QJM Advance Access originally published online on February 9, 2006
QJM 2006 99(3):181-192; doi:10.1093/qjmed/hcl011
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Masterclasses in medicine |
Unusual causes of hypokalaemia and paralysis
From the 1Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Canada, 2Renal Division, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (ROC), and 3Nephrology Unit and Department of Internal Medicine, Stellenbosch University, Cape Town, South Africa
Address correspondence to Professor M.L. Halperin, University of Toronto, St Michael's Hospital Annex, Lab #1, Research Wing, 38 Shuter Street, Toronto, Ontario, M5B 1A6, Canada. email: mitchell.halperin{at}utoronto.ca
 |
Summary |
|---|
Top
Summary
IntroductionWe demonstrate how the application of physiological principles may help to identify unusual causes of a very low plasma potassium (K+) concentration (PK) and paralysis. In the two patients described, the short time course of the illness suggested that there was an acute shift of K+ into cells. The combination of a low rate of excretion of K+, the absence of a metabolic acid-base disorder, and the fact that the clinical findings occurred very soon after a large intake of carbohydrate supported this impression. Surprisingly, the PK remained low for many hours after these stimuli to shift K+ into cells had abated. The missing link in this story was eventually provided by the attending medical team with the help of their mentor, Professor McCance.
|
Introduction |
|---|
In this teaching exercise, the central (imaginary) figure is Professor McCance, based on a real consultant who practiced medicine
70 years ago. The overall objective is to demonstrate how applying principles of integrative physiology at the bedside and relying on a quantitative analysis can be extremely helpful in revealing the pathophysiology of disease, making more accurate clinical diagnoses, and in planning optimal therapy. When these principles of physiology are combined with recent discoveries at the molecular and genetic levels, the features responsible for many disorders can be better understood. |
The consultation |
|---|
After their recent teaching session with Professor McCance, the medical team was confident that they would be able to work up the next patient with hypokalaemia and paralysis.1 They were therefore extremely disappointed to find themselves faced with two patients where they could not determine the cause of a very low plasma potassium (K+) concentration (PK) and paralysis. As was their custom in this situation, they asked their favourite consultant, Professor McCance, to join them on rounds and assist them in analysing the information.
The two patients in question, 45- and 35-year-old Asian males, had similar clinical presentations: acute hypokalaemia and paralysis that lasted 14 and 12 h, respectively (Table 1; more detailed descriptions in Appendix 1). Both recovered fully within two days and were asymptomatic since that time. There was no family history or an obvious cause for their illness. Both patients had several identical episodes in the past year. In each instance, there was a large intake of carbohydrate within hours of admission to hospital. The source of the carbohydrate was mixed in the first patient, but was a large volume of Coca-Cola (>5 l/day) in the second. Both had normal plasma electrolyte concentrations after the first 24 h.
|
Professor McCance began the analysis by asking about potential emergencies; ‘What are the major dangers faced by a patient with an extremely low PK?’
Question 1. What are the major dangers faced by a patient with an extremely low PK?
Physiology principle 1. When the PK is very low, there can be a voltage problem across cell membranes (hyper-polarization), because the resting membrane potential reflects (but is not equal to) the ratio of K+ concentrations inside and outside cells (Figure 1).
|
Return to the bedside: The major danger might be life-threatening cardiac arrhythmias; this threat is best evaluated by examining the EKG. A second danger is weakness of the respiratory muscles, especially if there were a need for increased ventilation (e.g. metabolic acidosis).
The intern replied that there were no emergencies demanding urgent therapy in either patient, so the team shifted the focus to diagnostic issues. Their first step was to establish whether there might be an acute shift of K+ into cells by assessing the time course of the illness.
Question 2. Did hypokalaemia develop over a short time interval?
Physiology principle 2. When hypokalaemia develops over a short time, its basis will likely be an acute shift of K+ into cells.
Return to the bedside: Both patients were asymptomatic until weakness began that day; paralysis developed over several hours. ‘The clinical story is compatible with an acute component to the hypokalaemia‘, agreed their professor. Nevertheless, he wanted additional evidence to support the clinical suspicion, and hence he asked, ‘What is the appropriate renal response to an acute shift of K+ into cells?’
Question 3. What is the appropriate renal response to an acute shift of K+ into cells?
Physiology principle 3. When faced with a low PK, the kidneys should excrete as little K+ as possible, unless the kidneys are the cause of the hypokalaemia.
Return to the bedside: In Paleolithic times, when our control mechanisms developed, the diet was rich in K+ and sugars, because fruits and berries were its major constituents. Therefore it is not surprising that the kidney has a large capacity to excrete K+. Nevertheless, unlike sodium (Na+), our kidneys have a relatively poorly developed capacity to conserve K+. In fact, when normal subjects were placed on a diet that had very little K+, they continued to excrete 10–15 mmol K+ per day.2 One member of the medical team asked, ‘Must we obtain a 24-h urine collection to assess the rate of excretion of K+?’
Question 4. Must we obtain a 24-h urine collection to assess the rate of K+ excretion?
Physiology principle 4. There are no normal values for the rate of excretion of water or electrolytes. Rather, there are expected excretion rates for a given stimulus—hypokalaemia in this case. Data are most valuable when the stimuli for excretion are known; hence a random urine sample at a time when the PK is very low is the most appropriate specimen to examine. An excretion rate can be deduced by comparing the excretion of K+ to another urine constituent that is excreted at a constant rate—such as creatinine.3
Return to the bedside: Because the rate of excretion of creatinine is 10–15 mmol/day in an adult, the urine K+ concentration (UK) should be equal to the urine creatinine concentration (Ucreatinine) in mmol/l terms, if the cause of the hypokalaemia is non-renal or if there was a large prior renal K+ loss (e.g. diuretic use/abuse in the past). Because the UK/Ucreatinine was 1.0 in each patient (Table 1) and there was no history of vomiting, diarrhoea or laxative abuse, there appeared to be an acute shift of K+ into cells and an appropriate renal response.
Before leaving the subject of non-renal K+ loss, Professor McCance had one other site to evaluate. Because these patients lived in a hot climate, he asked, ‘What might cause a large loss of K+ in the sweat?’
Question 5. What might cause a large loss of K+ in the sweat?
Physiology principle 5. To cause K+ to move across a membrane, there could, in theory, be active secretion of K+ or passive transport of K+. For the latter, there must be an electrical driving force (lumen-negative) and an open channel through which K+ can diffuse (Figure 2). This led to an additional question from their mentor. ‘In what disease might you find a more negative lumen voltage in the duct of the sweat gland?’
|
Question 6. In what disease might you find a more negative lumen voltage in the duct of the sweat gland?
Physiology principle 6. To generate a negative voltage, Na+ should be reabsorbed faster than Cl– ions.
Return to the bedside: The signal to open epithelial Na+ channels is aldosterone.4 In a patient with a low PK, this hormone is released in response to a contracted ECF volume.5 To generate a lumen-negative voltage, one needs a slower reabsorption of Cl–. The latter occurs when the usual Cl– ion channel (CFTR) is defective6—i.e. in a patient who has cystic fibrosis. Follow-up studies were negative for cystic fibrosis in these patients.
One other point merits emphasis, said Professor McCance. ‘How much K+ had to shift into our patient's cells to cause the PK to fall by 2 mmol/l? ’
Question 7. How much K+ had to shift into the patient's cells to cause the PK to fall by 2 mmol/l in these patients?
Physiology principle 7. ‘It is very important to think in quantitative terms‘, said Professor McCance. If a patient weighs 50 kg, the ICF volume is 20 l and the ECF is 10 l. Cells have an enormous amount (3000 mmol) of K+ because the [K+] in the ICF is 150 mmol/l. In contrast, only 20 mmol of K+ (10 l x 2 mmol/l) needs to shift into cells to cause a decline in the PK of 2 mmol/l. Because this small quantity of K+ will be matched by an even smaller H+ shift, there should not be an appreciable change in the concentration of bicarbonate (
) in plasma (PHCO3) in this setting.
Return to the bedside: Because the PHCO3 was in the normal range, this supported the view that there had been an acute shift of K+ into cells, rather than an acid-base disorder associated with hypokalaemia. Professor McCance wished to obtain additional evidence for this diagnostic impression. Although there was no family history of hypokalaemia, paralysis, or hyperthyroidism, there were other supporting features: the ethnic background, the fact that there were similar episodes in the past, and the association of the attacks with high dietary carbohydrate intake. Nevertheless, there was more detective work to be done!
Our Professor then asked about physical findings. Despite the negative features in the past history, he would not be surprised to find signs to suggest that these patients suffered from hyperthyroidism or a condition with an excess of ß-adrenergic activity. These signs included tachycardia, systolic hypertension, and a wide pulse pressure.7
Moving to laboratory tests, he enquired about hypophosphataemia and a low rate of excretion of phosphate, because these findings were common in thyrotoxic periodic paralysis.8 The low rate of phosphate excretion in both subjects became evident when the ratio of phosphate to creatinine in the urine was calculated. In normal subjects, the molar UPO4/Ucreatinine is 2.0, whereas it was 0.16 in patient 1 and 0.05 in patient 2 (Table 1). The low concentration of phosphate in plasma and a low rate of phosphate excretion were consistent with an acute shift of phosphate into cells.
|
Review of the physiology of a shift of K+ into cells |
|---|
Professor McCance briefly reviewed the physiology of a shift of K+ into cells to facilitate the interpretation of the data and to design therapy in these patients. He began by asking, ‘What is the driving force that can move K+ from the ECF compartment into cells?’
Question 8. What is the driving force that can move K+ from the ECF compartment into cells?
Physiology principle 5, restated. There are two factors that can influence the movement of K+ across cell membranes: the driving force is the negative voltage in the ICF compartment, and the presence of open K+ channels (Figure 1).9
Return to the bedside: The nephrology consultant summarized the relevant information. The greater negative voltage in cells could be caused by activation of the Na-K-ATPase or by increasing the concentration of one of its important substrates, the intracellular concentration of Na+. For the latter, Na+ must enter cells in an electroneutral fashion on the Na+/H+ exchanger (NHE) in cell membranes (Figure 3).10 The Na-K-ATPase creates the more negative voltage in cells, because it catalyses the net export of three sodium ions (Na+) for every two K+ ions that enter cells11,12 (Figure 1); the passive diffusion of K+ out of cells magnifies this negative intracellular voltage. The main hormones that increase the activity of the Na-K-ATPase are ß2-adrenergic agonists and thyroid hormone.13 Therefore we should look carefully for conditions where these adrenergic hormones may be acutely elevated.
|
will be exported and Cl– will enter cells when the AE is activated. The intracellular negative voltage will drive the exit of Cl– from cells via their specific ion channel. This latter step will lead to the export of negative voltage and the subsequent exit of K+ from cells.To have electroneutral entry of Na+ into cells, one must activate the Na+/H+ exchanger (NHE) in cell membranes, an ion exchanger that is normally inactive unless insulin levels rise appreciably (Figure 3).10 ‘This helped to prevent hyperkalaemia when K+ was ingested in Paleolithic times. Because the major source of dietary K+ was in foods that contained sugar, one could deduce that insulin might activate NHE’, said Professor McCance. Since H+ ions are exported from cells by NHE, the other activator of this cation exchanger is a rise in the ICF [H+].
Professor McCance felt he could eliminate some of these mechanisms as a cause for their patients’ hypokalaemia. First, since there was no cause for a high [H+] in the ICF compartment, intracellular acidosis should not have activated NHE in these patients. Second, although insulin could have been important initially when hypokalaemia developed, it was unlikely to play an important role in later stages of hypokalaemia, because the glucose concentration in plasma (PGlucose) was in the normal range throughout the hospital course.
If a larger negative voltage in cells were to play a role in the acute hypokalaemia, he would expect a condition with high levels of ß2-adrenergics, provided that this hormone could act for a long time. Therefore he asked the team to provide a list of conditions with very high adrenergic hormone levels and drugs that could cause a big adrenergic surge. The team had anticipated this question and handed a list they had prepared to their Professor (Table 2). With a smile, he noted that they had even indicated the half-lives of the different compounds!
|
Professor McCance was not finished with his requests. He now drew on his personal experience, relating how he had difficulty sleeping when he drank coffee or strong tea in the evening. Therefore he asked the team to check whether caffeine might produce an adrenergic effect to cause an acute shift of K+ into cells. He also wished to know if Coca-Cola was supplemented with caffeine. Nevertheless, he was slightly uncomfortable with his suggestion, because caffeine intake was so common while hypokalaemia and paralysis were so rare. Hence he was eager to consider alternative explanations.
The medical registrar volunteered to perform a literature search with the keywords 'acute hypokalaemia' and 'caffeine' or 'Coca-Cola'. She would also look for a link between caffeine and the Na-K-ATPase, NHE, K+ channel activity, and ß2-adrenergic activity, and bring the results of these searches to rounds the next day. The intern volunteered to examine the pharmacology of caffeine to see how this alkaloid or one of its metabolites might cause a stimulatory effect, and what might make this drug have a longer duration of action.
Professor McCance left the rounds deep in thought as he tried to determine how the effects of ß2-agonists and caffeine might cause such a prolonged shift of K+ into cells. He also wondered how this new knowledge might lead to therapeutic benefits, because he was most gratified when new information was directly beneficial for his patients.
|
After the adjournment |
|---|
Sources of ß-adrenergic agonists
Of the list of drugs with ß2-adrenergic action, the amphetamines had the longest duration of action (Table 2). The patients denied taking cocaine, but because patient 1 was obese, he was asked if he took amphetamine for appetite suppression. When he answered in the affirmative, Professor McCance said he would have treated the hypokalaemia and paralysis with propranalol, even though there was no prior literature to support such a decision. He based this recommendation on knowledge he had recently gained about the effectiveness of ß-blockers for patients with thyrotoxic periodic paralysis.14 In fact, the registrar had given the patient propranalol (3 mg/kg), and observed a dramatic rise in the PK and recovery from paralysis within 2–3 h after the drug was administered. Thus her quick thinking and sound reasoning led to the prevention of possible medical emergencies.
The source of ß-adrenergic stimulation was yet to be identified in the second patient. Results from the pharmacology review revealed that Coca-Cola had a high content of caffeine (Table 3). The caffeine load was particularly high on the day of admission (500 mg in 5 l of this beverage).
|
Results of the literature searches
This exercise provided additional clues to uncover the pathophysiology. There were a number of case reports where patients who drank large volumes of Coca-Cola developed a severe degree of hypokalaemia and paralysis, but the mechanisms responsible for this association were not clearly defined.15–19 While there were no direct links found between caffeine and Na-K-ATPase or NHE, there were studies linking caffeine and the K+ATP channel in cell membranes.20–22 Before revealing this information, the reader should anticipate whether a decrease or increase in K+ conductance would best fit with acute hypokalaemia (Figure 1).
Question 9. Will an increase or decrease in the conductance of the K+ATP channel cause hypokalaemia?
The nephrology consultant answered this question. When the K+ATP channels have a higher conductance, K+ can exit from cells. As a result, there is a higher PK and a more negative voltage in cells. In contrast, when K+ATP channels have a lower conductance, this would lead to trapping of K+ in cells and a lower PK. The literature search revealed that caffeine diminished conductance of K+ATP channels, both directly20,21 and indirectly, because caffeine prevents the adenosine-induced activation of this channel.24 Therefore if the Na-K-ATPase were stimulated while the exit of K+ from cells was impaired, there might be an acute retention of K+ into cells and a severe degree of hypokalaemia.
Question 10. How might caffeine cause the release of catecholamines?
The properties of caffeine are listed in Appendix 3. The linkage between caffeine and ß2-adrenergic release is indirect. The most important pharmacological action of caffeine at usual doses is to inhibit the binding of adenosine to its A2 receptor in the central nervous system, because of the very similar structure of caffeine and adenosine (Figure 4).25 In this setting, the release of catecholamines will be increased (Figure 5). The reader should pause and think how adenosine, acting through its A2 receptor, influences the release of adrenaline.
|
|
Adenosine, acting via its A2 receptor, diminishes the release of catecholamines. Therefore inhibition of this receptor by caffeine should decrease the inhibition of catecholamine release—the net result is a larger ß2-adrenergic effect on the Na-K-ATPase (Figure 5). Therefore the next question to address is, ‘How can caffeine have a prolonged duration of action?’
Question 11. How can caffeine have a prolonged duration of action?
Caffeine is detoxified by one of the cytochrome P-450 enzymes (Figure 4).25 The affinity of this enzyme for caffeine is high, but its maximum velocity is not that large. Hence, low doses of caffeine should be removed effectively, but high doses would be removed slowly, because the number of half-lives is large when the concentration of caffeine is much greater than the substrate concentration that causes half-maximal rate (Km) catalysed by this enzyme. Therefore the very large intake of caffeine in Coca-Cola (Table 4) might explain the prolonged clinical picture in the second patient.
|
Because caffeine rarely presents with such an impressive shift of K+ into cells, this suggests that there is an efficient mechanism to detoxify it in vivo. Two observations suggest that there are other properties of this detoxification process (Table 5). First, subjects often need a progressively larger caffeine intake to achieve its stimulant effect when caffeine intake is chronic. ‘This would be consistent with ‘induction’ of the system to detoxify caffeine in this setting’, said Professor McCance. Second, people who are heavy smokers drink much more coffee.25 If this reflected a need for a higher intake of coffee to obtain its stimulant properties, perhaps a component of cigarette smoke, such as nicotine, could cause a higher activity of the enzymes that detoxify caffeine.
|
Professor McCance thanked the team for their contributions. The team now knew much more about a shift of K+ into cells and the pharmacology of caffeine. Armed with this new information, they wished to suggest how they might tailor the therapy for this patient. As in the first patient, where the registrar had courageously (and wisely) elected to treat that patient with the ß-blocker propranalol, they would use the same rationale to treat the second patient, realizing that there were no data that directly supported the choice of therapy. Nevertheless, because of the possibility of a cardiac arrhythmia with profound hypokalaemia, they felt justified in giving propranalol, because the benefit might be substantial, whereas the risk was small.
|
Integrative physiology |
|---|
The nephrology registrar was puzzled by the fact that NHE seemed to be important for two functions, shift of K+ across cell membranes and defence of the pH in cells. Therefore, she asked, ‘Which of these two functions is the primary one?’ ‘This is a very good question’, replied Professor McCance, ‘I must speculate to answer this question. It also troubles me because there should be one primary function, yet this transporter and the Cl–/
anion exchanger (AE) have two separate functions, one regulating the PK and a second regulating the pH in cells ’.
Interaction of buffering of H+ and K+ physiology
Both the net voltage across cell membranes and the intracellular H+ concentration are critical and independent factors in biology.26 At times, a change in the ICF pH but not the ICF voltage may be needed (or vice versa). Therefore it is necessary to understand how each of these parameters is regulated.
Issues for H+
There are times when there is a need to buffer a large H+ load in cells (e.g. during hypoxia, when a large quantity of L-lactic acid is produced). Because H+ and K+ are both cations, one might think that they would both cross cell membranes in a similar fashion (using the negative ICF voltage and ion channels). However, there is a striking difference—there are ion channels for K+ while there are no ion channels for H+ (or 
) in cell membranes. In fact, the NHE cannot be directly involved in buffering of an ECF H+ load. The concentrations of Na+ in the ECF compartment and H+ and ICF compartment indicate that in vivo the NHE is inactive, because it is an electroneutral transporter and is appreciably displaced from its chemical equilibrium (Na+ concentration is 140 mmol/l in the ECF compartment and 14 mmol/l inside cells). Similarly, the H+ concentration is lower in the ECF compartment (40 nmol/l), whereas it is 80 nmol/l in cells. When the NHE is activated, the only direction for ion movement is the entry of Na+ ions into cells and the exit of H+ from cells (Figure 3).
Adjust the PK
This was the most important initial function to prevent hyperkalaemia when dietary K+ was absorbed in Paleolithic times. The signal to cause K+ ions to enter cells could be related to the major non-K+ constituent of primitive diets, carbohydrate. A rise in PGlucose stimulates the release of insulin. As shown in the left side of Figures 1 and 3, insulin activates NHE, which raises the concentration of Na+ in cells.27 This, in turn, increases Na+ ion exit via the Na-K-ATPase, and thereby K+ entry into cells.
Shift K+ out of cells in acute exercise
AE appears to be inactive at rest, because it is an electroneutral transporter and the concentration of Cl– is so much higher in the ECF compared to the ICF compartment, while the differences in the concentrations of 
in these two compartments are much smaller in magnitude. In contrast, AE appears to be active in intense exercise, because 
is exported into the ECF compartment (reviewed in reference 28). The net effect of flux through AE and subsequent exit of Cl– from cells via its specific ion channel results in the export of K+ and 
from cells.29 Hence it is this exit of Cl– down the electrochemical gradient that causes the ICF voltage to become less negative, so that K+ can exit from cells if K+ channels are open (Figure 3, right side).
Summary
The two ion exchangers, NHE and AE, have diametrically opposite effects on the net movement of H+ across cell membranes and the direction of the voltage change in cells: NHE exports H+, while AE exports 
. Some feel that this is an important feature in regulating cell pH. On the other hand, their function could be to regulate cell voltage and thereby the PK. ‘I leave it to each of you to decide what you think the primary function of these pair of ion exchangers might be’, said Professor McCance. Nevertheless, the team perceived that their Professor was placing more emphasis on the regulation of voltage in cells and/or the PK, compared to pH control.
|
Concluding remarks |
|---|
There are six messages that the medical registrar emphasized in her closing remarks before thanking Professor McCance for his didactic exercise. First, generic approaches, while useful as a guide, could not replace deductive interpretations based on integrative physiology for each individual case. Second, the short time, the low rate of K+ excretion, the absence of a metabolic acid base disorder, the association with a large intake of carbohydrate, and the adrenergic surge all indicated that both patients suffered from an acute shift of K+ into cells. Third, even in the absence of hyperthyroidism, there were clinical signs to suggest that there was high adrenergic activity, as evidenced by systolic hypertension and tachycardia. Hence there was a need to identify the basis for the high adrenergic state. A role for drug intake became important because of the absence of a positive family history and/or hyperthyroidism. Fourth, since the time course of the illness was longer than expected, the drugs involved should have a long duration of action. The use of amphetamine in the first patient and the high intake of caffeine in the second patient were plausible causative agents to explain this clinical picture. Fifth, it was important to diagnose the basis for a shift of K+ into cells due to high ß2-adrenergic activity, because there is a specific and effective therapy for this type of hypokalaemic paralysis (propranolol14). Sixth, there may be an underlying genetic basis for the acute K+ shift in these two patients and also in those patients with thyrotoxic periodic paralysis, because high intake of amphetamine and caffeine are common, and hyperthyroidism is not rare, yet periodic paralysis and a severe degree of hypokalaemia are very uncommon clinical disorders.
|
Appendix 1: Synopsis of the cases |
|---|
Patient 1
A 45-year-old Chinese male developed profound weakness in both the lower and upper extremities. He had had two similar episodes in the preceding two months. Thyroid function was normal. No medications, including laxatives or diuretics, or alcohol were used. There was no family history of hyperthyroidism, hypokalaemia, or periodic paralysis.
On physical examination, he was alert and somewhat obese (weight 80 kg). Blood pressure was 152/80 mmHg, heart rate 108 bpm, respiratory rate 14 breaths/min, and body temperature was 36.7°C. Examination of the head and neck was normal, with no exophthalmos, bruits, or an enlarged thyroid gland. There was a symmetric flaccid paralysis with areflexia in the lower and upper extremities. Fasciculations, myoclonus, and muscular atrophy were not observed. Cranial nerves were intact, as was sensation. The remainder of the physical examination was normal.
Laboratory studies are summarized in Table 1. There was marked hypokalaemia (2.1 mmol/l); other findings included a low urine K+/Cr ratio (0.7 mmol/mmol) and a normal PHCO3 (27 mmol/l). The electrocardiogram (EKG) showed sinus tachycardia of 108 bpm with flattened T waves.
Because the clinical picture and laboratory findings were almost identical to that of TPP despite normal thyroid function, it was considered possible that he might have taken a medication that caused a hyperadrenergic state. Because of his obesity, he was asked about the use of amphetamine use to control body weight. He confirmed this, and also volunteered the fact that he felt very hungry prior to each attack and ate a large quantity of carbohydrate at these times.
Treatment with a non-selective ß-blocker (propranolol) led to a dramatic improvement in muscle power within 2–3 h; before this, he had received KCl supplementation for several hours without biochemical or clinical improvement.
He was persuaded to discontinue amphetamine use and avoid high carbohydrate intake to prevent recurrent attacks. There have been no further episodes since.
Patient 2
A 35-year-old Chinese male presented to the emergency department with muscular weakness that progressed to paralysis involving all extremities within 6 h. He denied nausea, vomiting, diarrhoea, or the use of diuretics. There was no history of hyperthyroidism; he had two similar episodes of hypokalaemia and paralysis that occurred in the past 2 years. There was no family history of paralysis, hypokalaemia, or hyperthyroidism.
On physical examination, blood pressure was 139/74 mmHg, heart rate was 62 bpm, respiratory rate was 18 breaths/min, and body temperature 36.6°C. He was alert and orientated. Cardiopulmonary examination was unremarkable. On neurological examination, there was symmetrical flaccid paralysis with areflexia in all limbs. Fasciculation, myoclonus and muscular atrophy were not observed. The remainder of the physical examination was not remarkable. His EKG showed prominent U waves with a prolonged QT interval.
The biochemical studies are shown in Table 1. The UK/UCreatinine was 1.2 mmol/mmol, and the transtubular K+ concentration ratio (TTKG) was 2.8. There was no metabolic acid-base disorder (PHCO3 26 mmol/l, pH 7.42). Thyroid function tests were normal. Familial hypokalaemic paralysis was considered to be unlikely, because of the absence of a positive family history. A drug and food history revealed the regular intake of large amounts of Coca-Cola for a number of years. In the 2 days prior to the last admission, however, he had increased his daily intake of Coca-Cola to 5 l/day.
His therapy consisted of an infusion of KCl at a rate of 10 mmol/h for 6 h. His usual muscle strength returned when his PK rose to 2.4 mmol/l. At this point, the infusion of KCl was discontinued. His PK rose to the normal range on the fourth day. After recovering from the paralysis, he diminished his intake of Coca-Cola, and his PK remained in the normal range without K+ supplementation. At a 1-month follow-up visit, he had continued to avoid caffeine-containing beverages and was healthy, without hypokalaemia or muscle weakness.
|
Appendix 2: Caffeine and acetyl-CoA carboxylase |
|---|
In a previous case discussion by Professor McCance, an unusual type of ketoacidosis developed in a young male who also drank many litres of a caffeine-containing soft drink.30 In this case, an adrenergic surge also played a central role—it led to inhibition of acetyl-CoA carboxylase in hepatocytes. The other ingredient of the soft drink was fructose. Because this sugar is poorly absorbed in the intestinal tract, it was metabolized by bacteria in the colon, and this led to a high rate of production of acetic and butyric acids. These short-chain fatty acids were delivered to the liver, where they were metabolized to acetyl-CoA. It is of interest that in this patient the predominant effects of caffeine were metabolic without the development of hypokalaemia. There may be a different underlying genetic, nutritional or drug susceptibility in these two patients. It is also interesting to note that the patient who developed ketosis was taking an SSRI type of antidepressant—this class of drugs is one of the inhibitors of the relevant cytochrome P-450 responsible for caffeine metabolism (Table 5).
|
Appendix 3: Properties of caffeine |
|---|
Chemistry
Caffeine has been described as a ‘purine-alkaloid', because of its chemical similarity to uric acid and adenosine. It is moderately soluble in water, and crosses cell membranes and the blood-brain barrier very rapidly. Hence it is rapidly absorbed from the intestinal tract. Caffeine distributes in total body water, but there is also some protein binding, which causes its volume of distribution to be somewhat larger than total body water.
Metabolism
One member of the cytochrome P-450 family of enzymes, CYP-1A2, demethylates caffeine at the N3 position, producing paraxanthine in the liver (Figure 5).31 This latter compound retains many of the pharmacological effects of caffeine as an antagonist to the adenosine A2 receptor. In contrast, demethylation of caffeine at the N1 and N7 positions by CYP-1A2 and CYP-2E1 (ethanol inducible) yields theobromine or theophylline respectively.
Pharmacology
As mentioned in the text, the major pharmacological action of caffeine is to block the adenosine A2 receptor (Figure 4) (for review, see reference 25). At near-toxic levels in plasma (1 mmol/l), caffeine has different pharmacological actions; examples include the direct release of ionized calcium in cells and inhibition of phosphodiesterase, which raises the concentration of cyclic AMP in cells. Hence at very high doses, one could have a different clinical picture. Finally, metabolites such as theobromine or theophylline have different pharmacological properties from caffeine.
|
|
References |
|---|
1. Groeneveld JHM, Sijpkens YWJ, Lin S-H, Davids MR, Friedman O, Halperin ML. An approach to the patient with severe hypokalaemia: the potassium quiz. Q J Med 2005; 86:305–16.
2. Huth EJ, Squires RD, Elkinton JR. Experimental potassium depletion in normal human subjects. II. Renal and hormonal factors in the development of extracellular alkalosis during depletion. J Clin Invest 1959; 38:1149–65.[Web of Science][Medline]
3. Cockcroft DW and Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31–41.[Web of Science][Medline]
4. Rotin D. Regulation of the epithelial sodium channel (ENaC) by accessory proteins. Curr Opin Nephrol Hypertens 2000; 9:529–34.[CrossRef][Web of Science][Medline]
5. Kamynina E and Staub O. Concerted action of ENaC, NEdd4-2, and sgk1 in transepithelial Na+ transport. Am J Physiol 2002; 283:F377–87.
6. Devlin J, Beckett N, David T. Elevated sweat potassium, hyperaldosteronism and pseudo-Bartter's syndrome: a spectrum of disorders associated with cystic fibrosis. J R Soc Med 1989; 82:38–43.[Medline]
7. Lin SH, Lin YF, Halperin ML. Hypokalemia and paralysis. Q J Med 2001; 94:133–9.[Web of Science]
8. Lin SH, Davids MR, Halperin ML. Hypokalemia and paralysis. Q J Med 2003; 96:161–9.
9. Rosa RM, Williams ME, Epstein FH. Extrarenal potassium metabolism. In Seldin DW and Giebisch G (Eds.). The Kidney, Physiology and Pathophysiology 1992; 2nd edn. New York Raven Press pp. 2165–90.
10. Counillon LL and Pouyssegur RJ. The members of the Na+/H+ exchanger gene family: their structure, function, expression, and regulation. In Seldin DW and Giebisch G (Eds.). The Kidney: Physiology & Pathophysiology 2000;Philadelphia PA ippincott Williams & Wilkins pp. 223–34.
11. Russell JM. Sodium-potassium-chloride cotransport. Physiol Rev 2000; 80:211–76.
12. Clausen T. Regulation of active Na+-K+ transport in skeletal muscle. Physiol Rev 1986; 66:542–80.
13. Clausen T and Flatman JA. The effect of catecholamines on Na-K transport and membrane potential in rat soleus muscle. J Physiol 1977; 270:383–424.
14. Lin SH and Lin YF. Propranolol rapidly reverses paralysis, hypokalemia and hypophosphatemia in thyrotoxic periodic paralysis. Am J Kidney Dis 2001; 37:620–4.[Web of Science][Medline]
15. Appel CC and Myles TD. Caffeine-induced Hypokalemic Paralysis in Pregnancy. Obstet Gynecol 2001; 97:805–7.[CrossRef][Web of Science][Medline]
16. Mandel HG. Update on caffeine consumption, disposition and action. Food Chem Toxicol 2002; 40:1231–4.[Medline]
17. Matsunami K, Imai A, Tamaya T. Hypokalemia in a pregnant woman with long-term heavy cola consumption. Intl J Gynecol Obstet 1994; 44:283–4.[CrossRef]
18. Mudge DW and Johnson DW. Coca-Cola and Kangaroos. Lancet 2004; 364:1190.[Medline]
19. Rice JE and Faunt JD. Excessive cola consumption as a cause of hypokalaemic myopathy. Intern Med J 2001; 31:317–18.[CrossRef][Web of Science][Medline]
20. Varro A, Hester S, Papp JG. Caffeine-induced decreases in the inward rectifier potassium and the inward calcium currents in rat ventricular myocytes. Br J Pharmacol 1993; 109:895–7.[Web of Science][Medline]
21. Cui Y and Terrar DA. Effects of caffeine on background potassium current in isolated guinea pig ventricular myocytes. J Cardiovasc Pharmacol 1995; 25:691–5.[Web of Science][Medline]
22. Davie CS, Everitt DE, Standin NB. Increase in the vasorelaxant potency of KATP channel opening drugs by adenosine A1 and A2 receptors in the pig coronary artery. Eur J Pharmacol 1999; 383:155–62.[CrossRef][Medline]
23. Wollheim CB. Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes. Diabetologia 2000; 43:265–77.[CrossRef][Web of Science][Medline]
24. Li Q and Puro DG. Adenosiner activates ATP-sensitive K+ currents in pericytes of rat retinal microvessels: role of A1 and A2A receptors. Brain Res 2001; 907:93–9.[CrossRef][Web of Science][Medline]
25. Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999; 51:83–133.
26. Vasuvattakul S, Warner LC, Halperin ML. Quantitative role of the intracellular bicarbonate buffer system in response to an acute acid load. Am J Physiol 1992; 262:R305–9.[Web of Science][Medline]
27. Moore RD. Stimulation of Na:H exchange by insulin. Biophys J 1981; 33:203–10.[Medline]
28. Wasserman K, Stringer WW, Casaburi R, Zhang Y-Y. Mechanism of the exercise hyperkalemia: an alternate hypothesis. J Appl Physiol 1997; 83:631–43.
29. DeMars C, Hollister K, Tomassoni A, Himmelfarb J, Halperin ML. Citric acidosis: a life-threatening cause of metabolic acidosis. Ann Emerg Med 2001; 38:588–91.[CrossRef][Web of Science][Medline]
30. Davids MR, Segal AS, Brunengraber , Halperin ML. An unusual cause for ketoacidosis. Q J Med 2004; 97:365–76.[Web of Science]
31. Carrillo JA and Benitez J. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin Pharmacokinet 2000; 39:127–34.[CrossRef][Web of Science][Medline]
32. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology 2003; 5th edn. Edinburgh Churchill Livingstone.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||