Long-term liver allograft fibrosis: A review with emphasis on idiopathic post-transplant hepatitis and chronic antibody mediated rejection

Liver transplantation (LT) is a life-saving surgical procedure and the current standard of care for most patients with end stage liver disease. With improvements in organ preservation techniques, perioperative care, and immunosuppression, there is better patient and graft survival following LT, and assessment of the liver allograft in long-term survivors is becoming increasingly important. Recurrent or de novo viral or autoimmune injury remains the most common causes of chronic hepatitis and fibrosis following liver transplantation in adults. However, no obvious cause can be identified in many adults with controlled recurrent disease and the majority of pediatric LT recipients, as they have been transplanted for non-recurrent liver diseases. Serial surveillance liver biopsies post LT have been evaluated in several adult and pediatric centers to identify long-term pathological changes. Pathological findings are frequently present in liver biopsies obtained after a year post LT. The significance of these findings is uncertain as many of these are seen in protocol liver biopsies from patients with clinically good allograft function and normal liver chemistry parameters. This narrative review summaries the factors predisposing to long-term liver allograft fibrosis, highlighting the putative role of idiopathic post-LT hepatitis and chronic antibody mediated rejection in its pathogenesis.     

Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantion

Background/Aim: Alpha-1-antitrypsin deficiency (α₁ATD) is the commonest metabolic disease leading to liver transplantation (LT) in children. Approximately 10–15% of the PiZZ population develops liver disease. Five percent of them will require LT within the first 4 years of life. This study aimed to investigate the prognosis of the liver disease associated with PiZZ α₁ATD in the era of liver transplantation and to determine predictors of outcome.Methods: We reviewed retrospectively the clinical notes of 97 consecutive patients referred from January 1989, when LT became routinely available in our Unit, to July 1998.Results: Of 26 (27%) patients who developed endstage liver disease, 24 have been transplanted and two are waiting for LT. Twenty-one (81%) of these patients presented with neonatal hepatitis at a median age of 2.1 months. Of 71 (73%) children who have not required LT, 61 (86%) presented with neonatal hepatitis at a median age of 1.6 months. Among infants with neonatal hepatitis who required LT, 18 out of 21 (86%) had jaundice for more than 6 weeks compared with 34 of 61 (56%) who survived without LT (p<0.01). Children requiring LT had higher aspartate aminotransferase (AST) at presentation (p<0.0001) and both higher AST and gamma-glutamyl transferase (GGT) at 6 months (p<0.001), 1-year (p<0.0003) and 5-year (p0.01) follow up when compared to those who are well without LT. Furthermore, children who developed end-stage liver disease more frequently had severe bile duct reduplication (p<0.01), severe fibrosis (p<0.03) with bridging septa (p<0.02) and established cirrhosis (p<0.04) in the initial liver biopsy. Ninety-five of the 97 children (98%) are currently alive; two died after LT.Conclusions: The advent of liver transplantation has significantly improved the prognosis of liver disease associated with PiZZ α₁ATD. Duration of jaundice, severity of histological features and biochemical abnormalities predict outcome at an early stage of the disease.     

Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation

BACKGROUND/AIM: Alpha-1-antitrypsin deficiency (alpha1ATD) is the commonest metabolic disease leading to liver transplantation (LT) in children. Approximately 10-15% of the PiZZ population develops liver disease. Five percent of them will require LT within the first 4 years of life. This study aimed to investigate the prognosis of the liver disease associated with PiZZ alpha1ATD in the era of liver transplantation and to determine predictors of outcome. METHODS: We reviewed retrospectively the clinical notes of 97 consecutive patients referred from January 1989, when LT became routinely available in our Unit, to July 1998. RESULTS: Of 26 (27%) patients who developed end-stage liver disease, 24 have been transplanted and two are waiting for LT. Twenty-one (81%) of these patients presented with neonatal hepatitis at a median age of 2.1 months. Of 71 (73%) children who have not required LT, 61 (86%) presented with neonatal hepatitis at a median age of 1.6 months. Among infants with neonatal hepatitis who required LT, 18 out of 21 (86%) had jaundice for more than 6 weeks compared with 34 of 61 (56%) who survived without LT (p<0.01). Children requiring LT had higher aspartate aminotransferase (AST) at presentation (p<0.0001) and both higher AST and gamma-glutamyl transferase (GGT) at 6 months (p<0.001), 1-year (p<0.0003) and 5-year (p<0.01) follow up when compared to those who are well without LT. Furthermore, children who developed end-stage liver disease more frequently had severe bile duct reduplication (p<0.01), severe fibrosis (p<0.03) with bridging septa (p<0.02) and established cirrhosis (p<0.04) in the initial liver biopsy. Ninety-five of the 97 children (98%) are currently alive; two died after LT. CONCLUSIONS: The advent of liver transplantation has significantly improved the prognosis of liver disease associated with PiZZ alpha1ATD. Duration of jaundice, severity of histological features and biochemical abnormalities predict outcome at an early stage of the disease.     

Liver transplantation in the setting of chronic HCV

Recurrent HCV disease is the most common cause of graft loss and patient mortality in HCV-infected liver transplant (LT) recipients. Risk factors for more severe recurrence that are potentially modifiable are older donor age, prolonged cold ischaemia time, prior treated acute rejection, CMV hepatitis, IL28B donor genotype, and post-LT insulin resistance. The most effective means of preventing HCV recurrence is eradicating HCV prior to LT. Select wait-list candidates with compensated or mildly decompensated disease can be considered for antiviral treatment with peginterferon, ribavirin (and protease inhibitor if genotype 1). For the majority of LT patients, HCV treatment must be delayed until post-transplant. Treatment is generally undertaken if histologic severity reaches grade 3 or 4 necroinflammation or stage ≥2 fibrosis, or if cholestatic hepatitis. Achievement of sustained viral response (SVR) post-LT is associated with stabilization of fibrosis and improved graft survival. SVR is attained in ～30% of patients treated with peginterferon and ribavirin. Poor tolerability of therapy is a limitation. Combination therapy with telaprevir or boceprevir added to peginterferon and ribavirin is anticipated to increase efficacy but with higher rates of adverse effects and challenges in managing drug–drug interactions between the protease inhibitors and calcineurin inhibitors/sirolimus.     

Acute-on-chronic liver failure in children

Although various complex definitions of acute-on-chronic liver failure(ACLF)have been suggested in relation to adult patients, there is currently no universal definition of the syndrome in pediatric patients. In simplified terms, ACLF is characterized by the acute deterioration of the liver functions due to the effects of a precipitating factor on the basis of a chronic liver disease. Acute events and underlying liver diseases are very different in children from those seen in adults.Moreover, acute events and underlying chronic liver diseases vary among geographical regions, although it seems that the most common such diseases and acute events are autoimmune hepatitis, Wilson's disease, and their flares. ACLF is associated with a poor prognosis. While no scoring systems have been developed to predict the prognosis for children with ACLF, modified versions of the Asian Pacific Association for the Study of the liver's acute-on-chronic liver failure scoring system and the Chronic Liver Failure-Sequential Organ Failure Assessment criteria can be used in children until specific and validated scoring systems are available. Aside from liver transplantation, there is no proven treatment for ACLF. Thus, the early recognition of ACLF prior to the development of extrahepatic organ failure is important.     

Autoimmune hepatitis-primary biliary cirrhosis concurrent with biliary stricture after liver transplantation

Although the development of de novo autoimmune liver disease after liver transplantation(LT)has been described in both children and adults,autoimmune hepatitis(AIH)-primary biliary cirrhosis(PBC)overlap syndrome has rarely been seen in liver transplant recipients.Here,we report a 50-year-old man who underwent LT for decompensated liver disease secondary to alcoholic steatohepatitis.His liver function tests became markedly abnormal 8 years after LT.Standard autoimmune serological tests were positive for anti-nuclear and antimitochondrial antibodies,and a marked biochemical response was observed to a regimen consisting of prednisone and ursodeoxycholic acid added to maintain immunosuppressant tacrolimus.Liver biopsy showed moderate bile duct lesions and periportal lymphocytes infiltrating along with light fibrosis,which confirmed the diagnosis of AIH-PBC overlap syndrome.We believe that this may be a case of post-LT de novo AIH-PBC overlap syndrome;a novel type of autoimmune overlap syndrome.     

Hepatitis D virus and liver transplantation: Indications and outcomes

Hepatitis D virus(HDV) is a dependent virus that relies on hepatitis B virus for its replication and transmission. Chronic hepatitis D is a severe form of viral hepatitis that can result in end stage liver disease. Currently, pegylated interferon alpha is the only approved therapy for chronic HDV infection and is associated with significant side effects. Liver transplantation(LT) is the only treatment option for patients with end-stage liver disease, hepatocellular carcinoma, or fulminant hepatitis due to coinfection with HDV. As LT for HDV and hepatitis B virus coinfection is uncommon in the United States, most data on the long-term impact of LT on HDV are from international centers. In this review, we discuss the indications and results of LT with treatment options in HDV patients.     

Long‐term trends in chronic hepatitis B virus infection associated liver transplantation outcomes in the United States

With effective antiviral therapies, rates of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) and decompensated liver disease requiring liver transplantation (LT) are expected to decrease. We aim to evaluate overall trends in LT waitlist registrations, waitlist survival and likelihood of receiving LT among chronic HBV patients in the United States. Using the United Network for Organ Sharing database, we retrospectively evaluated adults (age≥18) with chronic HBV (with and without HCC) listed for LT from 1992 to 1996 (Era 1) vs 1997 to 2004 (Era 2) vs 2005‐2015 (Era 3). Multivariate Cox‐regression models evaluated probability of waitlist survival and receiving LT. Overall, 6797 chronic HBV adults were listed for LT. While the total number of HBV patients listed for LT remained stable, the proportion of HBV patients with HCC increased from 5.4% in Era 1 to 39.0% in Era 3. Compared to Era 1, waitlist mortality was higher in Era 2 (HR: 4.55, P<.001) and Era 3 (HR: 3.63, P<.001). However, in the most recent era, waitlist mortality significantly improved (compared to 2005‐2007: 2008‐2011: HR: 0.74, P=.05, 95% CI: 0.55‐0.99; 2012‐2015: HR: 0.53, P<.001, 95% CI: 0.38‐0.75). Probability of receiving LT was also lower with latter time periods (compared to 2005‐2007: 2008‐2011: HR: 0.77, P<.001 95% CI: 0.68‐0.86; 2012‐2015: HR: 0.61, P<.001, 95% CI: 0.54‐0.69). Although the number of HBV patients requiring LT remained stable, the proportion of HBV patients with HCC continues to rise. The decrease in waitlist mortality and lower likelihood of LT among HBV patients may reflect the effectiveness of antiviral therapies in delaying disease progression in the current era.     

Liver transplantation in patients with chronic viral hepatitis

Liver transplantation (LT) for end-stage liver disease secondary to hepatitis viruses has evolved rapidly during the last two decades. Currently, due to significant improvements in immunosuppressive therapy and surgical techniques, excellent survival rates and quality of life can be achieved. Among several circumstances that may pose a threat to long-term survival, the greatest is likely the recurrence of the original liver disease. Recurrence of viral infection and hepatitis is a common problem for patients undergoing LT for hepatitis B or hepatitis C. In the early 1980s, results of LT for chronic hepatitis B virus (HBV) infection were hampered by recurrent infection and subsequent allograft failure. However, following the introduction of passive immunoprophylaxis with hepatitis B immunoglobulin (HBIg) and treatment with potent oral nucleoside analogs, there has been a resurgence in the interest for this indication. HCV-related end-stage liver disease virus accounts for approximately 50% of LT in the United States and Europe. Despite the decrease in the number of new HCV infections, the prevalence of advanced HCV-related liver disease is steadily increasing. In light of the near universal recurrence of posttransplantation HCV infection and our limited ability to treat recurrent disease, transplantation is in danger of being overrun by viral hepatitis, unless effective strategies can be used to treat disease. This review summarizes available data and highlights appropriate strategies to improve outcomes.     

An Overview of Liver Transplant Pathology: Data from a Tertiary Referral Centre in Western India

Introduction and aim. 1. Study of liver explants - Etiologic types of end-stage chronic liver disease (ESCLD) and acute liver failure (ALF) in adults and children. 2. Assessment of donor steatosis and incidental granulomas. 3. Post-transplant liver biopsies.Material and methods. Specimens of 180 explant hepatectomies, 173 donor wedge and 30 core liver biopsies, and 58 post transplant liver biopsies received in our department from April 2013 to March 2017.Results. 1. Most common causes of ESCLD in adults were: alcohol related (30.32%), hepatitis virus related (18.71%) and non-alcoholic steatohepatitis related (18.06%); and in children < 12 years were: biliary atresia (27.27%), autoimmune disease (18.18%) and Wilson’s disease (18.18%). Most common causes of ALF in adults and children were anti-tubercular therapy induced and idiopathic, respectively. 2. Prevalence rate of moderate steatosis (between 30-60%) was 4.28%. Incidental granulomas were seen in 5 cases. 3. Most common diagnoses of post-transplant biopsies in adults included acute cellular rejection (ACR) (36.17%), recurrence of viral disease (8.51%) and moderate non-specific portal triaditis (8.51%). Among children < 12 years, most common diagnoses included unremarkable liver parenchyma, ACR and ischemia/reper fusion injury.Conclusion. 1. Alcohol- and hepatitis- virus related ESCLD, and biliary atresia are leading indications for liver transplantation in adults and children, respectively. 2. Prevalence of 4.28% of moderate steatosis, is much lower than that documented in western literature. Only 5 cases of incidental granulomas is unexpectedly low in a country endemic for tuberculosis. 3. Most common diagnoses of post-transplant liver biopsies in adults has been acute rejection, which is similar to the findings from much larger published series.     

Six month abstinence rule for liver transplantation in severe alcoholic liver disease patients

Alcoholic liver disease(ALD) is the second most common diagnosis among patients undergoing liver transplantation(LT). The recovery results of patients transplanted for ALD are often at least as good as those of patients transplanted for other diagnoses and better than those suffering from hepatitis C virus, cryptogenic cirrhosis, or hepatocellular carcinoma. Inthe case of medically non-responding patients with severe acute alcoholic hepatitis or acute-on chronic liver failure, the refusal of LT is often based on the lack of the required alcohol abstinence period of six months. The obligatory abidance of a period of abstinence as a transplant eligibility requirement for medically non-responding patients seems unfair and inhumane, since the majority of these patients will not survive the six-month abstinence period. Data from various studies have challenged the 6-mo rule, while excellent survival results of LT have been observed in selected patients with severe alcoholic hepatitis not responding to medical therapy. Patients with severe advanced ALD should have legal access to LT. The mere lack of pre-LT abstinence should not be an obstacle for being listed.     

Living donor liver transplantation

The introduction of living donor liver transplantation (LDLT) has been one of the most remarkable steps in the field of liver transplantation (LT). First introduced for children in 1989, its adoption for adults has followed only 10 years later. As the demand for LT continues to increase, LDLT provides life-saving therapy for many patients who would otherwise die awaiting a cadaveric organ. In recent years, LDLT has been shown to be a clinically safe addition to deceased donor liver transplantation (DDLT) and has been able to significantly extend the scarce donor pool. As long as the donor shortage continues to increase, LDLT will play an important role in the future of LT.     

Acute liver failure

Acute liver failure (ALF) (sometimes referred to as fulminant hepatic failure) is a clinical syndrome from a variety of causes resulting from rapid loss in hepatocyte function, typically associated with coagulopathy and encephalopathy in a patient without preexisting liver disease or cirrhosis. Cerebral edema is a cardinal feature and may produce uncal herniation, yielding brain stem compression and death. The typical interval from onset of symptoms to onset of encephalopathy is 1 to 2 weeks, but cases evolving more slowly, up to 6 months, may still be included in the definition. ALF is rare, affecting 2000 patients annually in the United States, and comprises ～7% of liver transplants annually. Currently, in the United States, acetaminophen accounts for ～50% of all cases of ALF, but other etiologies include hepatitis, drug-induced liver injury, autoimmune hepatitis. Prior to the availability of liver transplantation (LT), mortality of ALF was extremely high, often exceeding 90%; most common causes of death were multiorgan failure, hemorrhage, infection, and cerebral edema. Fortunately, survival has improved considerably in the last 3 decades (overall survival now exceeds 60%). In large part, this improved survival reflects the option of LT but also reflects the high frequency of acetaminophen toxicity as a cause of ALF. In fact, most patients with ALF are not candidates for LT. Critical care of patients with ALF is key to their survival, and decisions must sometimes be made with inadequate information. We review standard practices (medical, pharmacological, and LT) and new research initiatives and findings for this interesting but vexing orphan disease. Particular attention will be paid to practical matters for clinicians to consider in approaching the ALF patient.     

Assessment of liver stiffness in patients after living donor liver transplantation by transient elastography

Objective. Recurrence of hepatitis and progression of fibrosis are major problems in liver transplantation (LT) for patients with hepatitis C. Liver stiffness measurement (LSM) by transient elastography correlates well with histologic liver fibrosis stages in chronic liver diseases. The aim of this study was to evaluate the usefulness of transient elastography for the assessment of fibrosis in patients after living donor LT. Material and methods. Seventy-nine patients who visited our institution, and in whom LSM was successfully evaluated, were enrolled in the study. The patients were divided into three groups according to positivity for hepatitis C antibody and hepatitis B surface antigen as the hepatitis C virus (HCV) group (n=37), the hepatitis B virus (HBV) group (n=10), and the NBNC (negative for both hepatitis B and C) group (n=32). The correlation between LSM and histologic fibrosis stage was assessed in 36 patients. LSM was also compared with regard to the effect of interferon therapy in HCV patients. Results. The median value for liver stiffness was 6.8 kPa and the median time from LT was 3.1 years. In patients who underwent liver biopsy, stiffness was significantly correlated with the stages of fibrosis (p<0.001, rho = 0.848). In patients who received interferon therapy after LT, the LSM decreased over time in those with a sustained virological response, whereas LSM increased in patients without a response. Conclusion. Transient elastography may be an appropriate non-invasive procedure to sequentially assess the progression of liver fibrosis in patients after LT.     

Chronic viral hepatitis in childhood

In endemic areas infection with hepatitis B virus is a common cause of chronic liver disease in childhood. High levels of viral replication and mild ALT abnormalities are the rule in children infected perinatally and many of them are likely to maintain viral replication through their youth. Conversely about 90% of children infected later in life clear HBeAg and achieve sustained remission of liver disease before reaching adulthood. The eventual outcome of infection and disease in these patients remains unpredictable as reactivation of liver damage and viral replication may occur after several years of sustained remission. Cirrhosis is a rare and early complication of chronic HBV infection in children, and a risk factor for hepatocellular carcinoma. IFN therapy can accelerate HBV DNA clearance, improving the spontaneous anti-HBe seroconversion rate in Caucasian children by two to three times.Hepatitis delta is the most severe form of chronic viral hepatitis in childhood. Cirrhosis can be diagnosed in up to 26% of patients at presentation, and few cases respond to IFN therapy.Hepatitis C is relatively rare in children. Before the discovery of HCV blood transfusions were the most common source of infection. Hepatitis C is usually a mild, asymptomatic disease in otherwise healthy children, but has a poor propensity to spontaneous remission over the years. For this reason, and based on the experience in adults, IFN treatment is now being evaluated.     

Hepatoerythropoietic porphyria precipitated by viral hepatitis.

Porphyria cutanea tarda (PCT), the condition resulting from a deficiency of hepatic uroporphyrinogen decarboxylase activity, is the commonest form of porphyria. Both acquired and familial form exist and are commonly associated in adults with liver disease and hepatic iron overload. The condition is extremely rare in children; most cases of childhood PCT are familial and some particularly severe cases have been shown to have a hepatoerythropoietic porphyria or homozygous uroporphyrinogen decarboxylase deficiency. A case is described of hepatoerythropoietic porphyria in which the disease was first precipitated at the age of two by a coincidental hepatitis A infection and improved as the hepatitis cleared. This paper reviews the evidence that viral hepatitis may precipitate overt PCT in children in a manner analogous to the precipitation of PCT in adults by alcohol associated liver disease.     

Management of hepatitis C infection before and after liver transplantation

Chronic hepatitis C (CHC) is the most common indication for liver transplantation (LT). Aggressive treatment of hepatitis C virus (HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post-LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon (IFN)-based regimens can be used in dual-agent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals (e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN-based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post-LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free anti-HCV therapy for pre- and post-LT remains high.     

Key roles of hepatologists in successful liver transplantation

Liver transplantation (LT) has been carried out for acute liver failure, end‐stage liver disease, and congenital metabolic disease in more than 7000 cases in Japan. Liver transplantation has been established as a treatment option, and survival rates have improved. In 2016, a new registration/allocation policy and a new scoring system for deceased donor LT were established. The management of perioperative patients and preoperative therapy for liver failure, nutrition, and preventing infection were upgraded. Moreover, methods for preventing disease recurrence, and treating hepatitis C and B have been developed and are particularly crucial for good outcomes in LT. Treatment of the complications of obesity, lifestyle‐related diseases, and malignancy is also required post‐LT. Managing patients after LT contributes to better survival and quality of life. The role of hepatologists is becoming broader and more important.     

Skin cancer in immunosuppressed transplant patients: Vigilance matters

Liver transplantation(LT) is a widely-accepted, definitive therapy of irreversible liver diseases including hepatitis C, alcoholic liver disease and metabolic liver disease. After transplantation, patients generally use a variety of immunosuppressive medications for the rest of their lives to prevent rejection of transplanted liver. Mortality after LT is mainly caused by recurrence of alcoholic hepatitis which is mostly seen in the patients who resume heavy drinking. On the other hand, de-novo malignancies after LT are not seldom. Skin cancers make up 13.5% of the de-novo malignancies seen in these patients. Malignancies tend to affect survival earlier in the course with a 53% risk of death at 5 years after diagnosis. We aimed to report a case who underwent LT secondary to alcoholic liver disease and developed squamous cell carcinoma of the skin eighteen years after transplantation. In summary, transplant recipients are recommended to be educated on self examination for skin cancer; health care providers should be further suspicious during routine dermatological examinations of the transplant patients and biopsies of possible lesions for skin cancer is warranted even many years after transplantation.     

A prospective study on the causes of notably raised alanine aminotransferase (ALT)

Objective High levels of alanine aminotransferase (ALT) can be a marker of severe liver disease with variable aetiologies and prognosis. Very few prospective studies have been undertaken on the aetiology and prognosis of patients with high ALT levels. No population-based prospective study has systematically evaluated drug-induced liver injury (DILI) among these patients. The objective was to determine the aetiology and prognosis of patients with high ALT. Materials and methods In a catchment area of 160,000 inhabitants, a population-based prospective study identified all adult patients with serum level of ALT?>500 U/L during a 12-month period. All underwent thorough diagnostic work-up and follow-up. In suspected DILI, causality was assessed with Roussel Uclaf Causality Assessment Method. Results A total of 155 patients were identified with ALT?>500 U/L, 12 children and one with ALT of non-liver-related origin, leaving 142 patients for the analysis: 73 (51%) males, median age 52 (IQR 36–68, range 19–89 years). The most common causes were choledocholithiasis 48/142 (34%), ischaemic hepatitis 26 (18%), viral hepatitis 16 (11%) and DILI 15 (11%), hepatobiliary malignancy (n?=?6), surgery/interventions (n?=?8) and other aetiologies (n?=?23). No specific aetiology was found in 6% of cases. In the total study cohort 99 (70%) required hospitalisation, 78 (55%) had jaundice and 22 (16%) died, liver-related death in 10%, 35% in IH and 7% in DILI. Conclusions The most common cause of notably high ALT was choledocholithiasis. Ischaemic hepatitis was a common aetiology with approximately 35% liver-related mortality. Viral hepatitis and DILI were important aetiologies among these patients.