Muscle cramps in liver cirrhosis: Pathophysiology, burden, and emerging therapeutic approaches

Abstract

Muscle cramps are a frequent yet underrecognized complication in patients with liver cirrhosis, affecting up to 88% of this population and contributing substantially to morbidity and impaired quality of life. These painful, involuntary contractions are often overlooked due to the clinical emphasis on life-threatening complications of cirrhosis despite their independent association with poor functional status, sleep disturbance, and psychosocial decline. The precise pathophysiology remains incompletely understood, but proposed mechanisms include peripheral nerve hyperexcitability from oxidative stress, altered amino acid and energy metabolism, and deficiencies in taurine, carnitine, and branched-chain amino acids. Several therapeutic strategies have been explored with variable efficacy. Small clinical studies have demonstrated benefit from taurine, L-carnitine, branched-chain amino acids, intravenous albumin, and selected muscle relaxants while evidence for quinine, vitamin E, and zinc remains limited or conflicting. Although these interventions show promise in reducing cramp frequency, severity, and duration, most are supported only by small trials and case series with no definitive guideline-directed therapy currently available. This review highlighted the prevalence, pathophysiology, and therapeutic landscape of muscle cramps in cirrhosis, underscoring the urgent need for larger randomized controlled trials to validate existing strategies and identify novel treatments. Addressing this overlooked symptom could significantly improve quality of life for patients with advanced liver disease.

Key Words: Cirrhosis; Muscle cramps; Peripheral nerve hyperexcitability; Mitochondrial dysfunction; Involuntary contractions; Nerve stimulation; L-carnitine

Core Tip: Muscle cramps are an overlooked but highly debilitating complication of liver cirrhosis, affecting up to 88% of patients and severely impairing quality of life. Despite their prevalence, cramps remain undertreated due to limited clinician awareness and the absence of guideline-directed therapy. This review synthesized current evidence on the pathophysiology, including nerve hyperexcitability, altered amino acid metabolism, and energy depletion, and highlighted emerging therapeutic options such as taurine, L-carnitine, branched-chain amino acids, muscle relaxants, and albumin infusion. By summarizing available data and identifying gaps requiring larger randomized trials, this review provided clinicians with a practical framework to better recognize, evaluate, and manage muscle cramps in cirrhosis.

INTRODUCTION

True muscle cramps are palpable and visible muscle contractions that are acutely painful and may result in pain and tenderness lasting hours[1]. Muscle cramps can also be defined as involuntary painful contractions of muscles at rest and/or during sleep lasting for a few seconds to a few minutes[2]. Muscle cramps most notably occur in calf and thigh muscles and other small muscle groups such as fingers, hands, and feet but may also involve the neck and back muscles[3,4]. Muscle cramps may occur in healthy adults but are also prevalent in several disorders including hypothyroidism, hemodialysis, diarrhea, and cirrhosis[1]. In 1986 Konikoff and Theodor[5] established an association between liver cirrhosis and muscle cramps for the first time when they reported the incidence as high as 88%. Per the literature review, this may vary significantly ranging from 22%-88%[6]. However, true prevalence is likely underestimated as symptoms are frequently underreported due to limited targeted history taking and the clinical emphasis on more life-threatening complications of cirrhosis[2,7]. Kobayashi et al[8] and Angeli et al[9] have shown that muscle cramps occur significantly more frequently in patients with liver cirrhosis compared with healthy control groups (P < 0.01 and P < 0.001, respectively). Kalia et al[10] has reported the prevalence of muscle cramps in patients with Child-Pugh A or B cirrhosis to be 52% when compared with those with chronic hepatitis who had a prevalence of 7.5%.

Although muscle cramps are usually non-progressive, benign, and self-limiting, they not only lead to significant complications like functional decline and loss of muscle mass but also adversely affect quality of life[11]. It has been shown that muscle cramps affect different areas of performance like mobility, energy levels, general and mental health, and societal engagement[6]. Muscle cramps are known to be the second-leading cause of increased pain and distress in this population[12]. A recent study published in 2017 has shown that 81% of people with liver cirrhosis experience disturbed sleep in association with muscle cramps[13]. Another study published in 2012 has shown that patients with cirrhosis with muscle cramps experience a significant decrease in quality of life independent of hepatic encephalopathy[2]. While it is true that quality of life decreases with worsening Child-Pugh score, muscle cramps are an independent factor in decreasing quality of life in patients with cirrhosis[14].

LITERATURE SEARCH AND REVIEW METHODOLOGY

This review was conducted as narrative review. A structured literature search was performed using databases (PubMed/MEDLINE, EMBASE, Cochrane Library) and Google scholar. Search terms including keywords and Medical Subject Headings terms were used. Only English language human studies were included. Case reports, case series, observational studies, and randomized controlled trials were reviewed.

Despite the significant impact of muscle cramps on quality of life for these patients, the pathophysiology of muscle cramps in cirrhosis remains unclear to date. The only association that has been found is with the presence of cirrhosis, low albumin levels, and high total bilirubin[5]. No association has been found between muscle cramps and ascites, diuretic use, and edema. The aim of this review article was to summarize our understanding of the pathophysiology and the treatment options available to address muscle cramps in liver cirrhosis. A better understanding of the etiology and development of therapeutic options can lead to improved quality of life for these patients.

PREVALENCE AND BURDEN OF MUSCLE CRAMPS IN CIRRHOSIS

The reported prevalence of muscle cramps in cirrhosis ranges from 22% to 88%. Variability reflects differences in disease severity, ascertainment methods, and underreporting[3,4]. Comparative studies consistently demonstrate higher prevalence in patients with cirrhosis than in healthy controls or those with chronic hepatitis[6,10].

PATHOPHYSIOLOGY

Nerve function

Studies of nerve dysfunction in liver disease showed that it is likely secondary to impaired membrane conduction as a result of oxidative stress[15]. As evidenced by histologic studies, patients with liver disease have thinly myelinated nerve fibers and axonal loss, supporting the theory of a structural cause of nerve dysfunction[16]. Patients with cirrhosis have involuntary bursts of action potentials, which appear as fasciculations on electromyogram with origins in the peripheral nerve[17] and chronically depolarized and hyperexcitable motor neurons that induce inappropriate high-frequency repetitive firing of the motor nerve action potentials, ultimately resulting in muscle cramps[1,16,18]. Direct nerve studies conducted on median and peroneal nerves in patients with cirrhosis showed increased nerve excitability due to depolarization of resting axonal membrane potential resulting in decreased in action potentials[19]. Nerve dysfunction, possibly related to oxidative stress and structural alterations, plays an important role in sustained muscle contractions leading to the development of muscle cramps. Treatments for nerve dysfunction in liver disease have focused on decreasing motor neuron excitability and relieving oxidative injury[20].

Energy metabolism

The liver has a major role in amino acid metabolism, protein metabolism, modification of amino acids, and synthesis of amino acids into protein[21]. Therefore, amino acid regulation and protein metabolism is altered in patients with cirrhosis, and as a consequence there is a decrease in plasma and skeletal muscle concentrations of taurine, the most abundant amino acid in the skeletal muscle[21]. Taurine is a non-essential beta amino acid involved in cell membrane stabilization and may become semi-essential in some disease states[22]. Alterations in the concentration of taurine results from decreased production related to the imbalance in the ratio of branched-chain amino acids to aromatic amino acids and the increased release from muscles[21,23,24]. Taurine concentrations influence the function of several ion channels, including the voltage-gated chlorine channels and calcium-activated sodium and potassium channels, which modulate striated fiber electrical activity and stabilize the sarcolemma[25,26].

A study evaluated plasma taurine levels in cirrhotic patients with and without muscle cramps in comparison to control patients without cirrhosis. The mean plasma taurine level in patients with cirrhosis with cramps was 56.9 nmol/mL, patients with cirrhosis without cramps was 79.3 nmol/mL, and healthy controls had a level of 90.1 nmol/mL[27]. These findings support that taurine deficiency may alter skeletal muscle electrical properties, increasing the predisposition of these patients to muscle cramps. Another possible explanation is hyperexcitability of motor nerve terminals due to altered local electrochemical environments seen in dehydration, renal failure and cirrhosis. Taurine works as a membrane-stabilizing agent for hyperexcitable muscles, and thus decreased taurine synthesis in cirrhosis leads to increased incidence of cramps[28]. Studies have shown that taurine supplementation relieved muscle cramps in patients with cirrhosis as taurine levels rose[23,27].

Carnitine is a branched-chain amino acid produced by the liver and kidney and plays a critical role in fatty acid oxidation[29]. It is also present in dietary sources such as meat and dairy products[30]. L-carnitine is involved in the transfer of long-chain fatty acids across the mitochondrial membrane and release of energy[31]. The ability of L-carnitine to reduce ammonia levels and improve mitochondrial function possibly contributes to the prevention of skeletal muscle mass loss in patients with cirrhosis[32]. Prospective treatment studies have shown improvement in muscle cramps in 88% of patients with daily supplementation of L-carnitine[33]. It is hypothesized that L-carnitine may improve the lack of ATP in cirrhotic skeletal muscle, counteracting the diminished cycling of actin and myosin cross-bridging and restoring calcium release from the sarcoplasmic reticulum calcium adenosine triphosphatase pumps, preventing prolonged contraction[20].

Reduced ATP is another potential contributor to altered energy metabolism leading to muscle cramps in patients with cirrhosis. Skeletal muscle biopsies in patients with cirrhosis showed reduced ATP, phosphocreatine, and total adenine nucleotide levels[34]. Decreased ATP could reduce the cycling process of actin and myosin cross-bridging, causing prolonged muscle contraction[20].

Integrated mechanistic framework

Muscle cramps in cirrhosis likely arise from a convergence of peripheral nerve hyperexcitability and skeletal muscle energetic/ionic instability rather than a single defect. Electrophysiologic studies supported a neurogenic origin in many patients with abnormal spontaneous activity and altered axonal excitability, and metabolic studies demonstrated reduced high-energy phosphate stores in cirrhotic skeletal muscle. Together, these processes can lower the threshold for repetitive motor unit firing and prolong involuntary contraction once triggered[17,19].

Oxidative stress and membrane depolarization: Chronic liver disease is associated with systemic oxidative stress that may injure peripheral nerves and alter membrane conduction. Histologic studies have described thinly myelinated fibers and axonal loss in hepatic neuropathy. Axonal excitability testing in end-stage liver disease demonstrated a depolarized resting membrane potential and increased excitability of peripheral nerves, conditions that promote high-frequency repetitive discharges capable of initiating cramps[15,31].

Peripheral nerve hyperexcitability and motor unit firing: Motor axons in cirrhosis may be chronically depolarized, facilitating ectopic firing. Electromyography observations of involuntary bursts arising from the peripheral nerve (often perceived clinically as fasciculations) aligned with a model in which cramps were triggered by abnormal motor axon firing rather than primary myopathy alone. This provides mechanistic rationale for agents that reduce excitability while emphasizing the need to balance benefit against sedation and encephalopathy risk[19].

ATP depletion, mitochondrial dysfunction, and contractile persistence: Cirrhotic skeletal muscle biopsies have demonstrated reduced ATP, phosphocreatine, and total adenine nucleotide content, suggesting impaired energetic reserve. ATP depletion can impair relaxation by limiting energydependent ion pumps and calcium reuptake. Mitochondrial dysfunction, potentially related to altered substrate availability, inflammation, hyperammonemia, and carnitine deficiency, may further constrain ATP production, amplifying cramp propensity during nocturnal rest or after exertion[20].

Sarcoplasmic calcium handling as a final common pathway: Termination of contraction requires rapid sequestration of cytosolic Ca²⁺ into the sarcoplasmic reticulum via ATP-dependent sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase pumps. When ATP is depleted, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase activity falls, cytosolic Ca²⁺ remains elevated, and actin-myosin cross-bridge cycling cannot fully disengage, leading to a prolonged, painful contraction. This links energetic failure to the sustained duration of cramps and provides biologic rationale for interventions that improve muscle energetics (e.g., L-carnitine) or nutritional substrate (branched-chain amino acid; Figure 1)[20,34].

Figure 1 Integrated pathophysiologic mechanisms underlying muscle cramps in liver cirrhosis. BCAA: Branched-chain amino acids; SERCA: Sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase.

Taurine-mediated ion channel regulation and sarcolemmal stabilization: Taurine modulates ion channels (including chloride conductance and calcium-activated sodium/potassium currents) that stabilize the sarcolemma and regulate excitability. Patients with cirrhosis, particularly those with cramps, often demonstrate lower plasma taurine levels, reflecting altered amino acid metabolism. Reduced taurine may diminish stabilizing ionic currents, increasing susceptibility to afterdischarges and lowering the threshold for cramp initiation. Clinical trials showing symptom improvement with taurine supplementation along with mechanistic literature on the channel effects of taurine, support taurine deficiency as a biologically plausible, treatable contributor[23].

Proposed integrative model: Oxidative stress and neuropathic change may depolarize peripheral axons and increase spontaneous firing (cramp triggering). Concurrently, sarcopenia, impaired mitochondrial ATP production, and reduced high-energy phosphate reserves limit the ability of the muscle to restore ionic gradients and to resequester Ca²⁺ during relaxation (cramp persistence). Taurine deficiency may further destabilize ion channel function at nerve and muscle levels. This framework predicts that multipronged therapy targeting excitability (selected muscle relaxants), energetics (Lcarnitine; nutrition/branched-chain amino acids), and membrane stabilization (taurine) may be more effective than any single agent, warranting testing in adequately powered randomized trials[23,26].

Experimental and electrophysiological support

Electrophysiological investigations in cirrhosis demonstrated altered axonal excitability consistent with a depolarized resting membrane potential and increased propensity for repetitive discharges, supporting a peripheral nerve-driven trigger for cramps. Complementary electromyography observations of spontaneous bursts arising from peripheral nerve further reinforce this neurogenic component.

On the muscle side biopsy-based biochemical studies showing reduced ATP and phosphocreatine provide experimental support for an energetic mechanism that would impair calcium reuptake and relaxation. Mechanistic work describing the modulation of taurine in skeletal muscle ion channels and sarcolemmal stability provides additional experimental plausibility for taurine deficiency as a contributor to excitability and cramp susceptibility[20,23].

CLINICAL IMPACT AND QUALITY-OF-LIFE CONSEQUENCES

Muscle cramps independently worsen quality of life in cirrhosis, contributing to sleep disturbance, functional limitation, and psychosocial distress. Their impact is independent of hepatic encephalopathy and Child-Pugh class[1,5,10].

TREATMENT APPROACHES

Clinical perspectives

Routine screening for muscle cramps should be incorporated into cirrhosis care. Taurine, L-carnitine, and branched-chain amino acids offer favorable safety profiles, and baclofen or methocarbamol may be considered in refractory cases. Quinine is generally discouraged due to safety concerns.

Quinine

Quinine is a natural alkaloid derived from cinchona bark that has played a historically significant role in the treatment and prevention of malaria. It also holds some contentious value in the treatment of idiopathic muscle cramps. Quinine is thought to ameliorate muscle cramps by increasing the excitability of the motor end plate to nerve stimulation and therefore increasing the refractory period of skeletal muscular contraction[35]. El-Tawil et al[36] performed a meta-analysis examining the benefit of quinine on muscle cramps and found that a dose of or close to 300 mg/day reduced the number of cramps over 2 weeks by 28%, the cramp intensity by 10%, and the total number of days with cramps by 20%. The duration of cramps, however, was not significantly affected. The authors concluded that there was low quality evidence that 200-500 mg/day of quinine significantly reduced cramp number and cramp days and moderate quality evidence that quinine reduced cramp intensity.

Several studies also included compounds of quinine with other substances, such as theophylline, vitamin E, and glucosamine to assess for an added benefit[37]. Lee et al[38] conducted a single-blinded randomized controlled trial consisting of 31 participants in which quinidine, an optical isomer of quinine, was compared with placebo. The treatment group received 400 mg of oral quinidine sulfate per day for 4 weeks. At the end of the study, the authors observed that the number of cramps significantly decreased in the treatment group (14.4 ± 1.7 episodes to 1.4 ± 1.1 episodes, P < 0.0001) but remained unchanged in the control group. Furthermore, 88% of the treatment group displayed a greater than 50% reduction in muscle cramp episodes over the 4-week study period as compared with only 13% of the participants who received placebo.

Muscle relaxants

The administration of various antispasmodic agents has been shown to relieve symptoms of muscle cramps in general. Eperisone hydrochloride is a centrally acting muscle relaxant that acts by relaxing both skeletal and smooth muscles. In 1992 Kobayashi et al[8] demonstrated that the administration of 150-300 mg/day of eperisone hydrochloride in 21 patients with cirrhosis over an 8-week period resulted in a complete disappearance of symptoms in 61% of the participants and decreased frequency of muscle cramps in 33% of the participants. Further research has since shown benefit of other muscle relaxants in relieving muscle cramps in patients with cirrhosis. In a double-blinded randomized controlled trial consisting of 100 patients with hepatitis C-induced liver cirrhosis, Abd-Elsalam et al[39] studied the efficacy of methocarbamol in the treatment of muscle cramps. The authors found that after 1 month of administration of methocarbamol, patients displayed a decrease in the number of muscle cramps per week (11.0 ± 4.0 to 0.5 ± 1.0, P < 0.001), a reduction in the mean duration of muscle cramps (4.22 ± 1.55 min to 0.71 ± 1.06 min, P < 0.001), and an improvement in the mean score of the severity of pain experienced due to muscle cramps (6.52 ± 1.29 to 0.66 ± 1.18, P < 0.001). The only side effects reported were dry mouth and dizziness.

Two respective studies in 2016[40,41] examined the effects of baclofen, a γ-aminobutyric acid-derived muscle relaxant in the treatment of cirrhosis-associated muscle cramps. Henry and Northup[40] administered 5 mg or 10 mg of baclofen three times daily for 4 weeks to 8 patients. The authors found that baclofen appeared to reduce the frequency (5.5 ± 2.1 to 1.4 ± 2.0, P < 0.01) and the severity (8.5 ± 1.8 to 2.8 ± 2.7, P < 0.01) of muscle cramps.

Another study supporting these findings was a randomized open label trial conducted by Elfert et al[41]. They administered either baclofen or a placebo to 100 participants with cirrhosis for 3 months. The baclofen was increased by 10 mg weekly until the disappearance of cramps or development of side effects. The patients in the baclofen-treated group exhibited a statistically significant decrease in the median number of muscle cramps (14 cramps per week to 3 cramps per week, P < 0.005), pain intensity (4/10 to 0/10, P < 0.001), and duration (3 min to 0 min, P < 0.001). Intriguingly, the participants experienced a rebound in cramp frequency 2 weeks after the baclofen washout period. At the conclusion of the 3-month study, muscle cramps disappeared completely in 36 patients (72%), reduced in 10 patients (20%), and still showed no change in 4 patients (8%). The only adverse effects reported were drowsiness in 4 patients (8%), constipation in 5 patients (10%), and nausea in 2 patients (4%). The lack of significant adverse effects and reductions in muscle cramp frequency, duration, and symptoms indicate that muscle relaxants may be useful in treating muscle cramps in patients with cirrhosis.

Taurine

Taurine is an amino acid that influences the stability of skeletal muscle cell membranes patients with cirrhosis has been shown to provide relief from muscle cramps. Liu et al[23] administered 6 g of taurine 3 times daily for 4 weeks to 12 patients with cirrhosis. They observed that 8 patients reported complete resolution of cramps, 4 patients reported a significant decrease in cramp severity, and no patients complained of adverse events. Furthermore, Sivandzadeh et al[27] conducted a study to assess the relationship of plasma taurine concentration with the mechanism of cirrhosis-associated muscle cramps. The researchers recruited 28 patients with liver cirrhosis of which 15 experienced muscle cramps and 13 did not. They found that the plasma taurine concentration in patients with cirrhosis with muscle cramps (56.9 ± 17.3 nmol/mL) was significantly lower compared with patients with cirrhosis without muscle cramps (79.3 ± 16.7 nmol/mL) and normal controls (90.1 ± 12.1). The authors further administered 3 g of taurine per day for 4 weeks to 9 of the patients with cirrhosis with muscle cramps and reported a 2.2-fold increase in plasma taurine with improvement of symptoms in 67% of the subjects.

In 2018 Vidot et al[42] conducted a double-blinded, randomized controlled, crossover study that examined the effect of dose-variable taurine supplementation on 30 participants with chronic liver disease who suffered from three or more muscle cramps per week. The authors observed that patients receiving 2 g of taurine per day experienced a reduction in cramp frequency (7 fewer cramps per 2-week period, P = 0.03), duration (89 min less of endured cramps per 2-week period, P = 0.03), and severity (1.4 units less on a Likert scale P < 0.004).

In another recent trial in 2021, Jang et al[43] conducted a single-arm pilot study that examined the effect of taurine on 10 patients with cirrhosis-associated muscle cramps. The subjects were administered 1 g/50 mL of oral taurine 3 times per day for 4 weeks and followed for a total of 8 weeks. By week 4 a significant decrease in the intensity of muscle cramps compared with baseline was observed. Additionally, muscle cramp scores (frequency × intensity) improved in 7 patients (70%) by week 4 with another 2 patients (20%) reporting improvements by week 8. A low baseline plasma taurine concentration (< 65 μmol/L/L) was observed in 5 patients. Intriguingly, 3 of these patients (60%) reported an improvement in their symptoms at 4 weeks, and 4 (80%) reported an improvement at 8 weeks. Among the 5 subjects with normal or higher taurine concentrations, 4 (80%) reported an improvement in symptoms at week 4, and 3 (60%) reported an improvement at week 8. The only adverse effect reported was a mild case of dyspepsia.

Branched-chain amino acids

Supplementation of branched-chain amino acids, such as isoleucine, leucine, and valine, may improve albumin deficiency, insulin resistance, fatigue, sleep disturbances, hepatocarcinogenesis, and muscle cramps in patients suffering from cirrhosis[21]. Multiple investigations have examined the efficacy of branched-chain amino acids in the treatment of cirrhosis-associated muscle cramps. Sako et al[44] performed a prospective study that administered branched-chain amino acids to a group of 8 patients for 3 months. The authors found that nocturnal supplementation of branched-chain amino acids significantly reduced the frequency of muscle cramps (7.4 ± 2.0 times/week to 0.3 ± 0.5 times/week, P < 0.0001).

The value of branched-chain amino acid supplementation in cirrhosis-associated muscle cramp treatment was further investigated in a multicenter, randomized controlled trial conducted by Hidaka et al[45]. In this study 21 patients received daily branched-chain amino acid supplementation, and 16 received nocturnal supplementation for 3 months. At the end of the trial, all participants exhibited a significant decrease in the frequency of muscle cramps (P = 0.004) and significant improvement in general health as determined by a questionnaire (P = 0.01). The only adverse effects reported were abdominal distention in 2 patients and general itching in 1 patient. These promising outcomes suggest that the supplementation, especially nocturnal, of branched-chain amino acids may serve as a safe and beneficial treatment for patients suffering from cirrhosis associated muscle cramps.

In 2014 Tsuda et al[46] assessed the effects of branched-chain amino acid-enriched nutrition in patients previously unresponsive to branched-chain amino acid granules. Thirty-two patients with decompensated cirrhosis who had showed no improvement in serum albumin levels after 3 months of branched-chain amino acids granule administration were given 50 g of a flavored branched-chain amino acid-enriched oral nutrient twice daily. Serum albumin levels and major cirrhotic symptoms were examined at 1 month, 3 months, and 5 months of treatment. Serum albumin levels improved significantly 3 months after starting treatment (P < 0.01), and Child-Pugh scores decreased significantly (P < 0.01). In the majority (53%-80%) of patients, muscles cramps, fatigue, fatigability, edema, and sleep disturbance improved within 3 months after therapy initiation. Approximately 90% of the patients became symptom-free 5 months after treatment initiation.

Albumin

The infusion of intravenous albumin may benefit patients with cirrhosis suffering from muscle cramps. This effect is likely due to its positive effect on mean arterial pressure and plasma renin activity. Angeli et al[9] conducted a crossover study that examined the use of intravenous albumin infusions against placebo in 12 patients with cirrhosis. The participants underwent an 8-week run-in period to establish a baseline number of cramps, followed by a 4-week placebo period (100 mL 5% dextrose solution administered weekly), 4-week albumin period (100 mL 25% human albumin solution administered weekly), and finally a 2-month wash-out period. The authors observed no change in the frequency of cramps during the placebo period, a significant reduction in the frequency during the albumin period (2.5 ± 2.9, P < 0.001). Furthermore, the 9 participants who responded to the albumin infusions also exhibited a significant increase in mean arterial pressure (93 ± 6 to 98 ± 9, P < 0.01) and a significant decrease in the plasma renin activity (13.25 ± 12.11 ng/L/hour to 5.01 ± 5.59 ng/L/hour, P < 0.01) compared with the placebo period. The cramps gradually returned during the wash-out period with a mean duration of effect of 15 ± 6 days.

Vitamin E

Vitamin E is a fat-soluble vitamin that plays a role in protection from free radicals. It has been observed that patients suffering from alcoholic liver disease, hemochromatosis, and Wilson’s disease present with low serum levels of vitamin E[42,47]. There are two studies that have examined the effect of vitamin E supplementation in patients with cirrhosis suffering from muscle cramps. Liang et al[48] conducted a case-series report that examined 29 patients with cirrhosis, 23 of whom suffered from muscle cramps. The authors found that the patients experiencing muscle cramps had significantly lower serum levels of vitamin E than those who did not. Thirteen of these patients were supplemented with 200 mg of vitamin E three times per day for 4 weeks and reported a statistically significant improvement in the frequency, duration, and intensity of muscle cramps.

In 2011 Chandok et al[49] conducted a randomized double-blinded placebo-controlled crossover pilot study in 9 patients with cirrhosis suffering from muscle cramps and found that there was no statistically significant difference between vitamin E and placebo for the frequency (P = 0.98), duration (P = 0.93), and severity (P = 0.57) of cramps. Intriguingly, the authors reported a trend towards worse measures with vitamin E compared with placebo with all parameters except the need for analgesia. Due to these conflicting results, possibly as a result of a lack of a control group in the first study and absence of treatment specifications in the second, larger randomized double-blinded placebo-controlled trials are needed to identify whether vitamin E is a verifiable treatment option for patients with cirrhosis suffering from muscle cramps.

Zinc

The use of zinc supplementation has been assessed to treat muscle cramps in patients with cirrhosis. Kugelmas[50] administered 220 mg of zinc sulfate twice daily for 12 weeks to 12 patients with hypozincemia who suffered from cirrhosis-associated muscle cramps. The authors found that 10 of the participants reported an overall improvement in their symptoms with 7 patients reporting complete resolution. The only side effect experienced was mild diarrhea in 1 patient that resolved with cessation of supplementation. These findings suggest that oral zinc sulfate may possibly serve as a safe and affordable treatment for cirrhosis-associated muscle cramps.

L-carnitine

L-carnitine, a naturally occurring amino acid, has been hypothesized to play a role in preventing muscle wasting in chronic conditions by assisting the transport of long-chain fatty acids across mitochondrial membranes and helping with oxidative release of energy[51]. In 2015 Nakanishi et al[33] performed a prospective study to assess the role of L-carnitine in reducing muscle cramps in patients with cirrhosis. Patients were administered L-carnitine 300 mg 3 times a day (n = 19) or 4 times a day (n = 23) for 8 weeks. Questionnaires were used to assess the frequency of muscle cramps, and the Visual Analogue Scale was used to assess the degree of cramping. Muscle cramps were reduced in 88.1% of the patients and disappeared in 28.6% of patients by the end of 8 weeks. Visual Analogue Scale scores also decreased significantly from 69.9 ± 22.5 to 26.2 ± 29.1 after 8 weeks (P < 0.0001). No adverse events were reported in this study. The level of evidence supporting current therapeutic treatments are summarized in Tables 1 and 2.

Table 1 Comparative critical appraisal of therapies for muscle cramps in cirrhosis.

Treatment category	Proposed mechanism (in cirrhosis cramps)	Best available cirrhosis-specific evidence (design; n)	Effect signal (frequency/severity/duration)	Level of evidence1	Key limitations	Adverse events/cautions
Taurine	Membrane/ion-channel stabilization; may reduce peripheral nerve/muscle hyperexcitability in taurine-deficient cirrhosis	Double-blind randomized crossover trial (n = 30); multiple small open-label studies/case series (n = 9-12)	Generally, reduces cramp frequency and severity; response varies	Moderate	Small samples; heterogeneous populations; short follow-up; patient-reported outcomes	Usually well tolerated; occasional dyspepsia
L-carnitine	Improves mitochondrial fatty-acid transport/ATP availability; may improve muscle energetics and ammonia handling	Prospective treatment study (n = 42; 8 weeks)	High proportion report improvement; VAS cramp score decreases	Low	Non-randomized; placebo effect likely; short duration; limited objective endpoints	Typically, well tolerated; possible GI upset/odor; caution with severe renal impairment
Branched-chain amino acids	Restores amino-acid balance; supports muscle metabolism; may improve sarcopenia and albumin; may stabilize neuromuscular function	Multicenter randomized trial of timing regimens (n = 37; 3 months) + small prospective studies	Reduced frequency (notably nocturnal dosing) and improved patient-reported health/QoL	Low-moderate	Often compares regimens rather than placebo; nutritional co-interventions; adherence variability	Mostly mild GI symptoms (bloating/distention); rare pruritus
Muscle relaxant: Baclofen	Central GABA-B agonist; reduces motor neuron excitability	Randomized open-label placebo-controlled trial (n = 100; 3 months) + small case series	Large decreases in frequency, intensity and duration; rebound after washout described	Moderate	Open-label expectation bias; titration individualized; limited long-term data	Drowsiness/sedation, constipation, nausea; caution with encephalopathy risk and falls
Muscle relaxant: Methocarbamol/eperisone	Central antispasmodic effects; reduces spasm and perceived pain	Methocarbamol RCT (n = 100; 1 month); eperisone open-label (n = 21; 8 weeks)	Methocarbamol: Marked reduction in cramps and pain scores; eperisone: Complete/partial response in many	Moderate (methocarbamol); low (eperisone)	Short follow-up; limited replication; subjective endpoints; safety data limited in decompensated cirrhosis	Dry mouth, dizziness; sedation - caution with CNS depressants and fall risk
Albumin infusion (intravenous)	Improves effective arterial blood volume/renal-RAAS physiology; may reduce circulatory triggers	Randomized crossover vs placebo (n = 12; weekly infusions)	Reduced cramp frequency during infusion period; effect wanes after stopping	Low	Very small sample; intravenous therapy resource-intensive; optimal dose/schedule unclear	Cost/intravenous access burden; volume overload/pulmonary edema risk in susceptible patients
Zinc	Corrects hypozincemia; neuromuscular stabilization (uncertain)	Small uncontrolled study in hypozincemia patients (n = 12; 12 weeks)	Many report improvement/resolution	Very low	No control group; selection bias; unclear generalizability beyond deficiency states	Diarrhea; with prolonged/high dose - copper deficiency risk (monitor if long-term)
Vitamin E	Antioxidant; theoretical benefit via oxidative-stress pathways	Case series suggests benefit; randomized double-blind placebo-controlled crossover pilot (n = 9) negative	Conflicting; controlled data do not show consistent benefit	Very low	Small, underpowered studies; inconsistent designs; deficiency status not standardized	Generally tolerated; high-dose long-term vitamin E may increase bleeding risk - caution with coagulopathy/anticoagulation
Quinine/quinidine	Modulates excitability at motor endplate; prolongs refractory period	Cirrhosis RCT with quinidine (n = 31; 4 weeks); broader non-cirrhosis meta-analyses show modest benefit	May reduce frequency; duration effects inconsistent	Low (cirrhosis-specific)	Safety concerns outweigh benefit; limited cirrhosis-specific trials; not guideline-recommended	Serious risks: Immune thrombocytopenia/pancytopenia, TTP/HUS, QT prolongation/arrhythmias, hypoglycemia - generally avoid

¹Level of evidence is a pragmatic synthesis based on study design, sample size, risk of bias, and consistency (not a formal Grading of Recommendations, Assessment, Development and Evaluation assessment). GABA-B: γ-aminobutyric acid type B receptor; RAAS: Renin-angiotensin-aldosterone system; RCT: Randomized controlled trial; VAS: Visual Analogue Scale; QoL: Quality of life; GI: Gastrointestinal; CNS: Central nervous system; TTP: Thrombotic thrombocytopenic purpura; HUS: Hemolytic uremic syndrome; QT interval.

Table 2 Summary of therapeutic studies for muscle cramps in liver cirrhosis.

Therapy	Study design	Sample size (n)	Duration	Key outcomes	Major limitations	Strength of evidence
Taurine	Randomized crossover + open-label studies	9-30	4-8 weeks	↓Cramp frequency, severity, and duration	Small samples; subjective outcomes; short follow-up	Moderate
L-carnitine	Prospective observational study	42	8 weeks	↓Cramp frequency; ↓VAS scores	Non-randomized; placebo effect possible	Low
BCAA	Randomized trial (timing regimens)	37	3 months	↓Cramp frequency; ↑QoL	No placebo control; nutritional confounding	Low-Moderate
Baclofen	Randomized open-label placebo-controlled	100	3 months	↓Frequency, severity, duration	Open-label; sedation risk	Moderate
Methocarbamol	Randomized controlled trial	100	1 month	Marked ↓cramps and pain scores	Short duration; limited replication	Moderate
Albumin (intravenous)	Randomized crossover	12	4 weeks	↓Cramp frequency during treatment	Very small sample; intravenous burden	Low
Zinc	Uncontrolled pilot study	12	12 weeks	Symptom improvement in majority	No control group; selection bias	Very low
Vitamin E	Case series + RCT crossover	9-23	4 weeks	Conflicting results	Underpowered; inconsistent design	Very low
Quinine/quinidine	RCT	31	4 weeks	↓Cramp frequency	Serious adverse effects	Low

BCAA: Branched-chain amino acids; RCT: Randomized controlled trial; VAS: Visual Analogue Scale; QoL: Quality of life.

DISCUSSION

Chronic liver disease is a debilitating condition with significant morbidity and mortality. Globally, chronic liver disease and liver cirrhosis cause more than 2 million and 1 million deaths annually, respectively; this equated to about 2% of all deaths worldwide in 2010[52-54]. Liver disease is the seventh most common cause of death in Europe and the fifth-leading cause of death in people under age 65 in the United Kingdom[55,56]. In the United States this is the 12^th-leading cause of death, accounting for 12.5 deaths per 100000 people, and the 7^th-leading cause of death in population ranging from 25-64 years of age[57,58].

Given that chronic liver disease affects a relatively younger population compared with most other end-organ diseases with years of life lost estimated at 20, the need to manage symptoms and improve quality of life for these patients is pressing and requires more attention[56,59]. However, very often the focus of clinicians is on prevention and management of more life-threatening complications of cirrhosis such as esophageal varices, coagulopathy, ascites, and encephalopathy. Therefore, there may not be sufficient emphasis on other benign but debilitating symptoms that accompany cirrhosis and negatively impact quality of life. Patients with liver cirrhosis report a wide-ranging symptomatology including but not limited to pain, fatigue, breathlessness, muscle cramps, erectile dysfunction, sleep disturbance, and varying psychological symptoms. This review specifically focused on the prevalence, pathophysiology, and treatment options for muscle cramps in patients with chronic liver disease. Despite the need to enhance quality of life for this patient population, there are no definitive treatment options available that target muscle cramps.

Multiple small case series and observational studies have been performed exploring different potential therapeutic options, but there is a paucity of strong evidence supporting any particular treatment. More randomized controlled trials are needed to provide evidence regarding this. Several small studies have shown some benefits of treatment with quinine and quinine-derived products, taurine, branched-chain amino acids, intravenous albumin, and L-carnitine.

Data regarding the use of quinine and quinine-derived products on the treatment and prevention of cirrhosis-associated muscle cramps are limited. Due to the lack of evidence on optimal dosing and the risk of severe side effects such as pancytopenia, coagulopathy, renal insufficiency hemolytic uremia[60], hypoglycemia, and gastrointestinal adverse effects, the Food and Drug Administration withdrew quinine for off-label indications, such as muscle cramps. Quinine may also cause arrhythmias, convulsions, respiratory distress, and death[61]. Therefore, even though studies display a positive outcome on patients who use quinine or quinine-derived products for muscle cramps, its role in treatment remains debatable due to the risk of adverse side effects.

Taurine has also shown promising results in some studies. Patients with cirrhosis tend to have lower levels of plasma taurine due to defective methionine metabolism compounded by dietary restrictions[62,63]. Oral supplementation with taurine increases serum taurine level and potentially aids in membrane stabilization and neurotransmission leading to improvement in symptoms[63]. The positive outcomes of these studies indicate that taurine may serve as a safe and viable treatment option. Even though patients with a lower plasma taurine concentration seem to have more positive outcomes, patients with normal taurine levels may benefit as well.

Branched-chain amino acid supplementation in patients with cirrhosis increases albumin levels, restores amino acid balance in the body, and increases muscle mass[21]. This is particularly helpful as patients with cirrhosis have significant muscle wasting (up to 41% are sarcopenic)[64]. It appears to be a safe and effective treatment option. However, larger controlled studies are required to establish its efficacy.

L-carnitine, another amino acid, has shown a benefit in reducing muscle cramps with no significant side effects. It has been shown to improve cardiac muscle contractility and glucose utilization; however, the exact mechanism is unconfirmed as yet[65]. Hiraoka et al[66] performed a study to determine the efficacy of L-carnitine supplementation and exercise in reducing muscle complications in patients already receiving branched-chain amino acid supplementation. This study demonstrated a significant reduction in the frequency of muscle cramps (P = 0.025). It may be of interest to further explore synergistic effects of some of these therapies in the future. Furthermore, intravenous albumin infusions may also serve as an effective treatment with significant improvement in muscle cramps. However, it is a costly option with intravenous infusions making it inconvenient.

Other therapeutic options like vitamin E and zinc need further larger scale randomized controlled trials to determine efficacy. Vitamin E has shown conflicting results in the two studies that have been performed to assess its efficacy. Of note, there is very limited data regarding the use of magnesium supplementation in patients with cirrhosis even though it is often prescribed to this patient population for this indication[4]. Although many studies have been performed assessing the effects of magnesium supplementation on muscle cramps in patients who are pregnant, old, or have motor neuron disorders like amyotrophic lateral sclerosis[67], there is a paucity of data exploring its use in cirrhosis.

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

Muscle cramps should be routinely screened for in patients with cirrhosis as they are common, underreported, and substantially impair quality of life. In the absence of guideline-directed therapy, a mechanism-informed approach is warranted. Among available interventions, taurine, L-carnitine, and branched-chain amino acids emerged as the most promising therapies based on biologic plausibility, favorable safety profiles, and consistent signals of efficacy in small clinical studies. Taurine (approximately 2-6 g/day) may stabilize sarcolemma ion channel function, L-carnitine (900-1200 mg/day) may improve mitochondrial energetics and ATP availability, and nocturnal branched-chain amino acids supplementation (approximately 12 g/day) may enhance muscle metabolism while addressing sarcopenia. Future trials should prioritize integrated mechanistic targets linking peripheral nerve hyperexcitability with skeletal muscle energetic failure and incorporate objective biomarkers to better define treatment response[68]. Future research should focus on adequately powered randomized trials, standardized outcome measures, objective electrophysiological endpoints, and combination therapeutic strategies informed by mechanistic insights.

CONCLUSION

Muscle cramps are a highly prevalent yet underrecognized complication of liver cirrhosis, exerting a substantial impact on quality of life despite their non-life-threatening nature. Evidence increasingly supports that these symptoms reflect intrinsic pathophysiologic consequences of chronic liver disease rather than incidental or treatment-related phenomena. Beyond pain, muscle cramps contribute to sleep disturbance, functional limitation, and psychosocial distress, independent of hepatic encephalopathy or conventional measures of disease severity. Current data support a multifactorial mechanistic model in which oxidative stress-related neuropathic changes and peripheral nerve hyperexcitability converge with skeletal muscle energetic failure. Mitochondrial dysfunction, ATP depletion, impaired sarcoplasmic calcium reuptake, and taurine-dependent ion channel dysregulation collectively lower the threshold for cramp initiation and prolong contraction duration. This framework helps explain the variable and incomplete response to single-agent therapies. Although therapeutic evidence remains limited, agents targeting muscle energetics and membrane stabilization such as taurine, L-carnitine, and branched-chain amino acids appear to offer the most favorable balance of safety and potential benefit while centrally acting muscle relaxants may be effective in selected patients. Future progress will require well-designed randomized trials incorporating standardized outcomes and mechanistic biomarkers. Recognizing muscle cramps as a treatable manifestation of cirrhosis represents an important opportunity to meaningfully improve patient quality of life.

ACKNOWLEDGEMENTS

The authors thank all patients living with cirrhosis whose experiences having contributed to advancing our understanding of the disease physiology despite their suffering.