The management of severe alcoholic liver disease and variceal bleeding in the intensive care unit

PURPOSE OF REVIEW: To address recent advances in the understanding and management of alcohol-related chronic liver disease and its acute complications. RECENT FINDINGS: Refinements have been made in the prognosis and treatment of alcoholic hepatitis, and new insights have been gained into the pathophysiology of the hepatorenal syndrome. Further trial evidence has emerged concerning therapy in the hepatorenal syndrome, and there has been some clarification of the benefits and risks relating to albumin dialysis/extracorporeal liver support, and consensus in the early management of variceal haemorrhage. SUMMARY: Recent developments have led to modifications in the standard of care of patients with severe alcoholic liver disease, many of which are highly applicable to the general critical care setting. These changes apply specifically to alcoholic hepatitis, the hepatorenal syndrome and variceal bleeding, common conditions with a high mortality rate, upon which changes in practice can have a significant impact.     

How to use statins in patients with chronic liver disease

Clinicians may be concerned about prescribing statins to patients with chronic liver disease, but there is little evidence to suggest that drug-induced liver injury from statins is increased in these patients. Thus, we should prescribe statins for the same indications in patients with chronic liver disease as in patients without, but with closer monitoring. However, patients with acute liver disease (acute viral hepatitis, alcoholic hepatitis) should not take statins until they have recovered.     

Changes in the intermediate filament cytoskeleton of liver cells in alcoholic liver injury

Mallory bodies are a morphological key feature of severe alcoholic liver cell injury (alcoholic hepatitis) and the morphological expression of dysregulation and derangement of the intermediate filament cytoskeleton of the hepatocyte. Their pathogenesis is still unclear. Studies on Mallory body formation may not only help to elucidate the mechanisms of liver cell injury associated with alcoholic hepatitis, but may also contribute to our understanding of the regulation and function of the intermediate filament cytoskeleton.     

血清组织多肽特异性抗原检测在酒精性肝炎诊断中的应用研究

目的探讨血清组织多肽特异性抗原（TPS）检测在评估酒精性肝炎患者肝细胞凋亡程度的价值,并评估其在酒精性肝炎和脂肪肝鉴别诊断中的作用。方法全自动生化分析仪检测常规肝脏损伤标志物（AST、ALT、GGT和胆红素等）;电化学发光法检测血清TPS浓度;免疫组织化学染色法检测肝组织活检标本M30染色情况,对其凋亡得分进行评定;并分析各种指标与肝细胞凋亡得分之间的相关性。结果酒精性肝炎患者血清TPS水平与肝细胞凋亡得分呈明显正相关;血清TPS尝试和凋亡得分之间的相关性强于各项常规肝功能检测指标与凋亡得分之间的相关性;酒精性肝炎患者血清TPS浓度和肝细胞凋亡得分均明显高于脂肪肝患者（P〈O．05）。结论血清TPS可能是酒精性肝炎患者一个良好的肝细胞凋亡标志物,有助于对酒精性肝炎和脂肪肝的鉴别诊断。     

Liver disease of the alcoholic.

Significant liver disease including fatty metamorphosis, alcoholic hepatitis, cirrhosis, and hepatoma occur in two thirds of subjects who consume alcoholic beverages in sufficient quantities to interfere with work and social responsibilities; this is of major importance in the rapidly escalating morbidity and mortality from alcoholism. Chronic alcoholics should be routinely evaluated for the presence of altered liver function and structure. Clearance of indocyanine green using dichromatic ear densitometry and computer and analysis provides a simple and sensitive method for mass screening of such patients. Clinical studies of lymphocyte reactivity to purified alcoholic hyaline may be valuable in recognizing alcoholic hepatitis, the precursor of cirrhosis. Ethanol toxicity, malnutrition and constitutional factors contribute to the development of hepatic fibrosis and cirrhosis in alcoholics. Ethanol and/or acetaldehyde and the supernatant from lymphocytes stimulated by alcoholic hyaline cause a significant increase in the incorporation of proline into collagen of the damaged liver. Abstinence and correction of nutrient deficits are the cornerstones of treatment for alcoholic liver disease; a daily meal and dietary supplements should be provided for those with liver injury who continue to imbibe. Alcoholics with progressive liver disease despite supportive therapy may be aided by pharmacologic agents which suppress immunologic response and reduce fibrogenesis.     

Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in an improvement in treatment. Nutritional deficiencies should be corrected when present but, because of the alcohol-induced disease process, some of the nutritional requirements change. For instance, methionine, one of the essential amino acids for humans, must be activated to S-adenosylmethionine (SAMe), but, in severe liver disease, the activity of the corresponding enzyme is depressed. Therefore, the resulting deficiencies and associated pathology can be attenuated by the administration of SAMe, but not by methionine. Similarly, phosphatidylethanolamine methyltransferase (PEMT) activity, which is important for hepatic phosphatidylcholine (PC) synthesis, is also depressed in alcoholic liver disease, therefore calling for the administration of the products of the reaction. Inasmuch as free radical generation by the ethanol-induced CYP2E1 plays a key role in the oxidative stress, inhibitors of this enzyme have great promise and PPC, which is presently being evaluated clinically, is particularly interesting because of its innocuity. In view of the striking negative interaction between alcoholic liver injury and hepatitis C, an antiviral agent is eagerly awaited that, unlike Interferon, is not contraindicated in the alcoholic. Antiinflamatory agents may also be useful. In addition to steroids, down-regulators of cytokines and endotoxin are being considered. Finally, anticraving agents such as naltrexone or acamprosate should be incorporated into any contemplated therapeutic cocktail.     

The gamma-glutamyl transpeptidase (GGTP) as an index for the diagnosis of chronic alcoholic cholestatic hepatitis (author's transl)]

The GGTP is an enzyme localized, in the liver cell, inside microsome. At beginning the use of the GGTP was introduced for the diagnosis of chronic hepatitis; after it was noted as this was steady increased in the cholestasis and in the alcoholism. We have, hence, wanted to experiment if the changing of the level of the GGTP allowed to us a diagnosis of chronic alcoholic hepatitis. Our research is based on seventy-five patients with several liver diseases. It has been noted as the highest levels of the GGTP have appeared in cases of chronic alcoholic hepatitis with signs, histologicals and biochemicals, o cholestasis. In fact we have, on overage, levels of 955 mU/ml in the chronic alcoholic hepatitis with signs of cholestasis and of 135 mU/ml in that without it. In conclusion the GGTP is a good index for the diagnosis of chronic alcoholic cholestatic hepatitis.     

The aetiology, management and complications of alcoholic hepatitis

First described over 40 years ago, alcoholic hepatitis (AH) (an acute inflammation of the liver) is a common condition seen in 10-35% of heavy drinkers. In its severest form acute AH carries a high short-term mortality of up to 60%. Although the current treatment options are limited, many of the complications associated with increased mortality, such as hepatorenal syndrome, are preventable. The incidence of AH in the UK is set to rise as a result of the increase in heavy drinking. This article aims to increase awareness of the disease aetiology and to review current management strategies and nursing care.     

Pathogenesis, diagnosis, and treatment of alcoholic liver disease

Alcohol-related liver disease is a major cause of morbidity and mortality in the United States. Alcoholic liver disease encompasses a clinicohistological spectrum, including fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Fatty liver is a benign and reversible condition, but progression to alcoholic hepatitis and cirrhosis is life-threatening. Alcoholic hepatitis is diagnosed predominantly on clinical history, physical examination, and laboratory testing, although liver biopsy is often necessary to secure the diagnosis. The major focus of management is abstinence from alcohol, supportive care, treatment of complications of infection and portal hypertension, and maintenance of positive nitrogen balance through nutritional support. Corticosteroid therapy is controversial but should be considered in patients with a discriminant function greater than 32 and/or presence of spontaneous hepatic encephalopathy in the absence of infection, gastrointestinal bleeding, and renal failure. The only curative therapy for advanced alcoholic cirrhosis is liver transplantation. Several recent advances in understanding the pathogenesis of alcoholic liver disease may lead to novel future treatment approaches, including inhibition of tumor necrosis factor a, antioxidant therapy, stimulation of liver regeneration, and stimulation of collagen degradation.     

Alcoholic Liver Disease

Alcoholic liver disease consists of well defined entities. Fatty liver is the commonest hepatic abnormality in alcoholics and in most cases it is reversible. Possibly a sustained fatty liver occasionally may induce fibrosis. Alcoholic hepatitis or subclinical necrosis may also proceed to hepatic fibrosis. The latter can regress if no further injury occurs or it may develop into frank cirrhosis in case of continuing liver injury. A general model of alcoholic liver disease is presented.     

Selenium, alcohol and liver diseases

A possible pathogenetic role of selenium deficiency in alcoholic cirrhosis of the liver has previously been discussed. In the present study, serum concentrations of selenium, copper and zinc were analyzed in alcoholic cirrhosis as well as in chronic active hepatitis and primary biliary cirrhosis. The serum concentrations of selenium were consistently decreased in patients suffering from alcoholic cirrhosis. Zinc values were also low in these patients. Studies of a possible therapeutic effect of zinc and selenium supplementation are of interest. Other authors have reported increased hepatic lipoperoxidation and decreased hepatocellular glutathione levels in animals consuming ethanol. It is hypothesized that the low levels of Se and Zn, in combination with the reported glutathione depletion, makes the hepatocytes more vulnerable toward the toxicity of ethanol.     

Pharmacokinetics of antipyrine in viral and alcoholic lesions of the liver

Parameters of antipyrine pharmacokinetics have been studied in 82 patients with viral, alcoholic and combined liver affections and in 19 healthy subjects. All the patients exhibited changes showing a reduction of liver function responsible for drug metabolism. Disturbances of antipyrine pharmacokinetics were more pronounced in acute alcohol-aggravated hepatitis B than in hepatitis B without alcoholic aggravation.     

Treatment of pain or fever with paracetamol (acetaminophen) in the alcoholic patient: a systematic review

An unexpected clinical question has emerged in the treatment of pain or fever in the alcoholic patient: Is paracetamol a safe medication for the alcoholic patient? After decades of use in a variety of patients, sporadic reports suggest a relationship between liver injury and the use of paracetamol by alcoholic patients. We performed a systematic review of the medical literature to answer the question: Can administration of therapeutic doses of paracetamol cause hepatic injury in the alcoholic patient? After extensive data retrieval, each article in any language that involved the use of paracetamol by an alcoholic patient was abstracted and categorized for strength of evidence. Class I data (randomized, controlled trials) show that repeated ingestion of a therapeutic dose of paracetamol over 48 hours by patients with severe alcoholism did not produce an increase in hepatic aminotransferase enzyme levels nor any clinical manifestations compared with a placebo group. Class II data (prospective, nonrandomized trials) reveal that therapeutic doses of paracetamol have been administered to patients and an array of liver diseases (alcoholic, primary biliary, postnecrotic, or unspecified cirrhosis or alcoholic, acute viral, chronic active, or other infectious hepatitis) for periods up to 14 days without adverse effect. Finally, in several studies, a 1- to 2-g single dose of paracetamol was administered to alcoholic patients to study metabolism, again without adverse effect. In contrast, Class III data (retrospective case reviews and case reports) describe hepatic injury after repeated paracetamol ingestion with therapeutic intent, although usually not at therapeutic doses. Unfortunately, the information contained in Class III reports is often incomplete and contradictory. The history of ingestion is often unknown or contradicts other clinical information provided. For example, the history may indicate a therapeutic dose, but the serum paracetamol is elevated to levels only produced by ingestion much larger than the history indicates. In summary, all methodologically sound studies available indicate that therapeutic dosing of paracetamol to the alcoholic patient is not associated with hepatic injury. In fact, there is no change at all in hepatic aminotransferase enzymes, prothrombin time, or other biochemical parameters when compared with a placebo group in well-designed trials. Unless stronger evidence of a potentially dangerous interaction emerges, the use of paracetamol in the alcoholic patient is reasonable. During chronic treatment of pain, paracetamol may be preferred in the compliant alcoholic patients owing to the adverse effects associated with long-term use of nonsteroidal anti-inflammatory agents.     

酒精性肝病患者健康相关生存质量研究

目的研究酒精性肝病患者健康相关生存质量及其与疾病严重程度的关系以及对比酒精性肝病与慢性乙型肝炎患者健康相关生存质量的差别。方法 2010年12月至2011年10月收治的70例男性酒精性肝病患者(非肝硬化组45例,肝硬化组25例),56例男性慢性乙型肝炎患者(非肝硬化组24例,肝硬化组32例)以及42例男性健康对照组受试者参与试验。所有受试者回答SF-36V2(中文版)量表,通过SF-36V2软件计算出:生理功能、生理职能、躯体疼痛、总体健康、活力、社会功能、情感职能、精神健康共8个维度,以及躯体健康总评和精神健康总评。使用协方差分析对比健康对照组,酒精性肝病非肝硬化组,以及酒精性肝病肝硬化组健康相关生存质量;对比酒精性肝病与慢性乙型肝炎患者健康相关生存质量。结果和健康对照组相比,酒精性肝病患者随着疾病的加重,SF-36V2各维度评分明显降低(P<0.05)。酒精性肝病非肝硬化组患者较慢性乙型肝炎非肝硬化组患者仅生理功能、生理职能、活力、躯体健康总评四项评分轻度受损(P<0.05)。酒精性肝病肝硬化组与慢性乙型肝炎肝硬化组患者SF-36V2各维度评分相似(P>0.05)。结论酒精性肝病患者健康相关生存质量降低,且病情越重,健康相关生存质量越差。酒精性肝病患者健康相关生存质量与慢性乙型肝炎患者相似。     

Urea-Cycle Enzymes in Normal Liver and in Patients with Alcoholic Hepatitis

Abstract Urea-cycle enzymes and omithine-ketoacid-transaminase have been measured in biopsy specimens of liver from healthy subjects and from patients suffering from alcoholic hepatitis. Both groups of subjects received a hospital diet of about 100 g of protein daily. Extraction of enzymes from biopsy specimens was performed by a standardized technique.–The DNA content of liver did not vary significantly between the groups, whereas protein content was significantly lower in patients with alcoholic hepatitis than in controls ( p < 0.05). Of the enzymes tested, the activities of carbamyl-phosphate synthetase and arginase were significantly decreased ( p < 0.05 and p < 0.005 respectively) in patients with alcoholic hepatitis. Activities of arginosnccinate lyase, ornithine- ketoacid-transaminase and ornithine-carbamylphosphate transaminase remained unchanged in both groups.–These results demonstrate that alterations in arginase and carbamylphoa-phate synthetase-activities in the liver of patients with alcoholic hepatitis precede the histological manifestation of liver cirrhosis, which is associated with a significant decrease in some urea cycle enzymes [3, 15, 16]. Therefore the determination of arginase and carbamylphosphate synthetase in needle-biopsies of human liver represent sensitive parameters of liver cell necrosis during the course of alcoholic hepatitis.     

Role of Toll-like receptors in liver health and disease

TLRs (Toll-like receptors), as evolutionarily conserved germline-encoded pattern recognition receptors, have a crucial role in early host defence by recognizing so-called PAMPs (pathogen-associated molecular patterns) and may serve as an important link between innate and adaptive immunity. In the liver, TLRs play an important role in the wound healing and regeneration processes, but they are also involved in the pathogenesis and progression of various inflammatory liver diseases, including autoimmune liver disease, alcoholic liver disease, non-alcoholic steatohepatitis, fibrogenesis, and chronic HBV (hepatitis B virus) and HCV (hepatitis C virus) infection. Hepatitis viruses have developed different evading strategies to subvert the innate immune system. Thus recent studies have suggested that TLR-based therapies may represent a promising approach in the treatment in viral hepatitis. The present review focuses on the role of the local innate immune system, and TLRs in particular, in the liver.     

Studies of the influence of immunological and serological factors from patients with cholestasis due to alcoholic or viral hepatitis on biliary function in the rat

Abstract. Studies were undertaken to (a) determine if cholestasis in alcoholic or viral hepatitis is related to immunologic hyperreactivity as suggested for cholestasis due to type-II drug-induced hepatitis, and (b) evaluate possible mechanisms involved in lymphokine-induced cholestasis. Results indicate that a cholestatic factor exists in alcoholic and acute viral hepatitis. Supernatants of lymphocytes from patients with alcoholic hepatitis stimulated by an extract of alcoholic hyalin evoked a 28%pL7·3 SEM reduction in rat bile flow ( P <0·03). Supernatants of lymphocytes from patients with acute viral hepatitis activated by liver-specific protein caused a reduction in rat bile flow of 24%pL5·9 SEM ( P <0·03). A decrease in bile flow also occurred following injections of sera from patients with alcoholic or acute viral hepatitis. In contrast, injection of supernatants of non-stimulated lymphocytes or those from chronic active hepatitis or healthy subjects did not produce a significant change in bile flow. Supernatants of stimulated lymphocytes from tuberculin-sensitized guinea pigs caused a similar decrease in rat bile flow and reduced excretion of human secretory immunoglobulin A (IgA). Despite reductions in rat bile flow there were no alterations in liver morphology, liver plasma membrane Na-K-ATPase activity, microsomal cholesterol-7 α -hydroxylase activity or low-dose indocyanine green clearance during the period of observation.     

Hereditary hemochromatosis: laboratory evaluation

The condition of hereditary hemochromatosis (HH) is caused by gene-dependent protein abnormalities involved in iron absorption, storage, or modulation of iron; these abnormalities result in iron overload. The clinical laboratory plays a significant role in case finding, diagnostic validation, and monitoring HH therapy. Elevated serum iron, transferrin saturation, and ferritin suggest HH, but results can also indicate other forms of hepatocyte injury such as alcoholic or viral hepatitis, or other inflammatory disorders involving the liver. In the context of elevated serum iron, transferrin saturation, and ferritin, and after ruling out secondary causes of iron overload, HFE gene evaluation is the preferred test to confirm the diagnosis of HH. However, 5% to 15% of patients with phenotypic HH do not have HFE gene mutations. In these cases, MRI evaluation or liver biopsy with iron quantification is indicated. The clinical role of hepcidin, the iron modulating protein, is undetermined at this time. Because hepcidin also plays a key role in antimicrobial and inflammatory activities, interpretation of hepcidin serum or urine concentration will require thorough understanding of its complex role in iron regulation.     

Alcoholic liver disease in Scotland and northeastern England: presenting features in 510 patients

A study of 510 patients in Scotland and northeastern England with histological evidence of alcohol-induced liver disease showed no difference in the age of presentation between males and females. Single men and widowed females were particularly susceptible to alcoholic liver disease. The social class distribution was similar to the population in general. Women were more reluctant to volunteer a history of alcoholism than men, they had a higher incidence of previous psychiatric illness (usually due to alcohol abuse) and they developed liver disease at lower consumption thresholds of alcohol than men. Patients under 40 years of age were more likely to have alcoholic fatty liver and less likely to have active cirrhosis than those over 40. Most often, the presenting symptoms were non-specific and tended to be related to the gastrointestinal system, particularly in women. Five per cent of patients were asymptomatic and 14% came to hospital for conditions other than alcoholic liver disease. Important clues to asymptomatic alcoholic liver disease included hepatomegaly, clubbing of the fingers and abnormal liver function tests. Gastro-oesophageal varices accounted for 40% of instances of haemorrhage and the mortality from upper gastrointestinal bleeding was 17%. Anaemia was the most common haematological abnormality. Alcoholic hepatitis was observed more frequently in the Glasgow area then elsewhere.     

Hepatic collagen proline hydroxylase activity in alcoholic liver disease.

The activity of hepatic collagen proline hydroxylase was examined in biopsy samples as a factor in collagen synthesis in 77 patients with alcoholic liver disease. The urinary excretion of peptide bound hydroxyproline was also measured in most of the patients, as an index of collagen degradation. The highest activities of collagen proline hydroxylase were found in the patients with alcoholic hepatitis. Enzyme activity was markedly increased in patients with non-specific changes on liver biopsy, whereas, patients with fatty infiltration had only mild elevations, and those with inactive cirrhosis had normal enzyme activity. Urinary hydroxyproline was elevated only in patients with alcoholic hepatitis and inactive cirrhosis. Follow-up determinations in 16 patients with alcoholic hepatitis, after 4 to 5 weeks, revealed a decrease in enzyme activity, but no change in urinary hydroxyproline. We conclude that among the types of alcohol-related liver diseases, alcoholic hepatitis is associated with the greatest turnover of hepatic collagen.