Grip strength complements performance status in assessing general condition in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

AIM: An accurate assessment of the general condition of patients with hepatocellular carcinoma (HCC) is essential. We evaluated the impact of grip strength (GS) and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) on the clinical outcomes of patients with unresectable HCC (u-HCC) treated with atezolizumab plus bevacizumab. METHODS: This observational cohort study analyzed 89 patients with u-HCC treated with atezolizumab plus bevacizumab between October, 2020 and October, 2023. A Cox proportional hazards model and Kaplan-Meier curve were used to identify the prognostic factors associated with survival outcomes. RESULTS: There were 33 patients who had low GS and 16 had an ECOG-PS ≥1. The frequency of patients with low GS increased as the ECOG-PS score increased. The overall survival of the normal GS group was significantly higher than that of the low GS group (p < 0.01). There was no significant difference in progression-free survival between the normal GS group and low-GS group (p = 0.28). Among the patients in the ECOG-PS 0 groups, the overall survival in the normal GS group was significantly higher than that in the low GS group (p < 0.01). A multivariate analysis revealed that modified albumin-bilirubin 2b (HR 2.24; 95% confidence interval [CI] 1.06-4.73), α-fetoprotein ≥100 ng/mL (HR 2.35; 95% CI 1.20-4.58), and low GS (HR 2.87; 95% CI 1.31-6.27) were independently associated with a poor overall survival. CONCLUSIONS: The present study demonstrated that GS is a sensitive marker for detecting a subclinical decline in the general condition and is therefore a potential predictor of the outcome of u-HCC patients treated with atezolizumab plus bevacizumab.

Low liver reserve is a risk factor for acute pancreatitis in patients with acute liver failure.

AIM: Acute pancreatitis is a complication of acute liver failure (ALF). This study aimed to investigate the prevalence of and clinical features associated with acute pancreatitis in patients with ALF. METHODS: We retrospectively analyzed a cohort of ALF patients without hepatic encephalopathy diagnosed during a period 2011-2018, and compared clinical features between patients with acute pancreatitis and those without. Acute pancreatitis was diagnosed according to the Acute Pancreatitis Clinical Practice Guidelines 2021. A multivariate analysis was carried out to identify factors associated with acute pancreatitis. RESULTS: There were 83 ALF patients without hepatic encephalopathy (34 men; 11 deaths; 6 liver transplants; median age, 63 years). Acute pancreatitis occurred in nine patients (10.8%). The median time duration from ALF to the onset of acute pancreatitis was 8 days. The survival rate was lower in patients with than those without acute pancreatitis (22% vs. 86%). The model for end-stage liver disease score (hazard ratio 1.10, 95% confidence interval 1.03-1.18) was found to be a significant factor associated with acute pancreatitis, whereas triglyceride, age, and sex were not. CONCLUSIONS: A high model for end-stage liver disease score may be a marker to stratify patients with ALF at a risk of acute pancreatitis.

Spontaneous reactivation of hepatitis B virus with multiple novel mutations in an elderly patient with resolved hepatitis B virus infection.

Spontaneous reactivation of the Hepatitis B virus (HBV) is rare in individuals with previously resolved infections. This report presents the case of a 71 year-old Japanese woman who experienced HBV reactivation without any prior immunosuppressive therapy or chemotherapy. Before the onset of liver injury, the patient was negative for hepatitis B surface antigen (HBsAg) but positive for hepatitis B surface antibody. She subsequently developed liver injury, with the reappearance of HBsAg and HBV DNA. The patient was successfully treated with tenofovir alafenamide, and prednisolone. Full-genome sequencing of HBV revealed subgenotype B1 without hepatitis B e-negative mutations in the precore and core promoter regions and 12 amino acid alterations in the pre-S1/S, P, and X genes. Notably, the S gene mutations D144A and K160N, which alter the antigenicity of HBsAg and potentially contribute to its reactivation, were identified. This case emphasizes the importance of vigilance for spontaneous reactivation of resolved HBV, highlighting the need for comprehensive genomic analysis to understand the associated virological intricacies.

Positive impact of obesity on the prognosis of liver cirrhosis.

BACKGROUND AND AIM: The study aims to determine the prognostic impact of obesity, sarcopenic obesity, and dynapenic obesity in patients with chronic liver disease. METHODS: This retrospective observational study enrolled patients with chronic hepatitis (n = 746) and liver cirrhosis (n = 434) without hepatocellular carcinoma at entry. The patients were evaluated for sarcopenia and obesity between April 2016 and April 2022. Obesity was defined as a body mass index of ≥ 25 kg/m2. Sarcopenic obesity was defined as low skeletal muscle mass (pre-sarcopenia) with obesity and dynapenic obesity was defined as low muscle strength (dynapenia) with obesity. The effects of obesity on survival were evaluated retrospectively. RESULTS: The mean observation period was 2.5 years. Obesity, sarcopenic obesity, and dynapenic obesity were found in 271 (45.5%), 17 (2.9%), and 21 (3.5%) men, and 261 (44.7%), 59 (10.1%), and 53 (9.1%) women, respectively. A multivariate Cox proportional hazards model revealed that Child-Pugh class, dynapenia (hazard ratio [HR] 3.89), elderly (≥ 65 years old) (HR 2.11), and obesity (HR 0.58) were independently associated with overall survival (OS). However, neither sarcopenic nor dynapenic obesity were associated with OS. In patients with cirrhosis, the OS of the obese group was significantly higher than that of the non-obese group. The effect of obesity on OS was significant in elderly patients, but not in younger patients. CONCLUSIONS: Sarcopenic and dynapenic obesity seem unrelated to the prognosis of patients with chronic liver disease. Obesity has a positive effect on the prognosis of elderly patients with cirrhosis.

Seroprevalence and incidence of hepatitis E virus infection in the general population of Iwate prefecture, Japan: A retrospective cohort study.

AIM: Hepatitis E virus (HEV) causes subclinical or acute self-limiting hepatitis. We surveyed the current seroprevalence and incidence of HEV infection among the general population in Iwate Prefecture, Japan, where the endemic infection is presumed to be low. METHODS: Between 2014 and 2016, we recruited individuals from Iwate Prefecture, Japan, who visited a general medical work-up program. Serum anti-HEV antibody and HEV RNA were measured twice, with an interval of 2 years. Anti-HEV antibody was measured with enzyme-linked immunosorbent assay and HEV RNA with reverse transcription-polymerase chain reaction. RESULTS: Study participants comprised 1284 Japanese (650 men and 634 women) with age ranging 20-89 years. A total of 90 participants were found to be positive for anti-HEV immunoglobulin G on the first visit, with a prevalence of 7.0% (95% confidence interval [CI] 5.6%-8.4%). Seroprevalence was higher in men than in women (10.1% vs. 3.7%, p < 0.001), and in those aged in their 50s-80s than in those aged in their 20s-40s (p = 0.006). Positive seroconversion indicating new HEV infection was found in seven of 1194 seronegative participants (0.59%; 95% CI 0.15%-1.0%), indicating the incidence of HEV infection to be 272 per 100 000 person-years (95% CI 109-561). CONCLUSIONS: Our observations suggest that the incidence of HEV infection is high and that it is a leading cause of hepatitis virus infection in Iwate Prefecture, Japan.

A Case of Autoimmune Hepatitis Complicated by Undiagnosed Factor VII Deficiency: A Pitfall of Coagulopathy.

Prothrombin time (PT) is a key parameter for assessing the severity of liver disease. We present the case of a 37-year-old woman with severe acute liver injury due to autoimmune hepatitis. Although prednisolone drastically improved her hepatocyte function, her PT did not recover to the reference range. A review of her medical records revealed that the patient had normal transaminase levels and prolonged PT 2 years previously. Further examinations of her coagulopathy revealed that she had low factor VII activity, suggesting a diagnosis of factor VII deficiency. Our experience suggests that altered coagulopathy should be considered in cases of liver injury with an extraordinary PT.

Coincidental items in the definition of metabolic dysfunction-associated fatty liver are useful in identifying patients having significant fibrosis with fatty liver.

AIM: We aimed to establish a method that will identify patients at a high risk for progressive phenotype of fatty liver. METHODS: Patients with fatty liver who underwent liver biopsy between July 2008 and November 2019 were included as cohort 1, and those who underwent abdominal ultrasound screening examination by general physicians between August 2020 and May 2022 served as cohort 2. According to the definition of metabolic dysfunction-associated fatty liver (MAFLD), the subjects were classified by body mass index of ≥23, diabetes mellitus, and coexistence of two or more metabolic risk items. The progressive phenotype of MAFLD is defined by significant fibrosis complicated with either nonalcoholic fatty liver disease activity score ≥4 (BpMAFLD) or steatosis grade ≥2 by ultrasound examination (UpMAFLD). RESULTS: One hundred sixty-eight patients and 233 patients were enrolled in cohorts 1 and 2, respectively. In cohort 1, the prevalence of BpMAFLD was 0% in patients without a complicating factor (n = 10), 13% in those with one complicating factor (n = 67), 32% in those with two (n = 73), and 44% in those with all three complicating factors (n = 36). A logistic regression analysis revealed that factors in the MAFLD definition were significantly associated with BpMAFLD. In cohort 2, a criterion of two or more positive MAFLD definitions was found to have a 97.4% negative predictive value for the diagnosis of UpMAFLD. CONCLUSION: Patients with two or more complicating factors in the MAFLD definition should have further evaluation for liver fibrosis.

Current elimination status of hepatitis C virus-infected maintenance hemodialysis patients in Iwate Prefecture, Japan.

INTRODUCTION: The aim is to clarify the hepatitis C virus (HCV) status of hemodialysis (HD) patients and patient management after HCV elimination. METHODS: Questionnaire survey was conducted in Iwate prefecture, Japan from 2016 to 2021. RESULTS: Patients underwent HD was 2944, including 132 anti-HCV antibody-positive patients, with 91 HCV RNA-positive patients. Of the 91 HCV RNA-positive patients, 51 received antiviral treatment. Sustained virological response (SVR) rate was 94%. The patients treated with direct antiviral agents had significantly lower mortality rate than the untreated patients, and no liver-related deaths occurred in patients who achieved SVR or in HCV RNA-negative patients. The HCV RNA-positive prevalence was finally 0.79%. Approximately 40% of the facilities had dedicated beds and dialysis-related items for patients who achieved an SVR. CONCLUSION: To eliminate HCV in HD facilities, it is necessary to promote HCV RNA testing for anti-HCV antibody-positive patients and to provide antiviral treatment for HCV RNA-positive patients. Additionally, collaboration among hepatologists and HD specialists are essential.

Annual changes in grip strength and skeletal muscle mass in chronic liver disease: observational study.

Sarcopenia is a common complication in patients with chronic liver disease (CLD); however, the progression of sarcopenia over the course of CLD is unclear. The present study therefore determined the natural course of the progression of sarcopenia in patients with CLD and the effect of liver cirrhosis (LC) on this progression. This observational study analyzed patients with chronic hepatitis (CH) (n = 536) and LC (n = 320) who underwent evaluations of the grip strength and skeletal muscle mass of the arms, trunk, and legs for sarcopenia between 2016 and 2021. A bioelectrical impedance analysis was used to evaluate skeletal muscle mass. The annual rate of change (%/year) in two tests were compared between patients with CH and LC. The annual rates of change in grip strength and skeletal muscle of arms, trunk, and legs of patients with CH and LC were - 0.84% vs. - 2.93%, - 0.54% vs. - 1.71%, - 0.43% vs. - 1.02%, and - 0.76% vs. - 1.70% for men and - 0.12% vs. - 1.71%, - 0.66% vs. - 1.71%, - 0.49% vs. - 1.31%, and - 0.76% vs. - 1.54% for women, respectively. The progression of sarcopenia was greater in LC patients than in CH patients and that the decrease in grip strength was most prominent in the progression of sarcopenia in patients with LC.

Distinction of Drug-Induced Liver Injury From Autoimmune Hepatitis in Patients With Acute Liver Injury: Proposal of a Combination of Diagnostic Scores.

Background and Aims: Acute liver injury (ALI) due to autoimmune hepatitis (AIH) can be treated by immunosuppression. In contrast, idiosyncratic drug-induced liver injury (DILI) had a poor prognosis. DILI thus needs to be distinguished from non-DILI. Methods: Twenty-nine patients with DILI and 77 with non-DILI (42 of AIH and 35 with undetermined cause) diagnosed during 2005-2017 comprised the derivation cohort. 110 patients with ALI due to either AIH, DILI, or obscure causes at 6 liver centers during 2010-2015 were the validation cohort. Revised international AIH group scores (IAIHGs) and the Roussel-Uclaf Causality Assessment Method (RUCAM) were modified to calculate results using medical interviews and laboratory data without chronological changes. Diagnostic accuracy for the distinction of DILI and non-DILI was evaluated by receiver operating characteristic analysis and results were expressed as the area under the curve (AUC). This study received institutional institutional review board approval (MH2020-205). Results: The AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.96 and 1.00 when cut-off values were set at 3 for the modified RUCAM and 5 for the modified IAIHGs in the derivation cohort. In the validation cohort, the AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.95 and 0.97, respectively. The accuracy of the combination of the modified scores was 81% (89/110). Conclusion: Modified diagnostic scores based on detailed medical interviews and routine laboratory data can distinguish DILI from non-DILI in patients with ALI.

Viral eradication by direct-acting antivirals does not decrease the serum myostatin level in patients infected with hepatitis C virus.

OBJECTIVES: Myostatin has been assumed to be involved in the development of sarcopenia in patients with chronic liver disease, but the effect of hepatitis C virus (HCV) elimination on myostatin is unclear. The aim of this study was to assess the effect of a sustained virologic response at 24 wk (SVR24) after direct-acting antiviral (DAA) therapy on serum myostatin levels in patients infected with HCV. METHODS: In this single-center retrospective study based on data collected from a university hospital, we analyzed patients infected with HCV who were treated with DAA between 2014 and 2017. We compared the serum myostatin level before and after DAA treatment and evaluated the correlation between myostatin and laboratory data. RESULTS: In the 91 participants, the median myostatin level at the start of DAA and after achieving an SVR24 were 3042 (924-10177) and 3349 (498-7963) pg/mL, respectively. There was no significant difference in the myostatin level between the start of DAA treatment and after achieving an SVR24 (P = 0.79). The serum myostatin levels were significantly higher in men than in women and in patients with cirrhosis than in patients with chronic hepatitis both at the start of DAA and after achieving an SVR24. Serum myostatin levels showed a significant positive correlation with the skeletal muscle index and liver fibrosis markers (e.g., type Ⅳ collagen 7S, aspartate aminotransferase-platelet ratio index score, and fibrosis-4 index). CONCLUSIONS: Viral eradication by DAA treatment did not decrease the serum myostatin level in patients infected with HCV.

SEB genotyping: SmartAmp-Eprimer binary code genotyping for complex, highly variable targets applied to HBV.

BACKGROUND: SmartAmp-Eprimer Binary code (SEB) Genotyping is a novel isothermal amplification method for rapid genotyping of any variable target of interest. METHODS: After in silico alignment of a large number of sequences and computational analysis to determine the smallest number of regions to be targeted by SEB Genotyping, SmartAmp primer sets were designed to obtain a binary code of On/Off fluorescence signals, each code corresponding to a unique genotype. RESULTS: Applied to HBV, we selected 4 targets for which fluorescence amplification signals produce a specific binary code unique to each of the 8 main genotypes (A-H) found in patients worldwide. CONCLUSIONS: We present here the proof of concept of a new genotyping method specifically designed for complex and highly variable targets. Applied here to HBV, SEB Genotyping can be adapted to any other pathogen or disease carrying multiple known mutations. Using simple preparation steps, SEB Genotyping provides accurate results quickly and will enable physicians to choose the best adapted treatment for each of their patients.

Safety and efficacy of glecaprevir and pibrentasvir in north Tohoku Japanese patients with genotype 1/2 hepatitis C virus infection.

BACKGROUND AND AIMS: To assess the efficacy and safety of treatment with glecaprevir/pibrentasvir in Japanese patients with genotype (GT) 1/2 hepatitis C virus (HCV) infection in a real-world clinical setting. METHODS: A total of 230 patients from 12 centers in northern Tohoku Japan with chronic hepatitis (CH) or compensated liver cirrhosis (LC) and GT1/2 HCV infection were treated with glecaprevir/pibrentasvir and followed up for 12 weeks after treatment completion. Those patients were evaluated by dividing them into the following three groups: CH GT1/2 HCV-infected, direct-acting antiviral agents (DAA)-naive patients received 8 weeks of treatment (8-week initial treatment group), compensated LC GT1/2 HCV-infected, DAA-naive patients received 12 weeks of treatment (12-week initial treatment group), and GT1/2 HCV-infected patients with previous failed DAA treatment were assigned to 12-week treatment (12-week re-treatment group). RESULTS: The overall sustained virologic response (SVR) rate in the modified intention-to-treat population was 99% (222/225). The SVR rate in 8-week initial treatment group, 12-week initial treatment group, and 12-week re-treatment group were 99% (118/119), 98% (104/106), and 97% (56/58), respectively. SVR rates based on chronic kidney disease (CKD) stage were 99% in stage 1/2, 96% in stage 3, and 100% in stage 4/5 patients. SVR rate among the three treatment groups was not influenced by CKD stage. Furthermore, all 18 patients (six in the 8-week initial treatment group, 12 in 12-week initial treatment group) who underwent hemodialysis attained SVR. Serious treatment-associated adverse events (grade ≥ 3) occurred in 12 patients (5.2%). Five patients (2.2%) discontinued treatment because of adverse events; however, three of these patients achieved SVR. CONCLUSION: Primary treatment and re-treatment with glecaprevir/pibrentasvir are effective and safe for patients without decompensated LC and GT1/2 HCV infection in a real-world clinical setting. Furthermore, the SVR rate was not influenced by CKD stage.

A Novel Standard for Hepatocellular Carcinoma Screening Intensity After Hepatitis C Elimination.

PURPOSE: To investigate long-term incidence of hepatocellular carcinoma (HCC) and the factors associated with HCC occurrence after achieving sustained virological response (SVR) by direct-acting antiviral agent (DAA) treatment for hepatitis C virus (HCV). METHODS: A total of 476 patients (male 227, female 249; median age 68) with chronic HCV infection who were treated with DAAs and achieved SVR were analyzed. The incidence of HCC and factors related to the development of HCC after HCV elimination were evaluated. RESULTS: The median observation period was 46.4 months. During this period, 40 patients developed HCC. The incidence rates of HCC were 3.7%, 6.0%, 7.1%, 9.3%, and 10.6% at 1, 2, 3, 4, and 5 years post-SVR12, respectively. Multivariate analysis with pre-treatment factors revealed that platelet count, α-fetoprotein, fibrosis-4 (Fib-4) index, and previous HCC history were independent factors that contributed to development of HCC post-SVR following DAA treatment. Of these factors, previous HCC history was the most significant, followed by Fib-4 index. Using these two factors, a novel scoring system was established. The presence of previous HCC history was scored as 2, and then, the absence of previous HCC history was stratified by Fib-4 index (≥3.07, 1; <3.07, 0). The HCC occurrence rate at 5 years was 0.4% in the 0-point group, 6.8% in the 1-point group, and 55.6% in the 2-point group, respectively. CONCLUSION: Fib-4 index and previous HCC history were independent predictors for development of HCC after DAA treatment. Patients with these risk factors require careful observation.

A 55-Year-Old Japanese Man with Multiple Sclerosis Diagnosed with Disseminated Tuberculosis Identified by Liver Function Abnormalities: A Case Report.

BACKGROUND Reactivation of latent tuberculosis infection (LTBI) is a recognized complication of immunosuppressive treatment. However, immunosuppressed patients are also at risk of hematogenous disseminated spread from a primary infection with Mycobacterium tuberculosis. This report presents the case of a 55-year-old Japanese man with a 12-year history of multiple sclerosis who was hospitalized with worsening neurological symptoms and was diagnosed with disseminated tuberculosis identified by abnormalities on liver function test results. CASE REPORT A 55-year-old Japanese man was admitted to our hospital for the treatment of multiple sclerosis with worsening symptoms. He showed mild liver dysfunction at the time of admission. A laparoscopy and biopsy were performed to identify the cause of the liver dysfunction, which was the only positive finding. The liver surface was studded with yellowish-white nodular lesions. Histological examination of a liver biopsy specimen revealed a granuloma without caseous necrosis. The patient was suspected of having tuberculosis. Although the results of an interferon-γ-releasing assay were indeterminate, asymptomatic disseminated tuberculosis was diagnosed from the serum adenosine deaminase levels, a caseating granuloma in the cervical lymph node, detection of acid-fast bacilli DNA in the cervical lymph nodes on polymerase chain reaction, and tuberculin skin test findings. Anti-tuberculosis treatment led to improvement in the liver function test findings. CONCLUSIONS This case has highlighted that tuberculosis may have an atypical presentation in the immunosuppressed patient. In addition to the reactivation of LTBI, hematogenous spread of primary tuberculosis may result in disseminated disease involving multiple organs and requiring emergency treatment.

Health-related quality of life in patients with chronic hepatitis C treated with sofosbuvir-based treatment at 1-year post-sustained virological response.

PURPOSE: Long-term effects on patient health-related quality of life (HRQoL) after direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) are unknown. We assessed the impact of DAA-mediated HCV clearance on HRQoL from DAA initiation to 1 year after confirmed sustained virological response at 24 weeks post-treatment (SVR24). METHODS: HRQoL was evaluated using the eight-item Short Form Health Survey (SF-8). Chronic HCV-infected patients were treated for 12 weeks with sofosbuvir-based DAAs. SF-8 was administered at baseline, treatment cessation, SVR24, and 1-year post-SVR24. RESULTS: A total of 109 chronic HCV-infected patients were enrolled. The average SF-8 scores were higher than the Japanese national standard values for bodily pain (BP) and mental health at baseline and for general health at 1-year post-SVR24. None of the SF-8 scores differed significantly between baseline and 1-year post-SVR24. Regarding age, sex, liver status, and treatment regimen, the SF-8 scores at 1-year post-SVR24 were affected by only age; individuals aged < 65 years had significantly higher physical component score (PCS), physical functioning, role physical, and BP scores than older individuals. In the multivariable analysis, only age of ≥ 65 years was significantly associated with influencing PCS at 1-year post-SVR24. However, no significant factors were identified for mental component score. CONCLUSION: Upon long-term assessment, although more factors trended higher than national standard values at 1-year post-SVR24 than at baseline, there were no significant changes within factors. As PCS tended to be associated with age, patients aged ≥ 65 years should be carefully monitored for PCS.

A 51-Year-Old Woman with Drug-Induced Hypersensitivity Syndrome Associated with Carbamazepine, Reactivation of Human Herpesvirus 6, and Acute Liver Failure: A Case Report.

BACKGROUND Infection with human herpesvirus 6 (HHV-6) is a recognized risk factor for the development of drug-induced hypersensitivity syndrome (DIHS). DIHS is a systemic autoimmune condition that presents with mucocutaneous lesions of varying severity and comprises 3 subtypes: toxic epidermal necrolysis, Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS). Here, we describe the case of a 51-year-old woman with a diagnosis of DIHS associated with carbamazepine, reactivation of HHV-6, and acute liver failure, which was consistent with DRESS. CASE REPORT We present the case of a 51-year-old Japanese woman who had been taking carbamazepine for epilepsy for the past 3 weeks. She presented with a fever, liver dysfunction, eosinophilia, and the sudden appearance of a skin rash. Steroid therapy was started for suspected drug-induced liver injury. The skin eruption disappeared, and liver dysfunction showed an improving trend. However, after stopping steroid, the pyrexia and eosinophilia reappeared. Therefore, prednisolone was re-administrated. HHV-6 DNA was detected, so HHV-6 reactivation was confirmed. Carbamazepine was stopped, and the clinical manifestations improved. She was ultimately diagnosed with DIHS, consistent with DRESS, associated with carbamazepine and HHV-6 reactivation, and liver dysfunction was assessed histologically. Therefore, the drug-related hepatotoxicity of carbamazepine played a role in causing liver damage rather than HHV-6 infection at that time. CONCLUSIONS We describe a case of DIHS that was also associated with acute liver failure, consistent with DRESS. The case highlights the importance of making the correct diagnosis, as well as the management of mucocutaneous lesions and other systemic conditions (including acute liver failure).