Hepatic progenitor cells (HPCs) are thought to reside in the canals of Hering and can be activated and contribute to liver regeneration in response to liver injury by proliferating and ...differentiating towards both hepatocytes and biliary epithelial cells. In this setting, several cytokines, chemokines, and growth factors related to liver inflammation and other liver cells comprising the HPC niche, namely hepatic stellate cells (HSCs), play crucial roles in HPC activation and differentiation. In response to several types of liver injury, tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) is secreted by several inflammatory cells, including monocytes, T lymphocytes, and macrophages, and acts as an initiator of the HPC niche and HSC activation. Following TWEAK‐induced activation of the HPC niche, fibroblast growth factor 7 and hepatocyte growth factor released from activated HSC play central roles in maintaining HPC proliferation. In contrast, HGF‐MET and Wnt3a‐β‐catenin signals are the predominant mediators of the hepatocyte differentiation of HPC, whereas epidermal growth factor receptor–NOTCH signaling controls HPC differentiation towards biliary epithelial cells. These signals are maintained exclusively by activated HSC and inflammatory cells surrounding HPC. Together, HSC and inflammatory cells surrounding HPC are responsible for the precise control of HPC proliferation and differentiation fate. In this review, we discuss recent progress in understanding of interactions between HPC and other liver cells in HPC‐mediated liver regeneration in the setting of liver inflammation.
Background
Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We ...investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis.
Methods
The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment.
Results
In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (
n
= 31) or 100 mg (
n
= 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (
n
= 227) or deferred treatment (
n
= 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment.
Conclusion
Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection.
ClinicalTrials.gov identifier
NCT02203149.
Background
We developed a nationwide database that stores data of patients with primary liver cancer (PLC) and decompensated cirrhosis (DC) on an admission basis.
Methods
A database was constructed ...using the National Clinical Database, a nationwide registry platform for various diseases in Japan. Mutual data exchange was possible with the Nationwide Follow-up Survey of Primary Liver Cancer in Japan by the Liver Cancer Study Group of Japan. The stored data on the admission of patients with PLC, DC, or both, included treatment details as well as patient characteristics.
Results
A total of 37,705 admissions (29,489 PLC, 10,077 DC, and 1862 for both) in 21,376 patients from 224 hospitals were analyzed. The proportions of patients with hepatitis B, hepatitis C, and non-viral etiology were 11.9%, 36.2%, and 42.6%, respectively, in PLC, and 7.5%, 23.8%, and 55.0%, respectively, in DC. The mean ages (± standard deviation) on admission with PLC and DC were 73 ± 10 and 68 ± 13 years, respectively. The Barcelona Clinic Liver Cancer (BCLC) stage for PLC was 0, A, B, C, and D in 22.0%, 17.1%, 29.6%, 15.1%, and 5.1%, respectively. Treatment modalities for PLC were resection, ablation, transarterial chemoembolization, and systemic therapy in 18.4%, 22.8%, 33.7%, and 11.4%, respectively. A vasopressin receptor V2 antagonist was used in 38.2% in addition to conventionally used loop diuretics and aldosterone antagonists for DC.
Conclusions
The distribution of treatment options for PLC on admission differed from that of the initial treatment. Newly introduced drugs are widely used in patients with DC.
Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-α and IFN-γ, ...induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro- and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation.
Background
The once-daily, all oral, RBV-free, pangenotypic direct-acting anti-viral regimen consisting of co-formulated NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (G/P), ...demonstrated high rates of sustained virologic response (SVR) in phase 2 and 3 studies outside Japan.
Methods
CERTAIN-1 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in Japanese patients with chronic HCV GT1 infection. Patients without cirrhosis received 8 weeks of G/P or 12 weeks of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r, 25/150/100 mg); patients with cirrhosis received G/P for 12 weeks. The primary efficacy endpoint was non-inferiority of G/P compared to OBV/PTV/r by assessing SVR at post-treatment week 12 (SVR12) among non-cirrhotic patients without the NS5A Y93H polymorphism.
Results
SVR12 was achieved by 128/129 (99.2%; one patient lost to follow-up) non-cirrhotic patients in the 8-week G/P Arm (including 23/23 patients with the NS5A Y93H polymorphism) and 52/52 (100%) patients in the 12-week OBV/PTV/r Arm. No patients from the G/P Arm prematurely discontinued the study drug or experienced a treatment-emergent serious adverse event (TESAE). Three patients from the OBV/PTV/r Arm experienced five TESAEs and one of these patients discontinued the study drug due to TESAEs. All 38 (100%) patients with compensated cirrhosis achieved SVR12; in this group, no TESAEs were reported and one patient discontinued treatment due to an AE.
Conclusions
CERTAIN-1 study results demonstrate high efficacy and favorable tolerability of G/P in GT1-infected Japanese patients including those with the NS5A Y93H polymorphism, with no virologic failures observed.
Aim
Despite its relevant clinical impact and high prevalence, covert hepatic encephalopathy (HE) still remains underdiagnosed. As patients with liver cirrhosis tend to be older in Japan, more ...suitable tests for the elderly and cut‐off values based on this attribute are needed. Recently, a Stroop test has been developed and validated for the screening and diagnosis of covert HE in the United States. The present study aims to establish the cut‐off values of the Stroop test to screen covert HE.
Methods
This study was a prospective multicenter cross‐sectional endeavor. We undertook a survey of 311 cirrhotic patients, administering the number connection test (NCT)‐A and ‐B and the Stroop‐off and ‐on test.
Results
We determined the cut‐off values of Stroop test results for cirrhotic patients in a variety of age ranges. The cut‐off value of the Stroop test was strongly correlated with age. There was a significant correlation between the results of NCT‐B and age, and Stroop‐on test results showed a correlation with serum albumin (Alb) levels. Serum Alb ≤3.2 g/dl could have the potential to be an objective biomarker of covert HE. In addition, stepwise logistic regression analysis revealed a relationship between the results of the Stroop‐on test and plasma ammonia levels.
Conclusions
We established the cut‐off values of Stroop test results and confirmed the efficacy of the Stroop test as a simple tool for assessing cognitive alterations. The Stroop test could be suitable as a necessary minimum for the diagnosis of covert HE.
We herein report a rare concurrent case of ulcerative colitis (UC) in a pregnant woman with rheumatoid arthritis (RA), which was well managed by biologics. When a 32-year-old woman with seropositive ...RA became pregnant, she began experiencing hematochezia; colonoscopy revealed diffuse inflammation with multiple ulcers. Based on clinical examinations and pathological assessments, she was diagnosed with severe UC. Although prednisolone had no curative effect and infliximab caused an infusion reaction, golimumab successfully induced remission with normal delivery. This case report describes the successful treatment of a pregnant woman with UC and RA through biologics administration.
Background
It is widely understood that insulin resistance (IR) critically correlates with the development of liver fibrosis in several types of chronic liver injuries. Several experiments have ...proved that anti-IR treatment can alleviate liver fibrosis. Sodium–glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules, improving IR. The aim of this study was to elucidate the effect of an SGLT2 inhibitor on the development of liver fibrosis using obese diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and their littermate nondiabetic Long–Evans Tokushima Otsuka (LETO) rats.
Methods
Male OLETF and LETO rats were intraperitoneally injected with porcine serum twice a week for 12 weeks to augment liver fibrogenesis. Different concentrations of ipragliflozin (3 and 6 mg/kg) were orally administered during the experimental period. Serological and histological data were examined at the end of the experimental period. The direct effect of ipragliflozin on the proliferation of a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro.
Results
OLETF rats, but not LETO rats, received 12 weeks of porcine serum injection to induce severe fibrosis. Treatment with ipragliflozin markedly attenuated the development of liver fibrosis and expression of hepatic fibrosis markers, such as alpha smooth muscle actin, collagen 1A1, and transforming growth factor beta (TGF-β), and improved IR in a dose-dependent manner in OLETF rats. In contrast, the proliferation of LX-2 in vitro was not affected, suggesting that ipragliflozin had no significant direct effect on the proliferation of HSCs.
Conclusion
In conclusion, our dataset suggests that an SGLT2 inhibitor could alleviate the development of liver fibrosis by improving IR in naturally diabetic rats. This may provide the basis for creating new therapeutic strategies for chronic liver injuries with IR.
The Intractable Hepato‐Biliary Disease Study Group of Japan, sponsored by the Ministry of Health, Labor and Wealth, proposed in 2018 that patients with cirrhosis and a Child‐Pugh score of 5–9 should ...be diagnosed as having acute‐on‐chronic liver failure (ACLF) when a deterioration of liver function (“serum bilirubin level of 5.0 mg/dl or more” and “prothrombin time value of 40% or less of the standardized values and/or international normalization rates of 1.5 or more”) caused by severe liver damage develops within 28 days after an acute insult, including alcohol abuse, bacterial infection, gastrointestinal bleeding, and the exacerbation of underlying liver diseases. Disease severity can be classified into 4 grades depending on the extent of the deterioration in organ functions, including liver, kidney, cerebral, blood coagulation, circulatory and respiratory functions. The Study Group has since performed an annual nationwide survey of patients with ACLF diagnosed according to the proposed diagnostic criteria as well as those with disease conditions related to ACLF. A total of 501 patients, including 183 patients diagnosed as having ACLF, seen between 2017 and 2019 were enrolled, and univariate and multivariate analyses revealed that the proposed diagnostic criteria were useful for identifying cirrhotic patients with an unfavorable outcome following an acute insult. Consequently, the Study Group determined that the proposed diagnostic criteria should be used in both clinical practice and clinical research as formal diagnostic criteria.
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