Pathologic analysis of liver transplantation for primary biliary cirrhosis

A retrospective histopathologic review of all pathologic specimens from 394 adult liver transplant patients was undertaken with clinical correlation to determine if primary biliary cirrhosis has affected the posttrans‐plant course compared to all other indications for liver transplantation and if recurrent primary biliary cirrhosis has occurred after liver transplantation. We also compared the histopathologic features seen in native livers with primary biliary cirrhosis to failed allografts with chronic rejection. One hundred six of the 394 adult patients transplanted during this time (1981 to July, 1986) fulfilled clinicopathologic criteria for a diagnosis of primary biliary cirrhosis. Neither the incidence nor any qualitative pathologic feature of histologically documented acute cellular rejection differentiated subjects transplanted for primary biliary cirrhosis vs. other diseases. No correlation between the titers of antimitochon‐drial antibody and the presence of posttransplant hepatic dysfunction based on liver enzyme profiles or the development of chronic rejection was seen in patients transplanted for primary biliary cirrhosis. Minor differences noted in the posttransplant course of primary biliary cirrhosis patients as compared to other conditions (higher incidence of chronic rejection as a cause of graft failure) was seen, but this did not significantly affect graft or patient survival. Recurrent primary biliary cirrhosis could not be diagnosed with certainty in any patient. A comparison of failed chronically rejected allografts vs. native hepatectomies obtained from patients with primary biliary cirrhosis revealed the presence of chronic obliterative vasculopathy, centrilobular cholestasis, and lack of granulomas, cirrhosis, cholan‐giolar proliferation, copper‐associated protein deposition and Mallory's hyalin in specimens with chronic rejection. In contrast, livers removed from patients with primary biliary cirrhosis demonstrated a mild vasculopathy, cirrhosis, granulomas, copper‐associated protein deposition, Mallory's hyalin and periportal cholestasis. Both conditions demonstrated a nonsuppurative destructive cholangitis with bile duct paucity. Copyright © 1988 American Association for the Study of Liver Disease

Liver cirrhosis-epidemiological and Clinical Aspects

Liver cirrhosis is the end-stage of many different chronic liver diseases. Limited data exists on the epidemiology, natural history and complications of liver cirrhosis such as esophageal varices and malignancies in the Nordic countries after the discovery of hepatitis C (HCV). Most hepatocellular carcinomas (HCC) develop in patients with liver cirrhosis but data on the occurrence of other malignancies than HCCs in these patients are scarce. Gastrointestinal (GI) symptoms such as nausea, vomiting, abdominal pain, and diarrhea are common in patients with advanced liver disease but the importance of portal hypertension for these symptoms is unexplored. The aims of the present study were to evaluate the incidence, outcome and complications of liver cirrhosis in a Swedish population and in Iceland and the effects of portal hypertension on small bowel motility and small intestinal bacterial overgrowth (SIBO) in patients with liver cirrhosis. The annual incidence of liver cirrhosis in Gothenburg was 15.3 ±2.4/100.000 compared to 3.3 ±1.2/100.000 in Iceland, p<0.0001. In Gothenburg 50% of the patients had alcoholic cirrhosis compared to 29% in Iceland (p<0.0001). Only 9% of patients died in their first variceal bleeding, that is within one week of their first bleeding episode. Of the patients diagnosed with esophageal varices after a bleeding episode, 55% had a bleeding episode during follow-up compared to only 13% of the patients diagnosed without a bleeding episode. Variables predicting mortality in a multivariate analysis were: Child-Pugh class, bleeding before diagnosis, age and bilirubin levels. Causes of death were in 26% of cases liver failure, 19% variceal bleeding and the rest other causes. Patients with liver cirrhosis had 267 times increased risk of hepatocellular cancer. Among patients with HCV cirrhosis, 19% developed HCC and 20% of those with HCV and alcoholic liver disease (ALD). We observed 13 times increased risk of cholangiocarcinoma and also increased risk for esophageal, pancreatic, pulmonary and colorectal cancer than in the general population. Patients with liver cirrhosis and portal hypertension had more motility disturbances in the small intestine compared to those without portal hypertension and seemed to have a higher risk of small intestinal bacterial overgrowth. Conclusions: The incidence of liver cirrhosis is low in Iceland, 24% of the incidence in Gothenburg. The difference is due to lower incidence of alcoholic liver disease and HCV cirrhosis in Iceland. In patients with liver cirrhosis and esophageal varices a bleeding is still a strong risk factor for recurrent bleeding. The mortality is high but mainly from other causes than variceal bleeding and few die in the first bleeding. The risk of HCC in cirrhosis is mostly associated with HCV and is the same in HCV patients with and without alcohol overconsumption. Other malignancies than HCC are more common in patients with cirrhosis than in the general population. Abnormal small bowel motility and SIBO is common in patients with liver cirrhosis with concomitant portal hypertension. Portal hypertension per se might be significantly related to small bowel abnormalities observed in patients with liver cirrhosis

The burden of clostridium difficile infection in patients with liver cirrhosis

Clostridium Difficile Infection (CDI) has registered a dramatically increasing incidence in the general population over the past decades. Nowadays, Clostridium Difficile is the leading cause of hospital-acquired diarrhea in Europe and North America. Liver cirrhosis is the final stage of any chronic liver disease (CLD). The most common causes are chronic hepatitis C or B and viral co-infections, alcohol misuse, and nonalcoholic fatty liver disease (NAFLD). CLD and cirrhosis are listed among the ten leading causes of death in the US. Cirrhosis due to any etiology disrupts the homeostatic role of the liver in the body. Cirrhosis-associated immune dysfunction (CAID) leads to alterations in both inherited and acquired systemic and local liver immunity. CAID is caused by increased systemic inflammation and immunodeficiency and it is responsible for 30% of mortality rates all over the world. Clostridium Difficile infection frequently affects patients suffering from liver cirrhosis because of the high number of prolonged hospitalizations, regular use of antibiotics for the prevention or treatment of SBP, proton pump inhibitor (PPI) use, and an overall immunocompromised state. Clostridium Difficile is a Gram-positive bacterium responsible for the high morbidity and mortality rates in patients with cirrhosis, with an essential increase in a 30-day mortality

Right Heart Remodeling in Patients with End-Stage Alcoholic Liver Cirrhosis: Speckle Tracking Point of View

BACKGROUND: Data regarding cardiac remodeling in patients with alcoholic liver cirrhosis are scarce. We sought to investigate right atrial (RA) and right ventricular (RV) structure, function, and mechanics in patients with alcoholic liver cirrhosis. METHODS: This retrospective cross-sectional investigation included 67 end-stage cirrhotic patients, who were referred for evaluation for liver transplantation and 36 healthy controls. All participants underwent echocardiographic examination including strain analysis, which was performed offline. RESULTS: RV basal diameter and RV thickness were significantly higher in patients with cirrhosis. Conventional parameters of the RV systolic function were similar between the observed groups. Global, endocardial, and epicardial RV longitudinal strains were significantly lower in patients with cirrhosis. Active RA function was significantly higher in cirrhotic patients than in controls. The RA reservoir and conduit strains were significantly lower in cirrhotic patients, while there was no difference in the RA contractile strain. Early diastolic and systolic RA strain rates were significantly lower in cirrhotic patients than in controls, whereas there was no difference in the RA late diastolic strain rate between the two groups. Transaminases and bilirubin correlated negatively with RV global longitudinal strain and RV-free wall strain in patients with end-stage liver cirrhosis. The Model for End-stage Liver Disease (MELD) score, predictor of 3-month mortality, correlated with parameters of RV structure and systolic function, and RA active function in patients with end-stage liver cirrhosis. CONCLUSIONS: RA and RV remodeling is present in patients with end-stage liver cirrhosis even though RV systolic function is preserved. Liver enzymes, bilirubin, and the MELD score correlated with RV and RA remodeling

Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: A single-center study

AIM: To evaluate waiting list (WL) registration and liver transplantation (LT) rates in patients with hepatitis C virus (HCV)-related cirrhosis since the introduction of direct-acting antivirals (DAAs). METHODS: All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectively-updated database; patients with HCV-related cirrhosis were divided by indication for LT [dec-HCV vs HCV/ hepatocellular carcinoma (HCC)] and into two interval times (2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated. RESULTS: One thousand one hundred and ninty-four [male (M)/female (F): 925/269] patients were included. Considering the whole cohort, HCV-related cirrhosis was the main etiology at the time of WL registration (490/1194 patients, 41%). HCV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction (from 43.3% in 2006-2013 to 37.2% in 2014-2017, P = 0.05), especially amongst dec-HCV (from 24.2% in 2006-2013 to 15.9% in 2014-2017, P = 0.007). Even HCV remained the most common indication to LT over time (289/666, 43.4%), there was a trend towards a decrease after DAAs introduction (from 46.3% in 2006-2013 to 39% in 2014-2017, P = 0.06). HCV patients (M/F: 43/11, mean age: 57.7 \ub1 8 years) who achieved viral eradication in the WL had better transplant-free survival (log-rank test P = 0.02) and delisting rate (P = 0.002) than untreated HCV patients. CONCLUSION: Introduction of DAAs significantly reduced WL registrations for HCV related cirrhosis, especially in the setting of decompensated cirrhosis

Trends in Characteristics, Mortality, and Other Outcomes of Patients With Newly Diagnosed Cirrhosis

Importance: Changes in the characteristics of patients with cirrhosis are likely to affect future outcomes and are important to understand in planning for the care of this population. Objective: To identify changes in demographic and clinical characteristics and outcomes in patients with newly diagnosed cirrhosis. Design, Setting, and Participants: A retrospective cohort study of patients with a new diagnosis of cirrhosis was conducted using the Indiana Network for Patient Care, a large statewide regional health information exchange, between 2004 and 2014. Patients with at least 1 year of continuous follow-up before the cirrhosis diagnosis were followed up through August 1, 2015. The analysis was conducted from December 2018 to January 2019. Exposures: Age, cause of cirrhosis, and year of diagnosis. Main Outcomes and Measures: Overall rates for mortality, liver transplant, hepatocellular carcinoma, and hepatic decompensation (composite of ascites, hepatic encephalopathy, or variceal bleeding). Results: A total of 9261 patients with newly diagnosed cirrhosis were identified (mean [SD] age, 57.9 [12.6] years; 5109 [55.2%] male). A 69% increase in new diagnoses occurred over the course of the study period (620 in 2004 vs 1045 in 2014). The proportion of those younger than 40 years increased by 0.20% per year (95% CI, 0.04% to 0.36%; P for trend = .02), and the proportion of those aged 65 years and older increased by 0.81% per year (95% CI, 0.51% to 1.11%; P for trend < .001). The proportion of patients with alcoholic cirrhosis increased by 0.80% per year (95% CI, 0.49% to 1.12%), and the proportion with nonalcoholic steatohepatitis increased by 0.59% per year (95% CI, 0.30% to 0.87%), whereas the proportion with viral hepatitis decreased by 1.36% per year (95% CI, -1.68% to -1.03%) (P < .001 for all). In patients younger than 40 years, 40 to 64 years, and 65 years and older, mortality rates were 6.4 (95% CI, 5.4 to 7.6), 9.9 (95% CI, 9.5 to 10.4), and 16.2 (95% CI, 15.2 to 17.2) per 100 person-years, respectively (P < .001). Mortality rates decreased during the study period (11.9 [95% CI, 10.7-13.1] per 100 person-years in 2004 vs 10.0 [95% CI, 8.1-12.2] per 100 person-years in 2014; annual adjusted hazard ratio, 0.87 [95% CI, 0.86 to 0.88]) and were lower in those with alcoholic cirrhosis compared with patients with viral hepatitis (adjusted hazard ratio, 0.89 [95% CI, 0.80 to 0.98]). Rates of hepatocellular carcinoma were low in patients younger than 40 years (0.5 [95% CI, 0.2 to 0.9] per 100 person-years). Liver transplant rates were low throughout the study period (0.3 [95% CI, 0.3-0.4] per 100 person-years). In patients with compensated cirrhosis, rates of hepatic decompensation were lower in patients younger than 40 years (adjusted subhazard ratio 0.78; 95% CI, 0.62 to 0.99) and in patients with nonalcoholic steatohepatitis (adjusted subhazard ratio, 0.51; 95% CI, 0.43 to 0.60). Conclusions and Relevance: The population of patients with newly diagnosed cirrhosis in Indiana has experienced changes in the age distribution and cause of cirrhosis, with decreasing mortality rates. These findings support investment in the prevention and treatment of alcoholic liver disease and nonalcoholic steatohepatitis, particularly in younger and older patients. Additional study is needed to identify the reasons for decreasing mortality rates

Idiopathic noncirrhotic portal hypertension: current perspectives

The term idiopathic noncirrhotic portal hypertension (INCPH) has been recently proposed to replace terms, such as hepatoportal sclerosis, idiopathic portal hypertension, incomplete septal cirrhosis, and nodular regenerative hyperplasia, used to describe patients with a hepatic presinusoidal cause of portal hypertension of unknown etiology, characterized by features of portal hypertension (esophageal varices, nonmalignant ascites, porto-venous collaterals), splenomegaly, patent portal, and hepatic veins and no clinical and histological signs of cirrhosis. Physicians should learn to look for this condition in a number of clinical settings, including cryptogenic cirrhosis, a disease known to be associated with INCPH, drug administration, and even chronic alterations in liver function tests. Once INCPH is clinically suspected, liver histology becomes mandatory for the correct diagnosis. However, pathologists should be familiar with the histological features of INCPH, especially in cases in which histology is not only requested to exclude liver cirrhosis

Era of direct acting anti-viral agents for the treatment of hepatitis C.

Hepatitis C infection is universal and the most common indication of liver transplantation in the United States. The period of less effective interferon therapy with intolerable side effects has gone. Now we have stepped into the era of direct acting anti-viral agents (DAAs) against hepatitis C virus. Treatment of hepatitis C is now extremely effective, tolerable and requires a short duration of intake of oral agents. Less monitoring is required with the current therapy and drug-drug interactions are less than the previous regimen. The current treatment options of chronic hepatitis C with various DAAs are discussed in this article

Sex Differences in the Association Between Frailty and Sarcopenia in Patients With Cirrhosis.

ObjectivesFrailty is prevalent in patients with cirrhosis and is hypothesized to result in part from sarcopenia, but the precise contribution of sarcopenia to frailty in this population is poorly understood.MethodsIncluded were patients with cirrhosis from 2011 to 2014 who had an ambulatory frailty assessment and abdominal computed tomography scan within 3 months. Logistic regression assessed the associations between frailty (=Liver Frailty Index ≥4.5), and sarcopenia (=skeletal muscle index of &lt;39 cm/m for women and &lt;50 cm/m for men).ResultsTwo hundred ninety-one participants were included: 33% were female. The median (interquartile range) Liver Frailty Index was 3.7 (3.3-4.2); 19% were frail. The median (interquartile range) skeletal muscle index was 49 cm/m (31-69); 36% had sarcopenia. Among the 54 frail participants, 48% had sarcopenia. In univariable logistic regression, sarcopenia was associated with a 1.86× increased odds of being frail (95% confidence interval [CI], 1.02-3.38). After adjusting for sex, etiology, hepatocellular carcinoma, MELDNa, ascites, encephalopathy, and hypertension, sarcopenia was associated with a 2.38× increased odds of being frail (95% CI, 1.17-4.85). After stratifying by sex and adjusting for MELDNa, sarcopenia among males was associated with a significantly increased odds of frailty (odds ratio 2.81, 95% CI, 1.19-6.67), whereas sarcopenia among females was not (odds ratio 1.38; 95% CI, 0.45-4.25).DiscussionIn patients with cirrhosis, sarcopenia was associated with a nearly 2-fold increased odds of being frail. Two-thirds of frail men displayed sarcopenia compared with only one-quarter of frail women. Contributors to the frail phenotype may differ by sex and support the need for sex-specific strategies to reduce frailty in this population

Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease

Hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B (CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma (HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation