Hepatorenal syndrome: pathophysiology, diagnosis, and management

Hepatorenal syndrome (HRS), the extreme manifestation of renal impairment in patients with cirrhosis, is characterized by reduction in renal blood flow and glomerular filtration rate. Hepatorenal syndrome is diagnosed when kidney function is reduced but evidence of intrinsic kidney disease, such as hematuria, proteinuria, or abnormal kidney ultrasonography, is absent. Unlike other causes of acute kidney injury (AKI), hepatorenal syndrome results from functional changes in the renal circulation and is potentially reversible with liver transplantation or vasoconstrictor drugs. Two forms of hepatorenal syndrome are recognized depending on the acuity and progression of kidney injury. The first represents an acute impairment of kidney function, HRS-AKI, whereas the second represents a more chronic kidney dysfunction, HRS-CKD (chronic kidney disease). In this review, we provide critical insight into the definition, pathophysiology, diagnosis, and management of hepatorenal syndrome

Alcohol-related liver disease: Areas of consensus, unmet needs and opportunities for further study

A joint meeting of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) was held in London on September 30 and October 1, 2017. The goals of the meeting were to identify areas of broad agreement and disagreement, develop consensus, and determine future directions to ultimately reduce the burden, morbidity, and mortality of alcohol-related liver disease (previously termed alcoholic liver disease). The specific aims of the meeting were to identify unmet needs and areas for future investigation, in order to reduce alcohol consumption, develop markers for diagnosis and prognosis of disease, and create a framework to test novel pharmacological agents with pre-specified treatment endpoints

Current epidemiology of hepatitis E virus infection in the United States: Low seroprevalence in the National Health and Nutrition Evaluation Survey

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108373/1/hep27219.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/108373/2/hep27219-sup-0001-suppinfo.pd

Alcohol Abstinence Does Not Fully Reverse Abnormalities of Mucosal-Associated Invariant T Cells in the Blood of Patients With Alcoholic Hepatitis

OBJECTIVES: Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. METHODS: MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. RESULTS: At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). DISCUSSION: We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities

Acute-on-chronic liver failure in cirrhosis

The definition of acute-on-chronic liver failure (ACLF) remains contested. In Europe and North America, the term is generally applied according to the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium guidelines, which defines this condition as a syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure and high short-term mortality. One-third of patients who are hospitalized for acute decompensation present with ACLF at admission or develop the syndrome during hospitalization. ACLF frequently occurs in a closed temporal relationship to a precipitating event, such as bacterial infection or acute alcoholic, drug-induced or viral hepatitis. However, no precipitating event can be identified in approximately 40% of patients. The mechanisms of ACLF involve systemic inflammation due to infections, acute liver damage and, in cases without precipitating events, probably intestinal translocation of bacteria or bacterial products. ACLF is graded into three stages (ACLF grades 1-3) on the basis of the number of organ failures, with higher grades associated with increased mortality. Liver and renal failures are the most common organ failures, followed by coagulation, brain, circulatory and respiratory failure. The 28-day mortality rate associated with ACLF is 30%. Depending on the grade, ACLF can be reversed using standard therapy in only 16-51% of patients, leaving a considerable proportion of patients with ACLF that remains steady or progresses. Liver transplantation in selected patients with ACLF grade 2 and ACLF grade 3 increases the 6-month survival from 10% to 80%

Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia

Heavy drinkers are at risk for a spectrum of histologic alcohol-related liver injury: steatosis, alcoholic steatohepatitis (ASH), alcohol-related fibrosis, and cirrhosis. Alcoholic hepatitis (AH), the clinical entity associated with severe ASH, has high short-term mortality. The standard-of-care therapy, prednisolone, has limited efficacy and many side effects; no other treatment has consistently shown survival benefit. The National Institute on Alcohol Abuse and Alcoholism (NIAAA)-funded Alcoholic Hepatitis Consortia carry out translational research on pathophysiologic mechanisms, genetic and environmental risk factors, phase II clinical trials, and development of biomarkers. The consortia members were convened by the National Institutes of Health to address diagnostic criteria and practical issues related to clinical AH research, and to develop a set of common data elements to harmonize ongoing and future trials. This was accomplished through 3 face-to-face meetings of the investigators and representatives of the National Institutes of Health, and subsequent electronic communications over the course of 6 months. Evidence for the recommendations was based on published trials and observational data from several of the consortia members. A draft manuscript was iteratively reviewed by members of the consortia. The goal was to reach agreements on recommendations and definitions that could facilitate trial design, and simultaneously be tested by research groups pooling their data. The recommendations made here are specifically directed to achieve better uniformity in clinical trials, rather than serving as clinical practice guidelines

Alcohol Rehabilitation Within 30 Days of Hospital Discharge Is Associated With Reduced Readmission, Relapse, and Death in Patients With Alcoholic Hepatitis

Background & Aims Patients admitted to the hospital for alcoholic hepatitis (AH) are at increased risk of readmission and death. We aimed to identify factors associated with readmission, alcohol relapse, and mortality. Methods We performed a retrospective analysis of consecutive patients admitted with AH to a tertiary care hospital from 1999 through 2016 (test cohort, n = 135). We validated our findings in a prospective analysis of patients in a multi-center AH research consortium from 2013 through 2017 (validation cohort, n = 159). Alcohol relapse was defined as any amount of alcohol consumption within 30 days after hospital discharge. Early alcohol rehabilitation was defined as residential or outpatient addiction treatment or mutual support group participation within 30 days after hospital discharge. Results Thirty-day readmission rates were 30% in both cohorts. Alcohol relapse rates were 37% in the test and 34% in the validation cohort. Following hospital discharge, 27 patients (20%) in the test cohort and 19 patients (16%) in the validation cohort attended early alcohol rehabilitation. There were 53 deaths (39%) in a median follow-up time of 2.8 years and 42 deaths (26%) in a median follow-up time of 1.3 years, respectively. In the test cohort, early alcohol rehabilitation reduced odds for 30-day readmission (adjusted odds ratios [AOR] 0.16; 95% CI, 0.04–0.65; P = .01), 30-day alcohol relapse (AOR, 0.11; 95% CI, 0.02–0.53; P < .001), and death (adjusted hazard ratio [AHR], 0.20; 95% CI, 0.05–0.56; P = .001). In the validation cohort early alcohol rehabilitation reduced odds for 30-day readmission (AOR, 0.30; 95% CI, 0.09–0.98; P = .04), 30-day alcohol relapse (AOR 0.09; 95% CI, 0.01–0.73; P = .02), and death (AHR, 0.20; 95% CI, 0.01–0.94; P = .04). A model combining alcohol rehabilitation and bilirubin identified patients with readmission to the hospital within 30 days with an area under the receiver operating characteristic curve of 0.73. Conclusions In an analysis from two cohorts of patients admitted with AH, early alcohol rehabilitation can reduce risk of hospital readmission, alcohol relapse, and death and should be considered as a quality indicator in AH hospitalization treatment

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

Acute-on-Chronic Liver Failure: Getting ready for prime-time

Acute on chronic liver failure (ACLF) is a culmination of chronic liver disease and extra-hepatic organ failures, which is associated with a high short-term mortality and immense healthcare expenditure. There are varying definitions for organ failures and ACLF in Europe, North America and Asia. These differing definitions need to be reconciled to enhance progress in the field. The pathogenesis of ACLF is multi-factorial and related to interactions between the immuno-inflammatory system, microbiota and the precipitating factors. Individual organ failures related to the kidney, brain, lungs and circulation have cumulative adverse effects on mortality and are often complicated or precipitated by infections. Strategies to prevent and rapidly treat these organ failures are paramount in improving survival. With the aging population and paucity of organs for liver transplant, the prognosis of ACLF patients is poor, highlighting the need for novel therapeutic strategies. The role of liver transplant in ACLF is evolving and needs further investigation across large consortia. A role for early palliative care and management of frailty as approaches to alleviate disease burden and improve patient-reported outcomes is being increasingly recognized. CONCLUSION: ACLF is a clinically relevant syndrome that is epidemic worldwide and which requires a dedicated multi-national approach focused on prognostication and management. Investigations are underway worldwide to get ACLF ready for prime time. Compensated cirrhosis with \u3e 90% 1-year survival can transition into the decompensated stage with the onset of jaundice, ascites, variceal bleeding and hepatic encephalopathy (HE) (1)Acute on chronic liver failure (ACLF) is associated with rapid deterioration of liver function leading to liver failure, multiple extra-hepatic organ failures and high short-term mortality (2). Even if patients survive the acute insult, they may never return to their pre-episode functional state (3). The term acute decompensation has been used to characterize ascites, gastrointestinal bleeding, hepatic encephalopathy or infections without organ failure(4). There are several gaps in knowledge surrounding ACLF, which will be highlighted in this review. The prevalence of ACLF is difficult to assess due to varying regional definitions (5). ACLF, once thought to occur only in decompensated cirrhosis, has been recognized even in chronic liver disease without cirrhosis (5). ACLF occurs in approximately 10-30% of hospitalized cirrhotic patients (6-8). Because of its acuity, patients are frequently admitted into the intensive care unit (ICU), and every effort is made to stabilize these patients for liver transplantation (LT). This drives healthcare costs(9). Despite this intensive management, ACLF is associated with substantial morbidity and mortality. Because curative LT is only available to \u3c 10% of cirrhotic patients each year and ACLF patients are often delisted, the morbidity and mortality rates remain high, especially with an increasing number of organ failures (10)

Interaction between the patatin-like phospholipase domain-containing protein 3 genotype and coffee drinking and the risk for acute alcoholic hepatitis

Only a subset of subjects with excessive alcohol consumption develops alcoholic liver disease (ALD). One of the major risk factors for ALD is the genetic variant of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene. Coffee is one of the most commonly consumed beverages, and coffee consumption has been associated with lower levels of serum alanine aminotransferase. The aim of this study was to investigate the role of coffee drinking and PNPLA3 rs738409 and their association with alcoholic hepatitis (AH) in a well-characterized cohort of subjects from the Translational Research and Evolving Alcoholic Hepatitis Treatment consortium. AH subjects and heavy drinking controls without a history of liver disease who were enrolled between May 2013 and May 2016 were included (n = 339), and the details of alcohol and coffee consumption were assessed. The PNPLA3 variant was determined among participants of European ancestry (n = 183). Relationships between baseline data and AH status were determined, and multivariable logistic regression modeling was performed. During the study period, 189 cases with AH and 150 heavy drinking controls were prospectively enrolled. The prevalence of regular coffee consumption was significantly lower in patients with AH compared to controls (20% versus 43%; P < 0.0001). The overall minor allele frequency of the PNPLA3 variant was higher in AH cases. Multivariable logistic regression revealed that coffee consumption and PNPLA3 were significantly associated with AH status at baseline after adjusting for relevant patient characteristics. Conclusion: We found a higher prevalence of AH among heavy drinkers with PNPLA3 G/G and G/C genotypes regardless of coffee consumption status and a higher prevalence of AH among heavy drinkers who were not regular coffee drinkers. These findings remained after considering relevant baseline patient characteristics. Further studies are needed to confirm our observation