In patients with steatotic liver diseases (SLD), genetic factors may account for severe liver involvement despite mild or absence of triggering factors or a strong family history. Aim of this study was to examine the diagnostic uptake of targeted sequencing (TS), covering both coding and non-coding regions, of a broad panel of 82 liver and lipid metabolism genes in patients with unexplained SLD.
We enrolled 49 adult patients with SLD and a suspected genetic contribution. Genetic variants were detected through a customised TS panel, whereas the contribution of common genetic variation to the individual susceptibility to SLD was captured by a polygenic risk score (SLD-PRS).
A diagnosis of rare Mendelian disorder was established in 11 patients (22%), independently of age or family history. Rare variants possibly contributing to clinical phenotype were detected in additional 29 patients (59%). Increased SLD-PRS values were detected in 17 patients (35%), enabling an increase in diagnostic uptake of 24%, especially in those without a strong family history (p = 0.03). Genetic diagnosis allowed refinement of clinical management in 23 (47%) patients.
The diagnostic uptake of TS was 22% for Mendelian disorder and 59% for possible contribution to clinical phenotype in selected adult patients with SLD. Evaluation of common variants, as captured by SLD-PRS, yields complementary information increasing the overall utility of the genetic examination.
Patient, clinician, and system-related barriers may affect adherence to hepatocellular carcinoma (HCC) surveillance programmes. The impact of a dedicated automated recall HCC surveillance programme on retention rates in patients eligible for screening is unknown. We aimed to describe and evaluate a large HCC surveillance programme in a publicly funded healthcare system.
Data were collected from January 1, 2013, to December 31, 2022, from a retrospective cohort of subjects enrolled in a publicly funded automated recall semi-annual surveillance programme as per the American Association for the Study of Liver Disease HCC guidance in the Calgary Health Zone (~1.6 million), Canada. Patients were excluded if there was incomplete data or did not meet indications for surveillance. Cox regression was used to identify predictors of non-retention to surveillance.
A total of 7269 patients were included. The median was age 55.5 years (IQR: 45.5–63.8), 60% were male, 46% were of Asian descent, 51% had HBV infection, and 36% had cirrhosis (35% alcohol-related). Median follow-up was 4.9 years (IQR: 1.5–7.2). Overall, 52% (n = 3768) of patients were retained in the surveillance programme, while 8.3% (n = 603) left for potential medical reasons, and 40% (n = 2898) were lost in follow-up. The median time in the programme for those lost in follow-up was 0.81 years (IQR: 0.0–2.8) compared to 6.75 years if retained (IQR: 5.6–8.6; p < 0.001). In multivariable Cox regression analysis, HCV aetiology (HR 1.41; CI 1.23–1.62, p < 0.01), African ethnicity (HR 1.20, CI 1.02–1.42, p = 0.03), and cirrhosis (HR 1.16, CI 1.05–1.28, p < 0.01) increased risk of dropout. On interaction analysis, Hepatitis B amongst cirrhotic patients also increased risk of dropout (HR 1.48, CI 1.05–2.07, p = 0.02).
A dedicated automated recall HCC surveillance programme has a high retention rate in a large multi-ethnic cohort of patients while identifying certain marginalised patient populations, such as those with viral liver disease, cirrhosis, or African ethnicity, as particularly vulnerable to loss to follow-up.
The burden of cirrhosis and other chronic liver diseases has changed in recent years due to shifts in the contributing aetiologies. We estimated the burden of cirrhosis and other chronic liver diseases, including etiological and regional differences, across 204 countries and territories from 2010 to 2021.
We analysed temporal trends in the burden of cirrhosis and other chronic liver diseases utilising data from the Global Burden of Disease Study 2021. We estimated annual frequencies and age-standardised rates (ASRs) of incident cases, deaths and disability-adjusted life-years (DALYs) by sex, country, World Health Organisation region and its contributing aetiologies. In 2021, there were an estimated 58 417 006 incident cases, 1 425 142 deaths and 46 417 777 DALYs related to cirrhosis and other chronic liver diseases. From 2010 to 2021, there was a rise in age-standardised incidence rates (ASIRs) (APC: +0.35%) but age-standardised death rates (ASDRs) (APC: −1.74%) and age-standardised disability-adjusted life-years (ASDALYs) (APC: −1.85%) declined. Cirrhosis related to metabolic dysfunction-associated steatohepatitis (MASH) contributed to 48 310 981 incident cases in 2021 and was largely responsible for the overall increase in ASIRs from 2010 to 2021. Cirrhosis and other chronic liver diseases related to MASH were the only aetiology with a rise in ASIR (APC: +0.86%). Age-standardised deaths related to all aetiologies of cirrhosis and other chronic liver diseases declined during the study period. Age-standardised deaths and DALYs related to MASH increased in the Americas, unlike all other world regions where they declined or remained stable.
Age-adjusted deaths related to cirrhosis and other chronic liver diseases are declining. However, the age-adjusted incidence of cirrhosis and other chronic liver diseases is increasing, driven by increases in the incidence of MASH.
Drug-induced liver injury (DILI) is a global problem and can develop from exposure to prescription or over-the-counter medications as well as herbal and dietary supplements. The diagnosis of DILI is clinically challenging, and liver injury can be severe leading to liver failure, death, or liver transplantation. Patients with underlying chronic liver diseases (CLD) may be at increased risk for DILI, which is associated with factors related to drug or liver disease.
This review summarises current knowledge on the risk and outcomes of DILI in patients with CLD.
Patients with CLD may be at an increased risk for DILI. Additionally patients with underlying CLD are at risk for more severe liver injury and worse outcomes after DILI.
The risk for and poor outcomes from DILI are accentuated in patients with CLD and potentially leading to the worst-case scenario of acute-on-chronic liver failure. We highlight the key observations on DILI with a broad range of underlying liver diseases and the high-DILI risk agents implicated in those populations.
Hepatotoxicity is a known risk of oral and intravenous methotrexate (MTX), but whether intrathecal (IT) administration causes hepatotoxicity remains unknown. We aimed to explore whether IT-MTX causes acute hepatoxicity.
Retrospective single-centre analysis of all patients treated with IT-MTX from 2000 to 2020. We compared liver enzymes (LE) at baseline (within 7 days before IT-MTX) to post-MTX (within 7 days after IT-MTX). LE elevation was defined as ≥ 50% increase in LE from baseline and greater than upper limit of normal. Drug-induced liver injury (DILI) was defined based on established criteria.
A total of 270 patients (184 adults and 86 paediatric) received IT-MTX and had available LE data. Aminotransferase elevation was seen post-MTX in 107 (40%) patients, of whom 96 (36%) had ALT and 68 (25%) had AST elevation. DILI occurred in 16 (6%) patients. Aminotransferases peaked a median of 4 (3–5) days post-MTX, returning near baseline by day 7. Paediatric patients had higher incidence of aminotransferase elevations and DILI than adults (ALT 51% vs. 28%; AST 41% vs. 18%; DILI 11% vs. 3%; p < 0.01 for all). No significant predictors of LE elevation or DILI were identified, and no patient developed liver failure. The severity of ALT elevation after the first IT-MTX dose did not predict severity of a subsequent dose.
Acute transient aminotransferase elevation is common after IT-MTX, especially in paediatric patients. Only a fraction of patients developed DILI, which was self-limited with no sensitisation or liver failure.
Drug-induced liver injury (DILI) due to metamizole has gained increasing attention. Causality assessment remains a challenge, especially in patients with co-medications. We therefore aimed to further characterise metamizole DILI cases.
The data of patients with metamizole intake from our prospective study on acute liver injury with potential drug-related causes were analysed. Diagnosis and causality assessment were based on a thorough work-up and long-term follow-up.
DILI was associated with metamizole in 61 of 324 DILI patients (prevalence 18.8%). A highly characteristic clinical pattern was observed in 43 of the 61 patients, characterised by marked elevation of transaminases peaking at the time of DILI recognition and a more pronounced increase of bilirubin within the first 3 days of clinical presentation. Patients fitting this picture had higher rates of jaundice, coagulopathy, and acute liver failure, however outcomes did not differ significantly when compared to non-metamizole DILI and autoimmune hepatitis (AIH) patients. Overall, fatal adverse outcomes defined by death or liver transplantation were observed in 13.1% of metamizole DILI patients. On multivariate analysis, only aspartate aminotransferase (AST) and INR were independently associated with a fatal adverse outcome. INR, in particular, performed better than Hy's law, bilirubin, transaminases, and the model for end-stage liver disease (MELD), with a c-statistic of 0.85 (95% CI: 0.70–1.0). At a cut-off of ≥ 2.1, sensitivity and specificity for a fatal adverse outcome were 75% and 96%, respectively.
Metamizole DILI can present with a characteristic pattern that can help clinicians to identify metamizole as the causative agent. Outcome, however, is not associated with this clinical picture and should rather be predicted by INR at onset.
ClinicalTrials.gov identifier: NCT 02353455
Liver-related complications are frequent in patients with metabolic diseases, with limited treatment options currently available. This systematic review and meta-analysis aimed to assess the effect of fibroblast growth factor-21 (FGF21) analogues on hepatic steatosis, inflammation and fibrosis in patients with metabolic diseases.
We conducted a systematic literature search in Pubmed, Scopus and Web of Science for randomised controlled trials (RCTs) assessing the effect of FGF21 analogues on hepatic steatosis evaluated by hepatic fat fraction (HFF), inflammation and fibrosis compared to placebo. Adverse events (AEs) were also recorded.
Treatment with FGF21 analogues was associated with metabolic-associated steatohepatitis (MASH) resolution without fibrosis worsening (5 studies, risk ratio [RR] 4.40, 95% confidence interval [CI]: 2.41, 8.03, p < 0.001) and fibrosis improvement by 1 grade without MASH worsening (6 studies, RR 1.79, 95% CI: 1.24, 2.59, p = 0.002). FGF21 analogues significantly lowered HFF compared to placebo (6 studies, SMD -1.08, 95% CI: −1.28, −0.88, p < 0.001), while patients receiving FGF21 analogues were more likely to exhibit a reduction in HFF by 30% (10 studies, RR 4.08, 95% CI: 3.08, 5.40, p < 0.001) or 50% (6 studies, RR 10.43, 95% CI: 5.47, 19.87, p < 0.001). HFF normalisation (≤ 5%) was more frequently achieved with FGF21 analogues (6 studies, RR 14.58, 95% CI: 4.70, 45.18, p < 0.001). The results remained robust after sensitivity analyses. Serious AE and AE leading to drug discontinuation were similar in patients receiving FGF21 analogues or placebo.
FGF21 analogues can reduce hepatic steatosis, inflammation and fibrosis in patients with metabolic diseases, representing a possible treatment option for steatotic liver disease.
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