[Psychiatric assessment of alcoholic patients on a waiting list for liver transplantation: which prognostic criteria are empirically proven?]. / Psychiatrische Begutachtung zur Transplantationsfähigkeit bei Patienten mit alkoholischer Leberzirrhose Welche Prognosekriterien sind empirisch gesichert?

Liver disorders are the most frequent somatic complications of alcoholism. As 10­20% of alcoholic patients will develop liver cirrhosis, this is the most frequent reason for premature death in alcoholic patients. Liver transplantation is now an accepted therapy for alcoholic liver cirrhosis but psychiatric assessment is usually required for patients entering a waiting list for transplantation. Prognostic criteria are controversially discussed, especially the so-called 6-month rule. Numerous studies and recent meta-analyses have indicated that duration of alcoholism, family history, age, sex, comorbid substance use and psychiatric disorders, noncompliance and social instability are outcome predictors. The 6-month criterion is not well proven but some studies are indicative. Possible therapeutic interventions for alcoholic patients on a waiting list are discussed.

Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial.

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.

Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C.

Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient.

The alphavbeta6 integrin is a highly specific immunohistochemical marker for cholangiocarcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are common primary hepatic malignancies. Their immunohistological differentiation using specific markers is pivotal for treatment and prognosis. We found alphavbeta6 integrin strongly upregulated in biliary fibrosis, but its expression in primary and secondary liver tumours is unknown. Here, we aimed to evaluate the diagnostic applicability of alphavbeta6 integrin in differentiating primary liver cancers. METHODS: Expression of alphavbeta6 integrin was evaluated in liver tissues from patients with CC, HCC, fibrolamellar HCC, combined CC/HCC, hepatic metastases of colorectal and pancreatic carcinomas, primary sclerosing cholangitis (PSC), and in human primary and tumour-derived liver cell lines by immunohisto- and cytochemistry, and by TaqMan PCR. Diagnostic performance of the beta6 subunit was compared with CK7, CK20, and HepPar 1. RESULTS: In CC cells beta6 mRNA levels were induced 125-fold compared to primary cholangiocytes, while it was completely absent in hepatoma cells. In human tissues, beta6 transcripts were more than 100-fold upregulated in CC compared to normal liver. By immunohistochemistry, 88% of CC, 50% of PSC, 13% of colorectal carcinoma metastases, and 80% of pancreatic carcinoma metastases presented alphavbeta6, whereas all HCC, combined CC/HCC and fibrolamellar HCC stained negative. Specificity of beta6 immunohistochemistry for CC (100%) surpassed all other tested markers and sensitivity was equal to CK7 (86% vs. 90%). CONCLUSION: The alphavbeta6 integrin is strongly expressed in human CC but not in HCC and therefore can be considered as a specific immunohistochemical marker in the differential diagnosis of primary liver tumours.

Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation.

DRESS syndrome (drug rash with eosinophilia and systemic symptoms) is a rare drug hypersensitivity reaction with a significant mortality. We describe a 60-year-old man with polyarthritis treated with sulfasalazine who developed DRESS and fulminant liver failure after additional vancomycin treatment. Liver histology revealed infiltration of granzymeB+ CD3+ lymphocytes in close proximity to apoptotic hepatocytes. After a superurgent liver transplantation and initial recovery, the patient developed recurrent generalized exanthema and eosinophilia, but only moderate hepatitis. Histology showed infiltration of FasL+ lymphocytes and eosinophils in the transplanted liver. Treatment with high-dose methylprednisolone was unsuccessful. Postmortem examination revealed extensive necrosis of the liver transplant. This case report illustrates that patients with DRESS may develop fulminant liver failure and that DRESS recurrence can recur in the transplanted liver. Histological and immunological investigations suggest an important role of granzymeB and FasL mediated cell death in DRESS associated hepatitis.

Herbal medicine in the treatment of liver diseases.

Herbal drugs have become increasingly popular and their use is widespread. Licensing regulations and pharmacovigilance regarding herbal products are still incomplete and clearcut proof of their efficacy in liver diseases is sparse. Nevertheless, a number of herbals show promising activity including silymarin for antifibrotic treatment, phyllantus amarus in chronic hepatitis B, glycyrrhizin to treat chronic viral hepatitis, and a number of herbal combinations from China and Japan that deserve testing in appropriate studies. Apart from therapeutic properties, reports are accumulating about liver injury after the intake of herbals, including those advertised for liver diseases. Acute and/or chronic liver damage occurred after ingestion of some Chinese herbs, herbals that contain pyrrolizidine alkaloids, germander, greater celandine, kava, atractylis gummifera, callilepsis laureola, senna alkaloids, chaparral and many others. Since the evidence supporting the use of botanicals to treat chronic liver diseases is insufficient and only few of them are well standardised and free of potential serious side effects, most of these medications are not recommended outside clinical trials. Particularly with regard to the latter, adequately powered randomised-controlled clinical trials with well-selected end points are needed to assess the role of herbal therapy for liver diseases.

Review article: Nutritional therapy in alcoholic liver disease.

Chronic alcohol consumption may lead to primary and secondary malnutrition. In particular, protein energy malnutrition not only aggravates alcoholic liver disease but also correlates with impaired liver function and increased mortality. Therefore, in these patients, adequate nutritional support should be implemented in order to improve their prognosis. Clinical trials addressing this issue have shown that nutritional therapy either enterally or parenterally improves various aspects of malnutrition, and there is increasing evidence that it may also improve survival. Therefore, malnourished alcoholics should be administered a diet rich in carbohydrate- and protein-derived calories preferentially via the oral or enteral route. Micronutrient deficiencies typically encountered in alcoholics, such as for thiamine and folate, require specific supplementation. Patients with hepatic encephalopathy may be treated with branched-chain amino acids in order to achieve a positive nitrogen balance. Fatty liver represents the early stage of alcoholic liver disease, which is usually reversible with abstinence. Metadoxine appears to improve fatty liver but confirmatory studies are necessary. S-adenosyl-L-methionine may be helpful for patients with severe alcoholic liver damage, since various mechanisms of alcohol-related hepatotoxicity are counteracted with this essential methyl group donor, while a recent large trial showed that the use of polyenylphosphatidylcholine is of limited efficacy.

Acute hepatitis induced by Greater Celandine (Chelidonium majus).

We report on two cases of acute liver injury along with the intake of Greater Celandine (Chelidonium majus), a well-known herbal remedy frequently used for irritable bowel syndrome. All other possible causes of acute liver damage were excluded in both patients. In one patient, cholestatic hepatitis recurred rapidly after involuntary re-exposition. Both patients fully recovered after the withdrawal of Greater Celandine. The two cases add to the existing database about the potential hepatotoxicity of drugs containing Greater Celandine and raise the question whether the approval of this drug should be re-evaluated in the light of lacking evidence for a therapeutic benefit.

[Alcoholic liver disease--established treatment and new therapeutic approaches]. / Alkoholische Lebererkrankung--Etablierte und experimentelle Therapieansätze.

Alcoholic liver disease is the most frequent organ damage encountered in chronic alcoholics and the annual death rate attributed to alcohol-induced end-stage liver disease exceeds that of car accidents. Alcoholic liver damage occurs mainly due to the toxicity of its first metabolite acetaldehyde, and due to interactions with numerous macro- and micronutrients. Established treatment options comprise psychotherapy aiming to achieve abstinence, nutritional therapy, management of hepatological complications, and liver transplantation in selected individuals. Since these therapeutic approaches are unsuccessful in many patients, pharmacological therapies of alcoholic liver disease are being investigated. Many drugs failed to be beneficial or have even shown toxicity. However, some agents are promising, such as S-adenosyl-L-methionine (SAMe), pentoxifylline, metadoxin, polyenylphosphatidylcholine or inhibitors of the cytochrome P450 2E1 isoenzyme. In severely ill patients with alcoholic hepatitis, drugs with anti-tumor necrosis factor alpha activity are currently investigated in clinical trials. If and how far corticosteroids are beneficial remains controversial and their use should be restricted to selected patients. Anabolic steroids used to enhance the nutritional status may lead to serious side effects while having a marginal benefit. Silymarin has not been proven efficacious in alcoholic cirrhosis and clinical trials are ongoing which aim to elucidate its therapeutic value in less advanced stages of liver disease.

Antifibrotic properties of botanicals in chronic liver disease.

Cirrhosis of the liver is a major complication of various chronic liver diseases and results from excess production and decreased degradation of extracellular matrix. Proinflammatory cytokines, toxic metabolites and certain drugs can trigger enhanced fibrogenesis in hepatic stellate cells and myofibroblasts, the major matrix-producing cells. Since treatment of established cirrhosis is limited, therapeutic interventions that inhibit or mitigate fibrogenesis are needed. Numerous drugs have been investigated for their antifibrotic potential and botanicals constitute a significant fraction of them. Colchicine has been used to treat various chronic liver diseases with controversial results. To date, there is a lack of studies in appropriate animal models and well-controlled human trials to demonstrate its antifibrotic properties. Silymarin has so far failed to clearly show an antifibrotic effect in human studies, whereas animal experiments suggest that this mixture of flavolignanes may be beneficial in patients which have not yet developed cirrhosis. Animal studies indicate an antifibrotic potential of Shosaiko-to, a herbal combination frequently used in China and Japan for the treatment of chronic viral hepatitis, but mechanisms of action need to be further explored. Other botanicals include trans-resveratrol, a flavonoid extracted from grapevine, and Salvia miltiorrhiza which were shown to interfere with the process of hepatic stellate cell activation. Herbal combinations, such as compound 861 and LIV.52 were advocated as antifibrotics or hepatoprotectives, but studies in humans have either been of questionable design or resulted in cessation of the trial due to adverse outcomes.

Cocarcinogenic effects of alcohol in hepatocarcinogenesis.

Alcohol is a major aetiological factor in hepatocarcinogenesis but our understanding of its importance as a modulating factor is just beginning to emerge. In the present review, a number of possible cofactors and mechanisms are discussed by which alcohol may enhance the development of hepatoma. These include dietary or environmental carcinogens ingested along with alcoholic beverages, alcoholic cirrhosis as a precancerous condition, and the effects of alcohol metabolism.

Serum collagen type VI and XIV and hyaluronic acid as early indicators for altered connective tissue turnover in alcoholic liver disease.

Hepatic fibrosis in alcoholic liver disease often heralds progression to cirrhosis and, therefore, noninvasive parameters are required for early diagnosis and follow-up. Collagens VI and XIV, procollagen-III-N-propeptide, hyaluronic acid, and active transforming growth factor-beta1 (TGF-beta1) were measured in healthy volunteers, patients with alcoholic cirrhosis, and heavy drinkers without cirrhosis. Noncirrhotic alcoholics were assigned to two groups with either normal aspartate aminotransferase or levels > or = 2 normal. Collagens VI and XIV were elevated in all alcoholic patients compared to controls (P < 0.0001, all instances). Procollagen-III-N-propeptide and hyaluronic acid levels were higher in alcoholic patients with elevated liver enzymes and in cirrhotics as compared to controls. Procollagen-III-N-propeptide revealed a significant correlation with serum levels of TGF-beta1 (P < 0.0001). Collagens VI, and XIV, procollagen-III-N-propeptide, and hyaluronic acid appear to be sensitive markers indicating fibrotic transformation in alcoholics. The correlation between procollagen-III-N-propeptide and TGF-beta1 emphasizes its role in hepatic fibrogenesis.

[Liver toxicity of drugs of plant origin]. / Hepatotoxizität von Arzneimitteln pflanzlichen Ursprungs.

Herbal drugs are widely used and often contain highly active pharmacological compounds. Recently, reports have mounted about hepatotoxicity of herbal remedies which ranges from mild liver enzyme alterations to chronic liver disease and liver failure. Hepatotoxicity of Chinese herbs has been recognized, e.g. during treatment of patients with atopic eczema. However, the toxic compounds remain to be determined. Hepatic veno-occlusive disease may result from pyrrolizidine alkaloids which are contained in numerous plants worldwide. Teucrium chamaedrys, commonly referred to as germander, may cause hepatitis and even liver cirrhosis. Significant hepatotoxicity has also been observed after the ingestion of chaparral. Recently, greater celandine, which is widely used for biliary disorders and dyspepsia, was identified as a cause of cholestatic hepatitis. Hepatotoxic reactions have also been observed after the ingestion of Atractylis gummifera, Callilepsis laureola, Senna, Kavapyrone and Pulegium. The aim of this review is to summarize potentially hepatotoxic herbal remedies, to further elucidate their mechanisms of toxicity and thereby underline the likelihood of plants to be the cause of liver damage.

Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease.

BACKGROUND: Chronic alcohol ingestion leads to endotoxemia which is believed to play an important role in the pathogenesis of alcoholic liver disease (ALD). The purpose of this study was to determine if chronic ethanol consumption, in addition to affecting plasma endotoxin and cytokines, also affects the endotoxin-neutralizing capacity (ENC), sCD14, and sICAM-1, in patients with ALD. A second aim was to identify correlations between these latter parameters, endotoxin, and cytokines, especially IL-10. METHODS: Hospitalized patients with various degrees of ALD (n = 59), and 20 healthy volunteers were studied. Plasma endotoxin and ENC were determined using our kinetic Limulus amebocyte lysate test. Cytokines, sCD14, and sICAM-1 were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with ALD exhibited a mild endotoxemia (p < 0.01) and a marked decrease in ENC (p < 0.0002). TNF-alpha (p < 0.05), IL-6 (p < 0.0001), sICAM (p < 0.005), and sCD14 (p < 0.0005) were significantly elevated in all patients with ALD, and IL-10 (p < 0.05) in patients with cirrhotic ALD. With the exception of IL-10, the cytokines correlated with each other and with sICAM-1. No correlations occurred between endotoxin, ENC, and sCD14, and between these and the cytokines and sICAM-1. Elevated levels of endotoxin correlate with acute excessive alcohol ingestion. No gender differences were observed. CONCLUSIONS: Acute alcohol intoxication rather than severe ALD results in significant endotoxemia. The limited capacity of plasma to neutralize endotoxin in liver injury seems to be an important factor in ALD which may be responsible for the release of endotoxin-induced mediators, such as cytokines, as well as s-ICAM-1, that are relevant in the pathogenesis of ALD.

Hepatotoxicity of botanicals.

OBJECTIVE: Hepatic impairment resulting from the use of conventional drugs is widely acknowledged, but there is less awareness of the potential hepatotoxicity of herbal preparations and other botanicals, many of which are believed to be harmless and are commonly used for self-medication without supervision. The aim of this paper is to examine the evidence for hepatotoxicity of botanicals and draw conclusions regarding their pathology, safety and applications. DESIGN: Current literature on the hepatotoxicity of herbal drugs and other botanicals is reviewed. The aetiology, clinical picture and treatment of mushroom (Amanita) poisoning are described. RESULTS: Hepatotoxic effects have been reported for some Chinese herbal medicines (such as Jin Bu Huan, Ma-Huang and Sho-saiko-to), pyrrolizidine alkaloid-containing plants, germander (Teucrium chamaedrys), chaparral (Larrea tridentata), Atractylis gummifera, Callilepsis laureola, and others. The frequency with which botanicals cause hepatic damage is unclear. There is a lack of controlled treatment trials and the few studies published to date do not clarify the incidence of adverse effects. Many plant products do not seem to lead to toxic effects in everyone taking them, and they commonly lack a strict dose-dependency. For some products, such as Sho-saiko-to, the picture is confused further by demonstrations of hepatoprotective properties for some components. Mushroom poisoning is mostly due to the accidental consumption of Amanita species. Treatment with silymarin, thioctic acid, penicillin and liver transplantation have been shown to be effective but require early diagnosis. CONCLUSIONS: Severe liver injury, including acute and chronic abnormalities and even cirrhotic transformation and liver failure, has been described after the ingestion of a wide range of herbal products and other botanical ingredients, such as mushrooms. It is concluded that in certain situations herbal products may be just as harmful as conventional drugs.

Effect of chronic alcohol consumption on total plasma homocysteine level in rats.

BACKGROUND: Chronic alcoholism in humans is associated with the development of hyperhomocysteinemia, the mechanism of which remains unclear. Among the causes of hyperhomocysteinemia is depletion of folate, vitamin B12, or vitamin B6. Population-based studies indicate that folate is the strongest vitamin determinant of hyperhomocysteinemia and, in most settings, folate supplementation effectively lowers elevated homocysteine levels. However, it is not clear whether folate deficiency is the cause of alcohol-related hyperhomocysteinemia. METHODS: In the present study, 10 male Sprague Dawley rats were fed ethanol-containing Lieber-DeCarli diets with 13 mg of folic acid per kilogram of diet. This represents a folate intake more than 20 times the basal requirement. Ethanol represented 36% of total energy, which yielded a concentration of 6.2% (vol/vol). The same number of rats were pair-fed with isocaloric control diets that contained an identical level of folate in which ethanol was entirely replaced by maltodextrin. RESULTS: At the end of 4 weeks, alcohol-fed rats did not show any significant reduction in plasma or hepatic folate concentrations, plasma pyridoxal-5'-phosphate concentration, or plasma vitamin B12 concentration. On the other hand, alcohol-fed rats were significantly hyperhomocysteinemic (17.24 +/- 4.63 micromol/liter,p < 0.01) compared to the nonalcohol group (10.73 +/- 2.76 micromol/liter). Alcohol-fed rats also had a significantly lower hepatic S-adenosylmethionine and higher hepatic S-adenosylhomocysteine levels. CONCLUSIONS: Chronic alcohol consumption produces hyperhomocysteinemia by a mechanism that is related to interference with one-carbon metabolism, and not through vitamin depletion.

The efficacy and safety of comfrey.

Herbal medication has gathered increasing recognition in recent years with regard to both treatment options and health hazards. Pyrrolizidine alkaloids have been associated with substantial toxicity after their ingestion as tea and in the setting of contaminated cereals have led to endemic outbreaks in Jamaica, India and Afghanistan. In Western Europe, comfrey has been applied for inflammatory disorders such as arthritis, thrombophlebitis and gout and as a treatment for diarrhoea. Only recently was the use of comfrey leaves recognized as a substantial health hazard with hepatic toxicity in humans and carcinogenic potential in rodents. These effects are most likely due to various hepatotoxic pyrrolizidine alkaloids such as lasiocarpine and symphytine, and their related N-oxides. The mechanisms by which toxicity and mutagenicity are conveyed are still not fully understood, but seem to be mediated through a toxic mechanism related to the biotransformation of alkaloids by hepatic microsomal enzymes. This produces highly reactive pyrroles which act as powerful alkylating agents. The main liver injury caused by comfrey (Symphytum officinale) is veno-occlusive disease, a non-thrombotic obliteration of small hepatic veins leading to cirrhosis and eventually liver failure. Patients may present with either acute or chronic clinical signs with portal hypertension, hepatomegaly and abdominal pain as the main features. Therapeutic approaches include avoiding intake and, if hepatic failure is imminent, liver transplantation. In view of the known serious hazards and the ban on distributing comfrey in Germany and Canada, it is difficult to understand why comfrey is still freely available in the United States.

Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon.

Alcohol consumption has been implicated as an etiologic agent in colorectal carcinogenesis, but the mechanism by which alcohol enhances the development of colorectal cancer is not yet known. Recent reports indicate that alcohol consumption can diminish cellular S-adenosylmethionine levels, thus possibly altering normal patterns of DNA methylation, a phenomenon that is mediated by S-adenosylmethionine and whose abnormalities are observed in colonic neoplasia. This study investigated the effect of chronic alcohol consumption on genomic DNA methylation of rat colonic epithelium and methylation of the p53 tumor suppressor gene, abnormalities of which have been implicated in colonic carcinogenesis. Two groups of rats (n = 10/group) were pair-fed either an alcohol-containing or an isocaloric control Lieber-DeCarli diet for 4 wk. The extent of genomic DNA methylation was assessed by incubating the extracted DNA with [(3)H]S-adenosylmethionine and Sss1 methyltransferase. Gene-specific methylation was assessed by using semiquantitative polymerase chain reaction (PCR). Tritiated methyl uptake by colonic DNA (which is inversely correlated with genomic methylation) from alcohol-fed rats was 57% less than that in control DNA (P < 0.05). However, gene-specific DNA methylation, both in the p53 gene (exons 5-8) and in the beta-actin gene, a control gene, did not differ between the two groups. In conclusion, this study indicates that chronic alcohol consumption produces genomic DNA hypomethylation in the colonic mucosa. This may constitute a means by which carcinogenesis is enhanced, although further studies are required to establish causality.