Chronic Alcohol-related Liver Disease Research Articles

A Comparative Analysis of Heart Rate Variability Indices in Patients with Liver Cirrhosis.

Cardiac autonomic dysfunction (AD) in reference to chronic liver disease (CLD) has become widely accepted as a symptomatic burden. This study will be undertaken to measure heart rate variability (HRV) indices and detect the severity of cardiac autonomic dysfunction in CLD patients. This study was conducted on 150 patients with liver cirrhosis and compared with 110 healthy controls. Information concerning medical history, radiological and laboratory findings was extracted for interpretation and association among both groups. The HRV was assessed by recording with a polygraph (RMS Polyrite D, version 1.0), which was based on the principle of electrocardiography. Heart rate variability indices like standard deviation of each interval normal-to-normal (SDNN), percentage of successive RR intervals that differ by >50 ms (pNN50%), high frequency (HF), low frequency (LF), and the LF/HF ratio were found to be remarkably low in cases with CLD in comparison to the healthy control group (p < 0.05). The Child-Pugh (CP) score was class C (10-15) in 52%, class B (7-9) in 30%, and class A (5-6) in 18% of patients. The CP score in CLD patients had a statistically significant negative correlation with SDNN (r = -0.5429, p < 0.001), root mean square of successive differences (RMSSD) (r = -0.375, p < 0.001), pNN50% (r = -0.6037, p < 0.001), HF (r = -0.2033, p = 0.0125), and LF (r = -0.3674, p < 0.001). SDNN, pNN50%, and LF parameters were lowest in alcohol-related CLD, highest in hepatitis C virus (HCV)-related CLD, and intermediate in hepatitis B virus (HBV)-related CLD. Our study concluded that liver cirrhosis patients have reduced HRV compared to healthy individuals. A decrease in HRV highlights people at risk of death. This is a variable that can be used to track patients over time and aid in transplant selection.

MUP1 mediates urolithin A alleviation of chronic alcohol-related liver disease via gut-microbiota-liver axis

ABSTRACT Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of liver cancer-associated fatalities. Dysbiosis of the gut microbiome is associated with the development of ALD, with the gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and its underlying mechanism mediated by microbiota remain elusive. In this study, we provide evidence demonstrating that UA effectively ameliorates alcohol-induced metabolic disorders and hepatic endoplasmic reticulum (ER) stress through a specific gut-microbiota-liver axis mediated by major urinary protein 1 (MUP1). Moreover, UA exhibited the potential to restore alcohol-induced dysbiosis of the intestinal microbiota by enriching the abundance of Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila), along with their derived metabolite propionic acid. Partial attenuation of the hepatoprotective effects exerted by UA was observed upon depletion of gut microbiota using antibiotics. Subsequently, a fecal microbiota transplantation (FMT) experiment was conducted to evaluate the microbiota-dependent effects of UA in ALD. FMT derived from mice treated with UA exhibited comparable efficacy to direct UA treatment, as it effectively attenuated ER stress through modulation of MUP1. It was noteworthy that strong associations were observed among the hepatic MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched B. sartorii, P. distasonis, and A. muciniphila can enhance propionic acid production to effectively suppress ER stress via MUP1, mimicking UA treatment. Collectively, these findings elucidate the causal mechanism that UA alleviated ALD through the gut-microbiota-liver axis. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.

Modulatory Effect of Dihydromyricetin on Chronic Alcoholic Liver Injury Based on the FXR-NLRP3 Signaling Pathway and Serum and Liver Metabolomics

Background In modern diets, alcohol consumption has led to an increase in the number of cases of alcohol-related liver disease (ALD). Dihydromyricetin (DMY) is commonly used as a hepatoprotective agent owing to its remarkable efficacy in treating chronic alcoholic liver injury; however, its mechanism of action is unclear. The object of the study is to investigate the effect and mechanism of DMY in alleviating chronic ALD. Methods A mouse model of chronic ALD was established. Mice were treated with DMY for 56 days, and their biochemical parameters including liver function, blood lipids, and oxidative stress-related indices were measured. Farnesoid X receptor (FXR) expression, NOD-like receptor protein 3 (NLRP3) pathway-related protein expression, and inflammation-related gene expression were determined to elucidate the mechanism of DMY in mice with ALD. Lastly, serum and liver metabolomics-based UHPLC-Orbitrap Exploris MS analyses were used to determine the influence of the metabolism of DMY on mice with ALD. Results Pharmacodynamic studies showed that DMY could decrease aspartate transaminase, alanine transaminase, triglyceride, and low-density lipoprotein cholesterol levels, improve superoxide dismutase activity, and reduce inflammation in mice with ALD. DMY treatment protects the liver by increasing FXR protein expression and by decreasing NLRP3 pathway-related protein expression and inflammatory gene expression. Metabolomics analysis indicated that ethanol treatment mainly altered metabolism in mice. DMY could regulate 10 metabolites in serum, namely, N-α-acetyllysine, 1-pyrrolinecytosine, glutamyllysine, 5-methylcytosine, N-methylvaline, pyridoxamine, demethoxycurcumin, L-arginine, triacetin, and 15-methylpalmitate. It could also regulate 31 metabolites in the liver, including L-methionine and L-leucine. DMY treatment altered the following important pathways: valine, leucine, and isoleucine biosynthesis; cysteine and methionine metabolism; and valine, leucine, and isoleucine degradation. Correlation analyses using heatmaps revealed that the metabolic parameters are closely related to the pharmacodynamic index. Conclusion These findings indicated that DMY alleviated ALD by regulating the FXR-NLRP3 signaling pathway and could treat serum and liver metabolic disorders.

Improved Applicability and Diagnostic Accuracy of the Novel Spleen-Dedicated Transient Elastography Device for High-Risk Esophageal Varices.

Spleen stiffness measurement (SSM) by transient elastography (TE) has been repeatedly demonstrated as the reliable way to rule out the presence of high-risk esophageal varices (HRV). We aimed to evaluate and compare novel vs. standard TE-SSM module performance in diagnosing HRV in patients with compensated advanced chronic liver disease (cACLD). This retrospective study included patients with cACLD; blood data, upper digestive endoscopy performed within 3 months of TE, SSM@50Hz and SSM@100Hz were collected. Overall, 112 patients with cACLD were analyzed (75.9% males, average age of 66, 43.7% alcohol-related chronic liver disease, 22.3% metabolic-associated steatotic liver disease, 6.2% viral hepatitis). Reliable SSM was possible in 80.3% and 93.8% of patients by using SSM@50Hz and SSM@100Hz probe, respectively. At the cut-off 41.8 kPa and 40.9 kPa (Youden), SSM@50Hz and SSM@100Hz had AUROCs of 0.746 and 0.752, respectively, for diagnosing HRV (p = 0.71). At the respective cut-offs, sensitivities for HRV were 92.9% and 100%, resulting in misclassification rates of 7.1% and 0% by using SSM@50Hz and SSM@100Hz. SSM reliably excludes HRV in cACLD patients, with measurements below 41 kPa potentially avoiding EGD in around 50% of cases, with minimal risk of HRV omission. SSM@100Hz demonstrated less measurement failures and no HRV misclassification.

The Role of Cytokines in the Pathogenesis and Treatment of Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a major cause of chronic liver disease. This term covers a broad spectrum of liver lesions, from simple steatosis to alcoholic hepatitis and cirrhosis. The pathogenesis of ALD is multifactorial and not fully elucidated due to complex mechanisms related to direct ethanol toxicity with subsequent hepatic and systemic inflammation. The accumulation of pro-inflammatory cytokines and the reduction of anti-inflammatory cytokines promote the development and progression of ALD. To date, there are no targeted therapies to counter the progression of chronic alcohol-related liver disease and prevent acute liver failure. Corticosteroids reduce mortality by acting on the hepatic-systemic inflammation. On the other hand, several studies analyzed the effect of inhibiting pro-inflammatory cytokines and stimulating anti-inflammatory cytokines as potential therapeutic targets in ALD. This narrative review aims to clarify the role of the main cytokines involved in the pathogenesis and treatment of ALD.

Mice lacking α4 nicotinic acetylcholine receptors are protected against alcohol-associated liver injury.

Chronic heavy alcohol consumption is a major risk factor for the development of liver steatosis, fibrosis, and cirrhosis, but the mechanisms by which alcohol causes liver damage remain incompletely elucidated. This group has reported that α4 nicotinic acetylcholine receptors (α4 nAChRs) act as sensors for alcohol in lung cells. This study tested the hypothesis that α4 nAChRs mediate the effects of alcohol in the liver. Expression of acetylcholine receptor subunits in mouse liver was determined by RNA sequencing (RNA-seq). α4 nAChR knockout (α4 KO) mice were generated in C57BL/6J mice by introducing a mutation encoding an early stop codon in exon 4 of Chrna4, the gene encoding the α4 subunit of the nAChR. The presence of the inactivating mutation was established by polymerase chain reaction and genomic sequencing, and the lack of α4 nAChR function was confirmed in primary fibroblasts isolated from the α4 KO mice. Wild-type (WT) and α4 KO mice were fed the Lieber-DeCarli diet (with 36% of calories from alcohol) or pair fed an isocaloric maltose-dextrin control diet for a 6-week period that included a ramping up phase of increasing dietary alcohol. Chrna4 was the most abundantly expressed nAChR subunit gene in mouse livers. After 6 weeks of alcohol exposure, WT mice had elevated serum transaminases and their livers showed increased fat accumulation, decreased Sirt1 protein levels, and accumulation of markers of oxidative stress and inflammation including Cyp2E1, Nos2, Sod1, Slc7a11, TNFα, and PAI1. All these responses to alcohol were either absent or significantly attenuated in α4 KO animals. Together, these observations support the conclusion that activation of α4 nAChRs by alcohol or one of its metabolites is one of the initial events promoting the accumulation of excess fat and expression of inflammatory mediators. Thus, α4 nAChRs may represent viable targets for intervention in chronic alcohol-related liver disease.

Hepatitis E virus infection in a patient with alcohol related chronic liver disease: a case report of acute-on-chronic liver failure

BackgroundThe hepatitis E virus (HEV) infection has been described as a causing factor for acute-on-chronic-liver-failure (ACLF) in patients with underlying chronic liver disease (CLD), such as chronic hepatitis or cirrhosis, which could end in the failure of one or more organs and high short-term mortality. There are scarce data about the association of HEV in patients with chronic liver disorders in South America.Case presentationA 56-year-old hypertensive male with a history of type 2 diabetes was diagnosed with alcohol-related-liver cirrhosis in February 2019. A year later, the patient was admitted to hospital due to fatigue, jaundice and acholia. No evidence of hepatitis A virus, hepatitis B virus, hepatitis C virus, Epstein–Barr virus, herpes zoster virus and cytomegalovirus infections were found. Nevertheless, in February and March, 2020 the patient was positive for HEV-IgM and HEV-IgG, and HEV genotype 3 RNA was detected in sera. Afterwards, he presented grade I hepatic encephalopathy and, therefore, was diagnosed with acute hepatitis E-on-chronic liver disease. The patient reported a recent travel to the Argentine coast, where he consumed seafood. Besides, he reveled to have consumed pork meat and had no history of blood transfusion.ConclusionThis report describes a unique case of hepatitis E virus infection in a patient with alcohol-related cirrhosis. This is the first report of a patient with HEV-related ACLF in Argentina and it invokes the importance of HEV surveillance and treatment among patients with CLD, such as alcohol-related cirrhosis.

Racial disparities in alcohol-related liver disease mortality in a 75 year follow-up study of Michigan autoworkers

BackgroundSuicide, drug overdose, and alcohol-related liver disease (ALD) mortality have been rising in the United States. While suicide and overdose have received a great deal of attention, far less public health concern has focused on chronic ALD. To address this gap, we examine ALD mortality rates, by race, in a cohort of autoworkers to describe trends over the past 75 years, from the peak in automobile manufacturing employment through its decline. MethodsBased on the United Autoworkers-General Motors (UAW-GM) cohort we estimated temporal trends in age-adjusted ALD mortality rates from 1941 through 2015 at three automobile manufacturing plants in Michigan. We compared these rates to county, state, and U.S. rates, directly standardized to the 2000 U.S. census, to assess the roles of race and employment on ALD mortality. ResultsThe overall age-adjusted ALD mortality rate among 41,097 male autoworkers peaked at 46.1 per 100,000 in the 1970s, followed by a gradual decline and a recent rise. Rates were slightly higher for black than white men until early 2000s, when rates increased only for white men. ALD mortality rates in the study cohort tracked national, state, and county rates for white men until the most recent time period, but were lower throughout the study period for black men, especially in the 1970s and 1980s. ConclusionsEmployment in automobile manufacturing may have offered some protection against death from ALD for black men, and loss of those manufacturing jobs may have impacted white men without a college degree more in recent decades.

Pattern of Alcohol Consumption in Patients of Alcoholic Liver Disease in India

Background: Alcohol-related chronic liver disease (ALD) and its complications are major causes of morbidity and mortality. Predisposing factors for ALD include the amount, type, duration of alcohol consumption, patient’s genetic predisposition, race, sex, and other comorbid conditions. Â

Redo laparoscopic segment 2/3 hepatocellular carcinoma resection in alcohol-related chronic liver disease

Purpose: Hepatocellular Carcinoma is a leading cause of death in chronic liver disease and cirrhosis. Operative treatment options include surgical resection or liver transplantation. Minimally invasive approaches reduce patient morbidity and improve recovery and return to normal activity, but can be an operative challenge in fibrotic, cirrhotic liver parenchyma. Method: 72-year-old male presented with Hepatocellular Carcinoma in segment 2/3 on a background of alcohol-related Chronic Liver Disease. Multidisciplinary decision to proceed to Laparoscopic Non-anatomical Liver resection. Histology demonstrated mixed HCC, R0 resection with microvascular invasion present. 8/12 follow updemonstrated recurrence in left lateral segments 2/3. Multidisciplinary decision to proceed to Laparoscopic redo Liver resection of segment 2/3 Results: Laparoscopic non-anatomical resection of Segment 2/3 HCC was performed. Histology demonstrated HCC, R0 resection. The patient made an uncomplicated recovery and remains disease free at 4 years. Conclusion: Laparoscopic re-do liver resection for HCC with background chronic liver disease is a feasible and safe approach in selected cases. Careful haemostasis during laparoscopic dissection in cirrhosis is key to avoid intraoperative bleeding, and minimise the risk of losing the visual field and converting to open surgery.

Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States

The profile of chronic liver disease (CLD) in the United States has changed due to obesity trends and advances in treatment of viral hepatitis. We assessed liver transplant listing trends by CLD etiology. Adult candidates for liver transplantation were selected from the Scientific Registry of Transplant Recipients (2002 through 2019). We calculated proportion trends for common CLD etiologies at time of placement on the wait list, including chronic infection with hepatitis B virus, chronic infection with hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH, including cryptogenic cirrhosis), alcohol-related liver disease (ALD) without or with chronic HCV infection, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, in patients with and without hepatocellular carcinoma (HCC). From the 168,441 patients with known etiology and non-acute liver failure on the liver transplant waitlist, 27,799 patients (16.5%) had HCC. In 2002, the most common etiologies in patients without HCC were chronic HCV infection (37%) and ALD (16%), whereas only 5% had NASH. Among patients with HCC, 58% had chronic HCV infection and 10% had ALD and only 1% had NASH. In 2019, among patients without HCC, NASH was the second leading indication for liver transplantation (28% of patients), after ALD (38% of patients). Among patients with HCC, chronic HCV infection remained the leading indication (40% of patients) but NASH (24% of patients) surpassed ALD (16% of patients) to become the second leading indication. NASH was the leading indication in women without HCC (34%), in patients older than 54 years (36%), and in patients on Medicare (41%). In trend analysis, NASH was the most rapidly increasing indication for liver transplantation in patients without HCC (Kendall tau=0.97; P < .001) and in patients with HCC (tau=0.94; P < .0001). In an analysis of data from the Scientific Registry of Transplant Recipients (2002 through 2019), we found NASH to be the second most common indication for liver transplant in 2019, and the fastest increasing indication. In 2019, NASH was the leading indication for liver transplantation among women without HCC.

Prior Relapse, Ongoing Alcohol Consumption, and Failure to Engage in Treatment Predict Alcohol Relapse After Liver Transplantation.

Alcohol-related liver disease (ALD) is the leading indication for liver transplantation (LT) in the USA. Alcohol relapse post-LT can negatively impact long-term outcomes, and prognostic scoring systems are available for further study. Our study aims were to: (1) evaluate the relationship between alcohol relapse and rejection and mortality, (2) investigate risk factors for relapse, and (3) assess predictive validity of the SIPAT (Stanford Integrated Psychosocial Assessment for Transplant) and SALT (Sustained Alcohol Use Post-Liver Transplant) scores on post-LT alcohol relapse. We conducted a retrospective chart review of 155 patients transplanted for chronic ALD at a single transplant center. Cox proportional hazard models assessed the relationship between alcohol relapse and allograft rejection and psychosocial risk factors for relapse. 20% of patients met criteria for alcohol relapse. Alcohol relapse was associated with allograft rejection (HR 2.33, 95% CI 1.11-4.91, p = .03). Three variables most strongly associated with alcohol relapse: prior relapse, failure to engage in recommended alcohol treatment, and continued drinking with liver disease, which were combined into a psychosocial model. SIPAT score≥ 21 and SALT score ≥ 7 were associated with alcohol relapse (HR 6.40, 95% CI 1.36-30.18, p = .019 and HR 2.30, 95% CI 1.12-4.75, p = .024). Receiver operator characteristic analysis compared predictive ability of our psychosocial model to SIPAT (C-statistic .83 compared to .71) and SALT (C-statistic = .77 compared to .62). We identified important psychosocial predictors of post-LT alcohol relapse and validated SIPAT and SALT scores as pre-transplant risk factors for alcohol relapse.

Evaluating Surveillance for Excessive Alcohol Use in New Mexico.

Purpose and ObjectivesPrevalence of excessive alcohol use and alcohol-attributable mortality is much higher in New Mexico than in other US states. In 2010, excessive alcohol use cost the state roughly $2.2 billion. Moreover, age-adjusted deaths from alcohol-related chronic liver disease increased 52.5% from 14.1 cases in 2010 to 21.5 cases in 2016. In 2017, the New Mexico Department of Health piloted the Recommended Council of State and Territorial Epidemiologists (CSTE) Surveillance Indicators for Substance Abuse and Mental Health, using 5 indicators to monitor alcohol use and health consequences. The purpose of this study is to evaluate the alcohol surveillance system implemented in New Mexico to ensure that the system yields useful, timely data that can help create effective public health interventions and that resources required for surveillance are adequate.Intervention ApproachCSTE alcohol surveillance system data come from existing national and state-based surveys and vital statistics.Evaluation MethodsThis evaluation assessed attributes defined in Evaluating Behavioral Health Surveillance Systems and Centers for Disease Control and Prevention guidelines for evaluating public health surveillance systems. Assessment was informed through data collection, systematic literature review searches, and an interview with the alcohol epidemiologist at New Mexico Department of Health.ResultsThe CSTE alcohol surveillance system in New Mexico is a useful, stable, and accepted system with good representativeness and population coverage. Data sharing and collaboration between centers within New Mexico Department of Health are well-established, making data access easy and timely. Lastly, the resources required for data collection are accountable and adequate.Implications for Public HealthThe CSTE alcohol surveillance system brings together information (alcohol consumption behaviors and associated morbidity, mortality, and policy-related measures) necessary to show a clear picture of the alcohol effects in New Mexico. This information yields useable, timely data from which the state can monitor trends and develop interventions to reduce the prevalence of alcohol-attributable morbidity and mortality.

Characteristics and Changes over Time of Alcohol-Related Chronic Liver Diseases in Italy.

Introduction To evaluate the characteristics of alcohol-related chronic liver disease (CLD) in Italy and their potential changes over time. Patients and Methods Subjects with CLD were enrolled in two national surveys performed in 2001 and in 2014 in Italy. The two surveys prospectively recruited patients aged ≥ 18 years referring to more than 80 Italian liver units scattered all over the country using similar clinical approach, analytical methods, and threshold of risky alcohol intake definition (≥ 3 units/day in men and ≥ 2 units/day in women). Results Out of 12,256 enrolled subjects, 2,717 (22.2%) reported a risky alcohol intake. Of them, anti-HCV positive was observed in 48.3% of subjects. The overall sex ratio (M/F) was 3.1, decreasing from 3.8 in 2001 to 1.3 in 2014. Women were significantly older than men (58.9 versus 53.1 years; p < 0.01) and an increasing ageing over time was observed in both sexes. The proportion of subjects with liver cirrhosis increased over time in both sexes, and decompensated stage (Child B or C) was detected in 55.9% of cases in 2001 and 46.0% in 2014. Conclusions Risky alcohol intake plays a role in more than one-fifth of CLD in Italy, with a shift over time towards an older age and a more severe liver disease stage. These data put alcohol back in the spotlight with an important role in CLD in the years to come in Italy.

Constipation and upper gastrointestinal bleed: Leading precipitating factors of hepatic encephalopathy in Indian cirrhotic patients

Abstract Background Liver cirrhosis and its complications pose major health problems. In India, commonest causes of cirrhosis are alcohol abuse and viral hepatitis. Hepatic encephalopathy (HE) is a life-threatening complication of cirrhosis. This study aimed to determine clinical, etiological and laboratory profile of chronic liver disease patients presenting with HE. Methods Cross-sectional study was conducted in Institute of Internal Medicine at Madras Medical College, Chennai. Seventy-five diagnosed cases of chronic liver disease presenting with hepatic encephalopathy were enrolled. Hepatic encephalopathy was clinically graded according to West Haven grading. Results Middle aged group males comprised the largest affected group (30–50 year). Alcohol abuse was most common etiological factor. Jaundice (78%) was most common presenting complaint. Most common precipitating factors were constipation (54%) and upper gastrointestinal (GI) bleeding (45%). Thrombocytopenia was present in 78% cases while 16% cases presented with coagulopathy. The mean serum AST, ALT, bilirubin, ALP and albumin level were 90 U/l, 68.4 U/l, 9.66 mg/dl, 124.2U/l and 2.9 g m/dl, respectively. Mean serum urea and creatinine level were 43.22 mg/dl and 1.39 mg/dl respectively. Conclusion In the specific study group, alcohol-related chronic liver disease was the commonest, with constipation and upper gastrointestinal bleeding being the leading precipitating factors for hepatic encephalopathy.

Acute alcoholic hepatitis.

Chronic alcohol related liver disease is characterized by a cascade of events defined as follows: steatosis, steatohepatitis/steatofibrosi, cirrhosis and hepatocellular carcinoma. On one of these histologic patterns may overlap acute alcoholic hepatitis (AAE) (mild, moderate, severe). Severe AAE can cause a severe clinical picture: jaundice with a duration of less than three months, jaundice in the first decompensation event, serum bilirubin higher than 5 mg/dL, ratio AST/ALT >2:1, AST less than 500 IU/L ALT <300 IU/L, neutrophil leukocytosis and increased GGT. In addition, it is possible the presence of encephalopathy, fever, fatigue, coagulopathy. The onset can also be characterized by portal hypertension-related complications. An extremely severe clinical condition is the superposition of an acute insult to a chronic framework, not necessarily a cirrhotic one. This condition has been termed acute on chronic (acute on chronic liver failure - ACLF:), and it is possible to have a SIRS (systemic inflammation response syndrome) with a multi-organ system involvement. The diagnosis, in selected cases, can be confirmed by a transjugular biopsy that allows to reach a histologic prognostic stratification. Several indices are used for the assessment of prognosis and in particular the MDF and the MELD. In our clinical practice we use the MELD. In case of ACLF, the consortium organ failure score (CLIF-C OFS) is used. The therapy is characterized by alcohol abstention, and, in severe forms (MDF >32 and MELD >21) with absence of contraindications, it is possible to use steroids therapy. If a positive answers cannot be obtained, an early liver transplantation is proposed. This possibility, after a careful selection, now is promoted by several authors.

Temporal Trends in the Etiology of Chronic Liver Disease in Coastal Eastern Odisha

Background and Aim: The etiology of chronic liver disease (CLD) is known to change with time due to various factors including awareness, preventive interventions as well as life style changes in society. However there is scarce Indian data available about time trends in etiology of CLD. Methods: This is a retrospective study conducted in the Department of Gastroenterology, SCB Medical College, Cuttack from January 2005 to December 2016. Hospital records of indoor patients were searched manually and relevant parameters of CLD patients were noted, especially demographic profile, etiology and clinical features. A two way ANOVA was performed among the three groups of etiology, which are Alcoholism, Viral and “others”. All data were analysed using SPSS version 21 software. Results: Total 3645 patients were studied (male 84.7%; females 15.3%). There mean age was 46.18 ± 13.39 years. The mean age for males was 46.59 ± 12.73 and for the females was 43.91 ± 16.39. Alcoholism was the most common cause of CLD in our study; the proportion of CLD due to ALD increased over the years from 38.6% in 2005 to 60.2% in 2016. Viral infection including both chronic hepatitis B and chronic hepatitis C as the etiology of chronic liver disease declined from 39.4% in 2005 to 21.1% in 2016. The time trends of the etiology of CLD are summarized in Figure 1. Following post hoc Tukey test, it was observed that the disease population increased significantly over time for alcoholic liver disease patients over those due to viral and other etiologies (P < 0.0001). Conclusions: Alcohol is the most common cause of chronic liver disease and the burden of alcohol related chronic liver disease is significantly increasing in comparison to other causes including viral infection, NASH and autoimmune hepatitis. The authors have none to declare.

The Role of Ceramide in the Pathogenesis of Alcoholic Liver Disease.

Ceramide is an important second messenger in the sphingomyelin signaling pathway. In this review, we will focus on the potential role of ceramide in the pathogenesis of alcoholic liver disease (ALD). We have summarized the relevant studies and reviews about the role of ceramide in ALD. In addition, we have discussed the role of acid sphingomyelinase and protein phosphatase 2A in ALD, which are associated with ceramide and hepatic steatosis. Recent studies have proved that the immunoreactivity and content of ceramide were increased, both in experimental models of chronic alcohol-induced steatohepatitis and human livers with severe chronic alcohol-related liver disease. Consistent with that, the levels of protein phosphatase 2A and acid sphingomyelinase were increased. Of relevance, the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was inhibited, which could block the fatty acid oxidation and promote its synthesis. It was hypothesized that ethanol promoted ceramide accumulation and increased PP2A activity by activating ASMase, which may be an important mechanism in the inhibitory effect on AMPK phosphorylation and then contributed to the progression of steatosis. ASMase, a specific mechanism of ceramide generation, was proved to be a regulator of steatosis, fibrosis, lipotoxicity and endoplasmic reticulum stress.

Living donor liver transplantation using a graft with periportal fibrosis.

A 57-year-old woman with familial amyloid polyneuropathy (FAP) was scheduled to undergo living donor liver transplantation (LDLT), but the operation was cancelled because the only potential donor had chronic alcohol-related liver disease. One year later, FAP-related neurological symptoms progressed rapidly, and emergency LDLT was planned. The donor's hepatic function had returned to normal range after 1 year of abstinence. The left liver graft volume was equivalent to 37.7% of the standard liver volume (SLV) of the recipient. However, a liver biopsy revealed mild fibrosis (score, F1). LDLT was successfully performed without any complications. The recipient's neurological findings returned to normal. One year after LDLT, the liver graft volume was equivalent to approximately 90% of the SLV, and the fibrosis had improved. LDLT using a graft with a fibrosis score of up to F1 may be an acceptable alternative for recipients with normal hepatic function.

Therapeutic reversal of chronic alcohol‐related steatohepatitis with the ceramide inhibitor myriocin

Alcohol-related liver disease (ALD) is associated with steatohepatitis and insulin resistance. Insulin resistance impairs growth and disrupts lipid metabolism in hepatocytes. Dysregulated lipid metabolism promotes ceramide accumulation and oxidative stress, leading to lipotoxic states that activate endoplasmic reticulum (ER) stress pathways and worsen inflammation and insulin resistance. In a rat model of chronic alcohol feeding, we characterized the effects of a ceramide inhibitor, myriocin, on the histopathological and ultrastructural features of steatohepatitis, and the biochemical and molecular indices of hepatic steatosis, insulin resistance and ER stress. Myriocin reduced the severity of alcohol-related steatohepatitis including the abundance and sizes of lipid droplets and mitochondria, inflammation and architectural disruption of the ER. In addition, myriocin-mediated reductions in hepatic lipid and ceramide levels were associated with constitutive enhancement of insulin signalling through the insulin receptor and IRS-2, reduced hepatic oxidative stress and modulation of ER stress signalling mechanisms. In conclusion, ceramide accumulation in liver mediates tissue injury, insulin resistance and lipotoxicity in ALD. Reducing hepatic ceramide levels can help restore the structural and functional integrity of the liver in chronic ALD due to amelioration of insulin resistance and ER stress. However, additional measures are needed to protect the liver from alcohol-induced necroinflammatory responses vis-à-vis continued alcohol abuse.