Clinical characteristics and HLA associations of azithromycin-induced liver injury.

BACKGROUND: Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug-induced liver injury (DILI) due to AZ. METHODS: The clinical characteristics of individuals with definite, highly likely, or probable AZ-DILI enrolled in the US Drug-Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ-DILI cases was compared to population controls, other DILI cases, and other antibiotic-associated DILI cases. RESULTS: Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ-DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA-DQA1*03:01 was significantly more common in AZ-DILI versus population controls and amoxicillin-clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). CONCLUSION: Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA-DQA1*03:01 was significantly more common in AZ cases compared to controls.

Composite Plot for Visualizing Aminotransferase and Bilirubin Changes in Clinical Trials of Subjects with Abnormal Baseline Values.

INTRODUCTION: On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. OBJECTIVE: The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values. METHODS: The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects' baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. RESULTS: The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. CONCLUSION: For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject's baseline and population threshold values.

Amiodarone and Dronedarone Causes Liver Injury with Distinctly Different Clinical Presentations.

OBJECTIVE: To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database. METHODS: Hepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020. RESULTS: Among DILIN's 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause. Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes. CONCLUSION: Amiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.

Vancomycin-Induced Liver Injury, DRESS, and HLA-A∗32:01.

BACKGROUND: Intravenous vancomycin therapy can cause liver injury as well as "drug reaction with eosinophilia and systemic symptoms" (DRESS) syndrome. This study aimed to better define the clinical features and HLA associations of vancomycin-induced liver injury. OBJECTIVE: To describe clinical, biochemical, and temporal characteristics of vancomycin-induced liver injury. METHODS: Cases of liver injury with recent exposure to vancomycin who were enrolled in the US Drug-induced Liver Injury Network between 2004 and 2020 were assessed. Sequencing of HLA alleles was performed on stored blood samples. RESULTS: Among 1697 cases of drug-induced liver injury identified between 2004 and 2021, 9 (0.5%) were attributed to intravenous vancomycin. The 9 cases included 6 men, median age 60 years (range, 23-85 days), and treatment for 26 days (range, 1-34 days). The clinical presentation was DRESS syndrome in 8 patients, of whom 6 received corticosteroids. Liver injury varied from hepatocellular to cholestatic and from mild (n = 5) to fatal (n = 1). In survivors, liver injury and DRESS syndrome ultimately resolved. HLA typing demonstrated the HLA-A∗32:01 allele in 7 vancomycin cases (78%, all with DRESS syndrome), versus 1 of 81 cases (1.2%) exposed but not attributed to vancomycin, and 113 of 1708 cases (6.6%) without vancomycin exposure. The allele frequency in vancomycin cases was 0.44 compared with less than 0.04 in US populations. CONCLUSIONS: Vancomycin-induced liver injury is commonly associated with DRESS syndrome and linked to HLA-A∗32:01. HLA-A∗32:01 testing could be considered early to risk-stratify patients using long-term intravenous vancomycin therapy.

Liver biopsy for assessment of suspected drug-induced liver injury in metabolic dysfunction-associated steatohepatitis clinical trials: Expert consensus from the Liver Forum.

BACKGROUND: Causality assessment of suspected drug-induced liver injury (DILI) during metabolic dysfunction-associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non-invasive testing may be provided on histology. AIM: To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting. METHODS: From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment. RESULTS: Expert opinion, guidance and recommendations on the role of liver biopsy as part of causality assessment of suspected DILI occurring during clinical trials for a drug(s) being developed for MASH are provided. Lessons learned from prior MASH programs are reviewed and gaps identified. CONCLUSIONS: Although there are no pathognomonic features, histologic evaluation of suspected DILI during MASH clinical trials may alter patient management, define the pattern and severity of injury, detect findings that favour a diagnosis of DILI versus MASH progression, identify prognostic features, characterise the clinicopathological phenotype of DILI, and/or define lesions that influence decisions about trial discontinuation and further development of the drug.

Thermal ablation compared to stereotactic body radiation therapy for hepatocellular carcinoma: A multicenter retrospective comparative study.

BACKGROUND AIMS: Early-stage HCC can be treated with thermal ablation or stereotactic body radiation therapy (SBRT). We retrospectively compared local progression, mortality, and toxicity among patients with HCC treated with ablation or SBRT in a multicenter, US cohort. APPROACH RESULTS: We included adult patients with treatment-naïve HCC lesions without vascular invasion treated with thermal ablation or SBRT per individual physician or institutional preference from January 2012 to December 2018. Outcomes included local progression after a 3-month landmark period assessed at the lesion level and overall survival at the patient level. Inverse probability of treatment weighting was used to account for imbalances in treatment groups. The Cox proportional hazard modeling was used to compare progression and overall survival, and logistic regression was used for toxicity. There were 642 patients with 786 lesions (median size: 2.1 cm) treated with ablation or SBRT. In adjusted analyses, SBRT was associated with a reduced risk of local progression compared to ablation (aHR 0.30, 95% CI: 0.15-0.60). However, SBRT-treated patients had an increased risk of liver dysfunction at 3 months (absolute difference 5.5%, aOR 2.31, 95% CI: 1.13-4.73) and death (aHR 2.04, 95% CI: 1.44-2.88, p < 0.0001). CONCLUSIONS: In this multicenter study of patients with HCC, SBRT was associated with a lower risk of local progression compared to thermal ablation but higher all-cause mortality. Survival differences may be attributable to residual confounding, patient selection, or downstream treatments. These retrospective real-world data help guide treatment decisions while demonstrating the need for a prospective clinical trial.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Incidence of Hepatitis E Infection in American Patients With Suspected Drug-Induced Liver Injury Is Low and Declining: The DILIN Prospective Study.

INTRODUCTION: Hepatitis E virus (HEV) infection rarely causes icteric hepatitis, yet 10%-40% of adult Americans have serological evidence of previous infection. The aim of this study was to investigate the incidence, presentation, and outcome of acute and previous HEV infection in a large cohort of patients with suspected drug-induced liver injury (DILI). METHODS: Serum samples from 2012 patients enrolled in the DILI Network were tested for anti-HEV immunoglobulin G (IgG). Those with detectable anti-HEV IgG underwent testing for anti-HEV IgM; those with detectable anti-HEV immunoglobulin m (IgM) were tested for HEV RNA. RESULTS: Anti-HEV IgG was detected in 407 (20%) patients and associated with increasing subject age and earlier year of enrollment. The median age of seropositive subjects was more than a decade higher than seronegative subjects (59.8 vs 48.7 years). The overall prevalence of anti-HEV declined from 22% (2004-2011) to 18% (2012-2019), suggestive of a cohort effect. The frequency of acute hepatitis E (median ALT = 1231 IU/L) also decreased from 3% (2004-2008) to 1.2% (2009-2013) to 0.6% (2014-2019). These results suggest that acute HEV infection is usually subclinical and was much more frequent in this cohort before 2004. DISCUSSION: Acute HEV infection accounts for less than 1% of suspected American DILI cases and is more frequent in older men. Previous HEV infection is also most commonly seen in older individuals. Clinicians should consider testing for unsuspected acute HEV infection in older adult patients with acute hepatocellular DILI and jaundice.

Whole Exome Sequencing Reveals Genetic Variants in HLA Class II Genes Associated With Transplant-free Survival of Indeterminate Acute Liver Failure.

INTRODUCTION: Indeterminate acute liver failure (IND-ALF) is a rare clinical syndrome with a high mortality rate. Lacking a known etiology makes rapid evaluation and treatment difficult, with liver transplantation often considered as the only therapeutic option. Our aim was to identify genetic variants from whole exome sequencing data that might be associated with IND-ALF clinical outcomes. METHODS: Bioinformatics analysis was performed on whole exome sequencing data for 22 patients with IND-ALF. A 2-tier approach was used to identify significant single-nucleotide polymorphisms (SNPs) associated with IND-ALF clinical outcomes. Tier 1 identified the SNPs with a higher relative risk in the IND-ALF population compared with those identified in control populations. Tier 2 determined the SNPs connected to transplant-free survival and associated with model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores. RESULTS: Thirty-one SNPs were found associated with a higher relative risk in the IND-ALF population compared with those in controls, of which 11 belong to the human leukocyte antigen (HLA) class II genes but none for the class I. Further analysis showed that 5 SNPs: rs796202376, rs139189937, and rs113473719 of HLA-DRB5; rs9272712 of HLA-DQA1; and rs747397929 of IDO1 were associated with a higher probability of IND-ALF transplant-free survival. Using 3 selected SNPs, a model for the polygenic risk score was developed to predict IND-ALF prognoses, which are comparable with those by model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores. DISCUSSION: Certain gene variants in HLA-DRB5, HLA-DQA1, and IDO1 were found associated with IND-ALF transplant-free survival. Once validated, these identified SNPs may help elucidate the mechanism of IND-ALF and assist in its diagnosis and management.

Value of liver biopsy in the diagnosis of drug-induced liver injury.

BACKGROUND & AIMS: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. METHODS: Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. RESULTS: Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. CONCLUSIONS: Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. LAY SUMMARY: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.

A revised electronic version of RUCAM for the diagnosis of DILI.

BACKGROUND AND AIMS: Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI Registry, published literature, and iterative computer modeling. APPROACH AND RESULTS: RUCAM criteria were updated, clarified, and computerized. We removed criteria 3 (risk factors) for lack of added value and criteria 4 because we felt it more useful to assess each drug separately. Criteria 6 (drug-specific risk) was anchored to LiverTox likelihood scores. Iterative testing in subsets of 50-100 single-agent, nonherbal cases from both registries was done to optimize performance. We used classification tree analysis to establish diagnostic cutoffs for this revised electronic causality assessment method (RECAM) and compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 DILIN, 96 Spanish DILI). Area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for RECAM and RUCAM. However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, p = 0.14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, p = 0.02; 65 vs. 48 for unlikely/excluded, p = 0.08) than RUCAM diagnostic categories. CONCLUSIONS: RECAM is an evidence-based update that is at least as capable as RUCAM in diagnosing DILI compared with expert opinion but is better than RUCAM at the diagnostic extremes. RECAM's increased objectivity and clarity will improve precision, reliability, and standardization of DILI diagnosis, but further refinement and validation in other cohorts are needed.

Roux-en-Y Gastric Bypass Is Associated With Increased Hazard for De Novo Alcohol-related Complications and Liver Disease.

GOAL: The goal of this study was to determine if bariatric surgeries are associated with de novo alcohol-related complications. BACKGROUND: Bariatric surgery is associated with an increased risk of alcohol use disorders. The effect of bariatric surgeries on other alcohol-related outcomes, including liver disease, is understudied. MATERIALS AND METHODS: Using the IMS PharMetrics database, we performed a cohort study of adults undergoing bariatric surgery or cholecystectomy, excluding patients with an alcohol-related diagnosis within 1 year before surgery. The primary outcome was any alcohol-related diagnosis after surgery. We fit a multivariable Cox proportional hazards model to determine independent associations between bariatric surgeries [Roux-en-Y gastric bypass (RYGB); adjustable gastric band; sleeve gastrectomy] versus cholecystectomy and the development of de novo alcohol-related outcomes. We further fit complication-specific models for each alcohol-related diagnosis. RESULTS: RYGB was significantly associated with an increased hazard of any de novo alcohol-related diagnosis [adjusted hazard ratio (AHR)=1.51, 95% confidence interval (CI): 1.40-1.62], while adjustable gastric band (AHR=0.55, 95% CI: 0.48-0.63) and sleeve gastrectomy (AHR=0.77, 95% CI: 0.64-0.91) had decreased hazards. RYGB was associated with a 2- to 3-fold higher hazard for alcoholic hepatitis (AHR=1.98, 95% CI: 1.17-3.33), abuse (AHR=2.05, 95% CI: 1.88-2.24), and poisoning (3.14, 95% CI: 1.80-5.49). CONCLUSIONS: RYGB was associated with higher hazards of developing de novo alcohol-related hepatitis, abuse, and poisoning compared with a control group. Patients without a history of alcohol use disorder should still be counseled on the increased risk of alcohol use and alcohol-related complications, including alcohol-related liver disease, following RYGB, and should be monitored long term for the development of alcohol-related complications.

Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) in Clinical Trials.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community.

Medicare/Medicaid Insurance, Rurality, and Black Race Associated With Provision of Hepatocellular Carcinoma Treatment and Survival.

BACKGROUND: Early treatment of hepatocellular carcinoma (HCC) is associated with improved survival, but many patients with HCC do not receive therapy. We aimed to examine factors associated with HCC treatment and survival among incident patients with HCC in a statewide cancer registry. MATERIALS AND METHODS: All patients with HCC from 2003 through 2013 were identified in the North Carolina cancer registry. These patients were linked to insurance claims from Medicare, Medicaid, and large private insurers in North Carolina. Associations between prespecified covariates and more advanced HCC stage at diagnosis (ie, multifocal cancer), care at a liver transplant center, and provision of HCC treatment were examined using multivariate logistic regression. A Cox proportional hazards model was developed to assess the association between these factors and survival. RESULTS: Of 1,809 patients with HCC, 53% were seen at a transplant center <90 days from diagnosis, with lower odds among those who were Black (adjusted odds ratio [aOR], 0.54; 95% CI, 0.39-0.74), had Medicare insurance (aOR, 0.35; 95% CI, 0.21-0.59), had Medicaid insurance (aOR, 0.46; 95% CI, 0.28-0.77), and lived in a rural area; odds of transplant center visits were higher among those who had prediagnosis alpha fetoprotein screening (aOR, 1.74; 95% CI, 1.35-2.23) and PCP and gastroenterology care (aOR, 1.66; 95% CI, 1.27-2.18). Treatment was more likely among patients who had prediagnosis gastroenterology care (aOR, 1.68; 95% CI, 0.98-2.86) and transplant center visits (aOR, 2.42; 95% CI, 1.74-3.36). Survival was strongly associated with age, cancer stage, cirrhosis complications, and receipt of HCC treatment. Individuals with Medicare (adjusted hazard ratio [aHR], 1.58; 95% CI, 1.20-2.09) and Medicaid insurance (aHR, 1.55; 95% CI, 1.17-2.05) had shorter survival than those with private insurance. CONCLUSIONS: In this population-based cohort of patients with HCC, Medicare/Medicaid insurance, rural residence, and Black race were associated with lower provision of HCC treatment and poorer survival. Efforts should be made to improve access to care for these vulnerable populations.

Liver injury associated with kratom, a popular opioid-like product: Experience from the U.S. drug induced liver injury network and a review of the literature.

BACKGROUND: Kratom is a botanical product used as an opium substitute with abuse potential. METHODS: Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort. RESULTS: Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients. CONCLUSION: Kratom can cause severe liver injury with jaundice.

The Clinical Spectrum and Diagnosis of Oxaliplatin Liver Injury in the Era of Nonalcoholic Fatty Liver Disease.

Oxaliplatin is an alkylating agent given with fluorouracil and leucovorin as a mainstay adjuvant chemotherapy for stage III colorectal cancer (CRC). Liver injury from oxaliplatin ranges from mild liver enzyme increases in 42% to 57% of patients in clinical trials1 to rare severe injury leading to acute liver failure.2 Chronic injury from endothelial cell damage and architectural distortion may manifest years later with nodular regenerative hyperplasia (NRH), portal sclerosis, and noncirrhotic portal hypertension (NCPH).2,3 Chronic subclinical injury occurs in up to 78% of patients.3 Diagnosis may be confounded by nonalcoholic fatty liver disease (NAFLD), and long-term outcomes from chronic injury are unclear.