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.
Background
Although tolvaptan is an effective treatment for hepatic edema, there are no established criteria for assessment of the therapeutic effect. The present study evaluates the association ...between body weight change and clinical symptoms to identify an effective indicator of tolvaptan response.
Methods
The study comprised 460 patients. The first data set contained 147 patients with hepatic edema who received tolvaptan in Kagoshima Kouseiren Hospital, a representative institution of this study. From these data, an optimal cutoff value of body weight change, which accurately indicated symptom reduction, was identified. The response rates obtained based on the cutoff value were evaluated by receiver-operating characteristic (ROC) analysis and kappa coefficients. The kappa coefficient was then validated internally using the bootstrap method and externally using the validation data set of 313 patients from four other hospitals.
Results
A cutoff value for body weight loss of 1.5 kg/week produced the largest area under the ROC curve (0.961; sensitivity, 89.8%; specificity, 92.0%) and a high kappa coefficient (0.831). The correlation between symptom reduction and body weight loss of 1.5 kg/week was evaluated internally and externally, and the cutoff value was validated.
Conclusions
The cutoff value of body weight change that most accurately reflected symptom reduction was 1.5 kg/week; this value is expected to be an effective indicator of response to tolvaptan in clinical practice.
Background
The significance of the 2018 Japanese diagnostic criteria for acute-on-chronic liver failure (ACLF) has not yet been evaluated.
Methods
A nationwide survey was performed for patients with ...ACLF occurring between 2017 and 2019. Cirrhotic patients with a Child–Pugh score of 5–9 were diagnosed as having ACLF when liver failure (serum bilirubin level of ≥ 5.0 mg/dL and a prothrombin time international normalization rate INR of ≥ 1.5) occurred within 28 days after an acute insult. Patients who fulfilled either criterion (total serum bilirubin or INR) and/or those with indeterminate Child–Pugh scores at baseline were also enrolled.
Results
Among the 501 enrolled patients, 183 patients (37%) were diagnosed as having ACLF. The etiologies of the cirrhosis and acute insults were alcohol intake/abuse in 114 (62%) and 75 (41%) patients, respectively. Sixty-eight patients (37%) were also diagnosed as having severe alcoholic hepatitis. The survival rate without liver transplantation was 48% among the ACLF patients and 71% in the remaining patients (
P
< 0.01). A multivariate analysis revealed that the disease condition was significantly associated with mortality, with an odds ratio of 2.025 in ACLF patients relative to the remaining patients (
P
< 0.01), and patient age and the number of organs with functional failure were also associated with mortality among the ACLF patients.
Conclusion
The proposed diagnostic criteria for ACLF were useful for identifying cirrhotic patients with an unfavorable outcome following acute insults. A therapeutic strategy for patients with severe alcoholic hepatitis should be established, since such patients accounted for the majority of ACLF patients.
Amyloidosis causes various symptoms in many organs of the body, but amyloidosis that presents with liver damage alone has never been reported. We treated an 83-year-old man with amyloidosis who ...presented with liver damage alone. The liver damage in this patient was histologically proven to be liver amyloidosis. The administration of bortezomib and dexamethasone was not effective, so he rapidly died of liver failure. An aggressive liver biopsy should be considered when unexplained jaundice is observed.
A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c‐Met inhibitor tivantinib as second‐line treatment significantly prolonged progression‐free survival in a ...subpopulation whose tumor samples highly expressed c‐Met (MET‐high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. This randomized, double‐blind, placebo‐controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET‐high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice‐a‐day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression‐free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression‐free survival was 2.8 (95% confidence interval: 2.7‐2.9) and 2.3 (1.5‐2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52‐1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1‐11.6) and 8.5 (6.2‐11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58‐1.15). The most common tivantinib‐related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. (NCT02029157).
Results of JET‐HCC.
Liver cirrhosis is a severe illness, associated with multiple complications, which can lead to liver failure. One of the major complications of cirrhosis is ascites. This review describes a stepped ...treatment approach for the management of ascites in Japanese patients with cirrhosis. It is broadly based on the 2020 update of the Japanese clinical practice guidelines for liver cirrhosis, which is briefly compared with guidelines from Europe and the United States. Step 1 is sodium restriction at a level suitable for Japanese individuals (5–7 g/day), Step 2 is albumin treatment to counteract underlying hypoalbuminemia, Step 3 is initiation of diuretic treatment with spironolactone, followed by add‐on loop diuretic treatment at Step 4. Patients that are refractory to sodium restriction and sodium diuretics can be treated with tolvaptan (Step 5) – a vasopressin V2 receptor antagonist that is available in Japan. Patients at Steps 6 and 7 have refractory ascites and are treated with large volume paracentesis in combination with an albumin infusion. High‐dose albumin infusion (6–8 g/L) at the time of large volume paracentesis has recently become possible in Japan. Cell‐free and concentrated ascites reinfusion therapy is also an option at Step 6. Two of the treatment options at Step 7 are limited in Japan (transjugular intrahepatic portosystemic shunts are not approved, and access to liver donors is very limited), but patients can undergo a peritoneovenous shunt if no other options are available. While challenges remain in the treatment of ascites, adopting this stepwise treatment approach may improve patient outcomes.
Ascites, a condition in which fluid accumulates within the spaces in an individual's abdomen, is a major complication of liver cirrhosis. Management of ascites in Japanese patients with liver cirrhosis may be optimized with a seven‐step treatment approach. Treatment approaches range from restricting sodium intake to initiating various drug agents and performing liver transplantations.
Background
Administration of diuretics and the presence of ascites in patients with cirrhosis were reported to be associated with muscle cramps; however, the clinical evidence is limited. This study ...aimed to determine whether muscle cramps are a diuretic-induced complication and whether ascites was a factor related to muscle cramp.
Methods
A total of 1064 adult patients with cirrhosis were enrolled from 10 hospitals in Japan between June 2017 and December 2018. A questionnaire regarding cramps was completed by all patients. The ratio of extracellular water (ECW) was analyzed using the bioelectrical impedance analysis. Logistic regression analysis was performed to analyze the effects of diuretic administration and the ECW ratio on cramps.
Results
Patients using diuretics had a higher incidence rate, higher frequency, stronger pain, and longer duration of cramps than those who did not. In the multivariate analysis, diuretic administration and the ECW ratio values ≥ 0.4 were not significantly associated with the presence, frequency, intensity, or duration of cramps. However, in the case of patients limited to Child–Pugh B or C, diuretic use was significantly correlated with the cramp frequency.
Conclusions
These results demonstrated that muscle cramps were not a complication of diuretic use in patients with cirrhosis; however, in those limited to Child–Pugh B or C, diuretic use was a factor that affected the frequency of cramps. Moreover, no association was found between the presence of ascites and cramps.
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.
Aim
Although some relationships between gut microbiota and liver diseases have been reported, it remains uncertain whether changes in gut microbiota owing to differences in race, food and living ...environment have similar effects. Response to ursodeoxycholic acid (UDCA) may predict the long‐term prognosis of patients with primary biliary cholangitis (PBC); however, little is known about the significance of the gut microbiome in patients with PBC. We elucidated the relationships among clinical profiles, biochemical response to UDCA and gut microbiome composition in patients with PBC.
Methods
Fecal samples from 76 patients with PBC treated at our hospital were collected; patients whose UDCA intake period was <1 year were excluded. The microbiome structures of patients were determined using 16S ribosomal RNA gene sequencing and were statistically compared with those of healthy subjects. The structures of patients in the UDCA responder (n = 43) and non‐responder (n = 30) groups were compared according to the Nara criteria (reduction rate of gamma‐glutamyl transpeptidase, ≥69%, after 1 year).
Results
Compared with healthy subjects, bacterial diversity was lower in patients with PBC, with a decreased abundance of the order Clostridiales and increased abundance of Lactobacillales. The UDCA non‐responder group had a significantly lower population of the genus Faecalibacterium, known as butyrate‐producing beneficial bacteria (P < 0.05), although no significant differences in gender, body mass index, medicated drugs or other serological data were indicated between these two groups.
Conclusions
Gut dysbiosis with loss of beneficial Clostridiales commensals was observed in patients with PBC. Decrease in Faecalibacterium abundance might predict the long‐term prognosis of patients with PBC.
Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of ...liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called “leaky gut”. Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.
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