Biochemistry of alcoholic liver disease.

The biochemistry of alcohol liver disease as it relates to clinical medicine and experimental alcohol liver disease is presented. Clinical features are emphasized in the diagnosis of alcohol liver disease, particularly as it relates to staging the disease and predictors of prognosis. Currently, it is true that the biochemical diagnosis of alcohol liver disease is at best very limited in terms of the sensitivity tests and specificity of the test. It is particularly difficult to detect alcohol liver disease biochemically in the early stages when steatohepatitis is not severe. Consequently, 50% of the patients have already developed cirrhosis at the time they are diagnosed clinically. In this review indicators of malnutrition are emphasized because they have the strongest implications regarding survival during the acute hospitalization stage of the disease. They are also the best indicators of response to therapy during the recovery phase. With respect to experimental work on the pathogenesis of alcohol liver disease, it appears that necrosis is due to the inability to increase blood flow to compensate for increased oxygen utilization. The hypothesis that mitochondrial damage is the cause of liver cell damage is regarded as less important in the pathogenesis of necrosis. The shift in the redox state during alcohol metabolism accounts for the fatty change noted in the central lobular area of the liver in animals fed alcohol. Apparently, there is strong experimental evidence that highly reactive intermediates are important in the pathogenesis of liver damage due to the induction of the isozyme cytochrome P450 IIE1 by alcohol ingestion. This mechanism is enhanced by a diet high in polyunsaturated fatty acids.     

Collagen biosynthesis in liver disease of the alcoholic.

Percutaneous liver biopsies obtained from patients with a history of chronic alcoholism and normal liver, fatty liver, alcoholic hepatitis, or active cirrhosis were incubated with tritiated proline to determine the pattern of collagen biosynthesis in these conditions. Incorporation of labeled proline and hydroxyproline into salt-soluble and insoluble fractions of collagen was evaluated by radiochemical analysis and tissue localization documented by autoradiography. Biopsy specimens of alcoholic hepatitis and cirrhosis exhibit a significant increase in the amount of radioactive proline and hydroxyproline in salt-soluble and insoluble collagen. Marked accumulation of radioactivity occurred over bile ducts, fibroblasts, and collagen fibers in the portal area and over hepatocytes, fibroblasts, and collagen fibers in the centrilobular area. Fatty liver is associated with an increase in uptake of proline and hydroxyproline in the salt-soluble fraction of collagem; silver grains appear in the periphery of fat-laden cells and in areas of focal inflammation. Digestion by collagenase indicates that labeling over fibroblasts and collagen reflects active synthesis, whereas, entry of proline into the cell protein pool is responsible for accumulation of radioactivity in other sites. In vitro ethanol causes a significant increase in the incorporation of proline and hydroxyproline into collagen in biopsy specimens of alcoholic hepatitis or active cirrhosis, but has no effect on collagen synthesis by normal or fatty liver.     

Serum bile acids in alcoholic liver disease. Comparison with histological features of the disease.

Fasting serum bile acids were measured by gas-liquid chromatography in 64 patients with alcoholic liver disease and compared with histological features in their percutaneous liver biopsy specimens. Total bile acid concentrations were normal (less than 2 mug/ml) or minimally increased in 6 patients in whom fatty infiltration was the only hepatic lesion. In the remaining 58 patients with more severe histological lesions, levels were increased in 93%, whereas serum bilirubins were elevated in only 43%. Chenodeoxycholic acid was usually the predominant serum bile acid, regardless of the degree of necrosis or connective tissue change in the biopsy specimen. Only small amounts of the secondary bile acids, deoxycholic acid and lithocholic acid, were detected. Levels of these secondary bile acids did not correlate with histological features.     

Cardiac disease in the alcoholic patient

Ethanol in acute low doses is believed to be relatively nontoxic to the normal myocardium, despite data indicating low-level contractility impairment. In patients with myocardial disease, or as the serum ethanol concentration is increased to high levels, angina, myocardial infarction, and arrhythmia may be potentiated. Chronic ethanol use, at moderate doses, may be protective against coronary artery disease, despite increased rates of hypertension. Alcohol consumption at high doses may result in dilated cardiomyopathy and a dismal prognosis. Alcohol abuse is associated with increased mortality.     

Liver disease as presenting manifestation of Hodgkin's disease.

Six patients who were referred to the liver unit on account of jaundice are described. A different initial diagnosis has been made in each case, these being fulminant hepatic failure, severe hepatitis with renal failure, toxoplasma hepatitis, extrahepatic obstruction, sclerosing cholangitis, and liver abscess. After delays of four weeks to 12 months from the time of first symptoms all six patients were eventually found to have advanced Hodgkin's disease (stage 4). In four patients the diagnosis was made during life, but in two only at autopsy. In four lymphoma tissue was finally demonstrable in the liver, but in two liver biopsy showed only minor non-specific changes despite grossly abnormal liver function tests. Three of the six patients were treated with chemotherapy, and two of these recovered sufficiently to leave hospital. With the encouraging survival figures now being obtained in Hodgkin's disease, an awareness of the varied hepatic manifestations of the disease may allow treatment to be instituted at an earlier stage.     

去脂软肝汤联合硫普罗宁治疗酒精性肝病的疗效分析

目的观察去脂软肝汤联合硫普罗宁治疗酒精性肝病(ALD)的临床疗效。方法将120例确诊为ALD的患者分为治疗组和对照组,每组各60例,治疗组给予去脂软肝汤联合硫普罗宁治疗,对照组单纯给予硫普罗宁治疗,观察两组患者治疗前后症状、体征、肝功能、血脂改善情况。结果治疗组临床综合疗效总有效率为88.3%,明显高于对照组的51.6%,差异有统计学意义(P0.05)。治疗组中医症候疗效总有效率为83.3%,对照组为46.7%,差异有统计学意义(P0.05)。治疗后两组肝功能和血脂均优于治疗前,但治疗组疗效好于对照组,差异有统计学意义(P0.05)。结论去脂软肝汤联合硫普罗宁治疗ALD在提高临床综合疗效,改善患者各项中医症状等方面明显优于单纯口服硫普罗宁,具有理想的治疗效果,值得临床推广。     

Pharmacokinetics of metronidazole in patients with alcoholic liver disease.

The pharmacokinetics of metronidazole was evaluated in eight patients with alcoholic liver disease. Metronidazole (7.5 mg/kg) was administered to each patient intravenously. Serial blood samples were obtained after the dose. Serum metronidazole concentrations were determined by high-performance liquid chromatography. The following pharmacokinetic parameters (mean +/- standard deviations) were obtained: half-life, 18.31 +/- 6.06 h; elimination rate constant, 0.042 +/- 0.013 h-1; volume of distribution, 0.77 +/- 0.16 liters/kg; and total body clearance, 0.51 +/- 0.11 ml/min per kg. Compared with subjects with normal liver function, patients with liver disease showed a reduction in drug elimination rate and total body clearance. The half-life of metronizadole in serum and volume of distribution were increased. Large variations of these parameters were also observed among the patients. On the basis of these observations, a reduced dose of metronidazole should be given to patients with alcoholic liver disease to avoid accumulation of metronidazole and its metabolites. Monitoring of drug concentration in serum may also be necessary to optimize therapy.     

酒精性肝病发病机制

酒精性肝病（alcoholic liver disease, ALD）是因长期过量饮酒引起的肝脏疾病,其中包括轻症ALD、酒精性脂肪肝、酒精性肝炎、酒精性肝纤维化和酒精性肝硬化,我们就氧化应激、内质网应激、硝化应激及调脂因子在酒精性肝病发病机制中的作用等进行阐述。     

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.