A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH RESULTS: Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 controls from the Japanese population (GWAS-lead variant: rs8098858, p=2.6×10-8). In-silico and in-vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were confirmed in the portal area of the PBC-liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in-vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFN signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Survival Improvements in Advanced Hepatocellular Carcinoma with Sequential Therapy by Era.

Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009-2013, n = 86; period 2: 2014-2018, n = 132; period 3: 2019-2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1-3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin-bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival.

B-mode shear wave elastography can be an alternative method to vibration-controlled transient elastography according to a moderate-scale population study.

PURPOSE: We aimed to compare vibration-controlled transient elastography (VCTE) with shear wave elastography (SWE) without previous analysis and generate regression equations between VCTE and new point SWE using combination-elastography. METHODS: Overall, 829 patients with chronic liver disease were enrolled in this study. Patients with a skin-liver capsule distance > 25 mm were excluded. The reproducibility of VCTE and SWE was confirmed in a phantom study and a clinical study. Considering that combination-elastography allows measurement based on strain elastography, a similar analysis was performed for the liver fibrosis index (LFI), which is a quantitative value for evaluation of liver fibrosis calculated using strain elastography image features. Regression equations between the VCTE and SWE values were obtained based on linear regression analysis. RESULTS: In the phantom study and clinical study, there was a strong correlation between VCTE and SWE [r = 0.995 (p < 0.001) and r = 0.747 (p < 0.001), respectively). The regression equation between VCTE and SWE was VCTE (kPa) = 1.09 × point SWE (kPa) - 0.17. The Bland-Altman plots revealed no statistically significant bias. Meanwhile, there was no correlation between VCTE and LFI (r = 0.279). There was a statistically significant bias between VCTE and LFI in the Bland-Altman plots. The inter-operator reliability showed a good intraclass correlation coefficient of 0.760 (95% confidence interval: 0.720-0.779). CONCLUSION: Liver stiffness measured using point SWE was comparable to that measured using VCTE.

Simple new clinical score to predict hepatocellular carcinoma after sustained viral response with direct-acting antivirals.

The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.

Deep attenuation transducer to measure liver stiffness in obese patients with liver disease.

PURPOSE: Deep attenuation transducers (DAX) are capable of imaging at diagnostic depths of up to 40 cm. The feasibility of DAX for liver stiffness measurement (LSM) has not been reported clinically. We aimed to assess the feasibility and reliability of DAX for LSM. METHODS: Overall, 219 patients with chronic liver disease were enrolled. The success rate (acquired after ≥ 10 valid measurements) and inadequate measurements (interquartile range/median ≥ 0.3) for DAX were compared with those of conventional convex (c-convex) probes and M and XL probes of vibration-controlled transient elastography. RESULTS: LSM was successfully performed for all patients using DAX through all degrees of skin-to-liver capsular distance (SCD). Especially in patients with an SCD ≥ 30 mm, the difference in the rate of acquisition of 10 valid measurements was remarkable: M probe (8/33, 24.2%), XL probe (26/33, 78.8%), c-convex probe (33/43, 76.7%), and DAX (44/44, 100%). In patients with an SCD ≥ 30 mm, the inadequate measurement rate of M probe (1/8, 12.5%), XL probe (8/26, 30.8%), and c-convex probe (6/33, 18.2%) was higher than that of DAX (1/43, 2.3%). The areas under the curve for diagnosis of F4 with shear wave speed by c-convex and DAX were 0.916 and 0.918, respectively. Between DAX and c-convex probes, the intraclass correlation coefficient of 0.937 (95% CI 0.918-0.952) was excellent. Bland-Altman plots revealed that there was no statistically significant bias. CONCLUSION: Liver stiffness measured by DAX is feasible and reliable for all patient populations, while the XL probe is limited to use in obese patients.

Efficacy of B-mode ultrasound-based attenuation for the diagnosis of hepatic steatosis: a systematic review/meta-analysis.

The accuracy of attenuation coefficients and B-mode ultrasound for distinguishing between S0 (healthy, < 5% fat) and S1-3 (steatosis ≥ 5%) livers compared to a controlled attenuation parameter is unclear. This meta-analysis aimed to comprehensively assess the diagnostic performance of B-mode ultrasound imaging for evaluating steatosis of ≥ 5%. We searched the PubMed, Embase, and Web of Science databases for studies on the accuracy of B-mode ultrasound for differentiating S0 from S1-3 in adults with chronic liver disease. A bivariate random-effects model was performed to estimate the pooled sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and diagnostic odds ratios (DORs). Subgroup analyses by attenuation coefficient, conventional B-mode ultrasound findings, and B-mode ultrasound findings without semi-quantification methods were performed. Liver steatosis was scored as follows: S0, < 5%; S1, 5-33%; S2, 33-66%; and S3, > 66%. Nineteen studies involving 3240 patients were analyzed. The pooled sensitivity and specificity of B-mode ultrasound for detecting S1 were 0.70 (95% confidence interval [CI], 0.63-0.77) and 0.86 (95% CI 0.82-0.89), respectively. The pooled PLR, NLR, and DOR were 4.90 (95% CI 3.69-6.51), 0.35 (95% CI 0.27- 0.44), and 14.1 (95% CI 8.7-23.0), respectively. The diagnostic accuracy was better in patients with attenuation coefficients (area under the curve [AUC], 0.89; sensitivity, 0.75; specificity, 0.86) than in those with conventional B-mode findings (AUC, 0.80; sensitivity, 0.59; specificity, 0.83). In particular, the diagnostic value was better when the attenuation coefficient guided by B-mode ultrasound was utilized. To screen patients with steatosis of ≥ 5%, attenuation coefficient should be used.

[Case of ischemic ileitis complicated by portal venous gas].

A 65-year-old woman was admitted with sudden-onset abdominal pain. Abdominal computed tomography revealed hepatic portal venous gas. Physical and laboratory examination suggested that a conservative approach was appropriate; however, 4 days later, the pain recurred and severe ischemic enteritis was diagnosed. A stenosis was identified 60 cm distal to the start of the ileum, and partial resection of the small intestine was performed. The diagnosis of ischemic enteritis was confirmed. Ischemic enteritis affecting the small intestine is uncommon, and enteritis causing intestinal stenosis with hepatic portal vein gas is even rarer.

Doppler waveform pattern changes in a patient with primary Budd-Chiari syndrome before and after angioplasty.

A 34-year-old woman was admitted for treatment of esophageal varices. Seven years earlier, she had been diagnosed with Budd-Chiari syndrome, and percutaneous transluminal angioplasty (PTA) for right hepatic vein (RHV) stenosis was done. On admission, Doppler sonography showed a flat waveform in the RHV. RHV re-stenosis was confirmed on X-ray sonography. After PTA, the stenosis improved. Heterogeneous liver enhancement on enhanced computed tomography became homogeneous, her esophageal varices became inconspicuous, and the flat Doppler waveform pattern changed to a triphasic pattern. Doppler sonography was very useful for evaluating the effect of angioplasty and to diagnose re-stenosis.