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In recent years there has been a significant increase in the incidence of acute-on-chronic liver failure (ACLF). This syndrome is characterized by infections, organ failures, and high short-term mortality. Although progress in the management of these sick patients has been evident, liver transplantation (LT) remains the best treatment modality to date. Several studies have reported LT as a feasible option, despite organ failures. The outcomes following LT are inversely related to the grade of ACLF. This review discusses the current literature on the feasibility, futility, timing, and outcomes of LT in patients with ACLF., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hepatitis B virus (HBV) reactivation, in the background of cleared and overt chronic HBV infection, can be seen in patients receiving immunosuppressive agents. Risk of reactivation is variably associated with HBV serologic status and types of immunosuppressive therapy. Prevention of HBV reactivation by antiviral prophylaxis is an effective strategy to reduce morbidity and mortality in those with immunocompromised states. This article defines HBV reactivation, discusses risk stratification and common medications that can induce HBV reactivation as well as guideline recommendations for prevention of HBV reactivation, and describes the prognosis and management of patients who experience HBV reactivation., Competing Interests: Disclosure S. Ekpanyapong has nothing to disclose. K.R. Reddy is on the Advisory Board of Gilead, Merck and received grant support from Gilead, BMS, Merck., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Research increasingly shows that the gut-liver-brain axis is a crucial component in the pathophysiology of hepatic encephalopathy (HE). Due to the limitations of current standard-of-care medications, non-pharmacological treatments that target gut dysbiosis, including probiotics, nutritional management, and fecal microbiota transplants, are being considered as alternative and adjunct therapies. Meta-analyses note that probiotics could offer benefits in HE treatment, but have not shown superiority over lactulose. Emerging literature suggests that fecal microbiota transplants could offer a novel strategy to treat gut dysbiosis and favorably impact HE. Finally, liver support devices and liver transplantation could offer a last-resort treatment option for persistent HE., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Terlipressin, somatostatin, or octreotide are recommended as pharmacologic treatment of acute variceal hemorrhage. Nonselective β-blockers decrease the risk of variceal hemorrhage and hepatic decompensation, particularly in those 30% to 40% of patients with good hemodynamic response. Carvedilol, statins, and anticoagulants are promising agents in the management of portal hypertension. Recent advances in the pharmacologic treatment of portal hypertension have mainly focused on modifying an increased intrahepatic resistance through nitric oxide and/or modulation of vasoactive substances. Several novel pharmacologic agents for portal hypertension are being evaluated in humans., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hepatic abnormalities in patients with lymphoproliferative disorders are common and can occur from direct infiltration by abnormal cells, bile duct obstruction, paraneoplastic syndrome, hemophagocytic syndrome, drug-induced liver injury, opportunistic infections, and reactivation of viral hepatitis. Hepatic involvement by lymphoma is often in association with systemic disease and rarely seen as a primary hepatic lymphoma. Vanishing bile duct syndrome is a well-known complication of Hodgkin disease. Antiviral prophylaxis for hepatitis B virus (HBV) reactivation is recommended for all HBsAg +  patients undergoing chemotherapy and all resolved HBV patients undergoing rituximab therapy and stem cell transplantation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), although the worldwide frequency is variable. APAP hepatotoxicity develops either following intentional overdose or unintentional ingestion (therapeutic misadventure) in the background of several factors, such as concomitant use of alcohol and certain medications that facilitate the formation of reactive and toxic metabolites. Spontaneous survival is more common in APAP-induced ALF compared with non-APAP etiologies. N-acetylcysteine is recommended for all patients with APAP-induced ALF and it reduces mortality. Liver transplantation should be offered early to those who are unlikely to survive based on described prognostic criteria., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Acute liver failure (ALF) is a life-threatening condition of heterogeneous etiology. Outcomes are better with early recognition and prompt initiation of etiology-specific therapy, intensive care protocols, and liver transplantation (LT). Prognostic scoring systems include the King's College Criteria and Model for End-stage Liver Disease score. Cerebral edema and intracranial hypertension are reasons for high morbidity and mortality; hypertonic saline is suggested for patients with a high risk for developing intracranial hypertension, and when it does, mannitol is recommended as first-line therapy. Extracorporeal liver support system may serve as a bridge to LT and may increase LT-free survival in select cases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Idiosyncratic hepatotoxicity is one of the most common reasons for an approved drug being restricted. This article focuses on hepatotoxicity of selected and recently introduced agents, such as, tyrosine kinase inhibitors, monoclonal antibodies, novel oral anticoagulants, newer antiplatelets, antibiotics, anti-diabetics, anti-epileptics, anti-depressants, anti-psychotics and anti-retrovirals. Overall, the incidence of clinically relevant hepatotoxicity from newer agents seems to be lower than that of the older agents. Nevertheless, cases of severe hepatotoxicity have been reported due to some of these newer agents, including, trastuzumab, ipilimumab, infliximab, imatinib, bosutinib, dasatinib, gefitinib, erlotinib, sunitinib, ponatinib, lapatinib, vemurafenib, dabigatran, rivaroxaban, felbamate, lamotrigine, levetiracetam, venlafaxine, duloxetine, darunavir, and maraviroc., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Overlapping features between autoimmune hepatitis (AIH) and cholestatic disorders (primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or indeterminate cholestasis), so-called overlap syndromes, usually have a progressive course toward cirrhosis and liver failure without adequate treatment. The diagnosis of overlap syndrome requires the prominent features of classic AIH and secondary objective findings of PBC or PSC. Empiric treatment for patients with AIH-PBC overlap is immunosuppressive therapy plus ursodeoxycholic acid. Empiric treatment for patients with AIH-PSC and AIH-cholestatic overlap is immunosuppressive therapy with or without ursodeoxycholic acid. Liver transplantation is indicated for patients who have end-stage liver disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Acetaminophen (APAP) is the leading worldwide cause of drug overdose and acute liver failure (ALF). Single overdose ingestion and therapeutic misadventure may cause hepatotoxicity. Several factors, such as concomitant alcohol use or abuse, concurrent medications, genetic factors, and nutritional status, can influence the susceptibility and severity of APAP hepatotoxicity. Early manifestations of APAP hepatotoxicity are nonspecific, but require prompt recognition by physicians. Patients with repeated overdose tend to present late, and in such hepatotoxicity may have already evolved. N-acetylcysteine is a very effective antidote when giving within 8 hours, and is also recommended after a presentation of hepatotoxicity and ALF. The prognosis of patients with APAP-induced ALF is better than other causes of ALF. Liver transplantation should be offered to those who are unlikely to survive., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Pruritus is a troublesome complication in patients with cholestatic liver disease. Several links to its pathogenesis have been proposed, including the role of bile acids, endogenous opioid and serotonins, and lysophosphatidic acid. The management of pruritus in cholestasis is challenging. Medical treatment of the underlying cholestatic condition may provide benefit. Extracorporeal albumin dialysis can be pursued for those who have a poor quality of life and failed the various therapeutic interventions, while awaiting liver transplantation. Experimental interventions, and the management of pruritus in certain conditions such as intrahepatic cholestasis of pregnancy and benign recurrent intrahepatic cholestasis, are also briefly reviewed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hepatitis C virus (HCV) infection remains a large-scale and significant health concern. The combination of subcutaneously administered pegylated interferon and oral ribavirin is the FDA-approved regimen for the treatment of chronic HCV infection. Combination therapy may result in a sustained virologic response leading to HCV eradication, with a reduction in risk for cirrhosis, hepatic decompensation, and hepatocellular carcinoma. However, the combination of PEG-IFN and ribavirin does not universally result in cure in all patients who undergo treatment. In this article, the authors discuss immunomodulatory therapies and clinical trials in the treatment of HCV infection.

Incidentally discovered liver masses are becoming more common with the increasing application and power of imaging techniques for the evaluation of abdominal conditions. Although such masses are often benign, conclusive diagnoses must be established in order to provide appropriate patient care. Various imaging modalities can be utilized to accurately diagnose such masses without resort to more invasive diagnostic measures.

Primary liver cancer is the sixth most common cancer in the world and the third most common cause of death attributable to cancer. Most primary liver cancers are hepatocellular carcinoma (HCC), accounting for 85% to 90% of cases. There is a trend of growing incidence of HCC in the United States. One of the most important risk factors for developing HCC is chronic hepatitis C virus (HCV) infection. Although several studies suggested the preventive effect of interferon from developing HCC in HCV-infected individuals, these findings need to be validated in large prospective and randomized trials.

Abnormal LCTs after surgery are common, and consultants are frequently called on to evaluate critically ill patients with abnormal tests. All patients undergoing consideration for elective surgery and a history of either acute or chronic liver disease require careful presurgical evaluation. A thorough history and physical examination, complete blood count, routine electrolytes, LCTs, and a coagulation profile should be ordered. For patients with marginal hepatic reserve, it is important that patient well-being be maximized before any elective operation. The type of surgery to be performed should also be reviewed. All patients with postoperative jaundice should be evaluated for a history of liver disease. The consultant should also review the surgical procedure performed, anesthetic agents administered, other medications used, and whether blood products were given during the perioperative and postoperative periods. The pattern and timing of LCT abnormalities may also give a clue to the underlying disorder. As in the preoperative assessment, a routine complete blood count,electrolyte panel, LCTs, and coagulation profile should be ordered. Unconjugated hyperbilirubinemia can develop as a consequence of blood transfusions, underlying hemolytic disorders, resorbing hematomas, drug effects, or Gilbert's syndrome. A haptoglobin, reticulocyte count, LDH, and Coomb's test should be considered in patients with unconjugated hyperbilirubinemia. Treatment is directed toward the underlying condition. Conjugated hyperbilirubinemia can occur as a result of either intrahepatic or extrahepatic disorders. Markedly abnormal aminotransferases and LDH in conjunction with a normal abdominal ultrasound scan suggest ischemic liver injury, drug-induced hepatitis, or viral infections of the liver. Treatment entails restoration of hepatic perfusion, removal of offending medications, and supportive care or antiviral agents, respectively. Extrahepatic biliary obstruction must be considered in all patients with conjugated hyperbilirubinemia. Abdominal sonography is the best screening test to assess for obstruction. Patients with common bile duct stones usually require ERCP with sphincterotomy and stone removal. Biliary strictures or leaks may require ERCP with balloon dilation of strictures or stent placement for strictures and leaks; percutaneous drainage of bilomas in combination with broad-spectrum antibiotic agents is recommended for patients with bile leaks and large intra-abdominal fluid collections. Surgery may be required for patients with strictures or leaks not amenable to either endoscopic or percutaneous intervention or for patients who have transected bile ducts after laparoscopic cholecystectomy. Medication effects, benign postoperative jaundice, sepsis, TPN, and acalculous cholecystitis are responsible for intrahepatic cholestasis and conjugated hyperbilirubinemia. Treatment includes removal of offending drugs, supportive care, broad-spectrum antibiotic agents with drainage of infected fluid collections, adjustment of TPN, and either cholecystectomy or cholecystostomy, respectively.

Hepatocellular carcinoma caused by hepatitis B and hepatitis C are global scourges but are likely to peak in incidence in the next 2 decades and then decline. Universal vaccination has been effective in stemming the incidence of chronic hepatitis B and early-onset HCC in regions of high endemicity where implemented, but preventive measures in HCV are not yet available. After the attrition of older affected generations, the incidence of HCC will likely decline rapidly. While no vaccine is currently available for hepatitis C, cases are projected to peak and decline because of a marked reduction in transmission as a result of behavioral modification and safeguarding of blood supplies. Until these epidemiologic projections come to pass, management of hepatocellular carcinoma will continue to become a progressively more frequently encountered clinical challenge. Therapy for chronic hepatitis may ameliorate but will not eliminate the development of tumors. The demand for orthotopic liver transplantation will continue to climb, and palliative therapies for non-resectable cases will require studies aimed at optimization of benefit. LDLT may remain an option for high-risk patients affording tumor-free survival for some otherwise terminal patients.

Poor outcomes following OLT for HCV disease have been associated with several host, viral, and non-host/non-viral factors. As is evident from the literature, there is confounding data in favor of and against these factors in the pathogenesis of severe recurrent HCV. Nevertheless, from a viral perspective, the patient most likely to achieve a good outcome following OLT is someone with low-level (< or = 10(9) copies/mL) HCV RNA viremia both pre- and post-OLT and a genotype other than lb. In terms of host factors, the patients with best outcomes are: whites, men, less than 49 years of age, receiving a donor liver less than 40 years of age, not coinfected with CMV, and have low HAI or histologic activity indices during the early stage of follow-up. Host recipient immune homology may or may not be a major factor in outcomes. A non-host, non-viral factor favoring less severe recurrence of HCV is a shorter warm ischemia time. Finally, features that may influence outcomes over which there is no control include: recipient age, recipient gender, and donor age (in the case of cadaveric donors). Unfortunately, the best-case scenario is uncommon.

Dyslipidemic conditions and their cardiovascular related complications are common. Effective primary and secondary prevention strategies include therapies to lower LDL and total cholesterol and to increase HDL. Further, it seems that there is a need for therapeutic reduction in triglycerides as it emerges as an independent risk factor for CVD. Many clinical trials have been designed to evaluate pharmacologic compounds in the treatment of the dyslipidemias and they seem to have shown a safe profile, both in the experiment phases and in post-marketing observation studies. Nevertheless, sporadic reports of hepatotoxicity with statins and niacin still arise (Table 2). Although routine hepatic biochemical test monitoring is recommended, the cost-effectiveness is questionable because often these reactions are idiosyncratic and may not be identified by this routine screening. The risk/benefit ratio is in favor of using these medications in individuals at risk. There is no evidence to suggest intrinsic hepatotoxic activity as such. Drugs that lower triglycerides such as fibrates, have been observed to improve hepatic biochemical tests, although in small series. This leads to speculation whether treatment with fibrates would be beneficial for non-alcoholic fatty liver disease (NAFLD), a condition that is emerging as one of enormous magnitude.

In summary, pegylated IFNs have a longer half-life, reduced immunogenicity, better pharmacokinetics, and enhanced biological activity when compared with standard IFN. Better adherence rates are feasible because of the once weekly administration of pegylated IFN. The adverse event profile is largely comparable. The improved pharmacokinetics of pegylated IFNs, compared with standard IFN, has translated into greater efficacy with at least similar tolerability. Pegylated IFNs with ribavirin are the standard of care for treating patients with chronic HCV who have not been treated previously.

Noncirrhotic portal hypertension represents a heterogeneous group of conditions that have distinct clinical and hemodynamic features that often help distinguish them from cirrhosis. [figure: see text] The sites of portal flow resistance may not be precisely localized to one area of the hepatic lobule and may extend beyond the site where the pathogenetic process began. Even in patients with portal hypertension caused by an increased flow, there may be subsequent development of increased resistance. The prognosis is variable; outcomes are better in patients with presinusoidal portal hypertension. A good understanding of the presentation of the various noncirrhotic conditions that cause portal hypertension will help determine the cause, the site of resistance, and the therapeutic plan. Ascites is not a feature of presinusoidal portal hypertension, whereas it may be the predominant feature in postsinusoidal portal hypertension.

Postoperative jaundice is often multifactorial (Fig. 2). A precipitating or causative factor may be identified but seldom can a specific therapy be offered. A systematic approach will help eliminate a hepatotoxic drug or identify a biliary tract problem. Treatment involves discontinuation of an offending drug; however, the drug, such as an anesthetic agent, may not be in use when the jaundice is detected. Recognition of an anesthetic-induced injury would certainly warn the physician not to repeat its use in future surgery for that patient. Hyperalimentation may contribute to jaundice, but patients developing postoperative jaundice are generally very ill and require nutrition. Extrahepatic biliary tract disease should be readily recognized and treated. The physician should be alert to the possibility of acalculous cholecystitis so that it can be appropriately diagnosed and treated.