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.

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.

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 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.

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.

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.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population.

A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10-9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

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.

Clinicopathological investigation of steatohepatitic hepatocellular carcinoma: A multicenter study using immunohistochemical analysis of adenoma-related markers.

AIMS: Steatohepatitic hepatocellular carcinoma (SH-HCC) is a newly proposed concept, which shows histological features of steatohepatitis in HCC lesions, and it is strongly associated with metabolic syndrome (MS) and steatosis/steatohepatitis in non-cancerous lesions. Recently, a substantial number of HCC associated with MS were reported to have developed from pre-existing inflammatory hepatocellular adenoma (HCA). To elucidate the characteristic features of SH-HCC, we clinicopathologically investigated strictly diagnosed SH-HCC and non-SH-HCC (standard HCC). METHODS: This was a retrospective multicenter study. A clinicopathological investigation was undertaken to compare 62 cases with SH-HCC features to 31 age- and sex-matched standard HCC cases, including an immunohistochemical study using markers for classification of HCA and diagnosis of HCC. RESULTS: The characteristic features of SH-HCC compared with standard HCC include a higher rate of complications of MS, more frequent non-alcoholic fatty liver disease as an underlying liver disease, and HCC development in non-cirrhotic liver. The rate of solitary tumors showed no difference between the two groups, but the median diameter of the main tumor was greater in SH-HCCs (45 mm/20 mm, P = 0.01). The HCCs were mostly moderately differentiated, and the patterns were mainly trabecular in both groups. Positive findings for serum amyloid A and C-reactive proteins, classification markers of inflammatory HCA, were significantly higher in cancerous lesions of SH-HCC cases (50%/13%, P < 0.01 and 42%/16%, respectively; P = 0.01). CONCLUSIONS: We confirmed that SH-HCC was strongly associated with MS and NAFLD, and found that classification markers of inflammatory HCA were significantly higher in SH-HCC. Further studies are needed to elucidate the relationship between SH-CCC and HCA for understanding the carcinogenic pathways in these diseases.

Response to tolvaptan and its effect on prognosis in cirrhotic patients with ascites.

AIM: The vasopressin V2 receptor antagonist tolvaptan has been used for the treatment of cirrhotic patients with ascites; however, no predictor of efficacy and prognosis has been developed. We evaluated candidate predictors of response to tolvaptan treatment. METHODS: This was a single-center retrospective study. Overall, 97 Japanese cirrhotic patients (60 men, median age 63 years), who were hospitalized for ascites treatment including oral tolvaptan coupled with conventional diuretics, were enrolled. The efficacy of tolvaptan was defined as a urination increase of ≥500 mL or a urine volume ≥2000 mL/day on the day following treatment. The prognosis of tolvaptan treatment was evaluated by the post-treatment survival time by Kaplan-Meier analysis. RESULTS: Tolvaptan therapy was effective in 67% of cirrhotic patients. Patients showed -1.5 (-17.2 to +6.2) kg change in body weight and 40% achieved ≥2.0 kg reduction in body weight after 1 week of treatment. Platelet counts, urine sodium (Na) level, and urine Na/potassium (Na/K) ratio were higher, and the blood urea nitrogen (BUN)/creatinine (Cr) ratio was lower, in cases showing a response to tolvaptan. The combination of a BUN/Cr ratio ≥17.5 and urine Na/K ratio <3.09 was predictive of being non-responsive to tolvaptan, and the response rate in these patients was only 39% (P < 0.01). The mean post-treatment survival duration was significantly longer in patients who responded to tolvaptan therapy. CONCLUSIONS: Urinary BUN and Na excretion were predictive of a response to tolvaptan, and tolvaptan treatment may improve the prognosis of cirrhotic patients.

Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy.

Poorly controlled diabetes mellitus (DM) patients sometimes show serum transaminase elevations due to steatohepatitis. However, we experienced four cases with type 1 DM with sharp elevations in serum transaminases that could not be explained by steatohepatitis alone and showed bright liver. They were diagnosed with glycogenic hepatopathy (GH) clinicopathologically. The four patients had a median age of 22.5 years (range, 19-29 years) and 12.5 (4-15)-year histories of type 1 DM and showed marked increases in serum transaminases (aspartate aminotransferase, 698 U/L [469-2763 U/L]; alanine transaminase, 255 U/L [216-956 U/L]). Diabetes mellitus control was poor and hemoglobin A1c was 12.7% (11-16.5%). Three cases had a past history of diabetic ketoacidosis. Hepatomegaly and hyperdense liver were seen on computed tomography scans. Magnetic resonance imaging showed low intensity in T2-weighted images. The pathological findings revealed pale and swollen hepatocytes and glycogenated nuclei. The architecture of the liver was preserved, and steatosis and fibrosis were mild. The cytoplasm of hepatocytes stained densely positive with periodic acid-Schiff, and the positive staining disappeared after diastase digestion, suggesting glycogen deposition. No other cause of hepatitis was evident, and the diagnosis was GH. Elevated transaminases improved within 1 month with good glycemic control. Transaminase elevations were observed several times in three cases with poor glycemic control. Glycogenic hepatopathy is rare, but extremely high serum elevations of transaminases are important to identify clinically. Despite showing a good clinical course in general, GH sometimes recurs and requires strict glycemic control. Clinicians should be aware of and recognize GH when dealing with uncontrolled DM patients.

Safety and efficacy of long-term tolvaptan therapy for decompensated liver cirrhosis.

AIM: Recently, the short-term efficacy of the vasopressin V2 receptor antagonist tolvaptan for the treatment of ascites in cirrhosis was reported. However, the long-term effects remain unknown. Here, we report the clinical features of decompensated cirrhosis treated using long-term tolvaptan therapy, and evaluate its safety and efficacy. METHODS: Fifty-five cirrhotic patients hospitalized due to ascites, despite receiving appropriate diuretic treatment, were treated with tolvaptan. We excluded 35 patients due to liver transplant (20.0%), death (28.6%), poor general status (14.3%), improved ascites (5.7%) or other reasons (31.4%). In 20 cases treated with tolvaptan for 6 months, total body water (TBW) and extracellular fluids (ECW) were measured using bioelectric impedance analysis (BIA) with an InBody720. RESULTS: The median age of the 20 patients was 64 years (range, 48-90), and 60% were male. The etiology of cirrhosis included hepatitis C (45%), alcohol-induced (20%) and other (35%). The percentage of patients with Child-Pugh class A, B and C was 0%, 40% and 60%, respectively. Biochemical findings revealed that serum creatinine levels and estimated glomerular filtration rate were not affected during 6 months of treatment with tolvaptan, and there was no renal disturbance. The median serum sodium levels were increased from 138 to 139 mEq/L, but serious adverse events related to renal and liver function were not observed. Data also revealed that long-term treatment reduced the BIA-estimated ECW/TBW ratio. CONCLUSION: Long-term tolvaptan treatment was a safe and effective treatment for decompensated cirrhosis.

Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

Hepatocellular carcinoma based on cryptogenic liver disease: The most common non-viral hepatocellular carcinoma in patients aged over 80 years.

AIM: To clarify the clinical features of patients with hepatocellular carcinoma (HCC) with cryptogenic liver diseases, we analyzed the data from a nationwide survey in Japan. METHODS: The survey was conducted in 2009. The factors examined included age and underlying liver diseases: alcoholic liver disease (ALD; n = 991), non-alcoholic fatty liver disease (n = 292), modest alcohol intake (intake between 20 and 70 g/day, n = 214) and cryptogenic liver diseases (n = 316). We compared the clinical features of cryptogenic HCC among patient-age subgroups. RESULTS: HCC with ALD etiology was most common among the non-viral HCC patients under 80 years old; for those aged 80 years or older, cryptogenic HCC was the most common etiology. Among the cryptogenic HCC patients, the body mass index values and the prevalences of liver cirrhosis (LC) and diabetes mellitus (DM) were significantly lower in the 80 years or older group versus the 50-79 years group. In the 80 years or older group, 28% of the patients developed HCC without cirrhosis, obesity and DM. CONCLUSION: In the HCC patients aged 80 years and over, the etiology of most of the non-viral HCC cases was classified as cryptogenic. In light of our finding that the prevalences of obesity, DM and LC in the 80 years or older group of cryptogenic HCC patients were significantly lower those in the younger patients, it is apparent that analyses of HCC cases must take age differences into account.

Primary hyperoxaluria complicated with liver cirrhosis: A case report.

Primary hyperoxaluria (PH) is a rare, autosomal recessive disorder characterized by overproduction of oxalate caused by a deficiency in a hepatic enzyme. The excess oxalate combines with calcium in the kidneys to form deposits of calcium oxalate, which can lead to nephrocalcinosis and renal failure. PH type 1 (PH1), the most common form of this disease, is caused by a deficiency of the liver-specific enzyme alanine/glyoxylate aminotransferase (AGT). Liver transplantation is performed as a definitive therapy for PH to correct the enzyme defect. Usually, liver depositions are limited and liver function is normal without fibrosis. Here, we report an adult case of liver cirrhosis caused by PH1. A 28-year-old woman was admitted to our hospital under suspicion of PH1 and the presence of nephrocalcinosis. The patient had suffered from kidney stone recurrences from 17 years of age, and was initiated on hemodialysis due to renal failure at the age of 27 years. The serum level of oxalic acid was high, whereas the AGT level in the liver tissue was decreased. Thus, the patient was definitively diagnosed with PH1. Although she had normal liver function, surface nodularity and splenomegaly were detected by computed tomography, suggesting liver cirrhosis. The native liver showed micronodular cirrhosis and portal fibrosis. Several arterioles were filled with rhomboid and polyhedral refractile oxalate crystals and various portal tracts showed these crystals. Our case suggests that long-term oxalosis can lead to liver cirrhosis; thus, PH should be considered one of the causes of liver cirrhosis.

Autoantibody status and histological variables influence biochemical response to treatment and long-term outcomes in Japanese patients with primary biliary cirrhosis.

AIM: The aim of the present study is to evaluate the factors influencing biochemical response to treatment and the value of biochemical response for predicting long-term outcomes in Japanese patients with primary biliary cirrhosis (PBC). METHODS: Biochemical response to ursodeoxycholic acid (UDCA) or UDCA plus bezafibrate was defined as good (≤upper limit of normal [ULN]), fair (≤1.5 × ULN) or poor (>1.5 × ULN) at 2 years after initiation of UDCA treatment. Associations between various factors (including age, sex, autoantibody status and histological variables at baseline), biochemical response to treatment and long-term outcomes were evaluated in 164 Japanese PBC patients. RESULTS: Anti-gp210 positivity and a higher bile duct loss score were significant risk factors for worse alkaline phosphatase (ALP) response (odds ratios [OR], 2.78 and 1.85, respectively). Age, anti-gp210 positivity and anticentromere positivity were significant risk factors for worse alanine aminotransferase (ALT) response (OR, 1.05, 4.0 and 2.77, respectively). Anti-gp210 positivity and a higher hepatitis score were significant risk factors for worse immunoglobulin (Ig)M response (OR, 2.10 and 2.06, respectively). Worse ALP and IgM response were significant risk factors for progression to late-stage disease without jaundice (OR, 2.27 and 2.32, respectively). Worse ALT response was a significant risk factor for progression to late-stage disease with persistent jaundice (OR, 11.11). CONCLUSION: Biochemical response to treatment at 2 years, which is influenced by autoantibody status and histological variables at baseline, can predict long-term outcomes in Japanese patients with PBC.

Clinical profile of primary biliary cirrhosis with features of autoimmune hepatitis: Importance of corticosteroid therapy.

AIM: The aim of this study was to elucidate the clinical and histological features, response to corticosteroid therapy and long-term outcome of primary biliary cirrhosis (PBC) with features of autoimmune hepatitis (AIH). METHODS: Among 280 PBC patients under ursodeoxycholic acid administration, we identified 28 patients with AIH features fulfilling the following criteria: sustained high levels of serum aminotransferases and high immunoglobulin G levels with positivity for antinuclear antibodies or anti-smooth muscle antibodies (ASMA) and/or histological features of moderate to severe interface hepatitis or moderate to severe lobular hepatitis. We analyzed PBC patients with AIH features, focusing mainly on therapeutic responses to corticosteroids. RESULTS: Patients with PBC with AIH features included 26 women (93%). Their median age was 55 years, and the median follow-up period was 7.5 years. Eight of these 28 patients were not actually treated with corticosteroids due to medical conditions. Among the 20 patients receiving corticosteroid therapy, 15 were responders and five were non-responders. A high alkaline phosphatase (ALP) level, negativity for ASMA and positivity for gp210 were identified as risk factors for lack of a response to corticosteroid therapy. Among 28 PBC patients with AIH features, the responders to corticosteroids had an excellent prognosis, while those who could not be treated with corticosteroids and non-responders to corticosteroids had a poor outcome. CONCLUSION: Patients with PBC with AIH features benefit from corticosteroid therapy. Features of PBC such as high ALP level, negativity for ASMA and positivity for gp210 appear to predict a poor response to corticosteroids.