Showing posts with label Muscle Cramps. Show all posts
Showing posts with label Muscle Cramps. Show all posts

Tuesday, July 25, 2017

Most Individuals With Advanced Cirrhosis Have Sleep Disturbances, Which Are Associated With Poor Quality of Life

Clinical Gastroenterology and Hepatology
August 2017 Volume 15, Issue 8, Pages 1271–1278.e6

Most Individuals With Advanced Cirrhosis Have Sleep Disturbances, Which Are Associated With Poor Quality of Life
Marwan Ghabril , Mollie Jackson, Raghavender Gotur, Regina Weber, Eric Orman, Raj Vuppalanchi, Naga Chalasani
In summary, we describe a high prevalence of disturbed sleep in patients with cirrhosis at a large transplant center. Disturbed sleep was predicted by muscle cramps, which is an important although poorly understood complication of end-stage liver disease. Disturbed sleep in this population appears to be multifactorial in etiology and may be associated with neurocognitive dysfunction. Disturbed sleep is strongly associated with decreased quality of life, and its severity may be meaningfully categorized on the basis of PSQI. Further studies to elucidate the pathogenesis and therapies for disturbed sleep in patients with cirrhosis are needed in the face of this significant and unmet need.
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Background & Aims
Sleep disturbances are common in patients with cirrhosis, but their determinants and effects on health-related quality of life are not well-understood. We investigated the prevalence of disturbed sleep in these patients, factors associated with sleep disruption, and effects on quality of life.

We performed a prospective, cross-sectional study of 193 stable ambulatory patients with cirrhosis (154 with decompensated cirrhosis). Participants completed the Pittsburgh Sleep Quality Index (to assess sleep quality), the Chronic Liver Disease Questionnaire (CLDQ), and muscle cramp questionnaires and underwent neurocognitive testing. Actigraphy was performed in a subset of patients with normal and disturbed sleep. We collected serum samples from subjects with normal and disturbed sleep and performed non-targeted metabolomic analyses.

Of the study subjects, 157 (81%) had disturbed sleep, with Pittsburgh Sleep Quality Index scores >5. Disturbed sleep was associated with muscle cramps, daytime somnolence, and decreased quality of life on the basis of CLDQ scores. Factors independently associated with disturbed sleep in logistic regression analysis included hypoalbuminemia, opiate therapy, and muscle cramps. Disturbed sleep was independently associated with CLDQ score (correlation parameter, –36.6; 95% confidence interval, –24 to –49; P < .001) on linear regression. Disturbed sleep was associated with neurocognitive impairment and with significantly delayed bedtime and decreased total sleep time, measured by actigraphy. Disturbed sleep was associated with metabolome signatures of alterations to the intestinal microbiome and lipid, arginine, and urea cycle metabolism.

Most patients with advanced cirrhosis (81%) have disturbed sleep. This has negative effects on quality of life and is associated with disruptions of several metabolic pathways, including metabolism by the intestinal microbiota.

Saturday, January 30, 2016

Watch: New Treatments for HCV And Insomnia, Muscle Cramps, Fatigue, Itching In Cirrhotic Patients

Special Issue: New Treatments for HCV, Consultations in Hepatology, Integrated Health & Emerging Liver Scholars

The journal is an official digital educational resource from the American Association for the Study of Liver Diseases.

Visitors are able to view videos, review full data articles, and download files in either HTML or PDF formats.

Volume 7, Issue 1 Pages 1 - 20, January 2016
The latest issue of Clinical Liver Disease is available on Wiley Online Library

New Treatments for HCV

Guest Edited by Nancy Reau, MD
Integrating daclatasvir into hepatitis c therapy (pages 1–4)
Omobonike Oloruntoba and Andrew J. Muir
Article first published online: 29 JAN 2016 | DOI: 10.1002/cld.524
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Watch the interview with the author

Consultations in Hepatology
Guest Edited by Mary Rinella, MD
Evaluation and management of insomnia, muscle cramps, fatigue, and itching in cirrhotic patients(pages 5–7)
Christopher Moore
Article first published online: 29 JAN 2016 | DOI: 10.1002/cld.516
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Integrated Health
Guest Edited by Felix Stickel, MD
Silymarin in the treatment of liver diseases: What is the clinical evidence? (pages 8–10)
Peter Ferenci
Article first published online: 29 JAN 2016 | DOI: 10.1002/cld.522
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Watch the interview with the author

Emerging Liver Scholars
Guest Edited by William Sanchez, MD
Review of current and potential future pharmacological treatments in nonalcoholic steatohepatitis(pages 11–14)
Ahmed Akhter, Abhishek Pulla and Adnan Said
Article first published online: 29 JAN 2016 | DOI: 10.1002/cld.523
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Social determinants in liver transplantation (pages 15–17)
Joel T. Adler and Heidi Yeh
Article first published online: 29 JAN 2016 | DOI: 10.1002/cld.525
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Nutrition, fluid, and electrolytes in chronic liver disease (pages 18–20)
Miguel A. Lalama and Yasser Saloum
Article first published online: 29 JAN 2016 | DOI: 10.1002/cld.526
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Tuesday, August 18, 2015

Can we Reduce Muscle Cramps in Patients with Cirrhosis?

Can we Reduce Muscle Cramps in Patients with Cirrhosis?
Kristine Novak

L-carnitine appears to be safe and effective for reducing muscle cramps in patients with cirrhosis, researchers report in the August issue of Clinical Gastroenterology and Hepatology.

Many patients with cirrhosis develop frequent muscle cramps, which reduce their quality of lifeL-carnitine (L-beta-hydroxy-gamma-N-trimethyl aminobutyric acid) is an amino acid that transports long-chain fatty acids across the mitochondrial membrane, and has been proposed to provide energy for skeletal muscle. Hiroyuki Nakanishi et al evaluated its effects on muscle cramps in a prospective study.

Consecutive patients with cirrhosis and muscle cramps were given L-carnitine (300 mg) 3 times/day (900 mg/day total, n = 19) or 4 times/day (1200 mg/day total, n = 23) for 8 weeks. The frequency of muscle cramps was assessed by questionnaires, and the degree of muscle cramping was assessed by the visual analogue scale (VAS).

The VAS is a horizontal, 100 mm line with word descriptors at each end (left, totally without pain and right, unbearable pain). Patients mark points on the line the point that best indicates their current state. The VAS score is then determined by measuring millimeters from the left end of the line to the marked points.

At the end of the 8 week study period, muscle cramps decreased in 88.1% of all subjects; 28.6% of patients had no cramps at al.

Overall VAS scores decreased significantly, from a mean value of 69.9±22.5 at baseline to 26.2±29.1 after 8 weeks.

Muscle cramps were reduced in 43.5% of patients in the 1200 mg/day group and 10.5% in the 900 mg/day group. At the end of the 8-week study period, mean VAS scores were 9.9±13.5 in the 1200 mg/day group and 39.6±31.9 in the 900 mg/day group (see figure).

Nakanishi et al did not observe any adverse events.

VAS scores before and after 8 weeks of L-carnitine. Black lines indicate the 1200 mg group, gray the 900 mg group. (A) Overall, the mean VAS score was reduced significantly from 69.9 ± 22.5 to 26.2 ± 29.1 after 8 weeks of therapy. (B) VAS scores after 8 weeks were significantly lower in 1200 mg group than in 900 mg group

Why do patients with cirrhosis develop cramps, and why might L-carnitine reduce them? An analysis of skeletal muscle biopsies from patients with cirrhosis and found reductions in ATP, phosphocreatine, and total adenine nucleotides. Deficiencies in ATP result in insufficient dissociation of myosin from actin, and thereby prolonged muscle contraction and cramping.

Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so they can be broken down through β-oxidation to acetyl CoA to obtain usable energy via the citric acid cycle.

This process provides ATP for heart and skeletal muscles. Nakanishi et al propose that some patients with cirrhosis could have carnitine deficiency. Larger, randomized, controlled studies are necessary to further evaluate the efficacy of L-carnitine in reducing muscle cramps in patients with cirrhosis and other disorders.

Tuesday, November 19, 2013

Articles in Press - Muscle Cramps in Liver Disease

Muscle Cramps in Liver Disease

Just about everyone will experience muscle cramps, but for people living with liver disease and cirrhosis muscle cramps are more common, causing debilitating pain, adding a significant negative impact to an already difficult disease, according to a recent review "Muscle cramps in liver disease" published in the November issue of Clinical Gastroenterology and Hepatology.

In liver disease, a higher prevalence of muscle cramps were found in cirrhotic patients then in non-cirrhotic patients. Other factors associated with muscle cramps are medications such as lactulose and water pills (diuretics) used to treat cirrhosis. In the review, a study compared cirrhosis patients with congestive heart failure patients, both groups were taking a diuretic, the study resulted in 22% of people with cirrhosis having a significantly higher prevalence of weekly or daily cramps vs 5% of congestive heart failure patients.

As reported;
Interestingly, there was no difference in diuretic use or dosing between the 2 groups, supporting that factors other than diuretic-mediated effects explained the differences. Together, these studies suggest that unique physiological changes may occur in cirrhosis and predispose to the development of cramps. 

Muscle Cramps in Liver Disease, will focus on the signs and symptoms of muscle cramps associated with cirrhosis, physical examination and a review of current therapies.

Muscle Cramps in Liver Disease

Shivang S. Mehta Affiliations Corresponding Author InformationReprint requests Address requests for reprints to: Shivang S. Mehta, MD, University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 4.261, Houston, Texas 77030. fax: (713) 500-0635 email address , Michael B. Fallon University of Texas Health Science Center at Houston, Houston, Texas
published online 01 April 2013.

Clinical Gastroenterology and Hepatology
Volume 11, Issue 11 , Pages 1385-1391, November 2013

Muscle cramps are common in patients with liver disease and adversely influence quality of life. The exact mechanisms by which they occur remain unclear, although a number of pathophysiological events unique to liver disease may contribute. Clinical studies have identified alterations in 3 areas: nerve function, energy metabolism, and plasma volume/electrolytes. Treatments have focused on these particular areas with varied results. This review will focus on the clinical features of muscle cramps in patients with liver disease and review potential mechanisms and current therapies.

Muscle cramps 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 usually self-limiting.1, 2 Cramps are commonly found in a variety of diseases including liver disease (Table 1).3, 4 Although generally benign, the frequency and severity of cramps may be debilitating and have a significant negative effect on the quality of life (QOL) in affected patients. Despite the association of muscle cramps with liver disease, there is a paucity of information regarding pathogenesis and treatment in these patients.

Table 1. Diseases, Medications, and Physiological Changes Associated With Muscle Cramps

Neurologic disease
Peripheral neuropathy
Amyotrophic lateral sclerosis
Spinal cord stenosis
End-stage disease
Liver (cirrhosis)
Renal requiring hemodialysis
Beta blockers
Calcium channel blockers
Conjugated estrogens
Cardiac disease
Peripheral vascular disease (claudication)
Changes in physiology
Exercise induced
Pregnancy related

Prevalence and Clinical Significance

The first report of an association between cirrhosis and muscle cramps was made by Konikoff and Theodor5 in 1986. Of 33 patients with cirrhosis who were studied, 88% were found to have experienced more than 2 cramps in calf muscles within the prior week. Since this report, several subsequent studies have demonstrated a 22%–88% prevalence of muscle cramps in patients with liver disease, depending on differing definitions, frequency, and inclusion criteria (Table 2).5, 6, 7, 8, 9, 10, 11 The majority of studies have found a higher prevalence of cramps in cirrhotic patients relative to control groups. In addition, patients with cirrhosis in comparison with noncirrhotic patients with liver disease have been found to have a greater prevalence of cramps, 31% vs 5%, respectively.7 Abrams et al8 compared patients with cirrhosis with those with congestive heart failure and found a significantly higher prevalence of weekly or daily cramps with cirrhosis (22%) vs patients with congestive heart failure (5%). Interestingly, there was no difference in diuretic use or dosing between the 2 groups, supporting that factors other than diuretic-mediated effects explained the differences. Together, these studies suggest that unique physiological changes may occur in cirrhosis and predispose to the development of cramps.

Table 2. Prevalence of Muscle Cramps in Patients With Cirrhosis

AuthorYearNumber of patientsPrevalence (%)Comment
Konikoff et al519863388Severe pain occurring in calf muscles several times per week
Chao et al52198933164≥1 cramp per week that occurred mainly during sleep in the lower extremities and lasted for few minutes
Konikoff et al619912979Cirrhotic patients with any severity, duration, or frequency of cramps
Kobayashi et al719928031≥1 cramp per week
Abrams et al819969222Weekly or daily cramps, either occurring at rest or when awakening a patient from sleep
Angeli et al9199617129≥3 crises per week
Baskol et al10200410056≥1 painful muscle cramp occurring at rest, strong enough to waken a patient from sleep, or occurring once a week during a period of more than 12 months
Chatrath et al11201215067Painful, involuntary contraction of skeletal muscles, occurring at rest or strong enough to wake the patient from sleep in the preceding 12 weeks

The presence of cramps in cirrhosis also adversely influences QOL. Symptom experience in a cohort of 129 patients with cirrhosis found muscle cramps to be the second leading cause of distress and increased intensity of pain.3 Marchesini et al12 surveyed 544 patients with cirrhosis by using the Nottingham Health Profile and the Medical Outcome Study Short Form-36 questionnaires. Muscle cramps were identified as the most frequent variable associated with poor health-related QOL. In fact, muscle cramps were an independent impairment variable in both the physical and mental components of the questionnaire and were a significant factor in impairment in 13 of 14 domains.12, 13
A recent study investigated the QOL of cirrhotic patients experiencing cramps by using the Chronic Liver Disease Questionnaire, a more sensitive and specific survey for determining QOL in this particular group.11, 14, 15 Chatrath et al11 questioned 150 patients with cirrhosis and cramps and found significantly lower Chronic Liver Disease Questionnaire scores that were due to lower domain scores in abdominal symptoms, fatigue, systemic symptoms, activity, emotional functions, and worry relative to cirrhotic patients without cramps. These studies suggest that muscle cramps take a mental and physical toll on affected cirrhotic patients.


The pathophysiological mechanisms of muscle cramps in patients with cirrhosis are not clearly elucidated. However, a number of mechanisms have been considered and explored. Potential mechanisms may be divided into alterations in 3 overlapping areas: (1) nerve function, (2) energy metabolism, and (3) plasma volume and electrolytes (Figure 1).

Nerve Function

The first studies examining the role of nerve dysfunction in patients with liver disease were conducted 30 years ago. At that time, it was postulated that nerve dysfunction was likely due to impaired membrane conduction as a result of oxidative stress.16 Histologic studies revealed that those with liver disease exhibited thinly myelinated nerve fibers and axonal loss, supporting the presence of structural damage.17 In addition, patients with cirrhosis were observed to have involuntary bursts of action potentials that appeared as fasciculations on electromyogram with origins in the peripheral nerve.18 These findings suggested a chronically depolarized and hyperexcitable motor neuron in patients with liver disease, thus inducing inappropriate high-frequency repetitive firing of the motor nerve action potentials, resulting in muscle cramps.17, 19, 20 This concept was expanded by Ng et al,21 who performed direct nerve studies on the median and peroneal motor nerves in patients with cirrhosis. The study found increased nerve excitability that was due to depolarization of the resting axonal membrane potential resulting from a significant reduction in threshold potential. These studies supported that nerve dysfunction, possibly related to oxidative injury and structural alterations, plays an important role in sustained muscle contractions and the development of muscle cramps. Therefore, a number of treatments have focused on decreasing the excitability of motor neurons and relieving oxidative injury within nerves.

Energy Metabolism

The liver has a central role in amino acid and protein metabolism and is responsible for the deamination and modification of amino acids and the synthesis of amino acids into proteins.22 The regulation of amino acid and protein metabolism is altered in those with cirrhosis, which is reflected by decreased plasma and skeletal muscle concentrations of taurine (the most abundant amino acid in skeletal muscle). Altered taurine concentrations appear to result from both decreased production related to an imbalance in the ratio of branched-chain amino acids to aromatic amino acids and increased release from muscle.22, 23, 24 Taurine concentrations influence the function of a number of critical ion channels, including voltage-dependent chloride channels and calcium-activated sodium and potassium channels, which modulate striated fiber electrical activity and stabilize the sarcolemma.25, 26 The net result of taurine deficiency is a decrease in the threshold potential and hyperexcitability of skeletal muscle.27 Yamamoto et al28 directly measured the mean plasma taurine level in cirrhotic patients with and without muscle cramps in comparison with controls by using high-performance chromatography and found significant differences. The mean plasma taurine level in cirrhotic patients with cramps was 56.9 nmol/mL, whereas in those without cramps it was 79.3 nmol/mL, and healthy controls had a level of 90.1 nmol/mL. These findings support that taurine deficiency may alter skeletal muscle electrical properties, thereby predisposing these patients to cramps.

Another potential contributor to altered energy metabolism in cirrhosis is a reduction in adenosine triphosphate (ATP) production. Moller et al29 performed skeletal muscle biopsies in 10 cirrhotic patients and found a reduction in ATP, phosphocreatine, and total adenine nucleotide levels. A lack of ATP could diminish the cycling process of actin and myosin cross-bridging, causing prolonged muscle contraction particularly in the presence of abnormal electrical activity.

Plasma Volume, Electrolytes, and Zinc

Electrolyte abnormalities including hyponatremia, hypokalemia, and hypomagnesemia as well as shifts in plasma volume that can influence intracellular concentrations of electrolytes or cause hypovolemia have been implicated as factors in producing cramps.30, 31, 32 Angeli et al9 sought to determine whether plasma volume, plasma renin activity (PRA), mean arterial pressure (MAP), serum albumin, and electrolyte concentrations affected the occurrence of muscle cramps in 224 patients with cirrhosis with and without ascites compared with 194 healthy controls. In multivariate analysis only higher PRA, presence of ascites, and lower MAP were predictors of cramps occurring in patients with cirrhosis because serum electrolyte concentrations of sodium, potassium, phosphorus, and magnesium had no effect on cramp occurrence. These studies would support that shifts in plasma volume may influence cramps, possibly by decreasing perfusion to nerves. In the same year, Abrams et al8 compared 92 patients with cirrhosis, 40 with chronic hepatitis without evidence of cirrhosis, and 40 patients with congestive heart failure to control for diuretic use. This study found similar results to that of Angeli et al in that no clinically significant difference in serum electrolyte concentrations was observed between cirrhotic patients with and without cramps. Also in multivariate analysis, diuretic use was not a significant contributor for the occurrence of cramps (P = .48). Subsequent studies confirmed these results and found no significant difference in the concentrations of zinc, sodium, potassium, magnesium, or calcium in cirrhotic patients with and without cramps.10, 11 Together, these results suggest that shifts in plasma volume may contribute to cramps, whereas serum electrolyte concentrations and diuretic use do not directly influence the frequency of cramps in patients with cirrhosis. However, intracellular concentrations of electrolytes could influence muscle excitability and have not been measured in cirrhotic patients with and without cramps.


Therapies for muscle cramps in cirrhosis are generally directed at the 3 potential pathophysiological mechanisms or are empiric (Table 3).

Table 3. Potential Mechanisms of Action of Agents Used to Treat Cramps in Cirrhotic Patients

AgentMechanism of actionRoute of administration (dose studied)Side effects
Quinidine sulfateIncreases the muscle refractory period and decreases the excitability of motor end plate to nerve stimulationOral (400 mg daily)Mild diarrhea, thrombocytopenia, cardiac arrhythmias, cinchonism
Vitamin EImportant antioxidant in the cell membrane that acts to decrease circulating free radicalsOral (200 mg 3 times daily)None reported
Human albuminExpansion of plasma volume and improvement of hypovolemia and possible subsequent ischemia to neuronsIntravenous (100 mL 25% human albumin solution)None reported
ZincUnknownOral (220 mg twice daily)Mild diarrhea
TaurineSarcolemma stabilization via calcium channel regulation and conductanceOral (3 g daily)None reported
Eperisone hydrochlorideCentrally acting muscle relaxantOral (150–300 mg daily)Dizziness, fatigue, and epigastric discomfort
Branched-chain amino acidsIncreases serum albumin and taurine productionOral (4 g granules 3 times daily)None reported

Nerve Function Vitamin E 

Vitamin E is a fat-soluble vitamin with α-tocopherol as the major biologically active form. It has potent antioxidant effects and also stabilizes the phospholipid bilayer of cell membranes.33 Vitamin E deficiency in animal models results in myocyte necrosis and in humans in myopathy.34, 35 Von Herbay et al36 demonstrated that lower serum vitamin E levels were found in alcoholic liver disease, hemochromatosis, and Wilson's disease compared with healthy controls. Two additional studies have reported on treatment with vitamin E for cramps in patients with cirrhosis. Konikoff et al6 recruited 29 patients with cirrhosis and found 23 with cramps. Those with cramps had significantly lower serum vitamin E levels than those without cramps (6.3 ± 3.2 vs 11.5 ± 4.8 μg/mL, P = .01). Thirteen subjects were treated with vitamin E (200 mg 3 times daily for 4 weeks) and had significant improvement on the basis of a scoring system assessing cramp severity, frequency, and duration. A subsequent pilot randomized, double-blind, placebo-controlled crossover study in 9 adult cirrhotic subjects found no statistical significance between vitamin E and placebo in the frequency (P = .98), duration (P = .93), or severity of muscle cramps (P = .57).37 However, treatment dosage and duration of treatment in the vitamin E arm were not reported. Both studies identified no significant side effects to treatment. Further studies are needed to assess whether vitamin E is effective in treating cramps and to define whether serum vitamin E levels might predict responsiveness.

Quinine sulfate 

Quinine, an alkaloid powder derived from the bark of the cinchona tree, was first reported as a treatment for muscle cramps in patients without cirrhosis in the 1940s.38, 39 Although the mechanism of action of quinine in cramps is not elucidated, it is believed to reduce the excitability of the motor nerve by prolonging the refractory period of muscle to repetitive stimuli.40, 41 A number of studies and a recent meta-analysis comparing quinine with vitamin E for the treatment of muscle cramps in noncirrhotic subjects found improvement with both agents but no significant difference in efficacy between them.2 A single study has investigated quinidine sulfate (optical isomer of quinine) for the treatment of muscle cramps in cirrhosis. Lee et al42 conducted a single-blind study in 31 cirrhotic patients with a history of cramps at least twice weekly for the preceding year. Sixteen patients received quinidine sulfate 200 mg twice daily for 4 weeks, and these patients had a significant reduction in the number of episodes of cramps during treatment (14.4 ± 1.7 to 4.4 ± 1.1, P < .0001) relative to the placebo group (11.8 ± 1.0 to 11.5 ± 1.5, P > .05). Mild diarrhea (31%) was the only side effect reported in the treatment group. Quinine is no longer available over-the-counter in the United States because of rare significant adverse effects including thrombocytopenia, cardiac arrhythmias, hemolysis, and cinchonism.43 Therefore, the risk-benefit ratio for using quinine/quinidine in the treatment of cramps in cirrhosis is unfavorable.

Eperisone hydrochloride 

Eperisone hydrochloride is a centrally acting muscle relaxant that appears to suppress sympathetic stimulation in skeletal muscle.44 Kobayashi et al7 treated 21 cirrhotic patients who reported having cramps more than once weekly in an open-label study with eperisone hydrochloride (150–300 mg) daily for 8 weeks. A complete disappearance of symptoms was found in 11 patients (61%), with decreased frequency in 6 patients (33%) and 1 patient with no change in symptoms. Adverse effects included epigastric discomfort, fatigue, and dizziness. Although there did appear to be a decrease in cramp frequency with treatment, the study was not blinded, there were significant side effects, and no long-term follow up data are available.

Energy Metabolism

Three small open-label studies have evaluated taurine as a treatment for muscle cramps in cirrhosis. In the first study, 12 nonalcoholic cirrhotic patients were given 6 g taurine 3 times daily for 4 weeks.23 Eight patients had complete resolution of cramps, and 4 patients had a significant decrease in cramp severity by 1 month. No adverse effects were observed. In a second study, 35 cirrhotic patients were treated with 3 g taurine daily for 4 weeks. Twenty-five patients (71.4%) had significant improvement in cramps, with 13 (37.1%) having complete disappearance of symptoms. A third study by Yamamoto et al28 extended the prior studies by comparing plasma taurine concentrations in 15 cirrhotic patients with cramps and 13 without cramps. Plasma taurine concentrations were significantly lower in the cirrhotic patients with cramps. Nine of the cirrhotic patients with cramps were given 3 g taurine daily for 4 weeks, and all had increased plasma taurine levels and reported significant improvement in symptoms, with 6 (67%) reporting complete resolution. No adverse effects were reported. These encouraging studies support that taurine may be a useful agent to treat muscle cramps in cirrhotic patients, particularly in those with low plasma taurine levels. However, larger double-blind, placebo-controlled studies are needed to confirm these findings.

Branched-chain amino acids 

Administration of branched-chain amino acids (isoleucine, leucine, and valine) in cirrhosis has been reported to improve serum albumin levels, increase taurine production, and possibly decrease progression of liver disease.45, 46, 47 Two studies have explored the possibility that branched-chain amino acid supplementation might also decrease the frequency of muscle cramps in patients with cirrhosis. Sako et al48 treated 8 patients in an open-label study with nocturnal branched-chain amino acid supplements for 3 months and found a significant increase in serum albumin levels and a significant decrease in frequency of cramps relative to pretreatment values (7.4 ± 2 to 0.3 ± 0.5 times/week, P < .0001). Hidaka et al49 performed a small multicenter randomized study in 37 patients that compared daytime and nocturnal branched-chain amino acid supplementation for 3 months. The frequency of muscle cramps significantly decreased in both groups (P = .004), and no adverse effects were reported. These preliminary studies suggest that branched-chain amino acid supplementation may be an effective treatment for muscle cramps in cirrhosis.

Plasma Volume, Electrolytes, and Zinc
Human albumin 

A single small crossover study has reported the use of intravenous albumin for treatment of muscle cramps in cirrhosis.9 Twelve patients with compensated liver disease were given placebo or 100 mL 25% human albumin solution intravenously once weekly for 4 weeks. Compared with placebo administration, albumin significantly decreased cramp frequency (2.5 ± 2.9 vs 6.2 ± 2.5, P < .001) and also decreased PRA and improved MAP. These findings suggest that intravenous albumin may decrease cramps in cirrhosis, possibly by increasing intravascular plasma volume. From a practical perspective, the cost and requirement for intravenous access to deliver albumin limit feasibility as a therapy.

Electrolytes and zinc 

Serum electrolyte concentrations do not differ in cirrhotic patients with and without cramps. Therefore, studies have not focused on electrolyte replacement as a treatment for cramps. Empiric replacement of low serum electrolyte concentrations in cirrhotic patients with cramps is common, although whether this improves symptoms is unknown. Zinc has been used as empiric treatment for muscle cramps in cirrhosis.50 In a small study of 12 patients with low serum zinc concentrations (<70 μg/dL), oral zinc sulfate 220 mg twice daily for 12 weeks significantly decreased cramp frequency and increased serum zinc concentrations (40 ± 4.09 vs 63.8 ± 5.11 μg/dL, P = .0001). One patient reported mild diarrhea as an adverse effect. A subsequent study found low serum zinc concentrations in cirrhotic patients relative to healthy controls but no difference in levels between cirrhotic patients with and without cramps.10 These studies raise the possibility that zinc supplementation may be beneficial in cirrhotic patients with low serum zinc concentrations, but more data are needed.

Approach to the Cirrhotic Patient With Cramps

In patients with cirrhosis who present with muscle pain, a careful history should be obtained to differentiate cramps (spontaneous, chronic, and often nocturnal) from other causes of pain (Figure 2).

In particular, new-onset persistent muscle pain should trigger consideration of other diagnoses such as rhabdomyolysis, myositis, or acute kidney injury for which laboratory tests to assess electrolytes and other parameters would be appropriate. A standardized cramp questionnaire may be useful to define the presence and severity of cramps and in assessing the effectiveness of treatments (Figure 3).11, 51

In those found to have cramps, consideration of etiologies other than cirrhosis should be contemplated (Table 2). Serum electrolyte concentrations are frequently measured and, when low, repleted. When cramps related to cirrhosis are present and are clinically significant, an attempt at treatment is reasonable. Although large controlled trials are lacking, the use of over-the-counter, inexpensive agents with favorable side effect profiles (branched-chain amino acids, taurine, and vitamin E) may be considered. Branched-chain amino acids and taurine may have the greatest potential benefit on the basis of effects on proposed mechanisms for cramps and on possible improvement in nutritional parameters. Other treatments as outlined previously are not currently recommended because of ineffectiveness, expense, and/or the risk of side effects.

Approach to the cirrhotic patient with cramps. CK, creatinine kinase; CRP, C-reactive protein; CQ, cramp questionnaire; EMG, electromyogram; ESR, erythrocyte sedimentation rate.
Click To Enlarge

Cramp Questionnaire. Clinically significant cramp (frequency of cramps/week × severity of cramps) >12.
Click To Enlarge


Muscle cramps in patients with liver disease are common and are associated with a negative impact on QOL. Although a number of mechanisms for cramps in liver disease have been postulated and have been targeted by medical therapies, a clear picture of the causal events has not emerged. Several agents have shown benefit in small uncontrolled studies, although large randomized controlled trials are lacking. Treatments such as branched-chain amino acids and taurine may have the greatest potential benefit because they target proposed mechanisms and may also improve nutritional status.