Hepatic inflammation and fibrosis are profiles related to mid-term mortality in biopsy-proven MASLD: A multicenter study in Japan.

AIMS: A multi-stakeholder consensus has proposed MASLD (metabolic dysfunction-associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid-term mortality of patients with biopsy-proven MASLD in Japan. METHODS: We enrolled 1349 patients with biopsy-proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data-mining analysis. RESULTS: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty-five patients with MASLD died. Of these, liver-related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9-fold and 1.8-fold risk of mortality, respectively. In the decision-tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid-term prognosis of patients with MASLD. CONCLUSIONS: In patients with biopsy-proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver-related events. Hepatic inflammation and fibrosis were significant factors influencing mid-term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD.

Validation study of age-independent fibrosis score (Fibrosis-3 index) in patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. METHODS: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. RESULTS: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). CONCLUSION: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.

Dynamic ultrasonography for optimizing treatment position in superior mesenteric artery syndrome: Two case reports and review of literature.

BACKGROUND: Superior mesenteric artery (SMA) syndrome is a rare cause of duodenal obstruction by extrinsic compression between the SMA and the aorta (SMA-Ao). Although the left lateral recumbent position is considered effective in the treatment of SMA syndrome, individual variations in the optimal patient position have been noted. In this report, we present two elderly cases of SMA syndrome that exhibited rapid recovery due to ultrasonographic dynamic evaluation of the optimal position for each patient. CASE SUMMARY: Case 1: A 90-year-old man with nausea and vomiting. Following diagnosis of SMA syndrome by computed tomography (CT), ultrasonography (US) revealed the SMA-Ao distance in the supine position (4 mm), which slightly improved in the lateral position (5.7-7.0 mm) without the passage of duodenal contents. However, in the sitting position, the SMA-Ao distance was increased to 15 mm accompanied by improved content passage. Additionally, US indicated enhanced passage upon abdominal massage on the right side. By day 2, the patient could eat comfortably with the optimal position and massage. Case 2: An 87-year-old woman with vomiting. After the diagnosis of SMA syndrome and aspiration pneumonia by CT, dynamic US confirmed the optimal position (SMA-Ao distance was improved to 7 mm in forward-bent position, whereas it remained at 5 mm in the supine position). By day 7 when her pneumonia recovered, she could eat with the optimal position. CONCLUSION: The optimal position for SMA syndrome varies among individuals. Dynamic US appears to be a valuable tool in improving patient outcomes.

Prognosis of biopsy-confirmed metabolic dysfunction- associated steatotic liver disease: A sub-analysis of the CLIONE study.

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. METHODS: This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. RESULTS: Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P<0.001), in addition to significantly lower levels of inflammation, ballooning, NAFLD activity score, and fibrosis stage based on liver histology. These 17 patients had a median follow-up of 5.9 years, equivalent to 115 person-years, with no deaths, liver-related events, cardiovascular events, or extrahepatic cancers. The results showed that the prognosis for pure MASLD was similar to that for the original CLIONE cohort, with 47 deaths and one patient who underwent orthotopic liver transplantation. The leading cause of death was extrahepatic cancer (n=10), while the leading causes of liver-related death were liver failure (n=9), hepatocellular carcinoma (n=8), and cholangiocarcinoma (n=4). CONCLUSION: Approximately 99% of NAFLD cases were considered MASLD based on the 2023 liver disease nomenclature. The NAFLD-only group, which is not encompassed by MASLD, had a relatively mild histopathologic severity and a favorable prognosis. Consequently, the prognosis of MASLD is similar to that previously reported for NAFLD.

Association of lysophosphatidic acid molecules with liver fibrosis: different roles indicated.

Lysophosphatidic acid is composed of lysophosphatidic acid (LPA) molecules with varied chemical forms. The present cross-sectional study was conducted to investigate the associations of various LPA molecules with liver fibrosis. Forty-six patients affected by various types of liver disease who underwent an ultrasound-guided liver biopsy were recruited for this study. Liver fibrosis was evaluated using histological grading, as well as shear wave velocity (Vs) and serum level of type IV collagen 7S (T4c7s). Serum levels of LPA molecules were determined using liquid-chromatography tandem mass-spectrometry (LC-MSMS). Total LPA showed a significant positive association with fibrosis severity evaluated based on histological grading, Vs, and T4c7s used as parameters, following adjustment for other confounding factors, including disease type, age, gender, body mass index, and high-sensitivity C-reactive protein. This association was replicated when 16:0-LPA was substituted for total LPA. In contrast, when 20:4-LPA was substituted for total LPA, no significant association with liver fibrosis was observed. In conclusion, the degree of association varied among the different LPA molecule chemical forms, suggesting different pathophysiological roles of individual LPA molecules, although total LPA concentration was shown to be associated with liver fibrosis.

Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2014 to 2018 in Japan: A large-scale multicenter retrospective study.

AIM: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. The aim of this study was to determine the recent prevalence and clinical characteristics of NAFLD in Japan. METHODS: This study initially included 410 061 retrospectively enrolled adults from the medical health checkup registry for metabolic syndrome, chronic kidney disease, and fatty liver in Japan (MIRACLE-J; UMIN-CTR no. UMIN000049419), who were evaluated between 2014 and 2018 at 13 health centers in Japan. Individuals consuming >20 g of alcohol/day or with chronic liver disease were excluded. Fatty liver was diagnosed by ultrasonography. The probability of NAFLD with advanced fibrosis was estimated based on the fibrosis-4 index and NAFLD fibrosis score. RESULTS: A total of 71 254 participants were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, twofold difference in NAFLD prevalence between men (37.4%) and women (18.1%). Nonalcoholic fatty liver disease prevalence increased linearly with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even in the absence of obesity. Among patients with NAFLD, 14% had diabetes mellitus, 31% had hypertension, and 48% had dyslipidemia. The estimated prevalence of NAFLD with advanced fibrosis was 1.7% and 1.0% according to the fibrosis-4 index and NAFLD fibrosis score, respectively. CONCLUSIONS: The prevalence of NAFLD was approximately one-quarter of the general population in Japan. There was a linear relationship between NAFLD prevalence and various metabolic parameters, even in nonobese participants. The prevalence of NAFLD with advanced fibrosis was estimated to be 1%-2%.

Identification of clinical phenotypes associated with poor prognosis in patients with nonalcoholic fatty liver disease via unsupervised machine learning.

BACKGROUND AND AIMS: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method. METHODS: We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters. RESULTS: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3-4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m2 ). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease. CONCLUSIONS: Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.

Association of Serum Albumin Levels and Long-Term Prognosis in Patients with Biopsy-Confirmed Nonalcoholic Fatty Liver Disease.

The relationship between baseline serum albumin level and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) remains unknown. This is a sub-analysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) study. The main outcomes were: death or orthotopic liver transplantation (OLT), liver-related death, and liver-related events (hepatocellular carcinoma [HCC], decompensated cirrhosis, and gastroesophageal varices/bleeding). 1383 Japanese patients with biopsy-confirmed NAFLD were analyzed. They were divided into 3 groups based on serum albumin: high (>4.0 g/dL), intermediate (3.5-4.0 g/dL), and low (<3.5 g/dL). Unadjusted hazard ratio [HR] of the intermediate albumin group, compared with the high albumin group, were 3.6 for death or OLT, 11.2 for liver-related death, 4.6 for HCC, 8.2 for decompensated cirrhosis, and 6.2 for gastroesophageal varices (all risks were statistically significant). After adjusting confounding factors, albumin remained significantly associated with death or OLT (intermediate vs. high albumin group: HR 3.06, 95% confidence interval [CI] 1.59-5.91, p < 0.001; low vs. high albumin group: HR 22.9, 95% CI 8.21-63.9, p < 0.001). Among biopsy-confirmed NAFLD patients, those with intermediate or low serum albumin had a significantly higher risk of death or OLT than those with high serum albumin.

Superior mesenteric artery syndrome: Diagnosis and management.

Superior mesenteric artery (SMA) syndrome (also known as Wilkie's syndrome, cast syndrome, or aorto-mesenteric compass syndrome) is an obstruction of the duodenum caused by extrinsic compression between the SMA and the aorta. The median age of patients is 23 years old (range 0-91 years old) and predominant in females over males with a ratio of 3:2. The symptoms are variable, consisting of postprandial abdominal pain, nausea and vomiting, early satiety, anorexia, and weight loss and can mimic anorexia nervosa or functional dyspepsia. Because recurrent vomiting leads to aspiration pneumonia or respiratory depression via metabolic alkalosis, early diagnosis is required. The useful diagnostic modalities are computed tomography as a standard tool and ultrasonography, which has advantages in safety and capability of real-time assessments of SMA mobility and duodenum passage. The initial treatment is usually conservative, including postural change, gastroduodenal decompression, and nutrient management (success rates: 70%-80%). If conservative therapy fails, surgical treatment (i.e., laparoscopic duodenojejunostomy) is recommended (success rates: 80%-100%).

Immune-related adverse events in hepatitis treated with thiopurine-based immunosuppressants: A case report.

An 82-year-old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune-related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine-based immunosuppressant was effective against irAE hepatitis, therefore thiopurine-based immunosuppressants may be effective against steroid-refractory hepatitis.

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial.

The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 µg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-µg dose groups ranged from -10.7 to -16.5 U l-1 versus placebo (-7.8 U l-1) and tropifexor 140- and 200-µg groups were -18.0 U l-1 and -23.0 U l-1, respectively, versus placebo (-8.3 U l-1)) and % HFF (tropifexor 10-90-µg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-µg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164.

Noninvasive tests predict liver-related events and mortality in patients with nonalcoholic fatty liver disease: sub-analysis of the CLIONE-Asia study.

BACKGROUND AND AIMS: Noninvasive tests (NITs) have prognostic potential, but whether NITs are comparable with liver biopsy is unclear. This study aimed to examine the prognostic accuracy of NITs for liver-related mortality (LRM) and events (LREs) in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). METHODS: We investigated 1313 patients with NAFLD. Patients were assigned to low-risk, indeterminate-risk, and high-risk groups using conventional cutoff values of each FIB-4 and NAFLD fibrosis score (NFS) and to stage 0-2 and stage 3-4 groups using the fibrosis stage. Survival and Cox regression analyses of the prognostic potential of NITs for LRM/LREs were conducted. RESULTS: During a median follow-up of 4.5 years, regarding to FIB-4, the incidence rate (/1000 person-years) in the low risk was zero for LRM and 0.5 for LREs. In contrast, the rate in stage 0-2 was 1.3 for LRM and 2.8 for LRE. The adjusted hazard ratios (aHRs) for LREs in the high risk compared with the low risk were 32.85 (P < 0.01). The aHRs in stage 3-4 compared with stage 0-2 were 2.68 (P = 0.02) for LREs and 2.26 (P = 0.582) for LRM. In the same fibrosis stage, the incidence of LRM/LREs was more frequent with a higher risk stratification. The same trend was observed for NFS. CONCLUSIONS: NITs accurately predict LRM and LREs as well as a liver biopsy in Japanese patients with NAFLD. Patients in the low risk may not require close follow-up for at least 5 years. The simple NITs could be an acceptable alternative method to performing a liver biopsy for the prognosis of NAFLD.

Multicenter, retrospective, cohort study shows platelet counts predict hepatocellular carcinoma development in patients with nonalcoholic fatty liver disease.

AIM: Impacts of platelet counts at the time of liver biopsy on hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD) remain unknown. The aim of this study was to investigate the prognostic value of platelet counts in patients with biopsy-confirmed NAFLD using data from a multicenter study. METHODS: One thousand three hundred ninety-eight patients were included in this subanalysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia study. Liver biopsy specimens were pathologically diagnosed, and histologically scored using the NASH Clinical Research Network system. Demographic, clinical, laboratory, and pathological data were collected. RESULTS: During a median follow-up period of 4.6 years (range, 0.3-21.6 years), which corresponds to 8874 person-years, 37 patients developed HCC. Using a cut-off baseline platelet count of 192 × 109/L, the lower platelet group had a higher HCC rate than the higher platelet group (6.7% vs. 0.4%; p < 0.001). This cut-off value significantly stratified the event-free rate for HCC. Lower platelet counts were associated with an increased risk of HCC development. Relative to patients with platelet counts of 192 × 109/L, patients with platelet counts of 100 × 109/L had an unadjusted hazard ratio (HR) for HCC development of 7.37 (95% confidence interval [CI], 3.81-14.2) and an adjusted HR of 11.2 (95% CI, 3.81-32.7; p < 0.001), adjusting for age, sex, NASH, and diabetes. CONCLUSIONS: Baseline platelet counts of 192 × 109/L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance.

SWOT analysis of noninvasive tests for diagnosing NAFLD with severe fibrosis: an expert review by the JANIT Forum.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions.

Clinical Outcomes in Biopsy-Proven Nonalcoholic Fatty Liver Disease Patients: A Multicenter Registry-based Cohort Study.

BACKGROUND & AIMS: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage. METHODS: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients. RESULTS: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality. CONCLUSIONS: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.

Immune checkpoint inhibitor (ICI)-induced hepatitis diagnosed by liver biopsy followed by ICI-free chemotherapy leading to therapeutic effect: A case of lung cancer treatment.

In recent years, the combination of platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) has become the standard treatment for patients with lung cancer. Hepatitis is one of the common toxicities following ICI/chemotherapy. When drug-induced hepatitis occurs, the suspected drug must be discontinued. Since it may be difficult to determine the exact drug causing the hepatitis, liver biopsy may help identify this. We report the case of a patient diagnosed with immune-related adverse event hepatitis from liver biopsy and clinical course. A 45-year-old man with lung adenocarcinoma (stage IV, cT4N3M1c) negative for driver gene mutation was treated with carboplatin (CBDCA), pemetrexed (PEM), and pembrolizumab. Elevated blood aspartate aminotransferase and alanine aminotransferase levels after chemotherapy indicated hepatitis induced by cytotoxic anticancer agents and ICIs. As autoimmune hepatitis was also suspected, liver biopsy was performed and the findings suggested ICI-induced hepatitis. Pembrolizumab was discontinued and CBDCA/PEM was resumed, following which, the primary lesion shrank. When drug-induced hepatitis is suspected, clinicians should actively perform liver biopsy to confirm the diagnosis, so that appropriate therapeutic regimen can be administered.

Immune checkpoint inhibitor (ICI)-induced hepatitis diagnosed by liver biopsy followed by ICI-free chemotherapy leading to therapeutic effect: A case of lung cancer treatment.

In recent years, the combination of platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) has become the standard treatment for patients with lung cancer. Hepatitis is one of the common toxicities following ICI/chemotherapy. When drug-induced hepatitis occurs, the suspected drug must be discontinued. Since it may be difficult to determine the exact drug causing the hepatitis, liver biopsy may help identify this. We report the case of a patient diagnosed with immune-related adverse event hepatitis from liver biopsy and clinical course. A 45-year-old man with lung adenocarcinoma (stage IV, cT4N3M1c) negative for driver gene mutation was treated with carboplatin (CBDCA), pemetrexed (PEM), and pembrolizumab. Elevated blood aspartate aminotransferase and alanine aminotransferase levels after chemotherapy indicated hepatitis induced by cytotoxic anticancer agents and ICIs. As autoimmune hepatitis was also suspected, liver biopsy was performed and the findings suggested ICI-induced hepatitis. Pembrolizumab was discontinued and CBDCA/PEM was resumed, following which, the primary lesion shrank. When drug-induced hepatitis is suspected, clinicians should actively perform liver biopsy to confirm the diagnosis, so that appropriate therapeutic regimen can be administered.

Age-dependent effects of diabetes and obesity on liver-related events in non-alcoholic fatty liver disease: Subanalysis of CLIONE in Asia.

BACKGROUND AND AIM: Older age, type 2 diabetes mellitus (T2DM), and obesity are known risk factors for liver-related events (LREs). We investigated the impacts of T2DM and obesity on LRE according to age in Japanese patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We performed a subanalysis of a retrospective cohort study (CLIONE in Asia), including 1395 patients with biopsy-proven NAFLD. The median follow-up was 4.6 years. RESULTS: The median age was 57 years, and 36.2% had T2DM. The median body mass index (BMI) was 27.4, and 28.5% were severely obese (BMI ≥ 30). During follow-up, 37 patients developed hepatocellular carcinoma (HCC), and 58 patients developed LRE. In patients younger than 65 years, advanced fibrosis (hazard ratio [HR] 7.69, P < 0.001) and T2DM (HR 3.37, P = 0.017) were HCC risk factors, and advanced fibrosis (HR 9.40, P < 0.001) and T2DM (HR 2.51, P = 0.016) were LRE risk factors. In patients 65 years and older, advanced fibrosis (HR 4.24, P = 0.010) and obesity (HR 4.60, P = 0.006) were HCC risk factors, and advanced fibrosis (HR 4.22, P = 0.002) and obesity (HR 4.22, P = 0.002) were LRE risk factors. CONCLUSION: Type 2 diabetes mellitus and obesity contributed to LRE in younger and older patients, respectively, along with advanced fibrosis. Therefore, controlling T2DM in patients younger than 65 years and controlling weight in patients 65 years and older could prevent LRE. The development of age-dependent screening and management strategies is necessary for patients with NAFLD.

Chip-scale high-peak-power semiconductor/solid-state vertically integrated laser.

Compact lasers capable of producing kilowatt class peak power are highly desirable for applications in various fields, including laser remote sensing, laser micromachining, and biomedical photonics. In this paper, we propose a high-peak-power chip-scale semiconductor/solid-state vertically integrated laser in which two cavities are optically coupled at the solid-state laser gain medium. The first cavity is for the intra-pumping of ytterbium-doped yttrium aluminum garnet (Yb:YAG) with an electrically driven indium gallium arsenide (InGaAs) quantum well, and the second cavity consists of Yb:YAG and chromium-doped yttrium aluminum garnet (Cr:YAG) for passive Q-switching. The proposed laser produces pulses as short as 450 ps, and an estimated peak power of 57.0 kW with a laser chip dimension of 1 mm3. To the best of our knowledge, this is the first monolithic integration of semiconductor and solid-state laser gain mediums to realize a compact high-peak-power laser.

Calibrating Hepatitis E Virus Serological Assays Using Asymptomatic Specimens Obtained in Japan.

This study aimed to calibrate hepatitis E virus (HEV) serological assays. We optimized the previously developed in-house HEV antibody enzyme-linked immunosorbent assay (ELISA) by setting the cutoff with an in-house serological performance panel consisting of broad HEV antibody titers and subtracting nonspecific background values for anti-HEV IgM, IgA, and IgG. We also compared the assay's performance with that of commercial serological assay kits (four kits for IgM, one for IgA, and two for IgG). Although all serological assays readily detected HEV antibodies at high titers in the symptomatic hepatitis E population, considerable variations between assays were observed in the asymptomatic population. The in-house ELISA showed a higher sensitivity for HEV IgM, IgA, and IgG than the commercial kits and detected the seroconversion of HEV IgM and IgG earlier when testing a commercially available HEV seroconversion panel. The low sensitivity of the commercial kits was due to the high setting of the original cutoff, which was demonstrated by receiver operating characteristic analysis. However, the corrected cutoff value reduced assay specificity. Background subtraction is essential to achieve high specificity because the in-house ELISA without background subtraction reduced its specificity. These results indicate that asymptomatic specimens and background subtraction contribute to the optimization of HEV serological assays. IMPORTANCE Accurate diagnosis of hepatitis E virus (HEV) infection is essential for public health surveillance and for preventing HEV-contaminated blood transfusion. Anti-HEV IgM or IgA is used as a reliable marker of recent HEV infection. However, considerable variability in the sensitivity and specificity of HEV antibody detection is observed among several commercially available assay kits. In addition, none of the HEV antibody detection methods have been approved by the U.S. Food and Drug Administration (FDA). Here, we show that the in-house enzyme-linked immunosorbent assay (ELISA) could detect HEV IgM and IgA more sensitively than commercial kits in the asymptomatic population. We also suggest that the assay performance of commercial kits might be improved by optimizing the cutoff and reducing nonspecific background noise. A sensitive serological (IgM or IgA) assay in addition to HEV RNA testing will contribute to accurate diagnosis of acute HEV infection because HEV RNA-positive duration is relatively short.