Epigastric pain as presentation of an addisonian crisis in a patient with Schmidt syndrome

A 39-year-old woman presented with a 10-day history of epigastric pain accompanied by persistent fatigue and loss of appetite for 3 months. She had presented several weeks earlier with adhesive capsulitis, treated by local infiltration of corticosteroids. She was not taking any other medications. Results of heart, lung, and abdominal examinations were unremarkable, except for mild epigastric tenderness. Purple stretch marks were observed on examination of the skin. The only blood chemistry abnormalities were hyponatremia (125 mEq/L) and hyperkalemia (6.8 mEq/L). Based on the clinical and biologic picture, adrenal insufficiency was suspected. The patient was transferred to the intensive care unit and received hydrocortisone intravenously for 3 days. She was then given oral hydrocortisone and fludrocortisone. Biologic abnormalities reversed entirely; the final diagnosis was primary autoimmune adrenal insufficiency (Addison's disease) associated with autoimmune hypothyroidism (Schmidt syndrome). Adrenal insufficiency should be considered in patients with abdominal pain, especially when associated with electrolyte abnormalities.     

Infectious causes of adrenal insufficiency

More than 150 years ago, Thomas Addison first described the clinical features and pathogenesis of adrenal insufficiency. At that time, tuberculosis was the most common cause of this disease. The pathway to diagnosis and treatment of Addison's disease has been well described. However, determining the cause of the disorder remains a challenge. It is important to consider recently described infectious agents in the pathogenesis of Addison's disease. Mycobacterial, bacterial, viral, and fungal infections may lead to the development of adrenal insufficiency. Skin, pulmonary, and imaging findings can aid the clinician in making a prompt diagnosis of specific infections, which is crucial because early identification of infectious causes of Addison's disease may enable recovery of adrenal function. This review describes the clinical presentations of the multiple infectious causes of adrenal insufficiency.     

Adrenocortical insufficiency: a medical emergency.

Adrenal insufficiency is a deceptive disorder. Insidious in onset, chronic in nature, it can suddenly progress into an acute life-threatening condition that may mimic disorders of vastly different etiologies. The result can be a lethal delay in diagnosis. Prompt diagnosis and replacement of glucocorticoids and fluids are essential for survival. Acute adrenal insufficiency is frequently an exacerbation of an underlying chronic disorder of the adrenal cortex or pituitary gland. Yet any patient who has been treated with suppressive doses of glucocorticoids (e.g., cortisol, prednisone), experienced overwhelming sepsis, has received anticoagulant therapy, or has endstage metastatic carcinoma may suddenly develop adrenal insufficiency along with its deadly sequela of hypovolemic shock, hyperkalemia, hyponatremia, and hypoglycemia. Successful management of this condition requires not only a heightened clinical awareness of adrenal insufficiency, but effective stress reduction interventions and a thorough patient and family teaching program to support lifelong control of the disease.     

Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease.

Autoimmune polyendocrine syndrome type I (APS I) and idiopathic Addison's disease are both disorders with adrenal insufficiency but with differences in genetic background, clinical presentation, and extent of extraadrenal manifestations. In this study the major adrenal autoantigen identified with sera from patients with APS I was characterized by analyses using indirect immunofluorescence, Western blots of adrenal subcellular fractions and of recombinant proteins, immunoprecipitations of [35S]methionine-labeled lysates of a human steroid-producing cell line, and studies of enzymatic activity. Sera from patients with APS I, identifying cells in adrenal glands and testes involved in steroid synthesis, reacted in Western blots with a 53-kD antigen, which comigrated with the cytochrome P450 cholesterol side chain cleavage enzyme (SCC). The sera also immunoprecipitated this protein from lysates of radiolabeled adrenal cells. The enzymatic activity of SCC was inhibited by the APS I sera but not by control sera. Sera from patients with idiopathic Addison's disease did not react with the SCC. The results show that the autoimmune responses towards adrenal tissue in patients suffering from APS I and Addison's disease are remarkably selective and suggest that a determination of the antigen involved in a patient with autoimmune adrenal insufficiency will have diagnostic as well as prognostic implications.     

TNF mediates a murine model of Addison's crisis

Addison's crisis is the most serious complication of adrenal insufficiency. To elucidate the mechanism of this disorder following infection, the role of TNF in adrenalectomized murine models of Addison's crisis and Addison's disease (chronic hypoglucocorticoidism) were examined. Adrenalectomy conferred a 40-fold increased sensitivity to the lethal effects of lipopolysacharride (LPS) (P < .001). Enhanced sensitivity to LPS was found to increase with duration of adrenal insufficiency (P < .02). Enhanced lethality to heat-killed Streptococcus pneumonia was also demonstrated (P < 0.02). Necropsy of endotoxin-killed adrenalectomized mice demonstrated similar pathologic findings to those found by others when the control mice were administered a lethal dose of either LPS or TNF. Adrenalectomized TNF receptor Ia and Ib double null mice were demonstrated to be resistant to the lethal effects of LPS (P < 0.02). Pretreatment with anti-TNF, but not control antisera, was found to prevent death in LPS-treated wild-type adrenalectomized mice as well (P < 0.02). Studies into the mechanism by which TNF was precipitating Addison's crisis demonstrated enhanced sensitivity to TNF (3-fold; P < 0.02), and a marked increase in serum TNF concentration (approximately 5-fold; P < 0.001) following LPS challenge. The effect of TNF upon long-term survival in adrenalectomized mice was examined in TNF-receptor Ia- and Ib-deficient mice. Deficiencies in either the TNF-receptor Ia or Ib was noted to confer a survival advantage relative to colony controls following adrenalectomy (P < 0.02). In summary, both LPS-induced Addison's crisis and chronic adrenal insufficiency are disorders of TNF disregulation. Based upon these data, therapeutic strategies targeted at controlling TNF in adrenal insufficiency are suggested.     

Tuberculous Addison's disease

Addison's disease is a possible diagnosis in any patient who presents with weakness, weight loss, hyperpigmentation, hyponatremia, and hypotension. Laboratory findings, including depressed levels of cortisol and aldosterone, help to confirm the diagnosis. Computed tomography may reveal adrenal calcification and abnormal-sized adrenal glands. In most cases, autoimmune destruction of the adrenal cortex is the cause of Addison's disease; however, as in the patient described here, tuberculosis is a possible cause.     

University of Miami Division of Clinical Pharmacology Therapeutic Rounds: the water-intolerant patient and perioperative hyponatremia

Perioperative hyponatremia has been recognized as a serious in-hospital complication for many years. Because the kidney responds to changes in extracellular fluid tonicity by adjusting water excretion, a defect in any of several key elements of water excretion can lead to water retention and hyponatremia. Most cases of hyponatremia are caused by impaired renal water excretion in the presence of continued water intake. For the kidney to excrete excess free water and thereby protect the extracellular fluid against hyponatremia, there must be an adequate glomerular filtration rate (GFR), adequate delivery of glomerular filtrate to the diluting segments of the distal nephron, intact tubular diluting mechanisms, and appropriate inhibition of antidiuretic hormone (ADH) synthesis and release. Virtually all of the clinical disorders producing hyponatremia are based on abnormalities of these few mechanisms of water regulation. Finding the reason for impaired renal water excretion is the key to diagnosing the cause of hyponatremia. Impaired renal water excretion may be caused by impaired GFR (renal failure), impaired water delivery to the diluting segments of the distal nephron because of increased proximal reabsorption (decreased extracellular fluid volume and edematous states), impaired renal diluting mechanism (thiazide diuretics), the syndrome of inappropriate ADH (SIADH) due to a variety of causes including the perioperative state, and hypothyroidism or adrenal insufficiency. Any of the states that impair water excretion can produce hyponatremia in a patient with an initially normal serum sodium concentration if sufficient free water is supplied. Therefore, a patient who has one of the conditions listed above, including the perioperative state, may be considered "water intolerant" even if the serum sodium is normal. Such a patient is at risk for developing severe hyponatremia if given hypotonic IV fluids or a large oral water load. An understanding of the basic mechanisms leading to impaired water excretion and "water intolerance" is therefore an important key to avoiding perioperative hyponatremia.     

Addison's disease

Addison's disease is an uncommon endocrine condition manifested by a variety of nonspecific symptoms, such as malaise, anorexia and nausea. Symptoms usually do not occur until most of the adrenal gland has been destroyed. Autoimmune disease has surpassed tuberculosis as the primary cause of Addison's disease. Nevertheless, tuberculosis still accounts for a significant proportion of cases. The rapid adrenocorticotropic hormone (ACTH) stimulation test is useful for identifying adrenal insufficiency. Maintenance therapy consists of hydrocortisone and fludrocortisone.     

Addisonian crisis due to adrenal gland metastasis in Hodgkin's disease

Adrenal insufficiency or Addison's disease is a rare illness associated with multiple pathology. We describe the case of a 61-year-old male with Hodgkin's disease and metastases in both adrenal glands who was diagnosed with adrenal insufficiency as a result of an acute addisonian crisis.     

Addison's disease with enlarged adrenal glands in sonography and computer tomography. Differential diagnostic considerations based on 2 cases of tuberculous adrenalitis

One of the major causes of chronic adrenal insufficiency (Addison's disease) is tuberculous adrenalopathy. Since sonography and computed tomography have become generally available in recent years and are of potential help in the diagnosis of this disease the merits of these methods are discussed in the light of 2 cases of adrenal tuberculosis, followed by a review of the literature. Adrenal calcification is the most significant, although not specific sign of adrenal insufficiency due to tuberculosis. Computed tomography has proven to be the method of choice in the non-invasive diagnosis of tuberculous adrenalopathy and in the monitoring of tuberculostatic treatment in this disease. Sonography is helpful as a preliminary investigation.     

Technical notes and clinical use of radioimmunologic determination of plasma ACTH]

Particular aspects of plasma ACTH radioimmunoassay are examinated. The results obtained with this method in adrenocortical diseases (Addison's disease, Cushing's syndrome, congenital adrenal hyperplasia) are reported and clinical value in etiological diagnosis of Cushing's syndrome is outlined. Moreover the results obtained in other syndromes of endocrinologic interest (massive obesity, Turner's and Klinefelter's syndromes, Laurence-Moon-Biedl syndrome, true precocious puberty, primary hypothyroidism, hypopituitary dwarphism) are reported and discussed.     

Studies on Auditory Thresholds in Normal Man and in Patients with Adrenal Cortical Insufficiency: The Role of Adrenal Cortical Steroids

Auditory thresholds for sinusoidal tones were determined in eight patients with adrenal cortical insufficiency (four with Addison's disease and four with panhypopituitarism) and compared to those in normal volunteers. In adrenal cortical insufficiency (ACI) the auditory detection sensitivity is significantly more acute than that of normal subjects over most of the frequency range, but especially in the region of greatest hearing sensitivity of normal subjects, 1,000 to 2,000 cycles per second (cps).     

Polyglandular type I autoimmune syndrome]

Two HLA-identical sisters have developed the full picture of type I polyglandular autoimmune syndrome over a period of 12 years. Both girls have hypoparathyroidism and Addison's disease. One of them additionally developed diabetes mellitus, hypergonadotropic hypogonadism and hypothyroidism. Autoantibodies to the adrenal, parathyroid and thyroid glands are present in both patients, as well as antinuclear antibodies. HLA associations have been described recently for the type I polyglandular autoimmune syndrome, but this could not be confirmed in the present two cases. Although we assume that the same genetic defect is present in both girls, additional factors to the genetic disposition are important for the clinical expression of the disease. The linkage of the disease-causing gene with the HLA region is not very close.     

Myxedema coma: diagnosis and treatment

Myxedema coma, the extreme manifestation of hypothyroidism, is an uncommon but potentially lethal condition. Patients with hypothyroidism may exhibit a number of physiologic alterations to compensate for the lack of thyroid hormone. If these homeostatic mechanisms are overwhelmed by factors such as infection, the patient may decompensate into myxedema coma. Patients with hypothyroidism typically have a history of fatigue, weight gain, constipation and cold intolerance. Physicians should include hypothyroidism in the differential diagnosis of every patient with hyponatremia. Patients with suspected myxedema coma should be admitted to an intensive care unit for vigorous pulmonary and cardiovascular support. Most authorities recommend treatment with intravenous levothyroxine (T4) as opposed to intravenous liothyronine (T3). Hydrocortisone should be administered until coexisting adrenal insufficiency is ruled out. Family physicians are in an important position to prevent myxedema coma by maintaining a high level of suspicion for hypothyroidism.     

Reversible cardiomyopathy in a child with Addison's disease

An 11-year-old boy in acute adrenal crisis was subsequently diagnosed with Addison's disease and presumably had an unrecognized preceding chronic adrenal insufficiency. His adrenal insufficiency and hypovolemic shock were promptly diagnosed and treated in the emergency room. However, 24 h later, signs of congestive heart failure developed and an echocardiogram revealed cardiomyopathy. He responded to i.v. dopamine and his cardiomyopathy resolved over some days. Acute adrenal insufficiency and actual ventricular dysfunction had not been described in humans until last year; this is the second reported case of cardiomyopathy in a patient with acute adrenal insufficiency.     

Hypokalemic adrenal crisis in a patient with AIDS

Electrolyte disorders have been reported frequently in patients with AIDS. Adrenal insufficiency has been associated with hyponatremia in this group of patients. We have presented the case of a patient with AIDS whose early course was complicated by hyponatremia, hypoglycemia, and hyperkalemia. Shortly thereafter, hypokalemia developed due to gastrointestinal potassium losses from diarrhea. Although cosyntropin stimulation testing later confirmed the diagnosis of adrenal insufficiency, it was not considered because of coexistent hypokalemia. Diarrhea in patients with AIDS and diminished adrenal reserve may invalidate hypokalemia as an exclusion criterion for the diagnosis of adrenal crisis.     

Bilateral adrenal hemorrhage after anticoagulation prophylaxis for bilateral knee arthroplasty

After joint arthroplasty, the risk of deep vein thrombosis and pulmonary embolism increases exponentially. Inadequate anticoagulation prophylaxis may not sufficiently reduce the risk of thrombosis, whereas excessive anticoagulation therapy may predispose the patient to a bleed. Bilateral adrenal hemorrhage is a relatively rare but potentially catastrophic life-threatening event. An 82-yr-old woman is described who was rehospitalized from a subacute rehabilitation facility complaining of epigastric pain radiating into her flank. Eight days previously, she had undergone an uncomplicated bilateral total knee arthroplasty and was subsequently administered subcutaneous heparin and warfarin. An abdominal computed tomographic scan subsequently demonstrated bilateral small adrenal hemorrhages. Acute adrenal insufficiency (Addison's disease) caused by hemorrhage within the adrenal cortices, although still uncommon, can be expected to increase as anticoagulation prophylaxis after joint arthroplasty becomes routine.     

Autoimmune polyglandular syndrome, type II

The combination of autoimmune adrenal insufficiency with autoimmune thyroid disease and/or type 1 autoimmune diabetes mellitus defines autoimmune polyglandular syndrome, type II. The conditions may occur in any order, and diagnosis is confounded by the nonspecific nature of the symptoms of adrenal insufficiency and hypothyroidism. The disorder is not common, but consequences can be life threatening when the diagnosis is overlooked. The conditions usually present in midlife, and women are affected more often than men. The cosyntropin test is recommended for diagnosing adrenal insufficiency, which must be present to diagnose this syndrome. Hormone therapy for each condition is similar to treatment that would be provided if the conditions occurred separately, except that treatment for adrenal insufficiency must be given before thyroid therapy is started when the conditions occur together.     

慢性肾上腺皮质功能减退症70例临床分析

目的：复习原发性和继发性慢性肾上腺皮质功能减退症的病因和临床特点。方法：回顾性分析70例慢性肾上腺皮质功能减退症的临床资料。结果及结论：原发性和继发性的慢性肾上腺皮质功能减退症病因分别以结核及席汉综合征为多。两者共有表现为食欲减退、疲乏无力、体重减轻、低血压、贫血、低钠血症、低血糖和血皮质醇、尿皮质醇降低。原发性者以色素沉着和血浆促肾上腺皮质激素（ACTH）值升高为特点,可见高钾血症;继发性者则表现肤色浅淡,常有多种垂体激素缺乏表现,ACTH降低或正态,无高钾血症。     

Hyponatremia revisited: translating physiology to practice

The complexity of hyponatremia as a clinical problem is likely caused by the opposite scenarios that accompany this electrolyte disorder regarding pathophysiology (depletional versus dilutional hyponatremia, high versus low vasopressin levels) and therapy (rapid correction to treat cerebral edema versus slow correction to prevent osmotic demyelination, fluid restriction versus fluid resuscitation). For a balanced differentiation between these opposites, an understanding of the pathophysiology of hyponatremia is required. Therefore, in this review an attempt is made to translate the physiology of water balance regulation to strategies that improve the clinical management of hyponatremia. A physiology-based approach to the patient with hyponatremia is presented, first addressing the possibility of acute hyponatremia, and then asking if and if so why vasopressin is secreted non-osmotically. Additional diagnostic recommendations are not to rely too heavily of the assessment of the extracellular fluid volume, to regard the syndrome of inappropriate antidiuresis as a diagnosis of exclusion, and to rationally investigate the pathophysiology of hyponatremia rather than to rely on isolated laboratory values with arbitrary cutoff values. The features of the major hyponatremic disorders are discussed, including diuretic-induced hyponatremia, adrenal and pituitary insufficiency, the syndrome of inappropriate antidiuresis, cerebral salt wasting, and exercise-associated hyponatremia. The treatment of hyponatremia is reviewed from simple saline solutions to the recently introduced vasopressin receptor antagonists, including their promises and limitations. Given the persistently high rates of hospital-acquired hyponatremia, the importance of improving the management of hyponatremia seems both necessary and achievable.