An excessive intake of caffeine might explain our patient’s clinical features. The European Food Safety Authority stated that caffeine intakes up to 400 mg/day and single doses of 200 mg do not create safety concerns for adults in the general population . Our patient was reportedly ingesting > 1000 mg up to a maximum > 3000 mg of caffeine each day.
Caffeine is an effective stimulant, and many articles have been published on its toxicity following worldwide interests [4, 6, 8, 10, 11]. Although a number of case reports of caffeine-associated hypokalemia also have been reported, most of the previous reports are related to acute intake of a large quantity of caffeine and as a “one-off” [2,3,4,5,6,7,8, 12,13,14,15]. In one study, a caffeine ingestion of 500–600 mg/day was reported sufficient to provoke clinical symptoms (insomnia, irritability, anxiety, heart palpitations, muscle tension, heartburn, biliousness, gastritis, flatulence, and diarrhea) . There was a report of significant hypokalemia after the ingestion of 180 mg of caffeine, the equivalent of 2–3 cups of regular coffee or 1–2 cups of strong coffee . A regular cup of coffee has a minimum of 95 mg caffeine (range, 95–333 mg) per 8 fluid ounces ; however, hypokalemia has not been well-known complication of caffeine intake. In the current case, the event occurred intermittently, but repeated with a high daily intake of caffeine-containing beverages. We estimated that his potassium level was consistently lower than normal, but his symptoms and signs occurred only when his potassium level decreased to below the threshold required to maintain his muscle activity by ingesting excessive amounts of caffeine.
Hypokalemia can be induced due to a combination of the effects of caffeine and the diuretic effect of fluid drinking itself. In a recent study, the incidence of hypokalemia was significantly correlated in acute caffeine toxicity, and the higher the blood concentration of caffeine, the lower the potassium level was shown . Although the detailed mechanism has not yet been clarified, losing potassium via the urine stream due to the diuretic action of caffeine is proposed as one possibility [16, 17]. In addition, caffeine promotes diuresis and natriuresis by competitively binding to adenosine receptors A1 and A2A, and the lifestyle of high caffeine consumption while on a high sodium diet like this patient may be associated with more potent polyuria and subsequent potassium loss . Caffeine induces potassium redistribution into the cells and increases renal losses by inhibiting phosphodiesterase, which increases cyclic adenosine monophosphate (cAMP) levels. Increased cAMP activates sodium-potassium adenosine triphosphates (ATP), causing a shift of extracellular potassium into the intracellular compartment . It has been known that caffeine also reduces the conductance of potassium-ATP channels, but contradicting data exist on whether it mainly acts as an inhibitory or stimulatory effect on the channel [19,20,21]. In another potential mechanism, caffeine stimulates the beta-adrenergic system and increases renin release . When the renin-angiotensin-aldosterone system is activated, potassium loss increases. However, the patient in this case showed constant low plasma renin activity and aldosterone level in repeated tests. In general, caffeine is associated with renin-angiotensin-aldosterone system activation as an acute effect especially in subjects who have not been exposed to caffeine, but patients with chronic caffeine consumption have reported lower renin levels than normal . Severe hypokalemia also suppresses aldosterone secretion . He seldom drink still water, and mostly hydrated with coffee or soda. In addition to the effect of caffeine, a large amount of fluid intake itself may have intensified hypokalemia by increasing flow-induced potassium secretion through the large conductance Ca2+−activated potassium (BK) channel . Caffeine-induced elevated cardiac output increases the glomerular filtration rate, which induces caffeine-related diuresis and subsequent potassium excretion [15, 17]. Although it is a relatively minor effect, caffeine also activates the respiratory center of the brain, causing hyperventilation, and the resultant respiratory alkalosis possibly induces hypokalemia . In this patient, metabolic acidosis with respiratory compensation was observed, which is also reported as a part of acute toxicity of caffeine .
This patient had no history of diabetes, but was diagnosed with diabetes mellitus through serially measured blood sugar and hemoglobin A1c after hospitalization as the third event. Hypokalemia has been reported to be associated with diabetes mellitus in various ways. Hypokalemia is known to be associated with impaired insulin secretion by hypokalemia-mediated beta-cell dysfunction, increased hepatic glucose production, and decreased peripheral glucose utilization resulting in glucose intolerance and hyperglycemia [25, 26]. Also, there is a study showing that insulin sensitivity was restored after correction of hypokalemia . In this patient, chronic clinical or subclinical hypokalemia may have been associated with diabetes mellitus. However, although the hypokalemia was completely improved and did not recur through the change of the diet (mainly on reducing caffeine), the oral anti-diabetic drug was not able to stop, so it is considered that his diabetes was a part of metabolic syndrome.
At our patient’s first and second visits, we tried to calculate the TTKG from his spot urine values, but there was a limitation to interpreting the TTKG because his urine osmolality was lower than his serum osmolality. He reported urinating at least 10 times a day while awake, and our findings suggested that his polyuria was related to the excessive caffeine intake itself and urinary concentrating defect in hypokalemia . That also explained why his spot urine osmolality was too diluted to calculate TTKG. In this patient, 24-hour urine potassium excretion was measured once and high potassium excretion was shown. However, since clinically urgent potassium repletion was required at the time, the urine collection was proceeded with concomitant IV potassium replacement. Therefore, although the 24-hour urine potassium excretion is the most accurate method to measure urinary potassium excretion, it is thought that potassium excretion measured by spot urine is more meaningful than the value of 24-hours potassium excretion in this setting.
Excessive caffeine intake was not considered as a major cause of hypokalemia in previous studies. Although there are individual differences, modern people ingest reasonable amounts of caffeinated beverages daily. However, physicians should pay attention to patients’ drinking habits of caffeinated beverages during evaluations of hypokalemia.
In conclusion, excessive caffeine intake can cause repetitive episodes of hypokalemia. Physicians should pay more attention to patients’ caffeine intake as well as several metabolic or endocrinological causes during the work-up for hypokalemia by taking a detailed history.