Leaky cell syndrome: a rare cause of pseudohyperkalaemia

Abstract

Life-threatening situations of hyperkalaemia are often caused by renal failure, hyperglycaemia or medication. However pseudohyperkalaemia, a falsely elevated potassium concentration, is usually caused by haemolysis, repeated clenching of the fist during venepuncture or abnormal cell numbers. Another rare cause of pseudohyperkalaemia is familial pseudohyperkalaemia, an autosomal dominantly inherited trait, with increased leakage of potassium from erythrocytes. Under normal in vivo conditions, this increased leakage is compensated by augmented activity of the Na⁺/K⁺ ATPase pump. However, after venepuncture the blood cools down to room temperature, reducing the activity of the Na⁺/K⁺ ATPase pump whereby the increased potassium leakage becomes more apparent. Here, we present a Dutch patient with extreme familial pseudohyperkalaemia. Interestingly, his two children also show increased potassium leakage at room temperature, albeit at a lower level. Despite the low prevalence of familial pseudohyperkalaemia, it can have important clinical implications and rapid recognition is desired.

Introduction

Hyperkalaemia (>5.0 mmol/L) is a potentially life-threatening and frequently found condition among hospitalized patients, with a prevalence ranging between 1.0% and 10%. ¹ Cases of severe hyperkalaemia (>7.0 mmol/L) are accompanied by muscle weakness and abnormal cardiac signal conduction with electrocardiogram (ECG) alterations that can induce fatal cardiac arrhythmias. ¹ Hyperkalaemia in otherwise healthy persons is rare. This is mainly due to effective responses of the body to elevated potassium concentrations. Elevated plasma potassium concentrations are usually the result of a disturbance in the balance between intake, distribution and urinary excretion of potassium. Hyperkalaemia, as a result of potassium redistribution, is frequently found in patients with metabolic acidosis, insulin deficiency or increased tissue breakdown. A reduction in urinary potassium excretion is mainly caused by renal failure, effective circulating volume depletion or hypoaldosteronism (adrenal insufficiency, aldosteron resistance or decreased activity of the renin–angiotensin system). Hyperkalaemia, due to increased intake, is predominantly caused by intravenous infusion of potassium-rich medication. ¹

In contrast to physiological or in vivo hyperkalaemia, pseudohyperkalaemia is an elevated potassium concentration arising during or after venepuncture. The reason is often mechanical damage to erythrocytes, causing the intracellular potassium to leak out of the cells. Together with potassium, haemoglobin (Hb) and lactate dehydrogenase are also released from the damaged erythrocytes and this in vitro haemolysis can easily be detected by the measurement of lactate dehydrogenase and free Hb on routine clinical chemistry analysers. Repeated clenching of the fist during venepuncture can induce elevated potassium concentrations as well, due to the release of potassium from muscle cells. Pseudohyperkalaemia is also frequently observed in patients with thrombocytosis or leukocytosis, most likely due to high cell numbers and increased fragility of the cell membranes. ^2,3 Familial pseudohyperkalaemia is a rare, autosomal dominantly inherited condition resulting in increased potassium concentrations in vitro. ⁴ The erythrocyte membranes of patients with familial pseudohyperkalaemia have an increased permeability to potassium.

Case report

A 67-year-old male patient diagnosed with (non-alcoholic) liver steatosis with hyperlipidaemia, regularly visits our hospital's outpatient department for routine physical and laboratory examinations. Past laboratory analysis showed slightly elevated potassium concentrations without clear cause. However, a recent measurement revealed a potassium concentration of 6.8 mmol/L, without evidence of haemolysis, leukocytosis or thrombocytosis. Furthermore, no symptoms of hyperkalaemia were present. Analysis of a freshly drawn stat sample four hours later showed a normal potassium concentration of 4.0 mmol/L. Four months later, a similar situation occurred; routine analysis revealed a potassium concentration of 9.9 mmol/L, without signs of haemolysis or abnormal cell numbers (Table 1). Physical examination and ECG monitoring showed no symptoms of hyperkalaemia whereas laboratory analysis on a new stat sample showed normal potassium concentrations of 3.6 mmol/L. These two incidents of pseudohyperkalaemia without haemolysis or abnormal cell numbers in this patient suggested a possible role of familial pseudohyperkalaemia.

Table 1

Index case blood chemistry

	Sample 1	Sample 2	Reference values	Units
Haematology
ESR		12	<20	mm/h
Haemoglobin	10.4	10.6	8.5–11.0	mmol/L
Haematocrit	0.48	0.46	0.40–0.50	l/L
Erythrocytes		4.9	4.5–5.5	1012/L
MCV		94	80–100	Fl
Thrombocytes	150	154	150–400	109/L
Leukocytes	9.4	9.4	4.0–10.0	109/L
Eosinophils		0.1	<0.5	109/L
Basophils		0.1	<0.2	109/L
Neutrophils		5.4		109/L
Lymphocytes		3.3	1.0–3.5	109/L
Monocytes		0.5	0.1–1.0	109/L
Prothrombin time	20.3	21.7	12.5–14.5	s
Chemistry
BUN		2.0	2.9–7.5	mmol/L
Creatinine	55	53	65–105	μmol/l
Potassium	9.9	3.6	3.5–5.0	mmol/L
Sodium	134	135	135–145	mmol/L
Chloride		96	97–107	mmol/L
Bilirubin		<17	<17	μmol/L
Alkaline phosphatase	78	79	<120	U/L
ALT	85	80	<45	U/L
AST	70	67	<40	U/L
LDH	253	229	<250	U/L
γGT	785	737	<50	U/L
Amylase		74	<10	U/L
Albumin	46	46	35–50	g/L
C-reactive protein	<10	<10	<10	mg/L
Glucose		8.4	4.0–7.8	mmol/L
Arterial blood gas
pH		7.38	7.35–7.45
pCO2		5.0	4.7–6.4	kPa
HCO3 −		21	21–27	mmol/L
pO2		10.0	11.0–14.4	kPa

ESR, erythrocyte sedimentation rate; MCV, mean corpuscular volume; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine transaminase; LDH, lactate dehydrogenase; γGT, gamma-glutamyltransferase

Blood chemistry results from index case. Sample 1 represents a routine sample with 85 min between venepuncture and measurement. Sample 2 is drawn four hours later and is a stat sample with direct analysis within 30 min after venepuncture

To confirm familial pseudohyperkalaemia, we used a simple screening assay described before. ⁵ In brief, blood from the patient and a healthy control were drawn into heparinized tubes and incubated at 4, 20 and 37°C for two and four hours, respectively. Directly after venepuncture (timepoint zero) and at the indicated time intervals, plasma was separated from the cellular fraction by centrifugation. Plasma potassium concentrations were determined by ion selective electrode  measurement. Lactate dehydrogenase and free Hb were measured to estimate the degree of haemolysis. Interference studies in our laboratory indicated that there is no significant rise in plasma potassium concentration due to in vitro haemolysis as long as the free Hb concentration of a sample is below 53 μmol/L. Both patient and control samples showed normal electrolyte plasma concentrations directly after venepuncture (Table 2). However, patient material that had been incubated for two hours at 4 or 20°C showed a marked increase in potassium concentrations, 7.3 and 7.5 mmol/L, respectively. In all the samples, both the lactate dehydrogenase activity and free Hb remained low, thereby excluding a role of haemolysis for increased potassium concentrations. Also, a complete haematological cell count showed no increased numbers of thrombocytes or leukocytes (not shown). In contrast to the patient samples incubated at 4 or 20°C, both the patient sample incubated at 37°C and the samples from the healthy control incubated at different temperatures showed no significant changes in potassium concentrations. The results described above confirm that this patient has familial pseudohyperkalaemia and explain the cause of hyperkalaemia.

Table 2

Plasma potassium concentrations and measurements of haemolysis after incubation at different temperatures and time intervals

	0 h			2 h			4 h
Temperature (°C)	Potassium (mmol/L)	LDH (U/L)	Free Hb* (μmol/L)	Potassium (mmol/L)	LDH (U/L)	Free Hb* (μmol/L)	Potassium (mmol/L)	LDH (U/L)	Free Hb* (μmol/L)
Patient
4				7.3	203	10	10.3	204	10
20	4.7	190	6	7.5	200	5	9.7	201	4
37				3.9	206	12	3.8	216	16
Daughter A
4				4.6	179	6	5.6	173	5
20	3.8	160	5	4.5	165	5	4.9	170	5
37				3.6	194	11	3.4	234	26
Daughter B
4				4.9	167	7	5.5	167	5
20	3.8	167	5	5.1	155	4	4.7	156	1
37				3.9	196	15	3.4	183	10
Control 1
4				4.8	185	4	5.1	192	6
20	4.2	181	4	4.4	189	6	4.2	191	8
37				3.9	206	6	3.7	208	7
Control 2
20	4.2			3.8			4.0
Control 3
20	4.2			4.0			4.0
Control 4
20	3.9			3.8			3.7

LDH, lactate dehydrogenase; Hb, haemoglobin

*There is only a significant increase in potassium concentration due to in vitro haemolysis when free haemoglobulin in the sample is >53 μmol/L

Several reports have indicated that familial pseudohyperkalaemia is an autosomal dominantly inherited trait. ⁴ Therefore, we also tested the two daughters of this patient for familial pseudohyperkalaemia with the same test as described above. Both children had normal potassium concentrations of 3.79 and 3.81 mmol/L directly after venepuncture (Table 2). After four hours of incubation at 20°C, their potassium concentrations had risen to 4.93 and 4.70 mmol/L, respectively, without signs of haemolysis or abnormal cell numbers (Table 2). The elevation in the potassium concentration of 1 mmol/L during the four-hour incubation at 20°C from the two children was not as dramatic compared with the rise in potassium concentration in their father. However, it was significantly different from healthy controls. The potassium concentrations of healthy controls incubated at 20°C for 2–4 h varied only by 0.2 mmol/L. These findings indicated that both daughters displayed familial pseudohyperkalaemia, although at a lower level compared with their father.

Discussion

Severe hyperkalaemia accompanied by clinical signs requires direct medical attention and therapeutic intervention. However in situations without clear symptoms, it is important to distinguish between hyperkalaemia and pseudohyperkalaemia, because treatment of the latter might induce dangerous hypokalaemia.

Here we presented a case of a patient with severe hyperkalaemia without clinical symptoms due to familial pseudohyperkalaemia. The finding of a normal potassium concentration in a new freshly drawn and directly analysed blood sample suggested pseudohyperkalaemia. Both samples were obtained by an uncomplicated venepuncture; furthermore, there were no signs of haemolysis or abnormal cell numbers. In rare cases, pseudohyperkalaemia is caused by familial pseudohyperkalaemia. ⁴ The diagnoses of familial pseudohyperkalaemia can be confirmed with the above-described simple test. ⁵

Under normal physiological conditions, the steady-state erythrocyte intracellular concentrations of sodium and potassium reflects the balance between the active Na⁺/K⁺ ATPase pump and passive membrane leakage. The Na⁺/K⁺ ATPase pump uses ATP to maintain a high intracellular potassium and a low sodium concentration. The Na⁺/K⁺ ATPase pump is counteracted by a concentration-gradient-driven passive leak over the erythrocyte membrane of potassium and sodium. Several red-cell ion-channel disorders have been described with excessive leakage of potassium and sodium and are grouped under the name of hereditary stomatocytosis. It is important to realize that the cellular defect responsible for potassium leakage is not located in the Na⁺/K⁺ ATPase pump, but in a membrane ion channel of the erythrocyte. In the most severe phenotype, the excessive leak affects the osmotic integrity of the cell causing in vivo haemolysis. In these patients, excessive leakage of potassium from erythrocytes is corrected by increased renal secretion and therefore patients can have normal plasma potassium concentrations. Furthermore, abnormal erythrocyte parameters are usually present; for example, increased mean corpuscular volume, mean corpuscular haemoglobin concentrations (MCHC) and stomatocytes can been seen in a bloodfilm. In patients with milder versions of hereditary stomatocytosis, for example, familial pseudohyperkalaemia, the leakage is less severe and compensated by a temperature-dependent increased activity of the Na⁺/K⁺ ATPase pump. In these patients, there is no haemolysis because the cellular osmotic integrity is maintained by the increased Na⁺/K⁺ ATPase pump activity. However, after venepuncture when the blood cools down to room temperature, the activity of the Na⁺/K⁺ ATPase pump is lowered and the increased passive leakage becomes more apparent. ^6,7 Our patient probably had familial pseudohyperkalaemia, because there were no stomatocytes in the bloodfilm or signs of haemolysis (normal Hb concentration, no reticulocytosis and normal values of lactate dehydrogenase and bilirubin) and only a slightly elevated MCHC.

The prevalence of familial pseudohyperkalaemia is unknown; several families have been described in the UK, France and one in Japan. ^7,8 It has been suggested that the condition of familial pseudohyperkalaemia is autosomal dominantly inherited. At least two different genotypes have been described with relative similar phenotypes. Genetic defects have been found to map to either chromosome 16q23–q24 or chromosome 2q35–q36. ^9,10 This suggests that the protein responsible for the excessive leakage might be a heterodimer.

Because of the autosomal dominant inheritance pattern of familial pseudohyperkalaemia, we also tested the two daughters of the patient for increased potassium leakage. Both daughters showed increased leakage of potassium compared with healthy controls if the blood was incubated for four hours at 20°C. However, the difference between timepoint zero and four hours was not as dramatic as found for their father. This might indicate that the father has both the 16q23–q24 and 2q35–q36 mutations or other unknown underlying processes that enhance the potassium leakage, while both daughters harbour only one mutation. Furthermore, the haematocrit can also affect the in vitro plasma potassium concentration, since increased numbers of erythrocytes are available from which the intracellular potassium can leak into the plasma. However, both the father and the two daughters had comparable haematocrit values.

In conclusion, we present here, to our knowledge, the first Dutch family with elevated in vitro potassium concentrations due to familial pseudohyperkalaemia. Although a rare finding, it can have important implications for physicians. An inappropriate correction of pseudohyperkalaemia can lead to situations with dangerous hypokalaemia, and therefore rapid recognition of familial pseudohyperkalaemia is important.

DECLARATIONS

Competing interests: None.

Funding: Not applicable.

Ethical approval: Not applicable.

Guarantor: MVL.

Contributorship: MVL was involved in concept and design, data collection, analysis and interpretation of data, and drafting of manuscript. AdM was involved in concept and design and data collection. MJK-D was responsible for data collection and patient care. FAvdB carried out concept and design, and drafted the manuscript.