Non-liver-related mortality in the DAA era: Insights from post-SVR patients with and without previous HCC history.

BACKGROUND AND AIMS: Mortality after sustained virological response (SVR) with interferon-free direct-acting antiviral (IFN-free DAA) therapy is crucial for optimizing post-SVR patient care, but it remains unclear, especially regarding non-liver-related mortality. METHODS: Consecutive post-SVR patients from 14 institutions were stratified into three cohorts: A (without advanced fibrosis and without prior HCC), B (with advanced fibrosis and without prior HCC), and C (curative HCC treatment). We assessed mortality (per 1000 person-years [/1000PY]) post-SVR. Mortality rates were compared between cohorts A and B and the general population using age- and sex-adjusted standardized mortality ratio (SMR). Comparison of survival between each cohort was performed using propensity-score (PS) matching with sex, age, and comorbidity. RESULTS: In cohort A (n = 762; median age, 65 years), 22 patients died (median follow-up, 36 months); all-cause mortality was 10.0/1000PY, with 86.4% non-liver-related deaths. In cohort B (n = 519; median age, 73 years), 27 patients died (median follow-up, 39 months); all-cause mortality was 16.7/1000PY, with 88.9% non-liver-related deaths. In both cohorts, malignant neoplasm was the most common cause of death; all-cause mortality was comparable to that of the general population (SMR: 0.96 and 0.92). In cohort C (n = 108; median age, 75 years), 15 patients died (median follow-up, 51 months); all-cause mortality was 36.0/1000PY, with 53.3% liver-related deaths. PS matching showed no significant survival differences between cohorts A and B, both of which had better survival than cohort C. CONCLUSIONS: Mortality varies based on HCC history in the DAA era; nevertheless, attention should be paid to non-liver-related deaths in all post-SVR patients.

Calculated body muscle mass as a useful screening marker for low skeletal muscle mass and sarcopenia in chronic liver disease.

AIM: Sarcopenia is a harmful condition in patients with chronic liver disease. However, the evaluation of body muscle mass requires expensive instrumentation. The sarcopenia index (SI): (creatinine / cystatin C × 100) has been reported to correlate with muscle volume. A calculated body muscle mass (CBMM) using creatinine, cystatin C, and bodyweight also correlates with muscle mass. We evaluated the applicability of using SIs and CBMMs as screening methods for sarcopenia. METHODS: Patients (n = 303) with liver damage were evaluated for creatinine, cystatin C, and grip strength (GS). All patients were evaluated using cross-sectional computed tomography images of the third lumbar vertebrae to determine their skeletal muscle (SM) mass. CBMMs and SIs were compared with SMs, GSs, and sarcopenia. RESULTS: Correlation coefficients (R) between SMI (SM / height2 [m2 ]) and CBMM, and between GS and CBMM were 0.643 and 0.723, respectively. Factors contributing to low GSs; low SM indices; and sarcopenia were age and SM; sex, age, GS, SI, and CBMM indices; and sex, bodyweight, and CBMM, respectively, in the multivariate logistic analyses. Receiver operating characteristic curve analysis between sarcopenia and CBMM showed an area under the receiver operating characteristic curve of 0.78504 in women and 0.86067 in men. Cut-off CBMM values for sarcopenia were 27.903 (sensitivity 0.73958) in women and 39.731 (sensitivity 0.7941) in men. CONCLUSIONS: CBMMs and SIs are simple and minimally invasive screening methods in which low levels are indicative of sarcopenia in patients with liver disease.

PIVKA­II is associated with liver function, bone metabolism, and muscle function in patients with liver disease.

Protein induced by vitamin K (VK) absence-II (PIVKA-II) is a sensitive marker for diagnosing hepatoma but is occasionally detected in patients without hepatoma Here, the clinical significance of serum PIVKA-II levels in patients who were not administered warfarin and did not have hepatoma or liver disease were evaluated. As VK is related to muscle and bone metabolism, PIVKA-II and clinical factors related to bone and muscle were compared. A total of 441 patients with various liver diseases were evaluated. Of these, 236 patients were female. Clinical factors and anthropometric measurements were obtained for each participant during outpatient visits. Among the clinical factors, type I procollagen N-propeptide (P1NP), a low titer of undercarboxylated osteocalcin (ucOC), and 25(OH) vitamin D (VD) were used as bone metabolic markers, and SARC-F and grip strength were used as muscle-related markers. Serum PIVKA-II levels above the upper limit were associated with Child B/C (Child-Pugh score), high titers of total P1NP, and low titers of ucOC in females, and alcohol-related liver disease and low VD in males. The titer of PIVKA-II were associated with immunoglobulin (Ig) A and prothrombin time (PT)-international normalized ratio (INR) in females, and fibrosis-4-4, IgG, total bilirubin, PT-INR, and SARC-F in males. Elevated PIVKA-II levels were associated with abnormal bone physiology in females, weak muscles in males, and severe liver disease in both sexes. Assessing PIVKA-II may assist in evaluating the clinical and bone-muscle metabolic stages in liver disease. Nutrition and supplementation with fat-soluble vitamins, including VK and VD may thus serve as a potential method to alleviate or prevent bone-muscle pathophysiology in patients with liver disease.

Serum immunoglobulin A levels: Diagnostic utility in alcoholic liver disease and association with liver fibrosis in steatotic liver disease.

The relationship between immunoglobulin A (IgA) levels and chronic liver disease remains poorly understood. The present study evaluated the clinical significance of IgA in 478 new patients who visited the Outpatient Clinic of Nagasaki Harbor Medical Center (Nagasaki, Japan). Serum IgA levels in comparison to liver stiffness (LS), as measured using a FibroScan® device, were evaluated in 358 patients. Furthermore, in 270 patients, the associations between serum IgA levels and body composition were analyzed using computed tomography. The IgA levels of patients in the groups with Child-Pugh classification B and C (CPGBC), alcoholic liver disease (ALD), steatotic liver disease (SLD) or diabetes were higher than the IgA levels of patients in the groups with CPGA, non-ALD, non-SLD or no diabetes, respectively. Logistic regression analysis showed that CPGBC, ALD, high IgG (>1,700 mg/dl), high macrophage galactose-specific lectin-2 binding protein glycosylation isomer (M2BPGi) (>1 cut-off index) and diabetes were contributing factors for high serum IgA level (>410 mg/dl). The ratio of IgA level divided by IgG level was highest in patients with ALD, followed by those with metabolic dysfunction-associated SLD (MASLD) and non-SLD. In SLD, IgA level was associated more with LS than M2BPGi and fibrosis-4 (FIB-4) in multiple regression analysis. In the receiver operating characteristic analysis, IgA level, M2BPG, and FIB-4 had similar area under the curve values for discriminating high LS (>8 kPa) from low LS (≤8 kPa) in SLD. IgA levels were also associated with visceral fat, and this association was only found in women. In conclusion, elevated IgA is an indicator of liver fibrosis that also reflects the presence of diabetes and an increased visceral fat level. Therefore, IgA is considered a useful marker of liver disease severity in the current era of increased SLD.

Pemafibrate Reduced Liver Stiffness in Patients with Metabolic Dysfunction-associated Steatotic Liver Disease Complicated with Hyperlipidemia and Liver Fibrosis with a Fibrosis-4 Index Above 1.3.

Aim To evaluate the effect of pemafibrate (PEM) on metabolic dysfunction-associated steatotic liver disease (MASLD). Method We retrospectively evaluated 43 patients with hyperlipidemia and MASLD to determine changes in clinical factors between the start of PEM treatment and 0.5 years later. Using FibroScan, 39 of 43 patients were evaluated for liver stiffness (LS; kPa) and controlled attenuation parameter (CAP; dB/m). None of the patients had decompensated cirrhosis. Result Thirty patients were women, the median age was 66 years old, the median fibrosis-4 (FIB-4) score was 2.52, the median LS was 8.05 kPa, and the median CAP was 280.5 dB/m at the start of PEM treatment. AST, ALT, ALP, γGTP, and triglyceride levels decreased 0.5 years after starting PEM treatment, but FIB-4, LS, and CAP values did not decrease. However, LS decreased in patients with a FIB-4 index ≥1.3 at the start of PEM treatment, whereas it did not change in patients with a FIB-4 index <1.3. Similarly, LS decreased in patients with a value ≥8 kPa at the start of treatment and did not change in those with <8 kPa. The decreased LS group had higher baseline ALT and LS levels and lower ALT levels during 0.5 years of follow-up than the increased LS group. Conclusion At the initiation of PEM treatment, the LS decreased in patients with MASLD complicated by hyperlipidemia and moderate LS (FIB-4>1.3 or LS >8 kPa). Although there is currently no approved treatment for MASLD, PEM may be a viable treatment option for MASLD with mild LS.

Long-term Outcomes and Prognostic Factors of Stereotactic Body Radiotherapy for Hepatocellular Carcinoma.

BACKGROUND/AIM: This study was conducted to determine the prognosis and risk factors for survival in patients treated with stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This retrospective study analyzed 73 patients who underwent SBRT for HCC at Nagasaki University Hospital from December 2012 to July 2019 and examined the relationship between baseline information and prognosis. The Kaplan-Meier analysis and log-rank test were used to estimate the survival rate. Cox regression analysis was performed to determine the factors associated with overall survival (OS) after SBRT. RESULTS: The 1- and 2-year local control rates were 98.6% and 89.9%, respectively. Survival rates at 1, 3, and 5 years were 94.5%, 63.9%, and 45.5%, respectively. In the univariate analysis, baseline modified albumin-bilirubin grade (mALBI grade) [2b/3, hazard ratio (HR)=2.762, p=0.001], tumor size (≥2 cm, HR=2.479, p=0.003), and Barcelona Clinic Liver Cancer stage (BCLC) (B/C, HR=3.284, p<0.001) were significantly associated with poor prognosis. In multivariate analysis, baseline mALBI grade (2b/3, HR=2.283, p=0.009) and BCLC stage (B/C, HR=2.330, p=0.013) were significantly associated with poor prognosis. Only three patients (4.1%) developed grade 3 adverse events related to SBRT. CONCLUSION: SBRT is effective and safe in patients with HCC. The baseline mALBI grade is useful for predicting patient prognosis after SBRT. Patients with an mALBI grade of 1/2a are expected to have a better prognosis than patients with an mALBI grade of 2b/3.

Evaluating the Role of Hepatobiliary Phase of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging in Predicting Treatment Impact of Lenvatinib and Atezolizumab plus Bevacizumab on Unresectable Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab therapy has high response rates in patients with unresectable hepatocellular carcinoma (HCC). The hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) has been reported to be useful as an imaging biomarker for detecting ß-catenin mutations. We evaluated whether the pretreatment of the hepatobiliary phase of EOB-MRI could predict the therapeutic effect of lenvatinib and atezolizumab plus bevacizumab. METHODS: This study included 68 patients (lenvatinib group (n = 33) and atezolizumab plus bevacizumab group (n = 35)). The visual assessment and relative enhancement ratio (RER) of the largest HCC lesions were evaluated using the hepatobiliary phase of EOB-MRI. RESULTS: The hyperintensity type (RER ≥ 0.9) was 18.2% in the lenvatinib group and 20.0% in the atezolizumab plus bevacizumab group. In the lenvatinib group, progression-free survival (PFS) was not different between the heterogeneous and homogenous types (p = 0.688) or between the hyperintensity and hypointensity types (p = 0.757). In the atezolizumab plus bevacizumab group, the heterogeneous type had significantly shorter PFS than the homogenous type (p = 0.007), and the hyperintensity type had significantly shorter PFS than the hypointensity type (p = 0.012). CONCLUSIONS: The hepatobiliary phase of EOB-MRI was useful for predicting the therapeutic effect of atezolizumab plus bevacizumab therapy on unresectable HCC.

Change in tartrate-resistant acid phosphatase isoform 5b levels, a marker of bone metabolism, in patients with chronic hepatitis B treated with tenofovir alafenamide.

Hepatitis B virus (HBV) infection is associated with the risk of osteoporosis and bone mineral density (BMD) loss. Tenofovir alafenamide (TAF) is associated with a slightly lower degree of BMD loss compared with tenofovir disoproxil, without loss of the excellent anti-HBV effects. The aim of the present study was to verify the effect of bone metabolism in patients with HBV treated with TAF. A total of 87 patients were treated with TAF. Of these, 32 patients were treatment naïve, and 55 patients were treated with entecavir (ETV) for at least 1 year, after which ETV was switched to TAF. At the start of TAF and after 1 year, BMD in the lumbar and neck of the femur, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) levels as a marker of bone metabolism and serum inorganic phosphorus (P) were compared to estimate bone metabolism. Serum creatinine (Cr), cystatin C, urine protein and ß2 microglobulin levels were evaluated to estimate kidney function. Treatment with TAF for 1 year decreased TRACP-5b levels, particularly in patients with bone disease, except for a minimal significant change (MSC; decrease of 12.4%) in TRACP-5b levels. The change in rate of TRACP-5b levels were positively associated with changes in P, Cr-estimated glomerular filtration rate and TRACP-5b levels at the start of TAF. Logistic regression analysis showed that increased BMD in the lumbar region contributed to the switch from ETV to TAF. TAF induced a decrease in TRACP-5b levels in patients with HBV. Bone disease was a contributing factor for MSC. Since TRACP-5b can be used as a marker of bone metabolism and fractures, TAF may exhibit potential in preventing fractures in patients with HBV.

Direct­acting antiviral treatment decreases serum undercarboxylated osteocalcin in male patients with chronic hepatitis C.

Hepatic osteodystrophy (HOD) is a common complication of chronic liver disease, including viral hepatitis. Hepatitis C virus (HCV) infection is associated with an increased risk of osteoporosis and bone mineral density (BMD) loss. Direct-acting antiviral (DAA) treatment is used to treat HCV infections; however, its effects on bone metabolism have not been reported. We compared the clinical data and bone metabolic markers at the start of DAA treatment and 1 year later in 78 patients. There were 41 female and 37 male patients. HCV was successfully treated with DAA in all patients. Bone metabolic markers included undercarboxylated osteocalcin (ucOC), 25(OH) vitamin D (VD), total type I procollagen N-propeptide (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and BMD. BMD was measured in the lumbar spine (mean, L2-L4) and femoral neck using dual-energy X-ray absorptiometry. ucOC in males decreased at 1 year after treatment initiation but not in females. In males, ucOC changes were related to alterations in proteins induced by vitamin K absence-II (PIVKA-II), hemoglobin A1c, and TRACP-5b, which contributed to P1NP and lumbar BMD at the start of DAA. Changes in ucOC among women contributed to the changes in grip strength and TRACP-5b levels. DAA treatment improved ucOC, a useful bone metabolic marker, in HCV-infected male patients. Changes in ucOC contributed to changes in PIVKA-II that likely ameliorated the vitamin K deficiency. DAA treatment has been reported to improve various extrahepatic disorders and abnormal bone metabolism, especially in HOD.

Comparison of calculated body muscle mass and SARC-F as methods of screening for sarcopenia in patients with chronic liver disease.

A simple method is required to screen for sarcopenia in patients with chronic liver disease. In the present study, the value of the existing SARC-F questionnaire as well as calculated body muscle mass (CBMM) approaches were assessed for screening of sarcopenia. A total of 482 patients with chronic liver disease underwent CBMM, grip strength (GS) and SARC-F score assessments. Cross-sectional computed tomography images of the third lumbar vertebrae were analyzed to determine the skeletal muscle (SM) mass in 303 patients. Cutoff CBMM values for sarcopenia were <27.903 in females and <39.731 in males. The cutoff SARC-F score for sarcopenia was ≥4 points. Sarcopenia was diagnosed using the criteria described in the Japan Society of Hepatology. GS was moderately correlated with SARC-F score (females, R=-0.578; males, -0.453) and CBMM (females, R=0.497; males, 0.548). The SM index was moderately correlated with CBMM for both sexes (females, R=0.546; males, 0.612), but not with SARC-F score in females (females, R=-0.132; males, -0.246). The area under the curve (AUC) for CBMM against sarcopenia (0.85964) was significantly larger than that for SARC-F score (0.72013) amongst males (P=0.03577) but not females. The AUCs for a modified SARC-F questionnaire (encompassing the SARC-F questionnaire, CBMM, sex and age; mSARC-F) against sarcopenia were 0.864 in males and 0.78185 in females. As a screening method, SARC-F is less useful than CBMM. However, the AUC for mSARC-F is greater than SARC-F and CBMM.

Direct-acting Antivirals Improved the Quality of Life, Ameliorated Disease-related Symptoms, and Augmented Muscle Volume Three Years Later in Patients with Hepatitis C Virus.

Objective Patient-reported outcomes (PROs) are important measures of the quality of life (QOL) and symptoms in patients with hepatitis C virus (HCV). We evaluated the PROs at the beginning of direct-acting antiviral (DAA) treatment and three years later. A low QOL in patients with chronic liver disease suggested a low muscle mass. We compared the relationship between the QOL and muscle mass. Methods DAAs were administered to 100 patients with HCV infection. The PROs included the cirrhosis-related symptom score (CSS), presence of restless legs syndrome, Pittsburg sleep quality index (PSQI) to evaluate sleep disturbance, SF-36 to measure the QOL, and calculated body muscle mass (CBMM) measured at the beginning of treatment and three years later. Computed tomography (CT) was used to screen 82 patients for hepatocellular carcinoma at the beginning of treatment and three years later. Cross-sectional CT images of the third lumbar vertebrae were analyzed to evaluate the body composition. Results The general health perception (GHN) of SF-36 was better at three years after DAA administration than at the beginning. Changes in the GHN (dGHN) were related to an improved sleep quality on the PSQI and CSS and increased CBMM. The dGHN was positively related to changes in the skeletal muscle. The sleep quality, sleep latency, fatigue, and abdominal fullness were related to dGHN. Conclusion The QOL is related to sleep disturbance and several other symptoms. Furthermore, in patients with an increased muscle volume after DAA treatment, increased muscle mass is associated with an improvement in the QOL.

Indices calculated by serum creatinine and cystatin C as predictors of liver damage, muscle strength and sarcopenia in liver disease.

Serum creatinine (Cr)-based glomerular filtration rate (CrGFR) is overestimated in liver disease. The present study evaluated whether the difference in CrGFR and cystatin C (CysC) GFR (dGFR) is significant in liver disease. The Cr-to-CysC ratio and sarcopenia index (SI) have been reported to correlate with muscle volume. An estimated total body muscle mass with Cr, CysC and calculated body muscle mass (CBMM) has also been reported to correlate with muscle mass. The applicability of dGFR, SI and CBMM for liver disease were evaluated. A total of 313 patients with liver damage were evaluated for Child-Pugh score, albumin-bilirubin (ALBI) score, model for end-stage liver disease, fibrosis-4, Cr, CysC, Cr-based estimated GFR (CreGFR), CysCGFR and grip strength. Of the 313 patients, 199 were evaluated using cross-sectional computed tomography (CT) of the third lumbar vertebra to determine the skeletal muscle (SM) mass. dGFR, CBMM and SI were compared to liver damage, muscle strength and muscle mass. In the 313 patients, dGFR was correlated with age, ALBI and grip strength; CBMM was correlated with body mass index (BMI) and grip strength; and SI was correlated with BMI and grip strength. In patients evaluated with CT, the correlation coefficients for CBMM and SI with SM were 0.804 and 0.293, respectively. Thus, CBMM and SI were associated with sarcopenia. The relationship between dGFR and ALBI does not differ with different grades of CrGFR-based chronic kidney disease (CKD). dGFR is a marker of liver damage and muscle strength regardless of CKD. CBMM and SI are markers for sarcopenia in liver disease.

Ketone bodies as a predictor of prognosis of hepatocellular carcinoma after transcatheter arterial chemoembolization.

OBJECTIVE: Arterial ketone bodies, which reflect liver function, have been investigated. However, the relationship between venous ketone bodies and hepatocellular carcinoma (HCC) is unclear. We investigated whether prognosis of patients with HCC after transcatheter arterial chemoembolization (TACE) was associated with venous blood ketone bodies. METHODS: Sixty-eight patients with HCC who underwent TACE were recruited for this study. The venous blood ketone body levels were measured 1 d before (pretreatment) and 7 d after TACE (posttreatment). Skeletal muscle quality was evaluated using the intramuscular adipose tissue content (IMAC). RESULTS: Of the 68 patients, 43 (63.2%) were male, with median age of 73.0 y, and the IMAC was -0.274 (range -0.82 to 0.24). The median ketone body levels pre- and posttreatment were 63.0 µmol/L (13-310) and 48.0 µmol/L (8-896), respectively. The cumulative survival rate of patients with total ketone body ratio ([TKBR]: posttreatment/pretreatment total ketone bodies) <1 was 86.6%. The rate with TKBR ≥1 was 59.0% at 300 d (P < 0.05). Cox regression analysis identified the TKBR (≥1, hazard ratio: 2.954, 95% confidence interval [CI]: 1.040-8.390, P = 0.030) that independently and significantly predicted the patients' prognoses. Logistic regression analysis revealed the IMAC (>-0.2745, odds ratio: 3.958, 95% CI: 1.137-13.779, P = 0.031) that predicted TKBR. TKBR and IMAC were positively correlated (rS = 0.358, P = 0.003). CONCLUSIONS: The changes in the venous ketone body were associated with the muscle status and predicted the prognosis of patients with HCC who underwent TACE. The venous ketone bodies could be a new predictor of the prognosis of HCC patients after TACE.

Two difficulty diagnosis cases of severe veno-occlusive disease.

BACKGROUND: The occurrence of Hepatic veno-occlusive disease (VOD) is rale liver disease. However, severe VOD is often lethal and one of the most common causes of death following stem cell transplantation (SCT). CASE REPORTS: Case 1 was a 30-year-old woman who was diagnosed as Budd-Chiari syndrome with liver failure. She was admitted to our department to undergo liver transplantation. Four days after admission, she underwent liver transplantation. Her liver explant showed VOD. Case 2 was a 74-year-old woman who was admitted to a community hospital for further examination. Her condition continued to deteriorate with liver failure, and she died 39 days after admission. Liver autopsy also showed VOD. Either of the patients had difficulty in diagnose as VOD. Neither of the patients had a history of SCT. CONCLUSIONS: VOD should be considered as a cause of acute hepatic failure, even if the patient has no history of SCT.