The response of skeletal muscle to alcohol abuse: Gender differences

A gender analysis has been carried out to analyze changes in intracellular signaling pathways that lead to the development of chronic alcoholic myopathy. It is known that acute or chronic alcohol intoxication can result in alcohol-induced lesions in skeletal muscles. Chronic alcoholic myopathy occurs much more frequently and can develop either independently or in combination with other forms of alcoholic disease (liver and heart lesions, malabsorption syndrome, or alcohol polyneuropathy). This disease is manifested by atrophy of skeletal muscles and a performance decrement. Most of the studies on the pathogenesis of chronic alcoholic myopathy have been carried out on male patients. Studies on alcoholic myopathy-induced muscle damage in females have not been previously reported.     

Physiological basis of the pathogenesis of alcohol-induced skeletal muscle injury

Alcohol-induced muscle damage (AIMD) is an umbrella term that includes all forms of alcoholic myopathy developing in acute or chronic alcohol intoxication. The most common form of destruction of skeletal muscles in alcoholism is chronic alcoholic myopathy, which develops independently of other alcohol-induced disorders, such as polyneuropathy, the malabsorption syndrome, and liver damage, but may be combined with them. The atrophy of muscle fibers underlies skeletal muscle destruction in chronic AIMD. Type II muscle fibers are affected to a greater degree than type I muscle fibers. To date, the pathogenesis of chronic alcoholic myopathy has been studied insufficiently. The imbalance between protein synthesis and proteolysis, as well as increased apoptosis rate, is discussed.     

Free radicals in alcoholic myopathy: indices of damage and preventive studies

Chronic alcoholic myopathy affects up to two-thirds of all alcohol misusers and is characterized by selective atrophy of Type II (glycolytic, fast-twitch, anaerobic) fibers. In contrast, the Type I fibers (oxidative, slow-twitch, aerobic) are relatively protected. Alcohol increases the concentration of cholesterol hydroperoxides and malondialdehyde-protein adducts, though protein-carbonyl concentration levels do not appear to be overtly increased and may actually decrease in some studies. In alcoholics, plasma concentrations of alpha-tocopherol may be reduced in myopathic patients. However, alpha-tocopherol supplementation has failed to prevent either the loss of skeletal muscle protein or the reductions in protein synthesis in alcohol-dosed animals. The evidence for increased oxidative stress in alcohol-exposed skeletal muscle is thus inconsistent. Further work into the role of ROS in alcoholic myopathy is clearly warranted.     

Molecular mechanisms responsible for alcohol-induced myopathy in skeletal muscle and heart

Chronic alcohol abuse has the potential to modulate striated muscle physiology and function. The skeletal muscle alcoholic myopathy is characterized by muscle weakness and difficulties in gait and locomotion, while chronic alcohol consumption ultimately leads to a decrease in cardiac contractility and output. In both tissues a loss of protein mass results in part from a decreased protein synthesis that initially manifests as a defect in translational efficiency. This review focuses on recent developments in understanding the cellular and molecular mechanisms by which alcohol impairs mRNA translation in skeletal and cardiac muscle, including identification of the signaling pathways and biochemical sites negatively impacted. Defective signaling potentially results from resistance to the normal stimulating effects of anabolic hormones (insulin and insulin-like growth factor-I) and nutrients (leucine) as well as increased production of several negative regulators of muscle mass. Overall, the biochemical mechanisms contributing to the pathogenesis of loss of skeletal and cardiac muscle are reviewed.     

Alcoholic muscle disease and biomembrane perturbations (review)

Excessive alcohol ingestion is damaging and gives rise to a number of pathologies that influence nutritional status. Most organs of the body are affected such as the liver and gastrointestinal tract. However, skeletal muscle appears to be particularly susceptible, giving rise to the disease entity alcoholic myopathy. Alcoholic myopathy is far more common than overt liver disease such as cirrhosis or gastrointestinal tract pathologies. Alcohol myopathy is characterised by selective atrophy of Type II (anaerobic, white glycolic) muscle fibres: Type I (aerobic, red oxidative) muscle fibres are relatively protected. Affected patients have marked reductions in muscle mass and impaired muscle strength with subjective symptoms of cramps, myalgia and difficulty in gait. This affects 40-60% of chronic alcoholics (in contrast to cirrhosis, which only affects 15-20% of chronic alcohol misuers).Many, if not all, of these features of alcoholic myopathy can be reproduced in experimental animals, which are used to elucidate the pathological mechanisms responsible for the disease. However, membrane changes within these muscles are difficult to discern even under the normal light and electron microscope. Instead attention has focused on biochemical and other functional studies.In this review, we provide evidence from these models to show that alcohol-induced defects in the membrane occur, including the formation of acetaldehyde protein adducts and increases in sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (protein and enzyme activity). Concomitant increases in cholesterol hydroperoxides and oxysterol also arise, possibly reflecting free radical-mediated damage to the membrane. Overall, changes within muscle membranes may reflect, contribute to, or initiate the disturbances in muscle function or reductions in muscle mass seen in alcoholic myopathy. Present evidence suggest that the changes in alcoholic muscle disease are not due to dietary deficiencies but rather the direct effect of ethanol or its ensuing metabolites.     

Innate immunity in alcoholic liver disease

Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease.     

Signaling targets of alcoholic intoxication in human skeletal muscle

Intracellular signaling pathways were investigated in skeletal muscle cells at the early stages of alcohol addiction manifestations. No muscle fiber atrophy was observed in m. vastus lateralis of male patients. No significant changes in the signaling mechanisms that control protein degradation were detected as well. However, the concentration of the insulin-like growth factor (IGF-1) in blood plasma as well as the content of markers of intracellular signaling pathways regulating protein synthesis were significantly reduced compared to the control group.     

Notch Pathway Activation Contributes to Inhibition of C2C12 Myoblast Differentiation by Ethanol

The loss of muscle mass in alcoholic myopathy may reflect alcohol inhibition of myogenic cell differentiation into myotubes. Here, using a high content imaging system we show that ethanol inhibits C2C12 myoblast differentiation by reducing myogenic fusion, creating smaller and less complex myotubes compared with controls. Ethanol administration during C2C12 differentiation reduced MyoD and myogenin expression, and microarray analysis identified ethanol activation of the Notch signaling pathway target genes Hes1 and Hey1. A reporter plasmid regulated by the Hes1 proximal promoter was activated by alcohol treatment in C2C12 cells. Treatment of differentiating C2C12 cells with a gamma secretase inhibitor (GSI) abrogated induction of Hes1. On a morphological level GSI treatment completely rescued myogenic fusion defects and partially restored other myotube parameters in response to alcohol. We conclude that alcohol inhibits C2C12 myoblast differentiation and the inhibition of myogenic fusion is mediated by Notch pathway activation.     

彩超与GGT联合检测对酒精依赖患者酒精肝的诊断价值

目的:研究分析彩超和谷氨酰转肽酶(GGT)联合检测对酒精依赖患者酒精性脂肪肝诊断的临床意义。方法:对2013年5月-2014年4月于我院住院并诊断为酒精依赖的患者39例(研究组)行肝脏彩超及GGT检测,另选取同期来源于本院职工、进修医护人员40例为对照组,对其结果进行分析。结果:研究组血清GGT为(189.95±226.52)U/L,显著高于对照组的(26.85±18.94)U/L,差异有统计学意义(t=4.54,P0.001);研究组中彩超诊断为脂肪肝者的GGT水平与非脂肪肝者有明显差异(P0.05),且高于对照组中的脂肪肝者,差异有统计学意义(P0.05)。结论:对于酒精依赖患者,血清GGT是敏感性较高的检测指标,GGT的检测有利于酒精性疾病的早期发现。彩超与GGT联合检测能提高临床对酒精性脂肪肝的检出率。     

Skeletal muscle protein synthesis and degradation exhibit sexual dimorphism after chronic alcohol consumption but not acute intoxication

Epidemiological evidence suggests alcoholic myopathy is more severe in females than males, but comparable animal studies are lacking that make elucidating the biochemical locus for this defect problematic. The present study determined whether skeletal muscle protein synthesis and markers of degradation exhibit a sexual dimorphic response to either chronic alcohol consumption or acute intoxication. Male and female rats were fed an alcohol-containing diet, pair-fed for 26 wk (chronic), or received an intraperitoneal injection of alcohol (acute). In males, chronic alcohol decreased gastrocnemius protein synthesis by 20%. This reduction was associated with a twofold increase in the inactive eukaryotic initiation factor (eIF) 4E.4E-binding protein 1 (4E-BP1) complex and a 60% reduction in the active eIF4E.eIF4G complex. This redistribution of eIF4E was associated with decreased phosphorylation of both 4E-BP1 and eIF4G (50-55%). The phosphorylation of ribosomal protein S6 was also reduced 60% in alcohol-consuming male rats. In contrast, neither rates of protein synthesis nor indexes of translation initiation in muscle were altered in alcohol-fed female rats despite blood alcohol levels comparable to males. Chronic alcohol ingestion did not alter atrogin-1 or muscle RING finger-1 mRNA content (biomarkers of muscle proteolysis) in males but increased their expression in females 50-100%. Acute alcohol intoxication produced a comparable decrease in muscle protein synthesis and translation initiation in both male and female rats. Our data demonstrate a sexual dimorphism for muscle protein synthesis, translation initiation, and proteolysis in response to chronic, but not acute, alcohol intoxication; however, they do not support evidence indicating females are more sensitive toward the development of alcoholic skeletal muscle myopathy.     

Nitricoxide synthase-induced oxidative stress in prolonged alcoholic myopathies of rats

Previous studies showed that nitricoxide synthase (NOS) and oxidative stress can induce skeletal muscle atrophy in the muscular dystrophy and inclusion-body myopathy. There is a correlation between NOS and oxidative stress. However, it is not clear, whether there are some changes of the NOS activity in prolonged alcoholic myopathy (PAM), and whether NOS activity has relation to amyotrophy of PAM. We established experimental alcoholic myopathy model of rats by prolonged alcohol intake. We found that there is a reduction in GSH-px (P < 0.05) and an increase of SOD (P < 0.05), MDA (P < 0.05) and iNOS (P < 0.05) in the plantaris of the experimental group by spectrophotometer. In the soleus of the experimental group, except for MDA showed an increase (P < 0.05), the other enzymes showed no obvious difference (P > 0.05). The immunohistochemistry results showed that there was obvious expression of iNOS in the cytoplasm of plantaris in the experimental group and there was no expression of iNOS in the control group. There was a decrease of nNOS expression on the membranes of the plantaris cells in the experimental group by immunofluorescence. Meanwhile, we found the expression of nNOS in some cytoplasm. Our results suggested that NOS might be an important factor during the development of PAM. We could infer that there are some disturbances with regard to output and scavenging of free radical in PAM. Alcohol can induce the oxidative stress reaction and further result in imbalance of the oxidant-antioxidant status in the organism. Haiying Chu is the co-first author.     

Catecholamines are involved in the mechanism of the urinary alcohol level cycle in rats fed ethanol intragastrically at a constant rate

Studies have indicated that blood alcohol levels cycle exists when ethanol is fed continuously using the intragastric feeding rat model of early alcoholic liver disease. The aim of the present study was to determine the role played by catecholamines in the pathogenesis of the blood alcohol cycling observed when ethanol is fed at a constant rate. The rats were tested at the peaks and troughs of the urinary alcohol level (UAL) cycle and the results were compared with controls. Blood catecholamine levels were markedly increased at the peaks, but not at the troughs. Propranolol, a beta adrenergic blocker, attenuated the amplitude of the cycle. Phenoxybenzamine, an alpha blocker disrupted the cycle and elevated ethanol to fatal levels. The results indicate that both alpha and beta adrenergic mechanisms are required for the cycle to occur.     

Influence of gender on ethanol-induced ventricular myocyte contractile depression in transgenic mice with cardiac overexpression of alcohol dehydrogenase

Acute ethanol exposure depresses ventricular contractility and contributes to alcoholic cardiomyopathy in both men and women chronically consuming ethanol. However, a gender-related difference in the severity of myopathy exists with female being more sensitive to ethanol-induced tissue damage. Acetaldehyde (ACA), the major oxidized product of ethanol, has been implicated to play a role in the pathogenesis and gender-related difference of alcoholic cardiomyopathy, possibly due to its direct cardiac effect and interaction with estrogen. This study was designed to compare the effects of cardiac overexpression of alcohol dehydrogenase (ADH), which converts ethanol into ACA, on the cardiac contractile response to ethanol in ventricular myocytes isolated from age-matched adult male and female transgenic (ADH) and wild-type (FVB) mice. Mechanical properties were measured with an IonOptix SoftEdge system. ACA production was assessed by gas chromatography. The ADH myocytes from both genders exhibited similar mechanical properties but a higher efficacy to produce ACA compared to FVB myocytes. Exposure to ethanol (80-640 mg/dl) for 60 min elicited concentration-dependent decrease of cell shortening in both FVB and ADH groups. The ethanol-induced depression on cell shortening was significantly augmented in female but not male ADH group. ADH transgene did not exacerbate the ethanol-induced inhibition of maximal velocity of shortening/relengthening in either gender. In addition, neither ethanol nor ADH transgene affect the duration of shortening and relengthening in male or female mice. These data suggest that females may be more sensitive to ACA-induced cardiac contractile depression than male, which may attribute to the gender-related difference of alcoholic cardiomyopathy.     

Hydroxyl Radical Formation in Skeletal Muscle of Rats with Glucocorticoid-Induced Myopathy

Steroid myopathy is a well-known adverse effect of glucocorticoids that causes muscle weakness and atrophy; however, its pathogenic mechanism is still unclear. Recently, oxidative stress was reported to contribute to steroid myopathy, but there is no report that actually attempts to measure hydroxyl radical. I developed an animal model of steroid myopathy in rat with dexamethasone (9-Fluoro−11β,17, 21-trihydroxy−16α-methylpregna−1,4-diene−3,20-dione), and measured hydroxyl radical using the salicylate trapping method. There was significant dose-dependent relation between both 2,5- and 2,3-dihydroxybenzoic acids and dexamethasone in the treated group, compared to the control group. These results suggest that hydroxyl radical plays a role in the pathogenesis of steroid myopathy.     

Molecular insights on intracellular Wnt/β-catenin signaling in alcoholic liver disease

Alcoholic liver disease (ALD) is one of the most common health problems worldwide, especially in developing countries caused by chronic consumption of alcohol on a daily basis. The ALD spectrum is initiated with the early stages of alcoholic fatty liver (steatosis), progressing to alcoholic steatohepatitis, followed by the later stages of fibrosis and in some cases, cirrhosis and hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling required for healthy liver development, function, and regeneration is found to be aberrated in ALD, attributed to its progression. This review is to elucidate the association of Wnt/β-catenin signaling with various stages of ALD progression. Alcohol causes downregulation of Wnt/β-catenin signaling components and thereby suppressing the pathway. Reports have been published that aberrated Wnt/β-catenin signaling, especially the absence of β-catenin, results in decreased alcohol metabolism, causing steatosis followed by steatohepatitis via lipid accumulation, lipid peroxidation, liver injury, increased oxidative stress and apoptosis of hepatocytes, contributing to the advancement of ALD. Contrastingly, the progression of later stages of ALD like fibrosis and HCC depends on the increased activation of Wnt/β-catenin signaling and its components. Existing studies reveal the varied expression of Wnt/β-catenin signaling in ALD. However, the dual role of the Wnt/β-catenin pathway in earlier and later stages of ALD is not clear. Therefore, studies on the Wnt/β-catenin pathway and its components in various manifestations of ALD might provide insight in targeting the Wnt/β-catenin pathway in ALD treatment.     

The effects of acetaldehyde and acrolein on muscle catabolism in C2 myotubes

The toxic aldehydes acetaldehyde and acrolein were previously suggested to damage skeletal muscle. Several conditions in which exposure to acetaldehyde and acrolein is increased were associated with muscle wasting and dysfunction. These include alcoholic myopathy, renal failure, oxidative stress, and inflammation. A main exogenous source of both acetaldehyde and acrolein is cigarette smoking, which was previously associated with increased muscle catabolism. Recently, we have shown that exposure of skeletal myotubes to cigarette smoke stimulated muscle catabolism via increased oxidative stress, activation of p38 MAPK, and upregulation of muscle-specific E3 ubiquitin ligases. In this study, we aimed to investigate the effects of acetaldehyde and acrolein on catabolism of skeletal muscle. Skeletal myotubes differentiated from the C2 myoblast cell line were exposed to acetaldehyde or acrolein and their effects on signaling pathways related to muscle catabolism were studied. Exposure of myotubes to acetaldehyde did not promote muscle catabolism. However, exposure to acrolein caused increased generation of free radicals, activation of p38 MAPK, upregulation of the muscle-specific E3 ligases atrogin-1 and MuRF1, degradation of myosin heavy chain, and atrophy of myotubes. Inhibition of p38 MAPK by SB203580 abolished acrolein-induced muscle catabolism. Our findings demonstrate that acrolein but not acetaldehyde activates a signaling cascade resulting in muscle catabolism in skeletal myotubes. Although within the limitations of an in vitro study, these findings indicate that acrolein may promote muscle wasting in conditions of increased exposure to this aldehyde.     

Acetaldehyde adducts in blood and bone marrow of patients with ethanol-induced erythrocyte abnormalities

BACKGROUND: Although alcohol abuse is known to cause a wide array of adverse effects on blood cell formation, the molecular mechanisms by which alcohol exerts its toxic actions remain poorly defined. We examine here the formation of acetaldehyde-derived protein modifications in erythrocytes and in their bone marrow precursors using antibodies specifically recognizing acetaldehyde-modified epitopes in proteins independently of the nature of the carrier protein. MATERIALS AND METHODS: We studied 138 consecutive adult patients undergoing bone marrow aspiration due to macrocytosis (MCV values above 99 fL). Assessment included complete blood counts, morphologic review, assessment of alcohol consumption, and biochemical and immunocytochemical assays for acetaldehyde adducts. RESULTS: There were 68 patients (49%) with a history of excessive alcohol consumption, 28 (20%) of whom were patients with severe dependence. The blood smears prepared from the alcoholic patients with macrocytosis also contained stomatocytes and knizocytes. Bone marrow aspirates from 12 alcoholic patients showed vacuolization of pronormoblasts and the presence of ring sideroblasts was noted in 8 cases. In immunocytochemical analyses of the peripheral blood erythrocytes, acetaldehyde-derived epitopes were found to occur both on the cell membrane and inside the erythrocytes. Bone marrow aspirates also showed positive staining for acetaldehyde adducts in the erythropoietic cells in 8 of 11 (73%) consecutive alcoholic patients. Separation of the erythrocyte proteins from the samples of alcoholics on HPLC-chromatography revealed the formation of fast-eluting hemoglobin fractions, which also reacted with antibodies against acetaldehyde adducts. CONCLUSIONS: Current data suggest that acetaldehyde-erythrocyte adducts are formed in vivo in blood and bone marrow of patients with excessive alcohol consumption. This may contribute to the generation of the erythrocyte abnormalities, which are frequently observed in alcoholic patients.     

Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy

Type 1 diabetes, if poorly controlled, leads to skeletal muscle atrophy, decreasing the quality of life. We aimed to search highly responsive genes in diabetic muscle atrophy in a common diabetes model and to further characterize associated signaling pathways. Mice were killed 1, 3, or 5 wk after streptozotocin or control. Gene expression of calf muscles was analyzed using microarray and protein signaling with Western blotting. We identified translational repressor protein REDD1 (regulated in development and DNA damage responses) that increased seven- to eightfold and was associated with muscle atrophy in diabetes. The diabetes-induced increase in REDD1 was confirmed at the protein level. This result was accompanied by the increased gene expression of DNA damage/repair pathways and decreased expression in ATP production pathways. Concomitantly, increased phosphorylation of AMPK and dephosphorylation of the Akt/mTOR/S6K1/FoxO pathway of proteins were observed together with increased protein ubiquitination. These changes were especially evident during the first 3 wk, along with the strong decrease in muscle mass. Diabetes also induced an increase in myostatin protein and decreased MAPK signaling. These, together with decreased serum insulin and increased serum glucose, remained altered throughout the 5-wk period. In conclusion, diabetic myopathy induced by streptozotocin led to alteration of multiple signaling pathways. Of those, increased REDD1 and myostatin together with decreased Akt/mTOR/FoxO signaling are associated with diabetic muscle atrophy. The increased REDD1 and decreased Akt/mTOR/FoxO signaling followed a similar time course and thus may be explained, in part, by increased expression of genes in DNA damage/repair and possibly also decrease in ATP-production pathways.     

Failure of Electron Paramagnetic Resonance Spectroscopy Studies to Detect Elevated Free Radical Signals in Liver Biopsy Specimens from Patients with Alcoholic Liver Disease

Electron paramagnetic resonance spectroscopy (EPR) was used to study free radicals and transition metal complexes in liver tissue taken from patients with liver disease. Samples were frozen to 77K directly following biopsy to prevent deterioration. Our major aim was to compare signals from patients suffering from alcohol abuse with those from patients having liver damage not induced by alcohol. Samples were obtained from 19 chronic alcohol abusers and 7 non-alcoholic liver disease patients. Of the 19 alcoholic patients, 18 had an increased fat content, 6 had Mallory's hyaline, 12 had an acute inflammatory response, 9 had increased stainable iron and 4 had evidence of fibrosis. A signal derived from free radicals with a spectroscopic splitting factor of g = 2.0045 was found in all samples. This signal in the alcoholic patients had a mean amplitude of 2.96 cm (± 1.42 SD), and in patients with non-alcoholic liver disease 2.12cm (±0.82) (p = 0.10NS), measured under identical instrument settings.

The molar proportion of diene conjugated linoleic acid (DCLA), a free radical marker, in the sera of alcoholic patients was 2.68% (±1.93), but did not correlate with the free radical signals obtained by EPR spectroscopy. Also, there was no correlation between the free radical derived EPR signal and fat content, Mallory's hyaline, inflammatory infiltrate, iron or fibrosis in the liver biopsy specimens. Similarly the concentrations of aspartate transaminase, albumin, and gamma-glutamyl transferase in serum samples showed no correlations with free radical concentrations.

The absence of any significant increase in the stable free radical signal in the presence of alcohol induced liver disease and the lack of correlation between the signal and either histological or serological evidence of liver damage, suggests that alcohol derived free radicals may not be involved in the pathogenesis of alcoholic liver disease.

Unusually large sextet features characteristic of MN(II) complexes were observed for all liver samples. Such signals are very rare in human tissue, showing that there is a strong accumulation of Mn (II) in the liver. However, no systematic trends were observed. In some samples signals characteristic of iron-sulphur cluster units were detected, but again no correlations could be discovered.     

Severity of alcohol dependence in patients with alcoholic liver disease.

To determine the severity of dependence on alcohol in patients with alcoholic liver disease the severity of alcohol dependence questionnaire was administered to 193 patients with various types of alcoholic liver disease established histologically, in whom a detailed history of lifetime alcohol consumption was also obtained. Only 34 patients (18%) were classified as being severely dependent compared with 56% of patients without overt liver disease who were attending a neighbouring alcohol treatment unit. There was a significant correlation between the severity of dependence and mean daily alcohol consumption (r = 0.45 and 0.39 for men and women, respectively) but not duration of drinking. Dependence scores tended to be lower in patients with cirrhosis than in those with precirrhotic liver disease, but this difference reached significance only in women. These findings confirm that patients who develop chronic alcoholic liver disease are usually only mildly dependent on alcohol and support the hypothesis that patients who escape florid symptoms of alcohol dependence are at greater risk of developing liver damage because they are able to sustain a continual consumption of alcohol over many years.