Endocrine disorders: causes of hyponatremia not to neglect

Hyponatremia is a common electrolyte abnormality with the potential for significant morbidity and mortality. Endocrine disorders, including adrenal deficiency and hypothyroidism, are uncommon causes of hyponatremia. Primary adrenal insufficiency (i.e. Addison's disease) may well be recognized by clear hall-marks of the disease, such as pigmentation, salt craving, hypotension, and concomitant hyperkalemia. Addison's disease is an important diagnosis not to be missed since the consequences can be grave. On the other hand, hypothyroidism and secondary adrenocortical insufficiency originating from diseases of the hypothalamus and/or pituitary (hypopituitarism) require a high index of suspicion, because the clinical signs can be quite subtle. This review focuses on clinical and pathophysiological aspects of hyponatremia due to endocrine disorders.     

Adrenal and pituitary emergencies

Although loss of normal pituitary function may be silent and asymptomatic, sudden loss of gland function (pituitary apoplexy) typically results in characteristic presentations. Sheehan's syndrome is the development of hypopituitarism after postpartum hemorrhage or shock. Patients with Sheehan's syndrome may have typical or atypical presentations based on the extent of pituitary gland destruction. Patients with typical symptoms fail to lactate after giving birth; subsequently these patients also develop symptoms and signs of hypopituitarism. Measuring the serum prolactin level after giving thyrotropin-releasing hormone is a reasonable first step in the diagnosis of this condition in patients who fail to lactate after giving birth. The diagnosis of hypopituitarism is delayed for up to 7 years in patients with atypical symptoms. Acute symptomatic failure of the pituitary gland (pituitary apoplexy) commonly occurs in patients who have asymptomatic pituitary tumors. Many patients with pituitary tumors do not have signs of abnormal endocrine gland secretion and have a normal appearance. Most patients have the following signs or symptoms: headache; acute disturbances in visual acuity or visual fields; ophthalmoplegia, and changes in the level of consciousness. The syndrome of pituitary apoplexy usually evolves over hours to days. Subarachnoid hemorrhage and acute bacterial meningitis are the two most important mimics of pituitary apoplexy. Intravenous steroids and prompt neurosurgical consultation are mandatory in cases of pituitary apoplexy since both steroids and surgery can improve vision. Testings for acute or chronic hypopituitarism is challenging in the Emergency Department setting; however, carefully chosen tests will aid in the subsequent early correct diagnosis after initial Emergency Department management.     

脑损伤后内分泌功能的变化及其发生机制

在创伤性颅脑损伤和脑血管病急性期，均可出现下丘脑-垂体．肾上腺皮质轴、下丘脑-垂体-甲状腺轴和下丘脑-垂体-性腺轴功能紊乱，主要是由于下丘脑和垂体原发或继发性损伤所致。脑损伤后急性期的体内大多数激素水平的变化是暂时性的，也可能是可逆的，但部分病例在恢复期合并有垂体功能减退，出现分泌功能不足的表现。激素的缺乏可能会影响到脑损伤患者的预后，目前需要建立一个指南以明确哪部分患者、什么时候以及怎样进行激素替代治疗。     

Clinical approach to adrenal insufficiency in hospitalised patients

Primary adrenal insufficiency (Addison’s disease) refers to glucocorticoid deficiency resulting from adrenal gland disease. Central adrenal insufficiency is because of disorders of the pituitary gland (secondary) or the hypothalamus (tertiary). Long‐term hypothalamic‐pituitary‐adrenal (HPA) axis suppression is commonly seen after chronic glucocorticoid therapy (iatrogenic). Transient HPA axis suppression is increasingly being reported in hospitalised patients with acute illness (relative adrenal insufficiency). This article extensively reviews various aetiologies and management of adrenal insufficiency.     

Endocrine incidentalomas

Objectives: Endocrine incidentalomas are very common in the practice of every physician, mostly primary care and family physicians. Incidentalomas are discovered in the thyroid, pituitary and adrenal glands during imaging studies performed for non‐endocrine reasons. The aim of this review article is to familiarise health professionals with all three endocrine incidentalomas, and give some guidance on how to initiate the right endocrine workup. Methods: We reviewed the most pertinent literature published on this topic through PubMed and Medline. We also discussed our own approach to incidentalomas in the endocrine clinic at Thomas Jefferson Hospital in Philadelphia. Results/conclusions: Thyroid incidentalomas are very common, with a prevalence close to 50% on imaging studies. Thyroid‐stimulating hormone (TSH) is the first test to obtain; if not suppressed, next step is fine‐needle aspiration biopsy of any nodule above 1 cm and/or with suspicious ultrasound characteristics. Adrenal incidentalomas have a prevalence of almost 5%. All adrenal nodules above 4 cm should be resected. Regardless of the size, a workup for pheochromocytoma should always be done. Only hypertensive patients should be screened for primary hyperaldosteronism. Pituitary incidentalomas are also common, with a prevalence of 10–20%. All patients with pituitary masses should have a workup for hormonal hypersecretion. Only patients with macroadenomas will have additional screening for hypopituitarism and visual field defects. All hyperfunctioning adenomas are resected except prolactinomas which are treated medically. Similarly, if a macroadenoma is causing hypopituitarism or visual deficit, surgery should also be considered.     

Endocrine complications after radiotherapy for tumors of the head and neck

One hundred sixty-six patients 6 to 80 years of age with nasopharyngeal cancer and paranasal sinus tumors who were free of the primary disease were studied from 1 to 26 years after radiotherapy. Studies in 65 of these patients were performed prospectively. Both the hypothalamus and the anterior pituitary gland were in the field of irradiation. The median radiation dose was estimated to be 5700 rad to the anterior pituitary gland and 5000 rad to the hypothalamus. We found evidence of endocrine deficiencies in 134 of the 166 patients observed. One hundred eleven patients showed evidence suggestive of hypothalamic lesions and 67 patients showed evidence of primary pituitary deficiency. Forty-eight of the 110 patients who received radiotherapy to the neck for treatment or prevention of lymph node metastasis showed evidence of primary hypothyroidism. The median dose to the thyroid area was 5000 rad. Adolescents younger than 15 years of age had a higher incidence of growth hormone deficiency soon after radiotherapy, but the older group showed adrenocortical and luteinizing hormone deficiency. These results indicate that endocrine deficiencies after radiotherapy for tumors of the head and neck are common. The highest incidence of complications occurred 1 to 5 years after radiotherapy, but long-term follow-up is indicated because complications may appear years after radiotherapy.     

Anti-pituitary antibody-induced multiple endocrine disorders in mice

Circulating anti-pituitary antibodies (APAs) have been detected in patients with autoimmune diseases, although the role of autoantibodies in the pathogenesis of autoimmune diseases is still unclear. With the aim of elucidating the autoimmune mechanisms involved in patients with multiple endocrine disorders, we evaluated the pathological changes in the pituitary gland, thyroid, pancreas and adrenal gland of mice, both wild-type and using a murine model of autoimmune thyroid disease [MRL-lpr/lpr] that had been immunized with murine, rat, porcine or human pituitary glands. In four of seven mice, a 22 kD band corresponding to APA was detected by Western blotting in the serum from mice that had been immunized with human pituitary tissues but not in the serum from mice immunized with rat or pig tissue. Inflammatory changes were detected in all groups of mice, occurring in the hypophysis, pancreas and adrenal glands but not in the thyroid. In conclusion, APA-induced autoimmune endocrine disorders are likely to be important for studying the mechanisms involved in autoimmune syndromes.     

The pituitary gland in the Laurence-Moon syndrome

The apparent hypogonadism in patients with the Laurence-Moon syndrome has been variably attributed to unresponsiveness of target organs to gonadal hormones, primary end-organ failure, hypothalamic dysfunction, or pituitary failure. We report the first immunocytologic study of the pituitary gland in this rare disorder. No morphologic abnormalities were noted. The numbers and immunoreactivities of adenohypophyseal cell types were normal. No microscopic abnormalities were evident in the hypothalamus and target organs. The results of our study are consistent with recent biochemical data that suggest that pituitary function is normal in patients with this syndrome.     

Laboratory diagnosis of hypopituitarism

Hypopituitarism can be caused by failure or loss of one or more of the eight identifiable hormones in the anterior lobe of the pituitary gland. The endocrine manifestations of hypopituitarism are related to the type and degree of hormonal deficiency and the stage in life during which the deficiency occurs. In patients with suspected hypopituitarism, the diagnostic approach consists of determining the extent and the cause of the hormonal loss. Specific provocative tests for the diagnosis of hypopituitarism are reviewed in detail in this article.     

Diagnosis and therapy of diseases of the endocrine system: new trends in nuclear medicine

Diagnosis and therapy of endocrine disorders in nuclear medicine has been improved through the implementation of new techniques especially with positron emission tomography (PET). In modern concepts of parathyroid gland surgery an exact anatomic localisation of adenomas is necessary, which may be achieved with MIBI-Scintigraphy being the most sensitive method in primary hyperparathyroidism. The optimal access to localise adenomas is the investigation with combined SPECT/X-CT systems. The use of such systems for diagnosing neuroendocrine tumors of the gastrointestinal system may also be helpful. For neoplasms of the adrenal gland PET systems could be used to differentiate between benign and malignant entities or to detect primary tumours. In case of incidentalomas J131-Norcholesterol and MIGB-scintigraphy has been proven helpful. Indications for nuclear medicine studies to detect abnormalities of the hypothalamic-hypophyseal system are established rarely.     

Hypoglycaemic coma in Boeck's sarcoidosis (author's transl)]

The diversity of clinical manifestations of Boeck's sarcoidosis may also include endocrine disorders. One year after diagnosis of sarcoidosis in a 29 year-old female patient, endocrinological complications became manifest with amenorrhoea. The course of the disease was additionally complicated by hypoglycaemic episodes. Thorough clinical investigation of the patient revealed sarcoid involvement of the skin, lungs, liver and lymph nodes and an extensive retroperitoneal surgically-verified lymph tumour. After tolbutamide and in reaction to an intravenous glucose tolerance test the blood glucose was found to be very low, whilst the immunoreactive insulin was normal. Further investigation of the endocrine functions of the patient revealed normal functioning of the thyroid gland, subnormal values for the follicle stimulating hormone and extremely low serum ACTH and serum cortisol values, without any diurnal changes in these parameters. The clinical symptoms of the patient and the biochemical findings were regarded as manifestations of secondary adrenal failure due to sarcoid involvement of the hypothalamus and pituitary. Hence, treatment with corticosteroids was started. Hypoglycaemia has not since been observed in this patient and the other clinical features of (secondary) adrenal failure have disappeared slowly.     

Rhabdomyolysis in a patient complicated with hypopituitarism and multiple organ dysfunction syndrome and the literature review

Introduction

Muscular symptoms, including stiffness, myalgia, cramps, and fatigue, are present in the majority of the patients with hypopituitarism, adrenal insufficiency and hypothyroidism, but rhabdomyolysis, the rapid breakdown of skeletal muscle, is a rare manifestation. In most patients who develop rhabdomyolysis, precipitating factors, such as strenuous exercise or use of lipid-lowering drugs, can be identified.

Addisonian crisis precipitated by thyroxine therapy: a complication of type 2 autoimmune polyglandular syndrome

Hypothyroidism is a common condition. Rarely, it may occur in combination with autoimmune failure of other endocrine glands (autoimmune polyendocrinopathy syndrome type 2, previously known as Schmidt's syndrome). In such cases, restoring normal thyroid function may precipitate adrenal failure. Clinicians should have a high index of suspicion for this condition in patients with Addison's disease, those with a family history of autoimmune endocrine gland failure, patients with one autoimmune endocrine disease who develop nonspecific or serious illness, and patients with type 1 diabetes mellitus whose insulin requirements drop without obvious explanation.     

A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction

The paired-like homeobox gene expressed in embryonic stem cells Hesx1/HESX1 encodes a developmental repressor and is expressed in early development in a region fated to form the forebrain, with subsequent localization to Rathke's pouch, the primordium of the anterior pituitary gland. Mutations within the gene have been associated with septo-optic dysplasia, a constellation of phenotypes including eye, forebrain, and pituitary abnormalities, or milder degrees of hypopituitarism. We identified a novel homozygous nonconservative missense mutation (I26T) in the critical Engrailed homology repressor domain (eh1) of HESX1, the first, to our knowledge, to be described in humans, in a girl with evolving combined pituitary hormone deficiency born to consanguineous parents. Neuroimaging revealed a thin pituitary stalk with anterior pituitary hypoplasia and an ectopic posterior pituitary, but no midline or optic nerve abnormalities. This I26T mutation did not affect the DNA-binding ability of HESX1 but led to an impaired ability to recruit the mammalian Groucho homolog/Transducin-like enhancer of split-1 (Gro/TLE1), a crucial corepressor for HESX1, thereby leading to partial loss of repression. Thus, the novel pituitary phenotype highlighted here appears to be a specific consequence of the inability of HESX1 to recruit Groucho-related corepressors, suggesting that other molecular mechanisms govern HESX1 function in the forebrain.     

Central hypothyroidism and hyperthyroidism

Thyroid function is maintained by tonic secretion of TSH by the pituitary. TSH secretion, in turn, is dependent on hypothalamic TRH production. Therefore, diseases of the hypothalamus and pituitary are frequently associated with TSH deficiency, producing central hypothyroidism. All patients with hypothalamic or pituitary disease should have thyroid function tests including a serum TSH by radioimmunoassay (RIA). In central hypothyroidism the TSH RIA is inappropriately low in relationship to the degree of hypothyroxinemia but is not always undetectable. In fact, because of the production of biologically inactive TSH, the TSH RIA may be in the high range of normal. Therapy of central hypothyroidism includes the management of associated pituitary hormone deficiencies, particularly secondary adrenal failure, and neurologic defects. A rare cause of hyperthyroidism is excessive TSH secretion. This may be due to a TSH-secreting pituitary tumor or to a functional disturbance in TSH secretion. TSH-secreting pituitary tumors are often large and locally invasive. Selective pituitary resistance to thyroid hormone is the most common cause of functional TSH-induced hyperthyroidism. It is important to rule out generalized thyroid hormone resistance before use of antithyroid drugs or thyroid surgery in patients suspected of this disorder. This is because antithyroid treatment is contraindicated in generalized thyroid hormone resistance.     

Hypopituitarism following envenoming by Russell's vipers (Daboia siamensis and D. russelii) resembling Sheehan's syndrome: first case report from Sri Lanka, a review of the literature and recommendations for endocrine management

Russell's vipers (Daboia russelii and D. siamensis) inhabit 10 South and South East Asian countries. People envenomed by these snakes suffer coagulopathy, bleeding, shock, neurotoxicity, acute kidney injury and local tissue damage leading to severe morbidity and mortality. An unusual complication of Russell's viper bite envenoming in Burma (D. siamensis) and southern India (D. russelii) is hypopituitarism but until now it has not been reported elsewhere. Here, we describe the first case of hypopituitarism following Russell's viper bite in Sri Lanka, review the literature on this subject and make recommendations for endocrine investigation and management. A 49-year-old man was bitten and seriously envenomed by D. russelii in 2005. He was treated with antivenom but although he recovered from the acute effects he remained feeling unwell. Hypopituitarism, with deficiencies of gonadal, steroid and thyroid axes, was diagnosed 3 years later. He showed marked improvement after replacement of anterior pituitary hormones. We attribute his hypopituitarism to D. russelii envenoming. Russell's viper bite is known to cause acute and chronic hypopituitarism and diabetes insipidus, perhaps through deposition of fibrin microthrombi and haemorrhage in the pituitary gland resulting from the action of venom procoagulant enzymes and haemorrhagins. Forty nine cases of hypopituitarism following Russell's viper bite have been described in the English language literature. Patients with acute hypopituitarism may present with hypoglycaemia and hypotension during the acute phase of envenoming. Those with chronic hypopituitarism seem to have recovered from envenoming but present later with features of hypopituitarism. Over 85% of these patients had suffered acute kidney injury immediately after the bite. Steroid replacement in acute hypopituitarism is life saving. All 11 patients with chronic hypopituitarism in whom the outcome of treatment was reported, showed marked improvement with hormone replacement. Unrecognized acute hypopituitarism is potentially fatal while chronic hypopituitarism can be debilitating. Physicians should therefore be aware of this complication of severe envenoming by Russell's vipers, especially in Burma and South India, so that the diagnosis may be made without delay and replacement started with essential hormones such as hydrocortisone and thyroxine.     

Hypothyroidism: an update

Hypothyroidism is a clinical disorder commonly encountered by the primary care physician. Untreated hypothyroidism can contribute to hypertension, dyslipidemia, infertility, cognitive impairment, and neuromuscular dysfunction. Data derived from the National Health and Nutrition Examination Survey suggest that about one in 300 persons in the United States has hypothyroidism. The prevalence increases with age, and is higher in females than in males. Hypothyroidism may occur as a result of primary gland failure or insufficient thyroid gland stimulation by the hypothalamus or pituitary gland. Autoimmune thyroid disease is the most common etiology of hypothyroidism in the United States. Clinical symptoms of hypothyroidism are nonspecific and may be subtle, especially in older persons. The best laboratory assessment of thyroid function is a serum thyroid-stimulating hormone test. There is no evidence that screening asymptomatic adults improves outcomes. In the majority of patients, alleviation of symptoms can be accomplished through oral administration of synthetic levothyroxine, and most patients will require lifelong therapy. Combination triiodothyronine/thyroxine therapy has no advantages over thyroxine monotherapy and is not recommended. Among patients with subclinical hypothyroidism, those at greater risk of progressing to clinical disease, and who may be considered for therapy, include patients with thyroid-stimulating hormone levels greater than 10 mIU per L and those who have elevated thyroid peroxidase antibody titers.     

Endocrine and metabolic manifestations of invasive fungal infections and systemic antifungal treatment

Systemic fungal infections are increasingly reported in immunocompromised patients with hematological malignancies, recipients of bone marrow and solid organ allografts, and patients with AIDS. Mycoses may infiltrate endocrine organs and adversely affect their function or produce metabolic complications, such as hypopituitarism, hyperthyroidism or hypothyroidism, pancreatitis, hypoadrenalism, hypogonadism, hypernatremia or hyponatremia, and hypercalcemia. Antifungal agents used for prophylaxis and/or treatment of mycoses also have adverse endocrine and metabolic effects, including hypoadrenalism, hypogonadism, hypoglycemia, dyslipidemia, hypernatremia, hypocalcemia, hyperphosphatemia, hyperkalemia or hypokalemia, and hypomagnesemia. Herein, we review how mycoses and conventional systemic antifungal treatment can affect the endocrine system and cause metabolic abnormalities. If clinicians are equipped with better knowledge of the endocrine and metabolic complications of fungal infections and antifungal therapy, they can more readily recognize them and favorably affect outcome.     

Altered neuropeptide concentrations in spontaneously hypertensive rats: cause or consequence?

Changes in brain neuropeptide content in spontaneously hypertensive rats may be primarily related to the development of hypertension or may be secondary consequences of it. We have measured brain concentrations of beta-endorphin, Leu-enkephalin, arginine vasopressin (AVP) and oxytocin (OXT) in stroke-prone spontaneously hypertensive rats (SHRSP) and in age-matched normotensive Wistar Kyoto (WKY) controls, as well as in SHRSP with normalized blood pressure by chronic treatment with clonidine. Opioid peptide contents were measured in 12-, 18- and 24-week-old rats. beta-Endorphin was measured in the neuro-intermediate and anterior lobes of the pituitary, the hypothalamus, mid-brain and brain stem; Leu-enkephalin in the neuro-intermediate lobe of the pituitary, hypothalamus, mid-brain, brain stem, as well as in the spinal cord and adrenal glands. AVP and OXT were measured in the neuro-intermediate lobe of the pituitary, hypothalamus, brain stem and spinal cord. beta-Endorphin in the neuro-intermediate lobe of the pituitary was significantly higher in 12- and 18-week-old SHRSP. Adrenal gland Leu-enkephalin was lower in SHRSP as compared with the WKY. OXT and AVP contents were markedly reduced in all brain regions of SHRSP except the neuro-intermediate lobe of the pituitary, where no significant changes were found. In no case did long-term antihypertensive treatment with clonidine reverse the altered peptide content in the SHRSP. We conclude that alterations in brain neuropeptide content in SHRSP are not secondary to hypertension. The blood pressure lowering activity of clonidine appears not to depend on major alterations of peptide concentrations. A genetic defect in the synthesis of adrenal enkephalins and hypothalamic OXT and AVP seems likely from these studies.