Laboratory Endocrinology: Investigation of hypokalaemia

Dr. Anthony Norden

Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge

Summer School 11-14 July 2006
The Møller Centre, Storeys Way, Cambridge, UK

Investigation of hypokalaemia…is directed by the history and clinical findings. This truism will lead the clinician through the maze of investigations.

In practice the first consideration is whether the hypokalaemia is life-threatening. Despite a wealth of theoretical knowledge and treatment guidelines the threshold for concern has little evidence but is usually taken to be < 3.0 mmoL/L. Having said that, most clinicians come across patients with documented levels of <2 mmol/L who have survived for months, often with symptoms. A trap is that such severe hypokalemia may be attributed to a notional preanalytical artefact. This hardly ever happens, except in leukaemias, and unlike hyperkalaemia it is important to recognise that hypokalaemia, particularly in out-patients, is very rarely ‘pseudohypokalaemia’. Hypokalaemia almost always needs clinical attention, often urgently.

The cellular hyperpolarization caused by hypokalaemia increases the threshold for excitation and this is much of the explanation for the cardiac, neuromuscular, renal and endocrine sequelae.

The first line of clinical and laboratory investigations will help answer the question: is hypokalaemia due to transcellular shift or potassium depletion?

Transcellular shift: Alkalaemia will usually be seen as an elevated serum bicarbonate as part of a ’urea & electrolyte’ panel or ‘blood gas’. This is quite the opposite finding to the acidosis of renal tubular acidosis (see below) where the serum bicarbonate is often reduced. ß2-agonist medication as a cause of hypokalaemia will be evident in the history; recently risperidone and quetiapine have been reported to cause hypokalaemia due to cellular shift. Attacks of hypokalemic periodic paralysis, hereditary or acquired, are induced by high carbohydrate intake, rest after exercise and stress. These clues from the history may lead to this difficult diagnosis. The autosomal disorder is most commonly caused by mutation of the muscle Ca2+ channel a1 subunit gene (CACNA1S). Thyroid function tests will detect the acquired disorder of thyrotoxicosis which is more common in Asians.

Potassium depletion is the major cause of hypokalaemia and is where laboratory investigations come into their own. It is worth restating fundamentals: net potassium loss may be due to excess renal loss (usually) or gastrointestinal loss (less commonly). Decreased intake (‘Tea and toast diet’) is an uncommon cause. Renal conservation by the healthy kidney can reduce the loss of potassium to below 20 mmoL/24 hours. This provides one of the single most important ways of differentiating extrarenal from renal losses: measurement of 24 hour urine potassium excretion.

Extrarenal potassium depletion causes renal potassium conservation and 24 hour urine excretion of <=20 mmoL. Gastrointestinal losses are by a frequent cause of this and include villous adenoma and diarrhoea as well as laxative abuse. Urine is needed to diagnose laxative abuse and most local laboratories will rely on a toxicology centre for this. Diuretic abuse, also detectable by specialist urine screening may coexist. Diarrhoea can cause either metabolic acidosis (loss of bicarbonate) or metabolic alkalosis (chloride depletion) so bicarbonate levels are themselves not useful in differentiating the aetiology of diarrhoea-associated hypokalemia.

Renal depletion will usually cause excretion of urine potassium >20 mmol/24 hours with coexisting hypokalaemia.. If there is a low serum bicarbonate, both proximal (less common) and distal renal tubular acidosis (dRTA, Type 1 RTA) should be considered. Stone disease, with or without nephrocalcinosis, is a clue. A family history must be obtained whenever renal depletion is suspected but dRTA may be acquired and Sjögren syndrome is a common acquired form of dRTA. Finding a urine pH of <5.5 excludes classical dRTA but the pH must be measured on a laboratory pH meter and not ‘stix’. The ammonium chloride loading test remains the ‘gold standard’ but it is difficult to organise and often unpleasant for the patient: the fludrocortisone plus frusemide test may have advantages for screening.

The molecular genetics of dRTA are complex. The dominantly inherited form is usually caused by mutation of the chloride/bicarbonate exchanger gene, SLC4A1 encoding the AE1 exchanger. Recessive forms include mutation of the B1 subunit of the vacuolar H+-ATPase of the intercalated cells of the distal nephron. Laboratory molecular diagnoses are available.

If hypokalaemia is part of a renal Fanconi syndrome, then urine screening for albumin and aminoaciduria will be useful. Occasionally.

Chloride is often forgotten though every laboratory can measure it. In urine, conservation of chloride by the healthy kidney can reduce excretion to <10 mmol/24 hours. In chloride-losing states, the mechanisms involved in development of hypokalemia include excretion of potassium with bicarbonate as well as hyperaldosteronism. Diuretic therapy acting on both the thick ascending limb of the loop of Henle and on the distal tubule result in potassium loss though less commonly frank hypokaleaemia.. These diuretics mirror the effects of Bartter’s and Gitelman’s syndromes, respectively, at these sites and both syndromes are associated with hypokalaemia.

Mutations causing these syndromes can now be readily be detected by the genetics laboratory. Measurements of serum magnesium (low in Gitleman’s) and urine magnesium (high in Gitelman’s) are essential before embarking on complex molecular genetics. Gitelman’s is underdiagnosed and the two syndromes can be difficult to distinguish except by genetic analysis.

States of mineralocorticoid excess, all of which are associated with hypokalemaia, need diverse laboratory investigations. The most useful, in addition to measurement of cortisol status by serum and urine studies is the ratio of aldosterone to renin. The different methodologies in use by laboratories mean that the clinician must pay close attention to local reference ranges and discussion with the laboratory directly is often necessary. With increased diagnosis, hypokalaemia is becoming less prevalent among patients found to have primary hyperaldosteronism, including Conn’s syndrome. Hypokalaemia must not be relied on for screening. Also, in Cushing syndrome, overall only about one-third of patients are hypokalaemic most frequently in association with ectopic ACTH production. The use of the aldosterone/renin ratio in screening for the high-aldosterone states of primary hyperaldosteronism, glucocorticoid-remediable hypertension and renovascular disease and low aldosterone states such as 11-ß-hydroxysteroid dehydrogenase deficiency and Liddle syndrome will be discussed.

References

Oxford Textbook of Clinical Nephrology, Volume 1, pp 246-253, 3rd ed., Oxford University Press 2005. Includes full discussion of most endocrine causes of hypokalaemia.

‘Fluid, Electrolyte and Acid-Base Disturbances’ (‘NephSAP®), Nephrology Self-Assesmnet Program of the American Society of Nephrology R.J. Glassock ed., Jan 2006. Very succinct account of laboratory investigations.

Devonald MA, Smith AN, Poon JP, Ihrke G, Karet FE. Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis.
Nat Genet. 2003 Feb;33(2):125-7. Part of the molecular cell biology of this clinical disorder is explained.

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society

Revised: 24-Aug-2006