Autoimmune Adrenalitis Research Articles

The Approach to the Adult with Newly Diagnosed Adrenal Insufficiency

Adrenal insufficiency, primarily presenting as an adrenal crisis, is a life-threatening emergency and requires prompt therapeutic management including fluid resuscitation and stress dose hydrocortisone administration. Primary adrenal insufficiency is most frequently caused by autoimmune adrenalitis, and hypothalamic-pituitary tumors represent the most frequent cause of secondary adrenal insufficiency. However, the exact underlying diagnosis needs to be confirmed by a stepwise diagnostic approach, with an open eye for other differential diagnostic possibilities. Chronic replacement therapy with glucocorticoids and, in primary adrenal insufficiency, mineralocorticoids requires careful monitoring. However, current replacement strategies still require optimization as evidenced by recent studies demonstrating significantly impaired subjective health status and increased mortality in patients with primary and secondary adrenal insufficiency. Future studies will have to explore the potential of dehydroepiandrosterone replacement and modified delayed-release hydrocortisone to improve the prospects of patients with adrenal insufficiency.

Partial recovery of adrenal function in a patient with autoimmune Addison’s disease

To our knowledge, no case of remission in autoimmune Addison's disease has previously been reported. We describe a patient with primary adrenal insufficiency caused by autoimmune adrenalitis in whom partial remission was observed after 7 yr. A 39-yr-old male was referred because of extreme fatigue, weight loss, anorexia, nausea, and bouts of fever. During physical examination hyperpigmentation was seen. Laboratory tests showed a plasma cortisol of 0.02 micromol/l (08:30 h). Cortisol failed to increase during the ACTH stimulation test (0.02 to 0.03 micromol/l) and ACTH was markedly elevated (920 pmol/l). Adrenal auto-antibodies were weakly positive. A CT-scan showed no evidence of calcifications or other abnormalities of the adrenal glands. The diagnosis of autoimmune Addison's disease was made and replacement therapy with hydrocortisone and fludrocortisone was started. During the following years the dose of hydrocortisone was gradually decreased. Eventually, the patient decided to stop his medication completely. A repeated ACTH-stimulation test revealed a basal cortisol of 0.25 micromol/l and a peak cortisol of 0.30 micromol/l with a basal ACTH of 178 pmol/l. The patient did not have any complaints. Recovery of adrenal insufficiency, due to causes other than autoimmune adrenalitis, has been reported in the past. If our case of partial recovery of autoimmune adrenalitis is not unique this could have profound effects on treatment and follow-up of Addison's disease.

Glucocorticoid replacement therapy in patients with Addison’s disease

One hundred and fifty years ago, Thomas Addison published his classic paper on the ‘Constitutional and Local Effects of Disease of the Supra-renal Capsules’, in which he described 11 patients with the disorder that would come to bear his name. Adrenal insufficiency is a rare disease, but its prevalence is increasing. The most frequent causes of adrenal insufficiency in western countries are autoimmune adrenalitis, but other causes include, tuberculosis systemic fungal infections, AIDS, metastatic carcinoma and isolated glucocorticoid deficiency. It is clear that autoimmunity precedes overt Addison’s disease by years, as in many autoimmune endocrine disorders . Adrenocortical function is lost over a period of years as it progresses to overt Addison’s disease. This editorial discusses the controversial glucocorticoid replacement therapy in patients with Addison’s disease, and aims to provide a good review of literature and suggested guidelines for appropriate treatment of this disease.

Campylobacter sepsis with multiple organ failure in IgG subclass deficiency

Some patients with immunodeficiency develop clinical features of autoimmune disorders. A previously asymptomatic antibody deficiency can underlie the development of autoimmune diseases and a severe course of infection, with a risk of sepsis; such cases are known in selective IgA deficiency. On the other hand, little information is available on selective IgG subclass deficiencies. An unexpectedly severe course of Campylobacter infection in a 19-year-old woman with a previously undiagnosed complex immune disorder, including selective IgG1 immunodeficiency, Hashimoto's autoimmune thyroiditis with hypothyroidism combined with Addison's disease presumably due to autoimmune adrenalitis, autoimmunity and allergy is described. The pathophysiological mechanisms of autoimmunity in latent humoral defects are discussed.

Von der Sonne gebräunt und doch nicht gesund!

We describe a case of a 10 years old girl, which presented to the emergency room with non-specific gastro-intestinal symptoms, fatigue and low blood pressure. The clinical signs and laboratory value supported the diagnosis of Addison crisis with hypovolaemic shock. The pathophysiology and the therapy of this entity are discussed. Importantly, in children the aetiology may differ depending on age and sex. Based on the family history of autoimmune disorders, in our patient presenting with autoimmune adrenalitis and celiac disease, the diagnosis of an autoimmune polyendocrinopathy was made. A therapy of mineralcorticoids and glucocorticoids was initiated and a special gluten-free diet was prescribed. On this treatment our patient recovered promptly.

Adrenal crisis presenting as an acute abdomen

We report an interesting case of an ‘acute abdomen’. A 63-year-old female was admitted to the Emergency Department with a brief history of severe diarrhoea and rectal bleeding. Colonoscopic findings were normal. Over the next 24 h she developed lower abdominal pain with distension and became hypotensive. Her blood biochemistry results were sodium 133 mmol.l−1, potassium 5.3 mmol.l−1, urea 10.1 mmol.l−1 and creatinine 186 μmol.l−1 Suspecting peritonitis, surgeons performed a laparotomy which revealed a large quantity of uninfected peritoneal fluid, but no perforation of a viscus. Microbiological screening did not reveal any infection. In spite of all measures, she developed multi-organ failure and died a week later. Her past medical history included a head injury 35 years previously and she was maintained on carbamazepine and sodium valproate for post-traumatic seizures. She was hypothyroid on thyroxine supplementation. About 10 years prior to this admission she underwent Keller's operation on her foot and postoperatively had severe seizures and high fever. A few months later she underwent appendicectomy and had a difficult postoperative recovery with seizures and hyponatraemia (113 mmol.l−1), which was attributed to the syndrome of inappropriate ADH secretion secondary to her anti-epileptic medications. On another occasion she was admitted with tonsillitis and developed features of septic shock with a high fever and persistent hypotension requiring fluids and antibiotics. Her only uneventful hospital visit was for an orthopaedic procedure during which she was given a methyl prednisolone injection into her shoulder joint. At post mortem examination, despite a prolonged and extensive search, the adrenal glands were not identified. The thyroid gland was small and the pituitary fossa was considerably enlarged and the pituitary gland was largely replaced by non-functioning fibrous and calcified tissue. On review it appears complications during her previous hospital admissions could have been manifestations of adrenal insufficiency. The only uneventful hospital stay was when she had a steroid injection in her shoulder, which incidentally provided the steroid coverage during the stressful period. In this case, the adrenal failure could have been the result of the head injury she sustained several years earlier, resulting in damage to the pituitary gland. Against this possibility is the enlarged pituitary fossa found at autopsy. She had also suffered from unexplained episodes of headaches, perhaps due to a necrosed pituitary tumour? Histological examination of the pituitary gland revealed calcified and atrophic tissues. Similar cases have been described in the past where the cause was attributed to autoimmune adrenalitis [1]. Acute gastrointestinal symptoms and persistent unresponsive hypotension should raise the possibility of adrenal insufficiency. As our case demonstrates, missing this diagnosis can lead to unnecessary surgical exploration.

Management of adrenal insufficiency in different clinical settings

Adrenal insufficiency is a rare disease, but its prevalence is increasing. The most frequent cause of primary adrenal insufficiency in western countries is autoimmune adrenalitis, whereas secondary adrenal insufficiency is most often caused by pituitary tumours and their treatment (e.g., surgery). Chronic glucocorticoid replacement consists of hydrocortisone 15 – 25 mg/day in divided doses and dose monitoring is largely based on clinical judgement. Fludrocortisone 0.05 – 0.2 mg/day is given for substitution in mineralocorticoid deficiency aiming at normotension, normokalaemia and a plasma renin activity in the upper normal range. It has recently been shown that, despite adequate glucocorticoid and mineralocorticoid replacement well being in patients with adrenal insufficiency is still impaired. Several studies have demonstrated that dehydroepiandosterone 25 – 50 mg/day p.o. may improve mood, fatigue, well-being and, in women, also sexuality, suggesting that dehydroepiandosterone should become part of the standard treatment regime. However, large Phase III trials of dehydroepiandosterone for adrenal insufficiency are still lacking and it has not yet been approved for the treatment of this disease. Patients with adrenal insufficiency are at risk of adrenal crisis, usually precipitated by major stress, such as severe infection or surgery. Early dose adjustments are required to cover the increased glucocorticoid demand in stress. Careful and repeated education of patients and their partners is the best strategy to avoid this life-threatening emergency. Some recent studies suggest that during sepsis some patients with intact adrenal function may develop transient relative adrenal insufficiency and benefit from administration of hydrocortisone plus fludrocortisone. However, the pathophysiology and diagnosis criteria of relative adrenal insufficiency and its treatment remain unsettled issues.

Schmidt Syndrome Presenting as Acute Liver Failure

The Schmidt Syndrome (Type II Autoimmune-Syndrome) is characterised by an autoimmune adrenalitis in combination with a chronic lymphocellular thyreoiditis resulting in insufficiency of these organs in adulthood. Combination with diabetes is possible. The diagnosis is usually established by clinical examination and analysis of serum hormone levels (adrenocorticotropin hormone [ACTH], cortisol, thyroid stimulating hormone [TSH], triiodothyronine [fT3], thyroxine [fT4]). In the present case, initial diagnosis was rapid progressive liver failure of unknown origin with consecutive multiple organ dysfunction syndrome including dysfunction of heart, lungs, and kidneys. Frequent and less frequent causes of liver failure were ruled out, e.g. viral or autoimmune hepatitis, Budd-Chiari-syndrome, toxic, or drug induced liver failure. In retrospect, the multiple organ dysfunction syndrome was caused by hypoperfusion due to severe hypovolemia and hypoperfusion was induced by adrenocortical insufficiency proven by endocrinological testing. The clinical course of this case stresses the importance of the hormone balance in the critical ill patient. The guideline for treatment of patients with assumed hormonal dysregulation should include a full hormone status prior to substitution. The present case report also illustrates the importance of clinical signs and careful consideration of the medical history in detecting an autoimmune endocrine disease.

Assessment of adrenocortical function and autoantibodies in a baby born to a mother with autoimmune polyglandular syndrome Type 2

We describe the case of a baby born to a mother with Addison's disease in the context of Autoimmune Polyendocrine Syndrome Type 2. Adrenal cortex autoantibodies and steroid 21-hydroxylase autoantibodies were detectable in the sera of both mother and baby, suggesting the transplacental passage of these autoantibodies. Adrenal autoantibodies were present in the baby's serum at delivery, at 3, 6 and till 34 months of age but no signs of clinical or subclinical adrenal insufficiency were found in the baby during the observation period. These data suggest that the presence of adrenal autoantibodies in serum alone is not a sufficient cause for the development of autoimmune adrenalitis.

Time Course of 21-Hydroxylase Antibodies and Long-Term Remission of Subclinical Autoimmune Adrenalitis after Corticosteroid Therapy: Case Report

Time Course of 21-Hydroxylase Antibodies and Long-Term Remission of Subclinical Autoimmune Adrenalitis after Corticosteroid Therapy: Case Report

Vomiting and hyponatraemia in pregnancy

A 35 year old primigravida was admitted to hospital at 18 weeks of gestation with recurrent attacks of vomiting. Her symptoms first developed in the sixth week of pregnancy, and she had been admitted three times with a provisional diagnosis of hyperemesis gravidarium. On each occasion the w o r n was hyponatraemic (plasma sodium 119-128 mmol/L), with normal plasma potassium, urea, creatinine and glucose levels. During each admission she improved with anti-emetic drugs and intravenous normal saline and was then discharged. In the eight weeks before her pregnancy, the woman had experienced anorexia, weight loss and intermittent diarrhoea. On her fourth admission she appeared well, if slightly dehydrated, had a blood pressure of 100/80 mmHg with no postural hypotension and showed discolouration of skin and mucous membranes (ascribed initially to her Portuguese ancestry). Otherwise the clinical examination was normal. She was treated with intravenous normal saline, but despite this became hypotensive (blood pressure 80/40 mmHg) and remained hyponatraemic (plasma sodium 1OP-115 mmol/L). A presumptive diagnosis of Addison’s disease was made. Blood was taken to estimate random cortisol and adrenocorticotrophic hormone levels, and she was treated with intravenous hydrocortisone. Her random serum cortisol concentration was 106 nrnoVL and adrenocorticotrophic hormone concentration was > 1500 ng/L, confinnng primary adrenal failure. The serum was strongly positive for 21-hydroxylase antibodies, suggesting auto-immune adrenalitis, the commonest cause of Addison’s disease. Glutamic acid decarboxylase, thyroid peroxidase and thyroglobulin antibodies were also positive but glucose tolerance and thyroid function were normal. Following her intravenous steroid therapy the woman was given oral hydrocortisone and fludrocortisone and subsequently her blood pressure and plasma sodium concentration returned to normal, with restoration of her wellbeing. The remainder of her pregnancy was uneventful, and she was delivered at 41 weeks of a male infant weighing 2500 g. In her

Associated Autoimmunity in Addison's Disease

As the last extensive series of patients with Addison's disease and coincident autoimmune phenomena were published approximately two decades ago, we studied the cause of the disease, the prevalence of autoimmune disorders and the frequency of occurrence of autoantibodies in 91 patients (31 men and 60 women, mean age 45.3-years-old, range 12-77) with Addison's disease. The cause of Addison's disease in six patients was tuberculosis (6.6%), and autoimmune adrenalitis was considered to be the cause in 83 patients (91.2%). In two patients (2.2%) other causes were responsible for Addison's disease. In 47% of the patients with autoimmune Addison's disease at least one other autoimmune disorder was present. Primary hypothyroidism had the highest prevalence (20.5%), followed by vitiligo (9.6%), non-toxic goiter (8.4%), premature menopause (7.3% of the women), Graves' disease (6%), pernicious anaemia (4.8%), Sjögren's disease (2.4%), hypoparathyroidism (1.2%), type 1 diabetes mellitus (1.2%) and coeliac disease (1.2%). The frequency of autoantibodies in the patients with autoimmune Addison's disease was: adrenal antibodies (82.7%), antibodies against microsomal antigens (58%), thyroglobulin antibodies (23.4%), parietal cell antibodies (19.8%), pancreatic islet cell antibodies (6.2%) and ovary antibodies (3.7% of the women). In comparison with other extensive series of patients with Addison's disease, we found the highest prevalence of autoimmune adrenalitis as the cause of Addison's disease, the highest prevalence of hypothyroidism and vitiligo as concomitant autoimmune disorders and the lowest prevalence of type 1 diabetes mellitus.

Autoimmune Addison’s Disease after Treatment With interleukin-2 and Tumor-Infiltrating Lymphocytes

Autoimmune thyroiditis with hypothyroidism is a well-known complication of immunotherapy with interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. To date, however, no cases of IL-2/LAK-induced autoimmune adrenalitis with adrenal insufficiency have been reported. We describe a patient who developed primary adrenal insufficiency following IL-2/tumor-infiltrating lymphocytes (TIL) immunotherapy for renal cell carcinoma. A 64-year-old male with renal cell carcinoma metastatic to bone, skin, lung, and the central nervous system presented for IL-2/TIL treatment. Nine months earlier, he had undergone a right nephrectomy and adrenalectomy. He had already received two courses of IL-2 and one course of IL-4 following surgery. Dynamic studies of adrenal function performed prior to IL-2/TIL immunotherapy demonstrated intact cortisol and aldosterone responses to ACTH as well as negative adrenal antibodies. One week after IL-2/TIL therapy, the patient developed a nonanion gap metabolic acidosis, hypotension and hypoglycemia. Adrenocortical function was re-evaluated demonstrating blunted cortisol and aldosterone responses to ACTH with an elevated plasma ACTH confirming the presence of primary adrenal insufficiency. Adrenal antibodies were now positive. Hydrocortisone and fludrocortisone were given with a good clinical response. We suggest immunotherapy with IL-2/TIL may cause adrenal insufficiency by activating autoimmune adrenalitis.

Acute Adrenal Insufficiency

Acute adrenal insufficiency is a rare disorder associated with high morbidity and mortality if allowed to progress unrecognized. A constellation of nonspecific symptoms including weakness, easy fatigue, nausea, anorexia, and weight loss are typical features of adrenal insufficiency. The index of suspicion should be particularly high if the patient has hyperpigmentation; hyponatremia and/or hyperkalemia; a history of autoimmune disease (hypothyroidism, diabetes) or recent prior use of exogenous steroids or if the patient is on anticoagulant therapy. Any decline in clinical status (hypotension, fever, decreasing mental status), especially in the setting of an acute intercurrent illness, should be treated aggressively, even before laboratory confirmation of the diagnosis. Diagnostic testing is fairly straightforward and readily available. The development of purified synthetic corticosteroid preparations has provided a safe and effective means of replacement. Early awareness, recognition, and intervention remain significant steps in altering the course of acute adrenal insufficiency.

The adrenal autoantigen in APSI is the side-chain cleavage enzyme

Autoimmune potyendocrine syndrome type I (Blizzard's syndrome) is an autosomal recessively inherited disease associated with multiple endocrine and non-endocrine manifestations such as autoimmune hypoparathvroidism, adrenalitis, gonadal insufficiency, mucocutaneous candidiasis, alopecia and vitiligo. We have characterised the adrenal autoantigen recognized by autoantibodies in sera from this group of patients. The methods used include indirect immunofluore scenes on frozen sections of different tissues, immunoblotting of adrenal sub-cellular fractions and of proteins expressed in a prokaryotic system and immuno-precipi-ations of labelled lysates of a highly differentiated adrenocortical cell line. In addition, studies on enzyme inhibition were performed. The sera recognized a protein co-migrating in all systems with the rate-limiting enzyme of the steroid biosynthesis, the cholesterol side-chain cleavage enzyme (SCC). Bacterially expressed SCC was recognized by the APS I sera in immunoblotting, whereas no reactivity was found against bacterially expressed 17α-hydroxylase or 21-hydroxylase expressed in a eukaryotic system. SCC-activity in bovine adrenal mitochondria was inhibited by 80% in the presence of APS I sera.

Experimental autoimmune adrenalitis: a murine model for Addison's disease.

Experimental autoimmune adrenalitis was produced in mice by immunizing 8 times or more at intervals of 30 days with syngeneic adrenal extract mixed with Klebsiella O3 lipopolysaccharide (KO3 LPS) as a potent adjuvant. The cortex regions of the adrenal glands after the 8th injection were definitely infiltrated with polymorphonuclear leukocytes (PMN). The main infiltrates in the lesions after the 9th injection were replaced by mononuclear cells, such as small lymphocytes and macrophages, and further by fibrous connective tissues. There were no histological changes in the medullary regions. The repeated immunization developed the delayed type hypersensitivity to adrenal extract and production of anti-adrenocortical autoantibody in those immunized mice. Moreover, the adrenalitis could be produced in normal mice by transfer of spleen cells from hyperimmunized mice, suggesting the critical role of the cell-mediated immunity. This experimental model might be useful to study immunological phenomena in the pathogenesis of Addison's disease.

Autoimmune Adrenalitis, Asthma and Membranoproliferative Glomerulonephritis

We report the first case of membranoproliferative glomerulonephritis in a patient with chronic adrenal insufficiency due to autoimmune adrenalitis. In addition, this patient developed extrinsic asthma. The pathogenic implications of autoimmune adrenalitis with a long lasting hypocortisolemic state and the appearance of immunologically mediated diseases are discussed.

Isolated aldosterone deficiency in a patient with autoimmune adrenalitis

Isolated aldosterone deficiency in a patient with autoimmune adrenalitis

Class II MHC expression in normal adrenal cortex and cortical cells in autoimmune Addison's disease.

It has been proposed that aberrant expression of class II major histocompatibility complex (MHC) molecules by target cells may be an initiating factor in some forms of organ specific autoimmunity. This hypothesis was tested in relation to the autoimmune form of Addison's disease by studying autopsy adrenal glands from eight patients who had died of recent onset idiopathic Addison's disease. Using an immunohistochemical technique, class II MHC expression was found in a minority of adrenal cortical cells in the zona reticularis in 25 normal and four hyperplastic glands, while in Addison's disease almost all residual cortical cells expressed class II MHC. Three tuberculous adrenals showed increased staining of cortical cells around areas of chronic inflammation. It is concluded that since adrenal cortical cells of the normal gland express class II MHC, aberrant expression of this product cannot be invoked as an initiating mechanism in autoimmune adrenalitis. The increased cortical expression of class II MHC seen in idiopathic Addison's disease and tuberculosis may be due to local release of lymphokines by inflammatory cells.

Surreptitious Insulin Administration

Sir. — Dr Brouhard's editorial Insulin Administration in the January issue of AJDC discussed an important cause of unexplained hypoglycemia in the type I diabetic patient. Surreptitious insulin administration be considered seriously in any diabetic with drastically reduced insulin requirements. However, Dr Brouhard failed to mention the possibility of autoimmune adrenalitis presenting similarly. Any type I diabetic patient is at risk for other autoimmune disease as part of an autoimmune polyglandular syndrome. Although adrenal failure is uncommon in the pediatric patient, the life-threatening nature of this condition makes early diagnosis essential. Autoimmune adrenalitis should be considered in all type I diabetics with unexplained hypoglycemia, especially those with other autoimmune diseases (most commonly autoimmune thyroiditis) or a family history of an autoimmune polyglandular syndrome.