Trust the Patient: An Unusual Case of Metabolic Alkalosis

Case

A 69-year-old woman is evaluated for 3 days of muscle cramping, weakness, and fatigue. She reports difficulty walking up stairs. She reports no fever, chills, nausea, or vomiting, and no change in bowel movements.

In the past 6 months, she was admitted to hospitals elsewhere three times, for similar symptoms. Each time, she had hyponatremia, hypokalemia, and metabolic alkalosis. Each time, she received salt tablets, potassium repletion, and intravenous fluids, which led to improvement in her symptoms. She denies taking over-the-counter medications, such as nonsteroidal anti-inflammatory drugs, herbal supplements, laxatives, or diuretics. Her current medications are 1 g sodium chloride three times a day and 20 mEq potassium chloride three times a day.

Upon physical examination, her heart rate is 100/min and BP is 99/57 mm Hg. She has no edema. Her laboratory data are as follows: sodium 123 mEq/L, potassium 3.2 mEq/L, chloride 73 mEq/L, bicarbonate 38 mEq/L, urea nitrogen 72 mg/dl, creatinine 1.8 mg/dl, venous pH 7.5, Pco ₂ 52 mm Hg, and 9 am cortisol 37.4 µg/dl. Her urinalysis was as follows: sodium and chloride <20 mEq/L, potassium 45 mEq/L, creatinine 73 mg/dl, and osmolality 512 mOsm/kg.

Question 1

Which best explains this patient’s electrolyte abnormalities?

1. Gitelman syndrome

2. Intermittent diarrhea

3. Surreptitious use of a loop diuretic

4. Cushing syndrome

5. Primary hyperaldosteronism

Discussion of Question 1

The correct answer is B. This is a patient with recurrent admissions for weakness, hypotension, and electrolyte abnormalities characterized by metabolic alkalosis and hypokalemia. The key to understanding this case is to establish the cause of the metabolic alkalosis. Metabolic alkalosis can be divided into two broad categories: volume depleted (or “contracted”) and volume expanded (1). Because this patient has evidence of volume depletion, causes of metabolic alkalosis that are associated with volume expansion can be excluded. Although it is increasingly recognized that primary hyperaldosteronism may present as a spectrum and without frank hypertension, once severe hypokalemia and metabolic alkalosis are present, hypertension would most certainly be evident (2). Similarly, Cushing syndrome is unlikely. Admittedly, the morning cortisol value is above the reference range, but this represents an appropriate stress response to hypotension. To test for evidence of glucocorticoid excess, cortisol should be measured closer to midnight.

In cases of metabolic alkalosis associated with volume depletion, “generation” of the alkalosis occurs because of loss of chloride-containing fluids. This leads to volume depletion, which prompts a coordinated response of the sympathetic nervous system and the renin-angiotensin-aldosterone axis to limit urinary losses. Normally, when the filtered bicarbonate exceeds the tubular resorptive capacity of roughly 24 mEq/L, the excess bicarbonate is excreted along with a cation (largely sodium) until the serum bicarbonate concentration returns to normal levels (approximately 24 mEq/L). As volume depletion ensues, angiotensin II promotes reabsorption of sodium throughout the nephron, especially at the proximal tubule by activating the sodium hydrogen exchanger 3 (NHE3) antiporter and limiting distal delivery of Na⁺ and Cl⁻. In the distal nephron, angiotensin II leads to dephosphorylation/activation of the mineralocorticoid receptor. Aldosterone action via the mineralocorticoid receptor promotes further sodium retention by the epithelial sodium channel in the principal cells, along with H⁺-ATPase activity and chloride-bicarbonate exchange in the intercalated cells (3,4). In addition, hypokalemia promotes increased excretion of ammonium, which contributes to the perpetuation of the alkalosis (5). Importantly, the loss of chloride plays an critical role in the distal nephron and favors increased activity of pendrin, a luminal Cl⁻/HCO₃ ⁻ exchanger, but there is insufficient chloride for exchange with bicarbonate (6). Taken together, these responses are known as the maintenance phase in the clinical course of a metabolic alkalosis (Figure 1).

Figure 1.

Potential generation and maintenance phases of the metabolic alkalosis that may develop from a secretory villous adenoma. (A) Generation phase from colonic losses. Normal colonic mucosa features two cell types: the predominant cell is the absorptive cell. Dysfunction of the Cl⁻/HCO₃ ⁻ exchanger in absorptive cells or activation of the chloride efflux pathway via cystic fibrosis transmembrane conductance regulator in secretory cells could result in significant stool chloride losses. (B) Maintenance phase in the kidney. Kidney tubular response to volume depletion. Angiotensin II (Ang II) promotes reabsorption especially in the proximal tubule by activating the sodium hydrogen exchanger 3 (NHE3) antiporter. Hypokalemia promotes production and excretion of ammonium, which perpetuates the alkalosis. In the distal nephron, there is little remaining sodium and chloride delivery. Elevated intracellular pH activates pendrin, an apical Cl⁻/HCO₃ ⁻ exchanger, but there is insufficient chloride available for exchange with bicarbonate, thus preventing reversal of the alkalosis.

How did this patient develop volume depletion? What is the cause of her losses? Gitelman syndrome, a defect in the thiazide-sensitive sodium chloride cotransporter, is associated with hypotension, metabolic alkalosis, and hypokalemia. Although it is possible for this syndrome to present later in life, development in the seventh decade would be quite unusual. Furthermore, this defect would result in persistent urinary losses of sodium and chloride, rather than the low values seen in this case.

Intermittent use of either thiazide or loop diuretics could lead to this presentation, and explain the chloride-rich losses that must have occurred to generate the metabolic alkalosis. Indeed, this was initially considered the most likely diagnosis by the patient’s providers. Diuretic use can often be difficult to establish. Urinary sodium and chloride will be elevated if diuretic action is present when the urine electrolytes are measured. On the other hand, if the diuretic tubular effect has waned, urine sodium and chloride will be low because of the concurrent volume depletion. In some cases, repeating the urine [Cl⁻] several times can be a useful diagnostic maneuver. In this case, repeated urine [Cl⁻] measurements were persistently low, and a urinary screen for diuretics was unrevealing. Surreptitious diuretic use may occur in patients with anorexia nervosa, or diuretics may be used by athletes as a masking agent to promote a forced diuresis of other agents, to help achieve a certain weight for boxing, wrestling, or to help achieve a sculpted “look” for a performance as with body building (7).

On the second hospital day, the patient’s nurse noted copious mucinous material in the patient’s commode. The patient acknowledged that she had frequent mucinous bowel movements for months, but did not consider it diarrhea.

Her stool was analyzed for electrolyte content and yielded a sodium of 119 mEq/L, potassium of 43 mEq/L, and chloride of 145 mEq/L. The first step in the analysis of diarrhea is to calculate the stool osmolar gap. This is calculated from the serum osmolality minus twice the sum of the concentration of the major stool cations. Because the bowels have no concentrating or diluting mechanism, the stool osmolality is the same as that of serum but may be altered by fecal bacteria after collection, so a stool osmolality of 300 mOsm/kg is typically used for calculations (8): 300–2 (stool [Na⁺]+[K⁺]) = stool osmolar gap.

If the osmolar gap is small (<50 mOsm/kg), then the disorder is caused by an electrolyte transport–related phenomenon, whereas if the osmolar gap is >100 mOsm/kg, then stool output can be attributed to substrate-induced diarrhea, as seen with laxatives. In this case, the stool osmolar gap is 43 mOsm/kg, consistent with electrolyte transport–related causes (9). It is also worth noting that this patient’s stool chloride is very high. In series of patients with cholera, the stool chloride is more commonly closer to 100 mEq/L (10). High stool chloride explains the metabolic alkalosis in this patient rather than the typical findings of diarrhea, in which bicarbonate losses are greater and a nongap (or hyperchloremic) metabolic acidosis results.

On the basis of the additional history of mucinous bowel movements, the patient had a colonoscopy that demonstrated a circumferential adenomatous mass in the rectum, and a biopsy revealed villous adenoma. Villous adenoma can result in exaggerated mucous production compared with normal colonic mucosa. The predominant symptoms are frequent, watery, mucinous stools because most of the adenomatous epithelium is composed of prominent, clear, mucin-filled goblet cells. These tumors are often large, and most often located in the rectum or sigmoid colon. Most cause hyperchloremic metabolic acidosis by producing bicarbonate-rich fluid; however, 10%–20% secrete chloride rather than bicarbonate, as was the case with this patient (11).

This patient subsequently underwent laparoscopic abdominal perineal resection and placement of an end colostomy. The pathologic specimen demonstrated extensive rectosigmoid colonic involvement by a single, carpeting, sessile tubulovillous adenoma, with low-grade dysplasia and no evidence of adenocarcinoma. After the surgery, there was prompt resolution of her symptoms and electrolyte abnormalities.

Disclosures

M.P. Hoenig reports employment with Beth Israel Deaconess Medical Center and honoraria for the Primed conference. S.H. Lecker reports employment with Beth Israel Deaconess Medical Center.

Funding

None.