Chronic lymphocytic leukemia and apparent hyperkalemia

DIAGNOSING THE CAUSE OF THE APPARENT HYPERKALEMIA

3. Which is the most likely cause of hyperkalemia in this patient?

• Acute renal failure
• Tumor lysis syndrome
• Hemolysis
• Reverse pseudohyperkalemia
• Pseudohyperkalemia

DIFFERENTIAL DIAGNOSIS

The patient had normal levels of blood urea nitrogen and creatinine and adequate urine output, thus ruling out acute renal failure. Hyperuricemia, hyperphosphatemia, and hypocalcemia were not found, thus ruling out tumor lysis syndrome.

In vitro hemolysis is assessed by visual inspection showing a pink or red hue to serum or plasma, or by hemolysis index calculation using spectrophotometric measurements. Factors associated with in vitro hemolysis include vein fragility, the phlebotomist’s skill and technique, and transportation of the specimen, including duration, mode, and temperature. The plasma potassium level was repeatedly measured from a lithium-heparin tube, thus minimizing the possibility of laboratory error. No evidence of hemolysis was observed during the phlebotomy, transportation, or specimen analysis.

Serum and plasma potassium levels were simultaneously measured to test for pseudohyperkalemia, a falsely elevated serum potassium concentration caused by the release of platelet potassium during clot formation or after venipuncture. Contributing factors include the prolonged use of a tourniquet, hemolysis, and marked leukocytosis or thrombocytosis. A serum-to-plasma potassium gradient greater than 0.4 mmol/L is diagnostic of pseudohyperkalemia.

Reverse pseudohyperkalemia, a falsely high potassium level in plasma samples, is defined as a serum-to-plasma potassium gradient less than 0.4 mmol/L (Table 2). This was the most likely cause of the hyperkalemia in our patient.

On the second day after chemotherapy, two blood samples were collected simultaneously—one into a lithium heparin BD Vacutainer plasma separator tube, and the other into a plain, red-top BD Vacutainer serum collection tube without heparin. The specimens were transported to the laboratory by pneumatic tube and were centrifuged at 3,300 rpm for 10 minutes. The specimens were analyzed simultaneously 20 minutes after collection on a Unicel DXC 800 chemistry analyzer. The analysis revealed a serum-to-plasma potassium gradient of −7.1 mmol/L (serum potassium 3.6 mmol/L and plasma potassium 10.7 mmol/L).³ Repeated potassium measurements drawn in similar fashion after 1 hour continued to show a markedly elevated potassium concentration compared with the serum concentration (Table 1).

Serum and plasma samples were again measured simultaneously 24 hours after detecting hyperkalemia to evaluate for pseudohyperkalemia in this patient. In another published report, serum and plasma measurements were obtained 1 week after observing hyperkalemia.⁴ Blood gas analysis was done the same day in two other reported cases.^4,5

Of note, further review of our patient’s medical history noted hyperkalemia at the time he was diagnosed with CLL. At that time, his plasma potassium level was 7.5 mmol/L, a repeated plasma potassium level was 6.9 mmol/L, and a subsequent blood gas analysis—done 30 minutes after the repeated plasma potassium measurement using a Rapidlab analyzer (Siemens Healthcare Diagnostics, Washington, DC)—showed a potassium level of 3.4 mmol/L. The phenomenon of reverse pseudohyperkalemia was not recognized at that time.

The true mechanism of reverse pseudohyperkalemia has not yet been established. Even minor leakage of intracellular potassium from leukemic cells can have a major effect on the extracellular potassium level. Mechanical stressors in the form of pneumatic tube transport and specimen sampling into vacuum tubes have been implicated as causes of this artifact.^5,6 Another possible mechanism is heparin-induced lysis of leukocytes in the setting of hematologic malignancy during laboratory processing.^4,7,8

LESSONS LEARNED

In patients with hematologic proliferative disorders who develop hyperkalemia in the absence of electrocardiographic changes and an obvious cause of increased potassium levels (eg, acute renal failure, tumor lysis syndrome), we should entertain the possibility of hemolysis, laboratory error, pseudohyperkalemia, and reverse pseudohyperkalemia. The potassium level should be remeasured to rule out laboratory error and hemolysis. In patients with marked leukocytosis or thrombocytosis, simultaneous measurement of serum and plasma potassium levels helps diagnose pseudohyperkalemia and reverse pseudohyperkalemia. Also, prompt blood gas analysis can help identify spurious hyperkalemia.