Muscle cramps are described as an involuntary, sudden and painful squeezing or contraction of a muscle tissue (single muscle or group of muscles) at rest or during sleep, lasting seconds to minutes. Although muscle cramps are usually self-limiting and non-lethal, their occurrence is associated with decreased physical and social functioning and bodily pain. Common causes of muscle cramps are mentioned below in table 1.

Table 1: Diseases, medications, and physiological changes associated with muscle cramps

Data suggests that the prevalence of muscle cramps in patients with liver diseases ranges from 22% to 88%. However, among patients with liver disease, the prevalence of muscle cramps, particularly in cirrhotic patients, was considerably higher than non-cirrhotic patients (31% vs. 5%). When the occurrence of muscle cramps was studied in comorbid conditions, Abraham et al. compared cirrhotic patients to those with congestive heart failure (CHF) , and found a greater prevalence of muscle cramps in cirrhotic patients than patients with CHF (22% vs. 5%)irrespective of diuretic use. Collectively, all these studies suggest that physiological alterations unique to liver cirrhosis lead to the development of cramps in these patients.

The general health-related QoL, as measured by instruments such as the Medical Outcome Study Short Form-36 and the Nottingham Health Profile questionnaires, is diminished in cirrhotic patients with cramps. However, the Chronic Liver Disease Questionnaire (CLDQ) is a more sensitive and specific instrument to assess the QoL in patients with liver disease. In a survey of 544 cirrhotic patients, Marchecini et al. have reported that muscle cramps are the most frequent variable associated with a poor health-related QoL. These studies suggest that muscle cramps affect the physical and mental well-being of cirrhosis patients due to lower domain scores in abdominal symptoms, fatigue, systemic symptoms, activity, emotional functions, and stress relative to cirrhotic patients without cramps.

The exact pathophysiological events for the development of muscle cramps in liver cirrhosis are not clearly understood. Important findings in this regard have proposed alterations in three specific areas mentioned below:

Nerve Function
Studies suggest 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.

Structural damage to nerve tissue as documented on histological studies in patients with liver disease, suggests a loss of the myelin sheath, which leads to thinly myelinated nerve tissues along with axonal loss. Patients with liver cirrhosis also showed involuntary bursts of action potential from peripheral nerves which lead to chronic depolarization and hyper-excitability in the motor neurons, inducing repetitive motor nerve action potential of higher frequency.

Therapeutic approaches have, therefore, focused on reducing motor neuron excitability and decreasing oxidative stress within nerve tissues.

Energy Metabolism
Liver cirrhosis causes a dysregulation of protein and amino acid metabolism, which leads to reduction in taurine concentrations (the most abundant amino acid in skeletal muscle) in plasma and skeletal muscles. Taurine is an amino acid containing sulphur, which decreases the muscle hyper-excitability and stabilizes the cell membrane. Fluctuations in taurine concentrations may be due to both decreased production related to an imbalance in the ratio of branched chain amino acids to aromatic amino acids and increased release from muscle.

Voltage-dependent chloride channels and calcium-activated sodium and potassium channels regulate the electrical activity of striated fibers and stabilize the sarcolemma. The activity of these critical ion channels is controlled by taurine concentrations. Decrease in taurine levels leads to a reduction in the threshold potential and hyper-excitability of the skeletal muscles. This hypothesis is supported by Yamamoto et al. in a study measuring mean plasma taurine levels in cirrhotic patients with and without muscle cramps. It was observed that, cirrhotic patients with muscle cramps had lower mean plasma levels of taurine (56.9 nmol/mL) than cirrhotic patients without muscle cramps (79.3 nmol/mL) when compared with healthy controls (90.1 nmol/mL).

Reduced adenosine triphosphate (ATP) synthesis was found to be an another contributor to altered energy metabolism, studies in cirrhotic patients showed decreased levels of ATP, phosphocreatine and total adenine nucleotide levels. Decreased ATP levels curtail cyclic cross-bridging of actin and myosin filaments, thereby prolonging muscle contraction especially during abnormal electrical activity.

Plasma Volume, Zinc and Electrolytes
Factors that can alter intracellular electrolyte concentration such as hypokalemia, hyponatremia and hypomagnesemia as well as shifts in plasma volume leading to hypovolemia have been suspected to have a role in the development of muscle cramps. A shift/alteration in plasma volume reduces perfusion to the nerves and, thereby, may induce cramps.

A study showed that higher plasma renin activity, presence of ascites, and lower means arterial pressure were predictors of cramps occurring in patients with cirrhosis Results suggest that serum electrolyte concentrations and diuretic use do not directly influence the frequency of cramps in patients with cirrhosis however shifts in plasma volume may contribute to cramps. However, intracellular electrolyte levels could impact on muscle excitability and have not been evaluated in cirrhotic patients with or without cramps.

The treatment approach is generally empiric or directed against the pathophysiological factors.

Nerve Function

Vitamin E
Vitamin E is a fat-soluble vitamin with alpha-tocopherol as its active biological form. It has potent antioxidant properties and plays an important role in the stability of the phospholipid bilayer of cell membranes. Deficiency of vitamin E in humans leads to the development of myopathy and, in animals, myocyte necrosis. When compared with healthy controls, serum vitamin E levels were found to be lower in patients with alcoholic liver disease, hemochromatosis and Wilson's disease. In another study cirrhotic patients with cramps were found to have significant lower serum vitamin E levels than those without cramps (6.3 +/ 3.2 vs. 11.5 +/ 4.8 microgram/mL, P = 0.01). With regards to treatment with vitamin E for cramps, two additional studies have been published. One of these studies, which used a symptom scoring method in 13 subjects after 4 weeks treatment with vitamin E (200 mg 3 times daily), reported a significant improvement in the cramps symptom score (severity, frequency and duration).

However, another randomized, placebo-controlled crossover study reported no statistically significant difference after with treatment of either vitamin E or placebo in 9 adult cirrhotic patients. Additional studies are therefore, needed to assess the effectiveness of vitamin E treatment in controlling cramps.

Quinine Sulphate (an alkaloid derived from cinchona bark)

Though quinine has been used for the treatment of cramps in cirrhotic patients since the 1940s, it is, currently, not available over the counter in the United States due to an unfavorable risk benefit profile as well as significant and rare adverse events such as thrombocytopenia, cardiac arrhythmias, hemolysis, and cinchonism. Quinine is supposed to prolong the refractory period of the muscles for repetitive stimuli, thereby reducing motor nerve excitability. A recent meta-analysis has reported that the efficacy of quinine was comparable with vitamin E in the treatment of muscle cramps in non-cirrhotic patients. Furthermore, another single blind, placebo-controlled study in 31 cirrhotic patients reported a significant decrease in cramps episodes in patients treated with quinine 200 mg twice daily for 4 weeks (n = 16) than with placebo. The only side effect that was reported in this study was mild diarrhea (31%).

Eperisone Hydrochloride (central muscle relaxant)

The action of eperisone is mediated through the suppression of sympathetic stimulation in the skeletal muscles. The effect of eperisone hydrochloride (150-300 mg) for the treatment of muscle cramps (with a frequency of more than once weekly) was studied by Kobayashi et al. in 23 cirrhotic patients in a non-blinded, open-label study. While 11 patients reported the complete disappearance of cramps, 6 patients reported about reduced cramps frequency; however, no improvement was observed in 1 patient. Epigastric distress, fatigue and dizziness were the reported adverse effects of eperisone treatment. Although cramps severity was found to be decreased after treatment with eperisone, long-term follow-up data is not available.

Taurine
The role of taurine in the treatment of muscle cramps in cirrhosis has been studied in three small open-label studies. In the first study, a 4-week treatment with taurine (6 gram taurine thrice daily) in 12 cirrhotic patients resulted in complete resolution of cramps in 8 patients, whereas 4 patients reported a decrease in cramps severity after 1 month of therapy and no adverse effects were reported. In a second study, treatment with 3 gram taurine for 4 weeks in 35 cirrhotic patients lead to complete symptom resolution in 13 (37.1%) patients, whereas 25 patients (71.4%) reported significant improvement in cramps. In another study, Yamamoto et al. performed plasma taurine estimation in 15 cirrhotic patients with cramps and 13 without cramps, and observed that taurine levels were lower in cirrhotic patients with cramps. Of these, 9 patients with cramps were treated with taurine (3 gram daily for 4 weeks). Post treatment it was observed that taurine levels were elevated in all of these patients along with significant symptom improvement, whereas 6 patients reported complete resolution of cramps. No adverse event was reported in this study. Although double-blind and placebo-controlled trails are needed to validate these findings, data from available studies may favor the utility of taurine for the treatment of cramps in cirrhotic patients.

Branched-Chain Amino Acids

In cirrhosis, treatment with branched-chain amino acids, such as leucine, isoleucine and valine, has been reported to increase levels of serum albumin and the production of taurine along with a possible slowdown in the progression of liver disease. In an open-label study, conducted by Sako et al. 3 months of treatment with nocturnal amino acid supplements in 9 patients resulted in significant elevation in serum albumin levels along with a reduction in cramps frequency (p<0.0001). In an another study (a small multicenter, randomized study) performed by Hidaka et al. in 37 patients, treatment with daytime and nocturnal branched chain amino acids for 3 months resulted in significant improvement in frequency of muscle cramps (p=0.004). These exploratory studies may suggest the possible role of branched-chain amino acids for the treatment of muscle cramps in liver cirrhosis patients.

Human Albumin
In a crossover study, 12 patients with compensated liver disease were administered either intravenous albumin solution (25%, 100 ml) or placebo. Treatment with albumin significantly reduced cramps frequency, possibly by increasing the intravascular plasma volume. However, albumin therapy is limited in clinical practice due to the higher cost and the necessity for intravenous accessibility.

Electrolytes and Zinc
Serum electrolytes levels in cirrhotic patients with or without cramps do not differ significantly; therefore, clinical studies have not focused on this aspect. However, empiric treatment of low serum electrolytes such as zinc in cirrhotic patients with cramps is a routine procedure though its significance on symptom improvement remains unexploited. Treatment with zinc supplements may be useful in cirrhotic patients with low zinc levels and more studies are needed in this regard.

For the diagnosis of cramps (spontaneous, chronic and nocturnal) in patients with cirrhosis, muscle pain should be distinguished from other pain etiologies by taking a careful history. This is particularly more helpful in a new-onset persistent muscle pain, which might overlap with a diagnosis of rhabdomyolysis, myositis and acute kidney injury, and, for which, laboratory tests to assess electrolytes levels and other parameters may be necessary. A standardized cramp questionnaire may also be helpful to assess the presence and severity of cramps so as to evaluate the treatment effectiveness.

For patients with cramps, thoughtful evaluation of other etiologies may also be considered. Furthermore, estimation of serum electrolytes should be regularly carried out and electrolyte supplementation should also be considered those patients with lower levels of electrolytes. In patients with clinically significant cramps-associated cirrhosis, treatment attempts should be reasonable. In this regard, as large randomized trials are not available, treatment with inexpensive and over-the-counter agents with a favorable outcome (vitamin E, taurine and branched-chain amino acids) may be considered. Branched-chain amino acids and taurine may provide the highest potential benefit due to their effect on the proposed mechanism of cramps and improvement in nutritional parameters. Other treatments as described previously are not currently recommended because of ineffectiveness, expense, and/or the risk of side effects.

Patients with liver diseases often report muscle cramps that significantly decreases their health related quality of life. In this regard, various mechanisms and treatment approaches have been proposed. However, distinct representation of exact causal events has not developed. In smaller uncontrolled trials, a number of agents have shown promising results but data from larger controlled studies is lacking. Among the available treatment options, branched chain amino acids and taurine may provide potential benefits as these agents improve the nutritional status as well as target the suspected pathophysiological mechanisms.

Reference

Clin Gastroenterol Hepatol. 2013 Nov;11(11):1385-91