Viral Hepatitis-related Cirrhosis Research Articles

Recent Advances in the Pathogenesis and Clinical Evaluation of Portal Hypertension in Chronic Liver Disease.

In chronic liver disease, hepatic stellate cell activation and degeneration of liver sinusoidal endothelial cells lead to structural changes, which are secondary to fibrosis and the presence of regenerative nodules in the sinusoids, and to functional changes, which are related to vasoconstriction. The combination of such changes increases intrahepatic vascular resistance and causes portal hypertension. The subsequent increase in splanchnic and systemic hyperdynamic circulation further increases the portal blood flow, thereby exacerbating portal hypertension. In clinical practice, the hepatic venous pressure gradient is the gold-standard measure of portal hypertension; a value of ≥10 mm Hg is defined as clinically significant portal hypertension, which is severe and is associated with the risk of liver-related events. Hepatic venous pressure gradient measurement is somewhat invasive, so evidence on the utility of risk stratification by elastography and serum biomarkers is needed. The various stages of cirrhosis are associated with different outcomes. In viral hepatitis-related cirrhosis, viral suppression or elimination by nucleos(t)ide analog or direct-acting antivirals results in recompensation of liver function and portal pressure. However, careful follow-up should be continued, because some cases have residual clinically significant portal hypertension even after achieving sustained virologic response. In this study, we reviewed the current and future prospects for portal hypertension.

Etiological Spectrum of Cirrhosis in India: A Systematic Review and Meta-analysis

Cirrhosis is a significant cause of morbidity and mortality globally and in India. This systematic review and meta-analysis aimed to ascertain the etiological spectrum and changing trends of cirrhosis in India. We searched electronic databases, including Pubmed/Medline, Scopus, and Embase. We included original studies that reported the etiology of cirrhosis in the Indian population. We included 158 studies (adults: 147, children: 11). The overall pooled estimate of alcohol as a cause of cirrhosis in adults was 43.2% (95% confidence interval (CI) 39.8-46.6%; I2= 97.8%), followed by nonalcoholic fatty liver disease (NAFLD)/cryptogenic in 14.4%, 95% CI (11.7-17.3%; I2= 98.4%), hepatitis B virus (HBV) in 11.5%, 95% CI (9.8-13.3%; I2= 96.6%), and hepatitis C virus (HCV) in 6.2%, 95% CI (4.8-7.8%; I2= 97.2%) of the included patients. The most common cause of cirrhosis in all zones was alcohol-related. Comparison of etiologies over time revealed a reduction in the viral hepatitis-related and an increase in the proportion of alcohol-related and NAFLD/cryptogenic-related cirrhosis. The overall pooled estimates of various etiologies in children were: HBV in 10.7%, 95% CI (4.6-18.7%; I2= 91.0%), NAFLD/Cryptogenic in 22.3%, 95% CI (9.0-39.2%; I2= 96.7%), and HCV in 2.0%, 95% CI (0.0-8.5%; I2= 94.6%). Alcohol is the most common etiology of cirrhosis in adults in India. The proportions of alcohol and NAFLD-related cirrhosis are increasing, and those of viral hepatitis-related cirrhosis are reducing. The results of our meta-analysis will help formulate health policies and the allocation of resources.

A Therapeutic Hepatitis B Virus DNA Vaccine Induces Specific Immune Responses in Mice and Non-Human Primates

Despite the availability of an effective prophylactic vaccine for more than 30 years, nearly 300 million people worldwide are chronically infected with the hepatitis B virus (HBV), leading to 1 death every 30 s mainly from viral hepatitis-related cirrhosis and liver cancer. Chronic HBV patients exhibit weak, transient, or dysfunctional CD8+ T-cell responses to HBV, which contrasts with high CD8+ T-cell responses seen for resolvers of acute HBV infection. Therefore, a therapeutic DNA vaccine was designed, expressing both HBV core and polymerase proteins, and was sequence optimized to ensure high protein expression and secretion. Although the vaccine, administered intramuscularly via electroporation, had no effect on plasma viral parameters in a mouse model of persistent HBV infection, it did induce robust HBV-specific immune responses in healthy and adeno-associated hepatitis B virus (AAV-HBV) infected mice as well as in healthy non-human primates.

Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis

Wedge hepatic vein pressure (WHVP) accurately estimates portal pressure (PP) in alcohol- or viral hepatitis-related cirrhosis. Whether this also holds true in cirrhosis caused by non-alcoholic steatohepatitis (NASH) is unknown. We aimed to evaluate the agreement between WHVP and PP in patients with NASH cirrhosis in comparison to patients with alcohol- or HCV-related cirrhosis. All consecutive patients with NASH cirrhosis treated with a transjugular intrahepatic portosystemic shunt (TIPS) in 3 European centres were included (NASH group; n= 40) and matched with 2 controls (1 with alcohol-related and 1 with HCV-related cirrhosis) treated with TIPS contemporaneously (control group; n= 80). Agreement was assessed by Pearson's correlation (R), intra-class correlation coefficient (ICC), and Bland-Altman method. Disagreement between WHVP and PP occurred when both pressures differed by >10% of PP value. A binary logistic regression analysis was performed to identify factors associated with this disagreement. Correlation between WHVP and PP was excellent in the control group (R 0.92; p <0.001; ICC 0.96; p <0.001) and moderate in the NASH group (R 0.61; p <0.001; ICC 0.74; p <0.001). Disagreement between WHVP and PP was more frequent in the NASH group (37.5% vs. 14%; p= 0.003) and was mainly because of PP underestimation. In uni- and multivariate analyses, only NASH aetiology was associated with disagreement between WHVP and PP (odds ratio 4.03; 95% CI 1.60-10.15; p= 0.003). In patients with decompensated NASH cirrhosis, WHVP does not estimate PP as accurately as in patients with alcohol- or HCV-related cirrhosis, mainly because of PP underestimation. Further studies aimed to assess this agreement in patients with compensated NASH cirrhosis are needed. Portal pressure is usually assessed by measuring wedge hepatic vein pressure because of solid evidence demonstrating their excellent agreement in alcohol- and viral hepatitis-related cirrhosis. Our results show that in patients with decompensated cirrhosis caused by non-alcoholic steatohepatitis, wedge hepatic vein pressure estimates portal pressure with less accuracy than in patients with other aetiologies of cirrhosis, mainly because of portal pressure underestimation.

A Study on the Temporal Trends in the Etiology of Cirrhosis of Liver in Coastal Eastern Odisha.

ABSTRACTBackgroundThe etiology of cirrhosis of liver is known to change with time due to various factors including awareness, preventive interventions, and lifestyle changes in society. However, there is scarce Indian data available about temporal trends in etiology of cirrhosis of liver. Hence, the aim of this study was to study the temporal trends in the etiology of cirrhosis of liver.Materials and methodsThis is a retrospective study conducted in the Department of Gastroenterology, Srirama Chandra Bhanja Medical College and Hospital, Cuttack, from January 2005 to December 2017. Data were collected from hospital records of all patients admitted to the Gastroenterology unit. A Poisson regression model was used to compare the hospitalization rate for different etiologies of cirrhosis of liver. All data were analyzed using Stata version 5.1 software.ResultsA total of 4,331 hospitalized patients of cirrhosis of liver were included in the analysis, of whom 2,742 (63.3%) had alcohol-related cirrhosis, 858 (19.8%) had viral hepatitis-related cirrhosis, and 731 (16.9%) had cirrhosis of liver due to nonalcohol and nonviral causes. The proportion of alcohol-related cirrhosis was increased by 26% from 2005 to 2017 (RR 1.26, p for trend <0.001). Though there were minimal ups and downs observed in the admission rate of viral hepatitis-related liver cirrhosis during later years, this was remarkably reduced by 73% (RR 0.27, p for trend <0.001) in the year 2017 at the end of the study. Similarly, the proportion of cirrhosis due to nonalcohol and nonviral causes decreased by 26% (RR 0.74, p for trend <0.001) by 2017.ConclusionAlcohol is the most common cause of cirrhosis of liver and the burden of alcohol-related cirrhosis is significantly increasing in comparison to other causes including viral infection, nonalcoholic steatohepatitis (NASH), and autoimmune hepatitis.How to cite this articleMishra D, Dash KR, Khatua C, et al. A Study on the Temporal Trends in the Etiology of Cirrhosis of Liver in Coastal Eastern Odisha. Euroasian J Hepato-Gastroenterol 2020;10(1):1–6.

Effect of low-dose aspirin administration on long-term survival of cirrhotic patients after splenectomy: A retrospective single-center study.

BACKGROUNDCirrhosis is a major risk factor for the development of hepatocellular carcinoma (HCC). Portal vein thrombosis is not uncommon after splenectomy in cirrhotic patients, and many such patients take oral anticoagulants including aspirin. However, the long-term impact of postoperative aspirin on cirrhotic patients after splenectomy remains unknown.AIMThe main purpose of this study was to investigate the effect of postoperative long-term low-dose aspirin administration on the development of HCC and long-term survival of cirrhotic patients after splenectomy.METHODSThe clinical data of 264 adult patients with viral hepatitis-related cirrhosis who underwent splenectomy at the First Affiliated Hospital of Xi’an Jiaotong University from January 2000 to December 2014 were analyzed retrospectively. Among these patients, 59 who started taking 100 mg/d aspirin within seven days were enrolled in the aspirin group. The incidence of HCC and overall survival were analyzed.RESULTSDuring follow-up, 41 (15.53%) patients developed HCC and 37 (14.02%) died due to end-stage liver diseases or other serious complications. Postoperative long-term low-dose aspirin therapy reduced the incidence of HCC from 19.02% to 3.40% after splenectomy (log-rank test, P = 0.028). Univariate and multivariate analyses showed that not undertaking postoperative long-term low-dose aspirin therapy [odds ratio (OR) = 6.211, 95% confidence interval (CI): 1.142-27.324, P = 0.016] was the only independent risk factor for the development of HCC. Similarly, patients in the aspirin group survived longer than those in the control group (log-rank test, P = 0.041). Univariate and multivariate analyses showed that the only factor that independently associated with improved overall survival was postoperative long-term low-dose aspirin therapy [OR = 0.218, 95%CI: 0.049-0.960, P = 0.044].CONCLUSIONIn patients with viral hepatitis-related cirrhosis, long-term post-splenectomy administration of low-dose aspirin reduces the incidence of HCC and improves the long-term overall survival.

Low Risk of Variceal Bleeding in Patients With Cirrhosis After Variceal Screening Stratified by Liver/Spleen Stiffness

We previously demonstrated the possible noninferiority of a screening strategy for varices guided by liver and spleen stiffness measurement (LSSM) compared to universal endoscopic screening in detecting clinically significant varices in patients with cirrhosis. We now report the long-term outcome of the patients recruited in this trial for incident variceal bleeding and other hepatic events. This was a prospective follow-up study of a noninferiority, open-label, randomized controlled trial (NCT02024347) of 548 adult patients with known chronic liver diseases, radiological evidence of liver cirrhosis, and compensated liver function. The primary outcome of this prospective study was incident variceal bleeding confirmed with upper endoscopy. Between October 2013 and June 2016, 548 patients were randomized to an LSSM arm (n = 274) and a conventional arm (n = 274). Patients in both study arms were predominantly middle-aged men (mean age 59 years, male 68.9%) with viral hepatitis-related cirrhosis (85%). Upper endoscopy examination was performed in 127 (46.4%) patients in the LSSM arm and 263 (96.0%) in the conventional arm. During the follow-up period of 41.3 ± 12.6 months, 12/274 patients in the LSSM arm (4.4%) and 11/274 in the conventional arm (4.0%) developed incident variceal bleeding (log-rank test P = 0.724). The incident rates of hepatic events were also similar in both arms (P = 0.327). Conclusions: Patients with liver cirrhosis who had undergone LSSM-guided variceal screening were at similarly low risk of incident variceal bleeding in the future; patients with cirrhosis may first have LSSM measured to save up to half of the upper endoscopy examinations.

Update on global epidemiology of viral hepatitis and preventive strategies.

Viral hepatitis is one of the major public health concerns around the world but until recently it has drawn little attention or funding from global health policymakers. Every year 1.4 million people die from viral hepatitis-related cirrhosis and liver cancer. However, the majority of the infected population are unaware of their condition. This population have significant obstacles to overcome such as lack of awareness, vulnerability, increased migration, disease stigma, discrimination, as well as poor health resources, conflict in policy development and program implementation. Despite implementing infection control measures over the last few decades eradication or significant disease reduction remains elusive. This study aims to present the current global prevalence status and examines potential elimination strategies. The information for this research were obtained through a systematic review, published scientific literatures, the official websites of various government organisations, international public health organisations and internationally recognised regulatory bodies over a period of 40 years between 1978 and 2018.

Psoriatic patients with chronic viral hepatitis do not have an increased risk of liver cirrhosis despite long-term methotrexate use: Real-world data from a nationwide cohort study in Taiwan

Methotrexate (MTX) is commonly used in the treatment of patients with moderate-to-severe psoriasis. We conducted a nationwide population-based cohort study to investigate the impact of long-term MTX use on the risk of chronic viral hepatitis-related cirrhosis among psoriatic patients in Taiwan. This study obtained data from the National Health Insurance Research Database in Taiwan. We identified 2417 psoriatic patients with chronic hepatitis B (CHB) (370 MTX users and 2047 nonusers of MTX) and 1127 psoriatic patients with chronic hepatitis C (CHC) (174 MTX users and 953 nonusers of MTX) from January 1, 2000, to December 31, 2010. After a mean follow-up of more than 9years since the diagnosis of chronic viral hepatitis, a total of 125 patients with CHB (5%) and 120 patients with CHC (11%) developed liver cirrhosis. Comparable proportions of MTX users and nonusers of MTX developed liver cirrhosis (4% vs 5% in patients with CHB and 11% vs 11% in patients with CHC [both P >.05]). There is possible selection bias and medication nonadherence. Our real-world data show that long-term MTX use may not be associated with an increasedrisk of liver cirrhosis among psoriatic patients with chronic viral hepatitis.

Incidence and risk factors associated with a high comprehensive complication index score after splenectomy in cirrhotic patients with hypersplenism

BackgroundPostoperative complications after splenectomy are not rare and can be serious in cirrhotic patients. The purpose of this study was to assess postoperative complications using the comprehensive complication index (CCI) after splenectomy in cirrhotic patients and identify risk factors for those who developed a high postoperative CCI score. Materials and methodsThis retrospective study included 208 adult patients with viral hepatitis-related cirrhosis, who underwent elective splenectomy at our hospital from January 2002 to June 2012. The primary outcome was the CCI score. A CCI score >30 was considered to be a high CCI score. ResultsThe median CCI score in this cohort was 25.6 (range: 8.7-62.9), and 66 patients (31.7%) had a CCI score >30. Univariable and multivariable analyses showed that the risk factors independently associated with a high CCI score were a history of hypertension and a model for end-stage liver disease (MELD) score ≥10 prior to splenectomy. ConclusionsA high CCI score is common in cirrhotic patients undergoing splenectomy. The CCI is a useful grading system to assess postoperative morbidity in cirrhotic patients undergoing splenectomy. Preoperative blood pressure control is recommended and cirrhotic patients with an elevated MELD score should consider other treatment options for hypersplenism.

Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC

The AFP model was shown to be superior to the Milan criteria for predicting hepatocellular carcinoma (HCC) recurrence after liver transplantation in a French population. Our aim was to test the AFP model in a non-French, post-hepatitic cirrhosis-based population of HCC candidates. 574 patients transplanted for HCC in four Italian centers were studied. AFP score was assessed at the last evaluation before liver transplantation (LT). Probabilities of recurrence and survival were estimated by the log-rank test or competing risk analysis and compared according to the AFP model. 24.7% patients were beyond Milan criteria. HCC complicated hepatitis C virus (HCV) and hepatitis B virus (HBV) cirrhosis in 58.7% and 24% of the cases, respectively. Five-year probabilities of recurrence differed according to AFP score ⩽2 vs. >2 in the whole population (13.2±1.8% vs. 49.8±8.7%, p<0.001, HR=4.98), in patients within Milan criteria (12.8±2.0% vs. 32.4±12.1%, p=0.009, HR=3.51), beyond Milan criteria (14.9±4.2% vs. 58.9±11.5%, p<0.001, HR=4.26), HCV patients (14.9±2.5% vs. 67.6±14.7%, p<0.001, HR=6.56) and HBV patients (11.6±3.4% vs. 34.3±12.5%, p=0.012, HR=3.49). By net reclassification improvement analysis AFP score significantly improved prediction of non-recurrence compared to Milan criteria. Overall five-year survival rates according to AFP score ⩽2 or >2 were 71.7±2.2% vs. 42.2±8.3% (p<0.001, HR=2.14). The AFP model identifies HCC candidates at low risk of recurrence, otherwise excluded by Milan criteria in a population with a predominance of post-hepatitic-related HCC. The AFP score can be proposed for selection of HCC candidates in programs with a high proportion of viral/HCV-related cirrhosis. Selection criteria for liver transplantation of patients affected with hepatocellular carcinoma (HCC) are based on the Milan criteria, which have been shown to be too restrictive, precluding access to liver transplantation for some patients who might be cured by this operation. Recently, a French group of researchers developed a new selection model called the AFP model, or AFP score, allowing some patients with HCC not meeting Milan criteria to be transplanted with excellent results. In the present work, the AFP score was tested in a population of non-French patients transplanted for HCC occurring mainly on post-hepatitic (HCV or HBV) cirrhosis. The results confirm that in this specific population, as in the original French population of patients, the AFP model better selects patients with HCC eligible for transplantation, compared to Milan criteria. We conclude that the AFP score, which has been officially adopted by the French organization for Organ Sharing for HCC patients, can also be implemented in countries with an important burden of HCC occurring on post-hepatitic cirrhosis.

The Relation between Serum Serotonin and Esophageal Varices in Egyptian Patients with Viral Hepatitis Related Cirrhosis : A Case-Control Study

AIM: Serotonin is a one of the monoamine neurotransmitters secreted by serotonergic nerve endings in multiple sites in the brain and gastrointestinal tract wall. Serotonin can induce contraction in the smooth muscles of the gut wall enhancing gut motility and in blood vessels wall causing vasoconstriction. The presence of serotonin receptors on hepatic stellate cells can cause contraction of these cells closing the sinusoidal fenestrae and raising the portal vein pressure. The aim of this work is to study the relation between serotonin level and the presence and the severity of esophageal varices in Egyptian patients with viral hepatitis related cirrhosis. PATIENTS AND METHODS: Two hundred patients were included in the study group I: 120 patients with viral hepatitis related cirrhosis and group II: 90 healthy volunteers. Patients as well as healthy subjects performed all routine investigations, upper GI endoscopy and serum serotonin level. RESULTS: serum serotonin level in group I was significantly higher than group II (135 ± 33.7 vs 41 ± 19.6). serum serotonin level was significantly correlated to albumin, bilirubin, platelet, portal vein diameter, spleen size, esophageal varices grade, grade of portal hypertensive gastropathy and Child's score (r = -0.35, 0.45, -0.44, 0.5, 0.39, 0.33, 0.36 and 0.41 in succession). It was also clear that serotonin level rises significantly with higher grades of esophageal varices. CONCLUSION: serum serotonin level is significantly correlated to the grade of esophageal varices in patients with viral hepatitis related cirrhosis.

Pigment epithelium-derived factor and matrix metalloproteinase-9 in liver cirrhosis.

Background/Aim:The aim of this study was to assess the role of serum pigment epithelium-derived factor (PEDF) and matrix metalloproteinase-9 (MMP-9) in progression of liver cirrhosis and development of hepatocellular carcinoma (HCC).Patients and Methods:Serum levels of PEDF and MMP-9 were tested in 212 patients with liver cirrhosis and in a control group of 30 healthy volunteers. HCC was diagnosed in 45 of the 212 patients studied (21%).Results:Serum PEDF and MMP-9 were higher in the study group than that in the control group (P < 0.001). In patients with alcoholic or mixed (alcoholic and viral hepatitis-related) cirrhosis, serum PEDF was higher than that in other patients (13970.2 ± 13406.9 ng/ml vs. 8563.5 ± 9602.7 ng/ml, P = 0.008). In patients with viral hepatitis-related cirrhosis, significantly higher PEDF levels were recorded in those with HCC (13429.1 ± 12045.8) than that in patients without HCC (6660.1 ± 7927.1; P = 0.04). There was a trend for higher serum MMP-9 in patients with HCC (5778.7 ± 12426.6 vs. 1389.8 ± 1944.7 in those without HCC; P = 0.07). Significant negative correlation between serum MMP-9 and serum alpha-fetoprotein in patients with HCC was observed (r = −0.54; P = 0.04).Conclusion:Serum PEDF and MMP-9 could be auxiliary markers in diagnosis of HCC, especially in patients with low alpha-fetoprotein level. Alcohol consumption can affect serum PEDF.

Nonalcoholic Fatty Liver Disease (NAFLD) and Hepatocellular Carcinoma: How Common?

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common cause of chronic liver disease in Western countries. NAFLD can progress to cirrhosis and its related complications, including hepatocellular carcinoma (HCC). Review of available evidence suggests an increased risk of HCC among patients with NAFLD-related cirrhosis, although this risk is smaller than risk of HCC among patients with viral hepatitis-related cirrhosis. Preliminary evidence suggests that a proportion of NAFLD-related HCC could develop in the absence of advanced liver disease or cirrhosis. NAFLD-related HCC is expected to increase, given the increasing prevalence of NAFLD; but this increase is not yet evident. Risk factors for HCC in NAFLD include older age, coexisting obesity or diabetes, high hepatic iron, and the presence of cirrhosis.

The First Case Series of Combined Liver-Kidney Transplantation (CLKT) from Thailand

From the hospital database, four patients underwent CLKT. Three patients had ESRD and cirrhosis. Causes of cirrhosis were chronic hepatitis B and chronic hepatitis C in two and one patient. The fourth patient underwent CLKT due to subfulminant liver failure and prolonged acute renal failure with severely damaged kidney and required hemodialysis for 5 weeks. The waiting time ranged from 6 to 1988 days. After CLKT, one patient required hemodialysis for 45 days because of prolonged acute tubular necrosis. Mild early liver graft dysfunction occurred in one patient. Induction regimens were IL2-receptor blockers, steroids and tacrolimus in three patients, and steroids combining with tacrolimus in one patient. Maintenance regimens included tacrolimus, mycophenolate mofetil (with or without low-dose prednisolone). One-year graft and patient survival rate was 100%. Median follow-up time was 2.2 years. None developed liver or renal graft rejection. At 6 and 12 months, median creatinine levels were 1.30 and 1.13 mg/dl. At the last visits, median creatinine level was 1.05 mg/dl with median eGFR of 76.45 ml/min. CLKT may be done in the patients with ESRD and viral hepatitis-related cirrhosis even without portal hypertension. Other indication is for patients with acute liver failure with severely damaged ARF.

82 PET and MRI determination of the effects of Sunitinib on hypoxia and vasculature on a rat brain tumour model

Carcinogenic aromatic amines, derived from cooked meat, are activated or inactivated by hepatic N-acetyltransferase (NAT). The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms with hepatocellular carcinoma (HCC), with special reference to the interaction of dietary habits.Peripheral white blood cell DNA from 185 HCC patients and 185 matched controls were genotyped for NAT2 by a polymerase chain reaction-restriction fragment length polymorphism method. All the subjects studied were chronic viral hepatitis B or C carriers with liver cirrhosis. Dietary habits of the subjects were assessed using a semiquantitative food frequency questionnaire.There was no association between the susceptibility of HCC and the overall NAT2 genotypes. However, in rapid acetylators (with two wild type NAT2*4 alleles), there was a trend of increased HCC risk from low to intermediate and high red meat intake (OR = 1, 2.66, 3.89; ptrend = 0.016), even when adjusted for family history of HCC and habitual alcohol drinking. The interaction between red meat intake and the NAT2*4 acetylator status for an increased risk of HCC was significant (p = 0.007).Polymorphisms of the NAT2 gene may confer different susceptibilities to the effect of red meat intake on HCC. In rapid acetylators with chronic viral hepatitis-related cirrhosis, red meat intake may play a role in hepatocarcinogenesis.

Clinical significance of serum procalcitonin levels in patients with acute or chronic liver disease

To evaluate the diagnostic value of serum procalcitonin levels in patients with acute or chronic liver disease, with or without bacterial infections and to correlate the results with the clinical outcome and the laboratory findings for these patients. One hundred and six consecutive hospitalized patients with liver disease were evaluated for procalcitonin levels on admission. Fifteen of them (14.2%) had acute alcoholic hepatitis on cirrhotic background (group A), 20 (18.9%) had alcoholic cirrhosis without hepatitis and/or bacterial infection (group B), 16 (15.1%) had decompensated cirrhosis with proved bacterial infection (group C), 42 (39.6%) had uncomplicated viral hepatitis-related cirrhosis (group D) and 13 (12.3%) had acute icteric viral hepatitis (group E). Serum procalcitonin levels were measured using an immunoluminometric assay. Statistical analysis was based on Student's t-test and the non-parametric Kruskall-Wallis test (P<0.05). Serum procalcitonin levels were significantly higher in cirrhotic patients with bacterial infection (9.80+/-16.80 ng/ml) than in those without bacterial infection (0.21+/-0.13 ng/ml, P=0.001), whereas they were within normal range (<0.5 ng/ml) in all patients with uncomplicated cirrhosis, irrespective of the cause of cirrhosis. Seven of 15 group A patients (46.2%) and 4/13 group E patients (30.8%), all of them cirrhotics, had procalcitonin levels higher than 0.5 ng/ml on admission, without established bacterial infection. Serum procalcitonin levels remain below the threshold of 0.5 ng/ml in all patients with uncomplicated cirrhosis, irrespective of the cause of the disease, while they are significantly elevated when bacterial infection complicates the course of the disease. A significant proportion of patients with acute alcoholic hepatitis on a cirrhotic background as well as of patients with acute on chronic viral hepatitis, without bacterial infection, exhibit serum procalcitonin levels above 0.5 ng/ml, suggesting that this cut-off value is probably not enough to discriminate between patients with or without bacterial infection within these subgroups of patients with liver disease.

Polymorphism of the N-acetyltransferase 2 gene, red meat intake, and the susceptibility of hepatocellular carcinoma

Objective Carcinogenic aromatic amines, derived from cooked meat, are activated or inactivated by hepatic N-acetyltransferase (NAT). The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms with hepatocellular carcinoma (HCC), with special reference to the interaction of dietary habits. Methods Peripheral white blood cell DNA from 185 HCC patients and 185 matched controls were genotyped for NAT2 by a polymerase chain reaction-restriction fragment length polymorphism method. All the subjects studied were chronic viral hepatitis B or C carriers with liver cirrhosis. Dietary habits of the subjects were assessed using a semiquantitative food frequency questionnaire. Results There was no association between the susceptibility of HCC and the overall NAT2 genotypes. However, in rapid acetylators (with two wild type NAT2*4 alleles), there was a trend of increased HCC risk from low to intermediate and high red meat intake (OR = 1, 2.66, 3.89; p trend = 0.016), even when adjusted for family history of HCC and habitual alcohol drinking. The interaction between red meat intake and the NAT2*4 acetylator status for an increased risk of HCC was significant ( p = 0.007). Conclusions Polymorphisms of the NAT2 gene may confer different susceptibilities to the effect of red meat intake on HCC. In rapid acetylators with chronic viral hepatitis-related cirrhosis, red meat intake may play a role in hepatocarcinogenesis.

Polymorphism of the N-acetyltransferase 2 gene, red meat intake, and the susceptibility of hepatocellular carcinoma.

Carcinogenic aromatic amines, derived from cooked meat, are activated or inactivated by hepatic N-acetyltransferase (NAT). The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms with hepatocellular carcinoma (HCC), with special reference to the interaction of dietary habits. Peripheral white blood cell DNA from 185 HCC patients and 185 matched controls were genotyped for NAT2 by a polymerase chain reaction-restriction fragment length polymorphism method. All the subjects studied were chronic viral hepatitis B or C carriers with liver cirrhosis. Dietary habits of the subjects were assessed using a semiquantitative food frequency questionnaire. There was no association between the susceptibility of HCC and the overall NAT2 genotypes. However, in rapid acetylators (with two wild type NAT2*4 alleles), there was a trend of increased HCC risk from low to intermediate and high red meat intake (OR = 1, 2.66, 3.89; p(trend) = 0.016), even when adjusted for family history of HCC and habitual alcohol drinking. The interaction between red meat intake and the NAT2*4 acetylator status for an increased risk of HCC was significant (p = 0.007). Polymorphisms of the NAT2 gene may confer different susceptibilities to the effect of red meat intake on HCC. In rapid acetylators with chronic viral hepatitis-related cirrhosis, red meat intake may play a role in hepatocarcinogenesis.

Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in Chinese patients

Liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the principal enzymes responsible for the oxidation of ethanol, are polymorphic at the ADH2, ADH3 and ALDH2 loci in human beings. Our previous studies have shown that, compared with nonalcoholic individuals, Chinese alcoholic patients without liver disease had significantly lower frequencies of the ADH2*2 and ADH3*1 alleles, which encode high maximum velocity β2- and γ1-ADH subunits, respectively, as well as a lower frequency of the ALDH2*2 allele, which encodes an enzymatically inactive subunit. The data strongly suggest that genetic variation in both ADH and ALDH may influence drinking behavior and the risk of alcoholism developing through acetaldehyde formation. To further investigate the possible role of acetaldehyde in the pathogenesis of alcoholic liver disease, we determined the ADH and ALDH genotype frequencies in patients with alcohol-related cirrhosis (n = 27), viral hepatitis-related cirrhosis (n = 29) and gastric and duodenal ulcer without relevance to alcohol (n = 30). We developed a new restriction fragment length polymorphism method to genotype the mutant and normal ALDH2 alleles by using polymerase chain reaction–directed mutagenesis, which proved to be simpler and faster than the conventional detection methods that use hybridization with allele-specific oligonucleotide probes. We found that the frequencies of the alleles ADH2*2 (57), ADH3*1 (78) and ALDH2*2 (9) in the alcoholic cirrhotic patients were significantly lower than those in the healthy controls and in the patients with cirrhosis from viral hepatitis and with gastric and duodenal ulcer. No significant differences in the allele frequencies of these three genes between the alcoholic cirrhotic patients and the alcohol-dependent subjects without severe liver injury were found, although the alcoholic cirrhosis group tended to have a higher incidence of ALDH2*1/*2 heterozygotes (5 of 27) than did the alcohol-dependent group (6 of 50). The results confirm previous studies that the ADH2*2, ADH3*1 and ALDH2*2 genes can affect predisposition to alcoholism in Chinese patients and suggest that the mutant ALDH2*2 gene may influence susceptibility to alcoholic cirrhosis. (Hepatology 1994;19:360–366).