Autoimmune polyendocrine type 1 (APS-1) is a complex inherited autosomal recessive disorder. Classically, it appears within the first decade of life followed by adrenocortical insufficiency, mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. The clinical phenotype of APS-1 varies depending upon mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder, involving mainly the white matter and axons of the central nervous system, the adrenal cortex, and the testis and a frequent but under-recognized cause of primary adrenocortical insufficiency. X-ALD is caused by a defect in the gene ABCD1 that maps to Xq 28 locus. The primary biochemical disorder is the accumulation of saturated very long chain fatty acids (VLCFA) secondary to peroxisomal dysfunction. The incidence in males is estimated to be 1:21,000 and in females 1:14,000, without any difference in the prevalence among different ethnicities. At least six distinct phenotypes have been described that differ in the age and severity of clinical presentation; however, there is no correlation between X-ALD phenotype and mutations in the ABCD1 gene. When suspected, the diagnosis is established biochemically and prenatal testing is possible in affected families. Currently, there is no satisfying treatment to prevent the onset or modify the progression of the chronic myelopathy of X-ALD. The administration of a mixture of glyceryl-trioleate and glyceryl- trierucate, also referred as Lorenzo's Oil, has been shown to prevent disease progression in asymptomatic patients with cerebral involvement of X-ALD. Allogeneic hematopoietic stem cell (HSC) transplantation is the treatment of choice for individuals with early stages of the cerebral form of the disease. An alternative option for patients without HLA-matched donors is autologous HSC-gene therapy with lentivirally corrected cells. Once adrenal insufficiency is present, hormonal replacement therapy is identical to that of autoimmune Addison’s disease. For complete coverage of this area and all of Endocrinology, visit www.endotext.org.

Autoimmune polyendocrine syndrome type 1 (APS-1, OMIM 2403000) is a rare autosomal recessive disease that is caused by autoimmune regulator (AIRE). The main symptoms of APS-1 are chronic mucocutaneous candidiasis, autoimmune adrenocortical insufficiency (Addison's disease) and hypoparathyroidism. We collected APS-1 cases and analysed them. The AIRE genes of the patient and his family members were sequenced to identify whether the APS-1 patient had an AIRE mutation. We discovered a mutation site (c.206A>C) that had never before been reported in the AIRE gene located in exon 2 of the AIRE gene. This homogyzous mutation caused a substitution of the 69th amino acid of the AIRE protein from glutamine to proline (p.Q69P). A yeast two-hybrid assay, which was used to analyse the homodimerization properties of the mutant AIRE protein, showed that the mutant AIRE protein could not interact with the normal AIRE protein. Flow cytometry and RT-qPCR analyses indicated that the new mutation site could decrease the expression levels of the AIRE, glutamic acid decarboxylase 65 (GAD65) and tryptophan hydroxylase-1 (TPH1) proteins to affect central immune tolerance. In conclusion, our research has shown that the new mutation site (c.206A>C) may influence the homodimerization and expression levels and other aspects of the AIRE protein. It may also impact the expression levels of tissue-restricted antigens (TRAs), leading to a series of autoimmune diseases.

Recent progress in the immunopathology field has greatly improved our understanding of the natural history of autoimmune diseases, particularly of Addison's disease. Addison's disease is known to be a chronic illness characterized by adrenocortical gland insufficiency that develops following a long and mainly asymptomatic period, characterized by the presence of circulating autoantibodies directed to adrenal cortex antigens. In this chapter we describe the groups of subjects at risk of developing Addison's disease, together with the diagnostic tests considered the most appropriate for evaluating adrenal function: determination of basal plasma adrenocorticotropic hormone (ACTH) levels, plasma renin activity, plasma aldosterone and cortisol levels, and cortisol levels after intravenous stimulation with ACTH (ACTH test). The employment of specific clinical, immunological and functional criteria in the subjects with autoantibodies to the adrenal cortex allows identifying those at risk of developing overt disease. The independent risk factors for the progression to adrenal failure have also been identified and they contribute to different risks of developing clinical Addison's disease. Based on the risk level, the subjects should be monitored over time to observe early signs of adrenal dysfunction, and start substitutive treatment as soon as possible. For patients presenting with high risk, prevention strategies and trials might be available.

We herein describe a second Japanese case of sarcoidosis presenting Addison's disease. A 52-year-old man was diagnosed with sarcoidosis based on clinical and laboratory findings, including bilateral hilar lymphadenopathy and elevated levels of serum angiotensin-converting enzyme and lysozyme, as well as the presence of noncaseating epithelioid granulomas. The patient also exhibited general fatigue, pigmentation, weight loss, hypotension and hyponatremia, suggestive of chronic adrenocortical insufficiency. An endocrine examination confirmed primary adrenocortical insufficiency. This case suggests the direct involvement of sarcoid granuloma in the adrenal glands.

We herein report an autopsy case involving a 27-year-old Caucasian woman suffering from chronic adrenocortical insufficiency with a background of a polyendocrine disorder. Postmortem biochemistry revealed pathologically decreased aldosterone, cortisol, and dehydroepiandrosterone levels in postmortem serum from femoral blood as well as decreased cortisol and 17-hydroxycorticosteroid in urine. Decreased vitreous sodium and increased 3-beta-hydroxybutyrate and C-reactive protein concentrations were observed. The cause of death was determined to be acute adrenocortical insufficiency. Fasting ketoacidosis was postulated to have precipitated the Addisonian crisis. Traumatic causes of death and third-party involvement were excluded. The case highlights the importance of systematically performing exhaustive postmortem biochemical investigations to formulate appropriate hypothesis regarding the pathophysiological mechanisms involved in the death process.

The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases must be excluded in transaminase elevation of unknown cause. Drugs such as propylthiouracil, used in the treatment of hyperthyroidism, may induce liver damage, and other drugs such as amiodarone, carbamazepine, and several chemotherapeutic agents can lead to both thyroid and liver abnormalities. Liver diseases such as hepatitis, hepatocellular carcinoma, and cirrhosis may cause altered levels of thyroid hormones, and alcoholic liver disease, both due to the noxious substance ethanol as well as to the hepatic damage it causes, may be responsible for altered thyroid function. Both excess and insufficiency of adrenal function may result in altered liver function, and adrenocortical dysfunction may be present in patients with cirrhosis, especially during episodes of decompensation. Again an important player which affects both the endocrine system and the liver, alcohol may be associated with pseudo-Cushing syndrome. Sex hormones, both intrinsic as well as extrinsically administered, have an important impact on liver function. While oestrogens are related to cholestatic liver damage, androgens are the culprit of adenomas and hepatocellular carcinoma, among others. Chronic liver disease, on the other hand, has profound repercussions on sex hormone metabolism, inducing feminization in men and infertility and amenorrhoea in women. Lastly, metabolic syndrome, the pandemia of the present and future centuries, links the spectrum of liver damage ranging from steatosis to cirrhosis, to the array of endocrine alterations that are features of the syndrome, including insulin resistance, central obesity, and hyperlipidaemia. Clinical practice must integrally evaluate the effects of the intricate and tight relationship between the liver and the endocrine system, in order to better address all manifestations, complications, and prevent deterioration of one or the other organ-system.

An Addisonian crisis marks an acute adrenocortical failure which can be caused by decompensation of a chronic insufficiency due to stress, an infarct or bleeding of the adrenal cortex and also abrupt termination of a long-term glucocorticoid medication. This article reports the case of a 25-year-old patient with Crohn's disease who suffered an Addisonian crisis with hypotension, hyponatriemia and hypoglycemia during an emergency laparotomy after he had terminated prednisolone medication on his own authority. This necessitated an aggressive volume therapy in addition to an initial therapy with 100 mg hydrocortisone, 8 g glucose and a continuous administration of catecholamines. Under this treatment regimen hemodynamic stabilization was achieved. Reduction of the administration of hydrocortisone after 3 days resulted in cardiovascular insufficiency which required an escalation of the hydrocortisone substitution.

The first clinical evidence that an extract of animal adrenocortical tissue could counteract human adrenal failure was demonstrated in 1930. As chemical analyses of cortical extracts proceeded, mainly in the laboratories of Kendall at the Mayo Clinic and Reichstein in Zurich, it became evident that there is not one cortical hormone, but that all are steroids. By 1940 it was understood that there are two categories: those that cause sodium and fluid retention and those that counteract shock and inflammation. Structurally the presence or lack of oxygenation at C11 on the steroid skeleton was critical. In 1948 the first patient with rheumatoid arthritis was treated with cortisone and soon thereafter other rheumatologic patients received cortisone or, to stimulate native cortisone production, ACTH. Oral and intra-articular administration of cortisone and hydrocortisone began in 1950-51. Several lines of research to produce cortisone semi-synthetically showed some success by 1952. Between 1954 and 1958 six synthetic steroids were introduced for systemic anti-imflammatory therapy. By 1960 all of the toxic effects of chronic corticosteroid administration had been described, as well as protocols to withdraw such drugs while minimising symptoms of cortical insufficiency. To enable use of lower corticosteroid dosages, companion use of non-steroidal anti-inflammatory drugs began in the late 1950s, with phenylbutazone the first. In the 1970s the introduction of methotrexate and other anti-metabolites further circumscribed the dosages and indications for corticosteroids in the rheumatic diseases.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). Terminal 4q deletion is also a rare cytogenetic abnormality that causes a variable syndrome of dysmorphic features, mental retardation, growth retardation, and heart and limb defects. We report a 12-year-old Saudi boy with mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure consistent with APECED. In addition, he has dysmorphic facial features, growth retardation, and severe global developmental delay. Patient had late development of chronic renal failure. The blastogenesis revealed depressed lymphocytes' response to Candida albicans at 38% when compared to control. Chromosome analysis of the patient revealed 46,XY,del(4)(q33). FISH using a 4p/4q subtelomere DNA probe assay confirmed the deletion of qter subtelomere on chromosome 4. Parental chromosomes were normal. The deleted array was further defined using array CGH. AIRE full gene sequencing revealed a homozygous mutation namely 845_846insC. Renal biopsy revealed chronic interstitial nephritis with advanced fibrosis. In addition, there was mesangial deposition of C3, C1q, and IgM. This is, to the best of our knowledge, the first paper showing evidence of autoimmune nephropathy by renal immunofluorescence in a patient with APECED and terminal 4q deletion.

Primary adrenocortical insufficiency, or Addison's disease (AD), results from an adrenal cortex hypofunction/dysfunction with a deficient production of glucocorticoids, mineralocorticoids and androgens, and with high levels of both ACTH and plasma renin activity. The prevalence of AD is 110-144 cases per million population in the developed countries. Autoimmune AD is the most frequent etiological form in adult patients, accounting for about 80% of cases, followed by post-tuberculosis AD in 10-15%, the remaining 5% being cases are due to vascular, neoplastic or rare genetic forms. Congenital adrenal hyperplasia is the most frequent form of AD in children and accounts for 72% of cases, whereas autoimmune AD is seen in around 10-15% of cases. The markers of autoimmune AD are adrenal cortex (ACA) or 21-hydroxylase autoantibodies (21-OHAbs) and they are present at diagnosis in more than 90% of cases. In autoimmune AD, the adrenal cortex is infiltrated by lymphocytes and plasma cells and the glands are sclerotic and reduced in volume. Autoimmune AD occurs mainly in middle-aged females, alone or associated with other (clinical, subclinical or potential) autoimmune diseases, giving rise to various forms of autoimmune polyglandular syndrome (type 1, 2 or 4). Replacement therapy with gluco-and mineralocorticoids is life-saving for patients with chronic adrenal insufficiency.

Addison's disease, or chronic adrenocortical insufficiency, is the overproduction of adrenocorticotropic hormone by the pituitary gland as a compensatory mechanism for decreased cortisol production by the adrenal glands. Classically, patients affected with Addison's disease develop weakness, anorexia, electrolyte imbalances: decreased sodium and chloride with increased serum potassium resulting in hypotension, and hyperpigmentation of the skin and mucous membranes. Herein this case report, we focus on the subtle findings of diffuse hyperpigmentation and intermittent but repetitive "flu-like" symptoms in two patients to correctly identify the diagnosis of Addison's disease effectively and efficiently.

Apeced syndrome is a rare disease, with autosomal recessive transmission and associated with mutations of the AIRE gene, which is involved in central and peripheral immune tolerance mechanisms. Its diagnosis is classically based on the combination of any two of the following three major criteria: chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune chronic adrenocortical insufficiency (Addison disease). One single criterion is sufficient to diagnosis a sibling of a patient already diagnosed. Because of its great phenotypic variability, some atypical or oligosymptomatic forms may not be recognized. In the presence of one of the three major criteria, it is thus important to look for other clinical manifestations--digestive, cutaneous (including keratinized appendages) and ophthalmological (until then considered minor). In these atypical forms, the diagnosis depends on molecular genetics. Prognosis is influenced by different factors that may be genetic (AIRE mutations, HLA), hormonal (sex) or environmental (infections). Potentially fatal disease (hepatitis or severe malabsorption) requires immunosuppressant therapy. Before beginning this aggressive treatment, underlying infectious foci, especially of candidiasis, must be sought and treated to prevent the development of extremely serious systemic infections in this context. A workup for splenic atrophy is also recommended.

Common causes of chronically elevated serum liver enzymes include fatty liver disease, chronic viral hepatitis, autoimmune hepatitis, or hereditary metabolic disorders. Adrenocortical insufficiency can also cause elevated liver enzymes. Since 1990 only 11 cases have been reported. We here report a 52-year-old man with elevated liver enzymes (1.5 x upper limit of normal) over the past 10 years. Furthermore, hyponatremia and hyperkalemia were noted. He complained of fatigue and low blood pressure over the past few years. At physical examination a dark complexion was noted. After ruling out chronic viral hepatitis, autoimmune disease, metabolic or hereditary disorders, rare causes of elevated liver enzymes were considered. The endocrinological work-up revealed Addison's disease as cause of serum electrolyte disturbance and elevated liver enzymes. The patient was successfully treated with hydrocortisol and fludrocortisol. After one week, liver enzymes, serum electrolytes and arterial blood pressure had normalized. In conclusion, for patients with constantly elevated liver enzymes also rare, extrahepatic diseases have to be considered. Addison's disease is a rare but fully reversible cause for elevated liver enzymes.

The decrease in active hormones that characterizes chronic adrenal insufficiency results in hypovolemia. In some patients, residual adrenal function, mineralocorticoid therapy, and concomitant heart or liver failure, or both, can paradoxically provoke edema. The case report that follows describes a patient with iatrogenically induced anasarca resulting from the unhappy confluence of usually appropriate therapy and coexisting medical conditions.

Genitourinary tuberculosis (TB) rarely involves the adrenal gland. A 67-year-old man presented with progressively hyperpigmented skin and an enlarged mass over both testes. Early morning plasma cortisol concentration was low and adrenocorticotropic hormone (ACTH) concentration was high. A rapid ACTH stimulation test revealed the absence of plasma cortisol response and confirmed a diagnosis of primary adrenocortical insufficiency. An abdomen computed tomography (CT) scan disclosed enlargement of the right adrenal gland and punctuate calcification over the left one. This is compatible with tuberculous adrenalitis. Currettage biopsy of the prostate demonstrated chronic granulomatous inflammation with Langerhan's giant cells, but without TB bacilli. Anti-TB treatment, in addition to glucocorticoid and mineralocorticoid replacement, was administered. The testicular mass decreased progressively though the results of a subsequent ACTH stimulation test, six months later, disclosed no significant change. A follow-up CT scan, one and a half years later, showed a decrease in the size of the right adrenal mass.

Acute adrenal crisis in patients with unrecognized chronic adrenocortical failure is difficult to diagnose and potentially fatal. We describe 2 patients with acute adrenal crisis whose diagnoses were hindered because of concomitant glucocorticoid treatment. Acute adrenal insufficiency is primarily a state of mineralocorticoid deficiency. Prednisolone and prednisone, the most frequently prescribed anti-inflammatory corticosteroid agents, have minimal mineralocorticoid activity. Several conditions that may be treated with pharmacological glucocorticoids are associated with an increased risk of Addison disease. An acute adrenal crisis, against which concurrent glucocorticoid therapy does not confer adequate protection, may develop in such patients.

Idiopathic Addison's disease (IAD) is a chronic organ-specific autoimmune disease sometimes associated with other autoimmune endocrine diseases. The prevalence is 50-100/million with an incidence of 5-6 cases/million/year. A genetic predisposition to this disease has been reported in subjects with phenotype HLA-DR3, -DR4, -A1, -B8 or HLA-A28, -B8; a phenotype HLA-B8 has been described in subjects with adrenal autoantibodies (AA) not progressing toward an overt disease. There is strong evidence that AA can play a pathogenic role or at least can be considered good immunological markers in IAD. AA may damage adrenal function by a cytotoxic process directed at adrenal cell surface or other intracellular antigens. An antigenic activity has been recently attributed to P450c enzymes and in particular to P450c21. Clinical manifestations of IAD can be preceded by a long period of subclinical adrenocortical impairment, characterized only by the presence of AA with or without adrenocortical function findings. In our experience, where AA titers were 1:8 or higher, progression of adrenal disease was likely with time. A spontaneous remission can indeed occur with lower titers, especially in early stages of subclinical adrenal insufficiency. Finally, a reversal of previously significant AA positive titers in patients in more advanced stages of subclinical adrenal insufficiency seems to be induced by corticosteroid therapy.

Idiopathic Addison's disease is a chronic organ-specific autoimmune disorder with a long subclinical period characterized only by the presence of adrenal autoantibodies (AA) with or without adrenal function failure. The aim of this longitudinal study was to evaluate the behavior of AA using, an indirect fluorescence method, and adrenal function in 20 AA-positive and 50 AA-negative patients screened by an investigation of a large population of organ-specific autoimmune disease patients without clinical Addison's disease. As controls, 100 normal age-matched subjects were tested only once. In the 20 AA-positive and 50 negative patients, AA and adrenal functional tests were evaluated every 4 months for 5 yr. The AA-positive patients were grouped into 5 adrenal functional stages, specifically: stage 0, normal adrenal function; stage 1, high PRA and low (or normal) aldosterone levels alone; stage 2, along with impaired cortisol response to ACTH, stage 3, along with increased ACTH levels; and stage 4, clinically overt Addison's disease. On the basis of the behavior of AA, the 20 positive patients were grouped as follows: group A, 11 patients with AA titer of 1:8 or higher at the first observation and persistently AA positive in subsequent observations, with titers ranging from 1:8 to 1:64; group B, 6 patients with initial AA titers of 1:8 or lower and AA disappearance in subsequent observations; and group C, 3 patients with AA titer of 1:32 or higher, undergoing corticosteroid therapy after the start of the study and showing AA disappearance in subsequent observations. With respect to adrenal function in group A, 2 patients initially in stage 1 and 1 patient initially in stage 2 did not progress to the upper stages, whereas 5 patients initially in stage 0 and 3 initially in stage 1 progressed subsequently to the upper stages, in 2 cases reaching overt clinical Addison's disease (stage 4). On the other hand, all of the patients of group B showed both a spontaneous disappearance of AA and recovery of adrenal function during the study span. Also, the 3 patients of group C showed disappearance of AA after corticosteroid therapy with recovery of adrenal function. None of the 50 patients who were initially AA negative became AA positive subsequently or showed impairment of adrenal function. We reached the following conclusions. 1) AA, even if present initially in some subjects without clinical Addison's disease, can subsequently disappear. 2) Restoration of adrenal function after disappearance of AA indicates that a spontaneous remission of subclinical adrenocortical failure can occur.(ABSTRACT TRUNCATED AT 400 WORDS)

Three cases of hypercalcaemia secondary to acute adrenocortical insufficiency are described; all the patients had moderate to severe renal impairment, one being on chronic dialysis treatment with no residual diuresis. Parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D [1,25(OH)2D] were low, indicating a suppressed PTH-vitamin D axis. In the two patients with partial renal impairment, urine Ca excretion was increased, indicating increased load of the cation into the extracellular fluid (ECF), most probably from bone. Saline infusion, to correct any ECF depletion and to increase urine Ca excretion, could not fully correct the hypercalcaemia. Complete correction of plasma Ca levels was observed shortly after the institution of hormonal substitutive therapy. Despite the evidence of increased Ca mobilization from bone, bone biopsies in two patients did not show any signs of cell-mediated bone resorption; instead, bone cell activity appeared to be suppressed. Thus, glucocorticoid deficiency appears to induce Ca mobilization from bone stores by mechanism(s) unrelated to bone remodelling processes.

Some methodological aspects of the rapid ACTH stimulation test (RST) and the prolonged ACTH stimulation test (PST) remain heterogeneous, e.g. administration routes, time of the day, duration, interpretation criteria and clinical indications. To standardize both tests we studied the serum cortisol responses to ACTH in 16 normal subjects, 16 patients with Addison's disease (AD), 14 with hypopituitarism (HP) of different etiologies and 13 patients on chronic glucocorticoid (CG) treatment (doses equivalent to 5-20 mg/d of prednisone for at least 6 months). For the RST, 250mcg of Cortrosina Organon were injected as an IV bolus and blood collected before and 60 minutes later, whereas for the PST, 250mcg of Cortrosina-Depot Organon were injected IM, every 8 hours for 3 days, and blood drawn daily between 8 and 9 o'clock AM. The post-ACTH cortisol value was the single parameter chosen to interpret both tests (the absolute or percent increase was of no further value). The 95% lower confidence limits (mean minus 1.64 SD) for the RST and the 3rd day of PST were 19.1 and 49.0mcg/dL, respectively. AD patients did not increase cortisol in response to both the RST (1.1 +/- 1.2 to 1.2 +/- 1.1mcg/dL) or the PST (1.2 +/- 1.3 to 2.0 +/- 1.7mcg/dL). However, whereas 22 out of 27 patients with HP and CG showed a modest cortisol increase to the RST (1.6 +/- 2.3 to 5.6 +/- 4.7 mcg/dL), all had a gradual and nearly normal response on the 3rd day of the PST (1.6 +/- 2.1 to 29.6 +/- 16.6mcg/dL).(ABSTRACT TRUNCATED AT 250 WORDS)

The investigation of 55 patients with chronic adrenocortical insufficiency has shown an increase in the intensity of lipid peroxidation against a background of blood plasma alpha-tocopherol (the main endogenous antioxidant) concentration. The use of vitamin E in multimodality treatment together with substitution hormone therapy resulted in the normalization of indices of lipid peroxidation and antioxidant system necessitating the incorporation of the drug in therapeutic measures in chronic adrenocortical insufficiency.