Future Approaches and Therapeutic Modalities for Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) results from an acute decompensation of cirrhosis due to exogenous insult. The condition is characterized by a severe systemic inflammatory response, inappropriate compensatory anti-inflammatory response, multisystem extrahepatic organ failure, and high short-term mortality. Here, the authors evaluate the current status of potential treatments for ACLF and assess their efficacy and therapeutic potential.

Emerging Pharmacotherapies in Alcohol-Associated Hepatitis.

The incidence of alcoholic-associated hepatitis (AH) is increasing. The treatment options for severe AH (sAH) are scarce and limited to corticosteroid therapy which showed limited mortality benefit in short-term use only. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH and to improve their high mortality rates.This review article focuses on the current novel therapeutics targeting various mechanisms in the pathogenesis of alcohol-related hepatitis. Anti-inflammatory agents such as IL-1 inhibitor, Pan-caspase inhibitor, Apoptosis signal-regulating kinase-1, and CCL2 inhibitors are under investigation. Other group of agents include gut-liver axis modulators, hepatic regeneration, antioxidants, and Epigenic modulators. We describe the ongoing clinical trials of some of the new agents for alcohol-related hepatitis. Conclusion: A combination of therapies was investigated, possibly providing a synergistic effect of drugs with different mechanisms. Multiple clinical trials of novel therapies in AH remain ongoing. Their result could potentially make a difference in the clinical course of the disease. DUR-928 and granulocyte colony-stimulating factor had promising results and further trials are ongoing to evaluate their efficacy in the large patient sample.

Trends in hospitalization for alcoholic hepatitis from 2011 to 2017: A USA nationwide study.

BACKGROUND: Severe alcoholic hepatitis (AH) is one of the most lethal manifestations of alcohol-associated liver disease. In light of the increase in alcohol consumption worldwide, the incidence of AH is on the rise, and data examining the trends of AH admission is needed. AIM: To examine inpatient admission trends secondary to AH, along with their clinical outcomes and epidemiological characteristics. METHODS: The National Inpatient Sample (NIS) database was utilized, and data from 2011 to 2017 were reviewed. We included individuals aged ≥ 21 years who were admitted with a primary or secondary diagnosis of AH using the International Classification of Diseases (ICD)-9 and its correspondent ICD-10 codes. Hepatitis not related to alcohol was excluded. The national estimates of inpatient admissions were obtained using sample weights provided by the NIS. RESULTS: AH-related hospitalization demonstrated a significant increase in the USA from 281506 (0.7% of the total admission in 2011) to 324050 (0.9% of the total admission in 2017). The median age was 54 years. The most common age group was 45-65 years (range 57.8%-60.7%). The most common race was white (63.2%-66.4%), and patients were predominantly male (69.7%-71.2%). The primary healthcare payers were Medicare (29.4%-30.7%) and Medicaid (21.5%-32.5%). The most common geographical location was the Southern USA (33.6%-34.4%). Most patients were admitted to a tertiary care center (50.2%-62.3%) located in urban areas. Mortality of AH in this inpatient sample was 5.3% in 2011 and 5.5% in 2017. The most common mortality-associated risk factors were acute renal failure (59.6%-72.1%) and gastrointestinal hemorrhage (17.2%-20.3%). The total charges were noted to range between $25242.62 and $34874.50. CONCLUSION: The number of AH inpatient hospitalizations significantly increased from 2011 to 2017. This could have a substantial financial impact with increasing healthcare costs and utilization. AH-mortality remained the same.

Hepatitis E in immunocompromised individuals.

Hepatitis E virus (HEV) originally identified as a cause of acute icteric hepatitis in developing countries has grown to be a cause of zoonotic viral hepatitis in developed countries such as the United States. While there are eight identified genotypes to date, genotype 1 (HEV1), HEV2, HEV3, HEV4 are the most common to infect humans. HEV1 and HEV2 are most common in developing countries including Latina America, Africa and Asia, and are commonly transmitted through contaminated water supplies leading to regional outbreaks. In contrast HEV3 and HEV4 circulate freely in many mammalian animals and can lead to occasional transmission to humans through fecal contamination or consumption of undercooked meat. The incidence and prevalence of HEV in the United States is undetermined given the absence of FDA approved serological assays and the lack of commercially available testing. In majority of cases, HEV infection is a self-limiting hepatitis requiring only symptomatic treatment. However, this is not the case in immunocompromised individuals, including those that have undergone solid organ or stem cell transplantation. In this subset of patients, chronic infection can be life threatening as hepatic insult can lead to inflammation and fibrosis with subsequent cirrhosis and death. The need for re-transplantation as a result of post-transplant hepatitis is of great concern. In addition, there have been many reported incidents of extrahepatic manifestations, for which the exact mechanisms remain to be elucidated. The cornerstone of treatment in immunocompromised solid organ transplant recipients is reduction of immunosuppressive therapies, while attempting to minimize the risk of organ rejection. Subsequent treatment options include ribavirin, and pegylated interferon alpha in those who have demonstrated ribavirin resistance. Further investigation assessing safety and efficacy of anti-viral therapy is imperative given the rising global health burden. Given this concern, vaccination has been approved in China with other investigations underway throughout the world. In this review we introduce the epidemiology, diagnosis, clinical manifestations, and treatment of HEV, with emphasis on immunocompromised individuals in the United States.

Autoimmune Hepatitis Induced after Treatment of Syphilitic Hepatitis.

We present a unique case of biopsy-proven syphilitic hepatitis which presented as severe acute liver injury with significant elevation in aminotransferases and bilirubin, and improved with antibiotic therapy. However, the patient returned weeks after initial presentation with new-onset acute liver injury and had developed hypergammaglobulinemia, positive autoantibody titers, and repeat liver biopsy demonstrating interface hepatitis, supporting a diagnosis of autoimmune hepatitis. He had an otherwise unrevealing etiologic workup, and responded to glucocorticoid therapy. We believe that syphilitic hepatitis and its treatment subsequently triggered an immunogenic response, leading to autoimmune hepatitis. Autoimmune hepatitis is a chronic liver disease thought to manifest as a result of predisposing genetic factors in combination with environmental insults, especially hepatotropic pathogens. Syphilis is a sexually transmitted disease caused by Treponema pallidum that has been associated with autoimmunity and the development of autoantibodies. We propose that in the setting of syphilitic hepatitis, a molecular mimicry event resulting from structural similarities between T. pallidum and liver antigens, as well as impaired regulatory T-cell function, led to the breakdown of immune tolerance and the onset of autoimmune hepatitis. To support this hypothesis, further molecular analyses and case series are necessary to determine if syphilitic hepatitis and its treatment are risk factors for the onset of autoimmune hepatitis. Autoimmune hepatitis should be considered early as the cause of acute liver injury in susceptible patients with risk factors for the disease, as prompt recognition and appropriate treatment may prevent progression of liver injury and result in improved outcomes.

Liver transplant allocation policies and outcomes in United States: A comprehensive review.

Liver transplant allocation policies in the United States has evolved over 3 decades. The donor liver organs are matched, allocated and procured by the Organ Procurement and Transplantation Network which is administered by the United Network of Organ Sharing (UNOS), a not-for-profit organization governed by the United States human health services. We reviewed the evolution of liver transplant allocation policies. Prior to 2002, UNOS used Child-Turcotte-Pugh score to list and stratify patients for liver transplantation (LT). After 2002, UNOS changed its allocation policy based on model for end-stage liver disease (MELD) score. The serum sodium is the independent indicator of mortality risk in patients with chronic liver disease. The priority assignment of MELD-sodium score resulted in LT and prevented mortality on waitlist. MELD-Sodium score was implemented for liver allocation policy in 2016. Prior to the current and most recent policy, livers from adult donors were matched first to the status 1A/1B patients located within the boundaries of the UNOS regions and donor-service areas (DSA). We reviewed the disadvantages of the DSA-based allocation policies and the advantages of the newest acuity circle allocation model. We then reviewed the standard and non-standard indications for MELD exceptions and the decision-making process of the National Review Liver Review Board. Finally, we reviewed the liver transplant waitlist, donation and survival outcomes in the United States.

Acute Liver Injury as a Manifestation of Secondary Syphilis.

In the United States, the incidence of new cases of syphilis has been rising. The number of cases of primary and secondary syphilis has continued to increase almost every year over the past 2 decades. Secondary syphilis has a variety of clinical manifestations. A frequently overlooked presentation is that of syphilitic hepatitis, which should be part of the differential diagnosis for patients with elevated liver enzymes, a maculopapular rash, and/or risk factors for contracting syphilis. In this study, we report a rare and unusual case of a man with a remote history of syphilis infection who developed acute liver injury.

Liver Transplantation Beyond Milan Criteria.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, being the fifth most common cancer and the third most common cause of cancer-related mortality. The incidence of HCC has been rising in the USA over the last 20 years. Liver transplantation is an optimal treatment option, as it eliminates HCC as well as the underlying liver disease. The Milan criteria (1 lesion greater than or equal to 2 cm and less than or equal to 5 cm, or up to 3 lesions, each greater than or equal to 1 cm and less than or equal to 3 cm) have been adopted by many transplant societies worldwide as the criteria to determine whether patients with HCC can move forward with liver transplantation. However, many believe that the Milan criteria may be too strict in regard to its size requirements for lesions. This has led to a number of expanded criteria for liver transplantation, concerning both overall size and number of lesions, as well as incorporation of other markers of tumor biology. Tumor markers, such as alpha-fetoprotein, can also be used to follow treatment of HCC and possibly exclude patients from transplant. HCC presenting beyond Milan criteria can also be down-staged with locoregional therapy. Monitoring response to locoregional therapy and longer wait times after locoregional therapy prior to transplant can serve as surrogate markers of tumor biology as well.

A Case Report of Alloimmune Hepatitis after Direct-acting Antiviral Treatment in a Liver Transplant Patient.

Direct-acting antiviral (DAA) therapy is often well-tolerated, and adverse events from DAA therapy are uncommon. We report a case of a woman who underwent orthotopic liver transplant for chronic hepatitis C infection and later developed alloimmune hepatitis shortly after starting DAA therapy for recurrent hepatitis C infection. The patient developed acute alloimmune hepatitis approximately 2 weeks after starting treatment with sofosbuvir, velpatasvir, and voxilaprevir. This case report proposes a dysregulation of immune surveillance due to the DAA stimulation of host immunity and rapid elimination of hepatitis C viral load as a precipitating factor for the alloimmune process, leading to alloimmune hepatitis in a post-transplant patient who starts on DAA.

Anastrozole-induced liver injury after a prolonged latency: a very rare complication of a commonly prescribed medication.

Anastrozole is an aromatase inhibitor that has been used more frequently over the last decade especially for oestrogen receptor-positive breast cancer. It has a relatively safe side effect profile. However, occasionally it has been associated with serious adverse events. Here, we present the case of a 58-year-old woman who presented with significantly elevated liver enzymes 4 years after starting anastrozole. She was not taking any other medications and an extensive workup did not reveal any other cause for her liver injury. The patient's liver enzymes normalised after discounting the anastrozole. She scored 4 on the updated Roussel Uclaf Causality Assessment Method grading system which was possible for drug-induced liver injury. A review of the literature revealed six prior cases of anastrozole-related liver injury. Anastrozole should be considered as a possible culprit in patients who develop an unexplained acute liver injury.

Multiple Myeloma Light Chain Amyloidosis Presenting as Hepatic Failure.

Amyloidosis is characterized by abnormal deposition of aggregations of amyloid fibril proteins. Systemic amyloidosis usually involves multiple organs, with kidneys being the most common organ involved, followed by the heart. In general, the presentation of hepatic amyloidosis varies with minimal or no symptoms commonly seen. Hepatic amyloidosis is rarely associated with multiple myeloma. We report here a case of portal hypertension, ascites, and severe intrahepatic cholestasis as the initial presentation of hepatic amyloidosis and multiple myeloma, which followed a rapidly progressive clinical course.

An extended treatment protocol with pegylated interferon and ribavirin for hepatitis C recurrence after liver transplantation.

AIM: To evaluate the efficacy and tolerability of an extended treatment protocol and to determine the predictors of sustained virological response (SVR) after liver transplantation (LT). METHODS: Between August 2005 and November 2008, patients with recurrent hepatitis C virus (HCV) after LT were selected for treatment if liver biopsy showed at least grade 2 inflammation and/or stage 2 fibrosis. All patients were to receive pegylated interferon (PEG)/regimens combining ribavirin (RBV) for an additional 48 wk after HCV undetectability. RESULTS: Extended protocol treatment was initiated in thirty patients. Overall, 73% had end of treatment response and 60% had SVR. Nineteen patients completed treatment per protocol, of them, sixteen (84%) had end of treatment response, and fourteen (74%) achieved SVR. Both early virological response and 24-week virological response were individually associated with SVR but this association was not significant on multivariate analysis. Eleven patients (37%) discontinued therapy due to adverse effects. Cytopenias were the most common and most severe adverse effect, and required frquent growth factor use, dose adjustments and treatment cessations. The risk of rejection was not increased. CONCLUSION: Recurrent HCV after LT can be safely treated with extended virological response-guided therpy using PEG/RBV, but requires close monitoring for treatment-related adverse effects, particularly cytopenias.

Guillain-Barre syndrome associated with peginterferon alfa-2a for chronic hepatitis C: A case report.

The recommended therapy for chronic hepatitis C (CHC) infection is the combination of a Pegylated interferon and Ribavirin. Almost all such patients on combination therapy experience one or more adverse events during the course of treatment. Significant neurological side effects are rare. A few cases of Bell's Palsy, chronic inflammatory demyelinating polyneuropathy and even one case of acute demyelinating polyneuropathy with atypical features for Guillain-Barre syndrome (GBS) associated with Interferon therapy have been reported but no report of GBS with typical features has been published. We present a case report of typical GBS associated with Peginterferon alfa-2a and Ribavirin used for treatment of CHC infection.