Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury.

AIM: Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. METHODS: Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. RESULTS: The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed. CONCLUSIONS: The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

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.

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.

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.

Analysis of 307 cases with drug-induced liver injury between 2010 and 2018 in Japan.

AIM: In order to know the present status of drug-induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals. METHODS: Drug-induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level ≥150 U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria. RESULTS: In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86 years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug-induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty-three percent of DILI cases occurred within 30 days and 79% of DILI cases occurred within 90 days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)-Japan 2004 workshop, 93.8% of cases were diagnosed as "highly probable", and 5.9% as "possible". CONCLUSIONS: Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW-Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI.

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.

Copper deposition in oligodendroglial cells in an autopsied case of hepatolenticular degeneration.

We present a case of hepatolenticular degeneration, so-called Wilson's disease (WD), in a 31-year-old Japanese man with broader deposition of copper in the liver, kidney and brain. The liver showed severe cirrhotic changes with macronodular pseudolobule formation, but there was little difference in immunohistochemical expression patterns of the copper transporter ATP7B between the control and present case. In the brain, there were both WD-related lesions such as the scattering of Opalski cells and changes caused by hepatic encephalopathy including the appearance of Alzheimer type II glia. Of note, we identified copper deposits in the systemic organs, including hepatocytes, renal tubules, and in broad areas of the brain. Surprisingly, as a result of further pursuit, copper accumulation in the brain was rarely identified in neuronal cells, but in Olig2-positive glial cells with double immunohistochemical staining. Together, this rare autopsied case suggests a novel cellular candidate affected by abnormal copper metabolism and the necessity to perform the systemic examination of copper deposition in WD.

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.

Diagnosis and classification of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: Current concepts and remaining challenges.

The high prevalence of non-alcoholic fatty liver disease (NAFLD) has made the condition an important public health issue. Two clinical entities are manifestations of NAFLD, namely, non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). The former tends to be benign and non-progressive while the latter can progress to cirrhosis, which in rare cases gives rise to hepatocellular carcinoma. The diagnosis of NAFLD is based on: (i) a history of no or limited daily alcohol intake (<20 g for women and <30 g for men); (ii) presence of hepatic steatosis by imaging or by histology; and (iii) exclusion of other liver diseases. NAFL is defined histologically by the presence of bland, primarily macrovesicular, hepatocellular fatty change, while NASH features fatty change with inflammation and evidence of hepatocyte injury, such as ballooning degeneration. Presence of fibrosis is a sign of chronicity. Thus, the diagnosis of NAFL/NASH rests on clinicopathological criteria; it always requires both clinical and biopsy-based information. NAFLD could be both the result and the cause of metabolic syndrome, with a vicious cycle operating between these conditions. Remaining challenges are: (i) the lack of a clear threshold alcohol intake for defining "non-alcoholic"; (ii) a lacking consensus for the classification of fatty liver disease; and (iii) absence of a histological definition of NASH, which currently remains the gold standard for the diagnosis. Further challenges include the overlap of the criteria for NAFLD and alcoholic liver disease as many obese individuals also consume considerable volumes of alcohol.

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.

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

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various non-invasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 through January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.

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.