Acute liver failure (ALF) is a serious condition, typically in individuals without prior liver disease. Drug-induced ALF (DIALF) constitutes a major portion of ALF cases. Our research aimed to identify potential genetic predispositions to DIALF.
We analysed the potential genetic variants associated with DIALF using the whole exome sequencing data from 75 cases, including 40 non-Finnish European cases in the pilot study. Chi-square tests were performed for case–control analysis against the 1000 genomes project as the control. A replication study of 44 DIALF cases that included 24 non-Finnish Europeans was conducted to validate candidate variants. The association between clinical phenotype and genotypes was analysed using one-way analysis of variance.
Eight variants (rs561037, rs561042, rs608339, rs655260, rs1142886, rs1142888, rs1142889 and rs1142890) in the guanylate binding protein 4 (GBP4) were significantly associated with DIALF in non-Finnish Europeans in the pilot study and confirmed in the replication study. Rs561037 and rs561042 were highly significant with the lowest allele frequencies in both pilot and replication studies. An association was also found between these variants and milder clinical outcomes, indicated by lower peak levels of ALT, AST and higher Karnofsky performance scores.
Our study identified eight GBP4 missense variants linked to a lower risk of DIALF in the non-Finnish European population. The GBP4 protein, activated by interferon-gamma, plays a critical role in innate immunity. These findings suggest that GBP4 variants might influence immune and inflammatory responses in DIALF, though further studies are needed to elucidate the underlying mechanisms.
Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the treatment of cancer, though they come with the risk of immune-related adverse (irAEs) events such as hepatotoxicity or Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation of ICI and initiation of immunosuppression. Cytotoxic T Lymphocytes (CTLs) play a central role in ILICI; however, they are just part of the picture as immunotherapy broadly impacts all aspects of the immune microenvironment and can directly and indirectly activate innate and adaptive immune cells. Clinically, as our understanding of this entity grows, we encounter new challenges. The presentation of ILICI is heterogeneous with respect to latency, pattern of injury (hepatitis vs. cholangitis) and severity. This review focuses on our knowledge regarding risk factors, presentation and treatment of ILICI including ILICI refractory to steroids. An emerging topic, the possibility of rechallenge while accepting some risk, in patients who experience ILICI but require immunotherapy, is also discussed. This review provides an update on the current knowns and unknowns in ILICI and highlights several knowledge gaps where studies are needed.
Targeted therapies and immunotherapies have shown great promise as best-in-class treatments for several cancers with respect to efficacy and safety. While liver test abnormalities are rather common in patients treated with kinase inhibitors or immunotherapy, events of severe hepatotoxicity in these patients are rare in comparison with those associated with chemotherapeutics. The underlying mechanisms and risk factors for severe hepatotoxicity with novel oncology therapies are not well understood, complicating the drug-induced liver injury (DILI) risk assessment in the preclinical and clinical phases of drug development. The epidemiological and clinical characteristics, as well as mechanisms of liver toxicity, are described here to the current state of knowledge. Tools to study and assess the risk of DILI during drug development are concisely summarised, focusing on caveats thereof for novel oncology treatments. Emerging tools to optimise safety assessments and gather additional mechanistic insights into DILI are introduced. Particularly in oncology, where standard liver signals during drug development are tolerated to a marginally higher degree than in other indications due to the life-saving, life-extending and quality-of-life improvements for patients with severe or advanced cancers versus previous standard-of-care therapeutics, safety assessments must be tailored to the drug and indication. Trends in patient safety-centred drug development programmes and regulatory approval processes must continually be revisited and streamlined via obtaining an overall greater understanding of DILI and the tools available to assess mechanisms of injury, frequency, severity and prognosis.
Maternal obesity increases the risk of the paediatric form of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting up to 30% of youth, but the developmental origins remain poorly understood.
Using a Japanese macaque model, we investigated the impact of maternal Western-style diet (mWSD) or chow diet followed by postweaning WSD (pwWSD) or chow diet focusing on bile acid (BA) homeostasis and hepatic fibrosis in livers from third-trimester fetuses and 3-year-old juvenile offspring.
Juveniles exposed to mWSD had increased hepatic collagen I/III content and stellate cell activation in portal regions. mWSD increased transcriptional signatures of FXR activation, while pwWSD impaired FXR pathway genes and increased liver BA content. Both mWSD and pwWSD increased serum BA concentrations. Notably, mWSD-exposed juvenile offspring had increased periportal CK19 expression and cholangiocyte gene expression supporting proliferation compared with maternal chow-exposed offspring. Fetuses exposed to mWSD had increased CK19 expression and hepatic BAs which correlated positively with periportal collagen deposition and negatively with markers of fetal oxygenation. In juvenile offspring, increased serum BAs correlated positively with hepatic oxidative stress and portal fibrosis without elevated liver enzymes.
mWSD is associated with hallmarks of paediatric MASLD including portal bile ductular reaction, portal fibrosis and dysregulated BA homeostasis. These conditions begin in utero and persist in juvenile offspring regardless of their postweaning diet. These findings implicate changes in BA metabolism that may drive developmental programming of MASLD in juvenile offspring beginning in utero.
Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFNα-2a), with 24-week follow-up.
Ninety patients were enrolled into six arms of 15 each (A–F); 60 patients were included in the main randomisation (arms A–D), and 30 patients (arms E–F) were randomised to the extension phase: (A) Peg-IFNα-2a 180 μg once weekly (QW); (B) BLV 2 mg once daily (QD) + Peg-IFNα-2a 180 μg QW; (C) BLV 5 mg QD + Peg-IFNα-2a 180 μg QW; (D) BLV 2 mg QD; (E) BLV 10 mg QD + Peg-IFNα-2a 180 μg QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72.
At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log10 IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment.
BLV combined with Peg-IFNα-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment.
NCT02888106
The performance of non-invasive liver tests (NITs) is known to vary across settings and subgroups. We systematically evaluated whether the performance of three NITs in detecting advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) varies with age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) status or liver enzymes.
Data from 586 adult LITMUS Metacohort participants with histologically characterised MASLD were included. The diagnostic performance of the Fibrosis-4 Index (FIB-4), enhanced liver fibrosis (ELF) and vibration-controlled transient elastography liver stiffness measurement (VCTE LSM) was evaluated. Performance was expressed as the area under the receiver operating characteristics curve (AUC). Thresholds for detecting advanced fibrosis (≥F3) were calculated for each NIT for fixed (high) sensitivity, specificity and predictive values.
Differences in AUC between all subgroups were small and statistically not significant, indicating comparable performance in detecting ≥F3, irrespective of these clinical factors. However, different thresholds were needed to achieve the same level of accuracy with each test. For example, for a fixed sensitivity and specificity, the thresholds for all three NITs were higher in patients with T2DM. Effects for sex, age and liver enzymes were less pronounced.
Performance of the selected NITs in detecting advanced liver fibrosis does not vary substantially with clinical characteristics. However, different thresholds have to be selected to achieve the same sensitivity, specificity and predictive values in the respective subgroups. Large prospective studies are called for to study NIT accuracy considering multiple patient characteristics.
Chronic hepatitis D virus (HDV) infection can cause severe liver disease. With new treatment options available, it is important to identify patients at risk for liver-related complications. We aimed to investigate kinetics and predictive values of novel virological and immunological markers in the natural course of chronic HDV infection.
HBcrAg, HBV RNA and quantitative anti-HBc were analysed in samples from HDV-infected patients at three consecutive time points. Results were linked to clinical outcome by univariable and multivariable analyses. Primary endpoint was the composite endpoint of any liver-related event.
Samples from 190 individual patients were analysed with a median clinical follow-up time of 2.69 (IQR 1.13–6.51) years. The majority of patients had cirrhosis (98/190, 52%), and the primary endpoint occurred in 33% (62/190). In univariable analysis, age, cirrhosis, lower quantitative anti-HBc, higher ratio of HBcrAg/anti-HBc and detectable HDV RNA were associated with the primary endpoint. In multivariable analysis, only the presence of liver cirrhosis (HR 7.74, p < 0.001) and age (1.06, p < 0.001) remained independently associated with the primary endpoint. Kinetics of virological parameters during follow-up were similar between the groups. Quantitative anti-HBc was significantly lower in patients with liver cirrhosis (687 (IQR 188–3388) IU/ml vs. 309 (IQR 82–924) IU/ml, p < 0.0004), and lower levels were independently associated with the development of the primary endpoint (HR 1.0, p = 0.014).
In chronic HDV infection, neither baseline values nor kinetics of HBV RNA, HBcrAg and anti-HBc were independently associated with clinical outcome, while stage of liver disease and age were predictors of liver-related events.
Epidemiological data on mortality in autoimmune liver diseases (AILDs) are scarce. We examined all-cause and cancer-related mortality in individuals with AILD from Sweden.
We identified 9654 individuals with AILD (3342 with autoimmune hepatitis (AIH), 3751 with primary biliary cholangitis (PBC), and 2561 with primary sclerosing cholangitis (PSC)) using national Swedish registries between 2001 and 2020. These were matched with 80 685 comparators from the general population at a ratio of 1:10 on age, sex, year of diagnosis and municipality. Rates of outcomes were estimated using Cox regression models, adjusted for matching factors and cardiovascular disease, diabetes, inflammatory bowel disease, chronic obstructive pulmonary disease, and education.
Individuals with AILD had higher mortality than comparators (adjusted hazard ratio (aHR) = 2.3, 95% CI = 2.2–2.4) and higher rates of cancer-related death (aHR = 2.1, 95% CI = 1.9–2.3). The presence of liver cirrhosis in AILD was related to even higher mortality, with aHR 5.8 (95% CI = 5.1–6.6). Both males and females with AILD had increased mortality (males aHR = 2.6, 95% CI = 2.4–3.0, and females aHR = 2.2, 95% CI = 2.1–2.3). The mortality was higher in individuals aged 18–50 years (aHR = 4.6, 95% CI = 3.6–5.8), than in individuals above 50 years (aHR = 2.2, 95% CI = 2.1–2.3). Overall mortality rates and cancer-related death were particularly high in individuals with PSC compared to their matched comparators, with aHR = 4.1 (95% CI = 3.2–5.2) and aHR = 6.4 (95% CI = 4.0–10.3), respectively.
Patients with AILDs have increased rates of overall and cancer-related mortality compared to matched comparators, and relative risks are highest in cirrhosis, younger age and PSC.
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