Histological Characteristics and Management of Hepatitis on Immune Checkpoint Inhibitors: A Retrospective Descriptive Study.

BACKGROUND AND AIMS: the side effects of immune checkpoint inhibitors (ICI) pose a problem for the clinical management of cancer patients. There is a lack of knowledge of the value of liver biopsy in patients with ICI-related drug-induced liver injury (ICI-DILI). The aim of this study was to explore the impact of liver biopsy on clinical management and response to corticosteroids, according to histological findings. METHODS: We conducted a retrospective, single-center study to evaluate the biochemical, histological and clinical data of 35 patients with ICI-DILI between 2015 and 2021 in a university hospital in France. RESULTS: Of the 35 patients with ICI-DILI (median [interquartile range] age 62 [48-73] years, 40% males) studied, 20 underwent a liver biopsy. There was no difference in the management of ICI-DILI according to liver biopsy in terms of ICI withdrawal, reduction or rechallenge. According to the histological profile, patients with toxic and granulomatous profiles had a better response to corticosteroids, while patients with cholangitic lesions had the worst response. CONCLUSION: In ICI-DILI, liver biopsy must not delay patient care but may be useful in identifying patients with a cholangitic profile who have a poorer response to corticosteroids.

Transient elastography alone and in combination with FibroTest® for the diagnosis of hepatic fibrosis in alcoholic liver disease.

BACKGROUND & AIMS: The reliability of transient elastography (TE) to assess liver fibrosis is insufficiently validated in alcoholic liver disease (ALD). We aimed to validate the diagnostic utility of TE for liver fibrosis in patients with excessive alcohol consumption and evaluate whether Fibrotest® adds diagnostic value relative to or in combination with TE. METHODS: We conducted a multicentre prospective study on a total of 217 heavy drinkers with high serum aminotransferase levels. Patients underwent liver biopsy, TE, Fibrotest® , PGAA, APRI, FIB-4 and FORNS. The overall diagnostic performance was evaluated by the area under the receiver operating characteristic (AUROC) curves and Obuchowski measures. RESULTS: TE values correlated with fibrosis stage (r=.73; P<.0001) and steatosis stage (r=.19; P<.01). Patients with alcoholic hepatitis had higher TE values than those without alcoholic hepatitis (P<.0001). In an multivariate analysis, fibrosis stage and the presence of alcoholic hepatitis were the only parameters that correlated with liver stiffness. For the diagnosis of advanced fibrosis (F≥3), the AUROC curves were 0.90, 0.85, 0.83, 0.91 and 0.90 for TE, Fibrotest® , PGAA and associations TE-Fibrotest® , TE-PGAA respectively. For the diagnosis of cirrhosis, the AUROC curves were 0.93, 0.88, 0.89, 0.94 and 0.95 respectively. The Obuchowski measures for the diagnosis of fibrosis were 0.94, 0.92, 0.91, 0.95 and 0.94 respectively. The performance of TE was not significantly different than those of Fibrotest® , PGAA and combinations TE-Fibrotest® , TE-PGAA. CONCLUSIONS: TE has excellent diagnostic value for liver fibrosis in alcoholic liver disease. The combined use of TE-Fibrotest® or TE-PGAA does not improve the performance of TE.

Humoral immunity links Candida albicans infection and celiac disease.

OBJECTIVE: The protein Hwp1, expressed on the pathogenic phase of Candida albicans, presents sequence analogy with the gluten protein gliadin and is also a substrate for transglutaminase. This had led to the suggestion that C. albicans infection (CI) may be a triggering factor for Celiac disease (CeD) onset. We investigated cross-immune reactivity between CeD and CI. METHODS: Serum IgG levels against recombinant Hwp1 and serological markers of CeD were measured in 87 CeD patients, 41 CI patients, and 98 healthy controls (HC). IgA and IgG were also measured in 20 individuals from each of these groups using microchips sensitized with 38 peptides designed from the N-terminal of Hwp1. RESULTS: CI and CeD patients had higher levels of anti-Hwp1 (p=0.0005 and p=0.004) and anti-gliadin (p=0.002 and p=0.0009) antibodies than HC but there was no significant difference between CeD and CI patients. CeD and CI patients had higher levels of anti-transglutaminase IgA than HC (p=0.0001 and p=0.0039). During CI, the increase in anti-Hwp1 paralleled the increase in anti-gliadin antibodies. Microchip analysis showed that CeD patients were more reactive against some Hwp1 peptides than CI patients, and that some deamidated peptides were more reactive than their native analogs. Binding of IgG from CeD patients to Hwp1 peptides was inhibited by γIII gliadin peptides. CONCLUSIONS: Humoral cross-reactivity between Hwp1 and gliadin was observed during CeD and CI. Increased reactivity to Hwp1 deamidated peptide suggests that transglutaminase is involved in this interplay. These results support the hypothesis that CI may trigger CeD onset in genetically-susceptible individuals.

Investigating liver stiffness and viscosity for fibrosis, steatosis and activity staging using shear wave elastography.

BACKGROUND & AIMS: Quantitative shear wave elastography was shown to be an effective tool for the non-invasive diagnosis and staging of chronic liver diseases. The liver shear modulus, estimated from the propagation velocity of shear waves, is correlated to the degree of fibrosis and can therefore be used for the non-invasive staging of fibrosis. METHODS: We performed a clinical prospective study in a total of 120 patients with various chronic liver diseases to compare the accuracy of supersonic shear imaging (SSI), a technique based on acoustic radiation and ultrafast ultrasound imaging, to 1D transient elastography (FibroScan) for the staging and grading of fibrosis as assessed by liver biopsy. Since shear wave propagation spectroscopy can also provide additional mechanical information on soft tissues, such as viscosity, we also investigated those new mechanical parameters as possible predictors of fibrosis, steatosis, and disease activity. RESULTS: SSI was successfully performed in 98.3% of patients and it was shown to be as accurate as FibroScan for the staging of fibrosis both for the whole population (N=120) and for the subgroup with viral hepatitis (n=70) (AUC=0.85 [0.77-0.96] and 0.89 [0.81-0.97] for significant fibrosis, AUC=0.90 [0.83-0.97] and 0.87 [0.75-0.98] for cirrhosis, with respect to SSI [n=68/70] and FibroScan [n=66/68]). Viscosity could also be used to stage the degree of fibrosis (AUC=0.76 [0.64-0.87] for significant fibrosis and AUC=0.87 [0.74-0.99] for cirrhosis), for the subgroup of patients with viral hepatitis (n=67/70) but was a poor predictor of disease activity and steatosis levels. CONCLUSIONS: Supersonic shear imaging is a robust technique for the staging of liver fibrosis. Liver viscosity was found to be correlated with fibrosis but not to steatosis or disease activity.

[Treatment of hepatitis C: current status and perspectives]. / Traitement de l'hépatite C: état actuel et perspectives.

The treatment of hepatitis C virus (HCV) infection has significantly improved these last two decades. For nearly 15 years, the association of pegylated interferon alfa and ribavirin (PR) has allowed a sustained virologic response (SVR), i.e., a viral cure of the infection, in 45% of genotype 1-infected patients, 65% of genotype 4-, 70% in genotype 3- and around 85% of genotype 2-infected patients. A better understanding of the HCV life-cycle has led to the development of direct-acting antiviral drugs (DAAs) targeted against viral proteins (NS3/4A protease, NS5B polymerase with nucleos(t)idic and non nucleos(t)idic inhibitors, NS5A viral replication complex). The combination of first generation protease inhibitors with PR has showed a high antiviral efficiency (75% of SVR in genotypes 1) with substantial side effects for the first generation protease inhibitors, which have obtained approval to market in 2011 (Telaprevir and Boceprevir) and recommandations of use in HCV mono-infected patients in 2012 and in HCV/HIV coinfected in 2013. Then, the combination of second generation protease inhibitors with PR has increased SVR rates from 75 to 90%, while reducing treatment duration, side effects and number of pills. Next step is now interferon and ribavirin free combination of DAAs, about to become the standard of care in 2015. These excellent results in 'easy-to-treat' patients and in small population studies has now been confirmed in phase III studies and in 'difficult-to-treat' patients (treatment - especially protease inhibitors-experienced patients, cirrhotic patients, liver and renal transplant patients, HIV co-infected patients, and subjects with polypharmacy, at increased risk of drug interaction).

[Epidemiology, transmission and screening of viral hepatitis]. / Epidémiologie, transmission et dépistage des hépatites virales.

Epidemiological advances, new vaccines, early diagnosis as well as research into the ways the different forms of hepatitis are transmitted, have resulted in better prevention.The treatment of populations is more effective and faster.

Benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Hepatitis B virus (HBV) infection is more frequent in kidney recipients than in the general population with a higher rate of liver-related morbidity and mortality. We evaluated the benefit associated with HBV viral suppression by nucleos(t)ide analogues treatment in HBV-infected kidney recipients. METHODS: This retrospective study included 42 HBsAg-positive kidney recipients, 33 males, 9 females, median age 54 years, followed up during a mean of 15.4±11.8 years after kidney transplantation. Mean treatment duration by single or combined nucleos(t)ide analogues was 6.8±4.3 years. Fibrosis, before treatment, according to Metavir score was: F4 for 6 patients, F3 for 10, F2 for 6, and F0-F1 for 20 patients. The primary end point, the patient survival, was defined as patient death or liver transplantation, the secondary end point was graft survival. RESULTS: HBV DNA at the last evaluation was undetectable (<12 IU/ml) in 92.8% of patients. During the follow-up, 8 patients died (17.7%), death being related to hepatocellular carcinoma in 4 (9.5%), including 1 patient with baseline mild fibrosis, and to extrahepatic causes in 4. This mortality rate is strikingly lower than that previously reported in HBV-infected kidney recipients before oral antiviral therapies. Graft survival seems to be improved when compared to the former series. CONCLUSIONS: Suppression of HBV replication associated with nucleo(s)tide analogues treatment improves the survival of HBV-infected kidney recipients. Viral suppression does not exclude regular follow-up given the risk of occurrence of hepatocellular carcinoma even in non-cirrhotic patients.

Hepatitis C: epidemiology, diagnosis, natural history and therapy.

With an estimated prevalence of 3% in the world population (around 170 million infected individuals worldwide), hepatitis C virus (HCV) heavily burdens public health. Even though the incidence of new infections is declining, at least in industrialized countries where they are mainly restricted to intravenous drug users, morbidity and mortality (which means also HCV-induced costs) associated with HCV infection are expected to increase over the next decade. Models suggest that the incidence of hepatocellular carcinoma and HCV-related mortality will still increase until about 2015. The prevalence of the disease, the risk of progression of fibrosis to cirrhosis or hepatocellular carcinoma, mainly but not only in patients with liver comorbidities such as metabolic syndrome and/or heavy alcohol intake, evidences: (1) the need for a screening of chronic HCV infection as defined by both anti-HCV antibodies and detectable HCV RNA, (2) the evaluation of the extrahepatic (cryoglobulinemia-related vasculitis) or liver impact of chronic infection (by liver biopsy or noninvasive markers of fibrosis) and (3) the discussion of an antiviral treatment which is mainly the combination of pegylated interferon (one weekly subcutaneous injection) and ribavirin, a nucleosidic analogue with a twice daily oral intake. This 'standard of care' results in a mean of 60% of sustained virologic response corresponding to viral eradication, which allows the inactivation of necroinflammation and the remodeling of fibrosis. New antiviral treatments (direct-acting anti-virals like protease NS3/4, polymerase NS5B, NS5A, entry inhibitors or other drugs like cyclophilin inhibitors, new interferons, immune modulators or therapeutic vaccine) are being rapidly developed (the approval of the first generation protease inhibitors is expected for spring 2011). The next step appears to be the combination of these oral drugs allowing a better safety and efficacy of the treatment.