Pathology Lab VI - Diabetes Insipidus PATHOLOGY LAB VI-DIABETES INSIPIDUS. Arben Santo CASE OUTLINE.

Case Presentation: Gwen W. Introduction Central diabetes insipidus OBJECTIVES. Upon completion of this module, the student should be able to: 1. Explain the causes and pathogenesis of central diabetes insipidus. 2. Distinguish between central and nephrogenic diabetes insipidus 3. Describe the manifestations of central diabetes insipidus 4. Describe the pathological findings in hypothalamus and posterior hypophysis 5. Outline the laboratory and imaging findings REFERENCES. 1. Robbins and Cotran Pathologic Basis of Disease, 8th edition, 2010; 2. Williams Textbook of Endocrinology, 9th edition, 1998 CASE PRESENTATION: GWEN W. A 14-year-old girl presents with complaints of sudden onset of polyuria, polydipsia, fatigue, headaches and 10 lbs weight loss of 1 month duration (4.53 kg). Based on her history, she had been presumptively diagnosed with central diabetes insipidus (DI) and started on treatment with deamino-D-arginine vasopressin (dDAVP) by her primary physician 2 weeks prior to the referral to our clinic. Treatment with dDAVP resulted in remarkable improvement of her symptoms. She had had regular menstrual periods since 11 years of age until 3 months prior to presentation to our clinic, when these ceased. Her past medical history was unremarkable and she had no history of visual disturbance, fatigue, cold intolerance, galactorrhea, loss of pubic or axillary hair. On physical examination, her weight was 41.2 kg (10th percentile) and her height was 170.1 cm (95th percentile). Blood pressure was 119/64 mm Hg and pulse was 77/min. The thyroid gland was not palpable. She had stage 4 pubic hair and genital development. Neurologic examination was normal including visual acuity, pupillary size and reactivity, retina and optic discs on funduscopic examination and ocular alignment and movement. Visual fields were also normal by Goldman perimetry. A lateral skull X-ray showed a normal calvarium with no evidence of lytic lesions or abnormal calcifications. However, MRI of the brain revealed a 1.0 x 1.0 x 1.0 cm mass lesion in the pituitary stalk and inferior hypothalamus that was isointense on T1weighted images and enhanced homogenously with gadolinium; consistent with a neoplastic or inflammatory process. Tumor markers, alpha-fetoprotein and beta-HCG, were negative and evaluation for sarcoidosis and tuberculosis revealed a normal angiotensin converting enzyme level and negative tuberculin skin test. Moreover, no pulmonary lesions were found by thoracic CT. The neurohypophysis lacked the hyperintense signal on T1-weighted images seen in normal subjects. Laboratory tests were performed to evaluate the patient's hormonal status. ACTH, TSH and free T4 levels were all normal but FSH, LH and estradiol levels were all below the assay sensitivity, consistent with hypogonadotropic hypogonadism. IGF-1 (insulin-like growth factor-1) was obtained to indirectly assess growth hormone (GH) secretion. IGF-I was normal for her age. Bone age was 14 years. Biopsy of the pituitary stalk by right pterional craniotomy was obtained 8 months after the initial MRI. Histologic examination of the specimen showed chronic inflammation with an inflammatory infiltrate composed predominantly of lymphocytes along with some plasma cells. There were no neoplastic cells. The definitive diagnosis was central diabetes insipidus secondary to lymphocytic hypophysitis. The pituitary stalk mass has persisted on subsequent MRIs, showing slight puctuations in size and shape from scan to scan. On the most recent MRI, 21 months from diagnosis, it measured 0.9 x 0.6 x 0.9 cm. Clinically, the patient has not developed any neurologic signs or symptoms. She has gained 15 lbs (6.8 kg) while on dDAVP treatment and has been started on estrogen/progesterone cyclic hormonal replacement for her hypogonadotropic hypogonadism.

CLASSIFICATION. There are two types of diabetes insipidus: central diabetes insipidus and nephrogenic diabetes insipidus.

1. Central diabetes insipidus. Central diabetes insipidus (DI) is characterized by decreased secretion of antidiuretic hormone (ADH), also known as arginine vasopressin (AVP), that results in polyuria and polydipsia by diminishing the patient's ability to concentrate urine. Diminished or absent ADH can be the result of a defect in one or more sites involving the hypothalamic osmoreceptors, supraoptic or paraventricular nuclei, or the supraopticohypophyseal tract. In contrast, lesions of the posterior pituitary rarely cause permanent diabetes insipidus because ADH is produced in the hypothalamus and still can be secreted into the circulation. 2. Nephrogenic diabetes insipidus. Nephrogenic diabetes insipidus is characterized by a decrease in the ability to concentrate urine due to a resistance to ADH action in the kidney. Nephrogenic diabetes insipidus can be observed in chronic renal insufficiency, lithium toxicity, hypercalcemia, hypokalemia, and tubulointerstitial disease. The rare hereditary form of nephrogenic diabetes insipidus is transmitted as an Xlinked genetic defect of the V2 receptor gene. A rare autosomal variant is caused by mutation in the aquaporin gene AQP2, a water-channel exclusively expressed in the collecting ducts of the kidney.

DEFINITION. Diabetes insipidus was distinguished from diabetes mellitus in 1674 by the English physician Thomas Willis. Diabetes insipidus is characterized clinically by polyuria and polydipsia and biochemically by inappropriately diluted urine in the face of rising plasma osmolality. Central diabetes insipidus is due to deficiency of antidiuretic hormone (ADH) synthesis from the hypothalamus and/or secretion from the neurohypophysis Synonym: neurogenic diabetes insipidus PATHOPHYSIOLOGY. ADH is the primary determinant of free water excretion in the body. Its main target is the kidney, where it acts by altering the water permeability of the cortical and medullary collecting tubules. Water is reabsorbed by osmotic equilibration with the hypertonic interstitium and returned to the systemic circulation. The actions of ADH are mediated through at least 2 receptors V1 mediates vasoconstriction, enhancement of corticotrophin release, and renal prostaglandin synthesis; V2 mediates the antidiuretic response. EPIDEMIOLOGY. Diabetes insipidus is uncommon, with a prevalence of 1 case per 25,000 people. No significant sex differences in central or nephrogenic diabetes insipidus exist. Male and female prevalence are equal. ETIOLOGY. The etiology of central diabetes insipidus includes a familial form and forms secondary to cranial trauma, brain or pituitary tumor, surgery, or neurohypophyseal granulomatous diseases. However, the etiology of central diabetes insipidus remains unknown in over one third of cases, classified as idiopathic. Recent literature indicates 30% of cases to be idiopathic, 25% related to malignant or benign tumors of the brain or pituitary, 16% secondary to head trauma, and 20% following cranial surgery. 1. Idiopathic diabetes insipidus. Idiopathic diabetes insipidus is associated with destruction of cells in the hypothalamus, often as part of an autoimmune or inflammatory process. This type is characterized by lesions of hypophysitis (lymphocytic, granulomatous or xanthomatous hypophysitis). 2. Familial diabetes insipidus. Familial diabetes insipidus is rare. It is inherited as an autosomal dominant disorder, and mutations involving AVP-neurophysin gene have been identified. The mechanism by which the mutations impair AVP release is not understood but may involve the accumulation of the ADH precursor leading to the death of the ADH-producing cells. 3. Head trauma. Diabetes insipidus after neurosurgery or trauma varies with the extent of damage. Approximately 10-20% of patients will experience diabetes insipidus following transsphenoidal removal of an adenoma. This percentage increases to 60-80% with large tumors. Not all cases of diabetes insipidus are permanent. The most common causes of postoperative polyuria are excretion of excess fluid given during surgery and an osmotic diuresis as a result of treatment for cerebral edema. 4. Brain tumors. Primary intracranial tumors causing diabetes insipidus include craniopharyngioma or pineal tumors. Appearance of other hypothalamic manifestations may be delayed for as long as 10 years. Thus, periodic follow-up of patients diagnosed with idiopathic diabetes insipidus is necessary to detect slowly growing intracranial lesions. 5. Other causes. Other causes include cancer (e.g., lung cancer, lymphoma, leukemia), hypoxic encephalopathy, infiltrative disorders (histiocytosis X, sarcoidosis), anorexia nervosa, and vascular lesions such as arteriovenous malformations or aneurysms. MORPHOLOGY.

Pituitary inflammation underlies idiopathic diabetes insipidus. Pituitary inflammation causes mass effects and/or hypothalamichypophysial dysfunction. There are three different types of hypophysitis that underlie idiopathic diabetes insipidus: (a) lymphocytic hypophysitis, (b) granulomatous hypophysitis, and (c) xanthomatous hypophysitis.

(A) Lymphocytic hypophysitis. This chronic inflammatory condition of the pituitary gland is seen most commonly in young postpartum or pregnant females. The disorder is much less common in males; the female to male ratio is 8:1. An autoimmune etiology has been proposed as the basis for lymphocytic hypophysitis due to its association with a number of other autoimmune disorders and there is evidence for pituitary antibodies in patients with this disease. Recent data suggest that the precipitating antigen is alpha-enolase, a protein that is expressed by the placenta as well as pituitary, possibly explaining pregnancy as an initiating event. The symptoms and signs of lymphocytic hypophysitis tend to be nonspecific: mass effect such as headache and visual field defects, hyperprolactinemia, or isolated diabetes insipidus. Morphologically the pituitary gland is enlarged and soft. Microscopic examination reveals a diffuse inflammatory infiltrate composed mainly of lymphocytes and plasma cells and destruction of the adenohypophysial tissue. Untreated lymphocytic hypophysitis may result in permanent hypopituitarism may run a self-limited course followed by a full recovery. (B) Granulomatous hypophysitis. Idiopathic granulomatous hypophysitis is a rare chronic inflammatory disorder of unknown pathogenesis. This condition is characterized by chronic inflammatory cells accumulation in the pituitary gland: macrophages, lymphocytes, plasma cells and multinucleated giant cells combined with areas of necrosis. Clinical manifestations include adenohypophysial failure, hyperprolactinemia, diabetes insipidus, and meningitis. Patients may present with visual field deficits, cranial nerve palsies, or headaches. Other clinical manifestations include variable degrees of adenohypophysial failure, hyperprolactinemia, mass effect, diabetes insipidus, and meningitis. (C) Xanthomatous hypophysitis. This condition is characterized by a chronic inflammatory infiltrate composed mainly of foamy macrophages with scattered lymphocytes and plasma cells. Clinical presentation included headache, nausea, menstrual irregularity, and diabetes insipidus. CLINICAL MANIFESTATIONS. 1. Diabetes insipidus which follows trauma or surgery. Diabetes insipidus which follows trauma or surgery to the region of the pituitary and hypothalamus exhibits a triphasic pattern: First, a polyuric phase occurs secondary to inhibition of ADH and lasts 4-5 days. An immediate increase in urine volume and a concomitant fall in urine osmolality occur. Second, an antidiuretic phase of 5-6 days occurs, which results from release of stored hormone. The urine osmolality rises. The third phase can be permanent diabetes insipidus, when stores of ADH are exhausted and the cells that produce more ADH are absent or unable to produce. Polyuria, polydipsia, and nocturia (from 3-18 L/day) are the predominant symptoms in the third phase. In infants, crying, irritability, growth retardation, hyperthermia, and weight loss may be the most apparent signs. In children, enuresis, anorexia, linear growth defects, and fatigability typically predominate. 2. Non-traumatic diabetes insipidus.

Patients with a nontraumatic onset typically have a much more indolent course. Pregnancy is associated with an increased risk of diabetes insipidus. Polyuria, polydipsia, hydronephrosis, bladder enlargement, and signs of dehydration are common. The daily urine volume is highly variable (3-20 L/day), and patient tolerance of dehydration also varies among individuals. Neurologic symptoms vary with the patient's ability to access water; those with free access may have no symptoms at all. LABORATORY STUDIES. The diagnosis of diabetes insipidus is often made clinically, while the laboratory tests provide confirmation. Perform testing with the patient maximally dehydrated as tolerated, that is, at a time when ADH release would be highest and urine would be most concentrated. Ruling out secondary causes, such as diabetes mellitus, is also important. The clinician should measure serum electrolytes and glucose, urine specific gravity, urinary sodium, simultaneous serum and urine osmolality, and ADH levels. A urine specific gravity of 1.005 or less and a urine osmolality less than 200 mOsm/kg is the hallmark of diabetes insipidus. Random plasma osmolality generally is greater than 287 mOsm/kg. The water deprivation test (i.e. Miller-Moses test), a semiquantitative test to ensure adequate dehydration and maximal stimulation of ADH for diagnosis, is performed in ambiguous clinical circumstances, typically with more chronic forms of diabetes insipidus. All water intake is withheld and urine osmolality and body weight are measured hourly. When 2 sequential urine osmolalities vary by less than 30 mOsm or if the weight decreases by more than 3%, 5 U of aqueous vasopressin is administered subcutaneously. A final urine specimen is obtained 60 minutes later for osmolality measurement. In healthy individuals, water deprivation leads to a urine osmolality that is 2-4 times greater than plasma osmolality. Administration of vasopressin results in less than 9% increment in urine osmolality. The time required to achieve maximal urine concentration ranges from 4-18 hours. In complete central diabetes insipidus, testing reveals minimal ADH levels and activity, with failure of the urine to be concentrated despite excessively concentrated serum. In response to exogenous vasopressin, urine osmolality increases by more than 50%. Patients with nephrogenic diabetes insipidus have a normal-to-elevated serum ADH level and failure of the kidney to respond to exogenous ADH during the water deprivation test. IMAGING STUDIES. Pituitary MRI: T1-weighted images of the healthy posterior pituitary yield a hyperintense signal. In patients with central diabetes insipidus, this signal is absent. PRINCIPLES OF TREATMENT. In an emergency, most patients with diabetes insipidus can drink enough fluid to replace their urine losses. Replace losses with dextrose and water or IV fluid hyposmolar to the patient's serum. Frequent electrolyte monitoring is recommended. Avoid hyperglycemia, volume overload, and a correction of hypernatremia that is too rapid. A good rule of thumb is to reduce serum sodium by 0.5 mmol/L/h. Water deficit may be calculated based on the assumption that body water is approximately 60% of body weight in kilograms. In case of inadequate thirst, desmopressin (sysnthetic replacement for vasopressin) is the drug of choice. Pharmaceutical therapy for diabetes insipidus includes subcutaneous, nasal, and oral preparations of vasopressin analogues.

1. Symptoms of diabetes insipidus include all the following except: Hypokalemia Polydypsia Polyuria Nocturia Hypernatremia

2. The diagnostic hallmark of diabetes insipidus is: Potassium level greater than 4.5 mg/mL Urine osmolality less than 200 mOsm/kg Hydronephrosis Sodium level less than 110 mg/mL Urine production greater than 3 liters/day 3. A 12-year-old boy presents with 3 months of lethargy, headaches, and muscle weakness. His parents note that he drinks water excessively. His vital signs are normal. A 24-hour urine collection shows polyuria. The fasting blood sugar is normal. An X-ray film of the brain reveals a 1-cm diameter suprasellar mass. The patient underwent operation via a petrosal approach with total resection of the tumor. The histological diagnosis is craniopharyngioma. Which of the following is the most likely cause of polyuria in this patient? Prolactinoma Nephrogenic diabetes insipidus Cushing disease Gigantism Central diabetes insipidus 4. Which is a chronic inflammatory condition of the pituitary gland seen most commonly in post partum females? Granulomatous hypophysitis Xanthomatous hypophysitis Sheehan Syndrome Pituitary apoplexy Lymphocytic hypophysitis 5. The most common cause of diabetes insipidus is: Post operative Idiopathic Head trauma Benign or malignant neoplasms