Q J Med 2003; 96: 161-169
© 2003 Association of Physicians
Masterclasses in medicine |
Hypokalaemia and paralysis
From the 1 Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense National Center, Taipei, Taiwan, 2 Nephrology Unit and Department of Internal Medicine, University of Stellenbosch, Cape Town, South Africa, and 3 Division of Nephrology, St Michael's Hospital, University of Toronto, Toronto, Canada
Summary
A patient with a severe degree of hypokalaemia (1.8 mmol/l) and paralysis was brought to the emergency department. Hypokalaemic periodic paralysis was an unlikely diagnosis, because an acid-base disorder (metabolic alkalosis) and a high rate of potassium (K+) excretion were present. During an imaginary consultation with Professor McCance, the combination of emphasis on principles of integrative physiology, a deductive analysis, common sense, and clinical skills led to an obvious diagnosis. Nevertheless, a surprise was in store, because renal K+ wasting persisted for almost 2 weeks after removal of the causative agent. Possible explanations for the continued kaliuresis, as well as therapeutic strategies to avoid potential complications, were considered. This case illustrates the value of applying principles of physiology in a quantitative fashion at the bedside.
Introduction
This is our fifth article on the application of principles of integrative physiology at the bedside. Once again, the central theme is an imaginary consultation with the renal physiologist, Professor McCance, who deals with data from a real case. His emphasis is on concepts that depend on an understanding of physiology that crosses the usual subspecialty boundaries. To avoid overwhelming the reader with details, key facts are provided only when necessary. The overall objective of this teaching exercise is to demonstrate how an application of principles of integrative physiology (Table 1
) at the bedside can play an important role in clinical decision-making.
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The consultation
The medical resident on call was paged by the emergency department while on rounds with Professor McCance. A puzzling case is described succinctly—a more complete description will be provided later. The patient had two alarming findings, upper and lower limb paralysis of recent onset without other obvious neurological findings, and a very severe degree of hypokalaemia (1.8 mmol/l). Professor McCance asked the group, ‘Which area should we pursue first, therapeutic or diagnostic issues?’ A bright medical student offered her opinion: if an immediate threat to the patient's life could be ruled out, we should concentrate on diagnostic issues. Our Professor smiled and asked, ‘What are the major threats for this patient posed by the extremely low PK and/or the paralysis?’
Question 1. What are the major threats for this patient posed by the extremely low PK and/or the paralysis?
Physiology principle 1: potassium and the intracellular environment
Ion movement across a membrane requires two elements, a driving force and a hole (or ion channel), because these membranes have a lipid core. The driving force can be chemical (higher potassium (K+) concentration on one side of that membrane) or electrical. In the latter, K+ ions are retained in cells by a negative intracellular voltage. In steady state, the concentration of K+ is 30–40 times higher in the intracellular fluid (ICF) than in the extracellular fluid (ECF) compartment (Figure 1). Nevertheless, the number of positive and negative charges is virtually equal in each compartment.
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Return to the bedside: Our Professor stated that the ratio of K+ concentrations in the ICF and ECF compartments would reflect the resting electrical potential across cell membranes if they have open K+ channels. In quantitative terms, because his ECF K+ concentration has halved (now 1.8 mmol/l), but much less than half of the large intracellular K+ content of 4000 mmol was probably lost, he deduced that there is an electrical problem and/or a less-open K+ ion channel. He went on to say that the function of four organs, the brain, heart, skeletal muscle, and intestinal tract, should be considered in a patient who has hypokalaemia.
- Brain: Because the brain is surrounded by a tight membrane called the blood-brain-barrier that is impermeable to K+, this organ is protected against swings in the PK. Thus there are no CNS symptoms or signs due directly to hypokalaemia.
- Heart: A cardiac arrhythmia is an emergency which must be anticipated; the electrocardiogram (ECG) may reveal this potentially life-threatening complication.
- Skeletal muscle: An important function of skeletal muscle is breathing, so hypoventilation can become a medical emergency. This would be confirmed by finding a high arterial pCO2, because it is hard to detect a mild degree of hypoventilation at the bedside.
- Intestinal tract: The motility of the intestinal tract may decline so much with hypokalaemia that ileus can develop. If this were to occur, oral K+ therapy would be unreliable. Moreover, once motility returns, a large occult load of Na+, K+, Cl-, HCO3- and water may enter the body.
At this point, one member of the medical team phoned the emergency department, and established that there was no emergency demanding urgent therapy because only ‘U’ waves were seen on the ECG, and his arterial pCO2 was in the normal range (39 mmHg). Professor McCance made an interesting comment. He said, although the arterial pCO2 was normal, our patient probably had a lower alveolar ventilation rate, because his CO2 production rate in skeletal muscle was low, due to the paralysis.
Having ruled out an emergency, our Professor proceeded with diagnostic issues because these would guide therapy. If this were primarily a shift of K+ into cells, the goal of therapy would be to reverse this shift. In contrast, if the reason for the low PK were primarily a large overall deficit of K+, the major goal of therapy would be K+ replacement using a large amount of potassium chloride (Cl-) (KCl). Therefore our Professor asked, ‘What data would suggest that there is an acute shift of K+ into cells?’
Question 2: What data would suggest that there is an acute shift of K+ into cells?
Physiology principle 2: creation of a more negative voltage in cells
Professor McCance enunciated the principles involved, but he was not aware of the molecular mechanisms to carry out the process. He deduced that pumping cations out of cells would make their interior have a negative voltage. Further, from whole tissue measurement of the cations K+ and sodium (Na+), he guessed that there was a Na+ pump. He also concluded that the source of the Na+ pumped out of cells was endogenous ICF Na+ or Na+ that entered cells in an electroneutral fashion (Na+ enters while H+ exits1) to have the net export of positive charge (Figure 1
). Later it would be shown that the electrogenic pump is the Na+-K+-ATPase that pumps out 3 Na+ for every 2 K+ that enter cells.2,3 The main activator of this Na+-K+-ATPase is a ß2-adrenergic agent.4 On the other hand, insulin, by activating the Na+/H+ exchanger (NHE) in cell membranes,5 causes a rise in the concentration of Na+ in the ICF compartment without changing the voltage (the ICF compartment becomes more alkaline). This higher ICF Na+ concentration causes more Na+ to be pumped out of cell by the Na+-K+-ATPase. This latter effect helps prevent hyperkalaemia when food is absorbed.
Return to the bedside: Professor McCance had some more clinical information to gather before answering the question concerning an acute shift of K+ into cells. He wanted to know if the patient was Asian, male, aged 20–40 years, and if he either had a family history of episodic paralytic attacks or whether hyperthyroidism was present.6 Our resident replied that the patient was Asian and male, but he was 76 years old. He did not have a positive family history of paralysis or evidence for hyperthyroidism. Moreover, there was no basis for a surge in adrenergic activity or a prior carbohydrate-rich meal. One other fact was available—one year ago, his PK was 3.3 mmol/l, but this was not explored further.
Our Professor had one more clinical ‘trick’ up his sleeve. He remembered that patients who have the inherited disorder, hypokalaemic periodic paralysis (HPP), have marked hypokalaemia due to a K+ shift into cells during an acute attack. They have a low rate of excretion of K+ and no acid-base disturbance.6 Therefore he asked about the plasma acid-base status and the K+ excretion rate (Table 2). While Professor McCance had placed such an emphasis on physiology, the housestaff were surprised that he now relied simply on clinical observations. Although they were impressed with his clinical skills and memory, one member asked, ‘Why is an acid-base disturbance not a feature of an acute shift of K+ into cells (7,8)?’
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Question 3: Why is an acid-base disturbance not a feature of an acute shift of K+ into cells?
Physiology principle 3: the need for electrical neutrality in every body compartment
Electroneutrality must prevail because only a small fraction of a milliequivalent (mEq) difference in charge is needed to have a voltage difference across cell membranes.
Return to the bedside: (i) Metabolic acidosis. Professor McCance made two simple calculations. First, if the PK fell by 2 mmol/l in the ECF compartment due to an acute shift of K+ into cells, a total of 30 mmol of K+ would enter cells if the ECF volume in our patient were 15 l. As a worst case scenario, if electroneutrality were achieved by shifting one H+ out for every K+ that entered cells, 30 mmol of H+ would enter the ECF compartment. If every H+ were buffered by bicarbonate (HCO3-), the ECF bicarbonate content would decline from 375 mmol (25 mmolx15 l) to 345 mmol, resulting in a plasma HCO3– concentration (PHCO3) of 23 mmol/l. Moreover, because there was no evidence of compromised heart function or a seizure, L-lactic acidosis is unlikely in our patient. Therefore an appreciable degree of acidosis should not be anticipated in this setting, ruling out many conditions that have both hypokalaemia and paralysis (Table 3).
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(ii) Metabolic alkalosis. If this acid-base disorder were acute, it must be due to loss of HCl and/or a large input of HCO3-. Normal subjects secrete 1 l of HCl at pH 1 (100 mmol) into the stomach per day. Even if all of this daily HCl secretion were retained in his stomach (the patient did not vomit) and half of these 100 mmol of HCO3- were retained in his ECF compartment, his ECF HCO3- content would rise from 375 to 425 mmol. Thus his new PHCO3 would be 28 mmol/l (425 mmol/15 litres). Hence an appreciable degree of metabolic alkalosis should not occur in an acute setting in the absence of a sudden, large intravenous infusion of NaHCO3. Because their patient had a PHCO3 of 38 mmol/l, our Professor stated that there was a different basis for his metabolic alkalosis.
The housestaff were very receptive to the persuasive arguments of their Professor. They also saw the value of thinking at the bedside in quantitative terms. However, the basis for the metabolic alkalosis was still not clear to them so they asked, ‘Why might this patient have metabolic alkalosis?’
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Question 4: Why might this patient have metabolic alkalosis?
Physiology principle 4: basis of metabolic alkalosis
A concentration is a ratio that can be elevated by adding more of the numerator (HCO3-) or removing some of its denominator (ECF volume).9,10
Return to the bedside: If the ECF volume were contracted by 10%, the PHCO3 would rise by 2.5 mmol/l. Therefore with a large and chronic rise in the PHCO3, a significant quantity of HCO3– must be added to, and retained in, the ECF compartment.11 Common causes include a loss of HCl (vomiting), NH4Cl (diuretics), KCl (e.g. following the selective loss of HCl9), or NaCl. In all but the setting of diuretics, the total body Cl- deficit is accompanied by a very low urine Cl- concentration (UCl). Because the patient's UCl was elevated in every urine sample, Professor McCance deduced that he took diuretics or had metabolic alkalosis plus an expanded ECF volume (Table 4). Later, with the discovery of the physiological role of the calcium receptor in the loop of Henle,12 another explanation became possible. When this receptor is occupied, the loop of Henle behaves as if it is under the influence of a loop diuretic.
While his explanations about metabolic alkalosis were logical, the housestaff wished to confirm that this patient had a high activity of aldosterone. ‘What did Professor McCance ask the team of physicians to assess to provide supporting evidence that an ‘aldosterone-excess' syndrome was present?’
Question 5: What did Professor McCance ask the team of physicians to assess to provide supporting evidence that an ‘aldosterone-excess' syndrome was present
Physiology principle 5: secretion of aldosterone
Aldosterone causes augmented reabsorption of Na+ and Cl- and an increased kaliuresis;13 it acts by opening Na+ ion channels (ENaC) in the luminal membrane of the cortical collecting duct14 (Figure 2).
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Return to the bedside: Because the PK was low, Professor McCance looked for evidence of the other physiological stimulator of aldosterone release from the adrenal gland: a contracted ECF volume. He asked about clinical clues, fully aware of their limitations15,16—there was no clinical evidence of a low ECF volume. Data that became available later (a very low plasma renin activity) suggested that his ECF volume was expanded (Table 2
). Moreover, the patient had high blood pressure of recent onset suggesting a condition with excessive renal reabsorption of Na+ and Cl-. Therefore our Professor suspected a condition with high aldosterone actions. Before obtaining these data, the housestaff wanted to know how to asses the rate of excretion of K+ in the emergency department. Accordingly, he was asked, ‘Can the K+ excretion rate be determined without having a timed urine collection?’
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Question 6: Can the K+ excretion rate be determined without having a timed urine collection?
Physiology principle 6: assessing the rate of excretion of K+
The simplest way to determine the rate of excretion of K+ is to measure the urine flow rate and the urine K+ concentration (equation 1). Another way to measure it is to compare the rate of excretion of K+ to the rate of excretion of a constituent of the urine that is excreted at a constant rate, such as creatinine17 (equation 2).
 | (1) |
 | (2) |
Return to the bedside: Although the rate of excretion of creatinine is proportional to muscle mass, it may also be influenced by eating ‘cooked’ muscle. Subjects on a typical Western diet excrete close to 1 mmol of K+ per kg body weight per day,18 while their rate of excretion of creatinine is approximately 0.2 mmol/kg body weight/day. Therefore the (K+/creatinine)urine ratio is typically close to 5 in mmol terms. Because his urine K+ concentration was 26 mmol/l, he had a (K/creatinine)urine ratio of close to 4—this ratio is close to 1 in simple K+ depletion.19 Hence our Professor knew the rate of K+ excretion was inappropriately high given the severe degree of hypokalaemia. This analysis begged another question, ‘What is the reason for the high rate of excretion of K+?’
Question 7: What is the reason for the high rate of excretion of K+?
Physiology principle 7: control of excretion in the kidney is exerted at the last nephron site that reabsorbs/secretes a given ion
The nephron site where control of K+ excretion occurs is the last nephron segment that secretes K+, the cortical collecting duct (CCD).20 There are two ways to increase K+ excretion (equation 1). First, one must raise the concentration of K+ in each litre of fluid exiting the CCD. This process is electrically driven, and therefore is dependent on electrogenic Na+ ion absorption via ENaC (Figure 2). Moreover, this control of K+ secretion must occur at a site with enough delivery of Na+ to ensure the excretion of all the K+ that was ingested. Since control mechanisms were developed in prehistoric times when K+ intake (fruits, berries) was probably very high (
200–500 mmol/day), this site needs a delivery of at least 500 mmol of Na+ daily. Hence it should be prior to the medullary collecting duct (i.e. the CCD). Second, there must be a large volume of fluid delivered to this site. The next question for our Professor was, ‘Is the K+ concentration high in the lumen of his CCD?’
Question 8: Is the K+ concentration high in the lumen of his CCD?
Physiology principle 8: the concentration of K+ in the lumen of the CCD
When Na+ is reabsorbed faster than Cl-, the lumen of the CCD becomes more negatively charged (Figure 2). This is amplified when ENaC is in a more open configuration.21 The concentration of K+ in the lumen of the terminal CCD ([K+]CCD) can be deduced as follows. Because the CCD is the last nephron segment where the majority of K+ secretion is regulated, the only reason for a major change in the urine K+ concentration between the terminal CCD and the urine will be the result of water reabsorption in the medullary collecting duct. The degree of this water reabsorption is reflected by the urine:CCD luminal fluid osmolality ratio, where the osmolality in the lumen of the CCD is assumed to be equal to the plasma osmolality (Posm) when vasopressin is present (Figure 2).22
Return to the bedside: Because his Uosm was approximately 1.6-fold higher than his Posm, a reasonable estimate of his [K+]CCD was close to 16 mmol/l. Moreover, in a K+ deficient subject, this [K+]CCD should be close to his PK, yet this value was 9 in our patient. This will happen when ENaC is too open, and strongly suggests a state with actions simulating a high aldosterone activity.21
The housestaff were impressed by the logic of our Professor's approach. They thanked him for his help, and said that they could handle matters from here on in. They fully expected to find a high level of aldosterone in plasma due either to adrenal hyperplasia or an aldosterone-producing tumour (Table 4). There was dismay, however, when they later discovered that there was no detectable aldosterone in his plasma. To add to their surprise, his cortisol levels were in the middle of the normal range. An inherited molecular lesion as the basis for his renal K+ wasting was unlikely, taking into consideration his age and the negative family history. Again they called on Professor McCance, ‘What is needed to cause aldosterone actions in the absence of aldosterone?’ they asked, reminding him that the patient denied the intake of any drugs.
Question 9: What is needed to cause aldosterone actions in the absence of aldosterone?
Physiology principle 9: aldosterone actions in the CCD
Aldosterone must enter principal cells of the CCD, bind to its receptor, and cause the elements favouring K+ secretion to be activated.23 This receptor for aldosterone would bind cortisol just as avidly as aldosterone if it were to enter principal cells. There is an enzyme called 11 ß-hydroxysteroid dehydrogenase (11-ßHSDH) on the basolateral membrane of principal cells that inactivates cortisol, preventing it from entering these cells in an active form24 (Figure 3).
Return to the bedside: Professor McCance needed help from modern day molecular scientists to provide the details. Nevertheless, always the solid physician, he knew that people addicted to genuine licorice developed hypertension, hypokalaemia and an excessive excretion of K+.25 Meeting his team at the bedside, he asked the patient, ‘Do you take licorice?’ To the embarrassment of all, the patient readily admitted that he used licorice to flavour his tea, which he drank in large volumes.
The advice of our Professor was to persist with KCl replacement therapy because the active compound in licorice, glycyrrhizic acid, would be removed with time, but he added a word of caution. When humans have had K+ depletion for a prolonged period, renal mechanisms for K+ excretion remain down-regulated for 24–48 h, and if large doses of KCl continue to be given, rebound hyperkalaemia may ensue.19
The housestaff thanked Professor McCance for clearing up their problems. They were again confident that they could take care of their patient using their new knowledge. The diagnosis was an ‘apparent mineralocorticoid excess' (AME) syndrome due to a component of licorice (glycyrrhizic acid) that inhibits 11-ßHSDH. The expectation was that with a combination of stopping licorice use and a large supplement of KCl, the patient would regain his strength promptly, have a normal PK, and if the vascular changes were reversible, his blood pressure would fall to the normal range. However, one week later, with a fully compliant patient, his muscle strength had returned, but his PK was only 2.8 mmol/l. Moreover, his urine K+ excretion rate and his [K+]CCD were still surprisingly high. There was a urgent call to our Professor asking, ‘What could be the explanation for this high K+ excretion rate one week after discontinuing licorice?’
Question 10: What could be the explanation for this high K+ excretion rate one week after discontinuing licorice?
Given his age, lack of family history, and the presence of an obvious cause for the hypokalaemia and hypertension, Professor McCance preferred to think of reasons why the active component in licorice, glycyrrhizic acid, might still be acting, or if 11-ßHSDH had an unusually slow rate of synthesis. First, he asked one of the housestaff to review the literature to establish the biological half-life of glycyrrhizic acid. Second, he wondered whether there might be a slowly releasing pool of glycyrrhizic acid such as occurs with lipid solubility. Third, he wondered why its excretion pattern might be very slow.
Data that followed revealed first, a very long half-life of glycyrrhizic acid, due to both a large volume of distribution and failure to excrete glycyrrhizic acid.26 Professor McCance then offered some speculations concerning glycyrrhizic acid. First, glycyrrhizic acid must be transported in plasma and be delivered to the basolateral membrane of principal cells, where it will be transferred to 11-ßHSDH, leading to its inhibition. Second, this compound must not be excreted rapidly in the urine to have such a long half-life. Hence its concentration in water must either be very low to avoid renal filtration, or it must be avidly reabsorbed by the kidney. Therefore he deduced that glycyrrhizic acid would be protein-bound in plasma, and that it would not be a substrate for the anion secretory system of the kidney.
For this long half-life, its molecular structure must be sufficiently complex that it is not metabolized by body enzyme systems. Moreover, because glycyrrhizic acid undergoes enterohepatic circulation,26 the liver should extract this protein-bound ligand for secretion into the bile. This process also implies that there is avid absorption of glycyrrhizic acid in the intestinal tract, possibly involving a receptor. At this point, one could consider an analogy with unconjugated bilirubin or bile salts, with respect to their renal, liver, and intestinal properties. Nevertheless, there is one exception. Glycyrrhizic acid does not undergo further metabolism like glucuronidation, so it remains in its biologically active, toxic form for a long time. Hence this simple toxicity raises both theoretical and experimental avenues for pursuit by the interested reader.
One week later, the housestaff called to thank Professor McCance, stating that their patient had regained all his strength, had a PK of 4.1 mmol/l, and a blood pressure of 130/80 mmHg.
Concluding remarks
The combination of a knowledge of integrative physiology, an awareness of the modern molecular information, and an ability to review the medical literature provided our modern-day physicians with a powerful set of tools to understand the basis of the disease process in our patient and provided goals for its therapy. Nevertheless, this was not enough. As illustrated by our Professor, clinical experience, deductive reasoning, common sense, and a quantitative analysis were very valuable assets at the bedside. Not only did the arsenal of tools lead to an accurate diagnosis, it pointed out some of the potential hazards of well-meaning therapy.
Appendix 1: Case report
A 76-year-old Chinese male presented to the emergency department with muscular weakness that progressed to paralysis involving all extremities; he was unable to walk for the past 6 hours. He denied nausea, vomiting, diarrhoea or the use of drugs, including diuretics. However, he had used close to 100 g of licorice per day to flavour his tea for the past three years. One year ago, he was found to have mild hypokalaemia (3.3 mmol/l) and hypertension, but this was not investigated further. His family and past medical histories were unremarkable.
On physical examination, his blood pressure was 160/96 mmHg, heart rate 70 bpm, respiratory rate 16/min, and body temperature 36.7 °C. Body weight was 78 kg. His thyroid gland was not enlarged. Cardiopulmonary examination was unremarkable. There was a symmetric flaccid paralysis with areflexia in the lower and upper extremities. Fasciculations, myoclonus, and muscular atrophy were not observed. The remainder of the physical examination was normal. The major biochemical abnormalities are shown in Table 2.
His initial therapy included 20 mmol of potassium chloride (KCl) per hour given by the intravenous route. His muscle weakness improved when his PK reached 2.5 mmol/l. His PK was 2.8 mmol/l one week after stopping the use of licorice coupled with daily KCl supplements (average 64 mmol) and spironolactone (100 mg/day). At this time, his urinary excretion of K+ was 45 mmol/day, TTKG was 6, and his K+/creatinine ratio in urine was 4 mmol/mmol. Two weeks later, his PK and blood pressure had returned to normal levels, while his body weight decreased from 78 to 74.0 kg, presumably reflecting in part the excretion of retained saline.
Notes
Address correspondence to Professor M.L. Halperin, St. Michael's Hospital Annex, Lab #1, Research Wing, 38 Shuter Street, Toronto, Ontario, M5B 1A6, Canada. e-mail: mitchell.halperin{at}utoronto.ca 
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