A Rare Diagnosis for Vomiting and Polyuria: The Pituitary, the Adrenal Gland, the Thyroid

Vomiting and weight loss are often associated with gastrointestinal etiologies, and hypernatremia is often thought of as an indication of dehydration or iatrogenic hypernatremia. We discuss the importance of considering alternate etiologies, such as intracranial masses, especially when these signs and symptoms present together.After completing this article, readers should be able to:List the broad differential diagnosis for vomiting.Explain the importance of diagnosing and following electrolyte abnormalities that do not resolve with medical intervention.Describe the relationship between pituitary lesions and central hormonal dysfunction.The following true case illustrates that managing one clinical problem may unmask other, unexpected challenges.A 6-year-old previously healthy girl presents to the pediatric emergency department with 2 weeks of postprandial emesis and globus sensation in the throat. Her emesis is nonbloody, nonbilious, and occurs within minutes of each meal. She can only tolerate drinking thin liquids due to her globus sensation and has preferred water over other beverages. Her mother reports that her appetite has significantly decreased during the past month, resulting in a 7-lb (3.2-kg) weight loss, yet her thirst has increased significantly from baseline to the point of drinking upward of 2.5 L of water per day. The patient and her mother report increased frequency of urination but are unable to quantify occurrences or estimate volume. Her review of systems is negative for sick contacts, sore throat, cold intolerance, fatigue, brittle hair, dry skin, changes in stool patterns, or abdominal pain.Her initial evaluation occurred at an outside hospital where she received a 20-mL/kg bolus of normal saline fluid resuscitation for dehydration. Complete blood cell count, lipase level, urinalysis, upper gastrointestinal (GI) contrast study, neck and abdominal radiography, and computed tomography (CT) scan of the abdomen were all normal. She is transferred to our hospital for more specialized pediatric GI care and further evaluation.On arrival at the inpatient pediatric unit, she is afebrile, with a blood pressure of 86/51 mm Hg (97–120/57–80 mm Hg) and normal remaining vital signs. Her weight is below the first percentile (0.07%) at 14.9 kg, and her height is within the 35th percentile at 117.7 cm. Physical examination is notable for a cachectic child with dry mucous membranes but otherwise normal examination findings. Initial laboratory values on admission show hypernatremia with a sodium level of 155 mEq/L (155 mmol/L) (reference range [RR], 135–145 mEq/L [135–145 mmol/L]), hyperchloremia with a chloride level of 123 mEq/L (123 mmol/L) (RR, 98–108 mEq/L [98–108 mmol/L]), and an elevated creatinine level of 1.0 mg/dL (88.40 µmol/L) (reference range, 0.2–0.6 mg/dL [17.68–53.04 µmol/L]). Her initial urine laboratory values are normal, with urine osmolality of 611 mOsm/kg (611 mmol/kg) (RR, 250–1,200 mOsm/kg [250–1,200 mmol/kg]), a urine sodium level of 168 mEq/L (168 mmol/L), and specific gravity of 1.010 (RR, 1.005–1.030). Due to continued concern for dehydration, she is started on isotonic maintenance fluids. An esophagogastroduodenoscopy is performed on day 2 of hospitalization and shows mild reflux esophagitis. Initiation of a proton pump inhibitor results in improvement of her globus sensation. The patient’s polydipsia and creatinine level improve with the administration of fluids. However, her hypernatremia persists (sodium level, 150 mEq/L [150 mmol/L]) despite a transition to hypotonic maintenance fluids and oral intake of water, and she develops hypokalemia (potassium level, 3.5 mEq/L [3.5 mmol/L]) on day 2 of hospitalization. Additional investigations and imaging establish the diagnosis.The patient’s presentation of vomiting, anorexia, and weight loss can be considered to be due to a broad differential diagnosis, including GI versus extra-GI causes (Table). The pathophysiology of vomiting involves the emetic center located in the medulla and is composed of the reticular formation and the nucleus tractus solitarius. (1) In the GI tract, the enterochromaffin cells contain chemoreceptors and mechanoreceptors that signal the emesis center through the vagus nerve in response to local stimuli, including acid, irritants, toxins, and distention. Outside of the GI tract, the emesis center receives stimuli from the cerebral cortex, the vestibular system, and the chemoreceptor trigger zone, which is activated by systemic endogenous and exogenous chemicals. (1)Polyuria is defined as excessive urination measured at greater than 50 mL/kg of body weight per 24-hour period. (2) In patients younger than 2 years, a slightly larger volume of urine is acceptable due to the volume of fluid in the diet in this age range. (2) Polyuria is approached by considering whether increased urination is driven by osmotic diuresis, as seen with glucosuria in cases of diabetes mellitus, or by water diuresis. Due to our patient’s normal blood glucose level and lack of diuretic use, water diuresis is likely the cause of her polyuria. Water diuresis etiologies of polyuria include primary polydipsia (excessive free water consumption), arginine vasopressin (AVP) deficiency (AVP-D), and AVP resistance (AVP-R). (2)AVP regulates water homeostasis and is secreted by the hypothalamus in response to osmoreceptor stimulus and nonosmotic stimuli, including hypovolemia and the renin-angiotensin-aldosterone system. (3) AVP acts on V2 receptors in the collecting duct of the nephron to promote synthesis of aquaporin-2 channels, which reabsorb water, thereby concentrating urine. (2) AVP-D is due to decreased synthesis or secretion of AVP, most commonly due to head trauma, intracranial neoplasms, or vascular injury, and AVP-R is a reduced sensitivity to AVP at the level of the nephron, most commonly due to drugs, hypercalcemia, and hypokalemia. (2)The patient’s serum sodium level can help differentiate the causes of water diuresis as primary polydipsia typically causes hyponatremia due to the excess of intravascular free water; meanwhile, AVP abnormalities cause hypernatremia. In addition, AVP abnormalities present with low levels of urine osmolality, urine sodium, and specific gravity due to free water wasting through the aquaporins and sodium reabsorption as the nephron attempts to counter intravascular volume loss. Copeptin, a peptide derived from the precursor of AVP, is directly associated with levels of AVP and can be measured to further elucidate the cause of a patient’s polyuria. (3)Hypernatremia is defined as a serum sodium level greater than 145 mEq/L (>145 mmol/L) and remains an uncommon presentation in the pediatric population. (4) Serum sodium levels primarily reflect free water intake and excretion as dictated by levels of AVP and the thirst mechanism. The clinical presentation of hypernatremia includes irritability, restlessness, vomiting, increased muscle tone, brisk reflexes, polydipsia, and, if severe, lethargy, seizures, and cerebral contraction secondary to extracellular hypertonicity drawing water out of brain parenchyma.The differential diagnosis for hypernatremia can be delineated by considering 3 etiologies: increased free water loss, reduced free water intake, and excessive sodium intake or retention. There are several causes of increased free water loss, including insensible losses in patients with fevers and burns, gastroenteritis, and AVP-D or AVP-R. (4) The causes of reduced free water intake include an impaired thirst mechanism or restricted access to water in neonates or neurologically impaired children. An excessive sodium intake is generally iatrogenic due to patients receiving intravenous fluids, particularly hypertonic fluids, and hypertonic enteral feedings. In addition, sodium retention can occur at the level of the kidney due to excess sodium reabsorption, as seen in hyperaldosteronism and congenital adrenal hyperplasia due to aldosterone driving sodium uptake, potassium excretion, and hypertension from intravascular volume expansion. (4)Hypokalemia is defined as a serum potassium concentration below 3.5 mEq/L (<3.5 mmol/L) and is essential due to its critical role in the sodium-potassium ATPase and in the electrical gradient across cellular membranes. (5) Clinical symptoms of hypokalemia may include skeletal muscle weakness and cramps, constipation due to smooth muscle dysfunction, and, eventually, flaccid paralysis, hyporeflexia, and cardiac arrythmias. (6)There are 2 main causes of hypokalemia: the exogenous loss of potassium and the intracellular shift of potassium. (5) The exogenous loss of potassium can take place via the GI tract or the renal system. GI causes include diarrhea, nasogastric suction, and vomiting secondary to gastroenteritis and congenital pyloric stenosis. Renal losses of potassium include hyperaldosteronism and congenital adrenal hyperplasia due to aldosterone’s action of sodium reabsorption and potassium excretion in the nephron’s collecting duct via the epithelial sodium channels. In addition, intravascular volume depletion can drive sodium reabsorption and potassium excretion by upregulating aldosterone via the renin-angiotensin-aldosterone system. Cushing syndrome and ectopic corticotropin secretion also cause potassium wasting via the epithelial sodium channels due to cortisol’s ability to mimic aldosterone at mineralocorticoid receptors. (5)The intracellular shift of potassium may decrease serum concentrations through other mechanisms. (5) The main causes of intracellular potassium shifts include strenuous physical activity and stress as seen in patients with congenital heart disease (via catecholamine upregulation of sodium-potassium ATPase), refeeding syndrome, and diabetic ketoacidosis. In diabetic ketoacidosis, the serum pH decreases as ketones, β-hydroxybutyric acid, and acetoacetic acid release protons into the serum. In response, the cellular membrane’s potassium and hydrogen ion channels uptake hydrogen ions in exchange for potassium ions, increasing the concentration of potassium in the serum. Because hyperglycemia promotes diuresis, the serum potassium is wasted in the excretion of urine. Other causes of intracellular shifts of potassium include drugs and toxins, most commonly β-adrenergic agonists and insulin. (5)Given that our patient’s chief complaint is globus sensation and the vomiting of undigested food, the differential diagnosis is initially focused on GI etiologies. However, upper GI series, neck and abdominal radiographs, CT of the abdomen, and esophagogastroduodenoscopy with biopsies do not explain her clinical picture.At this juncture, the persistence of her hypernatremia and hypokalemia despite fluid resuscitation and attempts at electrolyte correction narrows the differential diagnoses to AVP-D, hyperaldosteronism, and congenital adrenal hyperplasia. Although the patient’s levels of urine osmolality, urine sodium, and specific gravity are all initially normal, repeated studies reveal the development of low urine osmolality (88 mOsm/kg [88 mmol/kg]), elevated serum osmolality (315 mOsm/kg [315 mmol/kg]), normal renin and aldosterone levels, and low copeptin levels. These results are consistent with AVP-D. Desmopressin therapy is started and resolves her hypernatremia and hypokalemia.To evaluate the etiology of her AVP-D and assess her pituitary function, the endocrinology team is consulted. Her laboratory values are notable for low morning cortisol level (2.2 g/dL [nmol/L]) and low-normal corticotropin level (18 pg/mL [3.96 pmol/L]), indicating a secondary adrenal insufficiency (AI), for which hydrocortisone replacement therapy is initiated. Her laboratory values are also notable for a low-normal thyrotropin level (0.66 IU/mL) and a low free thyroxine level (0.5 ng/dL [6.44 pmol/L]), indicating central hypothyroidism for which levothyroxine is initiated. Levels of luteinizing hormone, follicle-stimulating hormone, prolactin, growth hormone, β-human chorionic gonadotropin, lactate dehydrogenase, and α-fetoprotein are within normal limits.A magnetic resonance image (MRI) of the brain with and without contrast shows an enlarged pituitary gland with a midline, rim-enhancing lesion measuring 1.2 × 1.1 × 2.6 cm, which extends into the suprasellar region, involving the hypothalamus. Her imaging characteristics are initially thought to be most consistent with a neoplasm. A biopsy of the pituitary lesion shows inflammation with B-cell–rich inflammatory infiltrate with perivascular accentuation. The B cells appear small in size without atypical morphology, and immunophenotyping is negative for monotypic B-cell populations, ruling out leukemic neoplasia. Cerebrospinal fluid studies are negative for hematologic, infectious, or autoimmune processes. Based on the patient’s presentation, imaging findings, and pathology results, the diagnosis is suspected to be lymphocytic hypophysitis.Sellar and parasellar masses account for approximately 10% of pediatric brain tumors. (7) Clinical presentation correlates with the size and location of the mass and includes symptoms of increased intracranial pressure in addition to abnormalities in pituitary hormone secretion. The most common pituitary mass is a craniopharyngioma, which has an overall prevalence of 6% to 13% among intracranial masses and a prevalence of 50% to 90% among sellar and parasellar lesions in children. The second most common mass among the sellar and parasellar lesions is a pituitary adenoma, which accounts for only 3% of supratentorial tumors in children. (7) Among pituitary adenomas, most are functional and most commonly secrete prolactin, corticotropin, or growth hormone. Less commonly, children can present with nonfunctioning, thyrotropin-secreting, or gonadotropin-secreting pituitary adenomas. Uncommon sellar and parasellar lesions include Rathke cleft cysts, hypothalamic hamartomas, Langerhans cell histiocytosis, germ cell tumors, gliomas of the optic pathway and hypothalamus, meningiomas, sarcoidosis, and epidermoid and dermoid tumors. (7)The cause of our patient’s presentation is hypophysitis, which is defined as acute or chronic inflammation of the pituitary gland. (8) Hypophysitis is rare among hypothalamic-pituitary masses and lesions (with an estimated incidence of 1 in 9 million children each year) (9) and can mimic tumors in the sellar region. (8) Hypophysitis can also cause mass effect symptoms and pituitary or hypothalamic dysfunction due to tissue destruction secondary to inflammation or compression. Classification includes anatomy (adenohypophysitis, infundibuloneurohypophysitis, or panhypophysitis), histology (lymphocytic, granulomatous, xanthomatous, IgG4-related, or necrotizing), and etiology (primary if isolated or secondary if associated with systemic pathologies). The most common form in pediatrics is lymphocytic hypophysitis, and the proposed mechanism is an event that damages the pituitary gland, such as an infection, vascular accident, head trauma, or neoplasm, which can expose pituitary antigens to T and B cells, stimulating direct infiltration and the production of autoantibodies. (8)MRI serves as the main imaging modality for diagnosis when a sellar or suprasellar lesion is suspected due to its superior diagnostic capabilities paired with the ability to limit radiation exposure in pediatric patients. (3) However, CT may also be used for identifying calcifications characteristic of certain types of craniopharyngiomas, assessing involvement of regional vasculature, and better visualizing bony structures for surgical decision-making. In addition, thorough hormonal testing for pituitary function is warranted, including growth hormone, thyrotropin, corticotropin, prolactin, luteinizing hormone, and follicle-stimulating hormone. By investigating the levels of these hormones, the type and location of the sellar or parasellar lesion can be further elucidated and hormone replacement therapy can begin promptly. However, most cases necessitate histologic analysis for a definitive diagnosis. (3)Overall, management of sellar and suprasellar lesions proves difficult due to their anatomic location. (3) Surgical resection for masses introduces risks of damage to local structures. Total versus subtotal resection via a transsphenoidal approach is determined based on the extent of involvement. Radiotherapy may be used in combination with subtotal resection or as an alternative to excision with goals to preserve neurocognition and endocrine function. Chemotherapy is also used in certain cases along with radiation or alone based on tumor makeup. Drainage or fenestration may be used for cysts. Medical management of hormonal deficiencies is required in addition to, and sometimes as a result of, surgical approaches. (3)Review of the anatomy of the sellar and suprasellar regions helps to further explain our patient’s presentation. (3) The pituitary gland sits in the sella turcica, a midline depression of the sphenoid bone. The anterior lobe of the pituitary gland secretes GH, corticotropin, thyrotropin, prolactin, follicle-stimulating hormone, and luteinizing hormone, and the posterior lobe secretes oxytocin and AVP synthesized in the hypothalamus. The pituitary infundibulum passes superiorly through a layer of dura to connect with the hypothalamus in the suprasellar cistern. As a result, any lesion affecting the pituitary gland and extending into the suprasellar cistern can disrupt hormone release from the hypothalamic-pituitary system. (3) This explains our patient’s AVP-D (low AVP level), secondary (low corticotropin level), and central hypothyroidism (low thyrotropin Her hypernatremia and hypokalemia are secondary to AVP-D, free water loss and and to trigger sodium reabsorption and potassium excretion via the renin-angiotensin-aldosterone the cellular level, AVP production by the hypothalamus and secretion by the pituitary gland occurs in response to AVP, in the aquaporin-2 channels in the renal collecting duct (3) This to water reabsorption in the renal collecting system, thereby diuresis and hypernatremia. AVP-D to polyuria and a in which the thirst center and causes (3) Although our patient’s AVP-D is secondary to an intracranial is that is uncommon to AVP-D with a sellar or suprasellar lesion is hypothalamic involvement or disease and (3) This is the of in the posterior pituitary are from their cell in the hypothalamus. AVP synthesis may and release may shift in the with masses and In addition, with cell body destruction of at of AVP is required as the for a of to water point is that polydipsia may be due to of the hypothalamic osmoreceptor thirst mechanism. AVP-D can initially be in cases of secondary and be during with hydrocortisone replacement proposed AVP and of free water excretion as a mechanism. is a deficiency in the production or action of of primary adrenal or secondary is by a decrease in the production of corticotropin by the pituitary or a decrease in pituitary by hormone in the hypothalamus. The clinical presentation of primary and secondary is including fatigue, muscle and However, secondary not secretion of aldosterone and, not present with or In addition, the of corticotropin as is seen in primary adrenal that these patients do not present with the case of our the hypophysitis, tissue explains her low morning cortisol and corticotropin levels and the patient’s pathology to the level of the pituitary or hypothalamus, not the adrenal gland. The endocrinology team suspected that the patient secondary when the patient’s hypernatremia initially with normal levels of urine osmolality, urine sodium, and specific This occurs when AVP-D and AVP-R as the of aquaporin-2 channels in the collecting duct and the wasting of free water that results in low levels of urine osmolality, sodium, and specific is defined as a deficiency in hormone resulting in and studies of free thyroxine and thyrotropin can between primary and central In primary the thyroxine level be low and the thyrotropin level be elevated as the pituitary attempts to the production of hormone. In central the thyroxine level be low and the thyrotropin level be normal, or slightly elevated but This the pathophysiology of central hypothyroidism where the insufficiency of thyrotropin results in the secretion of hormone. The most common causes of central hypothyroidism include pituitary lesions and pituitary sella syndrome, head or autoimmune and Langerhans and the case of this she is suspected of an AVP-D, essential to the extent of her hypothalamic and pituitary the patient’s laboratory studies are her is to pituitary including the release of the the patient is on hormone replacement therapy for AVP-D, secondary and central The patient’s and vomiting symptoms and she reports polyuria or polydipsia that she is on a consistent of A repeated of the rim-enhancing hypothalamic and suprasellar indicating a patients with vomiting, is to causes outside of the gastrointestinal system, especially intracranial is to the cause of electrolyte abnormalities that do not resolve with intravenous oral sensation may be the primary of reflux resulting from a etiology of AVP-D is further evaluate the extent of pituitary and hypothalamic