Journal of the American College of Nutrition, Vol. 19, No. 1, 13-15 (2000)
Published by the American College of Nutrition
Preliminary Observation: Oral Zinc Sulfate Replacement is Effective in Treating Muscle Cramps in Cirrhotic Patients
Marcelo Kugelmas, MD
Division of Digestive Diseases and Nutrition, University of Kentucky, Lexington, Kentucky
Address reprint requests to: Marcelo Kugelmas, MD, 800 Rose Street, Room MN649, Lexington, KY 40536-0084.
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ABSTRACT
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Background: While not life threatening, muscle cramps severely affect the quality of life of patients with cirrhosis.
Aim: To determine whether oral zinc sulfate therapy decreases the frequency and severity of muscle cramps in cirrhotic patients.
Methods: 12 patients with cirrhosis (5 Child’s A, 3 Child’s B, and 4 Child’s C), hypozincemia and muscle cramps at least thrice weekly received oral zinc sulfate 220 mg BID for 12 weeks. Patients answered a questionnaire regarding their muscle cramps symptoms at the beginning and end of the study.
Results: Muscle cramps occurred in all patients at rest, mainly while sleeping (8/12), and in two patients also during exercise. Cramps were located in calves (10/12), feet (4/12) and hands (4/12) more commonly. Zinc supplementation improved cramps in 10/12 patients, and in seven of these patients the cramps completely resolved. One patient experienced mild watery diarrhea that resolved upon discontinuation of the zinc sulfate. No other complication of zinc supplementation was noted.
Conclusion: A potential relationship between zinc deficiency and muscle cramps in the setting of cirrhosis has not been suggested before. Zinc supplementation may lead to improvement in symptoms associated with muscle cramps in cirrhosis.
Key words: hypozincemia, liver cirrhosis, muscle cramps, zinc sulfate
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INTRODUCTION
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"True" or "ordinary" muscle cramps have been defined as asymmetric spasmodic painful involuntary contractions of voluntary muscles [1–3]. The ordinary cramp begins when a muscle already in its most shortened position voluntarily contracts [4,5]. Evidence points to a neural rather than muscular disorder, since electromyographic studies have shown that ordinary cramps begin with fasciculations in various parts of the muscle that progress to high frequency muscle action potentials [3,4,6]. It is unclear though, if the upper or lower motorneuron is responsible for the motor unit hyperactivity [3]. While electrolyte abnormalities and drug side-effects were initially associated with muscle cramp physiopathology, it was not until recently that the association between liver cirrhosis and cramps became evident. Nocturnal muscle cramps are common in cirrhotic patients, with an 80% prevalence being reported in one series [7].
I observed that symptoms due to muscle cramping seemed to improve in patients that were receiving oral zinc supplementation for the management of refractory porto-systemic encephalopathy in our liver transplant clinic. The aim of this study was to evaluate the possible role of oral zinc supplementation in the management of muscle cramps in patients with advanced liver disease.
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MATERIALS AND METHODS
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Twelve patients with liver cirrhosis seen at the Transplant Center at the University of Kentucky who complained of muscle cramps were invited to participate in this study. All of these were regularly followed during their evaluation for candidacy for a liver transplantation or while listed and awaiting a liver transplantation.
Patients were included if they had documented cirrhosis, serum zinc concentration below the normal range for our laboratory (70–150 µg/dL) and muscle cramps occurring at least thrice weekly. Patients were excluded if they had uncorrected electrolyte abnormalities (specifically K+, iCa++, Mg++ and PO4=), other conditions associated with muscle cramps or were receiving therapy for their cramps. Patients receiving diuretics and beta blockers were included in the study without changing these medications.
All patients were asked to answer a questionnaire regarding the frequency, location, time of day and degree of pain (visual analog scale) of their muscle cramps. They then received oral zinc sulfate 220 mg twice a day for 12 weeks. The same questionnaire was answered, and serum zinc concentration was determined.
Serum zinc concentration was determined using flame atomic absorption spectrometry [8]. Statistical analysis was done using paired t tests.
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RESULTS
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Seven patients had HCV-related liver cirrhosis, one patient had both HCV and hemochromatosis, and there was one patient with each of the following diagnoses: Laennec’s cirrhosis, hepatitis B, cryptogenic cirrhosis and hereditary hemochromatosis. Five of these patients had compensated cirrhosis (Child’s-Pugh category A), and seven had decompensated liver disease (3 Child’s-Pugh category B and 4 category C). Six patients received diuretics (spironolactone +/- furosemide), while one patient received both diuretics and non-selective ß blockers and one patient received diuretics and insulin for type II diabetes mellitus.
All twelve patients experienced muscle cramps at rest, mainly while sleeping (8/12), and two patients also during exercise. Cramps were located in calves (10/12), feet (4/12) and hands (4/12) more commonly, occurred with a frequency of 4.09+/-.56 times per week, and were quite painful (Table 1).
Zinc levels averaged 60% of the lower limit of normal (40 ±4.09 µg/dL). Zinc supplementation completely resolved muscle cramps in seven of 12 patients and significantly improved their symptoms in another three (Table 1). While oral zinc supplementation improved serum concentration, it did not correct it to normal in all patients (Table 1). One patient experienced mild watery diarrhea, which abated upon discontinuation of oral zinc sulfate replacement after he had completed the study. Nobody reported nausea.
No significant change in biochemistries was noted as a consequence of zinc supplementation (serum bilirubin 2.9± 3.3 mg/dL before vs. 2.8±3.5 mg/dL after, serum albumin 3.2±.7 g/dL before vs. 3.2±.6 g/dL after, and prothrombin time 14.6±2.9 seconds before vs. 14.7±2.9 seconds after).
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DISCUSSION
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A clinical observation led to the first detailed description of the prevalence and characteristics of muscle cramps in cirrhotic patients [9]. Thirty-three cirrhotic patients were compared to age and gender-matched controls. The prevalence of cramps was 88% in cirrhotics vs. 21% in controls. Neither biochemical characteristics nor the use of diuretics explained the greater incidence of cramps in patients with cirrhosis. The characteristic muscle cramps were found to be very painful (97%), to occur in calf muscles (90%), to occur several times a week (52%), mainly at rest (79%) or during sleep (10%) and to last for a few minutes (76%). No significant difference in these characteristics was observed between cirrhotic and non-cirrhotic controls. More recent work confirmed that cramps are associated with cirrhosis irrespective of its etiology, diuretic consumption, serum electrolyte alterations or differences in Child’s classification [10]. In a selected group of cirrhotics, cramps were more commonly seen in those with more advanced disease as evidenced by the presence of ascites, a lower mean arterial pressure and higher plasma renin activity [11]. In nine of 12 of these patients, improvement of intravascular volume depletion with albumin infusions improved cramps.
Oral vitamin E replacement has been used successfully in the management of nocturnal muscle cramps in cirrhotic patients. In a group of 23 cirrhotic patients (16 and 7 Child’s-Pugh category A and B respectively), oral vitamin E (tocopherol acetate) 200 mg t.i.d. significantly improved the frequency, duration and pain associated with nocturnal cramping without untoward effects [7]. Quinine and quinidine have also been used with success in the treatment of cirrhosis-associated muscle cramps, but their potential for cardiac and gastrointestinal toxicity make them less desirable therapeutic choices [12].
Patients with chronic liver disease are hypozincemic because of poor oral intake potentiated by protein restriction, increased gastrointestinal loss due to diarrhea or mild malabsorption, increased urinary losses and impaired albumin binding [13]. Many functional consequences of zinc deficiency have been described in patients with advanced liver disease, including neurosensory defects [14], skin lesions [15], hypogonadism [16], immune dysfunction [17], altered protein metabolism [18] and poor wound healing [19]. To date no report of an association of hypozincemia and nocturnal muscle cramps has been suggested. The mechanism(s) for the efficacy of zinc supplementation in treating nocturnal leg cramps in cirrhotic patients is not known. Two known effects of zinc which may be playing a role are membrane stabilization and antioxidant function.
This is the first report of the beneficial effect of zinc replacement in the treatment of nocturnal muscle cramps in patients with advanced liver disease. This therapy was also devoid of significant side effects. Given the known consequences of hypozincemia and the broad benefits of replacing zinc in this setting, it would make sense to replace zinc in patients with advanced liver disease who have muscle cramps and hypozincemia.
Received March 1, 2001.
Accepted September 1, 2001.
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ABSTRACT
INTRODUCTION
