Brief intervention for chronic liver disease patients with alcohol use disorder in a hepatology outpatient unit: Effects and limitations.

AIM: It is not uncommon to encounter outpatients in the hepatology department with harmful alcohol habits. When treating such chronic liver disease (CLD) patients, an adequate intervention method for harm reduction of alcohol use, such as brief intervention (BI) or BI and nalmefene, should be considered. This study aimed to elucidate the clinical effectiveness of BI for CLD patients affected by harmful alcohol use. METHODS: From June 2021 to 2023, 123 Japanese CLD outpatients (hepatitis B virus : hepatitis C virus : alcoholic liver disease : others = 32:18:42:31) with an Alcohol Use Disorders Identification Test (AUDIT) score of ≥8 at the initial interview and a repeat interview with AUDIT 9 months later were enrolled. Clinical features related to patient behavior following the initial AUDIT interview were retrospectively evaluated, and compared between patients without and with BI treatment. RESULTS: For the non-BI and BI groups, baseline AUDIT score (median 10 [interquartile range (IQR) 9-13] vs. 12 [IQR 10-17], p = 0.016) and relative change in AUDIT score (median 0 [IQR -3 to 2] vs. -3 [IQR -7 to 0], p < 0.01) showed significant differences, whereas there was no significant difference between the groups for AUDIT score at the time of the second interview (p = 0.156). Following BI, significant improvements were observed for items 1, 2, 3, 4, 5, 8, and 10 of AUDIT (each p < 0.05). CONCLUSION: Patients with an alcohol use disorder as well as those with alcohol dependency who received BI showed a significant decline in AUDIT score, although the score of the follow-up AUDIT indicated continued alcohol use disorder. In addition to BI, medication with nalmefene should be considered, based on individual factors.

Nupr1 deficiency downregulates HtrA1, enhances SMAD1 signaling, and suppresses age-related bone loss in male mice.

Nuclear protein 1 (NUPR1) is a stress-induced protein activated by various stresses, such as inflammation and oxidative stress. We previously reported that Nupr1 deficiency increased bone volume by enhancing bone formation in 11-week-old mice. Analysis of differentially expressed genes between wild-type (WT) and Nupr1-knockout (Nupr1-KO) osteocytes revealed that high temperature requirement A 1 (HTRA1), a serine protease implicated in osteogenesis and transforming growth factor-ß signaling was markedly downregulated in Nupr1-KO osteocytes. Nupr1 deficiency also markedly reduced HtrA1 expression, but enhanced SMAD1 signaling in in vitro-cultured primary osteoblasts. In contrast, Nupr1 overexpression enhanced HtrA1 expression in osteoblasts, suggesting that Nupr1 regulates HtrA1 expression, thereby suppressing osteoblastogenesis. Since HtrA1 is also involved in cellular senescence and age-related diseases, we analyzed aging-related bone loss in Nupr1-KO mice. Significant spine trabecular bone loss was noted in WT male and female mice during 6-19 months of age, whereas aging-related trabecular bone loss was attenuated, especially in Nupr1-KO male mice. Moreover, cellular senescence-related markers were upregulated in the osteocytes of 6-19-month-old WT male mice but markedly downregulated in the osteocytes of 19-month-old Nupr1-KO male mice. Oxidative stress-induced cellular senescence stimulated Nupr1 and HtrA1 expression in in vitro-cultured primary osteoblasts, and Nupr1 overexpression enhanced p16ink4a expression in osteoblasts. Finally, NUPR1 expression in osteocytes isolated from the bones of patients with osteoarthritis was correlated with age. Collectively, these results indicate that Nupr1 regulates HtrA1-mediated osteoblast differentiation and senescence. Our findings unveil a novel Nupr1/HtrA1 axis, which may play pivotal roles in bone formation and age-related bone loss.

Skeletal muscle atrophy is exacerbated by steatotic and fibrotic liver-derived TNF-α in senescence-accelerated mice.

BACKGROUND AND AIM: Although liver diseases, including non-alcoholic steatohepatitis, are associated with skeletal muscle atrophy, the mechanism behind their association has not been fully elucidated. In this study, the effects of aging and non-alcoholic steatohepatitis on the skeletal muscle, and the interaction between the liver and muscle were investigated using a diet-induced non-alcoholic steatohepatitis model in senescence-accelerated mice. METHODS: A total of four groups of senescence-accelerated mice and the control mice were fed either a non-alcoholic steatohepatitis-inducing or control diet, and their livers and skeletal muscles were removed for examinations. RESULTS: In the senescence-accelerated/non-alcoholic steatohepatitis group, serum level of alanine aminotransferase was markedly elevated and histopathology of non-alcoholic steatohepatitis was significant. Skeletal muscles were also markedly atrophied. The expression of the ubiquitin ligase Murf1 in the muscle was significantly increased with muscle atrophy, while that of Tnfa was not significantly different. In contrast, the hepatic Tnfa expression and serum TNF-α levels were significantly increased in the senescence-accelerated/non-alcoholic steatohepatitis group. These results suggest that liver-derived TNF-α might promote muscle atrophy associated with steatohepatitis and aging through Murf-1. The metabolomic analysis of skeletal muscle indicated higher spermidine and lower tryptophan levels in the steatohepatitis-diet group. CONCLUSIONS: The findings of this study revealed an aspect of liver-muscle interaction, which might be important in developing treatments for sarcopenia associated with liver diseases.

Leukemia/lymphoma-related factor (LRF) or osteoclast zinc finger protein (OCZF) overexpression promotes osteoclast survival by increasing Bcl-xl mRNA: A novel regulatory mechanism mediated by the RNA binding protein SAM68.

RANKL induces NFATc1, a key transcriptional factor to induce osteoclast-specific genes such as cathepsin K, whereas transcriptional control of osteoclast survival is not fully understood. Leukemia/lymphoma-related factor (LRF) in mouse and osteoclast zinc finger protein (OCZF) in rat are zinc finger and BTB domain-containing protein (zBTB) family of transcriptional regulators, and are critical regulators of hematopoiesis. We have previously shown that differentiation and survival were enhanced in osteoclasts from OCZF-Transgenic (Tg) mice. In the present study, we show a possible mechanism of osteoclast survival regulated by LRF/OCZF and the role of OCZF overexpression in pathological bone loss. In the in vitro cultures, LRF was highly colocalized with NFATc1 in cells of early stage in osteoclastogenesis, but only LRF expression persisted after differentiation into mature osteoclasts. LRF expression was further enhanced in resorbing osteoclasts formed on dentin slices. Osteoclast survival inhibitor such as alendronate, a bisphosphonate reduced LRF expression. Micro CT evaluation revealed that femurs of OCZF-Tg mice showed significantly lower bone volume compared to that of WT mice. Furthermore, OCZF overexpression markedly promoted bone loss in ovariectomy-induced osteolytic mouse model. The expression of anti-apoptotic Bcl-xl mRNA, which is formed by alternative splicing, was enhanced in the cultures in which osteoclasts are formed from OCZF-Tg mice. In contrast, the expression of pro-apoptotic Bcl-xs mRNA was lost in the culture derived from OCZF-Tg mice. We found that the expression levels of RNA binding splicing regulator, Src substrate associated in mitosis of 68 kDa (Sam68) protein were markedly decreased in OCZF-Tg mice-derived osteoclasts. In addition, shRNA-mediated knockdown of Sam68 expression increased the expression of Bcl-xl mRNA, suggesting that SAM68 regulates the expression of Bcl-xl. These results indicate that OCZF overexpression reduces protein levels of Sam68, thereby promotes osteoclast survival, and suggest that LRF/OCZF is a promising target for regulating pathological bone loss.

Impact of Controlling nutritional status (CONUT) in patients with unresectable advanced pancreatic cancer receiving multi-agent chemotherapy: A single center, retrospective cohort study.

Controlling nutritional status (CONUT) calculated using the serum albumin concentration, total lymphocyte count, and total cholesterol, was developed as a screening tool for the early detection of undernutrition. In addition, CONUT has been reported to be a prognostic predictor of various malignancies. AIM: To investigate the impact of CONUT in patients with advanced pancreatic cancer (APC). METHODS: Between June 2014 and October 2020, 110 consecutive patients with APC who received multi-agent chemotherapy were retrospectively reviewed. Patients were classified into four categories (normal, 1; light, 2; moderate, 3; severe, 4) based on CONUT. Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Thirty-nine (35.4%), 63 (57.2%), and 8 (7.2%) patients had CONUT 1, 2, and 3, respectively, but no patients for CONUT 4. The baseline characteristics did not differ significantly between CONUT classifications. In the multivariate analyses, the presence of metastasis (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.22-3.52), CONUT 2 (HR, 2.15; 95% CI, 1.32-3.54), and CONUT 3 (HR, 9.18; 95% CI, 2.67-23.50) were independent risk factors for PFS. The presence of metastasis (HR, 1.76; 95% CI, 1.04-3.07), CONUT 2 (HR, 1.92; 95% CI, 1.16-3.24), and CONUT 3 (HR, 10.71; 95% CI, 3.87-27.63) were also independent risk factors for OS. A median OS in CONUT 1, 2, and 3 were 20, 14.5, and 3.5 months (CONUT 1 vs. CONUT 2, p = 0.02; CONUT 1 vs. CONUT 3, p < 0.01; CONUT 2 vs. CONUT 3, p < 0.01), respectively. CONCLUSION: CONUT could be a predictor of prognosis for survival in patients with APC.

IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2.

Staphylococcus aureus is a main pathogen of osteomyelitis and protein A is a virulence factor with high affinity for IgG. In this study, we investigated whether S. aureus affects the differentiation and bone resorption of osteoclasts through the IgG-binding capacity of protein A. Staphylococcus aureus pre-treated with serum or IgG showed marked enhancement in osteoclastogenesis and bone resorption compared to non-treated S. aureus or a protein A-deficient mutant. Blocking of the Fc receptor and deletion of the Fcγ receptor gene in osteoclast precursor cells showed that enhanced osteoclastogenesis stimulated by S. aureus IgG immune complexes (ICs) was mediated by the Fc receptor on osteoclast precursor cells. In addition, osteoclastogenesis stimulated by S. aureus ICs but not the protein A-deficient mutant was markedly reduced in osteoclast precursor cells of Myd88-knockout mice. Moreover, NFATc1, Syk and NF-κB signals were necessary for osteoclastogenesis stimulated by S. aureus ICs. The results suggest the contribution of a of Toll-like receptor 2 (TLR2)-Myd88 signal to the activity of S. aureus ICs. We further examined the expression of pro-inflammatory cytokines that is known to be enhanced by FcγR-TLR cross-talk. Osteoclasts induced by S. aureus ICs showed higher expression of TNF-α and IL-1ß, and marked stimulation of proton secretion of osteoclasts activated by pro-inflammatory cytokines. Finally, injection of S. aureus, but not the protein A-deficient mutant, exacerbated bone loss in implantation and intra-peritoneal administration mouse models. Our results provide a novel mechanistic aspect of bone loss induced by S. aureus in which ICs and both Fc receptors and TLR pathways are involved.

The impact of sarcopenia and decrease in skeletal muscle mass in patients with advanced pancreatic cancer during FOLFIRINOX therapy.

Sarcopenia, defined as decrease in skeletal muscle mass (SMM) and strength, might be associated with reduced survival. We investigated the impact of sarcopenia and decrease in SMM in patients with advanced pancreatic cancer during FOLFIRINOX (FX) therapy. Consecutive sixty-nine patients who received FX were evaluated. Skeletal muscle index (SMI) (cm2/m2) was used to evaluate SMM. The cut-off value of sarcopenia was defined as SMI <42 for males and <38 for females, based on the Asian Working Group for sarcopenia criteria. Sarcopenia was diagnosed in thirty-three (48 %) subjects. Comparison of baseline characteristics of the two groups (sarcopenia group: non-sarcopenia group) showed a significant difference in sex, tumour size and BMI. There was no significant difference in the incidence of adverse events with grades 3-5 and progression-free survival (PFS) during FX between the two groups (PFS 8·1 and 8·8 months; P = 0·88). On the multivariate analysis, progressive disease at the first follow-up computed tomography (hazard ratio (HR) 3·87, 95 % CI 1·53, 9·67), decreased SMI ≥ 7·9 % in 2 months (HR 4·02, 95 % CI 1·87, 8·97) and carcinoembryonic antigen ≥ 4·6 (HR 2·52, 95 % CI 1·10, 6·11) were significant risk factors associated with poor overall survival (OS), but sarcopenia at diagnosis was not. OS in patients with decreased SMI of ≥7·9 % and <7·9 % were 10·9 and 21·0 months (P < 0·01), respectively. In conclusion, decrease in SMM within 2 months after the initiation of chemotherapy had significantly shorter OS, although sarcopenia at diagnosis did not affect OS. Therefore, it might be important to maintain SMM during chemotherapy for a better prognosis.

Skeletal Muscle Depletion: A Risk Factor for Pneumonia following Gastric Endoscopic Submucosal Dissection in Elderly Patients.

INTRODUCTION: Endoscopic submucosal dissection (ESD) is an effective treatment for gastric neoplasms in elderly patients; however, it involves several adverse events, including pneumonia. This study aimed to investigate whether skeletal muscle depletion (SMD) was associated with the development of pneumonia in elderly patients who underwent gastric ESD. METHODS: This retrospective observational cohort study included 157 patients (≥80 years) who had undergone gastric ESD. The skeletal muscle cross-sectional area was measured by CT, and the value of the third lumbar vertebra skeletal muscle index (L3 SMI) was evaluated. The SMD was defined as an L3 SMI value ≤38.0 cm2/m2 for women and ≤42.0 cm2/m2 for men. Pneumonia was also diagnosed using CT to identify all included patients. RESULTS: Among 157 patients, 66 (42.0%) showed SMD. In the SMD group, the incidence of pneumonia was 21.2%, whereas it was 7.7% in the non-SMD group (p = 0.018). The longest hospitalization duration was 19 days. Antibiotics were administered in 61.9% of the patients. Procedure time was not significantly different between the groups (72 ± 54 min vs. 62 ± 44 min, p = 0.201). On multivariate analysis, SMD was an independent risk factor for the development of pneumonia (odds ratio = 3.16, 95% confidence interval, 1.18-8.50, p = 0.023). CONCLUSIONS: SMD was not a rare entity in patients aged ≥80 years with gastric neoplasms. SMD was a significant risk factor for pneumonia related to gastric ESD in elderly patients.

Reduced handgrip strength predicts poorer survival in chronic liver diseases: A large multicenter study in Japan.

AIM: Sarcopenia has a high prevalence and can be an adverse predictor in patients with chronic liver diseases (CLDs). We sought to assess the prevalence of sarcopenia and its prognostic significance in patients with CLDs at multiple centers in Japan. METHODS: In this retrospective study, we collated the data of 1624 patients with CLDs (976 men). The diagnosis of sarcopenia was determined by the sarcopenia assessment criteria of the Japan Society of Hepatology. Predictors of mortality were identified using univariate and multivariate analyses. RESULTS: Muscle weakness and skeletal muscle loss occurred in 33.5% and 29.3% of all subjects, respectively, while sarcopenia occurred in 13.9% of all patients. Patients with sarcopenia had a poorer prognosis among all patients, patients with hepatocellular carcinoma (HCC), and those without HCC by log-rank test. The multivariate Cox proportional hazards model identified female gender (hazard ratio [HR], 0.59; p = 0.03), alcoholic liver disease (HR, 4.25; p < 0.01), presence of HCC (HR, 6.77; p < 0.01), Child-Pugh classes A (HR, 1.42; p < 0.05), B (HR, 2.70; p < 0.01), and C (HR, 6.30; p < 0.01), and muscle weakness (HR, 2.24; p < 0.01) as significant adverse predictors. The cut-off values of handgrip strength (HGS) for prognosis determined by maximally selected rank statistics were calculated as 27.8 kg for men and 18.8 kg for women. CONCLUSION: Reduced HGS in patients with CLD was an independent adverse predictor of mortality, with cut-off values of 27.8 kg for men and 18.8 kg for women.

Zinc deficiency predicts overt hepatic encephalopathy and mortality in liver cirrhosis patients with minimal hepatic encephalopathy.

AIM: Minimal hepatic encephalopathy (MHE) is associated with poor outcomes and the development of overt hepatic encephalopathy (OHE) in patients with liver cirrhosis (LC). Zinc plays a key role in the detoxification of ammonia, a risk factor of hepatic encephalopathy. This study aimed to investigate whether zinc deficiency predicts OHE occurrence and mortality in LC patients with MHE. METHOD: This retrospective study included 100 LC patients with MHE. MHE was diagnosed using a computer-aided neuropsychiatric test. Predictors associated with the development of OHE were analyzed using the Fine-Gray competing risk regression model. Cox proportional hazards regression analysis was carried out to evaluate the risk factors of mortality. Survival rates were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Of the 100 LC patients with MHE, 41% had zinc deficiency (<60 µg/dl). Zinc deficiency was observed more frequently in the patients with reduced liver function reserve. During the median follow-up period of 9.9 months, 16% of the patients with MHE developed OHE. The patients with zinc deficiency had a higher risk of OHE than those without zinc deficiency (p = 0.03). Zinc deficiency was also associated with poor survival (p = 0.004). Multivariate analyses showed that zinc predicts the development of OHE (subdistribution hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.92-0.99; p = 0.008) and mortality (HR, 0.96; 95% CI, 0.93-0.99; p = 0.02), independently of liver function reserves. CONCLUSION: Zinc deficiency is likely to be a predictor of both OHE development and mortality in LC patients with MHE.

Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption.

Osteoclasts derived from hematopoietic cells are activated on bone surface. To resorb bone, osteoclasts release acid and lysosome acid hydrolase via membrane transport. Prostate transmembrane protein androgen induced 1 (Pmepa1) is a type I transmembrane protein that regulates proliferation, migration, and metastasis of cancer cells. Because recent reports showed that Pmepa1 is involved in membrane transport in cancer cells, we investigated the role of Pmepa1 in osteoclast function. Pmepa1 expression was barely detected in osteoclasts formed on plastic surfaces in vitro, but was markedly increased in activated osteoclasts formed on calcified matrix. Inhibitors of bone resorption, such as alendronate, bafilomycin A1, and the PI3K inhibitor LY294002, suppressed the expression of Pmepa1 in osteoclasts. Knockdown of Pmepa1 expression impaired bone resorption activity and inhibited formation of a ring-like, actin-rich podosome belt that is essential for osteoclast function. Pmepa1 protein localized to lysosomes in osteoclasts. In addition, in sites of bone destruction observed in rats with adjuvant-induced arthritis, a marked high level of Pmepa1 expression was associated with the osteoclasts' resorbing bone. Our results suggest that Pmepa1 is a critical regulator of bone resorption and is a promising marker for activated osteoclasts and a potential therapeutic target in pathologic bone destruction.-Xu, X., Hirata, H., Shiraki, M., Kamohara, A., Nishioka, K., Miyamoto, H., Kukita, T., Kukita, A. Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption.

Deficiency of stress-associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts.

Nuclear protein 1 (NUPR1) is a multifunctional stress-induced protein involved in regulating tumorigenesis, apoptosis, and autophagy. Bone homeostasis is maintained by bone-resorbing osteoclasts and bone-forming osteoblasts and osteocytes. We aimed to determine the role of NUPR1 in bone metabolism. Using microcomputed tomography, we found that mice lacking Nupr1 exhibited increased bone volume. Histologic analysis showed that Nupr1 deficiency decreased osteoclast numbers but increased osteoblast numbers and osteoid formation. In vitro culture of bone marrow macrophages showed that receptor activator of NF-κB ligand-induced osteoclastogenesis was down-regulated in Nupr1-deficient mice. In contrast, primary osteoblasts from Nupr1-deficient mice revealed that proliferation of osteoblasts and expression of bone matrix proteins were markedly enhanced. In addition, expression of autophagy-related genes, formation of autophagosomes, and cell survival were up-regulated in Nupr1-deficient osteoblasts. In contract, deletion of Nupr1 reduced the formation of osteocyte cellular projection, which is an indicator of mature osteocytes. Importantly, we found that the expression of sclerostin (Sost), an inhibitor of bone formation, was down-regulated in the osteoblasts and osteocytes of Nupr1-deficient mice. Conversely, Nupr1 overexpression enhanced Sost expression in primary osteoblasts. Collectively, these results indicate that Nupr1 deficiency increases bone volume by attenuating production of Sost and osteoclastogenesis and enhancing differentiation of osteoblasts.-Shiraki, M., Xu, X., Iovanna, J. L., Kukita, T., Hirata, H., Kamohara, A., Kubota, Y., Miyamoto, H., Mawatari, M., Kukita, A. Deficiency of stress-associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts.

Prognostic impact of skeletal muscle assessed by computed tomography in patients with acute myeloid leukemia.

Skeletal muscle atrophy and loss of adipose tissue, referred to as sarcopenia and adipopenia, respectively, are often observed in cancer patients. We investigated the impact of sarcopenia and adipopenia on clinical outcomes in 90 adult patients with newly diagnosed acute myeloid leukemia (AML) who received induction chemotherapy. Computed tomography (CT) before treatment revealed sarcopenia in 39 patients (43%) and adipopenia in 35 patients (39%). We analyzed the treatment efficacy of induction chemotherapy and survival outcomes. Three-year overall survival (OS) was 35% in the sarcopenic group and 67% in the non-sarcopenic group (P < 0.001). Three-year OS was 33% in the adipopenic group and 67% in the non-adipopenic group (P < 0.005). Multivariate analysis showed an association between sarcopenia and lower OS (hazard ratio, 2.27; 95% confidence interval, 1.11-4.79; P < 0.05), with other prognostic factors of performance status > 2 (P < 0.05) and adverse cytogenetic risk (P < 0.05). In elderly patients over 60 years old, 3-year OS was 0% for the sarcopenic group and 49% for the non-sarcopenic group (P < 0.0005). These results indicate the prognostic values of sarcopenia in adult patients with AML.

Reduced handgrip strength is predictive of poor survival among patients with liver cirrhosis: A sex-stratified analysis.

AIM: Handgrip strength (HGS) is a marker of sarcopenia and has been used to stratify an individual's risk of death. We aimed to assess the prognostic significance of HGS in patients with liver cirrhosis. METHODS: In this retrospective study, we collated data of 563 consecutive patients admitted to our hospital with cirrhosis (375 men). A dynamometer was used to measure HGS. Body composition (including skeletal muscle and adipose tissue volumes) was estimated using computed tomography. Predictors of mortality were identified using sex-stratified multivariate analyses. RESULTS: After adjustments for age, cirrhosis etiology, Child-Pugh score, and other confounding variables, HGS, but not body composition, was independently associated with mortality in male patients (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94-0.99; P < 0.01) and female patients (HR, 0.91; 95% CI, 0.84-0.99; P = 0.02). Men with low HGS (<30 kg) had a higher risk of mortality (HR, 2.09; 95% CI, 1.39-3.17; P < 0.001), as did women with low (<15 kg) HGS (HR, 2.14; 95% CI, 1.16-4.01; P = 0.02). We could stratify the sex-specific risk of mortality in cirrhotic patients using HGS, regardless of coexistent hepatocellular carcinoma and the Child-Pugh class. CONCLUSIONS: Reduced HGS, rather than skeletal muscle and adipose tissue volumes, is associated with an increased risk of mortality in patients of both sexes with liver cirrhosis. Measurement of HGS is a simple, cost-effective, and appropriate bedside assessment for the prediction of survival in patients with cirrhosis.

Effect of loop diuretics on skeletal muscle depletion in patients with liver cirrhosis.

AIM: Sarcopenia, the loss of skeletal muscle mass, impairs prognosis of patients with liver cirrhosis. The aim of this study was to investigate the effect of loop diuretics, which are frequently used to treat hepatic edema/ascites, on skeletal muscle depletion and the prognosis in patients with liver cirrhosis. METHODS: This retrospective study evaluated 226 patients with liver cirrhosis. The skeletal muscle cross-sectional area at the level of the third lumbar vertebra was measured using computed tomography. The relative change in skeletal muscle area per year (ΔSMA) was calculated, and the association between ΔSMA and therapeutic dosage of loop diuretics was examined. RESULTS: The therapeutic dosage of loop diuretics was inversely correlated with ΔSMA by simple (r = -0.27, P < 0.0001) and multiple regression analyses (t = -3.07, P = 0.002). During a median follow-up period of 49 months, 82 patients died. Overall survival rates were lower in patients treated with loop diuretics at >20 mg than in those who received ≤20 mg (median, 66 vs. 97 months; P = 0.002). Multivariate analysis revealed that loop diuretics of >20 mg (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.03-3.24; P = 0.039) and ΔSMA of ≤-3.1% (HR, 3.87; 95% CI, 2.32-6.60; P < 0.0001) were independently associated with mortality. CONCLUSIONS: A higher dose of loop diuretic use was associated with more rapid skeletal muscle depletion and poor survival in patients with liver cirrhosis, independent of the severity of liver disease.

Hypozincemia is associated with human hepatocarcinogenesis in hepatitis C virus-related liver cirrhosis.

AIM: Hypozincemia is associated with the progression of chronic liver diseases, but it is unknown whether hypozincemia promotes human hepatocarcinogenesis. Our aim is to evaluate the serum zinc levels in liver cirrhosis (LC) patients and clarify the relationship between the serum zinc levels and the development of hepatocellular carcinoma (HCC). METHODS: Cirrhotic patients without HCC (n = 299) were enrolled from 14 medical institutes in Japan as a multicenter prospective study (No. 2028). Of the 299 patients, 157 were included in the present study based on reliable and consistent serum zinc levels and no history of oral zinc supplementation. Clinical parameters associated with the development of HCC were determined. Furthermore, the cumulative incidence of HCC was analyzed using Kaplan-Meier methods and was calculated using the log-rank test. A Cox regression analysis was utilized for the multivariate analysis to evaluate the predictors of hepatocarcinogenesis. RESULTS: Thirty of 157 patients (19.1%) developed HCC during an observation period of 3 years. Serum zinc levels were significantly decreased in hepatitis C virus-related LC (C-LC) patients with HCC (0.0180). The risk factors for incidence of HCC were hypozincemia (0.0014), high α-fetoprotein (0.0080), low branched chain amino acids-to-tyrosine ratio (0.0128), or female sex (0.0228). Hypozincemia (hazard ratio 1.61, 0.0324) was the only significant predictor of hepatocarcinogenesis by multivariate Cox regression analysis. CONCLUSIONS: Hypozincemia is associated with hepatocarcinogenesis in C-LC patients.

Prognostic significance of minimal hepatic encephalopathy in patients with liver cirrhosis in Japan: A propensity score-matching analysis.

BACKGROUND AND AIM: Minimal hepatic encephalopathy (MHE) represents the mildest form of the hepatic encephalopathy spectrum. This study aimed to clarify the prognostic significance of MHE in cirrhotic patients. METHODS: This retrospective study evaluated 357 consecutive patients with liver cirrhosis. MHE was diagnosed using a neuropsychiatric test. A propensity score-matching analysis was employed to adjust significant differences in the baseline characteristics between patients with and without MHE. RESULTS: Of 269 eligible patients, 56 patients (21%) were diagnosed as having MHE. The Child-Pugh score, model for end-stage liver disease score, and serum ammonia levels were significantly increased, while serum albumin levels were reduced in patients with MHE. By contrast, no significant difference was found between the two groups in matched patients. During the median follow-up period of 13.4 months, 67 patients (24.9%) died. Overall survival rates were significantly lower in patients with MHE (median, 25.4 vs 48.8 months; P < 0.001). Multivariate analysis revealed that male sex (hazard ratio [HR], 1.78; 95% confidence interval [CI], 1.03-3.18; P = 0.038), stage III/IV hepatocellular carcinoma (HR, 6.32; 95% CI, 3.30-12.79; P < 0.001), the Child-Pugh score (HR, 1.35; 95% CI, 1.12-1.62; P = 0.002), and MHE (HR, 1.92; 95% CI, 1.09-3.29; P = 0.024) were independently associated with mortality in all patients as well as in matched patients. CONCLUSION: Minimal hepatic encephalopathy is associated with an increased risk of mortality in patients with liver cirrhosis, independent of hepatocellular carcinoma stage or Child-Pugh score.

Homeostatic Model Assessment of Insulin Resistance for Predicting the Recurrence of Hepatocellular Carcinoma after Curative Treatment.

Diabetes mellitus (DM) is a risk factor for hepatocellular carcinoma (HCC). The purpose of this study was to investigate the impact of the disorder of glucose metabolism on the recurrence of HCC after curative treatment. Two hundred and eleven patients with HCC who received curative treatment in our hospital from 2006 to 2017 were enrolled in this study. Recurrence-free survival was estimated using the Kaplan⁻Meier method, and the differences between the groups partitioned by the presence or absence of DM and the values of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), fasting immunoreactive insulin (FIRI), and homeostasis model assessment-insulin resistance (HOMA-IR) were evaluated using the log-rank test. There were no significant differences in the recurrence-free survival rate between the patients with and without DM (p = 0.144), higher and lower levels of HbA1c (≥6.5 and <6.5%, respectively; p = 0.509), FPG (≥126 and <126 mg/dL, respectively; p = 0.143), and FIRI (≥10 and <10 µU/mL, respectively; p = 0.248). However, the higher HOMA-IR group (≥2.3) had HCC recurrence significantly earlier than the lower HOMA-IR group (<2.3, p = 0.013). Moreover, there was a significant difference between the higher and lower HOMA-IR groups without DM (p = 0.009), and there was no significant difference between those groups with DM (p = 0.759). A higher HOMA-IR level, particularly in non-diabetic patients, was a significant predictor for HCC recurrence after curative treatment.

Relationship of muscle cramps to quality of life and sleep disturbance in patients with chronic liver diseases: A nationwide study.

BACKGROUND & AIMS: Although muscle cramps frequently occur in patients with cirrhosis, the importance of muscle cramps remains unclear. The aims of this study were to investigate the relationship of muscle cramps with quality of life (QOL) and sleep disturbance. In addition, this multi-institutional collaborative study in Japan investigated factors associated with muscle cramps in patients with cirrhosis. METHODS: A total of 1788 patients with chronic liver diseases including both non-cirrhosis and cirrhosis completed a questionnaire survey investigating: (i) frequency of muscle cramps, (ii) relationship of muscle cramps to poor QOL and sleep disturbance, (iii) characteristics of patients who require therapeutic intervention and (iv) characteristics of patients prone to experiencing muscle cramps. RESULTS: This study revealed that 51.8% of patients with cirrhosis have experienced muscle cramps. People who experienced muscle cramps were more likely to have reduced QOL and sleep disturbance if muscle cramps had (i) high frequency (occurring daily to a few times per week, P < .01); (ii) long duration (between a few minutes and a few hours, P < .01) and (iii) intense severity (visual analogue scale ≥4, P < .01). Age, female sex, positive results for hepatitis C virus, low serum albumin concentration, and cirrhosis were independent factors related to the severity of muscle cramps. CONCLUSION: Muscle cramps occurred with great frequency and were associated with various factors such as age, sex, hepatitis C virus and liver function. Many patients experience poor QOL (26.3%) due to muscle cramps, and therapeutic interventions are therefore needed.

Carnitine dynamics and their effects on hyperammonemia in cirrhotic Japanese patients.

AIM: Supplementation with levocarnitine preparations has been reported to improve hepatic encephalopathy, but no detailed investigations have addressed the dynamics of carnitine or its supplementation indication in cirrhosis patients. We studied carnitine dynamics in cirrhotic patients by measuring serum and liver tissue carnitine levels and tested the effects of levocarnitine supplementation on concurrent hyperammonemia. METHODS: In a pilot cohort of seven patients with liver cirrhosis and five patients without cirrhosis, the serum and liver carnitine concentrations were measured. Then the serum carnitine fractions were analyzed in 70 liver cirrhosis patients. Among them, a levocarnitine preparation (1800 mg/day) was supplemented orally for 3 months in 27 patients with refractory hyperammonemia, and the effects were evaluated. RESULTS: A significant correlation was observed between serum and liver tissue carnitine concentrations (r = 0.69, P < 0.05). The serum total carnitine concentration was 68.4 ± 4.7 µmol/L, the free carnitine concentration was 53.2 ± 2.6 µmol/L, and the acylcarnitine concentration was 13.2 ± 1.1 µmol/L in 70 cirrhotic patients (reference values are 45-91, 36-74, 6-23 µmol/L, respectively). There was no correlation between blood ammonia and serum carnitine concentrations. The serum carnitine concentration rose with levocarnitine supplementation, reaching steady state after 1 month and, in parallel, refractory hyperammonemia was significantly improved. The cut-off level for a 20% decrease in blood ammonia was identified as 62.0 µmol/L total carnitine concentration by receiver-operating characteristic curve analysis, with an area under the curve of 0.69. CONCLUSION: Serum carnitine concentrations were within standard levels in the majority of liver cirrhosis patients. In patients with concurrent hyperammonemia, the levocarnitine supplementation reduced blood ammonia levels.