Effect of chronic alcohol consumption on the development and progression of non-alcoholic fatty liver disease (NAFLD)

A number of epidemiologic studies show a protective effect of light to moderate daily alcohol consumption on the development of non-alcoholic fatty liver disease (NAFLD). Although these small amounts of ethanol may prevent fatty liver, they may also be a risk factor for other diseases such as breast and colon cancer. Those individuals who have underlying hepatic steatosis or non-alcoholic steatohepatitis (NASH) should not use ethanol chronically since the data available at present do not support a beneficial effect of alcohol in this situation. Especially overweight and obese individuals may be more susceptible towards alcohol even at moderate doses. Animal experiments show a negative effect of ethanol on liver histology in either dietary or genetic NASH models. In addition, patients with NASH reveal a significant increased risk for hepatocellular cancer (HCC) even with social alcohol consumption. Thus, subjects with underlying NASH should abstain from alcohol at any amounts.     

Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neu^hi), but low levels of CD8⁺ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neu^hi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.     

Endoscopic Therapy with 2-Octyl-cyanoacrylate for the Treatment of Gastric Varices

Background

Gastric variceal bleeding is associated with significant morbidity and mortality and limited endoscopic therapeutic options.

Aim

The aim of this study was to evaluate the short- and long-term efficacy and safety of endoscopic therapy with 2-octyl-cyanoacrylate in patients with gastric variceal bleeding.

Methods

A single-center retrospective review of patients receiving endoscopic therapy for gastric variceal hemorrhage. Patient demographics, laboratory, and procedural data were collected. Patients were followed to death, liver transplantation, or last follow-up. Success rates were defined as immediate control of bleeding; early re-bleeding (1–7 days), short-term re-bleeding (1–12 weeks), overall survival, and serious procedure complications.

Results

A total of 41 patients (39 with cirrhosis) underwent 54 cyanoacrylate injections during study period. Mean age was 57 and 73 % were males. Twenty-four (58.5 %) patients had failed or were deemed ineligible for transjugular intra-hepatic portosystemic shunt, and 5 % were done for primary prophylaxis. Immediate hemostasis was achieved in five active bleeders. During a median survival time of 117 days, early re-bleeding was seen in 1 (2.4 %), short-term re-bleeding in five patients (12 %), and varices were eradicated in 15 (46.8 %) patients on follow-up. Mean MELD score at the time of the first injection was 17.1 ± 7.8. Mean volume injected was 3.4 cc and median number of varices injected per session was one. Eight patients died during the long-term follow-up: metastatic cancer (2), infections (3), liver failure (1), and re-bleeding (2). There were no serious procedure-related complications.

Conclusions

Endoscopic cyanoacrylate therapy appears effective and safe for treatment of patients with bleeding from gastric varices or high-risk stigmata.     

Deep vein thrombosis and pulmonary embolism in cirrhotic patients:Systematic review

Patients with liver cirrhosis were traditionally believed to be protected against development of blood clots.Lately,studies have shown that these patients may probably be at an increased risk of venous thrombotic complications.Although the hemostatic changes in the chronic liver disease patients and the factors that may predict bleeding vs thrombotic complications remains an area of active research,it is believed that the coagulation cascade is delicately balanced in these patients because of parallel reduced hepatic synthesis of pro and anticoagulant factors.Thrombotic state in cirrhotic patients is responsible for not only portal or non-portal thrombosis[deep vein thrombosis(DVT)and pulmonary embolism(PE)];it has also been associated with progression of liver fibrosis.The use of anticoagulants in cirrhosis patients is a challenging,and often a scary situation.This review summarizes the current literature on the prevalence of venous thrombosis(DVT and PE),risk factors and safety of prophylactic and therapeutic anticoagulation in patients with chronic liver disease.     

Challenges in Patient Enrollment and Retention in Clinical Studies for Alcoholic Hepatitis: Experience of the TREAT Consortium

The TREAT Consortium has carried out clinical studies on alcoholic hepatitis (AH) for over 4 years. We encountered problems with participant recruitment, retention, and eligibility for specific protocols. To improve our ability to carry out such trials, we reviewed recruitment screening logs, end of study logs, and surveyed study coordinators to learn the reasons for missing patients, why patients declined enrollment, and the number of patients eligible for treatment trials. Associations of the recruited subjects’ demographics with their adherence to follow‐up appointments were examined. Three hundred eight‐seven patients (AH and heavy drinking controls) were enrolled in the observational study, and 55 AH patients were recruited into treatment trials. About half of patients identified with AH could not be recruited; no specific reason could be determined for about two‐thirds of these. Among the patients who gave a reason for not participating, the most common reasons were feeling too sick to participate, desire to concentrate on abstinence, and lack of interest in research. Approximately a quarter of the AH patients met eligibility criteria for treatment trials for moderate or severe AH and we were able to recruit half to two‐thirds of those eligible. Approximately 35% of participants in the observational study returned for both 6‐ and 12‐month follow‐up visits. We did not identify biopsychosocial or demographic correlates of retention in the study. This analysis revealed that attempts at recruitment into trials for AH miss some subjects because of structural issues surrounding their hospital admission, and encounter a high rate of patient refusal to participate. Nonetheless, more than half of the patients who met the eligibility criteria for moderate or severe AH were entered into clinical trials. Retention rates for the observational study are relatively low. These findings need to be accounted for in clinical trial design and power analysis.     

Unexplained elevations in alanine aminotransferase in individuals with the metabolic syndrome: results from the third National Health and Nutrition Survey (NHANES III)

BACKGROUND: Unexplained elevations in alanine aminotransferase (ALT) level have been suggested to signify the presence of nonalcoholic fatty liver disease (NAFLD) in adult NHANES III participants. In this study, we examined the relationship between unexplained elevations in ALT level and the metabolic syndrome and the relationship between unexplained elevations in ALT level and microalbuminuria. METHODS: We examined the prevalence and predictors of unexplained elevations in ALT level in 4376 adult NHANES III participants with the metabolic syndrome. Metabolic syndrome was defined according to Adult Treatment Panel III criteria, and the presence of unexplained elevations in ALT level was defined based on the previously published criteria. Prevalence of microalbuminuria was compared between 710 individuals with unexplained elevations in ALT level and 1780 control subjects. RESULTS: Prevalence of unexplained elevations in ALT level in individuals with the metabolic syndrome was 7% and was significantly higher than in those without the metabolic syndrome (3.5%; OR, 2.07; 95% CI, 1.78-2.41). Younger age, male gender, higher triglycerides or serum iron levels, low levels of certain antioxidants, and insulin resistance (or diabetes) were independently associated with unexplained elevations in ALT level in the metabolic syndrome. Prevalence of microalbuminuria was not different between individuals with unexplained elevations in ALT level and their control subjects (4.8% versus 6.2%, respectively; P = 0.2). CONCLUSIONS: Individuals with the metabolic syndrome have a significantly higher prevalence of unexplained elevations in ALT level. Because unexplained elevations in ALT level may signify the presence of NAFLD, our data support the notion that NAFLD is part of the spectrum of the metabolic syndrome. However, no relationship was demonstrated between unexplained elevations in ALT level and microalbuminuria.     

Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States?

BACKGROUND AND AIM: The epidemiology of acute drug-induced liver injury (DILI) in the United States has not been well studied. We conducted a study of adults with new-onset jaundice at a nonreferral community hospital to better understand the epidemiology of acute DILI. METHODS: This is a retrospective study of adult outpatients and inpatients (> or =18 yr) with new-onset jaundice over a 5-yr period (1999-2003) at Wishard Memorial Hospital, Indiana. Patients with new-onset jaundice were identified using our electronic medical record system and individual medical records were reviewed to extract the required clinical data. New-onset jaundice was defined as the presence of total serum bilirubin >3 mg/dL in patients without a prior total bilirubin >3 mg/dL. RESULTS: A total of 732 eligible adults constituted our study cohort. Sepsis or altered hemodynamic state resulting in presumed ischemic liver injury is the single most common cause of jaundice (22%). Acute liver disease as a result of nonalcoholic etiologies caused new-onset jaundice in 97 patients (13%), with acute viral hepatitis in 66 patients (9%) and DILI in 29 patients (4%). Most cases of DILI were as a result of acetaminophen toxicity with idiosyncratic DILI occurring in only five patients (0.7%). No mortality was observed at 6 wk in patients who developed idiosyncratic DILI. CONCLUSION: Idiosyncratic DILI appears to be a rare cause of new-onset jaundice in a community hospital setting.