blood over time.
Complementary and Alternative Therapies
Calcium and vitamin D supplements are the main treatment for hypoparathyroidism. Your doctor will prescribe the right dose based on your blood tests. Do not change your dose without your doctor's supervision. Your doctor will also recommend taking calcium in divided doses several times a day, to help your body absorb it properly.
Nutrition and Supplements
Following these nutritional tips may help reduce symptoms of hypoparathyroidism. Do not take supplements without your doctor's supervision.
Eliminate all potential food allergens, including dairy, wheat (gluten), soy, corn, preservatives, and food additives. Your health care provider may want to test for food sensitivities.
Eat calcium rich foods, including beans, almonds, and dark green leafy vegetables (such as spinach and kale).
Avoid refined foods, such as white breads, pastas, and sugar.
Eat fewer red meats and more lean meats, cold-water fish, tofu (soy), or beans for protein.
Use healthy cooking oils, such as olive oil or vegetable oil.
Reduce or eliminate trans-fatty acids, found in commercially baked goods such as cookies, crackers, cakes, French fries, onion rings, donuts, processed foods, and margarine.
Limit carbonated beverages. They are high in phosphates, which can leach calcium from your bones.
Avoid coffee and other stimulants, alcohol, and tobacco.
Drink 6 - 8 glasses of filtered water daily.
Drink soy milk, for bone health unless allergic to soy.
Exercise moderately at least 30 minutes daily, 5 days a week.
You may address nutritional deficiencies with the following supplements:
A multivitamin daily, containing the antioxidant vitamins A, C, E, the B-complex vitamins, and trace minerals such as magnesium, calcium, zinc and selenium.
Calcium citrate, 500 - 1,000 mg daily, for bone support.
Vitamin D, 400 IU daily, for bone support and immunity.
Ipriflavone (soy isoflavones) standardized extract, 200 mg three times a day, for bone loss.
Omega-3 fatty acids, such as fish oils, 1 - 2 capsules or 1 - 2 tablespoonfuls of oil daily, to help decrease inflammation and support healthy metabolism.
Foods rich in calcium include:
Almonds
Legumes
Dark leafy greens
Blackstrap molasses
Oats
Sardines
Tahini
Prunes
Apricots
Your doctor may recommend you take calcium with a glass of orange juice; some forms of calcium are better absorbed in an acidic environment. You can also add acid to your diet by squeezing over lemon juice over leafy greens.
Herbs
Herbs are generally available as standardized dried extracts (pills, capsules, or tablets), teas, or tinctures/liquid extracts (alcohol extraction, unless otherwise noted). Mix liquid extracts with favorite beverage. Dose for teas is 1 - 2 heaping teaspoonfuls/cup water steeped for 10 - 15 minutes (roots need longer).
Chaste tree (Vitex agnus castus) standardized extract, 20 - 40 mg daily before breakfast, for support of the parathyroid gland.
Dandelion (Taraxacum officinale) leaf tincture, 5 - 10 mL two to three times a day, for its high mineral content. You can also prepare teas from the leaf.
Horsetail (Equisetum arvense) standardized extract, 300 mg three times daily for support of healthy bones and for its high mineral content.
Homeopathy
Although very few studies have examined the effectiveness of specific homeopathic therapies, professional homeopaths may consider the following remedies for the treatment of hypoparathyroidism based on their knowledge and experience. Before prescribing a remedy, homeopaths take into account a person's constitutional type -- your physical, emotional, and psychological makeup. An experienced homeopath assesses all of these factors when determining the most appropriate treatment for each individual.
Calcarea carbonica (calcium carbonate)
Calcarea phosphorica (calcium phosphate)
Prognosis/Possible Complications:
If hypoparathyroidism is diagnosed early, the prognosis is good. If it is not diagnosed early, complications may occur, including:
Acute muscle spasms leading to breathing problems
Cataracts
Muscle, ligament, and nervous system disorders
Stunted growth, tooth malformations, and mental retardation in childhood.
Following Up:
People with hypoparathyroidism require lifelong monitoring by a health care provider.
Alternative Names:
Parathyroid - underactive
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is a chronic disorder that causes depigmentation of patches of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress, neural, or viral causes.[1] The incidence worldwide is less than 1%.[2] The most common form is non-segmental vitiligo.
Signs and symptoms
The most notable symptom of vitiligo is depigmentation of patches of skin that occurs on the extremities.[3][4] Although patches are initially small, they often enlarge and change shape.[1][3] When skin lesions occur, they are most prominent on the face, hands and wrists.[3][4] Depigmentation is particularly noticeable around body orifices, such as the mouth, eyes, nostrils, genitalia and umbilicus.[3][4] Some lesions have hyperpigmentation around the edges.[5] Patients who are stigmatised for their condition may experience depression and similar mood disorders.[6]
[edit]Non-segmental
In non-segmental vitiligo (NSV), there is usually some form of symmetry in the location of the patches of depigmentation. New patches also appear over time and can be generalized over large portions of the body or localized to a particular area. Vitiligo where little pigmented skin remains is referred to as vitiligo universalis. NSV can come about at any age, unlike segmental vitiligo,which is far more prevalent in teenage years.[5]
Classes of non-segmental Vitiligo include:
Generalized Vitiligo: the most common pattern, wide and randomly distributed areas of depigmentation[7]
Universal Vitiligo: depigmentation encompasses most of the body[7]
Focal Vitiligo: one or a few scattered macules in one area, most common in children[7]
Acrofacial Vitiligo: fingers and periorificial areas[7]
Mucosal Vitiligo: depigmentation of only the mucous membranes[7]
[edit]Segmental
Segmental vitiligo (SV) differs in appearance, etiology and prevalence from associated illnesses. Its treatment is different from that of NSV. It tends to affect areas of skin that are associated with dorsal roots from the spine. It spreads much more rapidly than NSV and, without treatment, it is much more stable/ static in course and not associated with auto-immune diseases and a very treatable condition that responds to topical treatment.
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Differential diagnosis
Conditions with similar symptoms include:
Tinea versicolor[7]
piebaldism[7]
idiopathic guttate hypomelanosis[7]
progressive macular hypomelanosis[7]
[edit]Pathogenesis
Vitiligo is a disorder characterized by patchy loss of skin pigmentation due to immune attacks on melanocytes, which can be caused by defects in many genes. Variations in genes that are part of the immune system or part of melanocytes have both been associated with vitiligo. The immune system genes are associated with other autoimmune disorders.
In one case, the gene TYR, which makes the melanocyte more susceptible to the immune system in vitiligo, also makes the melanocyte more susceptible to the immune system in the skin cancer malignant melanoma. So people with vitiligo caused by the TYR gene are less likely to have malignant melanoma.
A genomewide association study found 10 independent susceptibility loci for generalized vitiligo, responsible for 7.4% of the genetic risk. Some patients had vitiligo alone; others had generalized vitiligo with other autoimmune diseases. Most loci were associated with both forms. (The exception was PTPN22, which was only associated with generalized vitiligo.) In the MHC region, which controls the immune system, major association signals were identified in the class I gene region (between HLA-A and HLA-HGC9) and class II gene region (between HLA-DRB1 and HLA-DQA1). Outside the MHC region, association signals were identified near RERE, PTPN22, LPP, IL2RA, GZMB, UBASH3A and C1QTNF6 genes, which are associated with other autoimmune diseases. TYR encodes tyrosinase, which is not a component of the immune system, but is an enzyme of the melanocyte that catalyzes melanin biosynthesis, and a major autoantigen in generalized vitiligo. The major alleles of TYR are associated with vitiligo, and the minor alleles are associated with malignant melanoma. Vitiligo-associated 402R tyrosinase may be more efficiently presented to the immune system. Melanoma-associated 402Q may fail to be identified by the immune system.[8]
The transcriptional profile of melanocytes from vitiligo patients have been studied. Oligonucleotide microarrays containing approximately 16,000 unique genes were used to analyse mRNA expression in melanocytes from vitiligo patients and age-matched healthy controls. In total, 859 genes were identified as differentially expressed.[9]
Vitiligo is sometime associated with autoimmune and inflammatory diseases,[10] commonly thyroid overexpression and underexpression. A study comparing 656 people with and without vitiligo in 114 families found several mutations (single-nucleotide polymorphisms) in the NALP1 gene.The NALP1 gene, which is on chromosome 17 located at 17p13, is on a cascade that regulates inflammation and cell death, including myeloid and lymphoid cells, which are white cells that are part of the immune response. NALP1 is expressed at high levels in T cells and Langerhan cells, white blood cells that are involved in skin autoimmunity.
Among the inflammatory products of NALP1 are caspase 1 and caspase 5, which activate the inflammatory cytokine interleukin-1?. Interleukin-1? is expressed at high levels in patients with vitiligo. There are compounds which inhibit caspase and interleukin-1?, and so might be useful drugs for vitiligo and associated autoimmune diseases. In one of the mutations, the amino acid leucine in the NALP1 protein was replaced by histidine (Leu155->His). The original protein and sequence is highly conserved in evolution, and found in humans, chimpanzee, rhesus monkey, and bush baby, which means that it is an important protein and an alteration is likely to be harmful. Addison's disease (typically an autoimmune destruction of the adrenal glands) may cause vitiligo
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Treatment
There is no cure for vitiligo, but there are a number of treatments that improve the condition. In fair-skinned people, avoiding tanning of normal skin can make patches of vitiligo much less noticeable. Treatment options generally fall into four groups:[13]
[edit]Sunblock
A high protection sun-block (factor 20 or above) is applied to areas of vitiligo to prevent sunburn. Affected areas of skin are protected when the sun is strong, especially in the middle of the day by wearing, for example, a wide brimmed hat and long sleeved clothing.[13]
[edit]Skin camouflage
In mild cases, vitiligo patches can be hidden with makeup or other cosmetic camouflage solutions. If the affected person is pale-skinned, the patches can be made less visible by avoiding sunlight and sun tanning of unaffected skin.[7]
[edit]Reversal
The traditional treatment used by dermatologists is the application of corticosteroid cream.[14]
Studies have shown that immunomodulator creams such as Protopic and Elidel also cause repigmentation in some cases, when used with UVB narrowband treatments.[15][16]
With one patient, repigmentation occurred significantly when another autoimmune disease, celiac disease, was treated. Eliminating gluten from the diet, a celiac patient who had Vitiligo reported repigmentation starting within 6 months of treatment. With the elimination of gluten, repigmentation continued to increase for 3–5 years, though not totally. This occurred with a patient who had Vitiligo for 25 years prior to learning of their diagnosis and treatment for Celiac Disease.
A 1997 report[17] suggests that combining Vitamin B12 and folic acid supplements with sun exposure caused repigmentation in 52% of cases.
In October 1993, a scientific report was published of successfully transplanting melanocytes to vitiligo affected areas, effectively repigmenting the region.[18] The procedure involved taking a thin layer of pigmented skin from the patient's gluteal region. Melanocytes were then separated out to a cellular suspension that was expanded in culture. The area to be treated was then denuded with a dermabrader and the melanocytes graft applied. Between 70 and 85 percent of patients experienced nearly complete repigmentation of their skin. The longevity of the repigmentation differed from person to person.[19]
Ultraviolet light (UVA) treatments are normally carried out in a hospital clinic. Psoralen and Ultraviolet A light (PUVA) treatment involves taking a drug which makes the skin very sensitive to light. The skin is then exposed to ultraviolet A light (UVA). Treatment is required twice a week for 6–12 months or longer. PUVA may cause side effects such as 'sunburn' type reactions or skin freckling.[13] Narrowband ultraviolet B (UVB) phototherapy is now used more commonly than PUVA as it is less damaging to the skin. As with PUVA, treatment is carried out twice weekly but there is no requirement to pre-sensitise the skin and the treatment sessions are much shorter.[13]
[edit]De-pigmenting
In cases of extensive vitiligo the option to de-pigment the unaffected skin with topical drugs like monobenzone, mequinol or hydroquinone may be considered to render the skin an even colour. The removal of all the skin pigment with monobenzone is permanent and vigorous sun-safety must be adhered to for life to avoid severe sun burn and melanomas. Depigmentation takes about a year to complete
Notable cases
Michael Jackson two years after he was diagnosed with vitiligo universalis, pictured in the early stages of the disease.[20]
Michael Jackson was diagnosed with vitiligo in 1986. In a 90-minute interview with Oprah Winfrey in February 1993, Jackson claimed that he didn't bleach his skin, stating for the first time that he had vitiligo. A friend claimed he started wearing his signature sequin glove to cover the vitiligo that had begun to appear in the early 80s.[21][22][23] It was also confirmed by Jackson during a leaked deposition tape in 1996, that he did not "bleach" his skin.[24] The tape was leaked months after his death in June 2009. According to police reports, 19 tubes of hydroquinone and 18 tubes of benoquin (monobenzone) were found in Michael Jackson's home after his death.[25] In July 2010, Michael Jackson's eldest son Prince Michael Jr is seen in a picture with a patch of de-pigmented skin on his right underarm leading to speculations that he may be affected by vitiligo like his father Michael Jackson.[26]
Graham Norton the Irish television personality.[27]
Lee Thomas, a news anchor and entertainment reporter for WJBK (Fox) Detroit.[28][29][30]
Yvette Fielding, British TV presenter, has had vitiligo from age 11; her mother developed it at age 24.[31][32]
John Wiley Price, the Dallas County Commissioner, also has vitiligo.[33]
Amitabh Bachchan, the famous Bollywood actor, also has vitiligo.[34]
Scott Jorgensen, the WEC fighter, also has vitiligo.[35]
Krizz Kaliko, the rapper, has vitiligo and even used the condition as the title of his first album.
Jon Hamm, Mad Men actor also has vitiligo.[36]
Bryan Danielson, a professional wrestler, has slight vitiligo on his arms and legs.
John Henson, one of the hosts of ABC's Wipeout has vitiligo and has a white patch of hair on the right side of his head from it. [37]
[edit]See also
Albinism
Alphos
Leucism
List of cutaneous conditions
Melanism
Nevus depigmentosus
Pityriasis alba
Quadrichrome vitiligo
Selective ultraviolet phototherapy
Vitiligoguide
Vitiligo (pronounced vit-ill-EYE-go) is a pigmentation disorder in which melanocytes (the cells that make pigment) in the skin are destroyed. As a result, white patches appear on the skin in different parts of the body. Similar patches also appear on both the mucous membranes (tissues that line the inside of the mouth and nose) and the retina (inner layer of the eyeball). The hair that grows on areas affected by vitiligo sometimes turns white.
The cause of vitiligo is not known, but doctors and researchers have several different theories. There is strong evidence that people with vitiligo inherit a group of three genes that make them susceptible to depigmentation. The most widely accepted view is that the depigmentation occurs because vitiligo is an autoimmune disease -- a disease in which a person's immune system reacts against the body's own organs or tissues. People's bodies produce proteins called cytokines that, in vitiligo, alter their pigment-producing cells and cause these cells to die. Another theory is that melanocytes destroy themselves. Finally, some people have reported that a single event such as sunburn or emotional distress triggered vitiligo; however, these events have not been scientifically proven as causes of vitiligo.
Who is affected by vitiligo?
About 0.5 to 1 percent of the world's population, or as many as 65 million people, have vitiligo. In the United States, 1 to 2 million people have the disorder. Half the people who have vitiligo develop it before age 20; most develop it before their 40th birthday. The disorder affects both sexes and all races equally; however, it is more noticeable in people with dark skin.
Vitiligo seems to be somewhat more common in people with certain autoimmune diseases, including hyperthyroidism (an overactive thyroid gland), adrenocortical insufficiency (the adrenal gland does not produce enough of the hormone called corticosteroid), alopecia areata (patches of baldness), and pernicious anemia (a low level of red blood cells caused by the failure of the body to absorb vitamin B12). Scientists do not know the reason for the association between vitiligo and these autoimmune diseases. However, most people with vitiligo have no other autoimmune disease.
Vitiligo may also be hereditary; that is, it can run in families. Children whose parents have the disorder are more likely to develop vitiligo. In fact, 30 percent of people with vitiligo have a family member with the disease. However, only 5 to 7 percent of children will get vitiligo even if a parent has it, and most people with vitiligo do not have a family history of the disorder.
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What are the symptoms vitiligo?
People who develop vitiligo usually first notice white patches (depigmentation) on their skin. These patches are more commonly found on sun-exposed areas of the body, including the hands, feet, arms, face, and lips. Other common areas for white patches to appear are the armpits and groin, and around the mouth, eyes, nostrils, navel, genitals, and rectum.
Vitiligo generally appears in one of three patterns:
focal pattern -- depigmentation limited to one or only a few areas
segmental pattern -- depigmented patches that develop on one side of the body
generalized pattern -- the most common pattern. Depigmentation occurs symmetrically on both sides of the body.
In addition to white patches on the skin, people with vitiligo may have premature graying of the scalp hair, eyelashes, eyebrows, and beard. People with dark skin may notice a loss of color inside their mouths.
Will the depigmented patches spread?
Focal pattern vitiligo and segmental vitiligo remain localized to one part of the body and do not spread. There is no way to predict if generalized vitiligo will spread. For some people, the depigmented patches do not spread. The disorder is usually progressive, however, and over time the white patches will spread to other areas of the body. For some people, vitiligo spreads slowly, over many years. For other people, spreading occurs rapidly. Some people have reported additional depigmentation following periods of physical or emotional stress.
How is vitiligo diagnosed?
The diagnosis of vitiligo is made based on a physical examination, medical history, and laboratory tests.
A doctor will likely suspect vitiligo if you report (or the physical examination reveals) white patches of skin on the body-particularly on sun-exposed areas, including the hands, feet, arms, face, and lips. If vitiligo is suspected, the doctor will ask about your medical history. Important factors in the diagnosis include a family history of vitiligo; a rash, sunburn, or other skin trauma that occurred at the site of vitiligo 2 to 3 months before depigmentation started; stress or physical illness; and premature graying of the hair (before age 35). In addition, the doctor will ask whether you or anyone in your family has had any autoimmune diseases and whether you are very sensitive to the sun.
To help confirm the diagnosis, the doctor may take a small sample (biopsy) of the affected skin to examine under a microscope. In vitiligo, the skin sample will usually show a complete absence of pigment-producing melanocytes. On the other hand, the presence of inflamed cells in the sample may suggest that another condition is responsible for the loss of pigmentation.
Because vitiligo may be associated with pernicious anemia (a condition in which an insufficient amount of vitamin B12 is absorbed from the gastrointestinal tract) or hyperthyroidism (an overactive thyroid gland), the doctor may also take a blood sample to check the blood-cell count and thyroid function. For some patients, the doctor may recommend an eye examination to check for uveitis (inflammation of part of the eye), which sometimes occurs with vitiligo. A blood test to look for the presence of antinuclear antibodies (a type of autoantibody) may also be done. This test helps determine if the patient has another autoimmune disease.
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Although vitiligo is usually not harmful medically and causes no physical pain, its emotional and psychological effects can be devastating. In fact, in India, those with the disease, especially women, are sometimes discriminated against in marriage. Developing vitiligo after marriage can be grounds for divorce.
Regardless of a person's race and culture, white patches of vitiligo can affect emotional and psychological well-being and self-esteem. People with vitiligo can experience emotional stress, particularly if the condition develops on visible areas of the body (such as the face, hands, arms, and feet) or on the genitals. Adolescents, who are often particularly concerned about their appearance, can be devastated by widespread vitiligo. Some people who have vitiligo feel embarrassed, ashamed, depressed, or worried about how others will react.
Fortunately, there are several strategies to help people cope with vitiligo. Also, various treatments -- discussed in the next section -- can minimize, camouflage, or, in some cases, even eliminate white patches. First, it is important to find a doctor who is knowledgeable about the disorder and takes it seriously. The doctor should also be a good listener and be able to provide emotional support. You must let your doctor know if you are feeling depressed, because doctors and other mental health professionals can help people deal with depression. You should also learn as much as possible about the disorder and treatment choices so that you can participate in making important decisions about your medical care.
Talking with other people who have vitiligo may also help. The National Vitiligo Foundation can provide information about vitiligo and refer you to local chapters that have support groups of patients, families, and doctors. Contact information for the foundation is listed at the end of this booklet. Family and friends are another source of support.
Some people with vitiligo have found that cosmetics that cover the white patches improve their appearance and help them feel better about themselves. You may need to experiment with several brands of concealing cosmetics before finding the product that works best.
The main goal of treating vitiligo is to improve appearance. Therapy for vitiligo takes a long time-it usually must be continued for 6 to 18 months. The choice of therapy depends on the number of white patches; their location, sizes, and how widespread they are; and what you prefer in terms of treatment. Each patient responds differently to therapy, and a particular treatment may not work for everyone. Current treatment options for vitiligo include medication, surgery, and adjunctive therapies (used along with surgical or medical treatments).
Medical therapies
A number of medical therapies, most of which are applied topically, can reduce the appearance of vitiligo. These are some of the most commonly used:
Topical steroid therapy. Steroid creams may be helpful in repigmenting (returning the color to) white patches, particularly if they are applied in the initial stages of the disease. Corticosteroids are a group of drugs similar to hormones such as cortisone, which are produced by the adrenal glands. Doctors often prescribe a mild topical corticosteroid cream for children under 10 years old and a stronger one for adults. You must apply the cream to the white patches on the skin for at least 3 months before seeing any results. Corticosteriod creams are the simplest and safest treatment for vitiligo, but are not as effective as psoralen photochemotherapy (see below). Yet, as with any medication, these creams can cause side effects. For this reason, the doctor will monitor you closely for skin shrinkage and skin striae (streaks or lines on the skin). These side effects are more likely to occur in areas where the skin is thin, such as on the face and armpits, or in the genital region. They can be minimized by using weaker formulations of steroid creams in these areas.
Psoralen photochemotherapy. Also known as psoralen and ultraviolet A therapy (PUVA) therapy, this is probably the most effective treatment for vitiligo available in the United States. The goal of PUVA therapy is to repigment the white patches. However, it is time-consuming, and care must be taken to avoid side effects, which can sometimes be severe. Psoralen is a drug that contains chemicals that react with ultraviolet light to cause darkening of the skin. The treatment involves taking psoralen by mouth (orally) or applying it to the skin (topically). This is followed by carefully timed exposure to sunlight or to ultraviolet A (UVA) light that comes from a special lamp. Typically, you will receive treatments in your doctor's office so you can be carefully watched for any side effects. You must minimize exposure to sunlight at other times. Both oral and topical psoralen photochemotherapy are described below.
Topical psoralen photochemotherapy. Often used for people with a small number of depigmented patches affecting a limited part of the body and for children age 2 and older who have localized patches of vitiligo. Treatments are done in a doctor's office under artificial UVA light once or twice a week. The doctor or nurse applies a thin coat of psoralen to your white patches about 30 minutes before exposing you to enough UVA light to turn the affected area pink. The doctor usually increases the dose of UVA light slowly over many weeks. Eventually, the pink areas fade and a more normal skin color appears. After each treatment, you wash your skin with soap and water and apply a sunscreen before leaving the doctor's office.
There are two major potential side effects of topical PUVA therapy: (1) severe sunburn and blistering and (2) too much repigmentation or darkening (hyperpigmentation) of the treated patches or the normal skin surrounding the vitiligo. You can minimize your chances of sunburn if you avoid exposure to direct sunlight after each treatment. Usually, hyperpigmentation is a temporary problem that eventually disappears when treatment is stopped.
Oral psoralen photochemotherapy. Used for people with extensive vitiligo (affecting more than 20 percent of the body) or for people who do not respond to topical PUVA therapy. Oral psoralen is not recommended for children under 10 years of age because it increases the risk of damage to the eyes caused by conditions such as cataracts. For oral PUVA therapy, you take a prescribed dose of psoralen by mouth about 2 hours before exposure to artificial UVA light or sunlight. If artificial light is used, the doctor adjusts the dose of light until the skin in the areas being treated becomes pink. Treatments are usually given two or three times a week, but never 2 days in a row.
For patients who cannot go to a facility to receive PUVA therapy, the doctor may prescribe psoralen that can be used with natural sunlight exposure. The doctor will give you careful instructions on carrying out treatment at home and monitor you during scheduled checkups.
Known side effects of oral psoralen include sunburn, nausea and vomiting, itching, abnormal hair growth, and hyperpigmentation. Oral psoralen photochemotherapy may also increase the risk of skin cancer, although the risk is minimal at doses used for vitiligo. If you are undergoing oral PUVA therapy, you should apply sunscreen and avoid direct sunlight for 24 to 48 hours after each treatment to avoid sunburn and reduce the risk of skin cancer. To avoid eye damage, particularly cataracts, you should also wear protective UVA sunglasses for 18 to 24 hours after each treatment.
Depigmentation. This treatment involves fading the rest of the skin on the body to match the areas that are already white. For people who have vitiligo on more than 50 percent of their bodies, depigmentation may be the best treatment option. Patients apply the drug monobenzyl ether of hydroquinone (monobenzone) twice a day to pigmented areas until they match the already-depigmented areas. You must avoid direct skin-to-skin contact with other people for at least 2 hours after applying the drug, as transfer of the drug may cause depigmentation of the other pe
All surgical therapies must be considered only after proper medical therapy is provided. Surgical techniques are time-consuming and expensive and usually not paid for by insurance carriers. They are appropriate only for carefully selected patients who have vitiligo that has been stable for at least 3 years:
Autologous skin grafts. The doctor removes skin from one area of your body and attaches it to another area. This type of skin grafting is sometimes used for patients with small patches of vitiligo. The doctor removes sections of the normal, pigmented skin (donor sites) and places them on the depigmented areas (recipient sites). There are several possible complications of autologous skin grafting. Infections may occur at the donor or recipient sites. The recipient and donor sites may develop scarring, a cobblestone appearance, or a spotty pigmentation, or may fail to repigment at all. Treatment with grafting takes time and is costly, and many people find it neither acceptable nor affordable.
Skin grafts using blisters. In this procedure, the doctor creates blisters on your pigmented skin by using heat, suction, or freezing cold. The tops of the blisters are then cut out and transplanted to a depigmented skin area. The risks of blister grafting include scarring and lack of repigmentation. However, there is less risk of scarring with this procedure than with other types of grafting.
Micropigmentation (tattooing). This procedure involves implanting pigment into the skin with a special surgical instrument. It works best for the lip area, particularly in people with dark skin. However, it is difficult for the doctor to match perfectly the color of the skin of the surrounding area.
The tattooed area will not change in color when exposed to sun, although the surrounding normal skin will. So even if the tattooed area matches the surrounding skin perfectly at first, it may not later on. Tattooing tends to fade over time. In addition, tattooing of the lips may lead to episodes of blister outbreaks caused by the herpes simplex virus.
Autologous melanocyte transplants. In this procedure, the doctor takes a sample of your normal pigmented skin and places it in a laboratory dish containing a special cell-culture solution to grow melanocytes. When the melanocytes in the culture solution have multiplied, the doctor transplants them to your depigmented skin patches. This procedure is currently experimental and is impractical for the routine care of people with vitiligo. It is also very expensive, and its side effects are not known.
In addition to medical and surgical therapies, there are many things you can do on your own to protect your skin, minimize the appearance of white patches, and cope with the emotional aspects of vitiligo:
Sunscreens. People who have vitiligo, particularly those with fair skin, should minimize sun exposure and use a sunscreen that provides protection from both UVA and ultraviolet B light. Tanning makes the contrast between normal and depigmented skin more noticeable. Sunscreen helps protect the skin from sunburn and long-term damage.
Cosmetics. Some patients with vitiligo cover depigmented patches with stains, makeup, or self-tanning lotions. These cosmetic products can be particularly effective for people whose vitiligo is limited to exposed areas of the body. Many cosmetic companies offer makeup or dyes that you may find helpful for covering up depigmented patches. Self-tanning lotions have an advantage over makeup in that the color will last for several days and will not come off with washing.
Counseling and support groups. Many people with vitiligo find it helpful to get counseling from a mental health professional. People often find they can talk to their counselor about issues that are difficult to discuss with anyone else. A mental health counselor can also offer support and help in coping with vitiligo. In addition, it may be helpful to attend a vitiligo support group.
Research Highlights
In the past two decades, research on the role that melanocytes play in vitiligo has greatly increased. A variety of technical advances, such as gene mapping and cloning, have permitted relatively rapid advances in knowledge of melanocytes at the cellular and molecular levels.
Much of the research that holds promise for understanding, treating, and possibly preventing vitiligo is supported by NIAMS. Researchers are looking at the immune response to see if interrupting certain signals given off by melanocytes can help stop the spread of the depigmentation. They are examining the way melanocytes receive signals from other skin cells that direct them to deposit the pigment.
And at the University of Colorado, NIAMS supports a large collaborative project looking for genes that may contribute to vitiligo in several ethnic groups. Researchers have found evidence of a link between vitiligo and a gene called NALP1. It is hoped that further genetic analyses of these groups will enable them to identify one or more additional vitiligo susceptibility genes. This work may lead to development of specific approaches to disease therapy and prevention for patients at high genetic risk.
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones (chemicals produced by the body that regulate organ function), primarily cortisol, but may also include impaired aldosterone production (a mineralcorticoid) which regulates sodium, potassium and water retention.[1][2] Craving for salt or salty foods due to the urinary losses of sodium is common.[3]
Addison's disease, congenital adrenal hyperplasia, and Cushing's syndrome can manifest as adrenal insufficiency. If not treated, adrenal insufficiency may result in severe abdominal pains, diarrhea, vomiting, profound muscle weakness and fatigue, depression, extremely low blood pressure (hypotension), weight loss, kidney failure, changes in mood and personality, and shock (adrenal crisis).[4] An adrenal crisis often occurs if the body is subjected to stress, such as an accident, injury, surgery, or severe infection; death may quickly follow.[4]
Adrenal insufficiency can also occur when the hypothalamus or the pituitary gland, both located at the base of the skull, does not make adequate amounts of the hormones that assist in regulating adrenal function.[1][5][6] This is called secondary adrenal insufficiency and is caused by lack of production of ACTH in the pituitary or lack of CRH in the hypothalamus.
Types
There are two major types of adrenal insufficiency.
Primary adrenal insufficiency is due to impairment of the adrenal glands.
The most common subtype is called idiopathic or unknown cause of adrenal insufficiency.
Some are due to an autoimmune disease called Addison's disease or autoimmune adrenalitis.
Other cases are due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland.
Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus.[8] These can be due to a form of cancer: a pituitary microadenoma, or a hypothalamic tumor; Sheehan's syndrome, which is associated with impairment of only the pituitary gland; or a past head injury.
Tertiary adrenal insufficiency is due to hypothalamic disease and decrease in corticotropin releasing factor (CRF).
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Causes
Causes of acute adrenal insufficiency are mainly Waterhouse-Friderichsen syndrome, sudden withdrawal of long-term corticosteroid therapy and stress in patients with underlying chronic adrenal insufficiency.[10] The latter is termed critical illness–related corticosteroid insufficiency.
For chronic adrenal insufficiency, the major contributors are autoimmune adrenalitis, tuberculosis, AIDS and metastatic disease.[10] Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections, hemochromatosis and sarcoidosis.[10]
Autoimmune adrenalitis may be part of Type 2 autoimmune polyglandular syndrome, which can include type 1 diabetes), hyperthyroidism, autoimmune thyroid disease (also known as autoimmune thyroiditis, Hashimoto's thyroiditis and Hashimoto's disease).[11] Hypogonadism and pernicious anemia may also present with this syndrome.
Adrenoleukodystrophy can also cause adrenal insufficiency.[12]
Adrenal Insufficiancy can also be caused is when a patient has a Craniopharyngioma which is a benign tumor that can damage the Pituitary gland causing the Adrenal Glands not to function. This would be an example of Secondary Adrenal Insufficiancy Syndrome.
[edit]Symptoms
The person may show symptoms of hypoglycemia, dehydration, weight loss, and disorientation. He or she may experience weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), muscle aches, nausea, vomiting, and diarrhea. These problems may develop gradually and insidiously. Addison's can present with tanning of the skin that may be patchy or even all over the body. Characteristic sites of tanning are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa). Goitre and vitiligo may also be present.[4]
[edit]Diagnosis
If the person is in adrenal crisis, the ACTH stimulation test may be given. If not in crisis, cortisol, ACTH, aldosterone, renin, potassium and sodium are tested from a blood sample before the decision is made if the ACTH stimulation test needs to be performed. X-rays or CT of the adrenals may also be done.[1] The best test for adrenal insufficiency of autoimmune origin, representing more than ninety percent of all cases in a Western population, is measurement of 21-hydroxylase autoantibodies.[13]
[edit]Treatment
Adrenal crisis
Intravenous fluids[4]
Intravenous steroid (Solu-Cortef or Solumedrol), later hydrocortisone, prednisone or methylpredisolone tablets[4]
Rest
Cortisol deficiency (primary and secondary)
Adrenal cortical extract (usually in the form of a supplement, non prescription in the United States)
Hydrocortisone (Cortef) (between 20 and 35 mg)[4]
Prednisone (Deltasone) (7.5 mg)
Prednisolone (Delta-Cortef) (7.5 mg)
Methylprednisolone (Medrol) (6 mg)
Dexamethasone (Decadron) (0.25 mg, rarely up to 1 mg, but higher doses tend to cause side effects resembling Cushing's disease.)
Mineralcorticoid deficiency (low aldosterone)
Fludrocortisone (Florinef) (To balance sodium, potassium and increase water retention
Adrenal failure: A condition in which the adrenal glands do not produce enough of the adrenal hormones that control important functions such as blood pressure.
The adrenal glands sit on top of the kidneys. The adrenal is made up of an outer layer (the cortex) and an inner portion (the medulla). The adrenal glands produce hormones that help control the heart rate, blood pressure, the way the body uses food, and other vital functions. The adrenal cortex secretes steroid (cortisone-related) hormones and mineralocortoids that regulate the levels of minerals such as sodium and potassium in the blood.
The adrenal medulla makes adrenaline (epinephrine) and noradrenaline (norepinephrine). Adrenaline is secreted in response to low blood levels of glucose as well as exercise and stress; it causes the breakdown of the storage product glycogen to the sugar glucose in the liver, facilitates the release of fatty acids from adipose (fat) tissue, causes dilation (widening) of the small arteries within muscle and increases the output of the heart. Noradrenaline is a neurohormone, a neurotransmitter, for of most of the so-called sympathetic nervous system.
The term "Addison's disease" refers to long-term insufficiency of the adrenal cortex. This may be due to a number of different insults to the adrenal including physical trauma, hemorrhage, and tuberculosis of the adrenal, and destruction of the cells in the pituitary gland that secrete ACTH (adrenocorticotropic hormone) which normally drives the adrenal. Addison's disease is characterized by bronzing of the skin, anemia, weakness, and low blood pressure. The U.S. President John F. Kennedy had Addison's disease. The condition is named after the British physician Thomas Addison (1793-1860).
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What is adrenal insufficiency?
Adrenal insufficiency is an endocrine—or hormonal—disorder that occurs when the adrenal glands do not produce enough of certain hormones. The adrenal glands are located just above the kidneys. Adrenal insufficiency can be primary or secondary.
Primary adrenal insufficiency, also called Addison’s disease, occurs when the adrenal glands are damaged and cannot produce enough of the hormone cortisol and often the hormone aldosterone. Addison’s disease affects one to four of every 100,000 people, in all age groups and both sexes.1
Secondary adrenal insufficiency occurs when the pituitary gland—a bean-sized organ in the brain—fails to produce enough adrenocorticotropin (ACTH), a hormone that stimulates the adrenal glands to produce cortisol. If ACTH output is too low, cortisol production drops. Eventually, the adrenal glands can shrink due to lack of ACTH stimulation. Secondary adrenal insufficiency is much more common than Addison’s disease.
1 Munver R, Volfson IA. Adrenal insufficiency: diagnosis and management. Current Urology Reports. 2006;7:80–85.
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What do adrenal hormones do?
Cortisol
Cortisol belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Cortisol’s most important job is to help the body respond to stress. Among its many vital tasks, cortisol helps
maintain blood pressure and cardiovascular function
slow the immune system’s inflammatory response
maintain levels of glucose—a form of sugar used for energy—in the blood
regulate the metabolism of proteins, carbohydrates, and fats
The amount of cortisol produced by the adrenals is precisely balanced. Like many other hormones, cortisol is regulated by the brain’s hypothalamus and the pituitary gland. First, the hypothalamus releases a “trigger” hormone called corticotropin-releasing hormone (CRH) that signals the pituitary gland. The pituitary responds by sending out ACTH, which in turn stimulates the adrenal glands. The adrenal glands respond by producing cortisol. Completing the cycle, cortisol then signals back to both the pituitary and hypothalamus to decrease these trigger hormones.
The hypothalamus sends CRH to the pituitary, which responds by sending out ACTH. ACTH then causes the adrenals to release cortisol into the bloodstream.
Aldosterone
Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. Aldosterone helps maintain blood pressure and water and salt balance in the body by helping the kidneys retain sodium and excrete potassium. When aldosterone production falls too low, the kidneys are not able to regulate water and salt balance, leading to a drop in both blood volume and blood pressure.
[Top]
What are the symptoms of adrenal insufficiency?
The symptoms of adrenal insufficiency usually begin gradually. The most common symptoms are
chronic, worsening fatigue
muscle weakness
loss of appetite
weight loss
Other symptoms can include
nausea
vomiting
diarrhea
low blood pressure that falls further when standing, causing dizziness or fainting
irritability and depression
a craving for salty foods due to salt loss
hypoglycemia, or low blood glucose
headache
sweating
in women, irregular or absent menstrual periods
Hyperpigmentation, or darkening of the skin, can occur in Addison’s disease but not in secondary adrenal insufficiency. This darkening is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles, and toes; lips; and mucous membranes such as the lining of the cheek.
Because the symptoms progress slowly, they are often ignored until a stressful event like an illness or accident causes them to worsen. Sudden, severe worsening of symptoms is called an Addisonian crisis, or acute adrenal insufficiency. In most cases, symptoms of adrenal insufficiency become serious enough that people seek medical treatment before a crisis occurs. However, sometimes symptoms first appear during an Addisonian crisis.
Symptoms of an Addisonian or “adrenal” crisis include
sudden, penetrating pain in the lower back, abdomen, or legs
severe vomiting and diarrhea
dehydration
low blood pressure
loss of consciousness
If not treated, an Addisonian crisis can be fatal.
from
What causes Addison’s disease?
Autoimmune Disorders
The gradual destruction of the adrenal cortex, the outer layer of the adrenal glands, by the body’s immune system causes up to 80 percent of Addison’s disease cases.2 In autoimmune disorders, the immune system makes antibodies that attack the body’s own tissues or organs and slowly destroy them.
Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed. As a result, often both cortisol and aldosterone are lacking. Sometimes only the adrenal glands are affected. Sometimes other endocrine glands are affected as well, as in polyendocrine deficiency syndrome.
Polyendocrine deficiency syndrome is classified into two separate forms, type 1 and type 2. Type 1 is inherited and occurs in children. In addition to adrenal insufficiency, these children may have
underactive parathyroid glands, which produce a hormone that regulates calcium and phosphorus balance in the body
slow sexual development
pernicious anemia, a severe type of anemia
chronic candida infections, a type of fungal infection
chronic active hepatitis, a liver disease
Type 2, sometimes called Schmidt’s syndrome, usually affects young adults and may include
an underactive thyroid gland, which produces hormones that regulate metabolism
slow sexual development
diabetes
vitiligo, a loss of pigment on areas of the skin
Scientists think type 2 polyendocrine deficiency syndrome is also inherited because often more than one family member has one or more endocrine deficiencies.
2Martorell PM, Roep BO, Smit JWA. Autoimmunity in Addison’s disease. The Netherlands Journal of Medicine. 2002;60(7):269–275.
Tuberculosis
Tuberculosis (TB), an infection that can destroy the adrenal glands, accounts for less than 20 percent of cases of Addison’s disease in developed countries.3 When adrenal insufficiency was first identified by Dr. Thomas Addison in 1849, TB was the most common cause of the disease. As TB treatment improved, the incidence of adrenal insufficiency due to TB of the adrenal glands greatly decreased.
3Munver R, Volfson IA. Adrenal insufficiency: diagnosis and management. Current Urology Reports. 2006;7:80–85.
Other Causes
Less common causes of Addison’s disease are
chronic infection, mainly fungal infections
cancer cells spreading from other parts of the body to the adrenal glands
amyloidosis, a disease that causes abnormal protein buildup in, and damage to, various organs
surgical removal of the adrenal glands
AIDS-associated infections
bleeding into the adrenal glands
genetic defects including abnormal adrenal gland development, an inability of the adrenal gland to respond to ACTH, or a defect in adrenal hormone production
[Top]
What causes secondary adrenal insufficiency?
Secondary adrenal insufficiency can be traced to a lack of ACTH. Without ACTH to stimulate the adrenal glands, the adrenals’ production of cortisol drops. Aldosterone production is not usually affected.
A temporary form of secondary adrenal insufficiency may occur when a person who has been taking a synthetic glucocorticoid hormone such as prednisone for a long time stops taking the medication, either abruptly or gradually. Glucocorticoid hormones, which are often used to treat inflammatory illnesses such as rheumatoid arthritis, asthma, and ulcerative colitis, block the release of both CRH and ACTH. As a result, the adrenals may begin to atrophy—or shrink—from lack of ACTH stimulation and then fail to secrete sufficient levels of cortisol.
A person who stops taking a synthetic glucocorticoid hormone may have enough ACTH to function when healthy. However, when a person is under the stress of an illness, accident, or surgery, the person’s body may not have enough ACTH to stimulate the adrenal glands to produce cortisol.
Another cause of secondary adrenal insufficiency is surgical removal of the noncancerous, ACTH-producing tumors of the pituitary gland that cause Cushing’s disease. Cushing’s disease is another disorder that leads to excess cortisol in the body. In this case, the source of ACTH is suddenly removed and replacement hormone must be taken until normal ACTH and cortisol production resumes.
Less commonly, adrenal insufficiency occurs when the pituitary gland either decreases in size or stops producing ACTH. These events can result from
tumors or infections of the area
loss of blood flow to the pituitary
radiation for the treatment of pituitary tumors
surgical removal of parts of the hypothalamus
surgical removal of the pituitary gland
from
How is adrenal insufficiency diagnosed?
In its early stages, adrenal insufficiency can be difficult to diagnose. A review of a patient’s medical history and symptoms may lead a doctor to suspect Addison’s disease.
A diagnosis of adrenal insufficiency is confirmed through laboratory tests. The aim of these tests is first to determine whether levels of cortisol are insufficient and then to establish the cause. Radiologic exams of the adrenal and pituitary glands also are useful in helping to establish the cause.
ACTH Stimulation Test
The ACTH stimulation test is the most commonly used test for diagnosing adrenal insufficiency. In this test, blood cortisol, urine cortisol, or both are measured before and after a synthetic form of ACTH is given by injection. The normal response after an ACTH injection is a rise in blood and urine cortisol levels. People with Addison’s disease or long-standing secondary adrenal insufficiency have little or no increase in cortisol levels.
Both low- and high-dose ACTH stimulation tests may be used depending on the suspected cause of adrenal insufficiency. For example, if secondary adrenal insufficiency is mild or of recent onset, the adrenal glands may still respond to ACTH because they have not yet atrophied. Some studies suggest a low dose—1 microgram—may be more effective in detecting secondary adrenal insufficiency because the low dose is still enough to raise cortisol levels in healthy people but not in people with mild or recent secondary adrenal insufficiency.
CRH Stimulation Test
When the response to the ACTH test is abnormal, a CRH stimulation test can help determine the cause of adrenal insufficiency. In this test, synthetic CRH is injected intravenously and blood cortisol is measured before and 30, 60, 90, and 120 minutes after the injection. People with Addison’s disease respond by producing high levels of ACTH but no cortisol. People with secondary adrenal insufficiency have absent or delayed ACTH responses. CRH will not stimulate ACTH secretion if the pituitary is damaged, so an absent ACTH response points to the pituitary as the cause. A delayed ACTH response points to the hypothalamus as the cause.
Diagnosis during an Emergency
In patients suspected of having an Addisonian crisis, health professionals must begin treatment with injections of salt, glucose-containing fluids, and glucocorticoid hormones immediately. Although a reliable diagnosis is not possible during crisis treatment, measurement of blood ACTH and cortisol during the crisis—before glucocorticoids are given—is enough to make a preliminary diagnosis. Low blood sodium, low blood glucose, and high blood potassium are also usually present at the time of an adrenal crisis. Once the crisis is controlled, an ACTH stimulation test can be performed to obtain the specific diagnosis. More complex laboratory tests are sometimes used if the diagnosis remains unclear.
Other Tests
Once a diagnosis of Addison’s disease is made, radiologic studies such as an x ray or an ultrasound of the abdomen may be taken to see if the adrenals have any signs of calcium deposits. Calcium deposits may indicate bleeding in the adrenal gland or TB, for which a tuberculin skin test also may be used. Blood tests can detect antibodies associated with autoimmune Addison’s disease.
If secondary adrenal insufficiency is diagnosed, doctors may use different imaging tools to reveal the size and shape of the pituitary gland. The most common is the computerized tomography (CT) scan, which produces a series of x-ray pictures giving cross-sectional images. A magnetic resonance imaging (MRI) scan may also be used to produce a three-dimensional image of this region. The function of the pituitary and its ability to produce other hormones also are assessed with blood tests.
[Top]
How is adrenal insufficiency treated?
Treatment of adrenal insufficiency involves replacing, or substituting, the hormones that the adrenal glands are not making. Cortisol is replaced with a synthetic glucocorticoid such as hydrocortisone, prednisone, or dexamethasone, taken orally once to three times each day, depending on which medication is chosen. If aldosterone is also deficient, it is replaced with oral doses of a mineralocorticoid, called fludrocortisone acetate (Florinef), taken once or twice a day. Doctors usually advise patients receiving aldosterone replacement therapy to increase their salt intake. Because people with secondary adrenal insufficiency normally maintain aldosterone production, they do not require aldosterone replacement therapy. The doses of each medication are adjusted to meet the needs of the individual.
During an Addisonian crisis, low blood pressure, low blood glucose, and high levels of potassium can be life threatening. Standard therapy involves intravenous injections of glucocorticoids and large volumes of intravenous saline solution with dextrose, a type of sugar. This treatment usually brings rapid improvement. When the patient can take fluids and medications by mouth, the amount of glucocorticoids is decreased until a maintenance dose is reached. If aldosterone is deficient, maintenance therapy also includes oral doses of fludrocortisone acetate.
[Top]
What special problems can occur with adrenal insufficiency?
Surgery
Because cortisol is a “stress hormone,” people with chronic adrenal insufficiency who need any type of surgery requiring general anesthesia must be treated with intravenous glucocorticoids and saline. Intravenous treatment begins before surgery and continues until the patient is fully awake after surgery and able to take medication by mouth. The “stress” dosage is adjusted as the patient recovers until the presurgery maintenance dose is reached.
In addition, people who are not currently taking glucocorticoids but who have taken long-term glucocorticoids in the past year should tell their doctor before surgery. These people may have sufficient ACTH for normal events, but they may need intravenous treatment for the stress of surgery.
Illness
During illness, oral dosing of glucocorticoid may be adjusted to mimic the normal response of the adrenal glands to this stress on the body. Significant fever or injury may require triple oral dosing. Once recovery from the stress event is achieved, dosing is then returned to maintenance levels. People with adrenal insufficiency should know how to increase medication during such periods of stress. Immediate medical attention is needed if severe infections, vomiting, or diarrhea occur. These conditions can precipitate an Addisonian crisis.
Pregnancy
Women with adrenal insufficiency who become pregnant are treated with standard replacement therapy. If nausea and vomiting in early pregnancy interfere with taking medication by mouth, injections of the hormone may be necessary. During delivery, treatment is similar to that of people needing surgery. Following delivery, the dose is gradually tapered and the usual maintenance doses of oral hydrocortisone and fludrocortisone acetate are reached about 10 days after childbirth.
[Top]
How can someone with adrenal insufficiency prepare for an emergency?
People with adrenal insufficiency should always carry identification stating their condition in case of an emergency. A card or medical alert tag should notify emergency health care providers of the need to inject cortisol if the person is found severely injured or unable to answer questions. The card or tag should also include the name and telephone number of the person’s doctor and the name and telephone number of a family member to be notified. The dose of hydrocortisone needed may vary with a person’s age or size. For example, a child younger than 2 years of age can receive 25 milligrams (mg), a child between 2 and 8 years of age can receive 50 mg, and a child older than 8 years should receive the adult dose of 100 mg. When traveling, people with adrenal insufficiency should carry a needle, syringe, and an injectable form of cortisol for emergencies.
[Top]
Points to Remember
Adrenal insufficiency is a disorder that occurs when the adrenal glands do not produce enough of certain hormones.
Primary a
(Secondary Addison's or Addison's Disease)
Overview
Addisons disease is a rare endocrine, or hormonal disorder that affects about 1 in 100,000 people. It occurs in all age groups and afflicts men and women equally. The disease is characterized by weight loss, muscle weakness, fatigue, low blood pressure, and sometimes darkening of the skin in both exposed and non-exposed parts of the body.
Addisons disease occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.
Cortisol is normally produced by the adrenal glands, located just above the kidneys. It belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Scientists think that cortisol has possibly hundreds of effects in the body. Cortisol's most important job is to help the body respond to stress. Among its other vital tasks, cortisol:
helps maintain blood pressure and cardiovascular function;
helps slow the immune systems inflammatory response;
helps balance the effects of insulin in breaking down sugar for energy; and
helps regulate the metabolism of proteins, carbohydrates, and fats.
Because cortisol is so vital to health, the amount of cortisol produced by the adrenal's is precisely balanced. Like many other hormones, cortisol is regulated by the brains hypothalamus and the pituitary gland, a bean-sized organ at the base of the brain. First, the hypothalamus sends "releasing hormones" to the pituitary gland. The pituitary responds by secreting other hormones that regulate growth, thyroid and adrenal function, and sex hormones such as estrogen and testosterone. One of the pituitarys main functions is to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals receive the pituitarys signal in the form of ACTH, they respond by producing cortisol. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.
Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. It helps maintain blood pressure and water and salt balance in the body by helping the kidney retain sodium and excrete potassium. When aldosterone production falls too low, the kidneys are not able to regulate salt and water balance, causing blood volume and blood pressure to drop.
Causes
Failure to produce adequate levels of cortisol, or adrenal insufficiency, can occur for different reasons. The problem may be due to a disorder of the adrenal glands themselves (primary adrenal insufficiency) or to inadequate secretion of ACTH by the pituitary gland (secondary adrenal insufficiency).
Primary Adrenal Insufficiency
Most cases of Addisons disease are caused by the gradual destruction of the adrenal cortex, the outer layer of the adrenal glands, by the body's own immune system. About 70 percent of reported cases of Addisons disease are due to autoimmune disorders, in which the immune system makes antibodies that attack the body's own tissues or organs and slowly destroy them. Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed. As a result, often both glucocorticoid and mineralocorticoid hormones are lacking. Sometimes only the adrenal gland is affected, as in idiopathic adrenal insufficiency; sometimes other glands also are affected, as in the polyendocrine deficiency syndrome.
The polyendocrine deficiency syndrome is classified into two separate forms, referred to as type I and type II. Type I occurs in children, and adrenal insufficiency may be accompanied by underactive parathyroid glands, slow sexual development, pernicious anemia, chronic candida infections, chronic active hepatitis, and, in very rare cases, hair loss. Type II, often called Schmidts syndrome, usually afflicts young adults. Features of type II may include an underactive thyroid gland, slow sexual development, and diabetes mellitus. About 10 percent of patients with type II have vitiligo, or loss of pigment, on areas of the skin. Scientists think that the polyendocrine deficiency syndrome is inherited because frequently more than one family member tends to have one or more endocrine deficiencies.
Tuberculosis (TB) accounts for about 20 percent of cases of primary adrenal insufficiency in developed countries. When adrenal insufficiency was first identified by Dr. Thomas Addison in 1849, TB was found at autopsy in 70 to 90 percent of cases. As the treatment for TB improved, however, the incidence of adrenal insufficiency due to TB of the adrenal glands has greatly decreased.
Less common causes of primary adrenal insufficiency are chronic infections, mainly fungal infections; cancer cells spreading from other parts of the body to the adrenal glands; amyloidosis; and surgical removal of the adrenal glands. Each of these causes is discussed in more detail below.
from
Secondary Adrenal Insufficiency
This form of Addisons disease can be traced to a lack of ACTH, which causes a drop in the adrenal glands production of cortisol but not aldosterone. A temporary form of secondary adrenal insufficiency may occur when a person who has been receiving a glucocorticoid hormone such as prednisone for a long time abruptly stops or interrupts taking the medication. Glucocorticoid hormones, which are often used to treat inflammatory illnesses like rheumatoid arthritis, asthma, or ulcerative colitis, block the release of both corticotropin-releasing hormone (CRH) and ACTH. Normally, CRH instructs the pituitary gland to release ACTH. If CRH levels drop, the pituitary is not stimulated to release ACTH, and the adrenals then fail to secrete sufficient levels of cortisol.
Another cause of secondary adrenal insufficiency is the surgical removal of benign, or noncancerous, ACTH-producing tumors of the pituitary gland (Cushings disease). In this case, the source of ACTH is suddenly removed, and replacement hormone must be taken until normal ACTH and cortisol production resumes. Less commonly, adrenal insufficiency occurs when the pituitary gland either decreases in size or stops producing ACTH. This can result from tumors or infections of the area, loss of blood flow to the pituitary, radiation for the treatment of pituitary tumors, or surgical removal of parts of the hypothalamus or the pituitary gland during neurosurgery of these areas.
SYMPTOMS
The symptoms of adrenal insufficiency usually begin gradually. Chronic, worsening fatigue and muscle weakness, loss of appetite, and weight loss are characteristic of the disease. Nausea, vomiting, and diarrhea occur in about 50 percent of cases. Blood pressure is low and falls further when standing, causing dizziness or fainting. Skin changes also are common in Addisons disease, with areas of hyperpigmentation, or dark tanning, covering exposed and nonexposed parts of the body. This darkening of the skin is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles, and toes; lips; and mucous membranes.
Addisons disease can cause irritability and depression. Because of salt loss, craving of salty foods also is common. Hypoglycemia, or low blood sugar, is more severe in children than in adults. In women, menstrual periods may become irregular or stop.
Because the symptoms progress slowly, they are usually ignored until a stressful event like an illness or an accident causes them to become worse. This is called an addisonian crisis, or acute adrenal insufficiency. In most patients, symptoms are severe enough to seek medical treatment before a crisis occurs. However, in about 25 percent of patients, symptoms first appear during an addisonian crisis.
Symptoms of an addisonian crisis include sudden penetrating pain in the lower back, abdomen, or legs; severe vomiting and diarrhea, followed by dehydration; low blood pressure; and loss of consciousness. Left untreated, an addisonian crisis can be fatal.
DIAGNOSIS
In its early stages, adrenal insufficiency can be difficult to diagnose. A review of a patients medical history based on the symptoms, especially the dark tanning of the skin, will lead a doctor to suspect Addisons disease.
A diagnosis of Addisons disease is made by biochemical laboratory tests. The aim of these tests is first to determine whether there are insufficient levels of cortisol and then to establish the cause. X-ray exams of the adrenal and pituitary glands also are useful in helping to establish the cause.
ACTH Stimulation Test
This is the most specific test for diagnosing Addisons disease. In this test, blood and/or urine cortisol levels are measured before and after a synthetic form of ACTH is given by injection. In the so called short, or rapid, ACTH test, cortisol measurement in blood is repeated 30 to 60 minutes after an intravenous ACTH injection. The normal response after an injection of ACTH is a rise in blood and urine cortisol levels. Patients with either form of adrenal insufficiency respond poorly or do not respond at all.
When the response to the short ACTH test is abnormal, a "long" ACTH stimulation test is required to determine the cause of adrenal insufficiency. In this test, synthetic ACTH is injected either intravenously or intramuscularly over a 48- to 72-hour period, and blood and/or urine cortisol are measured the day before and during the 2 to 3 days of the injection. Patients with primary adrenal insufficiency do not produce cortisol during the 48- to 72-hour period; however, patients with secondary adrenal insufficiency have adequate responses to the test on the second or third day.
In patients suspected of having an addisonian crisis, the doctor must begin treatment with injections of salt, fluids, and glucocorticoid hormones immediately. Although a reliable diagnosis is not possible while the patient is being treated, measurement of blood ACTH and cortisol during the crisis and before glucocorticoids are given is sufficient to make the diagnosis. Once the crisis is controlled and medication has been stopped, the doctor will delay further testing for up to 1 month to obtain an accurate diagnosis.
Insulin-Induced Hypoglycemia Test
A reliable test to determine how the hypothalamus and pituitary and adrenal glands respond to stress is the insulin-induced hypoglycemia test. In this test, blood is drawn to measure the blood glucose and cortisol levels, followed by an injection of fast-acting insulin. Blood glucose and cortisol levels are measured again at 30, 45, and 90 minutes after the insulin injection. The normal response is for blood glucose levels to fall and cortisol levels to rise.
Other Tests
Once a diagnosis of primary adrenal insufficiency has been made, x-ray exams of the abdomen may be taken to see if the adrenals have any signs of calcium deposits. Calcium deposits may indicate TB. A tuberculin skin test also may be used.
If secondary adrenal insufficiency is the cause, doctors may use different imaging tools to reveal the size and shape of the pituitary gland. The most common is the CT scan, which produces a series of x-ray pictures giving a cross-sectional image of a body part. The function of the pituitary and its ability to produce other hormones also are tested.
TREATMENT
Treatment of Addisons disease involves replacing, or substituting, the hormones that the adrenal glands are not making. Cortisol is replaced orally with hydrocortisone tablets, a synthetic glucocorticoid, taken once or twice a day. If aldosterone is also deficient, it is replaced with oral doses of a mineralocorticoid, called fludrocortisone acetate (Florinef)), which is taken once a day. Patients receiving aldosterone replacement therapy are usually advised by a doctor to increase their salt intake. Because patients with secondary adrenal insufficiency normally maintain aldosterone production, they do not require aldosterone replacement therapy. The doses of each of these medications are adjusted to meet the needs of individual patients.
During an addisonian crisis, low blood pressure, low blood sugar, and high levels of potassium can be life threatening. Standard therapy involves intravenous injections of hydrocortisone, saline (salt water), and dextrose (sugar). This treatment usually brings rapid improvement. When the patient can take fluids and medications by mouth, the amount of hydrocortisone is decreased until a maintenance dose is achieved. If aldosterone is deficient, maintenance therapy also includes oral doses of fludrocortisone acetate.
SPECIAL PROBLEMS
Surgery
Patients with chronic adrenal insufficiency who need surgery with general anesthesia are treated with injections of hydrocortisone and saline. Injections begin on the evening before surgery and continue until the patient is fully awake and able to take medication by mouth. The dosage is adjusted until the maintenance dosage given before surgery is reached.
Pregnancy
Women with primary adrenal insufficiency who become pregnant are treated with standard replacement therapy. If nausea and vomiting in early pregnancy interfere with oral medication, injections of the hormone may be necessary. During delivery, treatment is similar to that of patients needing surgery; following delivery, the dose is gradually tapered and the usual maintenance doses of hydrocortisone and fludrocortisone acetate by mouth are not reached until about 10 days after childbirth.
Patient Education
A person who has adrenal insufficiency should always carry identification stating his or her condition in case of an emergency. The card should alert emergency personnel about the need to inject 100 mg of cortisol if its bearer is found severely injured or unable to answer questions. The card should also include the doctors name and telephone number and the name and telephone number of the nearest relative to be notified. When traveling, it is important to have a needle, syringe, and an injectable form of cortisol for emergencies. A person with Addisons disease also should know how to increase medication during periods of stress or mild upper respiratory infections. Immediate medical attention is needed when severe infections or vomiting or diarrhea occur. These conditions can precipitate an addisonian crisis. A patient who is vomiting may require injections of hydrocortisone.
(Secondary Addison's or Addison's Disease)
Overview
Addisons disease is a rare endocrine, or hormonal disorder that affects about 1 in 100,000 people. It occurs in all age groups and afflicts men and women equally. The disease is characterized by weight loss, muscle weakness, fatigue, low blood pressure, and sometimes darkening of the skin in both exposed and non-exposed parts of the body.
Addisons disease occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.
Cortisol is normally produced by the adrenal glands, located just above the kidneys. It belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Scientists think that cortisol has possibly hundreds of effects in the body. Cortisol's most important job is to help the body respond to stress. Among its other vital tasks, cortisol:
helps maintain blood pressure and cardiovascular function;
helps slow the immune systems inflammatory response;
helps balance the effects of insulin in breaking down sugar for energy; and
helps regulate the metabolism of proteins, carbohydrates, and fats.
Because cortisol is so vital to health, the amount of cortisol produced by the adrenal's is precisely balanced. Like many other hormones, cortisol is regulated by the brains hypothalamus and the pituitary gland, a bean-sized organ at the base of the brain. First, the hypothalamus sends "releasing hormones" to the pituitary gland. The pituitary responds by secreting other hormones that regulate growth, thyroid and adrenal function, and sex hormones such as estrogen and testosterone. One of the pituitarys main functions is to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals receive the pituitarys signal in the form of ACTH, they respond by producing cortisol. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.
Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. It helps maintain blood pressure and water and salt balance in the body by helping the kidney retain sodium and excrete potassium. When aldosterone production falls too low, the kidneys are not able to regulate salt and water balance, causing blood volume and blood pressure to drop.
Causes
Failure to produce adequate levels of cortisol, or adrenal insufficiency, can occur for different reasons. The problem may be due to a disorder of the adrenal glands themselves (primary adrenal insufficiency) or to inadequate secretion of ACTH by the pituitary gland (secondary adrenal insufficiency).
Primary Adrenal Insufficiency
Most cases of Addisons disease are caused by the gradual destruction of the adrenal cortex, the outer layer of the adrenal glands, by the body's own immune system. About 70 percent of reported cases of Addisons disease are due to autoimmune disorders, in which the immune system makes antibodies that attack the body's own tissues or organs and slowly destroy them. Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed. As a result, often both glucocorticoid and mineralocorticoid hormones are lacking. Sometimes only the adrenal gland is affected, as in idiopathic adrenal insufficiency; sometimes other glands also are affected, as in the polyendocrine deficiency syndrome.
The polyendocrine deficiency syndrome is classified into two separate forms, referred to as type I and type II. Type I occurs in children, and adrenal insufficiency may be accompanied by underactive parathyroid glands, slow sexual development, pernicious anemia, chronic candida infections, chronic active hepatitis, and, in very rare cases, hair loss. Type II, often called Schmidts syndrome, usually afflicts young adults. Features of type II may include an underactive thyroid gland, slow sexual development, and diabetes mellitus. About 10 percent of patients with type II have vitiligo, or loss of pigment, on areas of the skin. Scientists think that the polyendocrine deficiency syndrome is inherited because frequently more than one family member tends to have one or more endocrine deficiencies.
from
Tuberculosis (TB) accounts for about 20 percent of cases of primary adrenal insufficiency in developed countries. When adrenal insufficiency was first identified by Dr. Thomas Addison in 1849, TB was found at autopsy in 70 to 90 percent of cases. As the treatment for TB improved, however, the incidence of adrenal insufficiency due to TB of the adrenal glands has greatly decreased.
Less common causes of primary adrenal insufficiency are chronic infections, mainly fungal infections; cancer cells spreading from other parts of the body to the adrenal glands; amyloidosis; and surgical removal of the adrenal glands. Each of these causes is discussed in more detail below.
Secondary Adrenal Insufficiency
This form of Addisons disease can be traced to a lack of ACTH, which causes a drop in the adrenal glands production of cortisol but not aldosterone. A temporary form of secondary adrenal insufficiency may occur when a person who has been receiving a glucocorticoid hormone such as prednisone for a long time abruptly stops or interrupts taking the medication. Glucocorticoid hormones, which are often used to treat inflammatory illnesses like rheumatoid arthritis, asthma, or ulcerative colitis, block the release of both corticotropin-releasing hormone (CRH) and ACTH. Normally, CRH instructs the pituitary gland to release ACTH. If CRH levels drop, the pituitary is not stimulated to release ACTH, and the adrenals then fail to secrete sufficient levels of cortisol.
Another cause of secondary adrenal insufficiency is the surgical removal of benign, or noncancerous, ACTH-producing tumors of the pituitary gland (Cushings disease). In this case, the source of ACTH is suddenly removed, and replacement hormone must be taken until normal ACTH and cortisol production resumes. Less commonly, adrenal insufficiency occurs when the pituitary gland either decreases in size or stops producing ACTH. This can result from tumors or infections of the area, loss of blood flow to the pituitary, radiation for the treatment of pituitary tumors, or surgical removal of parts of the hypothalamus or the pituitary gland during neurosurgery of these areas.
SYMPTOMS
The symptoms of adrenal insufficiency usually begin gradually. Chronic, worsening fatigue and muscle weakness, loss of appetite, and weight loss are characteristic of the disease. Nausea, vomiting, and diarrhea occur in about 50 percent of cases. Blood pressure is low and falls further when standing, causing dizziness or fainting. Skin changes also are common in Addisons disease, with areas of hyperpigmentation, or dark tanning, covering exposed and nonexposed parts of the body. This darkening of the skin is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles, and toes; lips; and mucous membranes.
Addisons disease can cause irritability and depression. Because of salt loss, craving of salty foods also is common. Hypoglycemia, or low blood sugar, is more severe in children than in adults. In women, menstrual periods may become irregular or stop.
Because the symptoms progress slowly, they are usually ignored until a stressful event like an illness or an accident causes them to become worse. This is called an addisonian crisis, or acute adrenal insufficiency. In most patients, symptoms are severe enough to seek medical treatment before a crisis occurs. However, in about 25 percent of patients, symptoms first appear during an addisonian crisis.
Symptoms of an addisonian crisis include sudden penetrating pain in the lower back, abdomen, or legs; severe vomiting and diarrhea, followed by dehydration; low blood pressure; and loss of consciousness. Left untreated, an addisonian crisis can be fatal.
DIAGNOSIS
In its early stages, adrenal insufficiency can be difficult to diagnose. A review of a patients medical history based on the symptoms, especially the dark tanning of the skin, will lead a doctor to suspect Addisons disease.
A diagnosis of Addisons disease is made by biochemical laboratory tests. The aim of these tests is first to determine whether there are insufficient levels of cortisol and then to establish the cause. X-ray exams of the adrenal and pituitary glands also are useful in helping to establish the cause.
ACTH Stimulation Test
This is the most specific test for diagnosing Addisons disease. In this test, blood and/or urine cortisol levels are measured before and after a synthetic form of ACTH is given by injection. In the so called short, or rapid, ACTH test, cortisol measurement in blood is repeated 30 to 60 minutes after an intravenous ACTH injection. The normal response after an injection of ACTH is a rise in blood and urine cortisol levels. Patients with either form of adrenal insufficiency respond poorly or do not respond at all.
When the response to the short ACTH test is abnormal, a "long" ACTH stimulation test is required to determine the cause of adrenal insufficiency. In this test, synthetic ACTH is injected either intravenously or intramuscularly over a 48- to 72-hour period, and blood and/or urine cortisol are measured the day before and during the 2 to 3 days of the injection. Patients with primary adrenal insufficiency do not produce cortisol during the 48- to 72-hour period; however, patients with secondary adrenal insufficiency have adequate responses to the test on the second or third day.
In patients suspected of having an addisonian crisis, the doctor must begin treatment with injections of salt, fluids, and glucocorticoid hormones immediately. Although a reliable diagnosis is not possible while the patient is being treated, measurement of blood ACTH and cortisol during the crisis and before glucocorticoids are given is sufficient to make the diagnosis. Once the crisis is controlled and medication has been stopped, the doctor will delay further testing for up to 1 month to obtain an accurate diagnosis.
Insulin-Induced Hypoglycemia Test
A reliable test to determine how the hypothalamus and pituitary and adrenal glands respond to stress is the insulin-induced hypoglycemia test. In this test, blood is drawn to measure the blood glucose and cortisol levels, followed by an injection of fast-acting insulin. Blood glucose and cortisol levels are measured again at 30, 45, and 90 minutes after the insulin injection. The normal response is for blood glucose levels to fall and cortisol levels to rise.
Other Tests
Once a diagnosis of primary adrenal insufficiency has been made, x-ray exams of the abdomen may be taken to see if the adrenals have any signs of calcium deposits. Calcium deposits may indicate TB. A tuberculin skin test also may be used.
If secondary adrenal insufficiency is the cause, doctors may use different imaging tools to reveal the size and shape of the pituitary gland. The most common is the CT scan, which produces a series of x-ray pictures giving a cross-sectional image of a body part. The function of the pituitary and its ability to produce other hormones also are tested.
TREATMENT
Treatment of Addisons disease involves replacing, or substituting, the hormones that the adrenal glands are not making. Cortisol is replaced orally with hydrocortisone tablets, a synthetic glucocorticoid, taken once or twice a day. If aldosterone is also deficient, it is replaced with oral doses of a mineralocorticoid, called fludrocortisone acetate (Florinef)), which is taken once a day. Patients receiving aldosterone replacement therapy are usually advised by a doctor to increase their salt intake. Because patients with secondary adrenal insufficiency normally maintain aldosterone production, they do not require aldosterone replacement therapy. The doses of each of these medications are adjusted to meet the needs of individual patients.
During an addisonian crisis, low blood pressure, low blood sugar, and high levels of potassium can be life threatening. Standard therapy involves intravenous injections of hydrocortisone, saline (salt water), and dextrose (sugar). This treatment usually brings rapid improvement. When the patient can take fluids and medications by mouth, the amount of hydrocortisone is decreased until a maintenance dose is achieved. If aldosterone is deficient, maintenance therapy also includes oral doses of fludrocortisone acetate.
SPECIAL PROBLEMS
Surgery
Patients with chronic adrenal insufficiency who need surgery with general anesthesia are treated with injections of hydrocortisone and saline. Injections begin on the evening before surgery and continue until the patient is fully awake and able to take medication by mouth. The dosage is adjusted until the maintenance dosage given before surgery is reached.
Pregnancy
Women with primary adrenal insufficiency who become pregnant are treated with standard replacement therapy. If nausea and vomiting in early pregnancy interfere with oral medication, injections of the hormone may be necessary. During delivery, treatment is similar to that of patients needing surgery; following delivery, the dose is gradually tapered and the usual maintenance doses of hydrocortisone and fludrocortisone acetate by mouth are not reached until about 10 days after childbirth.
Patient Education
A person who has adrenal insufficiency should always carry identification stating his or her condition in case of an emergency. The card should alert emergency personnel about the need to inject 100 mg of cortisol if its bearer is found severely injured or unable to answer questions. The card should also include the doctors name and telephone number and the name and telephone number of the nearest relative to be notified. When traveling, it is important to have a needle, syringe, and an injectable form of cortisol for emergencies. A person with Addisons disease also should know how to increase medication during periods of stress or mild upper respiratory infections. Immediate medical attention is needed when severe infections or vomiting or diarrhea occur. These conditions can precipitate an addisonian crisis. A patient who is vomiting may require
Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison–Biermer anemia) is one of many types of the larger family of megaloblastic anemias. It is caused by loss of gastric parietal cells, and subsequent inability to absorb vitamin B12.
Usually seated in an atrophic gastritis, the autoimmune destruction of gastric parietal cells leads to a lack of intrinsic factor.[1] Since the absorption from the gut of normal dietary amounts of vitamin B12[2] is dependent on intrinsic factor, the loss of intrinsic factor leads to vitamin B12 deficiency. While the term 'pernicious anemia' is sometimes also incorrectly used to indicate megaloblastic anemia due to any cause of vitamin B12 deficiency, its proper usage refers to that caused by atrophic gastritis, parietal cell loss, and lack of intrinsic factor only.
The loss of ability to absorb vitamin B12 is the most common cause of adult vitamin B12 deficiency.[3] Such a loss may be due to pernicious anemia (with loss of intrinsic factor) or to a number of other conditions which decrease production of gastric acid, which also plays a part in absorption of vitamin B12 from foods.
Historically, pernicious anemia (PA) was generally detected only after it became "clinical" (caused an overt disease state) and the anemia was well-established, i.e. liver stores of B12 had been depleted. The "pernicious" aspect of the disease - prior to the discovery of treatment - was its invariably fatal prognosis, similar to leukemia at that time. However, in the time since elucidation of the cause of the disease, modern tests which specifically target B12 absorption can be used to diagnose the disease before it becomes clinically apparent. In such cases, the disease may be diagnosed and treated without the patient ever becoming ill.
Replacement of vitamin stores does not correct the defect in absorption from loss of intrinsic factor, that technically defines the disease. A person who has pernicious anemia defined by inability to absorb vitamin B12 in this way, will have it for the remainder of his or her life. However, unless the patient has sustained permanent peripheral nerve damage before treatment, regular B12 replacement will keep pernicious anemia in check, with no anemia and no further symptoms.
Although initial treatment of the disease usually involves injections of B12 to rapidly replace body stores, a number of studies have shown that long-term vitamin replacement treatment may be maintained with high-dose oral B12 supplements, since sufficient B12 is absorbed from these by a normal intestine, even without any intrinsic factor. In this regard, nasal and sublingual forms of B12 have not been found to have any special value over simple swallowed tablets.
Signs and symptoms
Pernicious anemia presents insidiously, and many of the signs and symptoms are due to anemia itself, where anemia is present. While it may consist of the triad of paraesthesias, sore tongue and weakness, this is not the chief symptom complex. The patient may complain of fatigue, depression, forgetfulness, difficulty concentrating, low-grade fevers, nausea and gastrointestinal symptoms (heartburn), weight loss. Because PA may affect the spinal cord, the patient may also complain of impaired urination, loss of sensation in the feet, unsteady gait, weakness and clumsiness. Anemia may cause tachycardia (rapid heartbeat) and cardiac murmurs, along with a waxy pallor. In severe cases, the anemia may cause evidence of congestive heart failure.
Long term complications may include gastric cancer and carcinoids.[4]
Many signs and symptoms are attributed to pernicious anemia:
Fatigue, low blood pressure, rapid heart rate, high blood pressure, pallor, depression, muscle weakness and shortness of breath (known as 'the sighs')
Difficulty in proprioception
Mild cognitive impairment, including difficulty concentrating and sluggish responses, colloquially referred to as cognitive dysfunction|brain fog
Neuropathic pain
Frequent diarrhea
Paresthesias, such as pins and needles sensations or numbness in fingers or toes, due to B12 deficiency affecting nerve function
Jaundice due to impaired formation of blood cells
Glossitis (swollen red tongue) due to B12 deficiency
May present with hyperthyroidism or hypothyroidism
Personality or memory changes[5]
A complication of severe chronic PA is subacute combined degeneration of spinal cord, which leads to distal sensory loss (posterior column), absent ankle reflex, increased knee reflex response, and extensor plantar response.
[edit]Causes
Most commonly (in temperate climates), the cause for impaired binding of vitamin B12 by intrinsic factor is autoimmune atrophic gastritis,[6] in which autoantibodies are directed against parietal cells (resulting in their loss), as well as against the intrinsic factor itself (rendering it unable to bind vitamin B12).
Less frequently, loss of parietal cells may simply be part of a widespread atrophic gastritis of nonautoimmune origin, such as that frequently occurring in elderly people affected with long-standing chronic gastritis of any cause (including Helicobacter pylori infection).
Forms of vitamin B12 deficiency other than pernicious anemia must be considered in the differential diagnosis of megaloblastic anemia. For example, a B12 deficient state which causes megaloblastic anemia and which may be mistaken for classical pernicious anemia, may be caused by infection with the tapeworm Diphyllobothrium latum, possibly due to the parasite's competition for vitamin B12.[7]
A similar disorder involving impaired B12 absorption can also occur following gastric removal (gastrectomy) or gastric bypass surgery, especially the Roux-en-Y bypass. In this procedure, the stomach is separated into two sections, one a very small pouch for holding small amounts of food, and the other, the remainder of the stomach, which is resultingly nonfunctional. Therefore, the mucosal cells are no longer available, nor is the required intrinsic factor. This results in inadequate GI absorption of B12, and may result in a syndrome indistinguishable from pernicious anemia. Gastric bypass or gastrectomy patients must take B12 as in treatment of pernicious anemia: either oral megadoses, or B12 by injection.
Pathophysiology
Vitamin B12 cannot be produced by the human body, and must be obtained from the diet. Normally, dietary vitamin B12 is absorbed by the body in the small bowel only when it is bound by the intrinsic factor (IF) produced by parietal cells of the gastric mucosa. Pernicious anemia is thought to occur when the body's immune system mistakenly targets the intrinsic factor, with a loss of parietal cells. Insufficient IF results in insufficient absorption of the vitamin. Although the normal body stores three to five years' worth of vitamin B12 in the liver, the usually undetected autoimmune activity in one's gut over a prolonged period of time leads to vitamin B12 depletion and the resulting anemia. Inhibition of DNA synthesis in red blood cells results in the formation of large, fragile megaloblastic erythrocytes.
[edit]Diagnosis
The insidious nature of the disease, and the fact that there is no single definitive test for pernicious anemia, may mean that a diagnosis is delayed. Pernicious anemia is suspected when the patient's blood smear shows large, fragile, immature erythrocytes (megaloblasts). The Schilling test is no longer widely available, and the other main diagnostic signpost of low levels of serum B12 cannot be relied upon, as sufferers can have high levels of serum B12 and still have pernicious anemia.[8] Blood and urine tests for methylmalonic acid may indicate a B12 deficiency, even though serum B12 is within the normally-acceptable range. Serum B12 is not necessarily an indicator of efficient use by the body, in the muscles, for example.[9]
A diagnosis of pernicious anemia first requires demonstration of megaloblastic anemia (through a full blood count) which evaluates the mean corpuscular volume (MCV), as well the mean corpuscular hemoglobin concentration (MCHC). Pernicious anemia is identified with a high MCV and a normal MCHC (that is, it is a macrocytic, normochromic anemia).[10] Ovalocytes are also typically seen on the blood smear, and a pathognomonic feature of megaloblastic anemias (which include pernicious anemia and others) is hypersegmented neutrophils.
Pernicious anemia can also be diagnosed by evaluating its direct cause, vitamin B12 deficiency, by measuring B12 levels in serum. A Schilling test can then be used to distinguish pernicious anemia from other causes of vitamin B12 deficiency (notably malabsorption).[11]
The diagnosis of atrophic gastritis Type A should be confirmed by gastroscopy and stepwise biopsy.[12] Approximately 90% of individuals with PA have antibodies for parietal cells; however, only 50% of all individuals in the general population with these antibodies have pernicious anemia.[13]
[edit]Treatment
Main article: Vitamin B12
The treatment of pernicious anemia varies from country to country and from area to area. There is no permanent cure for pernicious anemia, although repletion of vitamin B12 should be expected to result in a cessation of anemia-related symptoms, a halt in neurological deterioration, and (in cases where neurological problems not advanced) neurological recovery and a complete and permanent remission of all symptoms, so long as B12 is supplemented. Repletion of B12 can be accomplished in a variety of ways.
The most accessible and inexpensive method of repletion is through dietary supplementation, in the form of oral or sublingual B12 tablets. B12 supplements are widely available at supermarkets, health food stores, and drug stores, though quality and cost may vary. In some countries, the cobalamin preparation may be available only via prescription. Doctors can prescribe cobalamin tablets that contain doses higher than what is commercially available.
A 2003 study[14] found that oral and sublingual B12 were absorbed equally well in a group of patients with very low B12. In this study, 22% of the subjects that agreed to undergo the test (5 of 23), had abnormal Schilling tests, but showed no difference in treatment levels from the other subjects. When oral tablets are used to treat PA,[15] higher-than-normal doses may be needed.[16] The efficacy of using high dose B12 tablets to treat ordinary PA (i.e. anemia due to atrophic gastritis) is well established. Oral supplementation allows B12 to be absorbed in places other than the terminal ileum (where B12 absorption usually takes place). A 2006 study[13] found that oral B12 repletion has the potential to be as effective as injections.
However, if oral and sublingual repletion of B12 is inadequate, the patient may require B12 injections,[17] which are usually given once a month, bypassing the need for gastrointestinal absorption altogether. Eventually, the patient may be able to do this at home. Cobalamin (one of the forms of B12) is usually injected into the patient's muscle (intramuscular or IM) using cyanocobalamin (the United States, Canada and most European countries) or hydroxocobalamin (Australia and the U.K.). The injections will typically need to be given for the remainder of the patient's life. The frequency of injections varies by country and health care practitioner, and may be as infrequent as once every three months in some countries. The most common complaint by members of the Pernicious Anaemia Society is that patients have different needs, with some patients needing more frequent injections than others.[18] Some medical professionals[who?] believe that subcutaneous injections are more effective than intramuscular injections,[citation needed] but the evidence for this is currently unclear.
There are other methods of administering B12, including nasal sprays and behind-the-ear patches. One small study from 1997, with six participants,[19] found that intranasal delivery of B12 led to increases in plasma cobalamin as high as eight times a given patient's baseline measurement. Further investigation of these delivery methods is needed.
History
The British physician Thomas Addison first described the disease in 1849, from which it acquired the common name of Addison's anemia. In 1907, Richard Clarke Cabot reported on a series of 1200 patients with PA. Their average survival was between one and three years. Dr. William Bosworth Castle performed an experiment whereby he ingested raw hamburger meat and regurgitated it after an hour, and subsequently fed it to a group of ten patients.[citation needed] A control group were fed untreated raw hamburger meat. The former group showed a disease response whereas the latter group did not. This was not a sustainable practice, but it demonstrated the existence of an 'intrinsic factor' from gastric juice.
Pernicious anemia was a fatal disease before about the year 1920, when George Whipple suggested raw liver as a treatment. The first workable treatment for pernicious anemia began when Whipple made a discovery in the course of experiments in which he bled dogs to make them anemic, then fed them various foods to see which would make them recover most rapidly (Whipple was looking for treatments for anemia from bleeding, not pernicious anemia). Whipple discovered that ingesting large amounts of liver seemed to cure anemia from blood loss, and tried liver ingestion as a treatment for pernicious anemia, reporting improvement there also, in a paper in 1920. George Minot and William Murphy then set about to partly isolate the curative property in liver and showed in 1926 that it was contained in raw liver juice (in the process also showing that ironically it was the iron in liver tissue, not the soluble factor in liver juice, which cured the anemia from bleeding in dogs; thus the discovery of the liver juice factor as a treatment for pernicious anemia had been by coincidence). For the discovery of the cure of a previously fatal disease of unknown etiology, the three men shared the 1934 Nobel Prize in Medicine.[20]
After Minot and Murphy's verification of Whipple's results in 1926, pernicious anemia victims ate or drank at least 1/2 a pound of raw liver, or drank raw liver juice, every day. This continued for several years, until a concentrate of liver juice became available. In 1928, chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural food (liver). The extract could even be injected into muscle, which meant that patients no longer needed to eat large amounts of liver or juice. This also reduced the cost of treatment considerably.
The active ingredient in liver remained unknown until 1948, when it was isolated by two chemists, Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. The substance was a cobalamin, which the discoverers named vitamin B12. The new vitamin in liver juice was eventually completely purified and characterized in the 1950s, and other methods of producing it from bacteria were developed. It could be injected into muscle with even less irritation, making it possible to treat pernicious anemia with even more ease. Pernicious anemia was eventually treated with either vitamin B12 injections, or else large oral doses of vitamin B12, typically between 1 and 4 mg (1000 to 4000 mcg) daily.
[edit]Notable cases
Alexander Graham Bell - Scottish-Canadian scientist and inventor[21]
Annie Oakley[22]
Gunnar Nordström Notable Finnish theoretical physicist. Possibly caused by handling of radioactive material and baths in a Finnish sauna where water containing radioactive material was used in the belief that it was healthy.[23][24]
Norman Warne - editor/publisher and fiancé of Beatrix Potter.[25]
Yoon Eun Hye - a South Korean actress
Alopecia areata (AA) is a medical condition in which hair is lost from some or all areas of the body, usually from the scalp.[1][2] Because it causes bald spots on the scalp, especially in the first stages, it is sometimes called spot baldness. In 1%–2% of cases, the condition can spread to the entire scalp (Alopecia totalis) or to the entire epidermis (Alopecia universalis). Conditions resembling AA, and having a similar cause, occur also in other species
Classification
The most common type of alopecia areata involves hair loss in one or more round spots on the scalp.[2][4]
Hair may also be lost more diffusely over the whole scalp, in which case the condition is called diffuse alopecia areata.[2]
Alopecia areata monolocularis describes baldness in only one spot. It may occur anywhere on the head.
Alopecia areata multilocularis refers to multiple areas of hair loss.
The disease may be limited only to the beard, in which case it is called Alopecia areata barbae.[2]
If the patient loses all the hair on his/her scalp, the disease is then called Alopecia areata totalis.
If all body hair, including pubic hair, is lost, the diagnosis then becomes Alopecia areata universalis.[5]
Alopecia areata totalis and universalis are rare.[5]
[edit]Signs and symptoms
Typical first symptoms are small, soft, bald patches which can take many shapes but are most usually round and "coin-shaped".[6] It most often affects the scalp and beard but may occur on any hair-bearing part of the body.[7] There may be different skin areas with hair loss and regrowth in the same body at the same time. It may also go into remission for a time, or permanently.
The area of hair loss may tingle or be very slightly painful.[8]
The hair tends to fall out over a short period of time, with the loss commonly occurring more on one side of the scalp than the other.[2]
Exclamation point hairs are often present. Exclamation point hairs are hairs that become narrower along the length of the strand closer to the base, producing a characteristic "exclamation point" appearance.[2]
In the case of healthy hair, if you were to try to pull some out, none should fall out, and ripped hair should not be distributed evenly across the tugged portion of the scalp. In cases of alopecia areata hair will tend to pull out more easily along the edge of the patch where the follicles are already being attacked by the body's immune system than away from the patch where they are still healthy.[citation needed]
Nails may have pitting or trachyonychia.[7]
Patients with alopecia can sometimes present with Ciceromegaly, which is characterized by short stature, hair loss and hypogonadism[citation needed].
[edit]Causes
Alopecia areata is noncommunicable, or not contagious.[2] It occurs more frequently in people who have affected family members, suggesting that heredity may be a factor.[2] Strong evidence that genes may increase risk for alopecia areata was found by studying families with two or more affected members. This study identified at least four regions in the genome that are likely to contain alopecia areata genes.[9] In addition, it is slightly more likely to occur in people who have relatives with autoimmune diseases.[5]
The condition is thought to be an autoimmune disorder in which the body attacks its own hair follicles and suppresses or stops hair growth.[2] There is evidence that T cell lymphocytes cluster around these follicles, causing inflammation and subsequent hair loss. An unknown environmental trigger such as emotional stress or a pathogen is thought to combine with hereditary factors to cause the condition.[7] There are a few recorded cases of babies being born with congenital alopecia areata; however, these are not cases of autoimmune disease because an infant is born without a fully developed immune system.
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Treatment
If the affected region is small, it is reasonable to observe the progression of the illness as the problem often spontaneously regresses and the hair may grow back.
In cases where there is severe hair loss, there has been limited success treating alopecia areata with clobetasol or fluocinonide, steroid injections, or cream. Steroid injections are commonly used in sites where there are small areas of hair loss on the head or especially where eyebrow hair has been lost. Some other medications used are minoxidil, elocon ointment (steroid cream) irritants (anthralin or topical coal tar), and topical immunotherapy cyclosporine, each of which are sometimes used in different combinations.
Oral corticosteroids decrease the hair loss, but only for the period during which they are taken, and these drugs have adverse side effects.[7]
For small patches on the beard or head it is possible to suppress with topical tacrolimus ointments like Protopic. Symptoms may remain suppressed until aggravated by stress or other factors.
Initial stages may be kept from increasing by applying topical corticosteroids. However, topical corticosteroids frequently fail to enter the skin deeply enough to affect the hair bulbs, which are the treatment target.[7]
In terms of adapting to the disease rather than treating in an effort to cure, there are also many options available. Wigs are often used by those with Alopecia, particularly Alopecia Totalis, in which hair is entirely lost from the scalp. Wigs are available at many levels of development and technology, including wigs with suction mechanisms to keep them firmly attached to the scalp.
[edit]Prognosis
In most cases that begin with a small number of patches of hair loss, hair grows back after a few months to a year.[8] In cases with a greater number of patches, hair can either grow back or progress to alopecia totalis or, in rare cases, universalis.[8]
Effects of alopecia areata are mainly psychological (loss of self image due to hair loss). However, patients also tend to have a slightly higher incidence of asthma, allergies, atopic dermal ailments, and even hypothyroidism. Loss of hair also means that the scalp sunburns more easily. Loss of nasal hair increases severity of hay fever and similar allergic conditions. Patients may also have aberrant nail formation because keratin forms both hair and nails.
Hair may grow back and then fall out again later.[5] This may not indicate a recurrence of the condition, however, but rather a natural cycle of growth-and-shedding from a relatively synchronised start; such a pattern will fade over time. Episodes of alopecia areata before puberty predispose one to chronic recurrence of the condition.[7]
Psychosocial issues: Alopecia can certainly be the cause of psychological stress. Because hair loss can lead to significant appearance changes, individuals may experience social phobia, anxiety, and depression.
[edit]Epidemiology
The condition affects 0.1%–0.2% of humans, occurring in both males and females. Alopecia areata occurs in people who are apparently healthy and have no skin disorder.[7] Initial presentation most commonly occurs in the late teenage years, early childhood, or young adulthood, but can happen with people of all ages.
Alopecia areata is a hair-loss condition which usually affects the scalp. It can, however, sometimes affect other areas of the body. Hair loss tends to be rather rapid and often involves one side of the head more than the other.
Alopecia areata affects both males and females. This type of hair loss is different than male-pattern baldness, an inherited condition.
What causes alopecia areata?
Current evidence suggests that alopecia areata is caused by an abnormality in the immune system. This particular abnormality leads to autoimmunity. As a result, the immune system attacks particular tissues of the body. In alopecia areata, for unknown reasons, the body's own immune system attacks the hair follicles and disrupts normal hair formation. Biopsies of affected skin show immune cells inside of the hair follicles where they are not normally present. What causes this is unknown. Alopecia areata is sometimes associated with other autoimmune conditions such as allergic disorders, thyroid disease, vitiligo, lupus, rheumatoid arthritis, and ulcerative colitis. Sometimes, alopecia areata occurs within family members, suggesting a role of genes and heredity.
What are the different patterns of alopecia areata?
The most common pattern is one or more spots of hair loss on the scalp. There is also a form of more generalized thinning of hair referred to as diffuse alopecia areata throughout the scalp. Occasionally, all of the scalp hair is lost, a condition referred to as alopecia totalis. Less frequently, the loss of all of the hairs on the entire body, called alopecia universalis, occurs. Sometimes the hair loss can involve the male beard, a condition known as alopecia areata barbe.
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Who is affected by alopecia areata?
Alopecia areata tends to occur most often in children, teens, and young adults. However, it can also affect older individuals and rarely toddlers. Alopecia areata in not contagious. It should not be confused with the hair shedding that may occur following the discontinuation of hormonal estrogen and progesterone therapies for birth control or the hair shedding associated with the end of pregnancy.
How is alopecia areata diagnosed?
The characteristic finding of alopecia areata is the exclamation point hair. These unusual hairs can be found in areas of hair loss. They are visible with a hand lens as short, broken off hairs that are narrower closer to the scalp (appearing like an exclamation point). A biopsy of the scalp is sometimes necessary for a diagnosis.
How is alopecia areata treated?
In approximately 50% of patients, hair will regrow within a year without any treatment. The longer the period of time of hair loss, the less likelihood that the hair will regrow. A variety of treatments can be tried. Steroid injections, creams, and shampoos (such as clobetasol or fluocinonide) for the scalp have been used for many years. Other medications include minoxidil, irritants (anthralin or topical coal tar), and topical immunotherapy (cyclosporine), each of which are sometimes used in different combinations.
A study reported in the journal Archives of Dermatology (vol. 134, 1998;1349-52) showed effectiveness of aromatherapy essential oils (cedarwood, lavender, thyme, and rosemary oils) in some patients. As with many chronic disorders for which there is no single treatment, a variety of remedies are promoted which in fact have no benefit. There is no known effective method of prevention, although the elimination of emotional stress is felt to be helpful. No drugs or hair-care products have been associated with the onset of alopecia areata. Much research remains to be completed on this complex condition.
Alopecia Areata At A Glance
Alopecia areata is a hair-loss condition which usually affects the scalp.
Alopecia areata typically causes one or more patches of hair loss.
Alopecia areata tends to affect younger individuals, both male and female.
An autoimmune disorder, in which the immune system attacks hair follicles, is believed to cause alopecia areata.
For most patients, the condition resolves without treatment within a year, but hair loss is sometimes permanent.
A number of treatments are known to aid in hair regrowth. Multiple treatments may be necessary, and none consistently works for all patients.
Many treatments are promoted which have not proven to be of benefit.
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The Facts on Alopecia
Alopecia refers to hair loss from any part of the body for any reason. There are several types, ranging from thinning hair to complete baldness.
Diffuse alopecia (thinning scalp hair) is common among seniors, both men and women alike.
Androgenic alopecia, also known as "male pattern baldness," can strike younger as well as older people. In spite of its masculine name, women can get this condition, too. It's genetic, so having a family history can predict if you might inherit it. In both men and women, it's linked to having an excess of male hormones (androgens) around the hair follicles, which can block hair growth. Women are more likely to develop androgenic alopecia after menopause, when they have fewer female hormones.
Most cases of hair loss are due to androgenic alopecia. Approximately 50% of men by the age of 50 years and 15% of women before the time they reach menopause have some degree of androgenic alopecia.
Alopecia areata typically causes a few temporary bald patches on the scalp. It tends to run in families and often strikes in childhood. The hair loss seems to be part of an immune system problem, in which the body's natural defences mistakenly attack its own tissue. Once the hair has fallen out in certain spots, new growth is suppressed for weeks or months. This type of alopecia usually affects people who have other "autoimmune" diseases like thyroid disease, lupus, or pernicious anemia. Sometimes, it may produce complete scalp baldness (alopecia totalis) or total loss of body hair (alopecia universalis).
Scarring alopecia is a kind of scarring caused by deep bacterial or fungal infections of the skin. Scarred areas will not regrow hair. For example, fungus can leave permanent bald patches.
Causes of Alopecia
There are many different potential causes of alopecia. Hair loss - temporary or permanent - can be triggered by any number of factors. These can include allergies, irritants, toxins, burns, injuries, and infections. We also know that certain medications (especially anabolic steroids), chronic kidney failure, radiation, and chemotherapy can cause hair to fall out. Sometimes, hair loss may be due to a vitamin A overdose, iron deficiency anemia, a malfunctioning thyroid gland, fever, or pregnancy.
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Chronic mucocutaneous candidiasis (CMC) refers to a heterogeneous group of disorders characterized by recurrent or persistent superficial infections of the skin, mucous membranes, and nails with Candida organisms, usually Candida albicans. These disorders are confined to the cutaneous surface, with little propensity for systemic dissemination. CMC does not represent a specific disease, but rather a phenotypic presentation of a spectrum of immunologic, endocrinologic, and autoimmune disorders. The unifying feature of these heterogeneous disorders is impaired cell-mediated immunity against Candida species.
The image below depicts CMC of the nails.
Thickened, fragmented, hyperkeratotic nails and erythematous periungual skin. Courtesy of Walter Reed Army Medical Center.
Pathophysiology
C albicans is an opportunistic yeast that is part of the normal flora of the gastrointestinal tract, skin, and mucous membranes. The fungus can exist in the yeast, the mycelial (pseudohyphal), or the chlamydospore phase. Invasive disease is rare; however, when it occurs, it is usually associated with mycelial elements. Several host factors are important in defending against infection by candidal organisms. Healthy, intact skin that continuously desquamates and regenerates is usually an effective initial barrier. An intact immune system is critical for keeping this opportunistic organism at bay.
CMC is associated with a defect in cell-mediated immunity that may either be limited to Candida antigens or be part of a more general immune abnormality. Recent data suggest alterations in cytokine production in response to Candida antigens. These alterations include decreased interleukin 2 and interferon-gamma levels (TH 1 cytokines) and increased interleukin 10 levels in some studies.1,2 Patients who lack T-cell immunity (eg, those with severe combined immune deficiency syndrome or DiGeorge syndrome) or patients with severely impaired T-cell function (eg, patients with AIDS) are susceptible to chronic candidal infections. Defects in humoral immunity are not commonly observed in patients with CMC, and patients with antibody deficiencies are not particularly prone to candidiasis.
Mortality/Morbidity
CMC is not associated with a high degree of mortality because disseminated invasive candidal infections are rare. In isolated CMC, the prognosis is good; however, significant morbidity is related to chronic and persistent skin, nail, and mucous membrane candidal infections. The risk of mycotic aneurysms, while low, remains a real possibility.3 In a subset of patients, malignant thymomas or cancers of the oral cavity and digestive tract may occur. Patients with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED) have significant morbidity from endocrinopathies or other autoimmune diseases associated with this condition. Several cases of Pneumocystis carinii pneumonia in patients with CMC are reported in the literature.
Race
No racial predilection is reported for CMC, although APECED is most prevalent in Finnish, Sardinian, and Iranian Jewish populations.
Sex
The male-to-female ratio for CMC is equal.
Age
CMC usually manifests in infancy or early childhood (60-80% of cases), with a mean age of onset of 3 years. Delayed or adult onset of the disease is reported and can be associated with thymoma, myasthenia gravis, and bone marrow abnormalities.
Clinical
History
Patients present with recurrent or persistent superficial candidal infections of the oral cavity (thrush) or intertriginous or periorificial areas. Infants often present with recalcitrant thrush, candidal diaper dermatitis, or both. More extensive scaling of skin lesions and thickened nails and red, swollen periungual tissues can follow these infections.
Systemic candidiasis and invasive fungal dermatitis, although rare, usually occur in premature infants, particularly those with extremely low birth weight.
Persistent and refractory candidal infections, which characterize CMC, must be distinguished from the more common and treatment-responsive overgrowth of Candida that occurs in the setting of systemic antibiotic therapy, local/systemic corticosteroid treatment, or hyperglycemia in persons with diabetes mellitus.
Physical
CMC is diagnosed based on physical examination findings, potassium chloride (KOH) preparation results, fungal culture, and a history of recurrent and refractory candidiasis infections. Oral examination may reveal the white adherent plaques of thrush or the angular cheilitis of perlèche. Oral involvement may extend to the esophagus, but further extension is extremely uncommon. Nails may be markedly thickened, fragmented, and discolored, with significant edema and erythema of the surrounding periungual tissue, simulating clubbing (see first image below). Skin lesions more frequently are acral and characterized by erythematous, hyperkeratotic, serpiginous plaques (see second image below). The scalp may be involved with similar hyperkeratotic plaques, which can result in scarring alopecia (see third image below).
Thickened, fragmented, hyperkeratotic nails and erythematous periungual skin. Courtesy of Walter Reed Army Medical Center.
Crusted hyperkeratotic plaques on and around the nose. Courtesy of Walter Reed Army Medical Center.
Crusted hyperkeratotic plaques on eyebrow, forehead, and scalp. Courtesy of Walter Reed Army Medical Center.
A subset of CMC patients has recurrent or severe noncandidal infections,4 including those from viral, bacterial, and other fungal pathogens. Some patients with CMC have low serum iron levels and decreased iron stores, possibly related to decreased iron absorption. Iron replacement should be initiated in these patients. Several patients reportedly have improved after parenteral iron therapy.
Several classifications exist for CMC. The authors categorize CMC based on its association with other conditions.
CMC without endocrinopathy
This category comprises a spectrum of clinical presentations.
Inheritance may be autosomal recessive or dominant, but many cases are sporadic.
Onset is in childhood, and no associated endocrine or autoimmune disorders are observed.
CMC with endocrinopathy
CMC may occur as part of autoimmune polyendocrinopathy syndrome type 1 (Online Mendelian Inheritance in Man #240300), also known as APECED.5
APECED is characterized by at least 2 of the following: CMC, hypoparathyroidism, and Addison disease. Other autoimmune disorders may be associated, such as, type 1 diabetes, autoimmune thyroiditis, Graves disease, alopecia areata, vitiligo, hypogonadism, biliary cirrhosis, hepatitis, idiopathic thrombocytopenic purpura, and pernicious anemia.
APECED is inherited in an autosomal recessive fashion and usually manifests early in childhood. It is caused by mutations in the autoimmune regulator gene (AIRE) on 21q22.3, which encodes a protein that plays an important role in establishing and maintaining tolerance in the thymus.6
A recent study found that APECED patients have defective receptor-mediated Candida internalization, leading to altered Candida -specific immune responses.5
Candidiasis is often the first manifestation of APECED, appearing before age 5 years in most cases, followed by manifestations of the other endocrine and nonendocrine conditions, including ectodermal dysplasia. Ectodermal dysplasia manifestations include dental enamel hypoplasia and pitted nail dystrophy. Keratopathy and calcifications of the tympanic membrane also may occur.
A 2006 review of 18 APECED patients found candidiasis in all patients as the presenting symptom, and researchers concluded that ectodermal dystrophy usually only occurs as a secondary phenomenon.6
No correlation exists between the severity of the endocrinopathy and the severity of the candidal infections. Treatment of the underlying endocrinopathy does not usually improve candidal infections.
CMC may be associated with thyroid disease. An autosomal dominant CMC associated with thyroid disease has been mapped to 2p.7
CMC with thymoma
Patients in this subgroup typically present after the third decade of life.
These patients are at increased risk of myasthenia gr
Laboratory Studies
When a patient presents with cutaneous manifestations of CMC, the following studies should be performed:
Scrapings from the infected site are suspended in 10-20% KOH and microscopically examined. The presence of yeast cells and pseudohyphae confirms the diagnosis. Fungal stains, such as chlorazol black E stain or Parker blue-black ink, may be added to highlight the organism.
Candidal organisms grow well on several culture media. They grow as yeasts on Sabouraud agar with chloramphenicol and cycloheximide. C albicans also grows on dermatophyte test medium but does not demonstrate the red color change characteristic of dermatophytes.
Screening laboratory tests for a CMC-associated endocrine dysfunction include blood glucose or glycosylated hemoglobin testing, thyroid function tests, liver functions tests, serum electrolyte evaluation, corticotropin testing, and serum cortisol values. Consider a complete blood cell count, to screen for leukopenia, and an HIV test. Other endocrine screening tests that may be considered include follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, parathyroid-stimulating hormone, calcium, phosphate, magnesium, and short synacthen test. Perform baseline and yearly follow-up tests to screen for associated endocrinopathy.
Other Tests
Results from cellular immunity tests, such as the prick-test with Candida antigens, may be negative. In vitro lymphocyte proliferation is usually reduced for C albicans extracts.
Immunoglobulin G subclass deficiencies have been reported in some patients with CMC, who have a predisposition toward respiratory tract infections. Isolated immunoglobulin A and immunoglobulin M deficiencies have also been reported, in addition to a single case of complete agammaglobulinemia.8
In patients with other recurrent infections, immune studies should be considered.
If the clinical suspicion for APECED is high, genetic analysis of the AIRE gene can be confirmatory.5,6
Recently, anti-interferon-1 antibodies were found to be highly specific for APECED and to precede the appearance of CMC, suggesting an important new diagnostic test.9
Procedures
A skin biopsy is rarely needed to make a diagnosis of Candida infection, but it may be performed to rule out the possibility of superinfection of a primary dermatosis. A periodic acid-Schiff stain can confirm the presence of pseudohyphae. Nutritional deficiencies with cutaneous manifestations should also be considered.
Histologic Findings
Routine hematoxylin and eosin–stained sections of superficial candidiasis lesions reveal subcorneal pustules. Granulomatous lesions of CMC show hyperkeratosis and parakeratosis, with a dense mixed dermal infiltrate containing lymphocytes and plasma cells. Periodic acid-Schiff or silver stains of skin biopsy specimens can help identify organisms in the stratum corneum and dermis.
Laboratory Studies
When a patient presents with cutaneous manifestations of CMC, the following studies should be performed:
Scrapings from the infected site are suspended in 10-20% KOH and microscopically examined. The presence of yeast cells and pseudohyphae confirms the diagnosis. Fungal stains, such as chlorazol black E stain or Parker blue-black ink, may be added to highlight the organism.
Candidal organisms grow well on several culture media. They grow as yeasts on Sabouraud agar with chloramphenicol and cycloheximide. C albicans also grows on dermatophyte test medium but does not demonstrate the red color change characteristic of dermatophytes.
Screening laboratory tests for a CMC-associated endocrine dysfunction include blood glucose or glycosylated hemoglobin testing, thyroid function tests, liver functions tests, serum electrolyte evaluation, corticotropin testing, and serum cortisol values. Consider a complete blood cell count, to screen for leukopenia, and an HIV test. Other endocrine screening tests that may be considered include follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, parathyroid-stimulating hormone, calcium, phosphate, magnesium, and short synacthen test. Perform baseline and yearly follow-up tests to screen for associated endocrinopathy.
Other Tests
Results from cellular immunity tests, such as the prick-test with Candida antigens, may be negative. In vitro lymphocyte proliferation is usually reduced for C albicans extracts.
Immunoglobulin G subclass deficiencies have been reported in some patients with CMC, who have a predisposition toward respiratory tract infections. Isolated immunoglobulin A and immunoglobulin M deficiencies have also been reported, in addition to a single case of complete agammaglobulinemia.8
In patients with other recurrent infections, immune studies should be considered.
If the clinical suspicion for APECED is high, genetic analysis of the AIRE gene can be confirmatory.5,6
Recently, anti-interferon-1 antibodies were found to be highly specific for APECED and to precede the appearance of CMC, suggesting an important new diagnostic test.9
Procedures
A skin biopsy is rarely needed to make a diagnosis of Candida infection, but it may be performed to rule out the possibility of superinfection of a primary dermatosis. A periodic acid-Schiff stain can confirm the presence of pseudohyphae. Nutritional deficiencies with cutaneous manifestations should also be considered.
Histologic Findings
Routine hematoxylin and eosin–stained sections of superficial candidiasis lesions reveal subcorneal pustules. Granulomatous lesions of CMC show hyperkeratosis and parakeratosis, with a dense mixed dermal infiltrate containing lymphocytes and plasma cells. Periodic acid-Schiff or silver stains of skin biopsy specimens can help identify organisms in the stratum corneum and dermis.
Management can be difficult, and relapse is common following discontinuation of therapy. Topical therapies are not usually effective in patients with CMC. Treatment of oral involvement in CMC can be aided by therapy with clotrimazole troches or oral nystatin solution. Treatment falls into 3 main categories: antifungal agents, immunologic therapies, and combination therapy.
Systemic antifungal therapy is the mainstay of CMC therapy. It may be used alone or in combination with an immunomodulatory agent. The drawbacks of systemic antifungal therapy include the risk of adverse effects or toxicity, a failure to correct the underlying immune deficiency, relapse following the cessation of therapy, and antifungal resistance to some antifungal agents.
Several immunologic therapies have been proposed in an effort to correct the underlying immune deficiency in persons with CMC. The most widely studied treatment is the use of transfer factor.10 Transfer factor is a cell-free protein extracted from the T lymphocytes of Candida -immune donors. Although the precise mechanism is unknown, it has been shown to transfer delayed-type hypersensitivity reactions to patients previously anergic to candidal skin testing.
Consultations
Refer patients to an endocrinologist if screening laboratory test results suggest an associated endocrine abnormality.
If familial CMC is suspected, consultation with a geneticist should be obtained.
Patients with recurrent infections or pneumonia should be referred to an immunologist.
Medication
Many good antifungal agents are available and usually are effective; however, upon cessation of therapy, most patients relapse. Specific immunotherapies are under investigation and have been used with some success. This area needs further research.
Antifungals
Ketoconazole and amphotericin B are commonly used to treat candidiasis. Patients being treated with systemic antifungal agents should be closely monitored for adverse effects.
Ketoconazole (Nizoral)
A broad-spectrum imidazole antifungal agent, which functions by inhibiting the synthesis of ergosterol and results in leakage of cellular components and fungal cell death. Readily absorbed in an acidic pH environment (eg, with orange juice) and with a fatty meal.
Chronic mucocutaneous candidiasis is a heterogeneous disorder of the immune system characterized by persistent candida (yeast) infections of the mucous membranes, scalp, skin and nails. Patients usually have problems with thrush (a yeast infection in the mouth) and yeast diaper rash as babies. Some patients also have problems with additional germs including bacteria and other fungi. Patients with mucocutaneous candidiasis have an increased incidence of autoimmune disorders including endocrine disorders, diabetes, hemolytic anemia, autoimmune hair loss (alopecia) or loss of skin pigment (vitiligo).
Clinical Features and Symptoms
persistent candida (yeast) infections of the mucous membranes, scalp, skin and nails
thrush (a yeast infection in the mouth) and yeast diaper rash as babies.
Some patients also have problems with:
additional germs including bacteria and other fungi.
increased incidence of autoimmune disorders including endocrine disorders, diabetes, hemolytic anemia, autoimmune hair loss (alopecia) or loss of skin pigment (vitiligo)
Treatment Strategies
Most patients with chronic mucocutaneous candidiasis are treated with chronic antibiotics that are specific for fungal infections. Patients should be evaluated periodically for endocrine disorders and those endocrine disorders should be treated as necessary.
Chronic mucocutaneous candidiasis is a hereditary immunodeficiency disorder due to malfunction of T cells (lymphocytes).
Because T cells malfunction, the body is less able to fight fungal infections, including infection with Candida (candidiasis—see Fungal Infections: Candidiasis), a yeast. The ability to fight other infections is not reduced.
Candidal infections develop and persist, usually beginning during infancy but sometimes during early adulthood. The fungus may cause mouth infections (thrush) and infections of the scalp, skin, and nails. Membranes lining the mouth, eyelids, digestive tract, and vagina may also be infected. In infants, the first symptoms are often thrush that is difficult to treat, diaper rash, or both. Severity varies. The disorder may affect one nail or cause a disfiguring rash that covers the face and scalp. The rash is crusted and thick and may ooze. On the scalp, the rash may cause hair to fall out. Many people also have endocrine disorders, such as underactive parathyroid glands (hypoparathyroidism) and underactive adrenal glands (Addison's disease), as well as hepatitis and autoimmune disorders, such as Graves' disease.
Doctors suspect this infection when people have the characteristic rash. The diagnosis can be confirmed by examining a sample from the infected area under a microscope and identifying the yeast.
Usually, the infections can be controlled with an antifungal drug applied to the skin. If infections persist, they can be effectively treated with fluconazole
or another similar antifungal drug taken by mouth. Drugs may have to be taken a long time. Usually, this disorder is chronic but does not affect life span.
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I like this information. Atleast, medical student will take note.
Absolutely useful and relevant information for a Biomedical Sciences student. Very comprehensive.
D.Virtual.Doctor Hub Author 18 months ago
Hello guys... SOrry, it took me some time to publish this one. Lots of information is as stake which needed to be gather and compiled in a pattern that will really inform and educate the general public and also I have been busy with ezine articles. I am partaking in their 5th HAND Marathon race of 100 articles in 100 days. Hubpages took 41 days of my time out of that tournament and I am now trying to catch up. So please enjoy this hub and do well to ask any questions as usual as well as give in your contributions.