Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

Incidence of cirrhosis in Iceland-impact of the TraP HepC nationwide HCV elimination program.

OBJECTIVE: In 2016, a nationwide elimination program for hepatitis C virus (HCV) was initiated in Iceland, entitled Treatment as Prevention for Hepatitis C (TraP HepC), providing unrestricted access to antiviral treatment. The aims were to describe the changes in etiology and epidemiology of cirrhosis in Iceland and to assess the trends in HCV-related cirrhosis following TraP HepC. METHODS: The study included all patients newly diagnosed with cirrhosis in 2016-2022. Diagnosis was based on liver elastography, histology, or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, or elevated international normalized ratio (INR). RESULTS: Over the study period, 342 new cirrhosis patients were identified, 223 (65%) males, median age 62 years. The crude overall incidence was 13.8 cases per 100,000 inhabitants annually. The most common etiologies were alcohol-related liver disease (ALD) (40%), metabolic dysfunction-associated steatotic liver disease (MASLD) (28%), and HCV with or without alcohol overconsumption (15%). The number of HCV cirrhosis cases was unusually high in 2016 (n = 23) due to intensified case-finding, but decreased significantly over the study period (p < 0.001) to n = 1 (2021) and n = 2 (2022). The overall 5-year survival was 55% (95% CI 48.9-62.3%). The most common causes of death were hepatocellular carcinoma (26%) and liver failure (25%). CONCLUSION: During the past two decades, the incidence of cirrhosis has increased extraordinarily in Iceland, associated with increased alcohol consumption, obesity, and HCV. ALD and MASLD now collectively make up two thirds of cases in Iceland. Following a nationwide elimination program, incidence of HCV cirrhosis has dropped rapidly in Iceland.

The Epidemiology of Newly Recognized Causes of Drug-Induced Liver Injury: An Update.

The incidence and prevalence of drug-induced liver injury appear to be increasing globally, for example, with the introduction of checkpoint inhibitors. Several reviews have been published in the last decade on the epidemiology of DILI, both among hospitalized patients and in the general population, as well as from retrospective and prospective studies on DILI. Most of these reviews have not focused on newly recognized agents that have recently changed the landscape of DILI. Apart from liver injury associated with antibiotics, oncological agents, particularly checkpoint inhibitors, are increasingly being recognized as causing liver injury. The type of liver injury associated with these agents is not idiosyncratic but rather an indirect type of injury. Furthermore, recently, COVID-19 vaccines and green tea extract have been found to lead to liver injury. Checkpoint inhibitors have revolutionized the treatment of many malignancies, such as malignant melanoma, lung cancer, and renal cancer. Via the activation of T cells, they can increase immune activity against malignant cells, but at the same time, they can decrease immune tolerance and therefore lead to immune-related adverse effects in many organs. The most common adverse effect in clinical practice is liver injury. A recent prospective study demonstrated an 8% frequency of DILI due to the use of checkpoint inhibitors among patients with malignant melanoma and renal cancer. This rate is much higher than observed with drugs, leading to idiosyncratic liver injury. Shortly after the implementation of the worldwide vaccination program against COVID-19, several case reports were published on suspected vaccination-induced autoimmune-like hepatitis occurring shortly after the vaccination. At first, these reports were met with skepticism, but currently, around 100 reports have been published, and cases of positive recurrence have been reported. The clinical, biochemical, immunological, and histological features are indistinguishable from classic autoimmune hepatitis (AIH). These reactions are very similar to drug-induced autoimmune-like hepatitis (DI-ALH) due to drugs such as nitrofurantoin, minocycline, and infliximab, which do not relapse after a short course of corticosteroids, which is the general rule in classic autoimmune hepatitis (AIH). Green tea extract has been found to be a well-documented cause of acute hepatocellular liver injury with jaundice. A strong HLA association has been reported, showing a high prevalence of HLA-B*35:01 among patients suffering from green tea-induced liver injury. Overall, 3% of patients recruited in the DILIN study were supplemented with green tea extract as one of the ingredients. In a prospective population-based study from Iceland, green tea was implicated in approximately 8% of patients with DILI.

The incidence and prevalence of proton pump inhibitor usage among internal medicine patients after hospital admission: A retrospective cohort study.

BACKGROUND: The use of proton pump inhibitors (PPIs) has increased over the past decades. One potential gateway into new PPI use is following a hospital admission. The study aimed to examine the incidence of new PPI usage following admission to internal medicine services and the ratio of new persistent users. METHODS: A retrospective descriptive study was conducted among all adults who had been admitted to internal medicine wards at the National University Hospital of Iceland from 2010-2020. Data was obtained from the Icelandic Internal Medicine Database. The proportion of patients who started treatment with PPI within 3 months of discharge (new users) and the proportion of patients who continued to use it after 3 months (persistent users) were examined. RESULTS: Among 85.942 admissions during the study period, 7238 (15.6%) became new users, and of those 4942 (68%) were new persistent users. The incidence of new PPI use was highest for patients discharged from gastroenterology (32.2%), hematology (31.8%), and oncology (29.2%). Patients with new PPI use more commonly had a history of malignancy (19.5%) and liver disease (22.7%) and more commonly were admitted to the ICU during their hospitalization. The highest ratio of persistent usage was among patients discharged from geriatric medicine (84%). CONCLUSION: One in every six patients admitted to internal medicine wards filled out a prescription for PPI within 3 months from discharge, and a large proportion of them became persistent users. The high rate of new PPI users from oncology and hematology is noteworthy and requires further research.

The Impact of Sex on the Response to Proton Pump Inhibitor Treatment.

Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. Hypergastrinemia secondary to PPIs has trophic effects on gastric mucosa, leading to enterochromaffin-like cell hyperplasia and gastric (fundic) polyp formation, and it is believed to provoke acid rebound following PPI withdrawal that induces PPI overutilization. Previous studies have found higher gastrin release following PPI therapy in females compared with males, and sex differences have also been demonstrated in pharmacokinetic parameters and dose requirements for acid reflux. It is conceivable that females might be at increased risk of PPI overuse, because they often receive higher milligram-per-kilogram doses. The prevalence of PPI use is more common among females, and the female sex is a risk factor for adverse drug reactions. This non-systematic review outlines the current knowledge of the impact of biological sex on the response to PPIs. The aim is to highlight the female sex as a potential risk factor that could be a step toward precision medicine and should be considered in future research on the response to PPI treatment.

The Evolving Profile of Idiosyncratic Drug-Induced Liver Injury.

Idiosyncratic drug-induced liver injury (DILI) is an infrequent but important cause of liver disease. Newly identified causes of DILI include the COVID vaccines, turmeric, green tea extract, and immune checkpoint inhibitors. DILI is largely a clinical diagnosis of exclusion that requires evaluation for more common causes of liver injury and a compatible temporal association with the suspect drug. Recent progress in DILI causality assessment includes the development of the semi-automated revised electronic causality assessment method (RECAM) instrument. In addition, several drug-specific HLA associations have been identified that can help with the confirmation or exclusion of DILI in individual patients. Various prognostic models can help identify the 5%-10% of patients at highest risk of death. Following suspect drug cessation, 80% of patients with DILI fully recover, whereas 10%-15% have persistently abnormal laboratory studies at 6 months of follow-up. Hospitalized patients with DILI with an elevated international normalized ratio or mental status changes should be considered for N-acetylcysteine therapy and urgent liver transplant evaluation. Selected patients with moderate to severe drug reaction with eosinophilia and systemic symptoms or autoimmune features on liver biopsy may benefit from short-term corticosteroids. However, prospective studies are needed to determine the optimal patients and dose and duration of steroids to use. LiverTox is a comprehensive, freely accessible Web site with important information regarding the hepatotoxicity profile of more than 1000 approved medications and 60 herbal and dietary supplement products. It is hoped that ongoing "omics" studies will lead to additional insight into DILI pathogenesis, improved diagnostic and prognostic biomarkers, and mechanism-based treatments.

Drug-Induced Liver Injury due to Biologics and Immune Check Point Inhibitors.

Biological agents have in the last two decades become very important therapeutic agents, particularly for the treatment of various autoimmune disorders. The most widely used biologics are the tumor necrosis factor-α (TNF-α) receptor antagonists: infliximab, adalimumab, and etanercept. Other commonly used biological agents are interleukin (IL)-1 receptor antagonist (Anakinra), interleukin (IL)-6 receptor antagonist (tocilizumab), and CD20 surface antigen antagonist (rituximab). The current review will however focus on TNF-α receptor antagonists.

A new framework for advancing in drug-induced liver injury research. The Prospective European DILI Registry.

BACKGROUND & AIMS: No multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported. METHODS: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016-2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled. RESULTS: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation. CONCLUSIONS: In this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI.

Gastrointestinal Bleeding on Oral Anticoagulation: What is Currently Known.

Gastrointestinal bleeding (GIB) is the most common type of bleeding occurring in patients on oral anticoagulation. A meta-analysis of the landmark randomized controlled trials (RCTs) for patients with atrial fibrillation demonstrated that direct oral anticoagulants (DOACs) were associated with higher GIB rates compared to warfarin. However, significant heterogeneity existed between studies. While rivaroxaban, high-dose dabigatran, and high-dose edoxaban were associated with higher GIB rates than warfarin, GIB rates were similar between warfarin users and both apixaban and low-dose dabigatran users. Additionally, previous observational studies have yielded conflicting reports on whether GIB rates differ between warfarin and DOACs. Meta-analyses of observational studies demonstrated that warfarin is associated with lower rates of GIB compared to rivaroxaban, similar or lower rates compared to dabigatran, and higher rates compared to apixaban. Importantly, no RCT has compared individual DOACs directly and due to the different selection criteria of the initial RCTs, indirect comparisons between DOACs using these studies are unreliable. The best available information of comparisons between individual DOACs is therefore limited to observational studies. There is mounting evidence that suggests that rivaroxaban is associated with a higher risk of GIB compared to other DOACs. Finally, GIB induced by oral anticoagulation may have some positive aspects. Interestingly, there are studies that indicate oral anticoagulation facilitates colorectal cancer detection. Furthermore, results from RCTs and observational studies suggest that warfarin may even decrease the incidence of cancer.

Multiomics study of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.

Checkpoint inhibitor-induced hepatotoxicity: Role of liver biopsy and management approach.

Immunological checkpoint inhibitors (ICIs) have revolutionized therapy of many different malignanices. Concomitant immune-mediated adverse effects are common and can affect many organs such as the skin, lungs, gastrointestinal and endocrine organs as well as the liver. Liver injury has been reported in 3%-8% of patients with grade III-IV hepatitis in retrospective studies. The liver injury is characterized by hepatocellular injury resembling autoimmune hepatitis biochemically but not immunologically as patients with ICI induced hepatoxicity rarely have auto-antibodies or IgG elevation. The role for liver biopsy (LB) in patients with suspected liver injury due to ICIs is controversial and it is not clear whether results of a LB will change clinical management. LB can be helpful when there is diagnostic uncertainty and pre-existing liver disease is suspected. Although there are no distinctive histological features, the finding of granulomas and endothelitis may suggest a specific type of hepatitis induced by ICIs. The natural history of hepatotoxicity of ICI therapy is not well known. Recent studies have demonstrated that 33%-50% of patients improve spontaneously with discontinuation of ICIs. In patients with jaundice and/or coagulopathy corticosteroids are used. The high doses of corticosteroids with 1-2 mg/kg/d of methylprednisolone recommended by the oncological societies are controversial. Recently it has shown that initial treatment with 1 mg/kg/d provided similar liver tests improvement which was also associated with a reduced risk of steroid-induced adverse effects in comparison with higher-dose regimens. Secondary immunosuppression mostly with mycophenolate mofetil has been reported to be helpful.

Drug induced liver injury by immunotherapy.

Immunotherapy has become the cornerstone of treatment of many malignancies. Check point inhibitors (CPIs) have been shown to be able to halt the progression of several types of advanced malignancies such as malignant melanoma and even keep patients in longstanding clinical remission (1-2). Thus, the use of CPIs has shown a substantial therapeutic benefit marked by signficant improvement in patient survival. However, this efficacy comes with a cost of several immune associated adverse effects due to the corollary reduction of immune self-tolerance. These adverse can be manifested as gastrointestinal symptoms (colitis), dermatological (dermatitis), lung symptoms (pneumonitis), endocrine manifestations (hypophysitis), apart from drug-induced liver injury (DILI), which is the focus of this editorial. Among 100 DILI patients due to CPIs of whom 53% had advanced melanoma, 45% had concomitant immune-mediated adverse effects, with dermatological (14%) and colitis (9%) being the most common (3).

A retrospective analysis of the duration of mechanical ventilation in Scandinavian paediatric heart centres.

AIM: Early extubation after cardiac surgery shortens paediatric intensive care unit (PICU) length of stay (LOS) and decreases complications from mechanical ventilation (MV). We explored the duration of MV in Scandinavian paediatric heart centres. METHODS: We retrospectively reviewed the MV duration and PICU LOS of 696 children operated for atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot (TOF) or total cavopulmonary connection (TCPC) in four Scandinavian centres in 2015-2016. Neonates (n = 90) were included regardless of heart surgery type. RESULTS: Patients with ASD were extubated at a median of 3.25 h (interquartile range [IQR] 2.00-4.83), followed by patients with TCPC (median 5.00 h, IQR 2.60-16.83), VSD (median 7.00 h, IQR 3.69-22.25) and TOF (median 18.08 h, IQR 6.00-41.38). Neonates were not extubated early (median 94.42 h, IQR 45.03-138.14). Although MV durations were reflected in PICU LOS, this was not as apparent among those extubated within 12 h. The Swedish centres had shortest MV durations and PICU LOS. Extubation failed in 24/696 (3.4%) of patients. CONCLUSION: Scandinavian paediatric heart centres differed in the duration of postoperative MV. Deferring extubation up to 12 h postoperatively did not markedly prolong PICU LOS.

Causes of gastrointestinal bleeding in oral anticoagulant users compared to non-users in a population-based study.

BACKGROUND/AIMS: Causes of gastrointestinal bleeding (GIB) in patients on oral anticoagulants (OACs) are not well established. The aims of the study were to compare the causes of GIB in patients on OACs and those not on OAC therapy. METHODS: A nationwide study of all GIB events in patients on OACs in Iceland from 2014-2019 was conducted. Bleeding events were obtained through ICD-10 codes and review of endoscopy databases, confirmed by review of medical records. For comparison, patients not on OACs from previous Icelandic population-based studies were used. RESULTS: Among 752 GIB events in 12,005 patients on OACs, 273 (1.9%) had verified upper and 391 (2.7%) had verified lower GIB. For lower GIB, multivariate analysis showed that OAC users were more likely to have colonic polyps (OR 6.6, 95% CI: 2.4 - 17.8, p < .001) or colorectal cancer (OR 3.7, 95% CI: 2.0 - 7.0, p < .001) but less likely to have ischemic colitis (OR 0.11, 95% CI: 0.04 - 0.26, p < .001). For upper GIB, bleeding from mucosal erosions (OR 4.0 95% CI: 2.5 - 7.9, p < .001) and angiodysplasia (OR 3.6, 95%CI: 1.5 - 8.6, p = .003) were more common in OAC users. CONCLUSIONS: A high proportion of GIB caused by colonic polyps and colorectal cancer among OAC patients indicates that OACs treatment may facilitate cancer diagnosis. The low proportion of ischemic colitis among those on OACs suggests that OACs provide a protective effect against ischemic colitis. OACs seem to increase the bleeding from angiodysplasia and mucosal erosive disease.

A nationwide population-based prospective study of cirrhosis in Iceland.

BACKGROUND & AIMS: The incidence of cirrhosis in Iceland has been the lowest in the world with only 3 cases per 100,000 inhabitants. Alcohol consumption has almost doubled in Iceland from 1980 to 2016. Obesity has also risen and hepatitis C virus has spread among people who inject drugs in Iceland. The aim of this study was to evaluate the effects of these risk factors on the incidence and aetiology of cirrhosis in Iceland. METHODS: The study included all patients diagnosed with cirrhosis for the first time during 2010-2015. Diagnosis was based on liver histology or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, and/or elevated INR. RESULTS: Overall, 157 patients were diagnosed, 105 (67%) males, mean age 61 years. The overall incidence was 9.7 cases per 100,000 inhabitants annually. Alcohol was the only underlying cause in 48/157 (31%), non-alcoholic fatty liver disease (NAFLD) in 34/157(22%), and alcohol and hepatitis C together in 23/157(15%) were the most common causes. Only 6% of patients had an unknown cause of cirrhosis. Upon diagnosis, the median model for end-stage liver disease score was 11 (IQR 8-15), 53% were of Child-Pugh class A whereas 61 (39%) had ascites, 11% encephalopathy, and 8% variceal bleeding. In all, 25% of deaths were from HCC and 25% from liver failure. CONCLUSION: A major increase in incidence of cirrhosis has occurred in Iceland associated with increases in alcohol consumption, obesity, and hepatitis C. In a high proportion NAFLD was the aetiology and very few had unknown cause of cirrhosis. The highest death rate was from HCC. LAY SUMMARY: In a nationwide population-based study from Iceland, including all patients diagnosed with cirrhosis of the liver over a period of 5 years, we found the incidence of new cases had increased 3-fold compared with a previous study 20 years ago. The increase is attributable to increased alcohol consumption, an epidemic of diabetes and obesity, and infection with the hepatitis C virus. Furthermore, we found that with thorough investigations, a specific cause for cirrhosis could be found in 94% of patients. Patients with cirrhosis frequently die of liver cancer and other complications related to their liver disease.

Clinical management of patients with drug-induced liver injury (DILI).

Drug-induced liver injury (DILI) should be considered in all patients with recent elevation of liver tests without obvious etiology and normal hepatobiliary imaging. There is currently no biomarker that is helpful in diagnosis which relies on clinical and laboratory findings. Diagnosis is dependent on temporal relationship with a recently started drug or herbal and dietary supplement and elevated liver tests with exclusion of competing etiologies. The implicated agent should be discontinued and the patient should be observed closely. This is particularly important in patients with jaundice who have approximately 10% risk of liver related mortality and/or need for liver transplantation. There is no specific therapy for DILI which is only symptomatic such as for itching. Patients with jaundice and coagulopathy usually require hospitalization.