Vibration Controlled Transient Elastography (Fibroscan®) in sickle cell liver disease - could we strike while the liver is hard?

Vibration controlled transient elastography (VCTE) is validated for the evaluation of hepatic fibrosis in different liver diseases. Sickle cell liver disease (SCLD) results from a cumulative hepatic injury and its lifelong and progressive nature raises the need for a non-invasive tool for fibrosis evaluation. Fifty patients, aged between 23 and 59 years with sickle cell disease and suspected SCLD underwent a VCTE followed by a liver biopsy. Biopsies were evaluated for various scores of liver disease that were then correlated to VCTE score. 90% of our patients had an Ishak Fibrosis (IF) score between 0-2 (Group A-minimal to no fibrosis) and 10% of the patients had IF score between 3-6 (Group B-advanced fibrosis). The median Transient Elastography (TE) for patients in Groups A and B was 4·8 kilopascals (kPa) and 17·6 kPa, respectively. A positive correlation was shown between TE and IF score, R = 0·0·68 (P = <0·0001); a positive correlation was also shown with Histology Activity Index fibrosis score, R = 0·64 (P = <0·0001). This study emphasises the need for further studies of non-invasive tools and their utility in liver fibrosis evaluation of patients with SCLD.

Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation.

BACKGROUND & AIMS: Chronic hepatitis affects phenotypes of innate and adaptive immune cells. Mucosal-associated invariant T (MAIT) cells are enriched in the liver as compared with the blood, respond to intra-hepatic cytokines, and (via the semi-invariant T-cell receptor) to bacteria translocated from the gut. Little is known about the role of MAIT cells in livers of patients with chronic hepatitis C virus (HCV) infection and their fate after antiviral therapy. METHODS: We collected blood samples from 42 patients with chronic HCV infection who achieved a sustained virologic response after 12 weeks of treatment with sofosbuvir and velpatasvir. Mononuclear cells were isolated from blood before treatment, at weeks 4 and 12 during treatment, and 24 weeks after the end of treatment. Liver biopsies were collected from 37 of the patients prior to and at week 4 of treatment. Mononuclear cells from 56 blood donors and 10 livers that were not suitable for transplantation were used as controls. Liver samples were assessed histologically for inflammation and fibrosis. Mononuclear cells from liver and blood were studied by flow cytometry and analyzed for responses to cytokine and bacterial stimulation. RESULTS: The frequency of MAIT cells among T cells was significantly lower in blood and liver samples of patients with HCV infection than of controls (median, 1.31% vs 2.32% for blood samples, P = .0048; and median, 4.34% vs 13.40% for liver samples, P = .001). There was an inverse correlation between the frequency of MAIT cells in the liver and histologically determined levels of liver inflammation (r = -.5437, P = .0006) and fibrosis (r = -.5829, P = .0002). MAIT cells from the liver had higher levels of activation and cytotoxicity than MAIT cells from blood (P < .0001). Production of interferon gamma by MAIT cells was dependent on monocyte-derived interleukin 18, and was reduced in patients with HCV infection in response to T-cell receptor-mediated but not cytokine-mediated stimulation, as compared with controls. Anti-viral therapy rapidly decreased liver inflammation and MAIT cell activation and cytotoxicity, and increased the MAIT cell frequency among intra-hepatic but not blood T cells. The MAIT cell response to T-cell receptor-mediated stimulation did not change during the 12 weeks of antiviral therapy. CONCLUSIONS: In analyses of paired blood and liver samples from patients with chronic HCV infection before, during, and after antiviral therapy with sofosbuvir and velpatasvir, we found that intrahepatic MAIT cells are activated by monocyte-derived cytokines and depleted in HCV-induced liver inflammation.

Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα.

OBJECTIVE: Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. DESIGN: Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα. RESULTS: The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα. CONCLUSIONS: IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. TRIAL REGISTRATION NUMBERS: NCT01888900 and NCT00718172.

Durability of antibody response against hepatitis B virus in healthcare workers vaccinated as adults.

BACKGROUND: Follow-up studies of recipients of hepatitis B vaccine from endemic areas have reported loss of antibody to hepatitis B surface antigen (anti-HBs) in a high proportion of persons vaccinated at birth. In contrast, the long-term durability of antibody in persons vaccinated as adults in nonendemic areas is not well defined. We aimed to assess the durability of anti-HBs among healthcare workers (HCWs) vaccinated as adults and response to a booster among those without protective levels of antibody. METHODS: Adult HCWs aged 18-60 at the time of initial vaccination were recruited. All were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and anti-HBs level. HCWs with anti-HBs <12 mIU/mL were offered a booster and levels were measured 1, 7, and 21 days afterward. RESULTS: Anti-HBs levels were <12 mIU/mL in 9 of 50 (18%), 13 of 50 (26%), and 14 of 59 (24%) HCWs 10-15, 16-20, and >20 years postvaccination, respectively, (P = ns). Four HCWs were anti-HBc positive; none had HBsAg. By logistic regression, older age at vaccination was the only predictor of inadequate anti-HBs level (P = .0005). Thirty-four of 36 subjects with inadequate anti-HBs levels received a booster and 32 (94%) developed levels >12 mIU/mL within 3 weeks. CONCLUSIONS: Anti-HBs levels decrease after 10-31 years and fall below a level considered protective in approximately 25% of cases. The rapid and robust response to a booster vaccine suggests a long-lasting amnestic response. Hepatitis B vaccination provides long-term protection against hepatitis B and booster vaccination does not appear to be necessary in HCWs. Clinical Trials Registration. NCT01182311.

An Epidemiologic Investigation of a Case of Acute Hepatitis E.

Hepatitis E virus (HEV) is considered a zoonotic infection in developed nations. A case of acute hepatitis E in a researcher following a scalpel injury while working on a pig prompted a seroepidemiologic study to identify potential modes of transmission and determine the seroprevalence of HEV among animal handlers at the institute. Sera from personnel (n = 64) in two animal facilities and age/sex-matched blood donors (n = 63) as controls were tested for IgG anti-HEV and, if positive, for IgM anti-HEV and HEV RNA. Sera and stool from pigs aged 6 to 12 weeks from the breeding farm and older pigs from animal facilities were tested similarly. The median age of personnel was 36 years, 74% were white, 56% were male, and 74% had direct exposure to pigs. The prevalence of anti-HEV was 3.1% among personnel compared to 3.2% among blood donors; none were positive for IgM anti-HEV or HEV RNA. IgG anti-HEV was detected in sera from 10% of pigs aged 6 to 8 weeks, 80% aged 10 weeks, 100% aged 12 weeks, and 76% aged >12 weeks. HEV RNA was detected in stool but not sera from three 12-week-old pigs. Sequencing revealed HEV genotype 3 with ∼10% difference between the patient and pig sequences. Parenteral transmission is a potential mode of acute HEV infection. The low and similar seroprevalence of anti-HEV between the at-risk group and age-matched blood donors suggests low transmission risk with universal precautions among animal handlers.

Factors associated with the platelet count in patients with chronic hepatitis C.

BACKGROUND: There are many potential causes of thrombocytopenia in patients with chronic hepatitis C (CHC). AIMS: We sought to determine the association between thrombopoietin (TPO) level, immature platelet fraction (IPF), immunoglobulin G (IgG) level, spleen size, and the platelet count in CHC. METHODS: We studied a consecutive sample of patients enrolled in an observational study at a referral-based research center, excluding subjects based on eligibility criteria. TPO, glycocalicin, and von Willebrand Factor (vWF) levels were determined using stored sera. Hepatic fibrosis was assessed via transient elastography (TE) when available, and clinical laboratory values and radiologic data were obtained from the medical record. We performed analyses of the relationships between independent variables and the platelet count. RESULTS: On univariate analysis, the following variables were significantly associated with the platelet count: age, alanine aminotransferase (ALT), direct bilirubin, total bilirubin, IPF, international normalized ratio (INR), spleen size, vWF, glycocalicin, fibrosis stage on liver biopsy, and TE (P-values all <0.05). A multivariable model determined that imputed TE score, TPO, IPF, and spleen size were independently associated with the platelet count (P-values all<0.05). CONCLUSIONS: The platelet count in CHC is significantly associated with fibrosis, TPO level, IPF, and spleen size. Our findings challenge the proposed mechanism of decreased TPO levels or decreased bone marrow production of platelets as a cause of thrombocytopenia in CHC. Future studies focusing on the effects of fibrosis and splenomegaly on platelets may shed more light on the pathophysiology of thrombocytopenia in patients with CHC.