A 66-year-old man was admitted to hospital with a plasma K+ concentration of 1.7 meq/L and profound weakness. The patient had noted progressive weakness over several days, to the point that he was unable to rise from bed. Past medical history was notable for SCLC with metastases to brain, liver, and adrenals. The patient had been treated with one cycle of cisplatin/etoposide 1 year before this admission, complicated by acute kidney injury (peak creatinine of 5, with residual chronic kidney disease), and three subsequent cycles of cyclophosphamide/doxorubicin/vincristine, in addition to 15 treatments with whole-brain radiation.
On physical examination the patient was jaundiced. BP was 130/70, increasing to 160/98 after a liter of saline, with a JVP at 8 cm. There was generalized muscle weakness.
|Laboratory Data ||2 Months PTA ||Admission ||HD2 ||Units |
|Sodium ||143 ||149 ||144 ||meq/L |
|Potassium ||3.7 ||1.7 ||3.5 ||meq/L |
|Chloride ||103 ||84 ||96 ||meq/L |
|Bicarbonate ||26 ||44 ||34 ||meq/L |
|Venous pH || ||7.47 || ||pH |
|Venous pCO2 || ||62 || ||mmHg |
|BUN ||21 ||41 ||40 ||mg/dL |
|Creatinine ||2.8 ||2.9 ||2.3 ||mg/dL |
|Magnesium ||1.3 ||1.6 ||2.4 ||mg/dL |
|Creatine phosphokinase (CPK) || ||183 || ||Units/L |
|Alanine aminotransferase (ALT) ||8 ||75 || ||Units/L |
|Albumin ||3.4 ||2.8 ||2.3 || |
|Adjusted anion gap ||15 ||24 ||18 || |
|Tot bilirubin ||0.65 ||5.19 || ||mg/dL |
|Alk phosphatase ||93 ||217 || ||Units/L |
|Urine sodium || ||35 ||28 ||meq/L |
|Urine potassium || ||25 ||49 ||meq/L |
|Urine chloride || ||48 ||51 ||meq/L |
|Urine osmolality || ||391 || ||mOsm/kg |
|Plasma osmolality || ||312 || ||mOsm/kg |
|Urine pH || ||5.5 || || |
|Plasma adrenocorticotropic hormone (ACTH) || ||185 || ||pg/mL (7–50 pg/mL) |
|Plasma cortisol || ||94 || ||pg/mL (3–16 pg/mL) |
|24 h urine cortisol || ||1044 || ||mcg/24 h (4–50 mcg/24 h) |
The patient’s hospital course was complicated by acute respiratory failure attributed to pulmonary embolism; he expired 2 weeks after admission.
Why was this patient hypokalemic? Why was he weak? Why did he have an alkalosis?
This patient suffered from metastatic SCLC, persistent despite several rounds of chemotherapy and radiotherapy. He presented with profound hypokalemia, alkalosis, hypertension, severe weakness, jaundice, and worsening liver function tests.
With respect to the hypokalemia, there was no evident cause of nonrenal potassium loss, e.g., diarrhea. The urinary TTKG was 11.7, at a plasma K+ concentration of 1.7 meq/L; this TTKG value is consistent with inappropriate renal K+ secretion, despite severe hypokalemia. The TTKG is calculated as (POsm × UPotassium)/(PPotassium × UOsm). The expected values for the TTKG are <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia (see also Case 2 and Case 6). Alternatively, a urinary K+-to-creatinine ratio of >13 mmol/g creatinine (>1.5 mmol/mmol creatinine) is compatible with excessive renal K+ excretion.
The patient had several explanations for excessive renal loss of potassium. First, he had a history of cisplatin-associated acute kidney injury, with residual chronic kidney disease. Cisplatin can cause persistent renal tubular defects, with prominent hypokalemia and hypomagnesemia; however, this patient had not previously required potassium or magnesium repletion, suggesting that cisplatin-associated renal tubular defects did not play a major role in this presentation with severe hypokalemia. Second, he was hypomagnesemic on presentation, suggesting total body magnesium depletion. Magnesium depletion has inhibitory effects on muscle Na+, K+-ATPase activity, reducing influx into muscle cells and causing a secondary increase in K+ excretion. Magnesium depletion also increases K+ secretion by the distal nephron; this is attributed to a reduction in the magnesium-dependent, intracellular block of K+ efflux through the secretory K+ channel of principal cells (renal outer medullary K+ channel [ROMK]—see Fig. S1-1). Clinically, hypomagnesemic patients are refractory to K+ replacement in the absence of Mg2+ repletion. Again, however, this patient had not previously developed significant hypokalemia, despite periodic hypomagnesemia, such that other factors must have caused the severe hypokalemia.
The associated hypertension in this case suggested an increase in mineralocorticoid activity, causing increased activity of ENaCs in principal cells, NaCl retention, hypertension, and hypokalemia. The increase an ENaC-mediated Na+ transport in principal cells would have led to an increase in the lumen-negative potential difference in the connecting tubule (CNT) and CCD, driving an increase in K+ secretion through apical K+ channels (see Fig. S1-1). This explanation is compatible with the very high TTKG, i.e., an increase in K+ excretion that is inappropriate for the plasma K+ concentration.
What caused an increase in mineralocorticoid activity in this patient? The patient had bilateral adrenal metastases, indicating that primary hyperaldosteronism was unlikely. The clinical presentation (hypokalemia, hypertension, and alkalosis) and the history of SCLC) suggested Cushing’s syndrome, with a massive increase in circulating glucocorticoids, in response to ectopic adrenocorticotropic hormone (ACTH) secretion by his SCLC tumor. Confirmation of this diagnosis was provided by a very high plasma cortisol level, high ACTH level, and increased urinary cortisol (see the laboratory data above).
Why would an increase in circulating cortisol cause an apparent increase in mineralocorticoid activity? Cortisol and aldosterone have equal affinity for the mineralocorticoid receptor (MLR); thus, cortisol has “mineralocorticoid-like” activity; however, cells in the aldosterone-sensitive distal nephron (the DCT, CNT, and collecting duct are protected from circulating cortisol by the enzyme 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2), which converts cortisol to cortisone (Fig. S1-2); cortisone has minimal affinity for the mineralocorticoid receptor (MLR). Activation of the causes activation of the basolateral Na+/K+-ATPase, activation of the thiazide-sensitive Na+-Cl− cotransporter in the DCT, and activation of apical ENaCs in principal cells of the CNT and collecting duct (see Fig. S1-2). Recessive loss-of-function mutations in the 11βHSD-2 gene lead to cortisol-dependent activation of the MLR and the “syndrome of apparent mineralocorticoid excess” (SAME), comprising hypertension, hypokalemia, hypercalciuria, and metabolic alkalosis, with suppressed plasma renin activity (PRA) and suppressed aldosterone. A similar syndrome is caused by biochemical inhibition of 11βHSD-2 by glycyrrhetinic/glycyrrhizinic acid (found in licorice, for example), and/or carbenoxolone.
11β-hydroxysteroid dehydrogenase-2 (11βHSD-2) and syndromes of apparent mineralocorticoid excess. The enzyme 11βHSD-2 protects cells in the aldosterone-sensitive distal nephron (the distal convoluted tubule [DNT], connecting tubule [CNT], and collecting duct) from the illicit activation of mineralocorticoid receptors (MLRs) by cortisol. Binding of aldosterone to the MLR leads to activation of the thiazide-sensitive Na+-Cl− cotransporter in DCT cells and the amiloride-sensitive epithelial sodium channel (ENaC) in principal cells (CNT and collecting duct). Aldosterone also activates basolateral Na+/K+-ATPase and, to a lesser extent, the apical secretory K+ channel ROMK. Cortisol has equivalent affinity for the MLR to that of aldosterone; metabolism of cortisol to cortisone, which has no affinity for the MLR, prevents these cells from activation by circulating cortisol. Genetic deficiency of 11βHSD-2 or inhibition of its activity causes the syndromes of apparent mineralocorticoid excess (see also Case 8).
In Cushing’s syndrome caused by increases in pituitary ACTH, the incidence of hypokalemia is only 10%, whereas it is ~70% in patients with ectopic secretion of ACTH, despite a similar incidence of hypertension. The activity of renal 11βHSD-2 is reduced in patients with ectopic ACTH compared with Cushing’s syndrome, resulting in a syndrome of apparent mineralocorticoid excess; the prevailing theory is that the much greater cortisol production in ectopic ACTH syndromes overwhelms the renal 11βHSD-2 enzyme, resulting in activation of renal MLRs by unmetabolized cortisol (see also Fig. S1-2).
Why was the patient so weak? The patient was profoundly weak due to the combined effect of hypokalemia and increased cortisol. Hypokalemia causes hyperpolarization of muscle, thereby impairing the capacity to depolarize and contract. Weakness and even ascending paralysis can frequently complicate severe hypokalemia. Hypokalemia also causes a myopathy and predisposes to rhabdomyolysis; notably, however, the patient had a normal creatine phosphokinase (CPK) level. Cushing’s syndrome is often accompanied by a proximal myopathy, due to the protein-wasting effects of cortisol excess.
The patient presented with a mixed acid-base disorder, with a significant metabolic alkalosis and a bicarbonate concentration of 44 meq/L. A venous blood gas was drawn soon after his presentation; venous and arterial blood gases demonstrate a high level of agreement in hemodynamically stable patients, allowing for the interpretation of acid-base disorders with venous blood gas results. In response to his metabolic alkalosis, the pCO2 should have increased by 0.75 mmHg for each 1 meq/L increase in bicarbonate; the expected pCO2 should have been ~55 mmHg. Given the pCO2 of 62 mmHg, he had an additional respiratory acidosis, likely caused by respiratory muscle weakness from his acute hypokalemia and subacute hypercortisolism.
The patient’s albumin-adjusted AG was 21 + (4 − 2.8) × 2.5 = 24; this suggests a third acid-base disorder, AG acidosis. Notably, the measured AG can increase in alkalosis, due to both increases in plasma protein concentrations (in hypovolemic alkalosis) and to the alkalemia-associated increase in net negative charge of plasma proteins, both causing an increase in “unmeasured anions”; however, this patient was neither volume-depleted nor particularly alkalemic, suggesting that these effects played a minimal role in his increased AG. Alkalosis also stimulates an increase in lactic acid production, due to activation of phosphofructokinase and accelerated glycolysis; unfortunately, however, a lactic acid level was not measured in this patient. It should be noted in this regard that alkalosis typically increases lactic acid levels by a mere 1.5–3 meq/L, and that the patient was not significantly alkalemic. Regardless of the underlying pathophysiology, the increased AG was likely related to the metabolic alkalosis, given that the AG had decreased to 18 by hospital day 2, coincident with a reduction in plasma bicarbonate.
Why did the patient have a metabolic alkalosis? The activation of MLRs in the distal nephron increases distal nephron acidification and net acid secretion. In consequence, mineralocorticoid excess causes a saline-resistant metabolic alkalosis, which is exacerbated significantly by the development of hypokalemia. Hypokalemia plays a key role in the generation of most forms of metabolic alkalosis, stimulating proximal tubular ammonium production, proximal tubular bicarbonate reabsorption, and distal tubular H+, K+-ATPase activity.
The first priority in the management of this patient was to increase his plasma K+ and magnesium concentrations rapidly; hypomagnesemic patients are refractory to K+ replacement alone, hence the need to correct hypomagnesemia immediately. This was accomplished via the administration of both oral and intravenous K+-Cl−, giving a total of 240 meq over the first 18 h; 5 g of intravenous magnesium sulfate was also administered. Multiple 100 mL “minibags” of saline containing 20 meq each were infused, with cardiac monitoring and frequent measurement of plasma electrolytes. Of note, intravenous K+-Cl− should always be given in saline solutions, since dextrose-containing solutions can increase insulin levels and exacerbate hypokalemia.
This case illustrates the difficulty in predicting the whole body deficit of K+ in hypokalemic patients. In the absence of abnormal K+ redistribution, the total deficit correlates with plasma K+ concentration, which drops by ~0.27 mM for every 100-mmol reduction in total body stores; this would suggest a deficit of ~650 meq of K+ in this patient, at the admission plasma K+ concentration of 1.7 meq/L. Notably, however, alkalemia induces a modest intracellular shift of circulating K+ such that this patient’s initial plasma K+ concentration was not an ideal indicator of the total potassium deficit. Regardless of the underlying pathophysiology in this case, close monitoring of plasma K+ concentration is always essential during the correction of severe hypokalemia in order to gauge the adequacy of repletion and to avoid overcorrection.
Subsequent management of this patient’s Cushing’s syndrome and ectopic ACTH secretion was complicated by the respiratory issues. The prognosis in patients with ectopic ACTH secretion depends on the tumor histology and the presence or the absence of distant metastases. This patient had an exceptionally poor prognosis, with widely metastatic SCLC that had failed treatment; other patients with ectopic ACTH secretion caused by more benign, isolated tumors, most commonly bronchial carcinoid tumors, have a much better prognosis. In the absence of successful surgical resection of the causative tumor, management of this syndrome can include surgical adrenalectomy or medical therapy to block adrenal steroid production.