Nephrology, Department of Medicine, University Hospital `Carl Gustav Carus' Dresden, Germany
Correspondence and offprint requests to: Peter Gross, M.D., Nephrology, Department of Medicine, University Hospital `Carl Gustav Carus', Fetscherstr. 74, D-01307 Dresden, Germany.
Case description
A 22-year-old house painter referred himself to the nephrology outpatient service because of a chronic unexplained hypokalaemia associated with chronic fatigue. The hypokalaemia had first been discovered 7 years previously. At that time he had appendicitis. When he was taken to the operating theatre there was a serious cardiac arrhythmia. It was then discovered for the first time that he had a serum potassium concentration of 2.4 mmol/l. The discharge report stated that the hypokalaemia never disappeared despite massive infusions of potassium. Six years ago he had suffered an episode of ileus which was attributed to surgical causes. During that hospitalization he had several episodes of muscle cramps involving his fingers. The hospital discharge notes did not mention serum potassium. Four years ago there was transient haematuria, which was thought to be somehow related to his job as a house painter. The haematuria later disappeared without obvious residual renal dysfunction. The patient's only indication of a physical abnormality was his report of having excessive thirst most of the time. He had even sought medical advice to exclude diabetes mellitus, which he did not have. During his presentation he denied having any of the following: syncope, tetany of the vocal cords, paralysis, muscle weakness or nycturia. He denied alcohol, liquorice, glue sniffing, paint sniffing, diuretics, laxatives and antibiotics. He claimed to be on a normal diet. According to his report he never vomited; however, he noticed a tendency towards having loose stools. He reported having had normal blood pressure. His older brother was also known to have chronic hypokalaemia. During the initial interview the patient showed obvious interest in obtaining disability compensation on account of his hypokalaemia.
Physical examination showed a 22-year-old white male of normal appearance, without physical disability or malformations. Vital signs were normal. Blood pressure was 130/80 mmHg, pulse rate was 78 beats/ min. There were pathologic orthostatic changes: the pulse increased from 78 to 90 beats/min after 2 min of standing upright. The cardiac rhythm was not exactly regular (the ECG later showed two supraventricular extrasystoles/min). The chest, lung, abdomen and skin showed no obvious abnormalities. Muscular strength was unremarkable.
The laboratory evaluation demonstrated that the patient's hypokalaemia ranged between 2.1 and 3.0 mmol/l, depending on how much K+ substitution he was taking. The urinary K+ concentration was ~80 mmol/l, i.e. inappropriately high for his degree of hypokalaemia. He had hypomagnesaemia of between 0.64 and 0.72 mmol/l (normal >0.75 mmol/l). There was metabolic alkalosis (pH 7.45, bicarbonate 29 mmol/l, pCO2 45 mmHg). Four different 24-h urinary samples all containing high concentrations of chloride (90150 mmol/l ) were sent to three independent laboratories each for measurement of diuretics and all reports were negative. Creatinine clearance (115 ml/min ), urinary sediment and 24-h protein excretion (100 mg) were all unremarkable. Aldosterone in the 24-h urine was also normal. The calcium excretion in the 24-h urinary samples was reduced at 1.1 mmol (normal range 2.58 mmol).
Specific tests were carried out to assess the possibility of a diagnosis of Bartter's syndrome. The urinary concentration test (final urinary osmolality: 920 mOsm/kg) and the urinary acidification test (final urinary pH 5.6 ) were both considered unremarkable for the degree of hypokalaemia. Urinary excretion of prostaglandin (PG)E2 was modestly elevated at 1.2 µg/24 h (normal range: 0.070.9), while PGE-M and PGE2 were normal. A measurement of the distal fractional chloride reabsorption while the patient was on oral potassium supplementation (150 mmol/24 h) yielded a factor of 0.8. (Bartter's syndrome: <0.6; normal: >0.95.) This test was repeated twice and the original results were confirmed both times.
Thus a final diagnosis of adult familial Gitelman's syndrome was proposed. DNA was sent for sequencing of the gene for the thiazide-sensitive Na/Cl cotransporter of the distale tubule. The diagnosis was considered established because the work-up had excluded gastrointestinal causes of hypokalaemia (excluded by the high urinary chloride excretion rate) as well as diuretic abuse (repeatedly negative measurements of diuretics in urinary samples), renal tubular acidosis, high-dose antibiotics excreted by the kidney and Bartter's syndrome. The evidence in favour of a diagnosis of Gitelman's syndrome in this setting was considered to be: the familial nature and the long duration of the hypokalaemia; the benign medical course and the mild degree of symptoms; the moderate degree of continuous loss of chloride by the renal route with mild plasma volume contraction; and the associated findings of hypomagnesaemia and hypocalciuria.
Comments
Hypokalaemia is a frequent finding in hospitalized patients [1]. In most cases the cause and the clinical setting will be obvious and no further investigation will be necessary. However, in a subgroup of patients with chronic hypokalaemia establishing the diagnosis may present difficulties. This type of patient with `chronic hypokalaemiacause unknown' is supposedly familiar to most nephrologists. The patient presented above is a case in point. Such patients may see many specialists over the years, causing significant cost, without reaching a definitive diagnosis. For instance the patient reported here had undergone unnecessary renal biopsy, yielding an erroneous `diagnosis' of classical Bartter's syndrome 5 years before the present admission. He had received treatment with indomethacin, to no avail other than the side-effects of this agent. The status of his renin/angiotensin system had been evaluated five times over the years, but the results failed to contribute to his diagnosis.
We would therefore like to make several comments as to the most efficient steps towards making the diagnosis in this kind of hypokalaemia.
Medical textbooks generally stress the importance of the urinary potassium concentration in the differential diagnosis of hypokalaemia [2]. We studied 27 patients with chronic hypokalaemia [3]. As our studies showed, the urinary potassium concentration failed to be a reliable criterion in the differential diagnosis. Textbooks usually point out that a low urinary potassium concentration is an indication of an extrarenal aetiology of the hypokalaemia. However, actual measurements obtained in our laboratory demonstrated a high urinary potassium concentration in most cases of extrarenal hypokalaemia. This surprising observation may be explained by the presence of secondary hyperaldosteronism in such cases. We feel that the urinary potassium concentration is rather useless in chronic hypokalaemia and we propose that it should not even be obtained [3; Table 1].
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In contrast the medical history, physical examination and selected laboratory tests will almost always permit one to establish the diagnosis of chronic hypokalaemia. Almost all such patients will turn out to have one of the following three diagnoses: surreptitious vomiting, diuretic abuse or Gitelman's syndrome. Chronic diarrhoea, laxative abuse and renal tubular acidosis are all quite rare, while classical Bartter's syndrome and hyperprostaglandin-E syndrome are useful for symptomatic purposes during childhood only.
Surreptitious vomiting
Surreptitious vomiting is a frequent cause of chronic hypokalaemia [4,5]. These patients have characteristic features. They often look emaciated and are frequently underweight. They have low normal blood pressure. There is evidence of mild renal insufficiency, hypochloraemia and urinary chloride excretion close to zero. These findings are explained by the loss of chloride caused by vomiting (Table 1). The latter also causes metabolic alkalosis, secondary hyperaldosteronism and renal loss of potassium. Therefore, the urinary potassium concentration is usually >10 mmol/l. Owing to the metabolic alkalosis and renal sodium bicarbonate excretion the urinary sodium concentration is commonly much higher than the urinary chloride. It is therefore not recommended that urinary sodium is measured. Surreptitious vomiting may be seen in women and men. There are almost always neurotic or psychotic causes of the vomiting. It may be difficult or even impossible to get the patient to accept her or his diagnosis. In our view the best approach is an infusion test using 0.45% NaCl, 2.5 l/day for 23 days under continuous medical supervision (ICU) while on a regular hospital diet. In this way the cycle of episodes of vomiting is interrupted, the chloride deficit will be replenished and the body potassium stores increase. In response to such `reversal of vomiting' the renal insufficiency and the metabolic alkalosis will improve, there will be an increase in urinary chloride content and the serum potassium will begin to rise, although the patients will often gain 23 kg of body weight. This chain of events serves to confirm the presumed diagnosis of surreptitious vomiting.
All such patients should be referred to a psychiatrist. Recent literature has indicated a high incidence of severe eating disorders, vomiting and hypokalaemia [6,7]. In addition Greenfeld et al. [6] pointed out that some of these patients are also laxative abusers. This will lead to worse hypokalaemia.
Diuretic abuse
Diuretic abuse is common in chronic hypokalaemia. Such patients sometimes give a report of excessive weight gain or of unexplained ankle swelling, usually causing significant anxiety. Diuretic abuse occurs in persons in whom strict weight control is of major importance to their lives, such as in models, ballet-dancers, stewardesses or wrestlers. Often these patients take the diuretics only intermittently and, as a consequence, their urinary chloride concentration may change between high (>70 mmol/l) and low (<20 mmol/l) values. They have blood pressure readings in the low normal range often together with pathological orthostatic changes. Laboratory results usually show mild degrees of renal insufficiency, hypochloramia and metabolic alkalosis (Table 1). Urinary samples containing high concentrations of chloride will test positive for diuretics, often for thiazides or for furosemide. Except for the presence of diuretics in the urine, diuretic abuse may be very similar to Gitelman's syndrome. Therefore, the measurement of diuretics in urine is of great importance in these patients. It pays to use professional laboratories with established experience in the measurement of diuretics, such as is the case in doping laboratories.
MacGregor et al. [8] reported an interesting phenomenon: diuretic-induced oedema. In their opinion the oedema is related to the time (days to weeks) it takes for the hyperaldosteronism to disappear after cessation of diuretic intake. Thus the aldosteronism-induced oedema may provoke more diuretic intake setting up a vicious cycle [8].
Gitelman's syndrome
This disorder may account for ~50% of all chronic hypokalaemia [3]. The patients are adults with chronic benign hypokalaemia, which is usually first discovered during a routine laboratory evaluation, often years previously. Although the hypokalaemia may be in the range 2.43.2 mmol/l (off potassium supplementation ), there are basically no significant health problems related to hypokalaemia in these patients. Low blood pressure, tiredness and increased fatigability are common, however. Patients often will have been given a `diagnosis' of Bartter's syndrome and futile attempts to treat with indomethacin are undertaken, as in the case presented initially [913]. There will be normal renal function, borderline hypochloraemia, metabolic alkalosis and secondary hyperaldosteronism (Table 1). Diagnostically useful are the presence of hypomagnesaemia and hypocalciuria. These features are found in most, although not all, patients with Gitelman's syndrome. The patients will have high urinary chloride excretion rates raising suspicions of diuretic abuse, however, it will not be possible to demonstrate diuretics in the urine. The measurement of the distal fractional chloride reabsorption will demonstrate mildly abnormal ratios indicating an inability of the distal nephron to conserve chloride completely.
In the past, the diagnosis of Gitelman's syndrome had to be made phenotypically and by exclusion of other disorders. In this way it depended heavily on the exclusion of diuretics in the urine. It has now been discovered that patients with Gitelman's syndrome have mutations of their thiazide-sensitive Na/Cl cotransporter in the distal tubule of the nephron [1418]. The discovery of these mutations opens up the possibility of diagnosing Gitelman's syndrome by genotyping. For instance Abuladze et al. [19] reported that peripheral blood mononuclear cells express thiazide-sensitive Na/Cl cotransporter mRNA and that this mRNA shows mutations in patients with Gitelman's syndrome.
It is indeed striking that many of the phenomena of Gitelman's syndrome closely resemble chronic abuse of thiazides. Whether there may be additional mutations beyond those of the thiazide-sensitive Na/Cl cotransporter is currently a matter of scientific scrutiny. These questions may be important for potential gene therapy in the future. To our knowledge no-one has proposed gene therapy for Gitelman's syndrome at this time. The issue of additionally mutated genes in Gitelman's syndrome has recently received support by the findings of Schultheiss et al. [20]. They generated a knockout model of the thiazide-sensitive Na/Cl cotransporter in mice. The model showed hypomagnesaemia and hypocalciuria, but there were no other electrolyte disturbances and the blood pressure was normal. Although it is possible to explain these findings in several ways, additional genetic modifications, beyond the thiazide-sensitive Na/Cl cotransporter, are clearly one such possibility.
It is important to point out that Gitelman's syndrome has a benign prognosis. In some of our patients hypokalaemia (<2.9 mmol/l ) had been documented for over 20 years [3]. However, they showed no evidence of renal functional disturbances, symptomatic cardiac arrhythmia or muscle disorders.
It is difficult to know whether Gitelman's syndrome should be treated at all. In view of the benign prognosis modest attempts at maintaining the serum potassium level around 2.83.0 mmol/l may be sufficient. This can be achieved by potassium-rich beverages and food, as well as by mild potassium supplementation. In our experience potassium-sparing diuretics (triamterene, amiloride, spironolactone) are counterproductive because they lower the blood pressure even further making the patients more tired.
Classical Bartter's syndrome
In 1962, Bartter described a disturbance of infancy or early childhood associated with a high incidence of polyhydramnion, prematurity and retardation of growth [9,21,22]. The patients were profoundly hypokalaemic and had polyuria, low blood pressure, secondary hyperaldosteronism and metabolic alkalosis [23]. They were usually normomagnesaemic and normocalciuric. A test for distal fractional chloride reabsorption yields values of 0.50.6 (normal 0.951.0), indicating continuous renal chloride loss. Most or all of the features of Bartter's syndrome are now explained by several possible mutations of the genes of the chloride reabsorption mechanism of the thick ascending limb of the loop of Henle.
In our experience `Bartter's syndrome' is the most frequently encountered erroneous diagnosis for chronic hypokalaemia in adults. We examined 12 such cases; it turned out that Gitelman's syndrome was present in all. Thus a diagnosis of `Bartter's syndrome' in an adult should always be subjected to intense scrutiny. It is expected that once genotyping becomes generally available for Gitelman's and Bartter's syndromes establishing these diagnoses will become more accurate.
Miscellaneous
Chronic diarrhoea and laxative abuse These are uncommon causes of chronic hypokalaemia. Such patients are usually conspicuous because of their metabolic acidosis (in the absence of renal tubular acidosis), associated with hypochloraemia, low urinary chloride excretion (<15 mmol/l) and high weight of 24-h stools (>200 g/24 h) [4,2426]. They have secondary hyperaldosteronism causing loss of potassium via the kidney and possibly also via the stool [26,27].
A rare case of hypokalaemia was reported by Walmsley and White [24]. A villous adenoma of the colon and rectum was associated with a diarrhoea of 3 l/day. The potassium concentration in the diarrhoeal fluid was 100 mmol/l, the serum potassium was 2.3 mmol/l and the urinary potassium was 6 mmol/l. The acidbase status showed a metabolic alkalosis. These changes were attributed to the high secretory activity of the villous adenoma, a tumour known for its large epithelial surface.
Renal tubular acidosis Renal tubular acidosis is characterized by a hyperchloraemic metabolic acidosis and an inability to acidify the urine. Two different types are known: proximal and distal tubular acidosis. In the former the inability to reabsorb bicarbonate in the proximal tubule is fully compensated by distal nephron segments at a plasma bicarbonate level of 18 mmol/l. Above this level the urinary pH will not be maximally lowered and the patients have renal sodium wasting, secondary hyperaldosteronism and mild hypokalaemia. In adults this tends to be a mild disturbance. In children it is often part of Fanconi's syndrome and bicarbonate supplementation is required for normal growth.
In distal renal acidosis the kidney is unable to acidify the urine at any level of acidosis. Therefore, these patients may get a life-threatening, severe metabolic acidosis. It is associated with hypokalaemia, renal sodium wasting, secondary hyperaldosteronism and usually nephrocalcinosis. Bicarbonate and potassium supplementation are required [2830].
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