Hiromitsu Mori

Serum levels of hepatitis C virus core protein in patients with chronic hepatitis C treated with interferon alfa

The quantitation of hepatitis C virus (HCV) viremia can be helpful in the diagnosis, therapy, and monitoring of patients with chronic hepatitis C. A sensitive and quantitative fluorescence enzyme immunoassay (FEIA) has recently been developed for assaying HCV core protein in serum. To assess the utility of measurements of serum HCV core protein during the course of treatment of chronic hepatitis C, we studied 27 patients who were treated with a single schedule of interferon alfa (IFN‐α) (9 million units per dose for 24 weeks; total dose, 720 million units). Eleven of the 27 patients responded with clearance of HCV RNA and fall of aminotransferase to normal; 16 patients did not respond to treatment. Before therapy, HCV core antigen was detectable in 25 of the 27 patients (93%). The initial serum concentration of HCV core protein was significantly (P < .01) higher in the nonresponders versus the responders. Two weeks after initiating IFN‐α therapy, HCV core protein was not detectable in any of the 11 responders, but was detected in 8 of 16 nonresponders (P < .01). All responders, but none of the nonresponders, remained negative for core protein after IFN‐α therapy. The measurement of HCV core protein by FEIA may be useful for predicting the response to IFN‐α and for monitoring its therapeutic efficacy.

Serum collagen type IV for the assessment of fibrosis and resistance to interferon therapy in chronic hepatitis C

Sixty-nine patients with chronic hepatitis C (CH-C) were treated with interferon therapy, and serum collagen type IV (s-collagen IV) levels were measured by enzyme immunoassay to analyze the responsiveness to interferon therapy. Classified by the improved pattern of serum alanine aminotransferase levels after interferon administration, 23 patients were judged as sustained responders, 23 as transient responders, and 23 as non-responders. Fibrotic grades of the liver sample correlated statistically with the levels of s-collagen IV (P < 0.01). Pre-therapy s-collagen IV levels of sustained responders were significantly lower than those of the other responders, and only sustained responders showed a significant decrease of s-collagen IV levels after interferon therapy, in accordance with histologic improvement. Multivariate analysis showed that s-collagen IV and hepatitis C virus genotype were the most important factors affecting the response to interferon therapy of all variates. Thus, s-collagen IV is one of the most useful aids for the evaluation of liver fibrotic grade in CH-C and a potent predicting indicator for the responsiveness to interferon therapy.

KIR3DL1-HLA-Bw4 combination and IL28B polymorphism predict response to Peg-IFN and ribavirin with and without telaprevir in chronic hepatitis C.

Natural killer cells play a key role in the immune control of viral infections. Killer immunoglobulin-like receptors (KIRs) regulate natural killer cell activation and inhibition through the recognition of their cognate HLA class I ligands. We assessed the predictive factors of a sustained virological response (SVR) in 200 Japanese patients with chronic genotype 1b hepatitis C who were treated with telaprevir (TVR), pegylated-interferon-α2b (PEG-IFN), and ribavirin (RBV) triple therapy (92 patients) or PEG-IFN/RBV therapy alone (108 patients). Sixteen KIR genotypes, HLA-A, -B and -C ligands, and an interleukin (IL) 28B polymorphism (rs8099917) were analyzed. We observed that triple therapy, white blood cell count, hemoglobin value, hepatitis C viral load, a rapid virological response (RVR), IL28B TT genotype, and KIR3DL1-HLA-Bw4 genotype were associated with an SVR. In multivariate regression analysis, we identified an RVR (P < 0.000001; odds ratio [OR] = 20.95), the IL28B TT genotype (P = 0.00014; OR = 5.53), and KIR3DL1-HLA-Bw4 (P = 0.004, OR = 3.42) as significant independent predictive factors of an SVR. In conclusion, IL28B and KIR3DL1/HLA-Bw4 are independent predictors of an SVR in Japanese patients infected with genotype 1b HCV receiving TVR/PEG-IFN/RBV or PEG-IFN/RBV therapy.

Vonoprazan-Based Regimen Is More Useful than PPI-Based One as a First-Line Helicobacter pylori Eradication: A Randomized Controlled Trial

Background. A new agent, potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer advantages over conventional H. pylori eradication therapies. We aimed to compare the eradication rate between VPZ-based treatment and PPI-based one. Methods. This randomized controlled trial was designed to assign 141 patients with H. pylori-positive gastritis to VPZ group (VPZ 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days) or PPI group (rabeprazole 20 mg or lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days). Primary endpoints were eradication rates and adverse events. Results. Seventy of 72 patients in VPZ group and 63 of 69 patients in PPI group completed the treatment after 7 days. The eradication rate was significantly higher in VPZ group than PPI group by intention-to-treat analysis (95.8% versus 69.6%, P = 0.00003, 95% confidence interval [CI] 88.3-99.1% versus 57.3-80.1%) and per-protocol analysis (95.7% versus 71.4%, P = 0.0002, 95% CI 88.0-99.1% versus 58.7-82.1%). The incidence of adverse events was not different between the groups (26.3% in VPZ group versus 37.7% in PPI group, P = 0.15). Conclusion. VPZ-based regimen is more useful than that PPI-based regimen as a first-line H. pylori eradication therapy.

Clinicopathological characteristics of non-B non-C hepatocellular carcinoma without past hepatitis B virus infection.

Past hepatitis B virus (HBV) infection is considered a risk factor for hepatocarcinogenesis, but the clinicopathological characteristics of non‐B non‐C hepatocellular carcinoma (NBNC‐HCC) excluding past HBV infection have not been investigated. This study aimed to clarify the clinicopathological features of strictly defined NBNC‐HCC.

Successful Treatment for Chronic Hepatitis C-Autoimmune Hepatitis Overlap Syndrome due to Daclatasvir and Asunaprevir

Persistent hepatitis C virus (HCV) infection may induce autoimmune diseases and chronic hepatitis C is sometimes accompanied by autoimmune hepatitis (AIH). However, we are worried about the treatment for chronic hepatitis C-AIH overlap syndrome because interferon-based antiviral therapies may enhance autoimmunity and immunosuppressive corticosteroid administration may promote viral replication. Here, we report a patient having chronic hepatitis C-AIH overlap syndrome treated with the direct-acting antivirals (DAA), daclatasvir and asunaprevir. A 50-year-old man was referred to our hospital because of positive anti-HCV antibody and liver dysfunction at a health checkup. Blood tests showed increased immunoglobulin G (IgG) and a high titer of antinuclear antibody (ANA) in addition to elevated serum alanine aminotransferase (ALT) and HCV-RNA. Infiltration of lymphocytes and plasma cells in Glisson’s capsule and severe interface hepatitis were observed in biopsied specimen, which fulfilled the criteria of AIH. We first started oral corticosteroid administration, and serum ALT levels decreased once but elevated again. We commenced daclatasvir and asunaprevir (60 and 200 mg/day, respectively) and serum HCV-RNA became negative after 6 weeks. Adverse effects were not found during the DAA treatment, and serum ALT, IgG, and ANA were significantly decreased. Corticosteroid could be tapered and stopped, but no recurrence occurred. DAA treatment appears to be effective and safe for the patients with chronic hepatitis C-AIH overlap syndrome.

Lymphocyte proliferative responses to recombinant hepatitis C virus antigens in patients with chronic hepatitis C

The purpose of the present study was to analyse lymphocyte proliferative responses to recombinant hepatitis C virus (HCV) antigens in chronic hepatitis C. Four recombinant peptides derived from the NS3, core, E1 and E2/NS1 regions of the HCV genome were used as antigens in lymphocyte proliferative responses. Forty‐two patients, classified into various sub‐groups, and 17 healthy control subjects were tested and the specific response was expressed as a stimulation index. Responses were analysed with alanine aminotransferase (ALT) level and histological diagnosis. NS3‐ and core‐antigen specific responses in all patient groups were significantly higher than in the healthy control group. E1‐ and E2/NS1‐antigen‐specific responses in the patient group with ALT levels exceeding 100 IU/L were significantly higher than those in other patient groups. Histological diagnosis was not correlated to the intensity of the core‐ and NS3‐specific responses. E1‐ and E2/NS1‐antigens induced significantly elevated responses in patients with chronic active hepatitis and liver cirrhosis compared with results in the healthy control group and in patients with chronic persistent hepatitis. In conclusion, the significantly elevated responses to core‐ and NS3‐antigens may be related to HCV infection and such responses to E1‐ and E2/NS1‐antigens could be related to the severity and activity of the disease.

Past history of hepatocellular carcinoma is an independent risk factor of treatment failure in patients with chronic hepatitis C virus infection receiving direct-acting antivirals

Direct‐acting antiviral (DAA) treatment can achieve a high sustained virological response (SVR) rate in patients with hepatitis C virus (HCV) infection regardless of a history of hepatocellular carcinoma (HCC [+]). We examined 838 patients (370 men, median age: 69 years) who were treated with DAAs for comparisons of clinical findings between 79 HCC (+) (9.4%) and 759 HCC (−) (90.6%) patients and associations with treatment outcome. Male frequency was significantly higher in the HCC (+) group (60.8% vs 42.4%, P = 0.006). There were significant differences between the HCC (+) and HCC (−) groups for platelet count (115 vs 152 ×109/L, P < 0.001), baseline alpha fetoprotein (AFP) (9.9 vs 4.5 ng/mL, P < 0.001) and the established fibrosis markers of FIB‐4 index (4.7 vs 3.0, P < 0.001), AST‐to‐platelet ratio index (APRI) (1.1 vs 0.7, P = 0.009), M2BPGi (3.80 vs 1.78 COI, P < 0.001) and autotaxin (1.91 vs 1.50 mg/L, P < 0.001). The overall SVR rate was 94.7% and significantly lower in the HCC (+) group (87.3 vs 95.5%, P = 0.001). Multivariate analysis revealed that a history of HCC was independently associated with DAA treatment failure (odds ratio: 3.56, 95% confidence interval: 1.32‐9.57, P = 0.01). In conclusion, patients with chronic HCV infection and prior HCC tended to exhibit more advanced disease progression at DAA commencement. HCC (+) status at the initiation of DAAs was significantly associated with adverse therapeutic outcomes. DAA treatment for HCV should therefore be started as early as possible, especially before complicating HCC.

Salmonella Enteritidis cholecystitis with chronic granulomatous disease

We describe a 40-year-old woman with Salmonella cholecystitis complicating adult-onset X-linked chronic granulomatous disease (CGD) caused by a de novo mutation in the paternal-origin CYBB gene. CGD was diagnosed by familial genetic analysis of the CYBB gene encoding NADPH oxidase gp91phox after detection of a refractory subcutaneous abscess at the age of 28. At age 40, she began experiencing frequent fever and diarrhea over a period of 3 months that were refractory to antibacterial treatment. Cholecystitis was evident. Her symptoms improved after percutaneous trans-hepatic gallbladder aspiration puncture with stand-by cholecystectomy. Salmonella enterica serotype Enteritidis (S. Enteritidis) was detected in blood, stool, and bile acid samples. Due to her suppressed bactericidal ability caused by CGD, S. Enteritidis was considered to have translocated from the gut to reside in the gallbladder, causing her repeated enteritis and sepsis. When encountering CGD with recurrent salmonellosis, the possibility of cholecystitis should be considered as another infection focus.

Emergence of anti-mitochondrial M2 antibody in patient with angioimmunoblastic T-cell lymphoma

A 68-year-old woman was referred to our hospital due to fever and rash on the neck and extremities. Laboratory findings revealed hepatic dysfunction and positivity for anti-mitochondrial M2 antibody (AMA-M2). Hepatosplenomegaly and systemic lymphadenopathy were detected by enhanced computed tomography. One week after her first visit, hypoxemia, ascites, and Coomb test-positive autoimmune hemolytic anemia had newly appeared in addition to worsened fever, hepatosplenomegaly, and lymphadenopathy. Results of axillary lymph node, skin, and bone-marrow biopsies led to the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), for which CEPP therapy (cyclophosphamide, etoposide, procarbazine, and prednisolone) was initiated. Her serum levels of hepatobiliary enzymes normalized and AMA-M2 became negative after treatment. The unexpected positivity for AMA-M2 might have been caused by AITL cell-activated intrahepatic immune cells or the tumor cells themselves inflicting bile duct injury that mimicked primary biliary cholangitis. Alternatively, cross reactivity due to the overproduction of immunoglobulins may have caused this phenomenon. The present case may shed light on of the mechanisms of liver dysfunction accompanying AITL.