Deep learning and digital pathology powers prediction of HCC development in steatotic liver disease.

BACKGROUND AND AIMS: Identifying patients with steatotic liver disease who are at a high risk of developing HCC remains challenging. We present a deep learning (DL) model to predict HCC development using hematoxylin and eosin-stained whole-slide images of biopsy-proven steatotic liver disease. APPROACH AND RESULTS: We included 639 patients who did not develop HCC for ≥7 years after biopsy (non-HCC class) and 46 patients who developed HCC <7 years after biopsy (HCC class). Paired cases of the HCC and non-HCC classes matched by biopsy date and institution were used for training, and the remaining nonpaired cases were used for validation. The DL model was trained using deep convolutional neural networks with 28,000 image tiles cropped from whole-slide images of the paired cases, with an accuracy of 81.0% and an AUC of 0.80 for predicting HCC development. Validation using the nonpaired cases also demonstrated a good accuracy of 82.3% and an AUC of 0.84. These results were comparable to the predictive ability of logistic regression model using fibrosis stage. Notably, the DL model also detected the cases of HCC development in patients with mild fibrosis. The saliency maps generated by the DL model highlighted various pathological features associated with HCC development, including nuclear atypia, hepatocytes with a high nuclear-cytoplasmic ratio, immune cell infiltration, fibrosis, and a lack of large fat droplets. CONCLUSIONS: The ability of the DL model to capture subtle pathological features beyond fibrosis suggests its potential for identifying early signs of hepatocarcinogenesis in patients with steatotic liver disease.

An Analysis of 10,000 Cases of Living Donor Liver Transplantation in Japan: Special Reference to the Graft-Versus-Recipient Weight Ratio and Donor Age.

OBJECTIVE: To analyze 10,000 cases of living donor liver transplantation (LDLT) recipient data to elucidate outcomes with special reference to the graft-versus-recipient weight ratio (GRWR), based on the Japanese Liver Transplantation Society (JLTS) registry. BACKGROUND: The JLTS registry has been accurate and complete in characterizing and following trends in patient characteristics and survival of all patients with LDLT. METHODS: Between November 1989 and August 2021, 10,000 patients underwent LDLT in Japan. The procedures performed during the study period included pediatric liver transplantation (age <18 years, n = 3572) and adult liver transplantation (age ≥18 years, n=6428). Factors related to patient survival (PS) and graft survival (GS) were also analyzed. RESULTS: The GRWR was <0.7, 0.7 to <0.8, 0.8 to <3, 3 to <5, and ≥5 in 0.2%, 2.0%, 61.8%, 31.8%, and 2.6% of pediatric patients and <0.6, 0.6 to <0.7, 0.7 to <0.8, and ≥0.8 in 8.0%, 12.7%, 17.7%, and 61.5% of adult patients, respectively. Among pediatric recipients, the PS rate up to 5 years was significantly better in cases with a GRWR ≤5 than in those with a GRWR >5. When the GRWR and donor age were combined, among adult recipients 50 to 60 years old, the early PS and GS up to 5 years were significantly better in cases with a GRWR ≥0.7, than in those with a GRWR <0.7. (P = 0.02). In adults, a multivariate analysis showed that GRWR <0.6, transplant era (<2011), donor age (>60 years), recipient age (>60 years), model for end-stage liver disease score (≥20), and center volume (<10) were significant prognostic factors for long-term PS. CONCLUSION: Although a satisfactory long-term PS and GS, especially in the recent era (2011-2021), was achieved in the JLTS series, a GRWR ≥5 in pediatric cases and relatively old donors with a GRWR <0.7 in adult cases should be managed with caution.

Efficacy and safety of tacrolimus in older adults with ulcerative colitis: a retrospective study.

BACKGROUND/AIMS: The prevalence of ulcerative colitis (UC) has been increasing, also in older adults. Here, we retrospectively compared the efficacy and safety of tacrolimus (TAC) in older and younger patients with UC. METHODS: We included younger (age < 65 years; n = 116) and older patients (age ≥ 65 years; n = 21) with UC who received TAC from April 2009 through December 2022(mean follow-up, 1230 ± 175 days) and achieved remission. Evaluations included age at onset, laboratory values, estimated glomerular filtration rate (eGFR), use of 5-aminosalicylic acid (5-ASA), biological experience, colonoscopy scores, remission at 1 month after treatment initiation, and adverse events. Treatment duration and renal function were assessed in patients with follow-up data (younger patients, n = 110; older patients, n = 19). RESULTS: Older patients had a higher age at onset and treatment initiation but less 5-ASA use and biological experience. Before treatment, hemoglobin, albumin, and eGFR were significantly lower in the older group and CRP was significantly higher. The remission rate was 80.1% in the younger group and 66.6% in the older group (P = 0.1862). Adverse events were similar in both groups. The older group had a shorter treatment duration and significantly less change in renal function at all time points. DISCUSSION: Rates of TAC-induced remission and adverse events were similar in older and younger adults with UC. CONCLUSION: TAC can be used safely in elderly patients with moderate to severe UC with careful monitoring.

New concept in fatty liver diseases.

In 2023, the nonalcoholic fatty liver disease (NAFLD) Nomenclature Consensus group proposed a new name and concept for NAFLD/nonalcoholic steatohepatitis. The Japanese Society of Gastroenterology and the Japanese Society of Hepatology have accepted these new names and concepts. It was reported that the terms "nonalcoholic" and "fatty" are misleading and inappropriate, because NAFLD does not reflect the etiology. Thus, appropriate disease names are discussed, and new concepts are published. First, the concept of steatotic liver disease (SLD) was proposed to encompass fatty liver diseases of various etiologies, which are classified into five categories. The diagnostic criteria for metabolic dysfunction-associated steatotic liver disease (MASLD) included fatty liver with at least one of the five cardiometabolic risk factors (body mass index or waist diameter, blood glucose or glycated hemoglobin, blood pressure, triglycerides, and high-density lipoprotein cholesterol) and the same restriction of alcohol consumption as NAFLD. A new fatty liver category was described, MetALD, to represent the intermediate drinker group (patients with MASLD with high weekly alcohol intake [140-350 g/week in women and 210-420 g/week in men]). The other five categories are alcohol-associated liver disease, fatty liver with an identifiable specific cause, and other fatty livers of unknown cause. Nonalcoholic steatohepatitis is an important pathological concept (metabolic dysfunction-associated steatohepatitis); however, its definition, including hepatocellular balloon-like degeneration, needs to be reassessed. In Japan, we should use these names and criteria to manage SLD, including hepatocellular carcinoma, which is markedly increasing.

Importance of gamma-glutamyl transferase elevation in patients with Fontan-associated liver disease.

AIM: In patients with Fontan-associated liver disease (FALD), gamma-glutamyl transferase (GGT) levels are often elevated, however, its clinical importance is unclear. We investigated the relationship between the clinical course of FALD and GGT levels. METHODS: We enrolled 145 patients with FALD who underwent right-heart catheterization (RHC) and visited our department. Ursodeoxycholic acid (UDCA) was administered to 62 of the patients. Patients with GGT levels <50 and ≥50 U/L were compared. Follow-up RHC was undertaken in 76 patients. Cases in which GGT levels decreased by ≥10% or <50 U/L were defined as improved (n = 33). RESULTS: Patients with GGT levels ≥50 U/L had significantly lower levels of albumin and higher levels of alanine transaminase (ALT) but no significant differences in RHC factors. Over a 4.6-year period, 43.4% showed improvement in GGT levels. Improved cases had significantly lower total bilirubin (1.1 vs. 1.6 mg/dL), AST (22 vs. 28 U/L), and ALT (18 vs. 27 U/L) levels than nonimproved cases (n = 29, p < 0.05), and the change in platelet count (-0.5 vs. -3.0 × 10-4/µL) was significantly lower in the latter (p = 0.03). The improvement rate was significantly higher in UDCA-treated cases (55.2%) with GGT levels ≥50 U/L compared to cases not treated with UDCA (18.2%, p = 0.04). CONCLUSION: In cases of FALD with no improvement in GGT level, the platelet count decreased over time, suggesting progression of fibrosis. Physicians should be aware of the importance of a high GGT level in patients with FALD.

A retrospective study to investigate the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis with ulcerative colitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis has a poor prognosis and can be accompanied by ulcerative colitis. Infection control is essential, so immunosuppressive drugs should ideally be preferably. Granulocyte and monocyte adsorptive apheresis does not suppress the immune system and is used to treat ulcerative colitis. Therefore, this study investigated the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis and ulcerative colitis. METHODS: We retrospectively evaluated data from patients with primary sclerosing cholangitis with ulcerative colitis who visited our hospital from April 2000 to December 2022 and underwent granulocyte and monocyte adsorptive apheresis (n = 10, number of treatment cycles = 15). Study endpoints were remission induction rate and safety, assessed as changes in liver functions and adverse events. RESULTS: Seven of the 10 patients were male. The median (min-max) age was 23 (18-77) years. The most common disease type was right-dominant pancolitis. Remission occurred after 86.6% of cycles (13/15). Serum alkaline phosphatase and Aspartate transaminase were significantly lower after treatment (P = .0124, P = .002), and no negative effects on liver function were seen. The only adverse events were headache (n = 1) and decreased blood pressure (n = 1). CONCLUSIONS: Granulocyte and monocyte adsorptive apheresis has high efficacy for intestinal lesions and improves alkaline phosphatase and aspartate transaminase levels (high levels are a poor prognosis factor). It appears to be a treatment option in patients with primary sclerosing cholangitis associated with ulcerative colitis.

Cell-free and concentrated ascites reinfusion therapy versus large-volume paracentesis for the treatment of cirrhotic patients with refractory ascites: A multicenter prospective observational study.

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) and large-volume paracentesis (LVP) with albumin infusion are useful for managing refractory ascites (RA). However, it remains unclear which therapy is more effective in patients with cirrhosis with RA. METHODS: From June 2018 to March 2022, 25 patients with RA treated with CART or LVP with albumin infusion were enrolled in this multicenter prospective observational study to investigate the number of abdominal paracenteses, albumin preparations used, and drainage volume during an 8-week observation period. RESULTS: Among all patients at entry (median age, 63 years; 52% men; 60% Child-Pugh B and 40% Child-Pugh C), 92% were treated with furosemide (median, 20 mg/day), 92% with spironolactone (25 mg/day), and all with tolvaptan (7.5 mg/day). Patients with RA had a poor health-related quality of life (HRQOL) and prominent ascites-related symptoms. Four of the 20 eligible patients were treated with CART, 11 with LVP with albumin infusion, and five with their combination. The median number of paracenteses, total drainage volume, and albumin infusions were 1.5, 7.4 L, and 0, respectively, in the CART group; 5.0, 22.0 L, and 5.0, respectively, in the LVP group; and 5.0, 30.0 L, and 5.0, respectively in their combination group. The treatment effects did not differ significantly among the three groups regarding weight loss, liver function, renal function, electrolytes, and HRQOL. However, patients treated with CART had fewer paracenteses and albumin infusions than those treated with LVP. CONCLUSIONS: CART and LVP have comparable therapeutic efficacy for RA in patients with cirrhosis.

Abdominal lymphatic pathway in Fontan circulation using non-invasive magnetic resonance lymphangiography.

Lymphatic congestion is known to play an important role in the development of late Fontan complications. This study aimed to (1) develop a gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) contrast three-dimensional heavily T2-weighed MR technique that can detect abnormal lymphatic pathway in the abdomen while simultaneously evaluating hepatocellular carcinoma (HCC) and to (2) propose a new classification of abnormal abdominal lymphatic pathway using a non-invasive method in adults with Fontan circulation. Twenty-seven adults with Fontan circulation who underwent Gd-EOB-DTPA abdominal MR imaging were prospectively enrolled in this study. We proposed MR lymphangiography that suppresses the vascular signal on heavily T2-weighted imaging after EOB contrast. The patients were classified as follows: grade 1 with almost no lymphatic pathway, grade 2 with a lymphatic pathway mainly around the bile duct and liver surface, and grade 3 with a lymphatic pathway mainly around the vertebral body and inferior vena cava. The grade 3 group showed the lowest oxygen saturation level, highest central venous pressure, highest incidence of massive ascites, HCC, and focal nodular hyperplasia. This group also tended to have patients with the oldest age and highest cardiac index; however, the difference was not statistically significant. As for the blood test, the grade 3 group showed the lowest platelet count and serum albumin level and the highest fibrosis-4 index. A novel technique, Gd-EOB-DTPA MR lymphangiography, can detect abnormal abdominal lymphatic pathways in Fontan circulation, which can reflect the severity of failing Fontan.

Prevalence of fatty liver disease after liver transplantation and risk factors for recipients and donors.

INTRODUCTION AND OBJECTIVES: Fatty liver disease (FLD) may develop in liver transplant recipients. We investigated the recipient and donor risk factors for FLD development after liver transplantation (LT). METHODS: A total of 108 liver transplant recipients (54 men [50.0%]; median age, 52 [20-68] years) treated from 2011-2020 was enrolled. Three recipients died at < 3 months as a result of infection or blood flow impairment, and were excluded from the long-term FLD study. On evaluation of 88 prospective living donors, fatty liver was observed in 21. The prevalence and risk factors for FLD and survival were evaluated. RESULTS: After LT, 28 of 105 recipients (26.7%) developed FLD. FLD was more common in patients with a high body mass index (BMI) and dyslipidemia (both p < 0.01), primary nonalcoholic steatohepatitis (p = 0.02), after living-donor LT (p = 0.03) and everolimus (EVL) use (p = 0.08). Factors predictive of FLD included EVL use and a high BMI (hazard ratios = 3.00 and 1.34; p = 0.05 and p < 0.01, respectively). Sixteen donors lost 6.5 kg (range: 2.0-16.0 kg) of body weight prior to LT. However, there were no cases of primary non-function, which did not affect the FLD prevalence. Development of FLD did not have a negative impact on LT outcome; the 5-year survival rate was 92.6%. CONCLUSIONS: Recipient factors were more important than donor factors for FLD onset after LT.

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020.

Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro- vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.

Outcomes of Japanese patients with non-alcoholic fatty liver disease according to genetic background and lifestyle-related diseases.

INTRODUCTION AND OBJECTIVES: Genetic background may be involved in the mechanisms of liver injury and the development of non-alcoholic fatty liver disease (NAFLD). However, its contributions to the long-term outcome of NAFLD have been unclear. METHODS: We enrolled 314 Japanese patients with biopsy-confirmed NAFLD from 2000 to 2018 (161 men [51.3%]; median age, 53 [14-84] years; 114 with advanced fibrosis [37.5%]) in the patients without hepatocellular carcinoma at diagnosis. Genomic DNA was extracted from peripheral blood and single nucleotide polymorphisms (SNPs) were analyzed. Associations of mortality with patatin-like phospholipase 3 (PNPLA3) and aldehyde dehydrogenase 2 (ALDH2) were analyzed. Finally, a subgroup analysis according to lifestyle-related disease was performed. RESULTS: During the median 7 years of follow-up, 20 patients (6.4%) died (13 liver-related [4.1%] and 7 non-liver-related deaths [2.2%]). Patients with ALDH2 (non-GG genotype) who had reduced alcohol metabolism tended to have a poor prognosis (p = 0.06). Patients carrying both risk SNPs of PNPLA3 (GG) and ALDH2 (non-GG) had a significantly poor prognosis (p = 0.01). In the subgroup analysis, patients with PNPLA3 (GG) who were non-diabetics (p = 0.06) or non-dyslipidemic (p = 0.03), with ALDH2 (non-GG) who were non-dyslipidemic (p = 0.01) or hypertensive (p = 0.03), also had a poor prognosis. The Cox analysis revealed that ALDH2 (non-GG) was associated with a poor prognosis (Hazard ratio: 4.568, 95% Confidence Interval: 1.294-16.131, p = 0.02) similar to the liver function tests. CONCLUSIONS: Genetic background may affect NAFLD prognosis and ALDH2 SNP could predict the outcome.

High Throughput Screening of Serum γ-Glutamyl Dipeptides for Risk Assessment of Nonalcoholic Steatohepatitis with Impaired Glutathione Salvage Pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most common preventable chronic liver disorder in developed countries, the prevalence of which is increasing worldwide due to its association with obesity and type 2 diabetes. However, the exact mechanisms of NAFLD pathophysiology remain poorly understood including its progression to the more severe nonalcoholic steatohepatitis (NASH). New advances for early detection and monitoring of NASH progression are limited due to the lack of specific blood biomarkers, thus requiring invasive liver biopsies for histopathology. Herein, multisegment injection-capillary electrophoresis-tandem mass spectrometry (MSI-CE-MS/MS) is validated as a high throughput, robust, and quantitative platform for targeted analysis of a panel of 16 serum γ-glutamyl dipeptides from a cohort of NASH adult patients from Japan (median age = 53 years, median BMI = 27 kg/m2, n = 116). Multiplexed separations based on MSI-CE-MS/MS enable the design of unique data workflows that rely on customizable serial sample injection formats for accurate determination of γ-glutamyl dipeptides with quality control. Also, the introduction of a liquid coolant device to the capillary outlet improves long-term migration time stability in CE. Unsupervised pattern recognition methods revealed two distinctive NASH subgroups based on their contrasting γ-glutamyl dipeptide status despite patients having similar clinical phenotypes and NASH activity scores (median NAS ≈ 6.0). There was an inverse correlation between serum γ-glutamyl dipeptide concentrations and γ-glutamyltransferease (GGT) enzyme activity (r = -0.46; p = 2.5 × 10-7), which was indicative of a low-risk (n = 64) as compared to a high-risk (n = 52) patient subgroup with impaired glutathione salvage pathway and likely poor clinical prognosis. Our findings highlight the key role of defects in the γ-glutamyl cycle for differentiation of NASH patients, which may enable better risk assessment of long-term survivorship as a complement to standard liver enzyme screens and histopathology.

Relationship between mucosal healing by tacrolimus and relapse of refractory ulcerative colitis: a retrospective study.

BACKGROUND: Tacrolimus (TAC) is a powerful remission-inducing drug for refractory ulcerative colitis (UC). However, it is unclear whether mucosal healing (MH) influences relapse after completion of TAC.We investigated whether MH is related to relapse after TAC. PATIENTS: Among 109 patients treated with TAC, 86 patients achieved clinical remission and 55 of them underwent colonoscopy at the end of TAC. These 55 patients were investigated. METHODS: Patients with MH at the end of TAC were classified into the MH group (n = 41), while patients without MH were classified into the non-MH group (n = 14). These groups were compared with respect to 1) clinical characteristics before treatment, 2) clinical characteristics on completion of treatment, and 3) the relapse rate and adverse events rates. This is a retrospective study conducted at a single institution. RESULTS: 1) There was a significant difference in baseline age between the two groups before TAC therapy, but there were no significant differences in other clinical characteristics. The NMH group was younger (MH group: 48.1 (23-79) years, NMH group: 36.3 (18-58) years, P = 0.007). Endoscopic scores showed significant differences between the 2 groups at the end of TAC. There were also significant differences in the steroid-free rate after 24 weeks (MH group: 85.3%, NMH group 50%, P = 0.012). There was no significant difference in the relapse rate between the 2 groups at 100 days after remission, but a significant difference was noted at 300 days (17% vs. 43%), 500 days (17% vs. 75%), and 1000 days (17% vs. 81%) (all P < 0.05). CONCLUSIONS: TAC is effective for refractory ulcerative colitis. However, even if clinical remission is achieved, relapse is frequent when colonoscopy shows that MH has not been achieved. It is important to evaluate the mucosal response by colonoscopy on completion of TAC.

Characteristics of hepatocellular carcinoma arising from Fontan-associated liver disease.

AIM: Hepatocellular carcinoma (HCC) can arise from Fontan-associated liver disease (FALD); this is known as FALD-HCC. The clinical features of FALD-HCC are unclear. Thus, we examined the incidence and clinical characteristics of FALD-HCC. METHODS: From 1972 to 2019, 122 patients developed liver disease after undergoing Fontan procedures. HCC was diagnosed in 12 (9.8%) FALD patients. We compared FALD-HCC and non-HCC patients. RESULTS: The incidence of HCC was 0.8% and 2.9% in FALD 10 and 20 years after the Fontan procedure, respectively. The median age of patients at diagnosis of HCC was 32.5 years (range 20.6-46.1 years), and seven of the 12 patients were men. Patients with FALD-HCC had a higher incidence of liver cirrhosis and polysplenia than non-HCC patients. Liver tumors were detected as single nodules in eight patients, and the median diameter was 47 mm (range 11-105 mm). HCC was treated by surgical resection in two patients, transcatheter arterial chemoembolization or chemotherapy in three patients, and proton beam therapy in four patients. Three patients could not be treated because of their poor condition. Four patients died of liver/cardiac failure and HCC, and HCC was controlled in three patients. The survival rate after 25 years was significantly lower in patients with FALD-HCC than non-HCC patients (68.6% vs. 97.9%, respectively; P < 0.01). CONCLUSIONS: Of the 122 patients with FALD, 12 developed HCC 20 years after surgery. Because complications of HCC are associated with poor prognosis, constant surveillance for HCC should begin 10 years after surgery.

Long-term outcomes of non-alcoholic fatty liver disease and the risk factors for mortality and hepatocellular carcinoma in a Japanese population.

BACKGROUND AND AIM: The incidence of mortality and hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) has been reported, but the long-term outcomes of Japanese patients with NAFLD are not fully evaluated. METHODS: We enrolled 365 Japanese patients with biopsy-confirmed NAFLD (1990-2008) followed for ≥ 6 months: 185 males (50.7%); median age (54 years); advanced fibrosis 108 (29.8%); HCC, n = 26 (7.1%); diabetes, n = 191 (52.3%); dyslipidemia, n = 234 (64.1%); and hypertension, n = 193 (52.9%). We analyzed the survival and new-onset HCC rates for hepatic fibrosis as well as complications and the treatment of lifestyle-related diseases. RESULTS: During the median 7.1-year follow-up, 44 patients (12.1%) died: n = 28 liver-related (10 years liver-related death, 9.4%) and n = 16 non-liver-related deaths (10 years non-liver-related death, 4.9%). Both incidence rates were significantly higher in the advanced fibrosis group. The incidence of HCC at 10 years was 20.1% in the advanced fibrosis group, and the mortality was increased in patients with higher age, history of HCC, lower seru\m level of albumin, higher level of γ-glutamyltransferase, and insulin treatment for diabetes. Risk factors for HCC onset were higher levels of aspartate aminotransferase and triglyceride and hypertension treatment. Platelet count < 11.5 × 104 /µL was revealed as a risk factor for death and HCC development. CONCLUSIONS: The rates of both liver-related and non-liver-related deaths and HCC development were significantly prominent in the patients with advanced fibrosis. It is important to identify and treat NAFLD patients who have several risk factors and advanced fibrosis, which might be predicable simply by the platelet count.

The characteristics and risk factors of hepatocellular carcinoma in nonalcoholic fatty liver disease without cirrhosis.

BACKGROUND AND AIM: We evaluated the characteristics of hepatocellular carcinoma (HCC) in patients who had non-alcoholic fatty liver disease (NAFLD) without cirrhosis. METHODS: We prospectively followed NAFLD patients at our University hospital. NAFLD was diagnosed from detection of steatosis by histology or imaging, no alcohol intake, and exclusion of other liver diseases. Cirrhosis was defined by histological features, imaging data, and symptoms. We compared NAFLD-related HCC with or without cirrhosis and non-cirrhotic NAFLD with or without HCC. RESULTS: There were 48 non-cirrhotic HCC patients and 71 cirrhotic HCC patients. Multiple logistic regression analysis revealed that other than liver function factors, male gender (OR: 5.603, 95%CI: 1.577-19.900), light drinker (OR: 2.797, 95%CI: 1.031-7.589), and tumor size (OR: 1.031, 95%CI 1.009-1.055) differ significantly between these two groups. The recurrence rate was significantly lower in the non-cirrhotic HCC group than the cirrhotic HCC group, with risk factors being des-γ-carboxy prothrombin and the number of HCCs. The non-cirrhotic HCC group showed significantly better survival because of absence of non-cancerous liver failure. Comparison between non-cirrhotic NAFLD patients with or without HCC (n = 612) revealed the following risk factors for HCC: male gender (OR: 7.774, 95%CI: 2.176-27.775), light drinker (OR: 4.893, 95%CI: 1.923-12.449), and high FIB4 index (OR 2.634, 95%CI: 1.787-3.884). CONCLUSION: In patients with non-cirrhotic NAFLD, important risk factors for HCC were male gender, alcohol consumption, and the FIB4 index. HCC recurrence and survival were only influenced by the tumor stage. We should be aware of alcohol consumption as a modifiable risk factor for HCC.

Comparison of Lewis Score and Capsule Endoscopy Crohn's Disease Activity Index in Patients with Crohn's Disease.

BACKGROUND/AIMS: Small bowel capsule endoscopy (SBCE) is used to visualize mucosal inflammatory changes in the small intestine of patients with Crohn's disease (CD). The Lewis score (LS) and Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) are used to evaluate the visualized images. We determined the score disagreement between LS and CECDAI in patients with CD. METHODS: We evaluated 184 SBCE procedures in 102 CD patients with small bowel lesions. Patients were classified according to the Montreal classification. LS and CECDAI were calculated, and cases with disagreement between the two scores were identified. We investigated the characteristics of disagreement, and analyzed the relationships with the Crohn's Disease Activity Index (CDAI) and C-reactive protein. RESULTS: LS (504 ± 1160) correlated strongly with CECDAI (6 ± 5.4) (Spearman's rank correlation coefficient ρ = 0.81, p < 0.0001). LS values of 135 and 790 were equivalent to CECDAI values of 4.9 and 6.9, respectively. The inflammatory changes by LS were significantly observed in several tertiles in the CECDAI discrepancy group (LS < 135, CECDAI ≥ 4.9) compared with the normal agreement group (LS < 135, CECDAI < 4.9) (p < 0.0001). In both groups, CDAI was also significantly different between Montreal L1 and L3 groups (p = 0.0232, p = 0.0196, respectively). LS inflammation score was 0 in six cases in the LS discrepancy group (LS ≥ 135, CECDAI ≤ 4.9, n = 10); the high LS scores were in patients with high stricture scores. CONCLUSIONS: Discrepancies between the LS and CECDAI scores were observed in some patients. Cases with high CECDAI alone exhibited extensive inflammation and high disease activity (clinical symptoms and biomarker levels). CECDAI seems to better reflect active intestinal inflammation than LS.

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis.

Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

Characteristics of acute hepatitis A virus infection before and after 2001: A hospital-based study in Tokyo, Japan.

BACKGROUND AND AIM: The incidence of acute hepatitis A [AH (A)] is decreasing because of improvements in hygiene; however, cases of sporadic severe hepatitis are still being reported. We assessed the epidemiology of AH (A) in Japan. METHODS: This was a hospital-based retrospective study, in which 126 AH (A) patients (96 men [76%], median age 39 [range, 19-66] years) were enrolled. Patients diagnosed with AH (A) before 2001 (n = 79) and after 2001 (n = 47) were compared. RESULTS: The incidence of AH (A) showed peaks in 1990, 1999, and 2018. After 2001, one patient had hepatitis B virus, four had human immunodeficiency virus, and three had syphilis coinfections. Before and after 2001, HAV was transmitted, respectively, by raw oysters (28% and 26%), overseas travel (19% and 28%), and sexual contact (0% and 19%) (P < 0.01). The frequencies of symptoms were appetite loss (51% and 32%), fever (63% and 81%), and diarrhea (3% and 13%) (all P < 0.05), respectively. On admission, the median levels of alanine aminotransferase (1455 and 3069 U/L) and γ-glutamyl transpeptidase (221 and 345 U/L) were significantly higher (P < 0.01), and the prothrombin time (77.5% and 65.9%) and platelet count (22.7 and 16.4 × 10/µL) were significantly lower after 2001 (P < 0.05). A time to normalization of the bilirubin level ≥ 30 days was associated with older age and a diagnosis of AH (A) after 2001. CONCLUSIONS: Outbreaks and severe AH (A) cases due to sexual transmission have been reported recently. It is necessary to examine their sexual behavior and other sexual infection.

Characteristics of non-alcoholic steatohepatitis among lean patients in Japan: Not uncommon and not always benign.

BACKGROUND AND AIM: To elucidate features of nonobese non-alcoholic fatty liver disease (NAFLD), we assessed Japanese patients with NAFLD stratified by body mass index (BMI) and by sex. METHODS: Biopsy-proven 762 NAFLD patients (404 men) were classified into three groups by the Japanese criteria: nonobese group (BMI < 25 kg/m2 ), obese group (25 to 30), and severely obese group (≥ 30). Clinicopathological features and single nucleotide polymorphism of patatin-like phospholipase 3 (PNPLA3) rs738409 were investigated, and body composition analysis was performed by bioelectrical impedance analysis and computed tomography. RESULTS: Over 25% of men and almost 40% of women were nonobese, but most of them had visceral fat obesity and/or insulin resistance. The median age (years) of the nonobese, obese, and severely obese men was 49.9, 46.8, and 40.5 (P < 0.01), respectively, while those of women was 60.2, 59.6, and 48.5 (P < 0.01), respectively. The prevalence of metabolic comorbidities and PNPLA3 risk alleles did not differ among these groups in both sexes. Also, the prevalence of non-alcoholic steatohepatitis was not significantly different in both sexes, although nonobese patients had a higher prevalence of mild steatosis. Advanced fibrosis showed a marked difference between men and women. Advanced fibrosis was significantly more frequent among severely obese men (nonobese: 31.0%, obese: 41.6%, severely obese: 60.9%; P < 0.01), but it was lower among severely obese women (51.4%, 62.9%, 33.7%; P < 0.01). Skeletal muscle mass was significantly lower in nonobese patients. CONCLUSIONS: Non-alcoholic fatty liver disease was not milder in nonobese patients. Histological steatosis was associated with BMI, but advanced fibrosis was not and showed a significant sex difference.