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.

Serum level of full-length connective tissue growth factor reflects liver fibrosis stage in patients with Fontan-associated liver disease.

BACKGROUND: Chronic liver disease leads to liver fibrosis, and an accurate diagnosis of the fibrosis stage is crucial for medical management. Connective tissue growth factor (CTGF) is produced by endothelial cells and platelets and plays a central role in inducing fibrosis in various organs. In the present study, we tested the validity of measuring the serum levels of two types of CTGF to estimate the biopsy-confirmed liver fibrosis stage. METHODS: We used two detection antibodies targeting the N- and C-terminal of CTGF to measure the serum levels of two forms of CTGF consisting of its full length and its N-terminal fragment. We analyzed the level of CTGF (via enzyme-linked immunosorbent assay) and the liver fibrosis stage in 38 patients with Fontan-associated liver disease (FALD) (26 cases of which were diagnosed pathologically). Correlations were determined by multivariate analysis and the area under the receiver operating characteristic curve. The 65 patients with nonalcoholic fatty liver disease (NAFLD) were included as a disease control group for examination. RESULTS: Full-length CTGF was significantly inversely correlated with liver fibrosis in patients with FALD. Although the platelet count was also associated with the liver fibrosis stage, full-length CTGF was more closely correlated with the fibrosis stage. Furthermore, the level of full-length CTGF was inversely associated with high central venous pressure. Conversely, the serum level of CTGF was not correlated with the fibrosis stage in NAFLD. CONCLUSION: The serum level of full-length CTGF may be useful for estimating the liver fibrosis stage in patients with FALD.

Risk factors for fatty pancreas and effects of fatty infiltration on pancreatic cancer.

Objective: This study clarified the risk factors and pathophysiology of pancreatic cancer by examining the factors associated with fatty pancreas. Methods: The degree of fatty pancreas, background factors, and incidence of pancreatic cancer were examined among nonalcoholic fatty liver disease (NAFLD) patients (n = 281) and intraductal papillary mucinous neoplasm (IPMN) patients with a family history of pancreatic cancer (n = 38). The presence of fatty pancreas was confirmed by the pancreatic CT value/splenic CT value ratio (P/S ratio). Immunohistochemical staining was performed on 10 cases with fatty pancreas, confirmed via postoperative pathology. Results: Fatty pancreas occurred in 126 patients (44.8%) in the NAFLD group who were older (p = 0.0002) and more likely to have hypertension (p < 0.0001). The IPMN group had 18 patients (47.4%) with fatty pancreas, included more men than women (p = 0.0056), and was more likely to have patients with hypertension (p = 0.0010). On histological examination, a significant infiltration of adipocytes into the acini from the pancreatic interstitium induced atrophy of the pancreatic parenchyma, and both M1 and M2 macrophages were detected in the area where adipocytes invaded the pancreatic parenchyma. Accumulation of p62 and increased positive staining of NQO1 molecules related to autophagy dysfunction were detected in pancreatic acinar cells in the fatty area, acinar-ductal metaplasia, and pancreatic cancer cells. The rate of p62-positive cell area and that of NQO1-positive cell area were significantly higher in the fatty pancreatic region than those in the control lesion (pancreatic region with few adipocyte infiltration). Furthermore, the rate of p62-positive cell area or that of NQO1-positive cell area showed strong positive correlations with the rate of fatty pancreatic lesion. These results suggest that adipocyte invasion into the pancreatic parenthyme induced macrophage infiltration and autophagy substrate p62 accumulation. High levels of NQO1 expression in the fatty area may be dependent on p62 accumulation. Conclusion: Hypertension was a significant risk factor for fatty pancreas in patients with NAFLD and IPMN. In fatty pancreas, fatty infiltration into the pancreatic parenchyme might induce autophagy dysfunction, resulting in activation of antioxidant proteins NQO1. Thus, patients with fatty pancreas require careful follow-up.

Analysis of genetic factors associated with fatty liver disease-related hepatocellular carcinoma.

AIM: Single-nucleotide polymorphisms (SNPs) in PNPLA3 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) genes are associated with fatty liver disease (FLD) progression and carcinogenesis. In the present study, we evaluated the characteristics of Japanese FLD patients according to HSD17B13 polymorphisms. METHODS: We enrolled 402 patients who were clinically and pathologically diagnosed with FLD (alcoholic: 63 cases, nonalcoholic: 339 cases) at our hospital in 1990-2018 (228 males; median age: 54.9 [14.6-83.6] years). FLD patients with HSD17B13 A/A (212 cases) and others (A/AA or AA/AA; 190 cases) were compared. RESULTS: Compared to patients with HSD17B13 A/A and others, those with the A/A genotype showed increased incidence of hepatocellular carcinoma (HCC) (A/A vs. others; 18.4% vs. 9.5%, p = 0.01), cardiovascular diseases (14.2% vs. 4.2%, p < 0.01), and hypertension (56.6% vs. 47.4%, p = 0.06). In patients without A/A, the HCC incidence was significantly reduced in those with alcohol-related FLD, fibrosis-4 index <2.67, and the PNPLA3 CC genotype; however, there was no significant difference in nonalcoholic-FLD. Patients without HSD17B13 A/A showed severe steatosis (77% vs. 88.6%, p < 0.01). New HCC developed in 11 cases and the 5-year incidence rate of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 A/A, which was significantly higher than the rate for those with other SNP profiles (0.6%, p = 0.03). CONCLUSIONS: Inhibiting HSD17B13 activity may prevent HCC development, particularly in alcohol-related FLD and low-risk patients. Therefore, combinations of SNPs and other risk factors can be used for screening FLD-HCC.

Outcomes of fatty liver disease with and without metabolic comorbidities and risk factors for mortality.

Background and Aim: As the clinical course of metabolic-associated fatty liver disease (MAFLD) is unclear, we compared the clinical courses of MAFLD and non-alcoholic FLD (NAFLD). Methods: Asian FLD patients (n = 987) from 1991 to 2021 (biopsy-proven in 939) were enrolled. The patients were divided into NAFLD (N-alone, n = 92), both MAFLD and N (M&N, n = 785), and M-alone (n = 90) groups. Clinical features, complications, and survival rates were compared among the three groups. Risk factors of mortality were subjected to Cox regression analysis. Results: The N-alone group patients were significantly younger (N alone, M&N, and M alone: 50, 53, and 57 years, respectively), more frequently male (54.3%, 52.6%, and 37.8%), and had a low body mass index (BMI, 23.1, 27.1, and 26.7 kg/m2) and FIB-4 index (1.20, 1.46, and 2.10). Hypopituitarism (5.4%) and hypothyroidism (7.6%) were significantly observed in the N-alone group. Hepatocellular carcinoma (HCC) developed in 0.0%, 4.2%, and 3.5% of the cases, and extrahepatic malignancies in 6.8%, 8.4%, and 4.7% of the cases, respectively, with no significant differences. The cardiovascular event rate was significantly higher in the M-alone group (1, 37, and 11 cases, P < 0.01). Survival rates were similar among the three groups. Risk factors for mortality were age and BMI in the N-alone group; age, HCC, alanine transaminase, and FIB-4 in the M&N group; and FIB-4 in the M-alone group. Conclusion: Different risk factors for mortality may exist among the FLD groups.

Risk factors for Fontan-associated hepatocellular carcinoma.

AIMS: The incidence of hepatocellular carcinoma (HCC) in patients with Fontan-associated liver disease (i.e., FALD-HCC) has increased over time. However, the risk factors for HCC development remain unclear. Here, we compared the levels of non-invasive markers to the survival rate of FALD-HCC patients. METHODS: From 2003 to 2021, 154 patients (66 men, 42.9%) developed liver disease after undergoing Fontan procedures. HCC was diagnosed in 15 (9.7%) (8 men, 53.3%) at a median age of 34 years (range, 21-45 years). We compared FALD-HCC and non-HCC cases; we generated marker level cutoffs using receiver operating characteristic curves. We sought to identify risk factors for HCC and mortality. RESULTS: The incidence of HCC was 4.9% in FALD patients within 20 years after the Fontan procedure. Compared with non-HCC patients, FALD-HCC patients exhibited higher incidences of polysplenia and esophageal varices. At the time of HCC development, the hyaluronic acid (HA) level (p = 0.04) and the fibrosis-4 index (p = 0.02) were significantly higher in FALD-HCC patients than in non-HCC patients; the total bilirubin (T-BIL) level (p = 0.07) and the model for end-stage liver disease score [excluding the international normalized ratio (MELD-XI)] (p = 0.06) tended to be higher in FALD-HCC patients. Within approximately 20 years of the Fontan procedure, 10 patients died (survival rate, 96.9%). Kaplan-Meier curve analysis indicated that patients with T-BIL levels ≥ 2.2 mg/dL, HA levels ≥ 55.5 ng/mL, and MELD-XI scores ≥ 18.7 were at high risk of HCC, a generally poor prognosis, and both polysplenia and esophageal varices. Multivariate Cox regression analyses indicated that the complication of polysplenia [Hazard ratio (HR): 10.915] and a higher MELD-XI score (HR: 1.148, both p < 0.01) were independent risk factors for FALD-HCC. CONCLUSIONS: The complication of polysplenia and a MELD-XI score may predict HCC development and mortality in FALD patients.

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.

Giant Hepatic Hemangioma Causing Prolonged Fever and Indicated for Resection.

Hepatic hemangiomas are benign liver tumors, and most of them progress asymptomatically. We report a case of hepatic hemangioma considered the cause of fever. A 53-year-old woman had a fever of 40°C for about 3 months without infection. Hepatic hemangiomas with internal bleeding of 10 cm in size on liver S8/7 and S3/2 were observed. These were resected laparoscopically for diagnostic treatment. She was afebrile after the operation. The pathological diagnosis was hematoma inside cavernous hemangioma. It should be noted that a bleeding hepatic hemangioma may cause fever of unknown origin and be indicated for resection.

Risk and protective factors of acute kidney injury in decompensated cirrhotic patients with ascites on tolvaptan.

BACKGROUND AND AIM: Acute kidney injury (AKI) is a life-threatening complication of liver cirrhosis. Here, we evaluated the risk factors and characteristics of AKI in cirrhosis. PATIENTS/METHODS: This was a single-center retrospective study. A total of 199 Japanese patients with decompensated liver cirrhosis (104 men, median age 61 years) were enrolled and received tolvaptan orally. Survival rates and new onset of AKI were monitored, and risk factors were evaluated. RESULTS: Forty-six patients (23.1%) suffered an AKI complication and exhibited significantly poorer survival (P < 0.01). The rates of hepatic encephalopathy (P < 0.01) and chronic kidney disease (CKD; P = 0.02) were significantly increased in patients with AKI. The rate of proton pump inhibitor (PPI)/H2 blocker treatment (P = 0.04) was significantly lower, whereas that of ascites drainage was significantly higher in the AKI cases (P < 0.01). The AKI risk was significantly increased in patients with hepatic encephalopathy (HR 4.18, 95% CI 1.618-10.771). In contrast, the incidence of AKI was significantly lower in patients with a higher serum albumin level (HR 0.36, 95% CI 0.142-0.914, P = 0.03). Treatment with PPI/H2 blockers (HR 0.30, 95% CI 0.126-0.711, P < 0.01) or kanamycin/rifaximin (HR 0.26, 95% CI 0.075-0.929, P = 0.04) was significantly associated with a reduced risk of AKI development. CONCLUSIONS: AKI incidence was increased in patients with decreased liver function and was associated with poor survival. PPI/H2 blocker or kanamycin/rifaximin treatment may reduce the risk of AKI.

Long-term outcome of Wilson's disease complicated by liver disease.

BACKGROUND AND AIM: Wilson's disease (WD) is a rare inherited disease that causes systemic copper accumulation. This study examined the long-term course of WD patients with liver disease. METHODS: The 12 patients (9 female patients) enrolled in the study had a median age of 28 years (range: 19-57 years) at their first visit to our hospital. Clinical course and fibrosis markers were assessed in all patients. RESULTS: The median age at diagnosis was 24 years (range: 5-42 years). One patient had acute liver failure (ALF) and 11 patients had chronic liver disease (CLD, 5 with cirrhosis). The patients were followed-up for >20 years. The patient with ALF underwent liver transplantation; the postoperative course during the subsequent 20 years was good. Of the six patients with CLD, liver cirrhosis developed in four patients with interrupted chelating therapy. Two of the patients with cirrhosis died; one of these two patients died at 21 years after liver transplantation. However, the remaining patients with continued treatment exhibited a favorable clinical course for 30 years and none developed hepatocellular carcinoma (HCC). The duration of chelation therapy was significantly negatively correlated (P < 0.05) with the fibrosis-4 index or aspartate aminotransferase to platelet ratio index (APRI) score at the last visit; lower values were indicative of greater treatment success. Patients with an APRI score ≥1.5 had a significantly worse prognosis (P < 0.05). CONCLUSION: Long-term survival of patients with WD was achieved without worsened liver function or carcinogenesis with appropriate treatment. Treatment disruption should be avoided.

Evidence-based clinical practice guidelines for liver cirrhosis 2020.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

Evidence-based clinical practice guidelines for Liver Cirrhosis 2020.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

The utility of liver transplantation to treat acute liver failure caused by adult-onset Still's disease: case reports.

PURPOSE: Adult-onset Still's disease (AOSD) is an inflammatory condition commonly complicated by mild liver dysfunction. However, severe liver failure is rarely reported. We report three cases of severe acute hepatic failure (ALF) associated with AOSD. We encountered three cases of acute liver failure (ALF) with encephalopathy. RESULTS: Case 1 was a 75-year-old female, who was started on a steroid (prednisolone, PSL) to treat AOSD; this was gradually tapered. Two months later, severe ALF developed. She died despite an increase in the PSL dose and artificial liver support. Case 2 was a 26-year-old-female taking PSL 30 mg/day to treat subacute thyroiditis. PSL was tapered, and she received methyl PSL pulse therapy and artificial liver support, but this did not cure the ALF. Liver transplantation (LT) was performed 25 days later. Three years later, the same symptoms were observed and we diagnosed AOSD. Case 3 was a 56-year-old-female who met the AOSD criteria. PSL 50 mg/day was started and then tapered. Methyl PSL pulse therapy was prescribed to treat hemophagocytic syndrome, but she required LT on hospital day 13. CONCLUSION: In AOSD cases, ALF is rarely complicated; urgent LT should be considered only for patients with AOSD-related severe ALF.

Long-term Follow-up of a Patient with Portal Hypertension and Hepatic Failure Due to Hepatic Hydatid Disease.

We observed liver failure with a presumed etiology of echinococcosis in an 89-year-old woman. Our patient had been born and then resided on Rebun Island until she was 12 years old. At 46 years old, she had been referred to our hospital due to right abdominal pain. Ultrasound had revealed multilocular cysts in the right lobe of the liver. At 84 years old, the hepatic cyst occupied nearly the entire liver with ring-shaped calcification along the cyst wall. The patient was diagnosed with decompensated cirrhosis and hepatic hydatid disease based on typical imaging and the long-term natural clinical course.

Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates. METHODS: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected. RESULTS: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%. CONCLUSION: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology.

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.

Development and course of diabetes according to genetic factors and diabetes treatment among patients with nonalcoholic fatty liver disease.

OBJECTIVES: Many patients with nonalcoholic fatty liver disease (NAFLD) also have diabetes. However, the genetic factors associated with diabetes in NAFLD are unclear. In this study, we investigated the clinical course and risk factors of diabetes development. METHODS: A total of 544 patients (275 men; 50.6%) with a median age of 53 y and biopsy-confirmed NAFLD enrolled in the study. Patatin-like phospholipase 3 and voltage-gated potassium channel KQT-like subfamily member 1 (KCNQ1) single nucleotide polymorphisms were identified in 287 cases. There were 272 patients without diabetes, and 64, 141, and 67 patients with diabetes not treated with an oral hypoglycemic agent, treated with an oral hypoglycemic agent, and treated with insulin, respectively. Changes in biochemical parameters and body weight over a 1-y period were determined in patients treated with incretin agents (n = 91), a sodium glucose cotransporter 2 inhibitor (n = 19), or both (n = 33). The prevalence and risk factors for diabetes development among patients with NAFLD were determined in nondiabetic patients. RESULTS: Among patients with NAFLD, half of the patients had diabetes and the incidence was high in those with advanced fibrosis. Reduction in body weight was higher after sodium glucose cotransporter 2 inhibitor treatment (P = .050) and in KCNQ1 CC genotype patients (P < .05). Reduction in hemoglobin A1c level was significantly lower in patatin-like phospholipase 3 GG subjects (P < .05). De novo diabetes developed in 44 patients (10-y incidence: 17.9%), especially in obese (P = .046) and KCNQ1 CC genotype patients (P < .01). CONCLUSIONS: Patient genetic background affected treatment response and incidence of diabetes in patients with NAFLD.

The transition in the etiologies of hepatocellular carcinoma-complicated liver cirrhosis in a nationwide survey of Japan.

BACKGROUND: We recently reported the real-world changes in the etiologies of liver cirrhosis (LC) based on nationwide survey data and assessed the etiologies of LC with hepatocellular carcinoma (HCC). METHODS: Fifty-five participants from 68 institutions provided data on 23,637 patients with HCC-complicated LC. The changing trends in etiologies were assessed. We further analyzed the data from 29 hospitals that provided the annual number of newly identified HCC-complicated LC patients from 2008 to 2016 (N = 9362) without any missing years and assessed the transition in the real number of newly identified HCC-complicated LC cases. RESULTS: In the overall cohort, hepatitis C virus (HCV) infection (60.3%) and hepatitis B virus (HBV) infection (12.9%) were the leading and third-most common causes of HCC-complicated LC in Japan, respectively. HCV infection was found to be the leading cause throughout Japan. The rate of viral hepatitis-related HCC decreased from 85.3 to 64.4%. Among non-viral etiologies, notable increases were observed in nonalcoholic steatohepatitis (NASH)-related HCC (from 1.5 to 7.2%) and alcoholic liver disease (ALD)-related HCC (from 8.5 to 18.6%). Regarding the real number of newly diagnosed patients, the number of patients with viral hepatitis-related HCC decreased, while the number of patients with non-viral HCC, particularly NASH-related HCC, increased. CONCLUSIONS: Viral hepatitis has remained the main cause of HCC in Japan. However, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC highly contributed to the etiological changes. In addition, the increased incidence of non-viral HCC, particularly NASH-related HCC, was involved in the changing etiologies of HCC-complicated LC in Japan.

A case of hemorrhage of hepatocellular carcinoma resembling a hepatic cyst arising from non-cirrhotic steatohepatitis.

A 70-year-old female was found to have multiple hepatic cysts at her annual checkup. In the posterior segment of the right lobe of the liver, an 81 × 67 mm circular cystic lesion was detected by contrast-enhanced computed tomography (CT). Magnetic resonance imaging (MRI) of the cyst revealed a solid component. The cyst had a capsule-like structure and non-uniform fluid accumulation suggested bleeding. Since the lesion was enlarged and malignancy could not be ruled out, it was surgically resected. Histopathologically, reticular fibers of the liver were seen in necrotic tissue and the lesion was diagnosed as a bleeding hepatocellular carcinoma (HCC). The non-cancerous liver tissue showed non-cirrhotic steatohepatitis. This was an unusual presentation of HCC.