Case Study 1
A 12-year-old male with a history of Hodgkin lymphoma and hypertension presented to the hospital with a 2-week duration of weakness and fatigue. He also reported a poor appetite and decreased oral intake but no weight loss. He denied shortness of breath, syncope, nausea, vomiting, or diarrhea. He also denied headache, confusion, polyuria, or polydipsia.
Home medications included amlodipine 10 mg once a day, lisinopril 10 mg once a day, and pembrolizumab 200 mg intravenously every 3 weeks. The latter was started 3 months prior to admission, and he had recently completed three cycles of therapy.
On admission, he was clinically euvolemic, blood pressure was 118/78 mmHg, and heart rate 62 beats/min. Initial work-up was notable for hyponatremia with serum sodium level of 120 mmol/L and metabolic acidosis with total bicarbonate of 16 mmol/L. Other laboratory results were: serum sodium 120 mmol/L, potassium 3.5 mmol/L, chloride 90 mmol/L, creatinine 0.6 mg/dL, BUN 8 mg/dL, phosphorous 2.6 mg/dL, aldosterone 5 ng/dL (reference: 7.4 to 29.8), thyroid-stimulating hormone (TSH) 1.04 mIU/L (reference: 0.44 to 3.98), adrenocorticotropic hormone (ACTH) 5.1 pg/mL (reference: 7.2 to 63.3), and cortisol level measured in the morning 1.0 μg/dL (reference: 2.5 to 20.0).
A spot urinary protein-creatinine ratio was 0.12 mg/mg, and urine pH was 6.0. Urine analysis did not show any microscopic hematuria or pyuria. There was no glycosuria. Urinary sodium was 52 mmol/L, potassium 19 mmol/L, chloride 63 mmol/L, and osmolality 299 mOsm/kg.
Computed tomography scan of the abdomen was normal. Other laboratory studies including titers of serum antinuclear antibody, anti-neutrophil cytoplasmic antibody, and anti-SSA/SSB; tests for hepatitis B and C virus; and levels of C3 and C4 were all unrevealing.
What are the MOST likely causes of this patient’s hyponatremia and metabolic acidosis? (Select all that apply)
- A.
Syndrome inappropriate antidiuretic hormone (SIADH) and distal renal tubular acidosis (dRTA) secondary to immune checkpoint inhibitor therapy
- B.
SIADH and proximal RTA secondary to immune checkpoint inhibitor therapy
- C.
Immune-mediated central adrenal insufficiency causing SIADH and dRTA
- D.
SIADH and dRTA secondary to immune checkpoint inhibitor therapy
The correct answers are A and C
Comment: This patient had hypophysitis, which precipitated adrenal insufficiency. Low levels of ACTH and cortisol support this conclusion.
The laboratory work-up for this patient (inappropriate high urine osmolality in the presence of serum hypoosmolality, normal renal function, and absence of clinical features of dehydration or volume overload) is highly suggestive of SIADH.
Hyponatremia caused by SIADH is common in cancer patients receiving immune checkpoint inhibitors, and acute hyponatremia secondary to pembrolizumab has been reported. This patient also had normal anion gap metabolic acidosis with positive urine anion gap and low positive urine osmolar gap (< 150 mOsm/kg), which is highly suggestive of dRTA. Although dRTA is usually associated with hypokalemia, simultaneous adrenal insufficiency could have offset this finding.
Diagnosis of the etiology of hyponatremia is necessary in order to provide appropriate treatment. Laboratory assessments, including measurements of plasma osmolality, urine osmolality, and urine sodium, and clinical assessment of extracellular volume status are critical to the differential diagnosis of hyponatremia.
There are various causes of SIADH in a cancer patient: it may be a result of ectopic vasopressin production by tumor cells or a consequence of stimulation of vasopressin secretion or potentiation of vasopressin effects by anticancer drugs or palliative medications. There are many traditional chemotherapeutic treatments that can cause hyponatremia. Recently, immune checkpoint inhibitors have revolutionized the treatment of various solid tumors. There are adverse kidney effects associated with the development of hyponatremia and possibly SIADH.
dRTA is a tubulopathy characterized by dysfunction of distal urinary acidification, which subsequently can lead to a normal anion gap metabolic acidosis. Common causes include autoimmune diseases, drugs, genetic diseases, and tubulointerstitial diseases; however, in many cases a cause is not identified.
In this patient, the dRTA is likely secondary to a renal immunotherapy-related adverse event. There has been extensive literature characterizing the various endocrinopathies associated with immune checkpoint inhibitors, including primary adrenal insufficiency, hypothyroidism, hyperthyroidism, and hypophysitis. Although the risk of immune checkpoint inhibitor–associated adrenal insufficiency is less than 1%, it is still associated with significant morbidity and mortality.
The combination of hyponatremia, dRTA, and adrenal insufficiency in this patient is highly suggestive that his hyponatremia was secondary to adrenal insufficiency, which in turn we considered as an immunotherapy-related adverse event.
The patient was started on hydrocortisone 40 mg daily. This was accompanied by improvement in serum sodium and bicarbonate levels. Two days later, the patient’s hyponatremia and metabolic acidosis had resolved. He was eventually discharged on a tapering dose of steroids. Rapid resolution of both conditions upon initiation of steroids suggests that they are both immune-mediated adverse effects associated with pembrolizumab.
Case Study 2
A 12-year-old girl with no significant medical history presented with 4 hours of acute left leg swelling. Venous ultrasonography of the affected limb showed acute deep vein thrombosis involving the left femoral vein with extension to the external iliac vein and inferior vena cava. The patient was started on treatment with noxaparin and warfarin. Despite anticoagulation therapy, she developed small bilateral pulmonary emboli, and an inferior vena cava filter was placed. Hypercoagulable work-up was positive for lupus anticoagulant, high titers of anticardiolipin antibodies, and moderately elevated titers of anti-2 glycoprotein antibodies suggestive of antiphospholipid syndrome. On the third day of hospitalization, the patient developed acute hyponatremia with a sodium level that decreased from 137 to 115 mmol/L and normal anion gap metabolic acidosis. At that time patient’s serum potassium was 4.8 mmol/L, chloride 90 mmol/L, bicarbonate 19 mmol/L, BUN 20 mg/dL, creatinine 0.7 mg/dL. Serum osmolality was 242 mOsm/kg, urine osmolality 290 mOsm/kg, and urine sodium 77 mmol/L. Serum cortisol level measured in the morning was 0.3 μg/dL (reference: 5 to 20 μg/dL). Arterial blood gas showed pH 7.31, PCO 2 37 mmHg, PO 2 80 mmHg, and bicarbonate 20 mmol/L.
Throughout this time, the patient was asymptomatic. On physical examination, pulse rate was 90 beats/min and blood pressure was 120/75 mmHg, with no orthostatic changes. Cardiovascular examination showed normal heart sounds, lungs were clear to auscultation, and there was no peripheral edema. Neurologic examination findings were normal.
What is the MOST likely cause of hyponatremia in this patient and how should be treated?
- A.
Syndrome inappropriate antidiuretic hormone (SIADH)
- B.
Liddle syndrome
- C.
Apparent mineralocorticoid excess
- D.
Primary adrenal insufficiency
The correct answer is D
Comment: The major causes of euvolemic hyponatremia are SIADH, hypothyroidism, glucocorticoid deficiency, and decreased urinary solute excretion, as in beer potomania or a very low-protein diet. SIADH is the most frequent cause of euvolemic hyponatremia and can be seen in pulmonary diseases, malignancies, central nervous system diseases, and with certain drugs.
In patients with SIADH, the non-physiologic secretion of antidiuretic hormone (ADH) leads to increased water reabsorption, resulting in dilutional hyponatremia when the intake of free water exceeds its excretory capacity. Hyponatremia in hypothyroidism is seen primarily in severe cases or myxedema. The mechanism by which hypothyroidism induces hyponatremia is incompletely understood. It is thought to be due to decreased cardiac output leading to the release of ADH through the carotid sinus baroreceptors.
Adrenal insufficiency should be ruled out before diagnosing SIADH. Glucocorticoid deficiency can cause hyponatremia in both primary and secondary adrenal insufficiency. Solute intake has a central role as a determinant of free water excretion. Inadequate dietary solute intake with reduced urinary solute excretion limits water excretion. This enables hyponatremia to develop with even modest water intake. This same mechanism is responsible for the hyponatremia seen in individuals who drink large quantities of beer (known as beer potomania) because beer has a low sodium content and these individuals often have limited overall dietary intake. This disturbance also can be observed in individuals with restricted protein or salt intake in combination with generous water intake.
The first step in the evaluation of euvolemic hyponatremia is to check for thyroid or adrenal abnormalities.
Our patient did not have hypertension and her thyroid-stimulating hormone level was normal. However, a random cortisol level was very low at 0.3 μg/dL, measured at 6 am (reference: 5 to 24 μg/dL). Corticotrophin level was elevated, and a cosyntropin stimulation test confirmed the diagnosis of primary adrenal insufficiency. Computed tomography of the abdomen showed bilateral adrenal enlargement with no contrast enhancement suggestive of hemorrhagic necrosis, possibly due to adrenal vein thrombosis from antiphospholipid syndrome. The patient’s sodium level corrected within 60 hours after giving 3% saline solutions in addition to intravenous steroid replacement with hydrocortisone. The patient was discharged on a regimen of warfarin and low-dose aspirin with oral steroid replacement therapy, including hydrocortisone and fludrocortisone. Repeated work-up 12 weeks later confirmed the diagnosis of antiphospholipid antibody syndrome. The levels of sodium and the rest of the electrolytes were normal.
Hyponatremia is the most common electrolyte abnormality encountered in clinical practice, occurring in up to 30% of hospitalized patients. Adrenal insufficiency, a rare but important endocrine disorder that results in hyponatremia, is caused by either primary adrenal failure (most commonly due to autoimmune adrenalitis) or impairment of the hypothalamic-pituitary axis (primarily pituitary disease). Hyponatremia in adrenal insufficiency is multifactorial. Mineralocorticoid deficiency is present only in primary adrenal insufficiency and results in hypovolemia, low blood pressure, postural hypotension, and occasionally prerenal acute kidney injury. Other metabolic features of primary adrenal insufficiency include hyponatremia (90% of patients with primary adrenal insufficiency), hyperkalemia (65%), and salt craving (15%). In addition, plasma ADH is stimulated by decreased circulating blood volume, which then triggers water retention. In addition to hyponatremia and hyperkalemia, mild hyperchloremic acidosis can occur with mineralocorticoid deficiency. Hyperkalemia suppresses the production of renal ammonia, leading to reduced ammonium ion excretion and thus reduced net acid excretion. Although the main cause of decreased ammonia production is hyperkalemia itself, aldosterone deficiency or resistance also may contribute to the decrease. Hyponatremia also can develop in secondary adrenal insufficiency due to failure to fully suppress ADH secretion in response to hypoosmolarity. ADH and corticotrophin-releasing hormone in the parvocellular neurons of the paraventricular nucleus are negatively regulated by glucocorticoids. When the negative feedback action of glucocorticoids is removed, the result is up regulation of corticotrophin-releasing hormone and ADH gene expression in the paraventricular nucleus neurons. Animal experimental studies showed that glucocorticoids also inhibit ADH gene transcription and decrease messenger RNA stability. In both glucocorticoid and mineralocorticoid deficiency, the changes in hemodynamics also have a role in causing hyponatremia, separately from ADH, because they limit the delivery of tubular fluid to the diluting segment of the nephron. The pathogenesis of adrenal insufficiency in antiphospholipid syndrome is related to vascular complications, including adrenal vein thrombosis and edema of the adrenal gland, resulting in obstructed arterial supply and hemorrhagic infarction. The adrenal glands’ unique vascular anatomy, featuring a rich arterial supply but only a single vein with limited drainage, predisposes these patients to thrombosis.
The primary therapy for all types of adrenal insufficiency is glucocorticoids. Although several types of glucocorticoids are available, hydrocortisone is preferred because its short half-life is the most similar to the normal circadian rhythm of cortisol. Patients with primary adrenal insufficiency also require mineralocorticoid therapy (fludrocortisone). The mineralocorticoid dose can be modified based on serum potassium level and plasma renin activity and the symptoms experienced by the patient, such as orthostatic dizziness or salt craving. Suppressed plasma renin activity can be a helpful indicator of an overdose of fludrocortisone, an overdose that may cause retention of fluid, edema, and hypertension.
Case Study 3
A 15-year-old woman is started on hydrochlorothiazide and a low-sodium diet for the treatment of hypertension. After 1 week, she complains of weakness, muscle cramps, and postural dizziness. On physical examination, the patient is found to be alert and oriented. The blood pressure is 130/86 mmHg (the pretreatment level was 150/100 mmHg). The skin turgor is decreased, and the jugular venous pressure is less than 5 cmH 2 O. The laboratory data are serum sodium 119 mmol/L, potassium 2.1 mmol/L, chloride 71 mmol/L, bicarbonate 34 mmol/L, plasma osmolality 252 mOsm/kg, urine osmolality 540 mOsm/kg, urine sodium 4 mmol/L.
What are the MOST likely causes for this patient’s hyponatremia? (Select all that apply)
- A.
Hydrochlorothiazide
- B.
Volume depletion
- C.
Increased ADH secretion
- D.
Water retention
- E.
Potassium depletion
The correct answers are A, B, C, and D
Comment: All of these factors contributed to hyponatremia. Hydrochlorothiazide-induced volume depletion (physical findings plus low urine sodium concentration), which enhanced antidiuretic hormone (ADH) release (high urine osmolality of 540 mOsm/kg), resulting in water retention and hyponatremia. The loss of potassium also played a contributory role via a transcellular K + -Na + exchange.
Therapy should include the administration of sodium and potassium in a hypertonic solution, such as 40 mmol of KCl added to each liter of isotonic saline. There is little justification for water restriction, since the patient is volume depleted. In view of the metabolic alkalosis, KCl, not potassium citrate is indicated (since citrate is metabolized into bicarbonate). Half-isotonic saline should also be avoided because it is a hypotonic solution that will further lower the plasma sodium concentration.
Case Study 4
A 17-year-old male with hypertension treated with unknown medications is admitted to the hospital in a comatose state, responding only to deep pain. On physical examination, the blood pressure is found to be 180/120 mmHg. The skin turgor is reduced, and the neck veins are flat. After appropriate studies, the diagnosis of an intracerebral hemorrhage is made. To minimize the degree of brain swelling, the patient is given a total of 25 g of mannitol. Only 100 mL of 5% dextrose in water is given. The laboratory data at this time include serum sodium 120 mmol/L, potassium 3.3 mmol/L, chloride 78 mmol/L, bicarbonate 29 mmol/L, plasma osmolality 253 mOsm/kg, urine osmolality 240 mOsm/kg, and urine sodium 45 mmol/L.
What is the MOST likely diagnosis of this patient’s hyponatremia?
- A.
Pseudohyponatremia due to mannitol
- B.
Volume depletion
- C.
SIADH
- D.
Neurogenic salt wasting syndrome
The correct answer is B
Comment: Hyponatremia in this patient is due to volume depletion, probably induced by diuretic therapy for hypertension. The physical findings suggestive of hypovolemia, hypokalemia, and high plasma bicarbonate concentration are all compatible with this diagnosis. Pseudohyponatremia due to mannitol is not present since the measured plasma osmolality is low and is similar to the calculated value [calculated plasma osmolality = 2 × 120 + (125 ÷ 18) + (15 ÷ 2.8) = 252 mOsml/kg]. SIADH due to stroke also cannot account for hyponatremia. Hyponatremia must have preceded the stroke, since the patient subsequently received only 100 mL of water, a quantity that is insufficient to lower the plasma sodium concentration.
Case Study 5
A 19-year-old man weighing 70 kg is admitted to the hospital with a 2-week history of progressive lethargy and obtundation. The physical examination is within normal limits except for the obtundation. The following laboratory studies are obtained: Serum sodium 105 mmol/L, potassium 4 mmol/L, chloride 72 mmol/L, bicarbonate 21 mmol/L, plasma osmolality 210 mOsm/kg, urine osmolality 604 mOsml/kg, and urine sodium 78 moml/L.
What is the most likely diagnosis and how and at what initial rate would you raise the plasma sodium concentration?
- A.
Pseudohyperaldosteronism
- B.
Diuretic abuse
- C.
Adrenal insufficiency
- D.
Syndrome of inappropriate antidiuretic secretion (SIADH)
The correct answer is D
Comment: The most likely diagnosis is SIADH. Hypertonic saline should be given initially in view of the marked hyponatremia and neurologic symptoms.
The approximate sodium deficit that must be corrected to raise the plasma sodium concentration to a safe value of 120 mmol/L can be estimated from Na + deficit = 0.6 × 70 (120 to 105) or 630 mmol.
This requires approximately 1200 mL of 3% saline, which should be given at the rate of 40 mL/h over 30 hours to raise the plasma sodium concentration by 0.5 mmol/L/h. Furosemide will enhance the efficacy of this regimen by lowering urine osmolality, thereby increasing free-water excretion.
Case Study 6
A previously healthy 18-year-old girl experienced three grand mal seizures 2 days after an appendectomy. She received 10 mg of diazepam and 150 mg of phenytoin intravenously and underwent laryngeal intubation with mechanical ventilation. She had been treated with 6 L of 5% dextrose containing 37-mmol sodium/L during the first 3 days after surgery. She is stuporous and responds to pain but not to commands. She is euvolemic, her weight is 46 kg, serum sodium is 110 mmol/L, potassium is 4.1 mmol/L, uric acid is 3.1 mg/dL, and osmolality is 228 mOsm/kg H 2 O. Urine osmolality is 510 mOsm/kg.
What is the appropriate initial fluid for treating this patient’s hyponatremia?
- A.
Infusion of 3% saline at 70 mL/h
- B.
Infusion of 0.9% saline at 150 mL/h
- C.
Infusion of 0.45% saline at 300 mL/h
- D.
Infusion of 0.2% saline at 600 mL/h
The correct answer is A
Comment: Hypotonic hyponatremia in this patient is a result of water retention (use of hypotonic solution) caused by the impaired water excretion due to her SIADH postoperatively on the presence of hypotonic hyponatremia and concentrated urine in a euvolemic patient, the absence of a history of diuretic use, and the absence of clinical evidence of hypothyroidism or hypoadrenalism.
The goal of treatment here is a rapid increase in serum sodium level to the point where mental status is improved and the risk of further seizures is decreased adequately. The infusion of 3% saline, diuretic use, and fluid restriction are management tools, which allow for these goals to be achieved.
The effect of 1 L of 3% hypertonic saline on serum sodium change is estimated by the following formula :
Na+changemmol/L=[infusateNa+mmol/L]–[serumNa+mmol/L]÷(TBWliters+1)
According to the formula, the infusion of 1 L of 3% saline will increase the serum sodium concentration by 14.4 mmol/L ([513–110] + [27 + 1] = 14.4).
Given the seriousness of the patient’s symptoms the initial goal is to raise the serum sodium concentration by 4 mmol/L over the next 2 hours; thus 139 mL of 3% hypertonic saline (2 ÷ 14.4), or 70 mL/h, was required.
At the end of 2 hours, patient’s mental status is substantially improved and her serum sodium concentration is 114 mmol/L. The goal of treatment now is to raise serum sodium slowly by additional 3 mmol/L over the next 3 hours, thus the infusion rate of 3% saline was reduced to 35 mL/h. Five hours after fluid therapy, the serum sodium concentration is 117 mmol/L. The patient is fully alert and oriented. The new goal of treatment is to slowly increase serum sodium concentration by 8 mmol/L over the next 24 hours. The 3% hypertonic is stopped and fluid therapy with 0.9% saline began; thus, 1.32 L of 0.9% saline (154 – 117) ÷ (27 + 1) or 55 mL/h was required.
Case Study 7
A 50-kg male has SIADH due to a tumor. He appears clinically euvolemic. The serum sodium is in steady state and 127 mmol/L, and K + is 4.0 mmol/L. There are no symptoms attributable to hyponatremia. Patient is clinically euvolemic and consuming a usual diet.
How much water restriction would correct the hyponatremia?
- A.
2200 mL
- B.
1900 mL
- C.
1600 mL
- D.
1300 mL
The correct answer is B
Comment: Hypotonic hyponatremia in this euvolemic patient is due to water retention in the presence of normal sodium stores due to SIADH. Physiologically, in patients with SIADH, the TBNa + is normal, but the TBW is increased proportionately to the fall in plasma sodium (PNa + ) concentration, due to overproduction of ADH. The treatment plan is to remove excess water. Because TBNa + is the product of TBW and PNa + concentration, the excess water gain in SIADH patients can be estimated using the following equation :
TBNa + at health = TBNa + in SIADH or (50 kg × 0.6) × 135 mmol / L = (TBW × 127mmol / L) or patient’s TBW = [30 L] × 135mmol / L ÷ 127 mEq / L or 31.9 L. Patient’s estimated water retention is 1.9 L (31.9 − 30).
This patient is alert and asymptomatic. The treatment plan includes water restriction and/or the intravenous administration of furosemide along with isotonic saline. Close monitoring of patient’s urine output, weight, and serum sodium concentration is required.
Case Study 8
A 14-year-old female is brought to the hospital because of watery diarrhea for the past 3 days. Past medical history is significant for essential hypertension. She has been on a low-sodium diet and hydrochlorothiazide daily for the control of hypertension.
On examination she appears mildly lethargic but consolable. She weighs 45 kg, blood pressure is 96/56 mmHg, and the pulse is 100 beats/min. The jugular vein is flat, and skin turgor is decreased. The serum sodium concentration is 121 mmol/L, potassium 3.2 mmol/L, bicarbonate 26 mmol/L, BUN 46 mg/dL, creatinine 1.4 mg/dL, osmolality 232 mOsm/kg H 2 O, and urine osmolality is 650 mOsm/kg H 2 O.
What is the appropriate initial fluid for treating this patient’s hyponatremia?
- A.
0.9% saline at 222 mL/h
- B.
0.45% saline at 444 mL/h
- C.
0.9% saline at 444 mL/h
- D.
0.45% saline at 222 mL/h
The correct answer is C
Comment: In this patient, hypotonic hyponatremia is due to sodium and water losses caused by thiazide diuretic, low-salt diet, and new onset of diarrhea. The sodium loss is greater than the water loss and that is why the patient has hyponatremia. The goal of treatment is to restore the extracellular volume depletion. Hydrochlorothiazide and water are withheld, and infusion of a 0.9% saline containing 30 mmol of KCl/L is initiated.
The effect of 1 L of 0.9% saline on serum sodium change can be estimated using the following formula :
Na+change=[infusate(Na+mmol/L+K+mmol/L)]–(serumNa+mmol/L)÷TBWliters+1
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