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Episodic weakness in a young woman

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Q1: What is the metabolic abnormality?

Hypokalaemic metabolic alkalosis.

Q2: What are the differential diagnoses?

Bartter's syndrome; Gitelman's syndrome; diuretic use; vomiting.

In this case, the history, the normal blood pressure, the presence of alkalosis, the presence of hypokalaemia between attacks, and a high 24 hour urine potassium excretion limits the possible diagnoses. These include Bartter's syndrome, Gitelman's syndrome, diuretic use, and vomiting. Figure 1 illustrates how we excluded the other possible diagnoses. Hypokalaemic periodic paralysis is characterised by recurrent attacks of paralysis and hypokalaemia with normal serum potassium concentration between attacks.

Figure 1

Investigation and differential diagnosis of potassium loss (CAH = congenital adrenal hyperplasia; GI = gastrointestinal; HBP = high blood pressure; TTKG = transtubular potassium gradient). (Figure adapted with permission from Internal Medicine. 4th Ed. Edited by J H Stein. St Louis: Mosby Year Book, 1994: 2681–92.)

Q3: What investigations will help distinguish between the possible diagnoses?

Twenty four hour urinary chloride and calcium; serum magnesium; urine diuretic screen.

Her urinary chloride was 142 mmol/24 hours and urinary calcium was 0.4 mmol/24 hours.

Her serum magnesium was 0.5 mmol/l (0.7–1.0). A diuretic screen was negative.

Q4: What is the likely diagnosis?

Gitelman's syndrome.

The high urinary chloride excludes vomiting as a potential cause. Vomiting results in hypochloraemia as a result of loss of hydrochloric acid in gastric fluid. In this setting the combination of hypochloraemia and hypovolaemia result in appropriate chloride retention by the kidneys, as a result urine chloride will be low. The urinary chloride concentration can be misleading in patients taking diuretics, if the diuretic effect has worn off the concentration will be low, if the diuretic is still acting the urine chloride concentration will be high.

The high urinary chloride concentration suggests continued diuretic ingestion, Bartter's syndrome, or Gitelman's syndrome. The low urinary calcium excludes the diagnosis of Bartter's syndrome and loop diuretic use. The combination of the low urine calcium and low serum magnesium makes the diagnosis of Gitelman's syndrome or thiazide diuretic use more likely. Gitelman's syndrome can often be diagnosed only after repeated urine samples for diuretic use.

It is important to remember that there are no “fixed normal” values for urine electrolytes, the kidney varies the rate of excretion to match dietary intake.

Discussion

Hypokalaemia is a common clinical problem. It is often serious and can be life threatening, with cardiac arrhythmias and paralysis as the most serious complications. Potassium enters the body in the diet, or in the form of an oral or intravenous drug; 98% of the total body potassium is intracellular. It is excreted by the kidneys with only small amounts lost via the intestine and skin.

Hypokalaemia, therefore, can only be caused by decreased intake, movement into cells, or increased loss of potassium. Decreased oral intake is an unusual cause of hypokalaemia, reduced intake is more often seen in hospital with incorrect intravenous replacement of potassium in patients who are taking nil by mouth. Movement of potassium into the cells can be the result of alkalosis, treatment of pernicious anaemia and other conditions with rapid turnover of cells, barium toxicity, and hypokalaemic periodic paralysis. The causes of potassium loss are highlighted in fig 1. Taking a careful history will often reveal the diagnosis. If the diagnosis is still in doubt, measurement of blood pressure, acid-base status, and urinary potassium are invaluable.

The normal renal response to hypokalaemia is to retain potassium. A high urinary potassium in the presence of hypokalaemia suggests the kidneys are the problem. If in doubt as to whether the cause is renal or extrarenal, measurement of the transtubular potassium gradient (TTKG) can help.1 The TTKG is a semiquantitative index of the activity of potassium secretion from the distal convoluted tubule and the cortical collecting duct.

The TTKG is defined as:

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In the presence of hypokalaemia a TTKG <2 suggests extrarenal loss, whereas a TTKG >2 suggest a renal cause.

Gitelman's syndrome and Bartter's syndrome

Gitelman's syndrome and Bartter's syndrome are usually autosomal recessive diseases. Both are caused by defects in renal tubular function.2 3 The tubular defects are similar to those caused by thiazide and loop diuretics respectively. Both syndromes cause hypokalaemia, metabolic alkalosis, hyper-reninaemia, and hyperaldosteronism. The differences are highlighted in table1.4 In Bartter's syndrome, prostaglandins stimulate renin release and contribute to the metabolic abnormalities.

Table 1

Bartter's syndrome and Gitelman's syndrome: distinguishing features between the two conditions

In both syndromes the main defect is at a tubular sodium chloride cotransporter. This results in sodium loss into the tubular fluid which produces a mild depletion of effective circulating volume and activation of the renin-angiotensin-aldosterone system. The hyperaldosteronism causes an increase in potassium and hydrogen secretion into the tubular fluid, resulting in a hypokalaemic metabolic alkalosis.

Treatment of these conditions is for life. Potassium sparing diuretics and potassium supplements are the mainstay. Non-steroidal anti-inflammatory drugs inhibit prostaglandin release and reverse most of the biochemical changes seen in Bartter's syndrome but have no effect in Gitelman's syndrome. Angiotensin converting enzyme inhibitors can also correct the hypokalaemia but tend to cause symptomatic hypotension. Magnesium supplements are sometimes required in Gitelman's syndrome, but diarrhoea is often intolerable and the coincident potassium loss counterproductive.

We prescribed amiloride 40 mg/day and potassium 108 mmol/day for our patient.

Compliance with this treatment keeps our patient symptom-free and her serum potassium concentration within the reference range. Her most recent serum potassium concentration was 4 mmol/l.

In summary, the cause of hypokalaemia can be diagnosed easily by taking a careful history, blood pressure measurements, and simple blood and urine tests. A diagnosis of Gitelman's syndrome or Bartter's syndrome has to be distinguished from thiazide and loop diuretic ingestion respectively. This may require repeated screening of the urine.

Final diagnosis

Gitelman's syndrome.

References

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