- Email: [email protected]
Muscle Cramps in Cirrhosis: A Moving Target
EDITORIAL Muscle Cramps in Cirrhosis: A Moving Target uscle cramps are a very common complaint in cirrhosis, with a reported prevalence as high as 88%.1 They are defined as involuntary painful contractions at rest or during sleep of a muscle or muscle group that may last for seconds to minutes and are
M
usually self-limiting.2,3 The presence of cramps significantly impairs mental and physical quality of life in cirrhosis.4–6 The pathogenesis of muscle cramps in cirrhosis is not fully understood, but several mechanisms have been proposed. The 3 most common mechanisms include impairment in energy metabolism reflected in part by a decrease in muscle adenosine triphosphate (ATP) production,7 nerve dysfunction, and changes in plasma
Figure 1. Potential mechanisms and treatments of muscle cramps in cirrhosis. Adapted with permission from Mehta SS, Fallon MB. Muscle cramps in liver disease. Clin Gastroenterol Hepatol 2013;11:1385–1391; quiz e80. Clinical Gastroenterology and Hepatology 2015;13:1544–1546
August 2015
volume/electrolytes.8 Many of the agents that have been studied in case series and uncontrolled trials including vitamin E, taurine, branched-chain amino acids, zinc, albumin, and quinidine influence aspects of these mechanisms (Figure 1). L-carnitine (L-beta-hydroxy-gamma-N-trimethyl aminobutyric acid) is a nutritional supplement that is naturally produced in liver and kidney but also present in dietary sources such as meat and dairy products.9 Administration of L-carnitine has been used for the treatment of mitochondrial myopathy and encephalomyopathy, as well as in primary and secondary L-carnitine deficiency.10 It is an obligatory cofactor in the transport of activated long-chain fatty acids from the cytosol to the mitochondria where catabolism via b-oxidation releases ATP.11 A single preliminary report of 23 patients with cirrhosis and muscle cramps showed 90% improvement in cramps in participants taking 300 mg L-carnitine twice daily.12 Therefore, it is hypothesized that L-carnitine may improve the lack of ATP in cirrhotic skeletal muscle. The increase in ATP counteracts the diminished cycling of actin and myosin cross-bridging and restores calcium release from sarcoplasmic reticulum calcium adenosine triphosphatase pumps, thereby preventing prolonged contraction8 (Figure 1). In this context, Nakanishi et al13 evaluated the effects of L-carnitine supplementation in 42 consecutive patients with cirrhosis and cramps. Cramps were defined as painful, involuntary contraction of skeletal muscles that occurred at rest or strong enough to wake the patient from sleep during the preceding 4 weeks. Frequency was determined by a questionnaire, and severity was assessed by using a visual analog scale (VAS). Patients with underlying comorbidities that might influence cramps and those previously taking carnitine were excluded. L-carnitine 300 mg 3 times a day (900 mg group) or 4 times a day (1200 mg group) was administered for 8 weeks (at the discretion of the physician). Compliance with treatment was reported as 80%. All patients completed questionnaires at the initiation and termination of treatment, and 31 completed the VAS. In all patients, the frequency of muscle cramps significantly decreased from 5.1 6 to 1.7 3 times a week (P ¼ .0019), with 29% of patients having complete resolution after 8 weeks. The VAS score decreased in 27 patients (87%) and increased in 3 (10%) after treatment. The dose of L-carnitine was significantly associated with increased resolution (43.5%, n ¼ 23 in 1200 mg group vs 10.5%, n ¼ 19 in 900 mg group; P ¼ .037) and severity (9.9 13.5 in 1200 mg group vs 39.6 31.9 in 900 mg group; P ¼ .003) of cramps. No adverse effects were noted. Although limited, this preliminary report suggests that L-carnitine treatment may provide benefit in alleviating muscle cramps in cirrhosis during an 8-week period. However, the study has a number of limitations and highlights some common problems in studies of muscle cramps in cirrhosis. First, the study lacks a control group, which undermines the ability to define the effectiveness
Editorial 1545
of therapy. Second, the 2 dosing groups were not randomized, and the clinical characteristics of these groups were not provided, impairing the ability to determine which variables influenced response. Third, L-carnitine supplementation was given during a short period only, and effective therapy of cramps would be expected to require chronic treatment. This aspect is of particular importance because of recent reports suggesting that long-term L-carnitine administration increases inflammation of the liver and kidneys in rodents.14 Like the majority of prior studies of muscle cramps in cirrhosis, this work suffers from small numbers of participants and methodological limitations that prevent us from making substantial progress in determining which mechanistic targets are the highest value in developing effective therapies. Future studies would benefit greatly from a clear mechanistic underpinning, rigorous controlled design, and larger, perhaps multicenter groups with long-term follow-up. Such studies would allow us to hit the target and provide effective relief for this common complication of cirrhosis. SHIVANG SARVOTTAM MEHTA, MD MICHAEL B. FALLON, MD Department of Internal Medicine Division of Gastroenterology, Hepatology, and Nutrition University of Texas Health Science Center at Houston Houston, Texas
References 1. Konikoff F, Theodor E. Painful muscle cramps: a symptom of liver cirrhosis? J Clin Gastroenterol 1986;8:669–672. 2. Katzberg HD, Khan AH, So YT. Assessment: symptomatic treatment for muscle cramps (an evidence-based review)— report of the therapeutics and technology assessment subcommittee of the American academy of neurology. Neurology 2010;74:691–696. 3. El-Tawil S, Al Musa T, Valli H, et al. Quinine for muscle cramps. Cochrane Database Syst Rev 2010;CD005044. 4. Allen RE, Kirby KA. Nocturnal leg cramps. Am Fam Physician 2012;86:350–355. 5. Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120:170–178. 6. Kim SH, Oh EG, Lee WH, et al. Symptom experience in Korean patients with liver cirrhosis. J Pain Symptom Manage 2006; 31:326–334. 7. Moller P, Bergstrom J, Furst P, et al. Muscle biopsy studies in patients with moderate liver cirrhosis with special reference to energy-rich phosphagens and electrolytes. Scand J Gastroenterol 1984;19:267–272. 8. Mehta SS, Fallon MB. Muscle cramps in liver disease. Clin Gastroenterol Hepatol 2013;11:1385–1391; quiz e80. 9. Malaguarnera M, Vacante M, Giordano M, et al. L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-alpha 2b plus ribavirin. World J Gastroenterol 2011;17:4414–4420.
1546 Mehta and Fallon
Clinical Gastroenterology and Hepatology Vol. 13, No. 8
10. Campos Y, Huertas R, Bautista J, et al. Muscle carnitine deficiency and lipid storage myopathy in patients with mitochondrial myopathy. Muscle Nerve 1993;16:778–781.
13. Nakanishi H, Kurosaki M, Tsuchiya K, et al. L-carnitine reduces muscle cramps in patients with cirrhosis. Clin Gastroenterol Hepatol 2015;13:1540–1543.
11. Agren R, Mardinoglu A, Asplund A, et al. Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling. Mol Syst Biol 2014; 10:721.
14. Liu L, Zhang DM, Wang MX, et al. The adverse effects of longterm l-carnitine supplementation on liver and kidney function in rats. Hum Exp Toxicol 2015.
12. Tsuda Y, Tsuchimoto Y, Ohama H, et al. The clinical benefit of Lcarnitine supplement on muscle cramp and peripheral blood cell abnormality in patients with liver cirrhosis. Gastroenterology 2013;144:S999.
Conflicts of interest The author discloses no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.02.033
M
usually self-limiting.2,3 The presence of cramps significantly impairs mental and physical quality of life in cirrhosis.4–6 The pathogenesis of muscle cramps in cirrhosis is not fully understood, but several mechanisms have been proposed. The 3 most common mechanisms include impairment in energy metabolism reflected in part by a decrease in muscle adenosine triphosphate (ATP) production,7 nerve dysfunction, and changes in plasma
Figure 1. Potential mechanisms and treatments of muscle cramps in cirrhosis. Adapted with permission from Mehta SS, Fallon MB. Muscle cramps in liver disease. Clin Gastroenterol Hepatol 2013;11:1385–1391; quiz e80. Clinical Gastroenterology and Hepatology 2015;13:1544–1546
August 2015
volume/electrolytes.8 Many of the agents that have been studied in case series and uncontrolled trials including vitamin E, taurine, branched-chain amino acids, zinc, albumin, and quinidine influence aspects of these mechanisms (Figure 1). L-carnitine (L-beta-hydroxy-gamma-N-trimethyl aminobutyric acid) is a nutritional supplement that is naturally produced in liver and kidney but also present in dietary sources such as meat and dairy products.9 Administration of L-carnitine has been used for the treatment of mitochondrial myopathy and encephalomyopathy, as well as in primary and secondary L-carnitine deficiency.10 It is an obligatory cofactor in the transport of activated long-chain fatty acids from the cytosol to the mitochondria where catabolism via b-oxidation releases ATP.11 A single preliminary report of 23 patients with cirrhosis and muscle cramps showed 90% improvement in cramps in participants taking 300 mg L-carnitine twice daily.12 Therefore, it is hypothesized that L-carnitine may improve the lack of ATP in cirrhotic skeletal muscle. The increase in ATP counteracts the diminished cycling of actin and myosin cross-bridging and restores calcium release from sarcoplasmic reticulum calcium adenosine triphosphatase pumps, thereby preventing prolonged contraction8 (Figure 1). In this context, Nakanishi et al13 evaluated the effects of L-carnitine supplementation in 42 consecutive patients with cirrhosis and cramps. Cramps were defined as painful, involuntary contraction of skeletal muscles that occurred at rest or strong enough to wake the patient from sleep during the preceding 4 weeks. Frequency was determined by a questionnaire, and severity was assessed by using a visual analog scale (VAS). Patients with underlying comorbidities that might influence cramps and those previously taking carnitine were excluded. L-carnitine 300 mg 3 times a day (900 mg group) or 4 times a day (1200 mg group) was administered for 8 weeks (at the discretion of the physician). Compliance with treatment was reported as 80%. All patients completed questionnaires at the initiation and termination of treatment, and 31 completed the VAS. In all patients, the frequency of muscle cramps significantly decreased from 5.1 6 to 1.7 3 times a week (P ¼ .0019), with 29% of patients having complete resolution after 8 weeks. The VAS score decreased in 27 patients (87%) and increased in 3 (10%) after treatment. The dose of L-carnitine was significantly associated with increased resolution (43.5%, n ¼ 23 in 1200 mg group vs 10.5%, n ¼ 19 in 900 mg group; P ¼ .037) and severity (9.9 13.5 in 1200 mg group vs 39.6 31.9 in 900 mg group; P ¼ .003) of cramps. No adverse effects were noted. Although limited, this preliminary report suggests that L-carnitine treatment may provide benefit in alleviating muscle cramps in cirrhosis during an 8-week period. However, the study has a number of limitations and highlights some common problems in studies of muscle cramps in cirrhosis. First, the study lacks a control group, which undermines the ability to define the effectiveness
Editorial 1545
of therapy. Second, the 2 dosing groups were not randomized, and the clinical characteristics of these groups were not provided, impairing the ability to determine which variables influenced response. Third, L-carnitine supplementation was given during a short period only, and effective therapy of cramps would be expected to require chronic treatment. This aspect is of particular importance because of recent reports suggesting that long-term L-carnitine administration increases inflammation of the liver and kidneys in rodents.14 Like the majority of prior studies of muscle cramps in cirrhosis, this work suffers from small numbers of participants and methodological limitations that prevent us from making substantial progress in determining which mechanistic targets are the highest value in developing effective therapies. Future studies would benefit greatly from a clear mechanistic underpinning, rigorous controlled design, and larger, perhaps multicenter groups with long-term follow-up. Such studies would allow us to hit the target and provide effective relief for this common complication of cirrhosis. SHIVANG SARVOTTAM MEHTA, MD MICHAEL B. FALLON, MD Department of Internal Medicine Division of Gastroenterology, Hepatology, and Nutrition University of Texas Health Science Center at Houston Houston, Texas
References 1. Konikoff F, Theodor E. Painful muscle cramps: a symptom of liver cirrhosis? J Clin Gastroenterol 1986;8:669–672. 2. Katzberg HD, Khan AH, So YT. Assessment: symptomatic treatment for muscle cramps (an evidence-based review)— report of the therapeutics and technology assessment subcommittee of the American academy of neurology. Neurology 2010;74:691–696. 3. El-Tawil S, Al Musa T, Valli H, et al. Quinine for muscle cramps. Cochrane Database Syst Rev 2010;CD005044. 4. Allen RE, Kirby KA. Nocturnal leg cramps. Am Fam Physician 2012;86:350–355. 5. Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120:170–178. 6. Kim SH, Oh EG, Lee WH, et al. Symptom experience in Korean patients with liver cirrhosis. J Pain Symptom Manage 2006; 31:326–334. 7. Moller P, Bergstrom J, Furst P, et al. Muscle biopsy studies in patients with moderate liver cirrhosis with special reference to energy-rich phosphagens and electrolytes. Scand J Gastroenterol 1984;19:267–272. 8. Mehta SS, Fallon MB. Muscle cramps in liver disease. Clin Gastroenterol Hepatol 2013;11:1385–1391; quiz e80. 9. Malaguarnera M, Vacante M, Giordano M, et al. L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-alpha 2b plus ribavirin. World J Gastroenterol 2011;17:4414–4420.
1546 Mehta and Fallon
Clinical Gastroenterology and Hepatology Vol. 13, No. 8
10. Campos Y, Huertas R, Bautista J, et al. Muscle carnitine deficiency and lipid storage myopathy in patients with mitochondrial myopathy. Muscle Nerve 1993;16:778–781.
13. Nakanishi H, Kurosaki M, Tsuchiya K, et al. L-carnitine reduces muscle cramps in patients with cirrhosis. Clin Gastroenterol Hepatol 2015;13:1540–1543.
11. Agren R, Mardinoglu A, Asplund A, et al. Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling. Mol Syst Biol 2014; 10:721.
14. Liu L, Zhang DM, Wang MX, et al. The adverse effects of longterm l-carnitine supplementation on liver and kidney function in rats. Hum Exp Toxicol 2015.
12. Tsuda Y, Tsuchimoto Y, Ohama H, et al. The clinical benefit of Lcarnitine supplement on muscle cramp and peripheral blood cell abnormality in patients with liver cirrhosis. Gastroenterology 2013;144:S999.
Conflicts of interest The author discloses no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.02.033