Influence of COVID-19 on Patients with Esophageal Varices under Prophylactic Endoscopic Band Ligation Therapy.

Background and Objectives: Endoscopic band ligation (EBL) plays a critical role in patients with clinically significant portal hypertension, as variceal eradication (VE) is essential to prevent further variceal upper gastrointestinal bleeding (GI). The emergence of COVID-19 has led to a dramatic reduction in endoscopic activity. Our study aimed to evaluate the effect of COVID-19 on VE, GI, and 6-month mortality of patients treated with prophylactic EBL therapy. In addition, our goal was to identify the risk factors for our proposed outcomes. Methods: A single-center retrospective cohort study included patients with esophageal varices treated with prophylactic EBL therapy between 2017 and 2021. To demonstrate the impact of COVID-19 on two independent groups on prophylactic EBL therapy with 1 year of follow-up, March 2019 was selected as the cut-off date. Clinical, laboratory, and endoscopic data were recovered from electronic reports. Results: Ninety-seven patients underwent 398 prophylactic EBL sessions, 75 men (77.3%) with mean age 59 ± 12 years. Most achieved VE (60.8%), 14.4% had GI bleeding post-therapy, and 15.5% died at 6 months. The rate of variceal obliteration was significantly lower in the pandemic group (40.9% vs. 77.4% in the pre-pandemic group, p = 0.001). Mean number of EBL sessions and pandemic group were independently associated with incomplete VE, while MELD-Na, portal vein thrombosis and failed VE were identified as risk factors associated with mortality at 6 months. Conclusions: Almost 60% of patients in the pandemic group failed to eradicate esophageal varices. Failure to achieve this result conferred a higher risk of GI bleeding and death at 6 months, the latter also significantly associated with the MELD-Na score and portal vein thrombosis. Our study is among the first to demonstrate the impact of COVID-19 in patients receiving prophylactic EBL therapy.

Introdução e objetivos: A laqueação elástica endoscópica (LEE) é crucial nos doentes com hipertensão portal clinicamente significativa, uma vez que permite a erradicação das varizes esofágicas (EVE) que, por sua vez, previne a hemorragia digestiva varicosa. Com o início da pandemia COVID-19, a atividade endoscópica foi drasticamente reduzida. Com este estudo pretendemos avaliar a influência da COVID-19 na EVE, hemorragia gastrointestinal (GI) e mortalidade aos 6 meses dos doentes sob LEE profilática, assim como identificar os seus fatores de risco. Métodos: Estudo de coorte monocêntrico e retrospetivo que incluiu doentes com varizes esofágicas sob LEE profilática entre 2017 e 2021. Para demonstrar o impacto da pandemia COVID-19 em dois grupos independentes sob LEE profilática durante um ano de follow-up, a escolha da data-limite foi Março de 2019. Os dados clínicos, laboratoriais e endoscópicos foram obtidos a partir dos relatórios eletrónicos. Resultados: Noventa e sete doentes cumpriram 398 sessões de LEE, 75 homens (77,3%), com idade média de 59 ± 12 anos. A maioria dos doentes obteve EVE (60,8%), 14,4% desenvolveu hemorragia GI e 15,5% faleceu nos primeiros 6 meses pós-terapêutica. A taxa de EVE foi significativamente inferior no grupo pandémico (40,9% vs. 77,4% no grupo pré-pandémico, p = 0.001). O número médio de sessões de LEE e o grupo pandémico foram independentemente associados à EVE incompleta; enquanto MELD-NA, trombose da veia porta e falha na EVE foram identificados como fatores de risco associados à mortalidade aos 6 meses. Conclusão: Cerca de 60% dos doentes no grupo pandémico não conseguiu erradicar as varizes esofágicas. A EVE incompleta aumenta o risco de hemorragia GI e mortalidade aos 6 meses, esta última também associada de forma significativa ao score MELD-Na e TVP. O nosso estudo foi pioneiro na demonstração do impacto da pandemia COVID-19 nos doentes sob LEE profilática.

Cirrhosis is associated with lower serological responses to COVID-19 vaccines in patients with chronic liver disease.

Background & Aims: The response of patients with chronic liver disease (CLD) to COVID-19 vaccines remains unclear. Our aim was to assess the humoral immune response and efficacy of two-dose COVID-19 vaccines among patients with CLD of different aetiologies and disease stages. Methods: A total of 357 patients were recruited in clinical centres from six European countries, and 132 healthy volunteers served as controls. Serum IgG (nM), IgM (nM), and neutralising antibodies (%) against the Wuhan-Hu-1, B.1.617, and B.1.1.529 SARS-CoV-2 spike proteins were determined before vaccination (T0) and 14 days (T2) and 6 months (T3) after the second-dose vaccination. Patients fulfilling inclusion criteria at T2 (n = 212) were stratified into 'low' or 'high' responders according to IgG levels. Infection rates and severity were collected throughout the study. Results: Wuhan-Hu-1 IgG, IgM, and neutralisation levels significantly increased from T0 to T2 in patients vaccinated with BNT162b2 (70.3%), mRNA-1273 (18.9%), or ChAdOx1 (10.8%). In multivariate analysis, age, cirrhosis, and type of vaccine (ChAdOx1 > BNT162b2 > mRNA-1273) predicted 'low' humoral response, whereas viral hepatitis and antiviral therapy predicted 'high' humoral response. Compared with Wuhan-Hu-1, B.1.617 and, further, B.1.1.529 IgG levels were significantly lower at both T2 and T3. Compared with healthy individuals, patients with CLD presented with lower B.1.1.529 IgGs at T2 with no additional key differences. No major clinical or immune IgG parameters associated with SARS-CoV-2 infection rates or vaccine efficacy. Conclusions: Patients with CLD and cirrhosis exhibit lower immune responses to COVID-19 vaccination, irrespective of disease aetiology. The type of vaccine leads to different antibody responses that appear not to associate with distinct efficacy, although this needs validation in larger cohorts with a more balanced representation of all vaccines. Impact and Implications: In patients with CLD vaccinated with two-dose vaccines, age, cirrhosis, and type of vaccine (Vaxzevria > Pfizer BioNTech > Moderna) predict a 'lower' humoral response, whereas viral hepatitis aetiology and prior antiviral therapy predict a 'higher' humoral response. This differential response appears not to associate with SARS-CoV-2 infection incidence or vaccine efficacy. However, compared with Wuhan-Hu-1, humoral immunity was lower for the Delta and Omicron variants, and all decreased after 6 months. As such, patients with CLD, particularly those older and with cirrhosis, should be prioritised for receiving booster doses and/or recently approved adapted vaccines.

Refractory benign esophageal strictures - Cut or dilate?

A 67-year-old male patient with long term gastroesophageal reflux disease (GERD) on double dose proton pump inhibitors, presented with dysphagia for soft foods. He underwent upper gastrointestinal (UGI) endoscopy which revealed a severe regular stricture at the level of the esophagogastric junction with a residual luminal orifice measuring 2 mm. Biopsies at the site of the stricture ruled out malignancy and were suggestive of peptic etiology. The patient underwent twelve endoscopic dilatation sessions, 11 of them with Savary-Guillard bougies and 1 with TTS balloon, up to a maximal diameter of 18 mm, with only partial relief of dysphagia symptoms. Due to the persistence of the stricture and dysphagia symptoms, incisional therapy was performed in two endoscopic sessions at the site of the stricture was performed with a Mori´s knife parallel to the longitudinal axis of the esophagus in a radial manner in all of the quadrants. There were no adverse events. On follow-up, 2 months later after the last session, the patient had a significant improvement and did not have any dysphagia symptoms. UGI endoscopy revealed minimal residual narrowing at the site of the previous stricture in the distal esophagus. He remains asymptomatic after 6 months follow-up.

Severe acute autoimmune hepatitis: How to early predict who will not respond to corticosteroids and needs urgent liver transplantation?

BACKROUND: In acute severe autoimmune hepatitis (AS-AIH), the early identification of predictors of non-response to corticosteroids and the optimal timing for liver transplantation (LT) remains controversial. AIMS: To determine early predictors of non-response to corticosteroids and to assess the usefulness of severity scores, namely the recently developed SURFASA. METHODS: Retrospective multicentre cohort study including consecutive patients admitted for AS-AIH between 2016 and 2020. Definitions- response to corticosteroids: LT-free survival at 90 days (D90); SURFASA score: -6.8 + 1.92x(D0-INR)+1.94xINR[(D3-D0)/D0]+1.64xbilirubin[(D3-D0)/D0]. RESULTS: We included 26 patients [median age 56 (45-69) years; 22 (84.6%) women]. All patients underwent corticosteroid therapy. Overall survival reached 73%. amongst the non-responders, 2 (7.8%) underwent LT and 5 (19.2%) died. The interval between admission and initiation of corticosteroids was not different between responders and non- responders [13 (7-23) vs. 8 (3-10), P:0.06], respectively. SURFASA and MELD-Na+ (D3) scores showed an AUROC of 0.96 (0.87-1) and 0.92 (0.82-0.99), respectively, for prediction of non-response. SURFASA >-2.5 had a sensitivity of 85.7% and a specificity of 100% and MELD-Na+ (D3) >26 had sensitivity of 85.7% and a specificity of 78% for the prediction of non-response. CONCLUSIONS: SURFASA and MELD-Na+ at D3 scores are useful in early identification of non-responders to corticosteroids.

Predictive factors for long-term survival in patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND AND AIMS: Sorafenib, used for advanced-stage hepatocellular carcinoma (HCC), has an overall survival (OS) of 10 months. However, some patients have better response and long-term survival (LTS). Aims to assess predictive factors for LTS. METHODS: Retrospectively reviewed 77 advanced HCC patients, starting sorafenib treatment between 2007 and 2016, with LTS (OS ≥24 months) as primary endpoint. Univariate and multivariable analysis of clinical variables were performed in order to identify predictive factors for LTS. RESULTS: Patients: seventy (90.9%) males; median age: 65 years (39-82). All had cirrhosis mostly HCV infection (n = 32, 41.6%). Majority were Child-Pugh class A (n = 50, 64.9%); median MELD-Na: 11 (6-30). Multinodular HCC: 74% (n = 57); portal vein invasion (PVI): 50.6% (n = 39); extrahepatic spread: 18.2% (n = 14). Median time between HCC diagnosis and sorafenib start: 3.3 months (0-37.6). Median OS: 13 months [95% confidence interval (CI) 8.2-17.8]. Twenty-five (32.5%) patients were considered LTS, with amedian OS: 52.3 months (95% CI 17.1-87.4). Multivariable analysis identified Child-Pugh class A [odds ratio (OR) 11.1, 95% CI 1.78-69.54] and absence of PVI (OR 7.88, 95% CI 1.56-39.8) as independent predictors of LTS. Sub-analysis of Child-Pugh class A: absence of PVI (OR 7.13, 95% CI 1.69-30.2) and alpha-fetoprotein <400 ng/ml (OR 5.82, 95% CI 1.18-28.75) independently related to LTS. CONCLUSION: Despite global short median OS, sorafenib treatment is associated with longer than 2-year survival in a sub-group, more likely in compensated liver disease and absence of PVI.

Lateral Spreading Tumor Arising in an Interposed Colonic Segment.

A 57-year-old woman developed dysphagia 30 years after esophagectomy with partial gastrectomy and colonic interposition due to severe and extensive caustic esophageal stricture. Upper gastrointestinal endoscopy showed a lateral spreading tumor in the colonic tube with a granular surface measuring 40 mm in diameter. The lesion was removed by piecemeal endoscopic mucosal resection. Histology revealed tubular adenoma with low/high-grade dysplasia. Although colonic interposition replacement is a relatively common procedure, especially in the past, the development of adenoma or adenocarcinoma as a late complication is very rare.

Impact of Futsal and Swimming Participation on Bone Health in Young Athletes.

Physical activity plays a crucial role in bone mass acquisition during childhood and adolescence, with weightbearing and high-impact sport activities being more beneficial. This study sought to evaluate the impact of different sports activities on bone mineral density and content in male Portuguese athletes. Seventy adolescent boys (aged 12-15 years) including 28 futsal players (FG), 20 swimmers (SG) and 22 non-athletic adolescents used as control subjects (CG), participated in the current study. Areal bone mineral density (aBMD) and areal bone mineral content (aBMC) were measured by dual energy x-ray absorptiometry (DEXA). Futsal players had significantly higher aBMD (lumbar spine - FG: 0.95 ± 0.18, SG: 0.80 ± 0.13, CG: 0.79 ± 0.13 g/cm2, p = 0.001; pelvis - FG: 1.17 ± 0.21, SG: 0.91 ± 0.12, CG: 0.98 ± 0.10 g/cm2, p < 0.001; lower limbs - FG: 1.21 ± 0.19, SG: 0.97 ± 0.10, CG: 0.99 ± 0.09 g/cm2, p < 0.001) and aBMC (lumbar spine - FG: 51.07 ± 16.53, SG: 40.19 ± 12.47, CG: 40.50 ± 10.53 g, p = 0.013; pelvis - FG: 299.5 ± 110.61, SG: 170.02 ± 55.82, CG: 183.11 ± 46.78 g, p < 0.001; lower limbs - FG: 427.21 ± 117.11, SG: 300.13 ± 76.42, CG: 312.26 ± 61.86 g/cm2, p < 0.001) than swimmers and control subjects. Data suggest that futsal, as a weightbearing and high or odd-impact sport, may improve bone mass during childhood and adolescence.

[Natural history and clinical manifestations of chronic hepatitis B virus]. / Historia natural y manifestaciones clínicas de la hepatitis B crónica.

Hepatitis B virus (HBV) infection is a serious public health problem worldwide. In the last few decades, major advances have been achieved that have contributed to greater understanding of the natural history and clinical manifestations of this infection. The fluctuation between viral replication and the host's immune response has implications in the pathogenesis and progression of the hepatic lesion. In immunocompetent adults, most HBV infections resolve spontaneously in contrast with progression to chronic infection in most infants. Patients with chronic hepatitis due to HBV or chronic hepatitis B can present at four phases: 1) the immune tolerance phase, 2) HBeAg-positive chronic hepatitis B, 3) inactive HBsAg carrier state, and 4) HBeAg-negative chronic hepatitis. HBeAg-positive or -negative chronic hepatitis can progress to cirrhosis, liver failure and hepatocellular carcinoma. Progression to these complications is more frequent in HBeAg-negative forms, associated with mutations that affect the pre-core region and maintain active viral replication. Risk factors are HBV-DNA positive serum levels, an increase in serum transaminase levels and some genotypes. These factors highlight the need to evaluate and monitor all HBV carriers to identify those who could benefit from early antiviral treatment, thus avoiding progression to more advanced forms of liver disease. These measures could improve prevention and treatment of hepatitis B.

Generalized peripheral lymphadenopathy in a patient treated for chronic HCV infection.

BACKGROUND: A 62-year-old white woman was admitted to hospital with a 2-month history of progressive, painless, left supraclavicular and axillary lymph node enlargement. The patient's history was significant for chronic HCV infection, for which she had just completed a 48-week course of treatment with pegylated interferon alpha (180 microg once weekly) plus ribavirin (1,000 mg daily). She attained an end-of-treatment response and subsequent qualitative measurement of HCV RNA confirmed a sustained virological response. The onset of progressive painless lymph node enlargement had been noted by the patient during the last 2 weeks of her treatment for HCV. INVESTIGATIONS: Physical examination, otorhinolaryngological examination, laboratory investigations (including complete blood counts, liver function tests and serological tests), mammography, thyroid and abdominal ultrasound, CT scans, abdominal MRI, upper gastrointestinal endoscopy, colonoscopy, supraclavicular lymph node biopsy, (67)Ga scintigraphy and bronchoalveolar lavage. DIAGNOSIS: Granulomatous lymphadenitis of uncertain etiology with sarcoid-type and tuberculoid-type granulomas. MANAGEMENT: Standard antituberculosis treatment with isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months, followed by isoniazid and rifampicin for 7 months.

Bile acid levels are increased in the liver of patients with steatohepatitis.

BACKGROUND/AIMS: The pathogenesis of steatohepatitis remains largely unknown; however, bile acids may play a role as potential mediators of liver damage. The aim of this study was to characterize bile acid profiles in liver tissue of patients with steatohepatitis. METHODS: Bile acid composition was determined by gas-liquid chromatography in liver tissue from patients with nonalcoholic steatohepatitis (NASH; n=15), patients with alcoholic steatohepatitis (ASH; n=14), and controls (n=8). Liver biopsies were graded for steatosis, inflammation, and fibrosis. RESULTS: Bile acids were moderately increased in liver tissue of steatohepatitis patients compared with controls (P<0.05). Deoxycholic, chenodeoxycholic, and cholic acids were elevated by 92, 64, and 43%, respectively, in patients with steatohepatitis (P<0.05). Cholic acid was the prevailing bile acid in NASH patients and in controls. More hydrophobic bile acid species were elevated in ASH patients compared with controls (P<0.05). Significant correlations were found in NASH patients between hepatic chenodeoxycholic acid and fibrosis, and between cholic acid and trihydroxy/dihydroxy bile acids and inflammation (P<0.05). In patients with ASH, cholic acid and trihydroxy/dihydroxy bile acids were correlated with steatosis (P<0.01). CONCLUSION: This study shows a distinct pattern of bile acids in the liver of patients with steatohepatitis. Further, the association between bile acids and histological liver injury suggests an association of specific bile acids and disease progression, possibly through bile acid-induced liver injury.

Elevated nitric oxide and 3',5' cyclic guanosine monophosphate levels in patients with alcoholic cirrhosis.

AIM: To evaluate whether serum levels of nitric oxide (NO*) and plasma levels of cyclic guanosine monophosphate (cGMP) and total glutathione (GSH) are altered in patients with alcoholic cirrhosis and to examine their correlation with the severity of liver disease. METHODS: Twenty-six patients with alcoholic liver cirrhosis were studied. Serum levels of NO* and plasma levels of cGMP and GSH were measured in 7 patients with compensated alcoholic cirrhosis (Child-Pugh A) and 19 patients with advanced cirrhosis (Child-Pugh B and C). The model for end-stage liver disease (MELD) score was evaluated. Sixteen healthy volunteers served as controls. Liver enzymes and creatinine levels were also tested. RESULTS: NO* and cGMP levels were higher in patients with Child-Pugh B and C cirrhosis than in Child-Pugh A cirrhosis or controls (NO*: 21.70 +/- 8.07 vs 11.70 +/- 2.74; 21.70 +/- 8.07 vs 7.26 +/- 2.47 micromol/L, respectively; P < 0.001) and (cGMP: 20.12 +/- 6.62 vs 10.14 +/- 2.78; 20.12 +/- 6.62 vs 4.95 +/- 1.21 pmol/L, respectively; P < 0.001). Total glutathione levels were lower in patients with Child-Pugh B and C cirrhosis than in patients with Child-Pugh A cirrhosis or controls (16.04 +/- 6.06 vs 23.01 +/- 4.38 or 16.04 +/- 6.06 vs 66.57 +/- 26.23 micromol/L, respectively; P < 0.001). There was a significant correlation between NO* and cGMP levels in all patients with alcoholic cirrhosis. A significant negative correlation between reduced glutathione/glutathione disulfide and the MELD score was found in all cirrhotic patients. CONCLUSION: Our results suggest a role for oxidative stress in alcoholic liver cirrhosis, which is more significant in decompensated patients with higher levels of NO* and cGMP and lower GSH levels than in compensated and control patients. Altered mediator levels in decompensated patients may influence the hemodynamic changes in and progression of liver disease.

Clastogenic factors in the plasma of patients with hepatitis C: their possible role at the origin of hepatocarcinoma.

Clastogenic factors (CF) are endogenous clastogens composed of lipid peroxidation products, cytokines, and abnormal nucleotides of inosine. They are regularly observed after radiation exposure and in chronic inflammatory diseases, where they are supposed to be risk factors for carcinogenesis. In the present study, we evaluate clastogenic activity in the plasma of patients with chronic hepatitis C, HCV-positive liver cirrhosis, and hepatocarcinoma in comparison to liver metastasis. Plasma ultrafiltrates from patients were added to blood cultures of healthy donors (CF test). The chromosomal aberration rates observed in 100 metaphases after 48 hours of cultivation were expressed as adjusted clastogenic scores (ACS). The differences in ACS between the four patient groups and controls were highly significant and represented a 10-fold increase in chromatid-type aberrations. The ACS of patients with cirrhosis and hepatocarcinoma were higher than those of hepatitis patients without these complications, but the differences did not reach statistical significance. Because of cytotoxic effects, the cultures did not grow for 10/17 patients with hepatocarcinoma and were repeated with a reduced volume of ultrafiltrate (0.1 instead of 0.25 mL). The ACS were highest in these 10 patients. When the CF activity of HCV-positive hepatocarcinoma was compared to metastasis because of other malignancies, the differences in ACS were highly significant for the cultures set up with the reduced quantity of ultrafiltrate. The percentage of CF-positive samples was 100% for hepatocarcinoma and 9% for metastasis. The results show that the chromosome-damaging effects of CF increase as the disease progresses to cirrhosis and liver cancer. Formed via the intermediacy of superoxide and generating more superoxide, CF are responsible for an autosustained, long-lived DNA-damaging process, which is documented at the chromosomal level by our technique.

Rising costs and hospital admissions for hepatocellular carcinoma in Portugal (1993-2005).

AIM: To determine, for hepatocellular carcinoma (HCC), the patient demographic profile and costs of their admissions to the hospitals of the Portuguese National Health System from 1993 to 2005. METHODS: The National Registry (ICD-9CM, Inter-national Classification of Diseases, 155.0) provided data from the 97 Hospitals in Portugal. RESULTS: We studied 7932 admissions that progressively rose from 292 in 1993 to 834 in 2005, having a male predominance of 78% (6130/7932). The global rate of hospital admissions for HCC rose from 3.1/10(5) in 1993 to 8.3/10(5) in 2005. The average length of stay decreased from 17.5 +/- 17.9 d in 1993 to 9.3 +/- 10.4 d in 2005, P < 0.001. The average hospital mortality for HCC remained high over these years, 22.3% in 1993 and 26.7% in 2005. Nationally, hospital costs (in Euros - EUR) rose in all variables studied: overall costs from 533,000 Euros in 1993, to 462,9000 Euros in 2005, cost per day of stay from 105 Euros in 1993, to 597 Euros in 2005, average cost of each admission from 1828 Euros in 1993, to 5550 Euros in 2005. In 2005, 1.8% (15/834) of hospital admissions for HCC were related to liver transplant, and responsible for a cost of about 1.5 million Euros, corresponding to one third of the overall costs for HCC admissions in that same year. CONCLUSION: From 1993 to 2005 hospital admissions in Portugal for HCC tripled. Overall costs for these admissions increased 9 times, with all variables related to cost analysis rising accordingly. Liver transplant, indicated in a small group of patients, showed a disproportionate increase in costs.

A ten-year prospective study on gallbladder stone recurrence after successful extracorporeal shock-wave lithotripsy.

OBJECTIVE: The risk of recurrence has limited the acceptability of conservative therapies of gallbladder stones. The aim of the present study was to determine the long-term rate of stone recurrence and its risk factors after successful extracorporeal shock-wave lithotripsy (ESWL). MATERIAL AND METHODS: The study comprised a prospective ultrasound follow-up at yearly intervals or whenever biliary pain was reported. A total of 192 consecutive patients (primary single stones, n=159; primary 2 or 3 stones, n=33) were followed for up to 11.2 years after becoming stone-free and after termination of adjuvant treatment with ursodeoxycholic acid (UDCA). RESULTS: Eighty-four patients developed recurrent stones after a median of 2.6 years (maximum?=?8.8 years). The 108 patients without recurrence were followed for a median of 6.7 years (maximum=11.2 years). By actuarial analysis, the cumulative recurrence rates for these 192 stone-free patients were 27%+/-3%, 41%+/-4% and 54%+/-4% (observed +/-SE) at 3, 5 and 10 years, respectively. Cox's regression analysis was used to identify the presence of slight calcification in the primary stone(s) as a protective feature against recurrence (p=0.03). CONCLUSIONS: 1) The risk of recurrence continues to increase over time, and although it rises less steeply after 5 years, it does not reach a plateau until at least 10 years. 2) Having had slightly calcified stone(s) seems to be associated with a reduced risk of recurrence and might signal a "burnt out" lithogenic process. 3) The long-term results are unsatisfactory and ESWL of gallbladder stones should be offered only in special cases.

Apoptosis and Bcl-2 expression in the livers of patients with steatohepatitis.

OBJECTIVES: Apoptosis may play a role in the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). In this study, we investigated the modulation of apoptosis-related liver proteins in steatohepatitis. METHODS: Hepatocyte apoptosis was evaluated by the TUNEL assay in liver tissue of 12 patients with NASH, 12 with ASH and in histologically normal controls. In addition, caspase-3 processing was evaluated by immunoblot analysis. Expression of death receptors, Bcl-2 family members, and NF-kappaB inhibitor (IkappaB) were determined by western blot. Liver biopsies were also graded for inflammation and fibrosis. RESULTS: Apoptotic hepatocytes were markedly increased in NASH (P<0.05) and ASH (P<0.001) as compared to controls. Active caspase-3 was also elevated in steatohepatitis (P<0.01), coinciding with upregulation of pro-apoptotic Bax (P<0.001). Further, production of tumour necrosis factor-receptor 1 was increased up to 4-fold (P<0.05). Degradation of IkappaB increased >70% in steatohepatitis (P<0.001). Notably, Bcl-2 was also strongly expressed (>100-fold; P<0.001). These data were significantly correlated with relative degrees of portal and lobular inflammation. CONCLUSION: The results show that liver injury in NASH and ASH is associated with apoptosis and NF-kappaB activation. Anti-apoptotic Bcl-2 is strongly expressed, probably reflecting an adaptive response to obesity or alcohol-related stress.

Are genetic polymorphisms of tumour necrosis factor alpha, interleukin-10, CD14 endotoxin receptor or manganese superoxide dismutase associated with alcoholic liver disease?

BACKGROUND: Four polymorphisms have been described associated with either increased risk for alcoholic liver disease (ALD) or more serious histological lesions: tumour necrosis factor alpha (TNF-alpha) G(-238)A, interleukin-10 (IL-10) C(-627)A, promoter of CD14 endotoxin receptor gene C(-159)T and manganese superoxide dismutase (MnSOD) C(-1183)T/valine --> alanine. METHODS: We sought confirmatory evidence, through individual and simultaneous analysis of the four aforementioned polymorphisms, in 176 heavy drinkers: ALD (n = 100) if histology-compatible or clinical evidence of hepatic decompensation; and no evidence of liver disease (NLD) (n = 76) if normal liver tests on two occasions or normal liver histology (steatosis alone). RESULTS: Patients with ALD were older (53+/-10 vs. 48+/-10 years, P<0.05), with a similar sex distribution. TNF-alpha G(-238)A showed no difference in heterozygous GA-genotype prevalence (ALD, 9.0%/NLD, 7.9%). IL-10 C(-627)A showed no difference between groups, either homozygote AA (8.0% vs. 10.5%) or heterozygote CA (34.0% vs. 39.5%). CD14 promoter C(-159)T showed no difference between groups in T-allele frequency, either homozygote TT (27% vs. 21%) or heterozygote CT (49% vs. 50%). Alanine MnSOD allele carriers showed no difference between groups in either the heterozygote (55.0% vs. 49.3%) or homozygote (22% vs. 25%). No difference was observed in the probability of having simultaneously two, three or four of the implicated polymorphisms: respectively, 43%, 33% and 0% in ALD, and 43%, 24% and 5% in NLD (not significant). CONCLUSIONS: No association was found between the previously implicated polymorphisms of TNF-alpha, IL-10, CD14 and MnSOD, either individually or simultaneously, and the presence of established ALD.

Oxidative stress in chronic hepatitis C: a preliminary study on the protective effects of antioxidant flavonoids.

BACKGROUND/AIMS: Oxidative stress is involved in chronic hepatitis C, and efforts have been made to influence the disease process with antioxidants. The present study evaluates the protective effects of a phenol-rich processed grain food with superoxide-scavenging properties (trade name antioxidant biofactor AOB). METHODOLOGY: Thirty patients participated in this placebo-controlled double-blind pilot study. AOB was taken orally by fifteen patients for 3 mo at the recommended daily dose of 3x2 sachets, containing 3 g of powder each. Another fifteen patients received a herbal extract with practically no superoxide scavenging properties as a placebo. Oxidative stress biomarkers, aminotransferase levels and viral load were evaluated immediately before and after treatment. RESULTS: AOB treatment considerably improved the antioxidant defenses. Also ALT and AST decreased in 11 of the 15 patients (-11% to -65%, mean -22%, p<0.05). The effects of placebo were not significant. Viral load remained unchanged. Control biopsies were not done after the short interval of 3 mo. There were no adverse effects. After the 3-mo treatment with AOB or placebo, 16 of the 30 patients received conventional antiviral treatment (pegylated interferon alpha and ribavirin). A sustained response was observed in 5 of 9 AOB pretreated patients six mo after discontinuation of the 12-mo antiviral therapy. The 7 patients pretreated with placebo were all non-responders. CONCLUSIONS: These preliminary results are encouraging to conduct more extensive clinical studies combining antioxidant with antiviral treatment in hepatitis C.

Factors associated with the development of cirrhosis in patients with HCV chronic infection.

BACKGROUND/AIMS: The natural history of chronic hepatitis C virus (HCV) infection still has some details to be established, namely in what concerns progression to hepatic cirrhosis (HC). The study aims to define predictive factors for progression to HC in patients with HCV chronic infection. METHODOLOGY: A cross-sectional study was performed on 129 patients consecutively submitted to liver biopsy. Thirty-six percent (n=46) had HC at histological evaluation. RESULTS: Patients with HC did not show statistically significant differences on gender, viruses genotypes, alcohol consumption or proportion of positivity to markers of previous hepatitis B virus (HBV) infection - anti-HBc/anti-HBs+. Patients with HC seem to have had their infection sporadically (50%) or post-transfusion (35%) -p=0.052, and iv drugs addiction was related to non-HC patients (39%) -p=0.006. Age at infection, time of infection and positivity for anti-HBc/anti-HBs were factors independently related to HC (multivariate analysis). Patients older than 40 years by the time of infection [OR=4.5 (95% CI=1.9-10.8], those with less than 5 years of time of infection [OR=4.2 (95% CI=1.6-10.8)], and patients with previous HBV infection [OR=2.51 (1.00-6.69)] are at higher risk for HC. CONCLUSIONS: We argue that older patients, with a shorter time interval between HCV infection and diagnosis, and namely those with markers for previous HBV infection represent patients with higher risk for progression to hepatic cirrhosis.