Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: A multicenter study.

AIMS: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.

Impact of non-obese metabolic dysfunction-associated fatty liver disease on risk factors for the recurrence of esophageal squamous cell carcinoma treated with endoscopic submucosal dissection: A multicenter study.

AIM: Metabolic dysfunction is a risk factor for esophageal squamous cell carcinoma (ESCC). We investigated the impact of the recently proposed metabolic dysfunction-associated fatty liver disease (MAFLD) and its subtypes on ESCC recurrence after endoscopic treatment. METHODS: This multicenter observational cohort study enrolled consecutive patients newly diagnosed with ESCC after endoscopic treatment. Patients were classified into MAFLD or non-MAFLD groups. The MAFLD group was further classified into non-obese and obese MAFLD groups with a body mass index cutoff value of 25 kg/m2 . The impact of MAFLD on the recurrence of ESCC was evaluated using a decision tree algorithm and random forest analysis. RESULTS: A total of 147 patients (average age 69 years; male : female, 127:20; observational period, 2.4 years) were enrolled. The 1-, 3-, and 5-year recurrence rates were 2.0%, 21.1%, and 33.7%, respectively. Independent risk factors for the recurrence of ESCC were MAFLD (HR 2.2812; 95% confidence interval 1.0497-4.9571; p = 0.0373), drinking status, and smoking status. Metabolic dysfunction-associated fatty liver disease was identified as the second most important classifier for recurrence, followed by drinking status. The cumulative incidence of ESCC recurrence was higher in the MAFLD group than in the non-MAFLD group. In a subanalysis, the cumulative incidence of recurrence was significantly higher in the non-obese than in the obese MAFLD group among abstainers/non-drinkers. Directed acyclic graphs revealed that MAFLD directly contributes to ESCC recurrence. CONCLUSIONS: MAFLD was independently and directly associated with ESCC recurrence after endoscopic treatment; a high recurrence rate was observed in patients with non-obese MAFLD. Metabolic dysfunction-associated fatty liver disease may identify patients at high risk for ESCC recurrence.

Impact of metabolic dysfunction-associated fatty liver disease on the incidence of Helicobacter pylori-negative gastric cancer.

AIM: The incidence of Helicobacter pylori-negative gastric cancer (HPNGC) is increasing worldwide. Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been reported to be associated with various cancers, but its association with HPNGC has not been reported. We aimed to identify important independent factors associated with HPNGC, including MAFLD. METHODS: This multicenter observational cohort study enrolled patients with gastric cancer (n = 1078) and health checkup examinees (n = 17 408). We analyzed patients with HPNGC (n = 26) and healthy participants with no H. pylori infection or any abnormal findings on upper gastrointestinal endoscopy (n = 1130). A logistic regression model was used to identify independent factors associated with HPNGC. The priority of the factors associated with HPNGC was evaluated using a decision-tree algorithm and random forest analysis. RESULTS: Among all patients with gastric cancer, 2.4% (26/1078) were diagnosed with HPNGC (mean age, 64 years; male/female, 13/13). In the logistic regression analysis, age, smoking, and MAFLD (odds ratio, 6.5359; 95% confidence interval, 2.5451-16.7841; p < 0.0001) were identified as independent factors associated with HPNGC. Metabolic dysfunction-associated fatty liver disease was also identified as the most important classifier for the presence of HPNGC in decision-tree analyses. Helicobacter pylori-negative gastric cancer was observed in 5.2% of patients with MAFLD and 0.8% of patients without MAFLD. In the random forest analysis of the HPNGC, MAFLD was identified as the distinguishing factor with the highest variable importance (0.32). CONCLUSIONS: Metabolic dysfunction-associated fatty liver disease was the most influential independent factor associated with HPNGC. These findings suggest that fatty liver and metabolic dysfunction could be involved in the pathogenesis of HPNGC.

Risk of malignancies in autoimmune hepatitis type 1 patients with a long-term follow-up in Japan.

AIM: The risk of malignancies in autoimmune diseases is high and is regarded to be due to immunological abnormalities, the use of immunosuppressive agents, and/or chronic inflammation. The aim of this study was to investigate the incidence and risk of malignancies in patients with autoimmune hepatitis (AIH) type 1 in Japan. METHODS: Two hundred and fifty-six patients diagnosed with AIH were enrolled. A person-year calculation was carried out for AIH patients, and the numbers of expected events were clarified using data from "The Monitoring of Cancer Incidence in Japan Project" in order to examine the standard incident rate (SIR) of each type of malignancy. Biochemical data regarding carcinogenesis and its background factors were also examined. RESULTS: Twenty-seven patients (10.5%) developed malignancies; 11 (4.3%) with hepatobiliary cancer and 16 (6.3%) with extrahepatic malignancies. The overall SIR for malignancies in AIH was significantly high at 2.04 (95% confidence interval [CI], 1.34-2.96), and was high among female patients at 2.49 (95% CI, 1.60-3.71). The SIR for hepatobiliary cancer was 14.14 (95% CI, 7.05-25.30), and was markedly high for female patients at 21.83 (95% CI, 10.45-40.16). The SIR for oral/pharyngeal cancer was significantly high for female patients at 14.61 (95% CI, 1.64-52.77). The risk factors for hepatobiliary cancer at the diagnosis of AIH were low levels of alanine aminotransferase (P = 0.0226), low platelet counts (P < 0.0001), and cirrhosis (P = 0.0004). The risk factor for extrahepatic malignancy was relapse of AIH (P = 0.0485). CONCLUSION: The risk of malignancies was generally high among AIH patients. Those with the risk factors of malignancies should be carefully followed up.

Rapidly growing hepatocellular carcinoma after direct-acting antiviral treatment of chronic hepatitis C.

We report on a 62-year-old man with chronic hepatitis C who developed rapidly growing hepatocellular carcinoma (HCC) after achieving sustained virological response at post-treatment week 24 (SVR 24) by direct-acting antiviral (DAA) treatment. In 2008, he failed interferon therapy at 56 years of age. He received daclatasvir plus asunaprevir for 24 weeks after confirmation of no liver tumor by abdominal ultrasonography. He had no advanced liver fibrosis. Three months after initiation of DAA treatment, a liver tumor measuring 6 mm in diameter was detected by ultrasonography and confirmed with magnetic resonance imaging. After achieving SVR 24, the tumor increased in size to 16 mm. Two months later, a tumor biopsy was performed, and histology revealed moderately to poorly differentiated HCC. The patient's alpha-fetoprotein (AFP) level was within the normal range, but the Lens culinaris agglutinin-reactive fraction of AFP level was elevated. The diameter of the tumor increased to 32 mm at 2 months after diagnosis. Lymph node metastasis in porta hepatis was found by positron emission tomography at 4 months after diagnosis. The patient received hepatic arterial infusion chemotherapy and radiation therapy, but died later. Careful monitoring is required during and after DAA treatment because HCC can grow fast even in patients with normal AFP and no advanced liver fibrosis.

Evaluation of Resistance-Associated Substitutions in NS5A Using Direct Sequence and Cycleave Method and Treatment Outcome with Daclatasvir and Asunaprevir for Chronic Hepatitis C Genotype 1.

BACKGROUND: The aim of this study was to evaluate the efficacy of daclatasvir plus asunaprevir therapy in patients infected with hepatitis C virus and determine its relevance to resistant variants. METHODS: A total of 629 consecutive patients infected with hepatitis C virus genotype 1 were assessed. Daclatasvir (60 mg/day) plus asunaprevir (200 mg/day) was given for 24 weeks. The virological responses and resistance-associated substitutions of hepatitis C virus mutants were examined by the direct sequence and cycleave methods were evaluated. RESULTS: Overall, 89.4% (555/621) of patients exhibited a sustained virological response (SVR). The SVR rates in the patients with wild type, mixed, and mutant type Y93 by direct sequencing were 92.5% (520/562), 70.3% (26/37), and 42.9% (9/21), respectively. The SVR rates in the patients with 100%, 90%, 80%-30%, and 20%-0% Y93 wild by the cycleave method were 93.4% (456/488), 88.2%(30/34), 56.0%(14/25), and 36.8%(7/19), respectively. In contrast, the SVR rates for the wild type and mixed/mutant type L31 by direct sequencing were 90.2% (534/592) and 72.4% (21/29), respectively. In the multivariate analyses, the wild type Y93, no history of simeprevir therapy, the wild type L31, and low HCV RNA level were independent factors of SVR. CONCLUSION: NS5A resistance-associated substitutions, especially Y93H, were major factors predicting the SVR. Although direct sequencing can predict the SVR rate, the cycleave method is considered to be more useful for predicting the SVR when used in combination.

An analysis of drug-induced liver injury, which showed histological findings similar to autoimmune hepatitis.

BACKGROUND: Drug-induced liver injury (DILI) sometimes resembles autoimmune hepatitis (AIH) in its hepatic histology. However, there is lacking data of a comparison of the characteristics between such DILI and DILI without histological findings like AIH. METHODS: We enrolled 62 patients with DILI who were diagnosed using the Roussel Uclaf Causality Assessment Method, and performed a liver biopsy. These patients were classified into two groups: DILI with histology like AIH (group A, n = 23) and DILI without such histology (group B, n = 39). Sixteen patients of group A could be further classified into two groups: patients with relapse of the liver injury (group C, n = 8) and without relapse (group D, n = 8), after the recovery of the DILI. We compared the clinical and histological findings between group A and B, and group C versus D. RESULTS: Group A was characterized by an older age (p = 0.043), higher immunoglobulin G level (p = 0.017), positive antinuclear antibody status (p = 0.044), and a higher frequency of complementary alternative medicines and Chinese herbal medicines as the causative drug (p = 0.008). There were no significant differences between group C and D regarding the clinical data and liver histological findings. CONCLUSIONS: The clinical characteristics of DILI, which showed histological findings similar to AIH, were revealed. In such patients, a liver biopsy is recommended in order to determine the appropriate treatment strategy. In DILI with histology like AIH patients, long-term follow-up is needed to perceive the relapse.

[Recurrent hepatocellular carcinoma and adrenal metastasis without intrahepatic metastasis detected 22 years after hepatic resection: a case report].

A 55-year-old man presented with general malaise in May 2012. On reviewing his clinical records in 1989, we found that he had a hepatocellular carcinoma (HCC) in the left lobe, for which he had undergone left lobectomy in November 1989. However, there was no record of any follow-up examination from 1996 to 2011. Computed tomography in May 2012 revealed a right adrenal gland tumor measuring 8.5×6.5cm, which we treated by right adrenalectomy. Postoperative pathological examination showed this to be a metastasis of poorly differentiated HCC. To the best of our knowledge, no previous study has reported HCC recurrence such a long duration after HCC resection.

Time trends of clinical characteristics in hepatocellular carcinoma patients with chronic hepatitis B virus infection: A field survey between 2000 and 2012.

The hepatitis B virus (HBV) carrier rate has decreased in Japan; however, the incidence of HBV infection among hepatocellular carcinoma (HCC) patients has not decreased accordingly. In this study, we aimed to assess the time trends of the clinical characteristics in HCC patients with chronic HBV infection. Between 2000 and 2012, we enrolled a total of 156 HCC patients with chronic HBV infection in our field survey. The HCC risk was evaluated using the HCC prediction score, which is constructed from the characteristics of age, presence of liver cirrhosis and serum levels of albumin, bilirubin and HBV DNA. Lifestyle factors and the presence of diabetes mellitus were also evaluated. The time trends of patient characteristics were analyzed using the Jonckheere-Terpstra proportion trend test. Among HCC patients with chronic HBV infection, the proportion of patients at high risk according to the HCC prediction score significantly decreased during the study period (P=0.0005). Similarly, the proportion of patients with liver cirrhosis, ≤3.5 g/dl serum albumin level, >4 log copies/ml serum HBV DNA level and ≥60 g/day alcohol intake were also significantly decreased. The proportion of male and obese patients was not significantly altered, whereas the proportion of elderly (≥65 years) and diabetic patients tended to increase during the study period (P=0.0654 and P=0.0528, respectively). In this study, we analyzed the time trends of the clinical characteristics in HCC patients with chronic HBV infection and demonstrated that aging and diabetes mellitus may be involved in the hepatocarcinogenesis in patients with chronic HBV infection.

Chronic HCV infection was associated with severe insulin resistance and mild atherosclerosis: a population-based study in an HCV hyperendemic area.

BACKGROUND: Hepatitis C virus (HCV) affects glucose and lipid metabolism in vitro; however, it is unclear whether HCV infection is associated with insulin resistance and atherosclerosis at the population level. We aimed to investigate this association in a Japanese cohort of the Seven Countries Study, and our investigation was conducted in Tanushimaru, an HCV hyperendemic area. METHODS: A total of 1908 inhabitants of Tanushimaru were classified into 3 groups according to HCV infection status: those who were uninfected (n = 1780), those with transient infection (n = 88), and those with chronic infection (n = 40). Insulin resistance and atherosclerosis were evaluated by homeostasis model assessment for insulin resistance (HOMA-IR) and carotid intima-media thickness (IMT), respectively. Intergroup differences in variables were evaluated by age- and sex-matched multivariate regression analysis. RESULTS: Significant intergroup differences were seen in fasting glucose and insulin levels. The HOMA-IR value was significantly higher in the group with chronic infection than the values in the uninfected and transiently infected groups (3.0 ± 0.39 vs. 1.3 ± 0.03 vs. 1.5 ± 0.14; P < 0.001). In contrast, low-density lipoprotein (LDL)-cholesterol and triglyceride levels were significantly lower in the group with chronic infection than the levels in the other groups. IMT was reduced in the group with chronic infection, with a significant intergroup difference (0.67 ± 0.02 vs. 0.71 ± 0.003 vs. 0.72 ± 0.01 mm; P = 0.003). CONCLUSIONS: This population-based study in an HCV hyperendemic area revealed that chronic HCV infection was associated with severe insulin resistance and with mild atherosclerosis, suggesting a unique characteristic of HCV-related metabolic abnormality.

Drug-induced liver injury associated with Agaricus blazei Murill which is very similar to autoimmune hepatitis.

Agaricus blazei Murill (ABM) is one of the most popular complementary alternative medicines (CAM). We experienced a case of a 60-year-old woman with severe hepatitis associated with extract of ABM and extract of Ganoderma lucidum, and a case of a 75-year-old man with drug-induced liver injury (DILI) associated with extract of ABM and fucoidan. Their clinical courses from the start of CAM until the onset of DILI were observed unexpectedly, because they were under observation for stable malignant neoplasms: stage III malignant thymoma and stage IV lung cancer, respectively. However, they did not talk about taking CAM with their physicians. There were two common points between these two cases. First, they were diagnosed as compatible with DILI by using an international diagnostic scale, the Roussel Uclaf Causality Assessment Method. The second point was that histological findings of the liver were very similar to autoimmune hepatitis (AIH). In addition, serum immunoglobulin G and zinc sulfate turbidity tests gradually increased from the start of CAM to the onset of DILI. Their clinical course and liver histology suggested that the immunostimulating action of ABM caused liver injury which was very similar to that seen in AIH.

Risk factors for hepatocellular carcinoma in Japanese patients with autoimmune hepatitis type 1.

BACKGROUND: Hepatocellular carcinoma (HCC) is occasionally seen even in patients with autoimmune hepatitis (AIH) without prior infection either with hepatitis C virus (HCV) or hepatitis B virus. The aim of this study was to identify the incidence of and risk factors for HCC with AIH in a large-scale population with a long-term follow-up in Japan. METHODS: One hundred and eighty patients diagnosed with AIH were enrolled (F/M = 159/21; mean age, 59.9 years; mean observation period, 80.2 months). Patients with positive HCV antibody/serum HCV RNA and/or positive HBs Ag were excluded. Initial treatment included immunosuppressant therapy (n = 147), other drugs (n = 28), and no drug (n = 5). Patients underwent abdominal ultrasonography at intervals of 3-6 months during observation. Patients' demographic factors, biochemical data, liver histology, medications, response to treatment, and complications were evaluated in relation to HCC. RESULTS: During the observation period, six patients (3.3%) developed HCC. Univariate analysis showed that risk factors for HCC were cirrhosis at diagnosis with AIH (p = 0.0002), absence of a treatment response (p = 0.033), abnormal alanine aminotransferase (ALT) at the final observation (p = 0.0002), and diabetes (p = 0.0015). Multivariate analysis showed that risk factors for HCC were cirrhosis at diagnosis of AIH (odds ratio 4.08) and abnormal ALT at final observation (odds ratio 3.66). CONCLUSION: This retrospective study showed that cirrhosis at diagnosis of AIH and abnormal ALT at final observation were independently associated with HCC development. It is important to pay attention to the presence of cirrhosis at diagnosis of AIH and to normalize ALT.

The importance of a prior psychiatric examination in pegylated interferon and ribavirin combination treatment for chronic hepatitis C.

UNLABELLED: Some patients receiving pegylated interferon and ribavirin treatment for chronic hepatitis C are forced to discontinue the treatment due to psychiatric disorders. We performed a retrospective study to evaluate whether pre-treatment psychiatric examinations could increase successful completion rates for this treatment. METHODS: A total of 535 patients who started pegylated interferon-α-2b and ribavirin treatment at 6 hospitals affiliated with our hospital were included in this study. The patients were divided into two groups. Those who had visited a psychiatric clinic before treatment were Group A (N=223), and those who did not visit a psychiatric clinic before treatment were Group B (N=312). We analyzed the rate of discontinuation due to psychiatric disorders in the two groups. RESULTS: The rate of discontinuation due to psychiatric disorders in Group A was found to be significantly lower than that of Group B (1.8% (4/223) vs. 6.1% (19/312), P=0.035). In Group A, 6.1% (4/65) discontinued the treatment due to psychiatric disorders, while the comparable rate in Group B was 27% (19/68) (P=0.0004). Among patients who presented with psychiatric symptoms during treatment, the rate of treatment completion was significantly higher in Group A than in Group B (69.2% (18/26) vs. 5.0% (1/20), P=0.0067). In patients with a history of psychiatric symptoms, no discontinuation due to psychiatric disorder was observed in Group A. CONCLUSIONS: A psychiatric examination before pegylated interferon and ribavirin treatment was found to positively contribute to the successful completion of the treatment.

A randomized study of extended treatment with peginterferon alpha-2b plus ribavirin based on time to HCV RNA negative-status in patients with genotype 1b chronic hepatitis C.

OBJECTIVES: The treatment of patients with hepatitis C virus (HCV) genotype 1 with peginterferon plus ribavirin treatment for more than 48 weeks demonstrated high sustained virological response (SVR) rates. Although many studies extended the duration of therapy from 48 weeks to 72 weeks, the optimal duration has not yet been determined. METHODS: A total of 113 genotype 1b patients with high viral load were randomized at baseline to the standard (n=56) or extended (n=57) treatment group. The standard group patients received 48 weeks of peginterferon plus ribavirin treatment. In the extended group, the treatment was performed for 44 weeks after patients became negative for HCV RNA (total duration 48-68 weeks). RESULTS: The SVR rate of the standard and extended group was 36% (20 of 56) and 53% (30 of 57; P=0.07). However, the extended group patients who became negative for HCV RNA between weeks 16 and 24 had a significantly higher SVR rate (78%; 7 of 9) than that of standard group (9%, 1 of 11; P=0.005). The predictive factors for the SVR were the treatment regimen (the standard vs. extended treatment) and the time to HCV RNA negative-status. CONCLUSIONS: The extended treatment significantly increased the SVR rate in patients who were HCV RNA negative at 16-24 weeks.

Immune sensitization in the skin is enhanced by antigen-independent effects of IgE on mast cells.

Contact sensitivity responses require both effective immune sensitization following cutaneous exposure to chemical haptens and antigen-specific elicitation of inflammation upon subsequent hapten challenge. We have observed that that antigen-independent effects of immunoglobulin E (IgE) antibodies promote immune sensitization to haptens in the skin. Contact sensitivity is markedly impaired in IgE-/- mice but can be restored by either transfer of sensitized cells from wild-type mice or administration of hapten-irrelevant IgE before sensitization. Moreover, IgE-/- mice exhibit impairment in the emigration of dendritic cells from the epidermis after hapten exposure. Monomeric IgE has been reported to influence mast cell function. We observe diminished contact sensitivity in mice lacking FcepsilonRI or mast cells, and mRNA for several mast cell-associated genes is reduced in IgE-/- vs. wild-type skin after hapten exposure. We propose that levels of IgE normally present in mice favour immune sensitization via antigen-independent effects on mast cells.

Immune sensitization in the skin is enhanced by antigen-independent effects of IgE.

Contact sensitivity responses require both effective immune sensitization following cutaneous exposure to chemical haptens and antigen-specific elicitation of inflammation upon subsequent hapten challenge. We report that antigen-independent effects of IgE antibodies can promote immune sensitization to haptens in the skin. Contact sensitivity was markedly impaired in IgE(-/-) mice but was restored by either transfer of sensitized cells from wild-type mice or administration of hapten-irrelevant IgE before sensitization. Moreover, IgE(-/-) mice exhibited impairment in the reduction of dendritic cell numbers in the epidermis after hapten exposure. Monomeric IgE has been reported to influence mast cell function. We observed diminished contact sensitivity in mice lacking FcepsilonRI or mast cells, and mRNA for several mast cell-associated genes was reduced in IgE(-/-) versus wild-type skin after hapten exposure. We speculate that levels of IgE normally present in mice favor immune sensitization via antigen-independent but FcepsilonRI-dependent effects on mast cells.

Interferon-gamma brings additive anti-viral environment when combined with interferon-alpha in patients with chronic hepatitis C.

T-cell hyporesponsiveness may lead to chronicity of hepatitis C virus (HCV) infection. We evaluated whether interferon (IFN)-gamma injection can bring a Th1-dominant environment to patients with chronic hepatitis C. Seventeen patients with genotype 1b received natural IFN-alpha 5MU daily for the first 2 weeks and three times a week for the next 22 weeks followed by natural IFN-gamma 1 MU daily for 2 weeks. In 4 of 17 patients (23.5%), alanine aminotransferase (ALT) was normalized and 3 of these 4 patients (75.0%) cleared HCV RNA. beta2 microglobulin (BMG), neopterin and soluble (s) Fas increased with IFN-alpha and increased more with IFN-gamma. Serum interleukin (IL)-12, CD4 and CD8 remained unchanged with IFN-alpha but increased after IFN-alpha was replaced by IFN-gamma. IL-10 was not changed either with IFN-alpha or gamma. Productions of IL-2, IFN-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells did not change by IFN-alpha therapy, however, they were enhanced at the end of IFN-gamma therapy. Productions of IL-2 and 4 were unaffected. These results show that some immune parameters become Th1-dominant by additional IFN-gamma in patients with chronic hepatitis C. Combination of these two IFNs should be explored.