Clinical manifestations

Presentation and course

Acute alcoholic myopathy. Acute alcoholic myopathy (also termed alcoholic rhabdomyolysis and acute necrotizing myopathy) is a syndrome of abrupt muscle injury that typically occurs in malnourished chronic alcoholics following a binge or in the first days of alcohol withdrawal (59; 43; 171; 127; 125; 118; 89; 09; 122; 159; 80). Experimental studies have demonstrated that both alcohol and nutritional factors are necessary to produce this syndrome (16; 82; 89). Severity ranges from asymptomatic transient elevation of creatine kinase to frank rhabdomyolysis with myoglobinuria (117; 172). The clinical presentation is characterized by muscle pain, tenderness, swelling, and proximal or generalized weakness that develop abruptly in association with pigmenturia and a rapid rise in "muscle" enzymes in serum but with preserved reflexes (assuming that they are not otherwise lost due to a peripheral neuropathy) (60; 125). The initial symptoms are often noted on awakening from an alcoholic stupor (43; 60; 127). Acute alcoholic myopathy is a monophasic illness that typically advances over hours to a few days and then recedes over the succeeding week if the affected individual abstains from alcohol (109; 125). Muscle symptoms are often generalized, but focal pain and swelling involving individual muscle groups may predominate. Selective involvement of the calves, mimicking thrombophlebitis, is common (126; 131). Acute alcoholic myopathy is often accompanied by manifestations of alcohol withdrawal ranging from tremulousness to delirium tremens (109), although muscle pain and weakness usually precede the onset of withdrawal symptoms. Coexisting cardiac injury compatible with alcoholic cardiomyopathy may occur (40; 131; 153). Full recovery usually occurs within days to weeks, but death may occur in the setting of acute renal failure and electrolyte disturbances (eg, hyperkalemia) (09; 122; 159).

The major laboratory features of acute alcoholic myopathy are pigmenturia and elevation of muscle enzymes. Serum creatine kinase increases in the first 3 days and then declines to the normal range, usually within 7 to 10 days (109). Muscle biopsy shows scattered muscle-fiber necrosis and regeneration (60; 34; 77; 68; 125; 102). Type I (high oxidative, low glycolytic, slow twitch) muscle fibers are selectively susceptible to injury in acute alcoholic myopathy (102; 53). In autopsied cases, rhabdomyolysis is typically widespread, involving pharyngeal, sternocleidomastoid, pectoral, and diaphragm muscles in addition to limb muscles (59; 68).

Hypokalemic alcoholic myopathy. Alcohol abuse may produce severe hypokalemia due to loss of potassium from the bowel. After several days, severe hypokalemia can produce a vacuolar myopathy associated with myalgia, weakness, and occasionally myoglobinuria (89). Hypokalemic alcoholic myopathy resolves with potassium replacement, cessation of alcohol intake, and resumption of a normal diet (107). Hypokalemic alcoholic vacuolar myopathy and acute necrotizing myopathy can be superimposed, but hypokalemia is not necessary for the development of acute necrotizing myopathy (82).

Reversible acute alcoholic muscular syndrome with muscle cramps. Individuals with chronic alcohol abuse may develop an acute reversible muscular syndrome with dramatic muscle cramps, tender muscles, weakness, variable myoglobinuria, increased creatine kinase blood levels, and a reduced ability to increase serum lactic acid levels in response to ischemic exercise (127; 126). Similarities were initially noted between this presentation and the clinical features of hereditary phosphorylase deficiency (McArdle disease), but phosphorylase levels were variable and sometimes entirely normal despite severely depressed lactic acid response to ischemic exercise (127; 126). Affected individuals recover within 2 to 4 weeks if they remain abstinent (127; 126).

Chronic alcoholic myopathy. Chronic alcoholic myopathy is a gradually evolving syndrome of proximal weakness and atrophy that complicates years of alcohol abuse (ie, 100 g to 400 g of ethanol per day for more than 3 years) (36; 126; 118; 89). Muscle strength correlates with lifetime consumption of ethanol (114). Painless weakness and atrophy, affecting predominantly the hip and shoulder girdles, with associated myopathic gait, develops insidiously over weeks or months (99; 107; 169; 89; 159). Muscle atrophy may be striking. Alcoholic peripheral neuropathy is associated in most cases (72% in one study) (99); other complications of alcohol abuse or nutritional deficiency such as confusional states and hepatic cirrhosis may also be present (126). Recovery occurs if alcohol is avoided, but the time frame of improvement is weeks to months, usually on the order of 6 months or more, in contrast to the rapid recovery typical of acute alcoholic myopathy (98; 128). Recovery occurs even without improvement in nutritional status and without clinical recovery from any coexisting neuropathy (98; 128; 89).

Serum creatine kinase levels are often within normal limits and muscle biopsy generally does not reveal muscle-fiber necrosis. The dominant histologic finding is muscle atrophy (36; 77), which affects predominantly type II, especially type IIb (high glycolytic, low oxidative, fast twitch) muscle fibers (73; 99). Despite the frequent coincidence, the muscle atrophy in alcoholic myopathy is independent of neuropathic lesions (132). Electromyography may show myopathic potentials (36), neuropathic features (88), or both (126). Alcoholic type II atrophy is reversible with many months of abstinence from alcohol (99).

In some cases, acute muscle injury, manifested by muscle tenderness and creatine kinase elevation, may be superimposed on chronic alcoholic myopathy (126; 145; 153). Typically, these episodes are related to a period of particularly heavy ethanol abuse (169).

Asymptomatic alcoholic myopathy. Asymptomatic forms of both acute and chronic alcoholic myopathy occur. A transient elevation in creatine kinase, compatible with acute muscle injury, accompanies heavy drinking in a substantial percentage (20% to 50%) of alcoholic individuals (117; 172; 109; 57), the majority of whom do not have overt muscle symptoms. Similarly, histologic features of type II muscle-fiber atrophy, compatible with chronic alcoholic myopathy, were present in approximately 60% of individuals who had consumed an average of 190 g of alcohol daily for an average of 11 years (99). Most of these patients had few, if any, overt muscle symptoms.

Alcoholic cardiomyopathy. Alcoholic cardiomyopathy (“alcoholic heart muscle disease”) is a specific disease of heart muscle that occurs in individuals with a history of chronic heavy alcohol ingestion and in the absence of significant coronary artery disease or other cardiac conditions (eg, myocarditis) (129). Presenting symptoms can include development of an often abrupt, unexplained cough or shortness of breath, fatigue, and weakness, followed by swelling of the legs and abdomen (05). Presenting signs may include jugular venous distention, tachypnea, few if any rales, persistent tachycardia, cold and cyanotic extremities, cardiomegaly, a diastolic gallop, an apical systolic murmur, a mildly enlarged and tender liver (due to cardiac congestion rather than cirrhosis), and evidence of neuropathy (eg, stocking-distribution hypesthesia and hyporeflexia in the legs) (05; 155).

Echocardiographic features of alcoholic cardiomyopathy include left ventricle dilation, normal or reduced left ventricular wall thickness, increased left ventricular mass, and ultimately a reduced left ventricular ejection fraction (< 40%) (129). Alcohol consumption is also a predictor of left atrial enlargement and subsequent incident atrial fibrillation (104). Because there are no pathognomonic markers the diagnosis of alcoholic cardiomyopathy is generally presumptive and is often considered as a diagnosis of exclusion (129).

Although the precise amount and duration of alcohol consumption that is necessary to cause alcoholic cardiomyopathy remain poorly defined, (1) consuming 90 g to 120 g/day of ethanol (approximately 7-15 standard drinks per day) over a 5- to 15-year period is sufficient to produce changes in cardiac structure and function; (2) consuming at least 90 g/day of ethanol on at least 4 days/week over a 5 to 9 year period is associated with left ventricular dilation, and over a 10- to 15-year period is associated with development of diastolic dysfunction and left ventricular enlargement (90; 129).

Beriberi cardiomyopathy (Shöshin beriberi). Alcoholics are prone to develop thiamine deficiency, which itself may produce beriberi cardiomyopathy and in its fulminant form with hemodynamic deterioration is known as Shöshin beriberi (42; 39; 28; 84; 66; 92; 20; 52; 65; 103; 76; 72; 153; 10; 47; 69; 18; 150; 154; 25; 37; 124; 121; 106; 110; 176; 111; 33; 14; 163; 158; 161; 27; 01; 70; 71; 81; 166; 26; 30; 180; 17; 95; 152; 21; 74; 83; 29; 62). Common clinical features include metabolic (lactic) acidosis (typically without hypoxemia), peripheral edema, low peripheral vascular resistance, increased central venous pressure, cardiomegally, T-wave abnormalities, a hyperkinetic (high output) circulatory state (except in Shoshin beriberi, which may be associated with low cardiac output), and increased circulating blood volume (69; 111; 154; 163; 161; 70; 71; 81; 180; 95; 83; 62). It may also be accompanied by signs of Wernicke encephalopathy (30). Improvement is often rapidly achieved following thiamine administration, improved nutrition, and rest (65; 69; 26; 74). Untreated cardiovascular beriberi has a high case fatality (33).

Table 1. Acute and Chronic Alcoholic Myopathy: Clinical and Laboratory Features

Prognosis and complications

Acute alcoholic myopathy. Massive muscle injury triggered by acute alcohol abuse may result in multiple organ failure and death. However, alcoholic rhabdomyolysis generally has a good prognosis if renal failure is avoided or is aggressively treated (09). Muscle can regenerate remarkably, and most patients with alcoholic rhabdomyolysis recover full muscle function. Even patients with multiple episodes of myoglobinuria may have no lasting skeletal muscle effects. In patients with chronic alcoholic myopathy, improvement also is usual when ethanol is avoided.

Reversible acute alcoholic muscular syndrome with muscle cramps. Individuals with acute alcoholic muscular syndrome with muscle cramps recover within 2 to 4 weeks if they remain abstinent (127; 126).

Chronic alcoholic myopathy. In contrast to the relatively good prognosis of acute alcoholic myopathies with abstinence, a 5-year study of the natural history of chronic alcoholic myopathy showed that only half of the sober patients recovered to normal strength, indicating that chronic alcoholic myopathy is only partially reversible. In some alcoholics, even a substantial reduction in alcohol consumption may be as effective as complete abstinence in improving muscle strength or preventing its deterioration (41).

Loss of paraspinal muscle mass is a male gender-specific consequence of cirrhosis that predicts complications and death (38). Loss of paraspinal muscle mass was an independent predictor of bacterial infections, spontaneous bacterial peritonitis, hepatic encephalopathy, and hepatorenal syndrome (38).

Alcoholic cardiomyopathy. The prognosis of alcoholic cardiomyopathy is good if the patient stops drinking after the first or second episode of congestive heart failure, but most patients continue to drink (05). Without complete abstinence, the 4-year mortality of alcoholic cardiomyopathy is approximately 50% (90), only modestly improved over what it had been more than 40 years earlier (05; 165; 06).

Clinical vignette

Acute alcoholic myopathy. A 58-year-old woman presented with a 1-day history of pain and numbness in the legs and feet (126). She had been a chronic alcoholic for 38 years. She had one prior hospital admission 10 months earlier for severe intoxication following ethanol and isopropyl alcohol ingestion; at that time, she had diffuse muscle weakness and evidence of peripheral neuropathy but nevertheless recovered uneventfully. She had subsequently been relatively abstinent until she began a binge 2 days before admission.

On the morning of admission, she developed severe sharp pain in her legs and fell. Her feet felt numb, and her legs were extremely tender. She urinated urine of normal color and then returned to bed, but when she urinated again a few hours later, the urine was “brownish-black.” Examination revealed an acutely ill, unkempt woman with gaze-evoked nystagmus, a reddened tongue, a palpable nontender liver, a palpable spleen 3 cm below the costal margin, severe tenderness and swelling of the calves, taut and abnormally warm skin over the swollen legs, severe tenderness of the leg muscles (but only minimal tenderness of the arm muscles), severe calf pain aggravated by motion, severe leg weakness (evaluation of which was confounded by her pain), and decreased proprioception in the legs. Her urine was brown and positive for myoglobin. A creatine kinase level was markedly elevated (using the reference ranges for the lab assay used at that time). The lactic acid response to ischemic exercise was flat. She became anuric after the second day of hospital admission, and this persisted for 8 days. Muscle tenderness continued to be severe for 48 hours and then improved somewhat but, nevertheless, persisted for more than 2 months.

She experienced slow, progressive improvement in strength. After 8 weeks, she could walk with crutches, but not without support, and could rise from a chair with difficulty but could not rise from a squat. When a muscle biopsy was performed on the day after admission, the swollen muscle bulged from the incised fascia and had a pale color with a yellow tinge. A repeat biopsy 6 weeks later showed scattered small fibers, nuclear rows, and endomysial fat. Electron microscopy showed mitochondrial inclusions, degenerating myofilaments, and regenerating muscle fibers.

Reversible acute alcoholic muscular syndrome with muscle cramps. A 47-year-old woman was admitted with alcoholism and severe muscle cramps (77; 126). She drank intermittently until 2.5 years before admission, when she started drinking progressively larger amounts, until 1.5 years previously, when she quit working and began drinking steadily. She lost approximately 50 pounds over the 2 years prior to admission 2 years. For the previous 5 months, she had progressively severe weakness; for the previous 3 months, she had episodic calf cramps, which were initially infrequent and nocturnal but then became frequent, increasingly severe, and no longer confined to one part of the day. She was confined to bed because of weakness and cramps for the previous 2 weeks. There was no change in urine color.

On examination, she was an ill-appearing, thin, disheveled woman. Her liver was palpable 10 cm below the costal margin but was not tender. Painful calf cramps were observed several times during the initial examination. Her neurologic examination demonstrated diffusely tender muscles, weakness, tremor, absent ankle jerks but otherwise normal and symmetric reflexes, and diminished pinprick sensation in the lower legs and feet. A creatine kinase level was markedly elevated (using the reference ranges for the lab assay used at that time), and she also had elevations of aspartate aminotransferase (AST, which was then called serum glutamic oxaloacetic transaminase or SGOT) and lactate dehydrogenase (LDH). Light microscopy of a quadriceps femoris muscle biopsy showed relatively minor and nonspecific abnormalities, including mildly increased nuclear rows, minimal scattered small fibers, and minimal granular cytoplasm. In contrast, electron microscopy showed marked abnormalities of both acute and chronic myopathy, including commonly present separation of myofilaments and myofibrils, and some mitochondrial inclusions and degenerating myofilaments.

She improved steadily over a 3-week period with symptomatic care. Over this interval, her muscle tenderness and cramps resolved, and her strength improved although she still had prominent proximal weakness affecting the shoulder and pelvic girdle muscles.

Chronic alcoholic myopathy (plus Wernicke encephalopathy and peripheral neuropathy). A 54-year-old woman was admitted with severe weakness (77; 126). She had been a heavy drinker for at least 4 years, consuming up to a case of beer daily. She had become increasingly confused and weak over the previous 2 to 3 months, and by 3 weeks before admission, she was so weak that she could not get out of bed. She vomited daily over the 3-week period before admission, usually in the morning.

On examination, she was disheveled, confused, agitated, and actively experiencing both visual and auditory hallucinations. She had a regular tachycardia. The liver and spleen were not palpable. Neurologic examination showed full eye movements, nystagmus, tremor, diffuse muscle atrophy, severe proximal weakness to the point where she was unable to raise her legs off of the bed, absent knee jerks but normal biceps and Achilles reflexes, and stocking-glove hypalgesia. A gastrocnemius muscle biopsy showed moderate scattered small muscle fibers, mild grouping of small fibers, mild nuclear rows, and minimal endomysial fat, consistent with a primary myopathy and a superimposed peripheral neuropathy. EMG showed a scarcity of motor units and fibrillations in the lower extremities and no abnormalities in the upper extremities (despite evident clinical involvement).

She improved steadily with conservative therapy. Four months later, she could walk with a cane and was able to care for herself.

Biological basis

Etiology and pathogenesis

Alcohol misuse, whether as acute intoxication or alcoholism, adversely affects skeletal, cardiac, and smooth muscle contraction (07). Alcohol-mediated disruption of muscle contractility involves various cellular molecules, including contractile proteins, their regulatory factors, membrane ion channels and pumps, and several signaling molecules (07).

Alcohol consumption negatively affects skeletal muscle health through different mechanisms, including an imbalance between anabolic and catabolic pathways, reduced regeneration, increased inflammation and fibrosis, and deficiencies in energetic balance and mitochondrial function (22). These pathological processes occur with various alcohol consumption patterns and are not restricted to chronic alcohol misuse (22).

Acute alcoholic myopathy. Acute alcoholic myopathy is caused by severe alcoholic binges, usually in drinkers of long duration. Clinical and experimental studies support the hypothesis that the muscle injury is the consequence of a toxic effect of high ethanol concentrations. Acute muscle injury occurs during bouts of high-intensity ethanol abuse. Serum creatine kinase elevations in alcoholics are linked to active drinking (117; 109; 57). Serum creatine kinase levels rose in human volunteers receiving 225 g of alcohol daily for 4 weeks, despite a nutritional diet (162). In a retrospective cohort study of 495 Dutch adolescents treated for symptoms of acute alcohol intoxication, elevated creatinine kinase (CK) levels were found in 60%, with a mean CK level of 254 U/I (normal value ≤ 145 U/I) (130). In a rat model of alcoholic rhabdomyolysis, mean serum creatine kinase levels increased with rising levels of blood alcohol (55; 53). The lack of caloric intake apart from ethanol during binge drinking also promotes high blood alcohol levels (116) because fasting retards alcohol clearance (174).

In some cases of acute alcoholic myopathy, additional factors may contribute to muscle injury. For example, muscle crush is a contributing mechanism in some cases, particularly when abuse of alcohol and narcotics are combined (43; 79). In these instances, muscle injury predominates in muscles that are compressed by the weight of the patient's body. Seizures (eg, due to alcohol withdrawal) may sometimes potentiate muscle injury.

Alcoholics are also prone to electrolyte disturbances, particularly depletion of magnesium, inorganic phosphate, and potassium, each of which can injure skeletal muscle (31; 56). Experimental magnesium deficiency causes a myopathy, and hypomagnesemia is common in withdrawing alcoholics. No link between serum magnesium levels and acute alcoholic myopathy has been found (125; 57; 48), but even when serum magnesium levels are normal, muscle magnesium may be low (08). Phosphate depletion and hypophosphatemia have been linked to rhabdomyolysis experimentally and in various clinical settings, including alcoholism (78; 31). However, severe and subclinical forms of acute alcoholic myopathy may occur without hypophosphatemia (57; 48). Potassium depletion may cause a rapidly evolving necrotizing myopathy that mimics alcoholic rhabdomyolysis. Potassium deficiency myopathy has been reported in alcoholic individuals with severe hypokalemia (ie, serum potassium less than 2.2 mM) (101); in such patients, potassium loss is usually due to vomiting or diarrhea. However, in most cases of acute alcoholic myopathy, hypokalemia is less severe, and low serum or muscle potassium levels do not correlate directly with muscle injury (125; 08; 57). In an experimental model of alcoholic rhabdomyolysis, mild hypokalemia coexisted with normal or elevated levels of muscle potassium, suggesting that alcohol promotes potassium redistribution between the intracellular and extracellular space; raising serum potassium by additional dietary supplements did not prevent myopathy in this model (54).

Chronic alcoholic myopathy. Chronic alcoholic myopathy is caused by prolonged, consistent alcohol abuse rather than binge drinking. Muscle strength in alcoholics who abused alcohol for less than 5 years was similar to that in control subjects, whereas progressive weakness was accompanied by longer periods of alcohol use (24). In a study of 50 alcoholic men, deltoid strength and the total lifetime alcohol dose were inversely correlated (169). Chronic alcoholic myopathy is characterized by a reduced cross-sectional area of muscle fibers and impaired anabolic signaling (157).

Duration and level of habitual alcohol consumption are associated with type-II-muscle-fiber atrophy (fast-twitch) and, particularly, with type-IIB-muscle-fiber atrophy (99; 135). Muscle-fiber types are classified by their histochemical, ultrastructural, biochemical, and physiologic properties (Table 2). The speed of muscle fiber contraction depends on myosin ATPase activity, whereas fatigability relates to oxidative capacity. Type IIB fibers (also labeled fast-twitch, fast-fatigable, and fast-glycolytic fibers) generate ATP by anaerobic glycolysis but utilize phosphocreatine as an accessible storage form for ATP to provide a short burst of energy. Type IIB fibers have a myosin heavy chain isoform (IIx) with high ATPase activity that can rapidly utilize the available ATP. The more energy transferred in a certain time, the greater the power. Consequently, type IIB fibers contract rapidly, create forceful contractions, and fatigue quickly. They are a predominant muscle-fiber type in arm muscles, whereas postural muscles of the neck and spine have large quantities of type I fibers, and leg muscles have large quantities of both type I and type IIA fibers.

Table 2. Muscle Fiber Types

Although myopathy and neuropathy are frequently both present in chronic alcoholics, the pathogenetic mechanisms involved in each of these forms of tissue damage are presumably not identical, because histologic and clinical evidence of myopathy may occur in the absence of symptoms or electrophysiologic signs of neuropathy or of malnutrition (99; 169).

Nutritional factors may contribute to the pathogenesis of chronic alcoholic myopathy because muscle weakness and histologic myopathy among alcoholics are both more severe in the presence of malnutrition (114), but no clear relationship has been identified for the following micronutrients: thiamine (vitamin B1), riboflavin (vitamin B2), pyridoxine (vitamin B6), folate (vitamin B9), cobalamin (vitamin B12), beta-carotene (provitamin A), retinol (vitamin A), vitamin D, copper, and zinc (175; 137; 141; 135). Deficiencies of alpha-tocopherol (vitamin E) and selenium have also been proposed as candidate risk factors for alcoholic myopathy (175; 135). Animal studies have established that a deficiency of either of these micronutrients can cause neuropathy, and human studies have shown that levels of each of these are lower in alcoholics with myopathy than in normal controls or in nonmyopathic alcoholics (175; 135). Selenium is a cofactor for several enzymes, but especially glutathione peroxidase, the major detoxification enzyme for hydrogen peroxide (H2O2), whereas alpha-tocopherol is critical in preventing the initiation and propagation of lipid peroxidation.

Myotoxic effects of alcohol have been demonstrated in animal models. For example, administration of alcohol with a nutritionally complete diet to rats caused atrophy of type II muscle fibers (167). In addition, chronic binge alcohol consumption in rhesus macaques disrupted myogenic gene expression and myotube formation, which likely impaired skeletal muscle regenerative capacity (160).

The pathogenesis of alcoholic myopathy involves multiple interrelated pathways (142; 141; 135). First, impaired gene expression and protein synthesis, as well as increased oxidative damage, act together to reduce the formation of myofibrillar proteins (137; 135). Second, impaired gene expression, increased oxidative damage, and the pro-apoptotic properties of alcohol act to increase apoptosis. Third, additional muscle damage comes from alterations in ion channels and cell-membrane permeability, impaired energy metabolism, protein adduct formation, and the toxicity of fatty acid ethyl esters. All of these processes contribute to the death and loss of myocytes and, hence, to progressive myopathy (46).

In a study of myoblasts isolated from the vastus lateralis muscle of alcohol-naive adult male and female rhesus macaques, alcohol decreased glycolytic metabolism and impaired myoblast differentiation, which may help explain the decrease in myogenesis with alcohol (93).

Chronic ethanol consumption in mice induces substantial weakness in vivo that is primarily due to muscle atrophy (ie, reduced muscle quantity) and possibly, to a lesser degree, loss of central neural drive (108).

Alcoholic cardiomyopathy. In alcoholic cardiomyopathy, gross examination of the heart shows dilation of all heart chambers, especially the left ventricle (05; 155). The myocardium is pale and flabby with a variable degree of fibrosis (05; 155). Light microscopy of the heart in alcoholic cardiomyopathy shows nonspecific changes, including patchy scarring in the subendocardial layer (05; 155). Histochemical studies demonstrate lipid deposits (mainly triglycerides) and a decrease in myocardial oxidative enzymes (155). Electron microscopy of the myocardium shows much more dramatic abnormalities, including myofibril loss and fragmentation, clusters of giant mitochondria with distorted cristae, cystic dilation of the sarcoplasmic reticulum, increased glycogen and fat deposits, and variable myofiber hypertrophy (05; 155). The dramatic mitochondrial abnormalities indicate a significant disturbance of oxidative metabolism and energy production, resulting in decreased myocardial contractility and congestive heart failure (05).

Several pathogenic mechanisms have been implicated, including oxidative stress, apoptosis, impaired mitochondrial bioenergetics (with consequent loss of energetic efficiency and an increase in the generation of damaging reactive oxygen species), disrupted fatty acid metabolism and transport, including the generation of toxic fatty acid ethyl esters (FAEEs) from the combination of fatty acids with ethanol, decreased protein synthesis that initially manifests as a defect in translational efficiency, and possibly enhanced autophagy and protein catabolism (140; 137; 142; 143; 136; 85; 185; 129). Polymorphic variants of the mitochondrial isoform of aldehyde dehydrogenase (ie, ALDH2) encode enzymes with significantly altered ability to metabolize acetaldehyde and significantly higher associated risk of alcoholism and alcohol-related complications (185). Nevertheless, genetic variations in ALDH2 and other enzymes related to ethanol metabolism have not been clearly shown to influence susceptibility to alcoholic cardiomyopathy (185; 129).

In rats, the combination of periodic fasting in the presence of continuous ethanol intake produces pronounced morphological changes in the myocardium and its organelles (15).

So far, no causal relationships have been established between significant alcohol-related micronutrient deficiencies and the development of alcoholic cardiomyopathy (129). However, thiamine deficiency (beriberi) is known to cause cardiomyopathy (under different labels: eg, “thiamine-deficiency cardiomyopathy,” “beriberi cardiomyopathy,” “beriberi heart disease,” or “Shoshin beriberi”), and certain micronutrient deficiencies, particularly of alpha-tocopherol (vitamin E) and selenium, can cause myopathies, and all of these are common metabolic consequences of alcoholism (177; 164; 12; 11; 135; 02; 01). In a rat model, thiamine supplementation was protective against acetaldehyde-induced cytotoxicity and cardiac contractile dysfunction through protective effects against protein damage and apoptosis in ventricular myocytes (01). In addition, in another rat model of the combined short-term toxic effects of acetaldehyde and nicotine on cardiac contractile function, cotreatment with folate (a vitamin required for DNA synthesis) obviated the toxic effects, possibly through mechanisms related to mitigating DNA damage (02).

Metabolism of ethanol. Ethyl alcohol (ie, ethanol), or commonly just “alcohol,” is metabolized mainly by the liver. As a first step, ethanol is primarily oxidized by the cytosolic enzyme alcohol dehydrogenase to form acetaldehyde. There are additional secondary routes for oxidative metabolism of ethanol to acetaldehyde using either an enzyme in the endoplasmic reticulum, cytochrome P450 IIE 1 (CYP2E1), which operates at high levels of alcohol consumption and is induced by chronic drinking, or a minor pathway utilizing a catalase-mediated reaction in peroxisomes. Acetaldehyde is then oxidized by the mitochondrial enzyme acetaldehyde dehydrogenase (aldehyde dehydrogenase 2) to acetate (184; 183).

Most of the acetate formed from the metabolism of alcohol in the liver escapes into the blood and is ultimately metabolized by peripheral tissues (67; 184; 183). Skeletal muscle, heart, and brain contain the mitochondrial matrix enzyme acetyl-CoA synthetase (or acetate-CoA ligase), which catalyzes the ligation of acetate with CoA to produce acetyl-CoA:

ATP + Acetate + CoA <=> AMP + Pyrophosphate + Acetyl-CoA

Acetyl-CoA is an essential molecule utilized in various metabolic pathways, including the tricarboxylic acid cycle (an alternate entrée into the TCA cycle, as the more common way is to produce acetyl-CoA from pyruvate through the pyruvate dehydrogenase complex), and also fatty acid and cholesterol synthesis.

Alcohol is not metabolized directly by skeletal muscle, and the injurious effects of alcohol abuse on muscle have been attributed to a toxic effect of ethanol or its metabolite, acetaldehyde (146; 32). Because the rate of acetaldehyde production plateaus at relatively low, nonintoxicating levels of ethanol, any toxic effects linked specifically to a high dose of alcohol are more likely the result of actions of ethanol itself rather than its metabolites.

Alteration of gene expression. Metabolites of alcohol can operate at an epigenetic level, binding to transcription factors or modifying chromatic structure (183). One of the most important epigenetic signals is DNA methylation, which marks or tags selected cytosine moieties in DNA with a methyl group. Chronic alcohol consumption significantly reduces s-adenosyl-methionine (SAM) levels, thereby contributing to DNA hypomethylation. Gene expression is also influenced by alcohol-induced posttranslational modifications of histone proteins (eg, methylation and acetylation) that determine the genome’s accessibility to transcription factors. Ethanol metabolism also alters the ratio of nicotinamide adenine dinucleotide (NAD+) to reduced NAD (NADH) and promotes the formation of reactive oxygen species and acetate, all of which impact epigenetic regulatory mechanisms for gene expression. As a result of such processes, alcohol metabolism can impact several different epigenetic mechanisms, leading to complex alterations in gene expression.

Impaired protein synthesis. Alcohol promotes muscle atrophy by impairing protein synthesis (134; 137; 136; 138). Changes in the regulation of anabolic and catabolic signaling pathways precede the development of skeletal muscle atrophy and clinical symptoms of alcoholic myopathy (156; 22).

Alcohol-induced modulations in transcription and translation are not mediated by the availability of amino acids, the effects of endocrine dysfunction (eg, of cortisol or growth hormone), or the presence of liver impairment or malnutrition (137). Although total messenger RNA falls after ethanol consumption, messenger RNA for specific myofibrillary contractile proteins are unaffected, which implies a role for translational modifications in the initial stages of alcoholic myopathy (137). The reductions in the rate of protein synthesis are related to changes in activation of translation initiation factors (86). For example, alcohol suppresses the insulin-like growth factor (IGF-1)-mediated phosphorylation of ribosomal kinases, thus, limiting the translation of selected mRNAs (137; 87).

Alcohol-induced decreases in protein synthesis are largely governed by impaired activity of a protein kinase, the mechanistic target of rapamycin (or mTOR) (75). mTOR is also known as the mammalian target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1). mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. In humans mTOR is encoded by the MTOR gene. mTOR regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription (58; 94). mTOR also promotes the activation of insulin receptors and insulin-like growth factor 1 receptors and is involved in the control and maintenance of the actin cytoskeleton (58; 63; 181).

Moreover, numerous studies have implicated the generation of reactive oxygen species and enhanced lipid peroxidation in the pathogenesis of reduced tissue protein synthesis.

Accelerated muscle breakdown. Although accelerated muscle protein breakdown was previously hypothesized to explain the development of chronic alcoholic myopathy, careful studies have not supported this (100).

Reactive oxygen species. The excessive generation of reactive oxygen species leading to enhanced lipid peroxidation is an important feature of alcohol toxicity. Ethanol metabolism causes oxidative stress and lipid peroxidation in liver and extrahepatic tissues, including muscle (03). In mice, oxidative stress due to ethanol metabolism causes extensive degradation and depletion of mitochondrial DNA in liver, brain, heart, and skeletal muscle (96); these effects could be prevented by 4-methylpyrazole, an inhibitor of ethanol metabolism, and attenuated by antioxidants such as vitamin E, melatonin, and coenzyme Q (96). Cholesterol-derived hydroperoxides as a product of lipid peroxidation are significantly elevated after acute ethanol treatment and may contribute to reductions in tissue protein synthesis (03). However, the alcohol-induced reductions in protein synthesis could not be prevented by vitamin E (144). Antioxidant muscle enzyme activities are partially disturbed in chronic alcoholism, although not related to the presence of myopathy, amount of ethanol consumed, or nutritional status of the patients (44). Supplementing the diets of alcohol-fed rats with the antioxidative glutathione precursor, Procysteine, attenuated alcohol-induced oxidant stress, stimulated gene expression of anabolic factors, and reduced the degree of plantaris atrophy. Therefore, antioxidant treatments may benefit individuals with alcoholic myopathy (120).

Apoptosis. Apoptosis has been implicated in the pathogenesis of alcoholic myopathy (45).

Cell membrane and ion channels. Increased muscle sodium and calcium concentrations have been found in alcoholic patients and with experimental alcohol administration (08). These changes in cellular ion composition may be nonspecific indices of cellular injury. However, ethanol directly affects the function of membrane proteins involved in regulating cellular levels of sodium and calcium. Ethanol may promote sodium accumulation in cells by increasing sodium permeability and acutely inhibiting Na⁺-K⁺ adenosine triphosphatase (146). Prolonged ethanol exposure increases membrane Na⁺-K⁺ adenosine triphosphatase activity, possibly in response to increased sodium permeability. Ethanol may also promote cellular calcium accumulation. Ethanol reduces calcium transport by the sarcoplasmic reticulum (162). Ethanol acutely inhibits voltage-sensitive calcium channels, but chronic alcohol administration increases the number of calcium channels (105). A specific role for ethanol-induced changes in calcium permeability in experimental alcoholic cardiomyopathy has been suggested by the finding that verapamil has a protective effect in this model (49).

Impaired cellular metabolism. Acute rhabdomyolysis, similar to that in acute alcoholic myopathy, is a feature of inborn errors of energy metabolism in skeletal muscle. The increase in lactic acid during ischemic exercise is less than normal in patients with alcoholic muscle disease, suggesting that impaired muscle glycogenolysis (akin to that in myophosphorylase deficiency) could contribute to alcohol-related muscle injury. 31P-magnetic resonance spectroscopy in alcoholics has also shown findings consistent with impaired muscular glycolysis or glycogenolysis during aerobic exercise (19). However, impaired lactate production has been found in other acute illnesses, suggesting this may be a nonspecific finding. Several studies have found lower levels of muscle glycolytic enzymes in chronic alcoholics (73; 54; 97; 168). The dominant mechanism is atrophy of type II muscle fibers, which in humans have 2- to 5-fold higher levels of glycolytic enzyme activity than type I fibers (149). In ultrastructural studies, mitochondrial abnormalities are an early feature of acute myopathy (34). However, isolated mitochondria from chronic alcoholics have shown no evidence of impaired oxidative metabolism (23), and oxidative enzyme activity in chronic alcoholic individuals is preserved (73; 168).

Protein adduct formation. Ethanol metabolism by alcohol dehydrogenase and CYP2E1 produces highly reactive molecules, such as acetaldehyde and reactive oxygen species, that can interact with amino acids to form stable and unstable adducts (139; 184; 133). Such adducts may contribute to reductions in protein synthesis, may initiate the formation of autoantibodies and trigger autoimmune damage, and may also interfere with proteins of the contractile system or signaling peptides (140; 142; 136; 179). Acute ethanol administration increased protein adducts with malondialdehyde and acetaldehyde in rats, primarily in type II muscle fibers; this may be associated with the increased susceptibility of anaerobic muscle to alcohol toxicity (115).

Fatty acid ethyl esters (FAEE). FAEE are nonoxidative metabolites of ethanol and are toxic to cells in vitro and in vivo (91). In rats, skeletal muscle contains high levels of FAEE after ethanol exposure, similar to the concentration in the liver (148), so FAEE may contribute to the development of alcoholic myopathy.

Epidemiology

Approximately half of chronic alcoholics have a loss of lean body mass due to loss of muscle tissue, decreased muscle strength, and associated gait abnormalities (141; 135). Between one third and two thirds of chronic alcoholics have skeletal muscle myopathies, making alcoholic myopathies the most prevalent type of myopathy (135). In addition, up to a third of chronic alcoholics have evidence of cardiomyopathy (135).

Acute alcoholic myopathy. Alcohol is a common cause of nontraumatic myoglobinuria and is implicated as the cause in approximately 20% of such cases (145; 51; 79; 123; 13). Alcoholic rhabdomyolysis predominates in men by a greater than 4-to-1 ratio and usually occurs in the 4th to 6th decades of life. Recurrent episodes are reported in about 30% of cases following an initial episode of rhabdomyolysis. The incidence and prevalence of alcoholic rhabdomyolysis has varied considerably in different studies, probably at least partly due to variations in the intensity and chronicity of drinking, and coexistent nutritional disorders, among the subjects studied. Most studies suggest that alcoholic rhabdomyolysis is infrequent in alcoholics, occurring in less than 5% of chronic alcoholics (137; 141; 135). Nevertheless, the rhabdomyolytic variant of acute alcoholic myopathy represents the most common nontraumatic cause of rhabdomyolysis in hospitalized patients (170; 159). Myerson and Lafair reported 10 cases in 330 patients (3%) with medical complications of alcoholism (109). In 100 autopsies of patients dying with alcoholic liver disease, clinically unsuspected severe rhabdomyolysis was identified in 8% (68). Subclinical muscle injury, as reflected in elevations in serum creatine kinase, has been found in 15% to 80% of patients admitted after active drinking (117; 172; 57; 99). Acute alcoholism or withdrawal accounted for approximately 40% of elevated serum creatine kinase levels in an acute medical ward (113).

Chronic alcoholic myopathy. In a series of patients with chronic alcoholic myopathy, males and females were equally affected (36; 126). Quantitative strength testing and histologic studies indicate that muscle abnormalities consistent with chronic alcoholic myopathy are common in habitual drinkers, affecting 40% to 60% of patients who chronically abuse alcohol (112). In one study, 90 of 151 patients (60%) with chronic alcohol use had type-II-fiber atrophy in needle biopsies of the quadriceps muscle (99). Similarly, 21 of 50 (42%) asymptomatic men with an average alcohol consumption of 240 g/day for 16 years had deltoid weakness on quantitative testing (169).

Alcoholic cardiomyopathy. Alcoholism is responsible for 21% to 36% of all cases of nonischemic dilated cardiomyopathy (90). Beer drinkers seem particularly susceptible to alcoholic cardiomyopathy (05; 155).

Prevention

Prevention requires abstinence from alcohol.

Differential diagnosis

Confusing conditions

In patients with symptoms suggesting acute alcoholic myopathy, the possibility of other acquired causes of rhabdomyolysis should be considered, such as drug abuse (eg, heroin, cocaine, amphetamines), trauma or crush injury, and depletion of phosphate or potassium. In patients with recurrent episodes of rhabdomyolysis, the possibility of an underlying metabolic defect in carbohydrate or lipid metabolism should be considered.

In patients with symptoms suggesting chronic alcoholic myopathy, care must be taken to exclude other causes of chronic myopathic weakness, such as inflammatory myopathies, acquired metabolic myopathies, and limb-girdle dystrophy. The muscle biopsy finding of type-II-muscle fiber atrophy is also a feature of steroid myopathy, hypophosphatemia, and muscle disuse.

Diagnostic workup

In alcoholics with acute myopathy, the workup should include a careful history and a toxicology screen to identify the possible contribution of other drugs or toxins known to produce myoglobinuria. Serum creatine kinase is moderately or severely increased. Screening for metabolic derangements that can cause myoglobinuria, particularly hypokalemia and hypophosphatemia, should be performed. Other causes of pigmenturia (eg, hematuria, hemoglobinuria, and porphyria) should be excluded. In an individual with recurrent rhabdomyolysis or evidence of muscle injury that has occurred apart from alcohol abuse, perform an evaluation for a possible inborn error of muscle metabolism. EMG shows myopathic potentials (short duration, small-amplitude units with normal recruitment) and a high frequency of spontaneous discharges (fibrillations and positive sharp waves) attributed to hyperirritability of muscle fibers associated with active muscle fiber necrosis (119). Muscle biopsy, if performed, shows muscle fiber necrosis (128).

In patients with symptoms suggesting chronic alcoholic myopathy, a family history should be obtained to exclude familial muscle disease, and laboratory screening should be employed to determine whether an underlying endocrine or electrolyte disorder exists. Serum creatine kinase is normal. Electromyography and muscle biopsy are necessary to exclude other causes of chronic proximal weakness and atrophy. EMG often shows mixed myopathic and neuropathic features with variable spontaneous discharges (119). The most frequent histological findings are myocytolysis, fiber-size variability, and type IIB-fiber atrophy (128). Cardiomyopathy and hepatic cirrhosis are more frequent in patients with chronic alcoholic myopathy and should be checked for in chronic alcoholics with skeletal myopathy (147).

Nerve conduction studies in patients with alcoholic myopathies often show coincident neuropathic abnormalities (ie, borderline or slowed conduction velocities and absent sensory potentials) because distal neuropathies often coexist with myopathy (119).

Management

The single most important therapeutic factor in treating alcoholic myopathies in the long term is abstinence from alcohol. Therefore, an alcohol treatment program is a critical component of the treatment of alcoholic myopathies.

Acute rhabdomyolysis with myoglobinuria requires urgent inpatient interventions to monitor and maintain renal function and to avoid or correct hyperkalemia. Aggressive intravenous fluid resuscitation may decrease the likelihood of acute renal failure and lessen the need for dialysis (151). Hemodialysis may, nevertheless, be needed (09; 122). Blood levels of potassium, phosphate, and magnesium should be determined, and deficiencies should be corrected, although some practice guidelines have conditionally recommended against treatment with bicarbonate or mannitol in patients with rhabdomyolysis (151).

In chronic alcoholic myopathy, associated nutritional deficiencies need to be corrected and a diet with adequate protein and carbohydrates ensured.

Vitamin D deficiency is found in a large proportion of alcoholics (55% of alcoholics had vitamin D deficiency in one study), and there are clinical and morphological similarities between hypovitaminosis D myopathy and chronic alcoholic myopathy (178). Moreover, alcoholics are prone to low bone mineral density and have a multifactorial increased risk of falls and falls with injury. Taken together, these data suggest that individuals with alcoholic myopathy may benefit from vitamin D supplementation, with target 25-hydroxy vitamin D levels above 30 ng/ml, preferably above 40 to 50 ng/ml. Although there are no human-controlled clinical trials to establish the effectiveness of vitamin D supplementation in subjects with alcoholic myopathy, in Sprague-Dawley rats with experimental alcoholic myopathy, low vitamin D levels correlated with muscle fiber atrophy (50).

Although there are no human randomized clinical trials of drugs or supplements that may impact the myopathy pathogenesis of alcoholic myopathy, antioxidant treatments may be considered in individuals with alcoholic myopathy based on the results from animal studies. In rodent models, ethanol-induced degradation and depletion of mitochondrial DNA were attenuated by the antioxidants vitamin E, melatonin, or coenzyme Q (96). Similarly, supplementing the diets of alcohol-fed rats with the antioxidative glutathione precursor, Procysteine, attenuated alcohol-induced oxidant stress, stimulated gene expression of anabolic factors, and reduced the degree of plantaris atrophy (120).

Special considerations

Pregnancy

Neonates born to alcoholic mothers may show a unique myopathic process termed "fetal alcohol myopathy." These neonates are flaccid, hypotonic, and weak and have weak movements in utero. Muscle biopsies in these neonates show hypotrophy, dominance of type II fibers, and central nuclei, with marked sarcomeric dysplasia at the ultrastructural level (04).

Anesthesia

There are no special requirements for anesthesia in patients with alcoholic myopathy. Several narcotics and sedatives may, however, cause or contribute to rhabdomyolysis.