Pregnancy and labor in cardiac patients

Hepatic fatty change is a common lesion. Two forms are recognized: micro- and macrovesicular steatosis, the former being much less frequent and more serious than the latter. The case of an alcoholic woman under anticonvulsivant therapy and with medications for a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) who presented with rapidly progressive cholestasis and hepatocellular failure is reported. Massive macro- and micro-vesicular hepatic steatosis was diagnosed at autopsy. The authors review the clinico-pathological features associated with this condition, and causal factors possibly implicated in this case are discussed in regard with currently considered pathophysiological mechanisms.     

Nonalcoholic fatty liver (NASH syndrome)

Nonalcoholic steatohepatitis (NASH) is the term used for a common form of fatty liver presenting in adults with varied clinical manifestations. The most common presentation is asymptomatic elevation of liver enzymes (AST or SGOT and ALT or SGPT), which can be discovered incidentally in the course of an annual checkup, life insurance examination, or as part of surrogate screening before blood donation. At the other end of the clinical spectrum is the patient with complications from cryptogenic cirrhosis, who also shows a lack of evidence of alcohol as an etiological factor in pathogenesis. Clinical associations of probable relevance include gender (female), obesity, diabetes, and hyperlipidemia, but many patients do not conform to any of these stereotypes (e.g., young men of normal weight with normal fasting glucose and lipid levels). Liver biopsy confirms the diagnosis of NASH, the association of steatosis with an inflammatory response being the sine qua non for the condition and "creeping fibrosis" being a variable but possibly sinister feature. Newer imaging techniques may provide convincing evidence of steatosis, but they give little insight into ongoing fibrosis, and liver biopsy therefore remains the gold standard. The mainstay of treatment remains judicious weight loss coupled with positive dietary advice, including the ingestion of adequate but not excessive vitamins. After initial encouraging data. the assessment of ursodeoxycholic acid currently being studied under randomized controlled conditions is eagerly awaited.     

Biologically active metabolites from fungi. 3. Sporothriolide, discosiolide, and 4-epi-ethisolide--new furofurandiones from Sporothrix sp., Discosia sp., and Pezicula livida

Apoptosis is a type of cell death which is clearly distinguishable from necrosis in its morphological and biochemical features. To clarify the role of apoptosis in alcoholic liver injury, we investigated the expression of apoptosis-related Lewis(Le)(y) antigen by immunohistochemistry in liver samples from patients suffering from alcoholic liver disease. Liver biopsy samples were taken from 20 patients who drank more than 80 g of ethanol per day on average. Indirect immunohistochemical staining was carried out using anti-cytokeratin and anti-Le(y) antibodies. To examine the relationship between Mallory bodies and apoptosis, double staining was performed using both antibodies. In alcoholic hepatitis, many Mallory bodies were stained with anti-cytokeratin antibody in hepatocytes of the centrilobular area. Le(y) antigen was also detected in hepatocytes in the same area. Immunohistochemical double staining showed that some of the hepatocytes containing Mallory bodies were stained with anti-Le(y) antibody. Few hepatocytes expressing Le(y) antigens, however, were observed in other types of alcoholic liver disease, including steatosis, fibrosis and cirrhosis. From these results, it is suggested that apoptosis may also be involved in alcoholic hepatitis and that hepatocytes containing Mallory bodies can be eliminated by apoptosis.     

Nonalcoholic steatohepatitis. Clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients

This study reports a clinicopathological analysis of 105 patients whose liver histology showed a pattern of alcohol-like steatohepatitis. There were 32 nonalcoholic, 21 asymptomatic ambulatory, and 52 hospitalized alcoholic hepatitis patients. Female sex, obesity, and diabetes predominated in nonalcoholics. Clinical and laboratory presentation were similar in nonalcoholics and ambulatory alcoholics, but different from the hospitalized alcoholics. Histology showed an increasing degree of severity of hepatocellular damage, Mallory bodies, neutrophil and mononuclear infiltration, and pericellular and portal fibrosis from the nonalcoholics to the hospitalized alcoholics, with ambulatory alcoholics displaying an intermediate degree of severity. Steatosis and glycogenated nuclei were prevalent in the obese, diabetic nonalcoholics, of whom 47% had significant fibrosis and 8% cirrhosis, the latter present in 38% and 89% of ambulatory and hospitalized alcoholic hepatitis (P = 0.0001), respectively. In asymptomatic subjects with suspected liver disease, a liver biopsy is the only way of establishing the type and severity of liver lesions.     

Alcoholic liver disease. Treatment strategies for the potentially reversible stages

Even modest alcohol ingestion can increase the risk of steatosis, and long-term, excessive consumption can lead to alcoholic hepatitis and eventually cirrhosis. Most patients with clinically significant alcoholic liver disease have histologic findings typical of all three conditions. The only clearly beneficial treatment is abstinence from alcohol. Abstinence in combination with proper nutrition and general supportive care is state of the art. Steatosis is reversible upon withdrawal of alcohol, but alcoholic hepatitis can persist even with abstinence and may progress to cirrhosis. Corticosteroid therapy may reduce short-term mortality rates in patients with moderate or severe alcoholic hepatitis who have hepatic encephalopathy but no evidence of infection or gastrointestinal bleeding. Treatment with colchicine may decrease the risk of cirrhosis; however, once cirrhosis has developed, the liver damage is irreversible. The prognosis is improved with abstinence, but complications (e.g., ascites, gastrointestinal bleeding) often occur. Liver transplantation may be considered in patients with severe complications.     

Angiosarcoma of the bladder: a review

BACKGROUND/AIMS: Correlations between serum levels of soluble tumor necrosis factor receptors p55 (TNFsRp55) and Child Pugh index have previously been reported in alcoholic patients with cirrhosis. We have undertaken this study to improve understanding of the role of tumor necrosis factor soluble receptors (TNFsRs) in alcoholic liver disease. METHODS: One hundred and two patients with alcoholic liver disease of various severity (23 pure steatosis, 22 fibrosis, seven acute alcoholic hepatitis without cirrhosis, 12 cirrhosis without acute alcoholic hepatitis, 14 cirrhosis with mild acute alcoholic hepatitis and 24 cirrhosis with severe acute alcoholic hepatitis) were studied. Blood was collected on EDTA and plasma was tested for TNFsR concentrations using ELISA assays. RESULTS: Plasma levels of TNFsRp55 and p75 increased progressively with the severity of liver disease, reaching a maximum in cirrhotic patients with severe acute alcoholic hepatitis. Plasma levels of TNFsRp55 in patients with fibrosis and of TNFsRp75 in patients with acute alcoholic hepatitis without cirrhosis were already higher than in healthy controls. In cirrhotic patients with or without acute alcoholic hepatitis TNFsRp55 and p75 were significantly increased compared with controls. In cirrhotic patients, plasma levels of TNFsRp55 correlated positively with all parameters of liver injury, whereas the TNFsRp75/ TNFsRp55 ratio correlated negatively. In cirrhotic patients with severe acute alcoholic hepatitis, the TNFsRp75/TNFsRp55 ratio was significantly lower than in all other groups. In cirrhotic patients with severe acute alcoholic hepatitis treated by prednisolone, the decrease in TNFsRp55 plasma levels between day 1 and day 15 was significantly more important in patients still alive at 2 months than in patients who died within 2 months. CONCLUSIONS: These results show that the expression of TNF-soluble receptors (TNFsRs) participates in the early phases of the alcoholic liver disease and that the TNFsRp75/TNFsRp55 ratio and plasma levels of TNFsRp55 may help to determine the diagnosis and the prognosis of severe acute alcoholic hepatitis in cirrhotics.     

Clinical significance of hepatitis GB virus C infection in alcoholic liver disease

Recently, hepatitis GB virus C (HGBV-C) has been recovered from patients with non-A-E hepatitis. However, it has been unclear whether HGBV-C may be related to the development of alcoholic liver disease (ALD) or not. In this study, we determined HGBV-C RNA in sera from alcoholic patients without markers for hepatitis C and B viruses to evaluate the role of HGBV-C in ALD. Serum samples were obtained from 68 patients with ALD and 40 nonalcoholic patients with chronic type C liver disease. HGBV-C RNA was detected in only 3 of 68 (4.4%) patients with ALD, in 2 of 27 patients with hepatic fibrosis, and in 1 of 5 patients with chronic hepatitis. There was no HGBV-C RNA in sera from patients with fatty liver, alcoholic hepatitis, or cirrhosis. Serum levels of AST, ALT, and gamma-glutamyltranspeptidase in alcoholic patients with, as well as without, HGBV-C RNA decreased to normal levels after abstinence. In addition, an inflammatory change was not observed in liver biopsy specimens obtained from two HGBV-C-positive patients with alcoholic hepatic fibrosis. Our results clearly suggest that the prevalence of HGBV-C infection in patients with ALD is rare and that HGBV-C may not play an important role in the development of liver disease in alcoholics.     

Human hepatic macrovesicular steatosis: a noninvasive study of mitochondrial ketoisocaproic acid decarboxylation

Differentiating between alcoholic and nonalcoholic hepatic steatosis is often a difficult clinical task. However, decreased fatty acid mitochondrial oxidation appears as the main factor for alcoholic steatosis, whereas nonalcoholic steatosis may be due to other causes. We studied mitochondrial function, based on a 13C-ketoisocaproic acid (13C-KIC) breath test, in nine alcoholic and 12 nonalcoholic steatosis patients and 10 healthy volunteers. Our results showed a 42% 13C-KIC decarboxylation decrease in alcoholic steatosis patients, but not in nonalcoholic steatosis patients. This noninvasive breath test appears helpful for the diagnostic work-up of hepatic steatosis.     

De novo non-alcoholic fatty liver disease following orthotopic liver transplantation

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized clinico-pathologic entity typically associated with obesity, type II diabetes and hyperlipidemia. It has been noted to recur after orthotopic liver transplantation (OLT). We report four patients who developed de novo NAFLD within 3 months of OLT without the typical predisposing factors of diabetes mellitus or obesity. Three of the four patients underwent OLT for hepatitis C-related cirrhosis, and the other for alcoholic cirrhosis. Examination of the liver explants revealed no evidence of steatosis. No surreptitious alcohol use or a drug-induced process could be identified in these patients. Treatment of recurrent hepatitis C infection in one patient with interferon and ribavirin led to sustained suppression of the viral RNA to undetectable levels, but no improvement in histology or liver enzymes. All four patients had histologic evidence of preservation injury on the initial post-OLT biopsies, but the significance of this finding in relationship to the development of NAFLD is unknown. NAFLD can develop without any of the known predisposing conditions after transplantation, and this raises further questions about the pathogenesis of this condition.     

Non-alcoholic steatohepatitis. Report of five cases and review of the literature

We describe three men and two women, aged 18-50, with an occasional finding of increased aspartate and alanine aminotransferase and gamma-glutamyl transpeptidase levels in the absence of any drug treatment and past or current alcohol abuse. Two patients were overweight (body mass index 29 and 32, respectively) and physical examination was normal in all but one case. Tests for hepatitis A, B and C, Epstein-Barr virus, cytomegalovirus, toxoplasma and autoimmune hepatitis were negative and metabolic diseases (Wilson's disease, haemochromatosis, alpha-l-antitrypsin deficiency) were excluded by specific tests. Ultrasound liver scan revealed massive steatosis in all patients. Liver histology showed diffuse steatosis and parenchymal inflammation in all cases, with concomitant fibrosis and Mallory bodies in three of them. Findings were consistent with non-alcoholic steatohepatitis, a rare condition with potential progression to cirrhosis in a minority of cases. This disease, for which no treatment is currently available, must be considered in all subjects with elevated aminotransferases, in the absence of known causes of liver damage.     

Evidence for a tyrosine kinase-dependent activation of the adenylyl Cyclase/PKA cascade downstream from the G-protein-linked endothelin ETA receptor in vascular smooth muscle

Body retinoids are stored in the lipid droplets of hepatic stellate (Ito) cells. In chronic liver disease, the stellate cells differentiate into myofibroblast-like cells, a process whereby they lose their retinoid-containing lipid droplets. We studied the relation between liver retinoid content, the number of lipid droplets per stellate cell, and the number of stellate cells per mm2 in human alcoholic liver disease. Semithin sections of liver biopsies from normal subjects and patients with early (steatosis, inflammation, and mild fibrosis) and late (cirrhosis and cirrhosis with acute alcoholic hepatitis) alcoholic liver disease were morphometrically evaluated. Liver retinoid content was determined by HPLC. In normal patients, liver retinoid content was 901 +/- 213 IU/g of liver (mean +/- SEM). There was a decrease in liver retinoid content in early alcoholic liver disease (409 +/- 50 IU/g) and a further reduction in cirrhosis (153 +/- 50 IU/g). In patients with acute alcoholic hepatitis, retinoid content was strikingly low (5.2 +/- 1.8 IU/g). There was a progressive decrease in the number of stellate cells per mm2 associated with progressive liver damage. We found a fair correlation between the number of stellate cells per mm2 and liver retinoid content in all patient groups (overall correlation: 0.71). In normal subjects, the mean number of lipid droplets per stellate cell was 7.4 +/- 0.7. In patients with early alcoholic liver disease and in patients with alcoholic cirrhosis, this value was increased to 13.6 +/- 0.8 and 10.4 +/- 2.0, respectively. In patients with acute alcoholic hepatitis, only a few lipid droplets were present (4.2 +/- 0.5). There was a good correlation between liver retinoid content and mean number of lipid droplets in normal patients (r = 0.58). In alcoholic cirrhosis, however, correlation was poor (r = 0.34). In early alcoholic liver disease, the correlation was absent (r = 0.004). In conclusion, the major finding of our study is that the correlation between the mean number of lipid droplets per stellate cell and liver retinoid content varies according to the hepatic pathology considered. Marked lipid droplet accumulation occurs in stellate cells in early alcoholic liver disease and, to a lesser extent, in alcoholic cirrhosis, but there is no correlation between the mean number of lipid droplets per stellate cell and liver retinoid content. Therefore, not retinoids but probably lipids are responsible for the accumulation of lipid droplets. We also find that there is a fair correlation between the number of stellate cells per mm2 and liver retinoid content in all patient groups. Finally, we confirm the decrease in hepatic retinoid content that occurs in alcoholic liver disease in humans, even at the early stages of the disease.     

Effect of the type of beverage and meat consumed by alcoholics with alcoholic liver disease

We analyzed meat products and alcoholic beverage preference in patients with the three stages of alcoholic liver disease (ALD) compared with controls using diet history data. Daily consumption of total alcohol, types of alcoholic beverages, and types of meat and meat products in grams was obtained by dietary history taken from patients with biopsy proven stage of ALD. A strong association was found between the ALD subjects and total alcohol and beer consumption. There was a significant increase in the consumption of total pig products, pork, and offal in the ALD groups compared with controls. There was a significant positive correlation between beer consumption and pork in alcoholic hepatitis, total pork products in alcoholic hepatitis, and cirrhosis and offal in alcoholic hepatitis and cirrhosis. There was no correlation with the fatty liver stage of ALD. The strongest correlation was between beer and total pig products in the alcoholic hepatitis group. Wine consumption was negatively correlated with the consumption of pig products and beer in the alcoholic cirrhosis group. In conclusion, the association of total pig product consumption with cirrhosis mortality in various countries was validated by personal diet history data obtained from ALD patients in a tested clinical microcosm. The results suggest that this association may be modified by the type of alcoholic beverage that is preferentially consumed.     

Expression of cyclin-dependent kinase inhibitor p21 in human liver

The p21 protein is a universal inhibitor of cyclin-dependent kinases and of cell-cycle progression and is involved in numerous growth-inhibitory pathways in cell culture systems. Recent studies suggest that p21 regulates hepatocyte cell cycle progression in models of liver regeneration. The present study was designed to investigate the possible involvement of p21 in the control of hepatocyte proliferation in human liver diseases. To examine that, the expression of p21 in clinical liver biopsy specimens was determined by immunohistochemistry. This was correlated with hepatocyte Ki-67 immunostaining (a marker of hepatocyte proliferation in vivo) as well as histologic features. Little p21 or Ki-67 expression was detected in normal human liver or in specimens of nonalcoholic steatohepatitis. In patients with alcoholic hepatitis, increased expression of p21, but not of Ki-67, was observed. In specimens with chronic hepatitis C, hepatocyte p21 expression was significantly correlated with Ki-67 immunostaining, as well as with the degree of inflammation and fibrosis. These results indicate that hepatocyte p21 expression is upregulated in response to hepatic injury and correlates with histologic markers of proliferation and disease activity. This study provides evidence that p21 plays a role in the regulation of hepatocyte proliferation in human liver diseases.     

Medical treatment for alcoholic liver disease

The most effective treatment for alcoholic liver disease is abstinence from alcohol and it is the only treatment for patients with alcoholic fatty liver. Although many empirical therapeutic agents have been studied in the short-term and long-term treatment of alcoholic hepatitis, results have been mainly inconclusive. To date, only corticosteroids have proved to decrease the short-term mortality rate of patients with severe forms of acute alcoholic hepatitis. Corticosteroids are not beneficial to the majority of patients with mild or moderate forms of acute alcoholic hepatitis; such patients improve with abstinence from alcohol and general supportive measures and do not need a specific short-term treatment. Most long-term trials have only showed that most patients with alcoholic liver disease were neither abstinent nor compliant, and that long-term survival was strongly correlated to abstinence from alcohol. In one study, propylthiouracil decreased the long-term mortality rate of compliant patients with severe alcoholic liver disease who reduced their alcohol intake; however, further clinical trials are needed before propylthiouracil can be recommended. In another study, colchicine decreased the long-term mortality rate of cirrhotic patients, 45% of whom had alcoholic cirrhosis. Results were highly significant, and the need for further clinical trials of colchicine in the long-term treatment of alcoholic and non-alcoholic cirrhosis is imperative. Enteral nutrition should also be studied in severely malnourished cirrhotic patients, since it was shown to decrease the short-term mortality rate of such patients in a recent study.     

The effect of the heptoprotective agent LIV 52 on liver damage

BACKGROUND: The action of hepatoprotective drugs is a steady subject of discussions. Despite the equivocal character of action hepatoprotective drugs are used, despite the fact that the effect is partly a placebo effect. In the literature are reports on preparation LIV 52 which is a mixture of substances of plant origin and improves the subjective complaints of patients as well as the objective condition of patients with liver disease. METHODS AND RESULTS: The effect of preparation LIV 52 was investigated in a retrospective study in 19 patients with liver damage. In the majority liver damage caused by alcohol was involved, steatosis and persisting hepatitis without the finding of chronic hepatitis B and C. The authors investigated biochemical parameters (bilirubin, ALT, AST, ALP, TZR, cholesterol). The size of the liver was assessed by ultrasonography and the subjective status of the patients was recorded. Within one year of administration of the preparation subjective improvement occurred, hepatomegaly diminished and the activity of aminotransferases declined. CONCLUSIONS: Administration of LIV 52 can improve the subjective condition and clinical parameters in patients with liver damage, in particular in alcoholic liver damage and in steatosis. The effect is certainly due also to better motivation on the patients part, better lifestyle and dietary measures. After one year of treatment no undesirable side-effects were detected.     

Detection and identification of microcystins in the drinking water of Haimen City, China

The main method of classification of chronic viral hepatitis is now by cause, and the old histology-based classification is no longer considered appropriate. However, liver biopsy remains an important part of patient assessment and, in the context of clinical trials, biopsy findings are often scored in a semiquantitative manner. The concepts of grading and staging, borrowed from tumour pathology, have been introduced, representing the severity of the necroinflammatory lesion and the extent of its structural consequences respectively. The pathology of the individual forms of viral hepatitis A to G shows more similarities than differences. However, some pathological features are commonly associated with specific viruses. The combination of portal lymphoid follicles, bile duct damage, lobular activity and steatosis give chronic hepatitis C a characteristic histological profile. Very similar appearances have been noted in the limited number of biopsies so far reported from patients with known combined hepatitis C and G virus infection.     

Molecular mechanisms of male germ cell differentiation

Liver steatosis is often attributed to dietary habits. Our previous results have shown that fatty acid synthesis is considerably increased by high carbohydrates-fat free diet (HCFF) given to rats after fasting, and leads to lipid accumulation and morphological alterations in the liver, defined as steatosis. As n-3 polyunsaturated fatty acids are able to counteract lipogenesis induction in vivo and in vitro, we hypothesized that the addition of menhaden oil in a carbohydrate-rich diet might be able to protect the liver against steatosis induced by a fasting-re-feeding transition. Male Wistar rats were first fasted for 48 hr, then re-fed ad lib. for 24 hr with either (1) standard diet; (2) high carbohydrates-fat free diet (HCFF), containing 40% (w/w) starch, 40% saccharose, 16% casein and 4% vitamin mineral mix; or (3) the latter diet containing additionally 5% menhaden oil (HCMO) for 24 hr. Triglyceride (TG) accumulation occurred in liver tissue of rats re-fed with HCFF and HCMO diets after fasting. The addition of menhaden oil led to a strong decrease in serum TG; however, both TG and phospholipid (PL) levels, as well as fatty acid synthase activity, were increased in the liver of HCMO rats as compared with the values obtained in HCFF re-fed rats. Histologically diagnosed steatosis was even more severe when rats received HCMO than HCFF. These results indicate that menhaden oil supplementation does not avoid, but even increases, the degree of steatosis generated in vivo by re-feeding a high carbohydrate diet after fasting.     

Frozen section evaluation of donor livers before transplantation

Frozen section examination was performed on 385 donor livers before transplantation. Exclusion criteria were applied to the donor livers examined to exclude potentially dysfunctional livers. The exclusion criteria included the following: severe macrovesicular steatosis, ischemic necrosis, prominent chronic portal inflammation, prominent periductular fibrosis, granulomatous inflammation, bridging fibrosis, and malignancy. Twenty-seven of the 385 donor livers examined were excluded before transplantation. The following histologic features were present in the excluded livers: severe steatosis (22), ischemic necrosis (2), portal inflammation (1), and periductular fibrosis (2). Steatosis was present in 51 of the 385 (13.25%) organs examined, including 22 of the donor organs excluded before transplantation. Twenty-nine livers with mild to moderate steatosis were implanted into size and blood type-matched recipients. Indicators of allograft function (prothrombin time and bilirubin) and damage (aspartate aminotransferase and alanine aminotransferase) were measured daily for the first 10 days after transplant. There was no statistically significant difference between the group of nonfat livers and donor livers containing mild steatosis. Statistically significant higher posttransplant serum alanine aminotransferase and prothrombin time levels were present in the patients with livers implanted with mild versus moderate steatosis. The 1-year survival rate for patients receiving fatty versus nonfatty donor livers was not statistically different (Kaplan-Meier, P = 0.592). No significant differences were found in the clinical and laboratory characteristics of donors whose organs were implanted compared with the clinical and laboratory characteristics of donors whose organs were excluded. The primary nonfunction rate after applying the exclusion criteria was 1.4%, which is a significant decrease compared with our primary nonfunction rate of 8.5% before using frozen section examination. Frozen section examination is useful in excluding donor organs which may become dysfunctional after transplantation.     

Chronic non-B, non-C hepatitis among blood donors assessed with HCV third generation tests and polymerase chain reaction

Forty five blood donors with increased serum aminotransferases levels had liver histologic assessment and were tested for antibodies to hepatitis C virus (anti-HCV) with second and third generation ELISAs and RIBAs, and for HCV RNA with polymerase chain reaction (PCR) in serum and liver tissue. Twenty-nine of these 45 donors (65%) had steatosis without chronic hepatitis. Sixteen (35%) had chronic hepatitis. Twelve had evidence of HCV infection. Four had no evidence of HCV infection demonstrable by ELISA, RIBA or PCR. These four patients had no known cause of chronic hepatitis and no risk factor for parenterally acquired viral infection was found in them. This observation supports the hypothesis that a non-B, non-C virus might be implicated in chronic hepatitis. However, this hypothesis remains to be demonstrated.