Bruha R, Dvorak K, Petrtyl J. Alcoholic liver disease. World J Hepatol 2012; 4(3): 81-90
Corresponding Author of This Article
Radan Bruha, MD, PhD, 4th Department of Internal Medicine, General Teaching Hospital, First Faculty of Medicine, Charles University, U Nemocnice 2 st, 12808 Prague, Czech Republic. email@example.com
Article-Type of This Article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Radan Bruha, 4th Department of Internal Medicine, General Teaching Hospital, First Faculty of Medicine, Charles University, 12808 Prague, Czech Republic
Karel Dvorak, Jaromir Petrtyl, 4th Department of Internal Medicine, General Teaching Hospital, First Faculty of Medicine, Charles University, 12808 Prague, Czech Republic
ORCID number: $[AuthorORCIDs]
Author contributions: Bruha R contributed to this work as the main author; Dvorak K and Petrtyl J wrote the revisited chapters “Treatment” and “Introduction (Epidemiology)”.
Supported by Grant IGA MZCR NT 11 247 (The role of protective mechanisms, oxidative stress and inflammatory reaction in the progression of liver damage in patient with metabolic syndrome and possible influence of antioxidative factors on the prevention of liver damage in experimental model of NASH); UK SVV 3362 (Regulatory parameters in the pathogenesis of inflammatory and oncologic diseases)
Correspondence to: Radan Bruha, MD, PhD, 4th Department of Internal Medicine, General Teaching Hospital, First Faculty of Medicine, Charles University, U Nemocnice 2 st, 12808 Prague, Czech Republic. firstname.lastname@example.org
Telephone: +420-224-962506 Fax: +420-224-923524
Received: February 28, 2011 Revised: September 7, 2011 Accepted: March 17, 2012 Published online: March 27, 2012
Alcohol use disorders affect millions of individuals worldwide. Alcohol consumption is directly associated with liver disease mortality and accounts for elevated social and economic costs. Alcoholic liver disease (ALD) may take the form of acute involvement (alcoholic hepatitis) or chronic liver disease (steatosis, steatohepatitis, fibrosis and cirrhosis). The severity and prognosis of alcohol-induced liver disease depends on the amount, pattern and duration of alcohol consumption, as well as on the presence of liver inflammation, diet, nutritional status and genetic predisposition of an individual. While steatosis is an almost completely benign disease, liver cirrhosis is associated with marked morbidity, mortality and life expectancy shortening. The median survival of patients with advanced cirrhosis is 1-2 years. Severe acute alcoholic hepatitis (AH) is associated with mortality as high as 50%. It has been managed with corticoids, pentoxifylline and enteral nutrition, although evidence based data are still conflicting. Some author suggest that pentoxifylline could be a better first-line treatment in patients with severe AH. Absolute abstinence is a basic condition for any treatment of acute or chronic ALD, the other therapeutical procedure being of a supportive nature and questionable significance. Acamprosate appears to be an effective treatment strategy for supporting continuous abstinence in alcohol dependent patients. Patients with advanced liver cirrhosis who demonstrably abstain can be considered for liver transplantation, which leads to a markedly prolonged life expectancy. The crucial step in ALD prevention is in the prevention of alcohol abuse, whereas the prevention of liver injury in active alcohol abusers is not clinically applicable.
Citation: Bruha R, Dvorak K, Petrtyl J. Alcoholic liver disease. World J Hepatol 2012; 4(3): 81-90
Alcohol is a most frequent cause of liver disease in western countries. Mortality due to liver cirrhosis in those countries is in direct proportion to absolute alcohol consumption per capita-the highest in France and Spain (over 30 deaths per a population of 100 000 per year), the lowest in the northern European countries (up to 5 deaths per 100 000 inhabitants per year). In Central Europe, the figure is 15 deaths due to cirrhosis per 100 000. The highest mortality is in men aged 35-64 years, lower in women (Figure 1). The past two to three decades have seen a stabilization if not a drop in the intake of alcohol in western countries, while a very adverse trend is reported from Eastern Europe and developing countries.
Figure 1 Mortality from cirrhosis in Czech Republic.
In what is an alarming development, alcohol abuse also afflicts societies and nations without any “drinking tradition”, such as in Asia. For example, in a cross-sectional study of two rural communities in China (in which almost 10 000 inhabitants were interviewed for current and lifetime alcohol use), the age-standardized prevalence of lifetime alcohol dependence ranged from 4.8% to 11.8% in different regions. Unlike most western reports, alcohol dependence shows a higher prevalence than the abuse itself.
Coincidence with HIV infection is another attribute of alcohol abuse. This was described in India for example, where the recent increase in alcohol consumption in many sectors of the general population is coupled with strong evidence of the role of alcohol in the spread of HIV infection and other health risks. An even more critical situation appears to have developed in Africa. Pithey et al performed a systematic review of sub-Saharan African studies concerning the association between alcohol abuse and HIV infection. Their findings strongly support an association between the two factors. A Fisher et al study of high-risk African women showed, even after adjustment for demographic and employment variables, that drinkers were more likely to be HIV positive than non-drinkers (relative risk 2.1). Problem drinkers were also more likely to have engaged in several types of high-risk sexual behavior and to have other sexually transmitted infections, including HSV-2.
Many studies have shown that the amount of undiluted (“pure”) alcohol consumed and the duration of that consumption are closely related to cirrhosis. According to some reports, cirrhosis does not develop below a lifetime alcohol consumption of 100 kg of undiluted alcohol. This amount corresponds to an average daily intake of 30 grams of undiluted alcohol for 10 years. Heavy alcoholics consuming at least 80 g of alcohol per day for more than 10 years will develop liver disease at a rate of nearly 100%. A detailed study of 256 heavy drinkers admitted to hospital not because of liver complaints, found steatosis at a rate of 45%, steatohepatitis at 34%, steatohepatitis with cirrhosis at 10% and cirrhosis alone at 10% in their liver biopsies. Formerly, 40-60 g of undiluted alcohol (i.e., 2-3 beers) per day used to be reported as a safe limit for men, less (20 g/d) for women. Data from the “Dionysos” study show, however, that consumption of more than 30 g of pure alcohol daily, regardless of sex, already increases the risk of liver disease.
For practical purposes, alcohol intake is rated by the count of “drinks”. The National Institute on Alcohol Abuse and Alcoholism defines a standard drink as 11-14 g of alcohol, which corresponds to approximately one drink of 40% spirit, one glass of wine or one 0.33 l (12-oz) beer. Hence, a “safe” daily intake of alcohol should not be more than two “drinks”. On the contrary, moderate ethanol consumption (mainly wine) may mean a reduced cardiovascular risk, especially in women.
Much the same applies to Asians. For example, in the Chinese population, the ethanol risk threshold for developing alcoholic liver disease (ALD) is 20 g per day with the risk increasing in proportion to the daily intake. Those drinking 20 g of ethanol per day and for less than 5 years are safe from ALD. In this study of 1270 alcohol drinkers, obesity also increases the risk. Abstinence and weight reduction will directly improve the prognosis of ALD.
As for liver injury, it has been postulated for many years that the type of alcoholic beverage makes little, if any difference. Nevertheless, some authors have proposed that mortality from cirrhosis is associated with the consumption of spirits more strongly than with other alcoholic beverages. It is not clear whether this effect can be put down to the drinkers’ socio-behavioral characteristics or to increased toxicity of alcoholic beverages.
ALD may take the form of acute involvement (alcoholic hepatitis) or chronic liver disease (steatosis, steatohepatitis, fibrosis and cirrhosis). Their progression also depends on the pattern of alcohol intake-drinking alcohol at mealtimes results in a lower risk of liver disease than consumption at other times; fitful, intermittent drinking is more sparing for the liver than a continuous supply of alcohol.
Although ALD is a disease that displays an absolute requirement for a voluntary environmental exposure (the consumption of alcohol), many other factors, including genetic host system attributes, are involved in the ALD evolution and progression.
ETIOLOGY, PATHOGENESIS, NATURAL COURSE AND PROGNOSIS OF ALCOHOLIC LIVER DISEASE
The liver is the main organ of alcohol metabolism. Alcohol is metabolized in the liver in three ways: (1) by the enzyme alcohol dehydrogenase (ADH); (2) by cytochrome P-4502E1 (CYP2E1); and (3) by mitochondrial catalase. Only the first two pathways are of practical significance-ADH finds use in the degradation of limited quantities of alcohol, while alcohol-induced CYP2E1 takes place in excessive alcohol intake. Apart from the liver, ADH is also present in the gastric mucosa and the assumption is that individuals with low gastric ADH activity are more susceptible to alcoholic liver disease. This may also help to explain why women who have decreased gastric ADH activity are more susceptible to developing alcoholic liver disease.
Both enzymes convert alcohol to acetaldehyde, which is in part responsible for the liver injury too. However, the process of liver injury is much more complex (Figure 2)-resulting from biochemical, genetic, cellular, immunological and humoral disorders in connection with the intake and metabolism of excessive quantities of alcohol. A major role is played there by oxidative stress (which is mainly due to alcohol-induced CYP2E1), by simultaneous shortage of antioxidants in the hepatocytes and, last but not least, by acetaldehyde alone and altered balance of many cytokines-mainly tumor necrosis factor (TNF)-α. Changes in lipid metabolism and in adipose tissue also enhance the process of liver injury. All above mentioned changes result in the injury of cell membranes and organelles (especially mitochondria). The mechanisms of hepatocytic damage due to excessive intake of alcohol show some similarity to changes seen in non-alcoholic steatohepatitis, except that the primary insult is different.
Figure 2 Pathogenesis of inflammatory changes in alcoholic liver disease.
ADH: Alcohol dehydrogenase; HSC: Hepatic stellate cell.
Individual susceptibility is another factor to take into account; moreover, any other liver involvement such as viral hepatitis or metabolic disease adds to the risks of alcoholism, as does obesity and metabolic syndrome.
In fact, alcoholics were clearly shown to have an increased prevalence of HCV when compared with non-alcoholics and this combination synergistically accelerates liver injury. As for alcohol influence on the liver, the caloric intake should also be taken in account. Increased caloric intake leads to excessive fat deposition and obesity in some patients and can aggravate the liver injury.
Of late, there has been an influx of information on correlations between genetic polymorphisms of alcohol-metabolizing enzymes and alcoholic liver disease. The genetics of ALD development involves an inherited predisposition to alcohol dependence, as well as the resulting development of liver injury. Family studies have established an important role of genetics in alcohol dependence. To date, only two genes, which are involved in alcohol metabolism, have shown significant involvement. The alcohol dehydrogenase ADH1B*1 allele was found to be associated with an approximately threefold increase in alcohol dependence and the aldehyde dehydrogenase ALDH2*2 allele was found to be instrumental in a 10-fold reduction of the alcohol dependence risk. This association was described in Asian populations. Also reported have been links between alcohol dependence and certain genetic polymorphisms of genes for the GABA receptor or some other neuropeptides.
Although most heavy drinkers do develop fatty liver, only a minority progress to liver cirrhosis, suggesting that some other genetic or environmental factors are important for the disease progression. Evidence of genetic involvement in the progression of alcoholic fatty liver to advanced ALD comes from a twin study. The rate of alcoholic cirrhosis was described to be significantly higher in monozygotic twins than in dizygotic twins (16.9% vs 5.3%, respectively). A study of genes involved in alcohol metabolism (e.g., alcohol and aldehyde dehydrogenase and cytochrome P450 2E1) and genes associated with inflammation (e.g., TNF-α and interleukin-10) proved to be inconclusive, with several allelic associations detected but not verified in follow-up studies. The Asian population’s hypersensitivity to alcohol could be put down to polymorphisms of genes for the enzymes ADH and CYP2E1. Perhaps the most compelling genetic finding for advanced ALD risk involves the immune regulatory cytotoxic T lymphocyte antigen-4 gene, in which homozygosity for the A49G polymorphism was found to confer a significant risk of alcoholic cirrhosis (odds ratio 3.5) in Italians. However, this finding has yet to be confirmed in follow-up studies.
Polymorphisms for TNF-α co-responsible for an increased risk of liver disease have been discovered in a similar way. For the time being, though, we do not know how to make use of this new knowledge in routine practice.
Malnutrition is another clinical situation with an impact on the evolution of ALD. Heavy alcohol drinkers often lack proper diets or consume diets which are compromised in various nutrients, such as proteins, polyunsaturated fatty acids and vitamins.
Liver steatosis is the most frequent primary change in chronic alcohol abuse. Changes associated with alcohol metabolism may subsequently trigger an inflammatory reaction, resulting in alcoholic hepatitis or chronic liver disease (Figure 3).
Figure 3 Spectrum of alcoholic liver disease.
Liver disease in alcohol abusers is more likely to take the form of chronic changes (steato-hepatitis and fibrosis), leading to cirrhosis later in life. The spectrum of histological findings can be described as a dynamic process (Figure 4). Simple steatosis is reversible after a number of weeks of abstinence; steatohepatitis, a condition seen in only some alcoholics, is a fibrogenic process which can induce changes leading to cirrhosis. Steatohepatitis is also reversible, although a certain degree of fibrosis may persist. The reversibility of steatohepatitis or even fibrosis in humans is well documented by trials on the treatment of chronic hepatitis C and experimentally on NASH models. Steatohepatitis, in particular, often coincides with liver cirrhosis in active alcoholics and is a frequent cause of decompensation of cirrhosis.
Figure 4 Dynamic process of alcoholic liver disease.
ALD: alcoholic liver disease.
Simple steatosis is regarded as a benign condition; nevertheless, given continued abuse, it too, can induce fibrogenesis; in any case, up to 20% of the patients with simple steatosis are likely to develop fibrosis or cirrhosis within a period of ten years. The prognosis of a patient with cirrhosis depends mainly on the presence of complications because of portal hypertension and continued abuse of alcohol. Abstainers with decompensated cirrhosis have a five year survival at a rate of 60% against the 30% survival rate in those who continue in the abuse.
Severe alcoholic hepatitis, although relatively rare, has a death rate of up to 50%. Identifying individuals with a high mortality risk is crucial in the management of acute alcoholic hepatitis. Multiple prognostic factors were studied over the last decade, including Child-Pugh classification (CTP), Maddrey score (bilirubin mg/dL + 4.6 × prothrombin time) and others. The MELD score was found a more valuable model than CTP or the Maddrey score in the detection of high risk patients admitted with alcoholic hepatitis. Alternatively, the more recent Glasgow alcoholic hepatitis score could be used. A Glasgow score exceeding 9 points is associated with poor prognosis (Table 1).
The score is to be added to each parameter, the sum total being between 5 and 12 points. The value of 9 and higher implies poor prognosis in alcoholic hepatitis. INR: International normalised ratio.
CLINICAL MANIFESTATION AND LABORATORY FINDINGS
Patients with steatosis are usually symptom-free; they may have slightly elevated liver function tests and enlarged liver (both are often discovered accidentally during examination for other reasons).
In the stage of acute alcoholic hepatitis, there may be nausea, loss of appetite, gradual loss of weight, icterus and other symptoms of liver dysfunction (prolonged prothrombin time, hypoalbuminemia, ascites, and hepatic encephalopathy). Patients with alcoholic hepatitis usually show increased liver test results, including gamma-glutamyl transferase (GGT), hypergammaglobulinemia and enlarged liver.
Sonography is the basic imaging technique for liver examination. Liver biopsy, while not always necessary, can help to differentiate simple steatosis from steatohepatitis, fibrosis or incipient cirrhosis. Precise definition of the liver fibrosis stage is essential for management and prognosis in clinical practice. Recently, blood markers and instrumental methods have been proposed for non-invasive assessment of liver fibrosis. However, there are still some doubts as to their implementation in clinical use. Non-invasive examination with transient elastography takes advantage of the fibrotic liver tissue ability to change the velocity of ultrasound propagation. The results of this method correlate well with the bioptically proved degree of fibrosis. Similar results could be obtained from a combination of biochemical and clinical parameters of fibrosis. As for the clinical picture, the state of alcoholic liver cirrhosis shows no difference from cirrhosis of other etiology.
ASSESSMENT OF ACTIVE ALCOHOL ABUSE
Assessment of continued alcohol abuse in patients with alcoholic liver disease is essential for their treatment as well as prognosis. Those with alcoholic cirrhosis also make up a significant part of patients indicated for liver transplantation (30%-50%), bearing in mind that abstinence is an essential condition for considering this treatment. Continued alcohol abuse is evaluated on the basis of clinical history, psychological examination and laboratory testing. Thorough clinical and psychological examination is the crucial condition for alcohol abuse diagnosis. Regarding the clinical history, the diagnosis of alcohol abuse and dependence was substantially improved by implementation of simple methods such as a single question inquiring how often the maximum daily alcohol limit has been exceeded. Other clinical screening tools such as the need to cut down, annoyed by criticism, guilty about drinking need for an eye-opener in the morning (CAGE), and the alcohol use disorders identification test (AUDIT-C) are also very easy to apply. With the CAGE questionnaire, two positive answers indicate alcohol dependence with a sensitivity of more than 70% and specificity of more than 90%. The AUDIT-C screening thresholds for the detection of alcohol abuse are ≥ 4 points for men (sensitivity 86%, specificity 89%) and ≥ 3 points for women (sensitivity 73%, specificity 91%).
As for laboratory tests, continued abuse can be read from higher GGT values, increased AST/ALT ratio or an increased volume of red blood cells (MCV). In advanced liver cirrhosis, however, the values of hepatic enzymes fall short of sufficient sensitivity or specificity levels. More information about the actual abuse of alcohol can be derived from the percentage of carboxy-deficient transferrin estimation (%CDT) in serum or ethyl glucuronide in urine or hair. A CDT value greater than 2.8% has a 79% sensitivity and 92% specificity for active alcohol abuse detection in patients with advanced cirrhosis.
PREVENTION OF ALD
Prevention of or treatment for alcohol abuse are crucial steps in the prevention of ALD. Alcohol dependence is a chronic relapsing medical disorder which is treatable when efficacious medicines are added to enhance the effects of psychosocial treatment. Medication with, e.g., naltrexone and acamprosate showed mixed results in previous clinical trials. Rősner et al recently performed a meta-analysis to determine the efficacy and tolerability of acamprosate in comparison with placebo and other pharmacological agents. Almost 7000 patients in 24 double-blind randomised controlled trials were evaluated. Compared to placebo, acamprosate was shown to significantly reduce the risk of any drinking (RR 0.86) and to significantly increase the cumulative abstinence duration. The only side effect that was more frequently reported under acamprosate than with placebo was diarrhea. The authors of this Cochrane review conclude that acamprosate appears to be an effective and safe treatment strategy for supporting continuous abstinence after detoxification in alcohol dependent patients. Indeed, without a pharmacological adjunct to psychosocial therapy, the clinical outcome is poor, with up to 70% of patients resuming drinking within one year.
The prevention of liver injury in active alcohol abusers is not clinically applicable. For example, in an experiment, the addition to the diet of polyunsaturated fatty acids prevented alcohol-induced fatty liver and mitochondrial dysfunction in an animal model of ALD by protecting various mitochondrial enzymes, most likely through reducing oxidative/nitrosative stress. The clinical use of similar medicaments would probably be always hampered by alcohol abusers´ failure to comply.
Absolute abstinence is essential to consider any treatment for alcoholic liver disease. Even major changes, including cirrhotic restructuring, may show partial regression during total abstinence. Portal hypertension declines and even regression of esophageal varices have been reported in abstainers. This, however, appears to have resulted from the remission of inflammatory changes and steatosis rather than from regressing fibrosis or cirrhosis. Sustained abstinence markedly improves the patient’s prognosis in any phase of the liver disease, prevents the progression of the disease and fibrosis and, probably, also the development of hepatocellular carcinoma.
Pharmacotherapy of liver disease has but a supportive and rather dubious relevance. Treatment with silymarin, essential phospholipids or vitamin preparations was very popular in the past. Since an oxidative stress has been implicated in the pathophysiology of hepatic insult, the use of natural compounds with anti-oxidant properties represents an extremely popular therapeutic option for the treatment of liver disease. One such phytochemical, resveratrol, is remarkable as it is known as a major constituent of an alcoholic beverage, red wine. Resveratrol was shown to prevent liver injury by means of scavenging free radicals and inflammatory cytokines in experimental studies. Its clinical utilization, though, is still far away. There are no conclusive data to prove the efficacy of any antioxidant medicaments for longer survival time or improved clinical conditions in the treatment of ALD. These are mostly cases of rather costly placebo. In contrast, dietary readjustment in the sense of sufficient energy intake and adequate supply of proteins is of value because malnutrition is a very poor prognostic factor in liver diseases. What has been described as “liver diet”with increased supply of saccharides at the restriction of proteins and fats has no substantiation. Appropriate caloric intake with sufficient supply of proteins and polyunsaturated fats is important[34,61].
Severe alcoholic hepatitis has been treated with corticoids in many trials, with the best results in patients with hepatic encephalopathy, Maddrey score > 32 or Glasgow score > 9. The Glasgow score is very simple to evaluate and its prognostic value is also greater than that of any other classification (Figure 5). The corticoid dose in that case is 40 mg prednisolone per day. The side effects of glucocorticosteroids must be also taken into consideration, as some patients on glucocorticosteroids experience adverse effects, mainly in the form hyperglycemia, Cushing’s syndrome and increased risk of infection. Despite the fact that the available trials are rather heterogeneous and some authors do not recommend the use of steroids in alcoholic hepatitis, recently published data emphasize the effect of corticosteroids on short-term survival of patients with severe alcoholic hepatitis, particularly in those with Maddrey score > 32.
Figure 5 Kaplan-Meier survival analysis relative to the modified Maddrey discriminant function (mDF) (A) and the Glasgow alcoholic hepatitis score (GAHS) (B).
The Glasgow score was developed on 241 patients and validated on 195 separate patients.
Some trials and reviews of pentoxifylline (PTX) have shown a better risk/benefit profile than that of steroids and suggested that PTX could be a better first-line treatment in patients with severe AH. The efficacy of PTX in severe AH was first demonstrated by Akrividais et al in 2000 on a group of 101 patients with severe AH. 24.5% of the patients who received PTX died during their index hospitalization, compared to a 46.1% mortality in the placebo group (P = 0.037). Remarkably, hepatorenal syndrome was the cause of death in 50% of patients on PTX compared to 91.7% of the HRS-related deaths in the placebo group (P = 0.009). According to the authors, the benefit appears to be related to a significant decrease in the risk of developing hepatorenal syndrome. In fact, renal dysfunction is frequent in patients with severe alcoholic hepatitis and, it seems, could be prevented with PTX.
Even in direct comparison with corticosteroids in a randomized trial, pentoxifylline was found to be superior to prednisolone for the management of severe alcoholic hepatitis regarding reduced mortality, improved risk-benefit profile and renoprotective effect. Nevertheless, this observation should be confirmed on a larger cohort of patients. A recent study by Lebrec et al stopped short of confirming the effect of PTX on better survival but, unlike a previous study, only Child-Pugh class C patients were included. However, the study did confirm a reduced risk of complications, such as bacterial infection, renal insufficiency, hepatic encephalopathy or gastrointestinal hemorrhage in patients treated with PTX compared to placebo.
Some centers recommend the use of PTX as the routine first line treatment of severe alcoholic hepatitis at a dose of 400 mg orally 3 times daily for a period of at least 4 wk. They point to its safety, low cost and scope for long-term treatment. Significantly enough, the sweeping use of PTX as a first-line option is not generally recommended and steroids should be used in patients with severe alcoholic hepatitis. Pentoxifylline could be used in patients with ineffectiveness or contraindications to steroids. The combination of pentoxifylline and steroids waits for clinical evaluation.
Biological treatment with anti- TNF-α antibodies fell short of expectations[72,73] so it can no longer be recommended for the management of alcoholic hepatitis.
Many studies with diverse conclusions have been published on the subject of nutrition and alcoholic hepatitis. In general, patients with alcoholic liver disease are frequently malnourished, a condition which worsens the prognosis. However, the situation is not all that easy, as the spectrum of nutritional status in these patients may range from severe malnutrition to morbid obesity. The nutritional intervention on an outpatient basis depends on the degree of malnutrition, obesity and cooperation. In general, supplementation of multivitamins, folic acid and thiamine could be of value in chronic alcohol abuse, but data in the relevant literature are limited. Night-time nutritional supplements (approximately 700 kcal/d) may prevent muscle wasting and improve lean muscle mass in patients with liver cirrhosis and should be considered, also relative to alcoholic hepatitis in patients with evidence of liver cirrhosis.
More data are available regarding the treatment of severe alcoholic hepatitis by enteral nutrition. The benefit of tube-feeding over the regular diet was demonstrated previously. Patients on tube-fed nutrition had improved PSE scores, bilirubin and antipyrine clearance.
Many reviews and recommendations refer to a study by Cabre et al, which clearly demonstrated the efficacy of tube-fed nutrition. In their multi-center study, 71 patients with severe alcoholic hepatitis were randomized to receive 40 mg/d prednisolone or enteral tube feeding for 28 d and were followed up for 1 year. Mortality during the treatment was similar in both groups but during the follow-up significantly higher with steroids (37% vs 8%; P = 0.04), mainly because of infections with steroid treatment. The authors concluded that, unlike steroids, enteral nutrition had similar short-term mortality rates, improved 1 year mortality rates and reduced infectious complications. While some studies refrain from confirming any favorable effect of enteral feeding on survival, the implementation of tube-feeding in the treatment of acute alcoholic hepatitis is generally accepted. There are only inconsistent data concerning the use of parenteral nutrition.
Despite the progress in the treatment of severe acute alcoholic hepatitis, the prognosis is still poor.
Alcoholic cirrhosis as such is treated in the same way as cirrhosis of other etiology; in particular, with adequate nutrition, bone disease prevention and prevention or treatment of liver cirrhosis complications (e.g., bleeding from esophageal varices, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy).
Quite a few medicinal products were tested for the treatment of alcoholic cirrhosis: antiphlogistics/propylthiuracil, colchicine, antioxidants/silymarin[83,84] and also phosphatidylcholine. However, none of these were found to have a favorable effect on survival time and none are recommended for this particular indication any longer. Medicaments with a direct antifibrotic effect are still under evaluation.
Patients with advanced cirrhosis can be considered for liver transplantation, provided they are total abstainers. In such cases, a five year post-transplantation survival can reach anything up to 85%.
Long-term intake of more than 30 g of absolute alcohol per day increases the risk of alcoholic liver disease; liver disease is nearly certain in long-term consumption in excess of 80 g of absolute alcohol per day. Alcoholic liver disease may take the chronic form (steatosis, steatohepatitis, fibrosis, cirrhosis) or that of acute hepatitis. Steatosis is fully reversible, which does not apply to the other conditions; cirrhosis is associated with a markedly shortened life expectancy. The results of laboratory testing in alcoholic liver disease usually include: increased GGT, AST/ALT ratio greater than 2 and increased MCV. Sonography will reveal enlarged liver and signs of steatosis. Absolute abstinence is an essential therapeutic precaution; no hepatoprotective treatment has been shown to improve the course of the disease. Likewise, there is no medicine that would demonstrably “protect” from the effects of alcohol.
The clinical course of severe alcoholic hepatitis could be improved with corticoids, enteral nutrition and pentoxifylline, although more clinical data are necessary to standardize or combine this treatment.
Patients with advanced cirrhosis should be considered for liver transplantation, provided they are verifiable abstainers.
Peer reviewers: Dr. Henning Gronbaek, cal Department V, Aarhus University Hospital, Norrebrogade 44, Aarhus 8000, Denmark; Dr. Hongzhi Xu, Massachusetts General Hospital, 51 Blossom Street, Room 435, Boston, MA 02148, United States
S- Editor Wu X L- Editor Roemmele A E- Editor Zhang DN
Sherlock S, Dooley J. Diseases of the Liver and Biliary System. 11th ed. Oxford: Blackwell Publishing; 2002;381-398.
Bosetti C, Levi F, Lucchini F, Zatonski WA, Negri E, La Vecchia C. Worldwide mortality from cirrhosis: an update to 2002.J Hepatol. 2007;46:827-839.
Caballeria J. Epidemiological aspects of alcoholic liver disease.Textbook of Hepatology. Oxford: Blackwell Publishing; 2007;1129-1134.
Zhou L, Conner KR, Phillips MR, Caine ED, Xiao S, Zhang R, Gong Y. Epidemiology of alcohol abuse and dependence in rural chinese men.Alcohol Clin Exp Res. 2009;33:1770-1776.
Sharma HK, Tripathi BM, Pelto PJ. The evolution of alcohol use in India.AIDS Behav. 2010;14 Suppl 1:S8-17.
Pithey A, Parry C. Descriptive systematic review of Sub-Saharan African studies on the association between alcohol use and HIV infection.SAHARA J. 2009;6:155-169.
Fisher JC, Cook PA, Sam NE, Kapiga SH. Patterns of alcohol use, problem drinking, and HIV infection among high-risk African women.Sex Transm Dis. 2008;35:537-544.
Bellentani S, Tiribelli C. The spectrum of liver disease in the general population: lesson from the Dionysos study.J Hepatol. 2001;35:531-537.
Barrio E, Tomé S, Rodríguez I, Gude F, Sánchez-Leira J, Pérez-Becerra E, González-Quintela A. Liver disease in heavy drinkers with and without alcohol withdrawal syndrome.Alcohol Clin Exp Res. 2004;28:131-136.
Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, Saveria Crocè L, Sasso F, Pozzato G, Cristianini G. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group.Gut. 1997;41:845-850.
Snow WM, Murray R, Ekuma O, Tyas SL, Barnes GE. Alcohol use and cardiovascular health outcomes: a comparison across age and gender in the Winnipeg Health and Drinking Survey Cohort.Age Ageing. 2009;38:206-212.
Harriss LR, English DR, Hopper JL, Powles J, Simpson JA, O'Dea K, Giles GG, Tonkin AM. Alcohol consumption and cardiovascular mortality accounting for possible misclassification of intake: 11-year follow-up of the Melbourne Collaborative Cohort Study.Addiction. 2007;102:1574-1585.
Lu XL, Luo JY, Tao M, Gen Y, Zhao P, Zhao HL, Zhang XD, Dong N. Risk factors for alcoholic liver disease in China.World J Gastroenterol. 2004;10:2423-2426.
Roizen R, Kerr WC, Fillmore KM. Cirrhosis mortality and per capita consumption of distilled spirits, United States, 1949-94: trend analysis.BMJ. 1999;319:666-670.
Kerr WC, Fillmore KM, Marvy P. Beverage-specific alcohol consumption and cirrhosis mortality in a group of English-speaking beer-drinking countries.Addiction. 2000;95:339-346.
Marugame T, Yamamoto S, Yoshimi I, Sobue T, Inoue M, Tsugane S. Patterns of alcohol drinking and all-cause mortality: results from a large-scale population-based cohort study in Japan.Am J Epidemiol. 2007;165:1039-1046.
Frezza M, di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism.N Engl J Med. 1990;322:95-99.
Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice.Gastroenterology. 1999;117:942-952.
Song Z, Zhou Z, Deaciuc I, Chen T, McClain CJ. Inhibition of adiponectin production by homocysteine: a potential mechanism for alcoholic liver disease.Hepatology. 2008;47:867-879.
Bhattacharya R, Shuhart MC. Hepatitis C and alcohol: interactions, outcomes, and implications.J Clin Gastroenterol. 2003;36:242-252.
Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC. Excess weight risk factor for alcoholic liver disease.Hepatology. 1997;25:108-111.
Siu L, Foont J, Wands JR. Hepatitis C virus and alcohol.Semin Liver Dis. 2009;29:188-199.
Shen Z, Li Y, Yu C, Shen Y, Xu L, Xu C, Xu G. A cohort study of the effect of alcohol consumption and obesity on serum liver enzyme levels.Eur J Gastroenterol Hepatol. 2010;22:820-825.
Wilfred de Alwis NM, Day CP. Genetics of alcoholic liver disease and nonalcoholic fatty liver disease.Semin Liver Dis. 2007;27:44-54.
Juran BD, Lazaridis KN. Genomics and complex liver disease: Challenges and opportunities.Hepatology. 2006;44:1380-1390.
Whitfield JB. Meta-analysis of the effects of alcohol dehydrogenase genotype on alcohol dependence and alcoholic liver disease.Alcohol Alcohol. 1997;32:613-619.
Thomasson HR, Crabb DW, Edenberg HJ, Li TK, Hwu HG, Chen CC, Yeh EK, Yin SJ. Low frequency of the ADH2*2 allele among Atayal natives of Taiwan with alcohol use disorders.Alcohol Clin Exp Res. 1994;18:640-643.
Edenberg HJ, Dick DM, Xuei X, Tian H, Almasy L, Bauer LO, Crowe RR, Goate A, Hesselbrock V, Jones K. Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.Am J Hum Genet. 2004;74:705-714.
Reed T, Page WF, Viken RJ, Christian JC. Genetic predisposition to organ-specific endpoints of alcoholism.Alcohol Clin Exp Res. 1996;20:1528-1533.
Willner IR, Reuben A. Alcohol and the liver.Curr Opin Gastroenterol. 2005;21:323-330.
Valenti L, De Feo T, Fracanzani AL, Fatta E, Salvagnini M, Aricò S, Rossi G, Fiorelli G, Fargion S. Cytotoxic T-lymphocyte antigen-4 A49G polymorphism is associated with susceptibility to and severity of alcoholic liver disease in Italian patients.Alcohol Alcohol. 2004;39:276-280.
Plauth M, Cabré E, Campillo B, Kondrup J, Marchesini G, Schütz T, Shenkin A, Wendon J. ESPEN Guidelines on Parenteral Nutrition: hepatology.Clin Nutr. 2009;28:436-444.
Teli MR, Day CP, Burt AD, Bennett MK, James OF. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver.Lancet. 1995;346:987-990.
Poynard T, McHutchison J, Davis GL, Esteban-Mur R, Goodman Z, Bedossa P, Albrecht J. Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C.Hepatology. 2000;32:1131-1137.
Mu YP, Ogawa T, Kawada N. Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine-choline-deficient diet.Lab Invest. 2010;90:245-256.
Stewart SF, Day CP: Alcoholic liver disease. In: Boyer TD, Wright TL, Manns MP, editors. Zakim and Boyer’s Hepatology. A textbook of liver disease. Philalphia: Elsevier; 2006;579-623.
Reeves HL, Burt AD, Wood S, Day CP. Hepatic stellate cell activation occurs in the absence of hepatitis in alcoholic liver disease and correlates with the severity of steatosis.J Hepatol. 1996;25:677-683.
Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study.Hepatology. 1995;22:1714-1719.
Maddrey WC, Boitnott JK, Bedine MS, Weber FL, Mezey E, White RI. Corticosteroid therapy of alcoholic hepatitis.Gastroenterology. 1978;75:193-199.
Srikureja W, Kyulo NL, Runyon BA, Hu KQ. MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant Function score in patients with alcoholic hepatitis.J Hepatol. 2005;42:700-706.
Forrest EH, Evans CD, Stewart S, Phillips M, Oo YH, McAvoy NC, Fisher NC, Singhal S, Brind A, Haydon G. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.Gut. 2005;54:1174-1179.
Sebastiani G. Non-invasive assessment of liver fibrosis in chronic liver diseases: implementation in clinical practice and decisional algorithms.World J Gastroenterol. 2009;15:2190-2203.
Yeshua H, Oren R. Non invasive assessment of liver fibrosis.Ann Transplant. 2008;13:5-11.
Willenbring ML, Massey SH, Gardner MB. Helping patients who drink too much: an evidence-based guide for primary care clinicians.Am Fam Physician. 2009;80:44-50.
Bradley KA, DeBenedetti AF, Volk RJ, Williams EC, Frank D, Kivlahan DR. AUDIT-C as a brief screen for alcohol misuse in primary care.Alcohol Clin Exp Res. 2007;31:1208-1217.
Palmer RB. A review of the use of ethyl glucuronide as a marker for ethanol consumption in forensic and clinical medicine.Semin Diagn Pathol. 2009;26:18-27.
Dousa M, Zima T, Bruha R, Svestka T, Petrtyl J. Sensitivity and specificity of CDT in the evaluation of alcohol abuse in cirrhotic patients.Gut. 2006;55:A307.
Tsukamoto H. Conceptual importance of identifying alcoholic liver disease as a lifestyle disease.J Gastroenterol. 2007;42:603-609.
Johnson BA. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings.Biochem Pharmacol. 2008;75:34-56.
Rösner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence.Cochrane Database Syst Rev. 2010;CD004332.
Finney JW, Hahn AC, Moos RH. The effectiveness of inpatient and outpatient treatment for alcohol abuse: the need to focus on mediators and moderators of setting effects.Addiction. 1996;91:1773-196; discussion 1773-196;.
Song BJ, Moon KH, Olsson NU, Salem N. Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids.J Hepatol. 2008;49:262-273.
Tilg H, Day CP. Management strategies in alcoholic liver disease.Nat Clin Pract Gastroenterol Hepatol. 2007;4:24-34.
Powell WJ, Klatskin G. Duration of survival in patients with Laennec's cirrhosis. Influence of alcohol withdrawal, and possible effects of recent changes in general management of the disease.Am J Med. 1968;44:406-420.
Morgan MY. The prognosis and outcome of alcoholic liver disease.Alcohol Alcohol Suppl. 1994;2:335-343.
Bishayee A, Darvesh AS, Politis T, McGory R. Resveratrol and liver disease: from bench to bedside and community.Liver Int. 2010;30:1103-1114.
Alberino F, Gatta A, Amodio P, Merkel C, Di Pascoli L, Boffo G, Caregaro L. Nutrition and survival in patients with liver cirrhosis.Nutrition. 2001;17:445-450.
ASPEN Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients.JPEN J Parenter Enteral Nutr. 2002;26:1SA-138SA.
Forrest EH, Morris AJ, Stewart S, Phillips M, Oo YH, Fisher NC, Haydon G, O'Grady J, Day CP. The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.Gut. 2007;56:1743-1746.
Rambaldi A, Saconato HH, Christensen E, Thorlund K, Wetterslev J, Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.Aliment Pharmacol Ther. 2008;27:1167-1178.
Mathurin P, O'Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, Naveau S, Maddrey WC, Morgan TR. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.Gut. 2011;60:255-260.
Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.Gastroenterology. 2000;119:1637-1648.
Arora R, Kathuria S, Jalandhara N. Acute renal dysfunction in patients with alcoholic hepatitis.World J Hepatol. 2011;3:121-124.
De BK, Gangopadhyay S, Dutta D, Baksi SD, Pani A, Ghosh P. Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial.World J Gastroenterol. 2009;15:1613-1619.
Whitfield K, Rambaldi A, Wetterslev J, Gluud C. Pentoxifylline for alcoholic hepatitis.Cochrane Database Syst Rev. 2009;CD007339.
Lebrec D, Thabut D, Oberti F, Perarnau JM, Condat B, Barraud H, Saliba F, Carbonell N, Renard P, Ramond MJ. Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis.Gastroenterology. 2010;138:1755-1762.
Amini M, Runyon BA. Alcoholic hepatitis 2010: a clinician's guide to diagnosis and therapy.World J Gastroenterol. 2010;16:4905-4912.
Braillon A. Severe alcoholic hepatitis: glucocorticoid saves lives and transplantation is promising.World J Gastroenterol. 2011;17:2454.
Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broët P, Emilie D. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.Hepatology. 2004;39:1390-1397.
Boetticher NC, Peine CJ, Kwo P, Abrams GA, Patel T, Aqel B, Boardman L, Gores GJ, Harmsen WS, McClain CJ. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis.Gastroenterology. 2008;135:1953-1960.
Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis.N Engl J Med. 2009;360:2758-2769.
Plank LD, Gane EJ, Peng S, Muthu C, Mathur S, Gillanders L, McIlroy K, Donaghy AJ, McCall JL. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial.Hepatology. 2008;48:557-566.
Kearns PJ, Young H, Garcia G, Blaschke T, O'Hanlon G, Rinki M, Sucher K, Gregory P. Accelerated improvement of alcoholic liver disease with enteral nutrition.Gastroenterology. 1992;102:200-205.
Cabré E, Rodríguez-Iglesias P, Caballería J, Quer JC, Sánchez-Lombraña JL, Parés A, Papo M, Planas R, Gassull MA. Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.Hepatology. 2000;32:36-42.
Plauth M, Cabré E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, Ferenci P, Holm E, Vom Dahl S, Müller MJ. ESPEN Guidelines on Enteral Nutrition: Liver disease.Clin Nutr. 2006;25:285-294.
Brůha R, Petrtýl J, Urbánek P, Svestka T, Kaláb M, Marecek Z. [Long-term pharmacological treatment of portal hypertension].Cas Lek Cesk. 2005;144 Suppl 1:63-66.
Orrego H, Blake JE, Blendis LM, Compton KV, Israel Y. Long-term treatment of alcoholic liver disease with propylthiouracil.N Engl J Med. 1987;317:1421-1427.
Morgan TR, Weiss DG, Nemchausky B, Schiff ER, Anand B, Simon F, Kidao J, Cecil B, Mendenhall CL, Nelson D. Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival.Gastroenterology. 2005;128:882-890.
Parés A, Planas R, Torres M, Caballería J, Viver JM, Acero D, Panés J, Rigau J, Santos J, Rodés J. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial.J Hepatol. 1998;28:615-621.
Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Milk thistle for the treatment of liver disease: a systematic review and meta-analysis.Am J Med. 2002;113:506-515.
Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S. II. Veterans Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver disease.Alcohol Clin Exp Res. 2003;27:1765-1772.
Popov Y, Schuppan D. Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies.Hepatology. 2009;50:1294-1306.
McCallum S, Masterton G. Liver transplantation for alcoholic liver disease: a systematic review of psychosocial selection criteria.Alcohol Alcohol. 2006;41:358-363.
Ryska M, Trunecka P. [Liver transplantation--present status worldwide and in the Czech Republic].Cas Lek Cesk. 2003;142:717-726.