Gut microbiota in alcoholic liver disease: Pathogenetic role and therapeutic perspectives

Alcoholic liver disease(ALD) is the commonest cause of cirrhosis in many Western countries and it has a high rate of morbidity and mortality. The pathogenesis is characterized by complex interactions between metabolic intermediates of alcohol. Bacterial intestinal flora is itself responsible for production of endogenous ethanol through the fermentation of carbohydrates. The intestinal metabolism of alcohol produces a high concentration of toxic acetaldehyde that modifies gut permeability and microbiota equilibrium. Furthermore it causes direct hepatocyte damage. In patients who consume alcohol over a long period, there is a modification of gut microbiota and, in particular, an increment of Gram negative bacteria. This causes endotoxemia and hyperactivation of the immune system. Endotoxin is a constituent of Gram negative bacteria cell walls. Two types of receptors, cluster of differentiation 14 and Toll-like receptors-4, present on Kupffer cells, recognize endotoxins. Several studies have demonstrated the importance of gut-liver axis and new treatments have been studied in recent years to reduce progression of ALD modifying gut microbiota. It has focused attention on antibiotics, prebiotics, probiotics and synbiotics.

Circulating adhesion molecules in patients with virus-related chronic diseases of the liver

AIM: In the inflammatory state, intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1) play a key role in promoting migration of immunological cells from the circulation to target site.Aim of our study was to investigate soluble forms of these molecules in patients with virus-related chronic liver diseases, to assess their behavior in different pathologies and correlation with severity of liver damage.METHODS: Circulating ICAM-1 and VCAM-1 were assayed by EIA commercial kits (R&D System Co.,Abington, UK) in 23 patients with chronic active hepatitis (CH), 50 subjects affected by liver cirrhosis (LC) and 15 healthy controls comparable for sex and age. In patients, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also detected by autoanalyzer.RESULTS: LC patients had significantly higher ICAM-1 values than CH patients (38.56±7.4 ng/mL vs 20.89±6.42 ng/mL; P＜0.001) and these ones had significantly higher values than controls (12.92±1.08 ng/mL; P＜0.001). In CH group, ICAM-1 levels were significantly related to inflammatory activity (P= 0.041) and ALT values (r= 0.77;P＜0.05). VCAM-1 values were significantly increased only in LC patients (P＜0.001) and related to severity of liver impairment.CONCLUSION: These findings suggest that the determination of serum ICAM-1 can be considered as an additional useful marker of hepatocellular necrosis and inflammatory activity in chronic hepatitis, while serum VCAM-1 is an indicator of liver fibrogenesis and severity of disease in cirrhosis.

Chronic hepatitis C:This and the new era of treatment

Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.

Giant cavernous liver hemangiomas： is it the time to change the size categories？

BACKGROUND： Four different sizes （4, 5, 8 and 10 cm in diameter） can be found in the literature to categorize a liver hemangioma as giant. The present review aims to clarify the appropriateness of the size category ＂giant＂ for liver heman- gioma. DATA SOURCES： We reviewed the reports on the categoriza- tion of hemangioma published between 1970 and 2014. The number of hemangiomas, size criteria, mean and range of hemangioma sizes, and number of asymptomatic and symp- tomatic patients were investigated in patients aged over 18 years. Liver hemangiomas were divided into four groups： 〈5.0 cm, 5.0-9.9 cm, 10.0-14.9 cm and 〉15.0 cm in diameter. Inclu- sion criteria were noted in 34 articles involving 1972 （43.0%） hemangiomas （〉4.0 cm）. RESULTS： The patients were divided into the following groups： 154 patients （30.0%） with hemangiomas less than 5.0 cm in diameter （small）, 182 （35.5%） between 5.0 cm and 9.9 cm （large）, 75 （14.6%） between 10.0 and 14.9 cm （giant）, and 102 （19.9%） more than 15.0 cm （enormous）. There were 786 （39.9%） asymptomatic patients and 791 （40.1%） symptomatic patients. Indications for surgery related to symptoms were reported in only 75 （3.8%） patients. Operations including 137 non-anatomical resection （12.9%） and 469 enudeation （44.1%） were undearly related to size and symptoms.CONCLUSIONS： The term ＂giant＂ seems to be justified for liver hemangiomas with a diameter of 10 cm. Hemangiomas categorized as ＂giant＂ are not indicated for surgery. Surgery should be performed only when other symptoms are apparent.

Plasma erythropoietin levels in anaemic and non-anaemic patients with chronic liver diseases

AIM: To investigate the serum erythropoietin (Epo) levels in patients with chronic liver diseases and to compare to subjects with iron-deficiency anaemia and healthy controls.METHODS: We examined 31 anaemic (ALC) and 22 non-anaemic (NALC) cirrhotic patients, 21 non-anaemic subjects with chronic active hepatitis (CAH), 24 patients with iron-deficiency anaemia (ID) and 15 healthy controls. Circulating Epo levels (ELISA; R&D Systems, Europe Ltd, Abingdon,UK) and haemoglobin (Hb) concentration were determined in all subjects.RESULTS: Mean±SD of Epo values was 26.9±10.8 mU/mL in ALC patients, 12.5±8.0 mU/mL in NALC subjects,11.6±6.3 mU/mL in CAH patients, 56.4±12.7 mU/mL in the cases of ID and 9.3±2.6 mU/mL in controls. No significant difference (P>0.05) was found in Epo levels between controls, CAH and NALC patients. ALC individuals had higher Epo levels (P<0.01) than these groups whereas ID subjects had even higher levels (P<0.001) than patients suffering from ALC.CONCLUSION: Increased Epo values in cirrhotics, are only detectable when haemoglobin was lesser than 12 g/dL.Nevertheless, this rise in value is lower than that observed in anaemic patients with iron-deficiency and appears blunted and inadequate in comparison to the degree of anaemia.

Hepatocellular carcinoma and the risk of occupational exposure

Hepatocellular carcinoma(HCC)is the most common type of liver cancer.The main risk factors for HCC are alcoholism,hepatitis B virus,hepatitis C virus,nonalcoholic steatohepatitis,obesity,type 2 diabetes,cirrhosis,aflatoxin,hemochromatosis,Wilson’s disease and hemophilia.Occupational exposure to chemicals is another risk factor for HCC.Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent.This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem.

L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-α 2b plus ribavirin

AIM：To evaluate the efficacy of L-carnitine on alleviating anemia,thrombocytopenia and leukopenia,and minimizing dose reductions in patients with chronic hepatitis C virus（HCV）in treatment with Interferonα（IFN-α）plus ribavirin.METHODS：Sixty-nine patients with chronic hepatitis C were enrolled in the study and divided into two groups.group A（n=35）received Peg-IFN-α2b plus ribavirin plus L-carnitine,and group B（n=34）received Peg-IFN-αand ribavirin for 12 mo.All patients underwent laboratory investigations including：red cell count,he-moglobin,white cell count,platelets,bilirubin,alanineaminotransferase（ALT）,aspartate aminotransferase（AST）,and viremia.RESULTS：After 12 mo in group A compared to group B we observed significant differences in AST 108.8 vs 76.8（IU/L;P0.001）,ALT 137.vs 112.3（IU/L;P 0.001）,viremia 4.04 vs 2.36（106 copies/mL;P 0.001）,Hb 1 vs 3.5（g/dL;P0.05）,red blood cells 0.3 vs 1.1（1012/L;P0.001）,white blood cells 1.5 vs 3（10/L;P0.001）and platelets 86 vs 85（×10/L;P0.001）.The end treatment responders were 18 vs 12（60%vs 44%）and the non responders were 12 vs 15（40%vs 50%）[odds ratio（OR）1.65,5%CI =0.65-5.37,P0.05.In group A compared to group B there was a significant improvement of sustained vi-rological response in 15 vs 7 patients（50%vs25%）,while the relapsers were 3 vs 5（10%vs 18%）（OR 3.57,5%CI=0.65-1.3,P0.001）.CONCLUSION：L-carnitine supplementations modulate erythropoiesis,leucopoiesis and thrombocytopoiesis,and may be useful in patients treated for HCV.L-carni-tine treatment offers the possibility of achieving a sus-tained virological response while preventing overtreat-ment.

Endozepine-4 levels are increased in hepatic coma

AIM:To evaluate the serum levels of endozepine-4,their relation with ammonia serum levels,the grading of coma and the severity of cirrhosis,in patients with hepatic coma. METHODS:In this study we included 20 subjects with Hepatic coma,20 subjects with minimal hepatic encephalopathy(MHE) and 20 subjects control. All subjects underwent blood analysis,Child Pugh and Model for End- stage liver disease(MELD) assessment,endozepine-4 analysis. RESULTS:Subjects with hepatic coma showed significant difference in endozepine-4(P < 0.001) and NH3 levels(P < 0.001) compared both to MHE and controls patients. Between NH3 and endozepine-4 we observed a significant correlation(P = 0.009; Pearson correlation 0.570). There was a significant correlation between endozepine-4 and MELD(P = 0.017; Pearsoncorrelation = 0.529). In our study blood ammonia concentration was noted to be raised in patients with hepatic coma,with the highest ammonia levels being found in those who were comatose. We also found a high correlation between endozepine-4 and ammonia(P < 0.001). In patients with grade Ⅳ hepatic coma,endozepine levels were significantly higher compared to other groups. CONCLUSION:This study suggests that an increased level of endozepine in subjects with higher levels of MELD was observed. In conclusion,data concerning involvement of the GABA-ergic system in HE coma could be explained by stage-specific alterations.

Responsibility of hepatitis C virus in the development of hepatocellular carcinoma:From molecular alterations to possible solutions

There are several causes of hepatocellular carcinoma(HCC), but certainly the hepatitis C virus(HCV) is one of the most common. The HCV is able to contribute, both directly and indirectly, to the development of HCC. Determining early HCV clearance before an advanced liver disease develops, is absolutely necessary as this prevents the initiation of the cascade of events induced by HCV that may result in the development of HCC. The early treatment of the infection and the clearance of HCV represents today, in the age of the direct antiviral agents(DAAs), an extraordinary opportunity for true prevention of the development of HCV-related HCC.

Erythropoietin in liver cirrhosis: Two questions without answers

TO THE EDITORIn a recent paper[1], and in a subsequent letter[2], Tacke et al. reported the investigation of plasma erythropoietin (Epo) levels in patients affected by chronic liver disease of various aetiologies. The authors also compared[2] their data to our previous work[3]. The results show a substantial agreement but also some important differences between the two works. We would like to highlight, from our point of view, this issue. Both the papers demonstrated increased Epo values in anaemic cirrhotic subjects when compared to healthy controls and non-anemic patients with liver disease.