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.

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.

Immune checkpoint inhibitor-associated colitis in unresectable hepatocellular carcinoma: two cases of early onset after treatment with durvalumab plus tremelimumab.

The HIMALAYA trial is the first chemotherapeutic trial to demonstrate the efficacy of combined immune checkpoint inhibitors (ICIs) for unresectable hepatocellular carcinoma (u-HCC). The STRIDE regimen used in this trial consists of a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor and programmed cell death ligand 1 (PD-L1) inhibitor. Herein, we report two cases of ICI-colitis that occurred immediately after the initiation of the STRIDE regimen for u-HCC. A 73-year-old man and 75-year-old man with u-HCC were treated with the STRIDE regimen. Both patients developed grade 3 diarrhea (Common Terminology Criteria for Adverse Events, ver. 5.0) within 10 days of treatment initiation. Colonoscopy revealed aphthous erosions and erythema extending from the terminal ileum to the rectum in one case, while the other showed aphthous ulcers in the terminal ileum and shallow ulcers in the colorectum. Histopathological examination of a biopsy specimen revealed epithelial cell apoptosis and neutrophil infiltration bodies, consistent with ICI-colitis. Prednisolone (0.5 mg/kg) was effective in both patients. Our experience suggests the need for both careful monitoring and early endoscopic examination of ICI colitis in patients with unresectable HCC treated with the STRIDE regimen.

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.

Longitudinal changes in mental health outcomes after COVID-19 hospitalization: A prospective study.

BACKGROUND: The long-term trends of COVID-19 mental sequelae remain unknown. Thus, this study aimed to survey the one-year temporal trends of PTSD and health-related quality of life of COVID-19 survivors. METHODS: Patients hospitalized with COVID-19 were followed up at three, six, and 12 months after discharge. Patients with COVID-19 who were able to communicate and complete the questionnaires were included in the study. All participants were asked to complete the Medical Outcomes Study 36-Item Short-Form Health (SF-36) survey and the Impact of Event Scale-Revised (IES-R). The cutoff point of 24/25 of IES-R was defined as preliminary PTSD. Patients exhibiting PTSD symptoms at six months or later were regarded as "delayed patients," while those exhibiting PTSD symptoms at all the time points were "persistent patients." RESULTS: Of the 98 patients screened between June and November 2020, 72 participated in the study. A total of 11 (15.3%) had preliminary PTSD at three months, 10 (13.9%) at six months, and 10 (13.9%) at 12 months; delayed and persistent patients were four patients (7.54%) each. Patients with preliminary PTSD had lower mental summary scores in SF-36; 47 (IQR 45, 53) for patients with preliminary PTSD and 60 (49, 64) without preliminary PTSD at three months, 50 (45, 51) and 58 (52, 64) at six months, and 46 (38, 52) and 59 (52, 64) at 12 months. CONCLUSION: Healthcare providers should care about the courses of PTSD in COVID-19 survivors and be aware that patients with PTSD symptoms may have a lower health-related quality of life.

Systematic genetic identification of functional domains on collided di-ribosomes responsible for rescue pathways upon translation arrest in Saccharomyces cerevisiae.

Translation elongation becomes arrested when various obstacles arise, such as a series of inefficient rare codons or stable RNA secondary structures, thus causing ribosomal stalling along the mRNA. Certain wasteful and persistent stalling states are resolved by ribosome rescue pathways. For instance, collisions between stalled and subsequent ribosomes are thought to induce ubiquitination of ribosomal S20 protein by the E3 ubiquitin ligase Hel2, which triggers subsequent rescue reactions. Although structural studies have revealed specific contact sites between collided ribosomes, the ribosomal regions crucial for the rescue reaction remain uncharacterized. In this study, we performed a systematic genetic analysis to identify the molecular regions required for ribosome rescue in Saccharomyces cerevisiae. A series of dominant negative mutations capable of abolishing the rescue reaction were isolated in ribosomal proteins S20 and Asc1. Moreover, mutations in both proteins clustered on the surface of ribosomes between the collided ribosome interfaces, aligned in such a way that they seemingly faced each other. Further analysis via the application of the split-TRP1 protein assay revealed that the mutation of either protein distinctively affected the functional interaction between Hel2 and Asc1, suggesting the development of differential functionality at the interface between collided ribosomes. Our results provide novel and complementary insights into the detailed molecular mechanisms of ribosomal rescue pathways.

Antimicrobial Stewardship Program for Patients in the Hematological Department Receiving Carbapenem Therapy: A Single-Center and Interrupted Time Series Analysis.

As antibiotic resistance has become a global problem, the intervention of an antimicrobial stewardship team (AST) is warranted. In hematological disorders, infectious complications are crucial owing to abnormal neutrophil function and decreased cell-mediated immunity. Despite the widespread implementation of AST intervention, the effectiveness of stewardship practices for immunocompromised patients remains uncertain. We determined the effect of AST interventions on carbapenem therapy in the department of hematology. Patients admitted to the department and undergoing carbapenem therapy were enrolled. We compared carbapenem use between the pre-AST (April 2016-March 2018) and post-AST (April 2018-March 2021) periods. Factors associated with long-term carbapenem therapy were investigated. Overall, 515 episodes of carbapenem therapy in 264 patients in the department were evaluated. According to the interrupted time series analysis, the number of days of therapy decreased with AST intervention (ß = -0.263, p = 0.011). In multivariate analysis, predictive factors associated with long-term carbapenem therapy (>8 days) were outpatient onset, chronic obstructive pulmonary disease, acute myeloid leukemia, multiple myeloma, and infection with resistant bacteria (such as extended spectrum ß-lactamases and AmpC) (95% confidence interval, 1.030-2.818, 1.067-66.667, 1.057-2.782, 0.168-0.742, and 1.382-5.750, respectively). The AST intervention reduced carbapenem use in patients with hematological disorders.

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.

Clinical characteristics and efficacy of pioglitazone in a Japanese patient with familial partial lipodystrophy due to peroxisome proliferator-activated receptor γ gene mutation.

Familial partial lipodystrophy (FPLD) 3 is a rare genetic disorder caused by peroxisome proliferator-activated receptor γ gene (PPARG) mutations. Most cases have been reported in Western patients. Here, we describe a first pedigree of FPLD 3 in Japanese. The proband was a 51-year-old woman. She was diagnosed with fatty liver at age 32 years, dyslipidemia at age 37 years, and diabetes mellitus at age 41 years. Her body mass index was 18.5 kg/m2, and body fat percentage was 19.2%. On physical examination, she had less subcutaneous fat in the upper limbs than in other sites. On magnetic resonance imaging, atrophy of subcutaneous adipose tissue was seen in the upper limbs and lower legs. Fasting serum C-peptide immunoreactivity was high (3.4 ng/mL), and the plasma glucose disappearance rate was low (2.07%/min) on an insulin tolerance test, both suggesting apparent insulin resistance. The serum total adiponectin level was low (2.3 µg/mL). Mild fatty liver was seen on abdominal computed tomography. On genetic analysis, a P495L mutation in PPARG was identified. The same mutation was also seen in her father, who had non-obese diabetes mellitus, and FPLD 3 was diagnosed. Modest increases in body fat and serum total adiponectin were seen with pioglitazone treatment. Attention should be paid to avoid overlooking lipodystrophy syndromes even in non-obese diabetic patients if they show features of insulin resistance.

Diabetic family history in young Japanese persons with normal glucose tolerance associates with k-means clustering of glucose response to oral glucose load, insulinogenic index and Matsuda index.

Aims: The present study aimed to clarify the relationships between diabetic family history (FH), and dysglycemic response to the oral glucose tolerance test (OGTT), insulin secretion, and insulin sensitivity in young Japanese persons with normal glucose tolerance (NGT). Methods: We measured plasma glucose (PG) and immunoreactive insulin levels in 1,309 young Japanese persons (age <40 years) with NGT before and at 30, 60, and 120 min during a 75-g OGTT. Dysglycemia during OGTT was analyzed by k-means clustering analysis. Body mass index (BMI), blood pressure (BP), and lipids were measured. Insulin secretion and sensitivity indices were calculated. Results: PG levels during OGTT were classified by k-means clustering analysis into three groups with stepwise decreases in glucose tolerance even among individuals with NGT. In these clusters, proportion of males, BMI, BP and frequency of FH were higher, and lipid levels were worse, together with decreasing glucose tolerance. Subjects with a diabetic FH showed increases in PG after glucose loading and decreases in insulinogenic index and Matsuda index. Conclusions: Dysglycemic response to OGTT by k-means clustering analysis was associated with FH in young Japanese persons with NGT. FH was also associated with post-loading glucose, insulinogenic index, and Matsuda index.

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.

Association between sarcopenia and the severity of diabetic polyneuropathy assessed by nerve conduction studies in Japanese patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: This study examined the association between the severity of diabetic polyneuropathy (DPN) based on the Baba classification, and sarcopenia and its related factors. MATERIALS AND METHODS: The participants were 261 patients with type 2 diabetes mellitus. DPN was classified as stages 0-4 according to the Baba classification. Sarcopenia was diagnosed based on measurements of the skeletal mass index, grip strength and walking speed, using the Asia Working Group for Sarcopenia 2019 diagnostic criteria. RESULTS: The median age of the participants was 67 years, the proportion of men was 58.6%, the median estimated duration of diabetes was 10 years and the median values for glycated hemoglobin were 10.3%. With regard to DPN, the prevalence of Baba classification stages 0-2 was 90.8% (n = 237), and that of stage 3 or 4 was 9.2% (n = 24). The prevalence of sarcopenia was 19.9%. A trend toward an increase in the frequency of slow walking speed was seen as the stage of DPN progressed. The frequencies of sarcopenia and slow walking speed were higher in the group with the Baba classification stages 3 and 4 than in the group with stages 0-2. On multiple logistic regression analyses, however, DPN was not significantly related to sarcopenia and walking speed. CONCLUSIONS: Although severe DPN might be related to sarcopenia, the frequency of severe DPN is low in the clinical setting, indicating that its contribution to sarcopenia is modest.

Secondary Hypogonadism due to Excessive Ingestion of Isoflavone in a Man.

A 54-year-old man had been drinking approximately 1.2 L of soy milk (equivalent to approximately 310 mg of isoflavones) per day for the previous 3 years. He then developed erectile dysfunction and gynecomastia. On an examination in our department in May, blood tests showed low gonadotropin and testosterone levels, indicative of secondary hypogonadism. He stopped drinking soy milk on his own in June of that year. When he was admitted in August, blood tests showed an improved gonadal function. Secondary hypogonadism caused by the excessive intake of isoflavones in soy milk was diagnosed. In men, an excessive intake of isoflavones may cause feminization and secondary hypogonadism.

Long-Term Efficacy and Safety of Rifaximin in Japanese Patients with Hepatic Encephalopathy: A Multicenter Retrospective Study.

Background: Rifaximin is commonly used for hepatic encephalopathy (HE). However, the effects of long-term treatment for Japanese people are limited. Therefore, this study aimed to investigate the effects and safety of long-term treatment with rifaximin on HE. Methods: A total of 215 patients with cirrhosis administered with rifaximin developed overt or covert HE, which was diagnosed by an attending physician for >12 months. Laboratory data were extracted at pretreatment and 3, 6, and 12 months after rifaximin administration. The long-term effect of rifaximin was evaluated, and the incidence of overt HE during 12 months and adverse events was extracted. Results: Ammonia levels were significantly improved after 3 months of rifaximin administration and were continued until 12 months. There were no serious adverse events after rifaximin administration. The number of overt HE incidents was 9, 14, and 27 patients within 3, 6, and 12 months, respectively. Liver enzymes, renal function, and electrolytes did not change after rifaximin administration. Prothrombin activity is a significant risk factor for the occurrence of overt HE. The serum albumin, prothrombin activity, and albumin−bilirubin (ALBI) scores were statistically improved after 3 and 6 months of rifaximin administration. Moreover, the same results were obtained in patients with Child−Pugh C. Conclusions: The long-term rifaximin treatment was effective and safe for patients with HE, including Child−Pugh C.