Clinical outcomes of transarterial chemoembolization in Child-Turcotte Pugh class A patients with a single small (≤3 cm) hepatocellular carcinoma.

BACKGROUND AND AIM: Transarterial chemoembolization (TACE) is one of the standard modalities used to treat unresectable hepatocellular carcinoma (HCC), but the effectiveness of TACE for treating patients with a solitary small (≤3 cm) HCC and well-preserved liver function has not been definitively established. This study aimed to determine the therapeutic impact of TACE in patients with these characteristics. METHODS: This multicenter (four university hospitals) retrospective cohort study analyzed the medical records of 250 patients with a solitary small (≤3 cm) HCC and Child-Turcotte-Pugh (CTP) class A liver function diagnosed over 10 years. Posttreatment outcomes, including overall survival (OS), recurrence-free survival (RFS), and adverse events, were assessed following TACE therapy. RESULTS: One hundred and thirty-eight of the 250 patients (55.2%) treated with TACE achieved complete remission (CR). Overall median OS was 77.7 months, and median OS was significantly longer in the CR group than in the non-CR group (89.1 vs. 58.8 months, P = 0.001). Median RFS was 19.1 months in the CR group. Subgroup analysis identified hypertension, an elevated serum albumin level, and achieving CR as significant positive predictors of OS, whereas diabetes, hepatitis c virus infection, and tumor size (>2 cm) were poor prognostic factors of OS. CONCLUSIONS: The study demonstrates the effectiveness of TACE as a viable alternative for treating solitary small (≤3 cm) HCC in CTP class A patients.

Immune signature and therapeutic approach of natural killer cell in chronic liver disease and hepatocellular carcinoma.

Natural killer (NK) cells are one of the key members of innate immunity that predominantly reside in the liver, potentiating immune responses against viral infections or malignant tumors. It has been reported that changes in cell numbers and function of NK cells are associated with the development and progression of chronic liver diseases (CLDs) including non-alcoholic fatty liver disease, alcoholic liver disease, and chronic viral hepatitis. Also, it is known that the crosstalk between NK cells and hepatic stellate cells plays an important role in liver fibrosis and cirrhosis. In particular, the impaired functions of NK cells observed in CLDs consequently contribute to occurrence and progression of hepatocellular carcinoma (HCC). Chronic infections by hepatitis B or C viruses counteract the anti-tumor immunity of the host by producing the sheddases. Soluble major histocompatibility complex class I polypeptide-related sequence A (sMICA), released from the cell surfaces by sheddases, disrupts the interaction and affects the function of NK cells. Recently, the MICA/B-NK stimulatory receptor NK group 2 member D (NKG2D) axis has been extensively studied in HCC. HCC patients with low membrane-bound MICA or high sMICA concentration have been associated with poor prognosis. Therefore, reversing the sMICA-mediated downregulation of NKG2D has been proposed as an attractive strategy to enhance both innate and adaptive immune responses against HCC. This review aims to summarize recent studies on NK cell immune signatures and its roles in CLD and hepatocellular carcinogenesis and discusses the therapeutic approaches of MICA/B-NKG2D-based or NK cell-based immunotherapy for HCC.

Estimating postsurgical outcomes of patients with a single hepatocellular carcinoma using gadoxetic acid-enhanced MRI: risk scoring system development and validation.

OBJECTIVES: To develop and validate risk scoring systems using gadoxetic acid-enhanced liver MRI features and clinical factors that predict recurrence-free survival (RFS) of a single hepatocellular carcinoma (HCC). METHODS: Consecutive 295 patients with treatment-naïve single HCC who underwent curative surgery were retrospectively enrolled from two centers. Cox proportional hazard models developed risk scoring systems whose discriminatory powers were validated using external data and compared to the Barcelona Clinic Liver Cancer (BCLC) or American Joint Committee on Cancer (AJCC) staging systems using Harrell's C-index. RESULTS: Independent variables-tumor size (per cm; hazard ratio [HR], 1.07; 95% confidence interval [CI]: 1.02-1.13; p = 0.005), targetoid appearance (HR, 1.74; 95% CI: 1.07-2.83; p = 0.025), radiologic tumor in vein or tumor vascular invasion (HR, 2.59; 95% CI: 1.69-3.97; p < 0.001), the presence of a nonhypervascular hypointense nodule on the hepatobiliary phase (HR, 4.65; 95% CI: 3.03-7.14; p < 0.001), and pathologic macrovascular invasion (HR, 2.60; 95% CI: 1.51-4.48; p = 0.001)-with tumor markers (AFP ≥ 206 ng/mL or PIVKA-II ≥ 419 mAU/mL) derived pre- and postoperative risk scoring systems. The risk scores showed comparably good discriminatory powers in the validation set (C-index, 0.75-0.82) and outperformed the BCLC (C-index, 0.61) and AJCC staging systems (C-index, 0.58; ps < 0.05). The preoperative scoring system stratified the patients into low-, intermediate-, and high-risk for recurrence, whose 2-year recurrence rate was 3.3%, 31.8%, and 85.7%, respectively. CONCLUSION: The developed and validated pre- and postoperative risk scoring systems can estimate RFS after surgery for a single HCC. KEY POINTS: • The risk scoring systems predicted RFS better than the BCLC and AJCC staging systems (C-index, 0.75-0.82 vs. 0.58-0.61; ps < 0.05). • Five variables-tumor size, targetoid appearance, radiologic tumor in vein or vascular invasion, the presence of a nonhypervascular hypointense nodule on the hepatobiliary phase, and pathologic macrovascular invasion-combined with tumor markers derived risk scoring systems predicting postsurgical RFS for a single HCC. • In the risk scoring system using preoperatively-available factors, patients were classified into three distinct risk groups, with 2-year recurrence rates in the low-, intermediate-, and high-risk groups being 3.3%, 31.8%, and 85.7% in the validation set.

Clinical Significance of Combined Epithelial-Mesenchymal Transition Markers Expression and Role of Rac1 in Hepatocellular Carcinoma.

Epithelial-mesenchymal transition (EMT) has been implicated in cancer progression, invasion, and metastasis. We aimed to evaluate the correlations between clinicopathological characteristics and EMT markers in patients with hepatocellular carcinoma (HCC) who underwent surgical resection and to identify the key regulator in EMT process. Fresh-frozen HCC tissues and adjacent nontumor liver tissues from 30 patients who underwent surgical resection were provided by the Gachon University Gil Medical Center Bio Bank. Human HCC cell lines, Hep3B, SNU449, and Huh7 cells were transfected with Rac1 siRNA and exposed to hypoxic conditions. The combined EMT markers expression (down-expression of E-cadherin and overexpression of p21-activated kinases 1 (PAK1)/Snail) by Western blot in HCC tissues when compared to adjacent nontumor liver tissues was significantly associated with macrovascular invasion (p = 0.021), microvascular invasion (p = 0.001), large tumor size (p = 0.021), and advanced tumor stage (p = 0.015). Patients with combined EMT markers expression showed early recurrence and poor overall survival. In vitro studies showed that Rac1 knockdown decreased the expression of EMT markers including PAK1 and Snail in hypoxia-induced Hep3B cells and suppressed the migration and invasion of hypoxia-induced HCC cells. Rac1 may be a potential therapeutic target for inhibition of EMT process through the inhibition of PAK1 and Snail in HCC.

Plasma Aldo-Keto Reductase Family 1 Member B10 as a Biomarker Performs Well in the Diagnosis of Nonalcoholic Steatohepatitis and Fibrosis.

We found several blood biomarkers through computational secretome analyses, including aldo-keto reductase family 1 member B10 (AKR1B10), which reflected the progression of nonalcoholic fatty liver disease (NAFLD). After confirming that hepatic AKR1B10 reflected the progression of NAFLD in a subgroup with NAFLD, we evaluated the diagnostic accuracy of plasma AKR1B10 and other biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) and fibrosis in replication cohort. We enrolled healthy control subjects and patients with biopsy-proven NAFLD (n = 102) and evaluated the performance of various diagnostic markers. Plasma AKR1B10 performed well in the diagnosis of NASH with an area under the receiver operating characteristic (AUROC) curve of 0.834 and a cutoff value of 1078.2 pg/mL, as well as advanced fibrosis (AUROC curve value of 0.914 and cutoff level 1078.2 pg/mL), with further improvement in combination with C3. When we monitored a subgroup of obese patients who underwent bariatric surgery (n = 35), plasma AKR1B10 decreased dramatically, and 40.0% of patients with NASH at baseline showed a decrease in plasma AKR1B10 levels to below the cutoff level after the surgery. In an independent validation study, we proved that plasma AKR1B10 was a specific biomarker of NAFLD progression across varying degrees of renal dysfunction. Despite perfect correlation between plasma and serum levels of AKR1B10 in paired sample analysis, its serum level was 1.4-fold higher than that in plasma. Plasma AKR1B10 alone and in combination with C3 could be a useful noninvasive biomarker for the diagnosis of NASH and hepatic fibrosis.

Exogenous 8-hydroxydeoxyguanosine ameliorates liver fibrosis through the inhibition of Rac1-NADPH oxidase signaling.

BACKGROUND AND AIM: Exogenous 8-hydroxydeoxyguanosine (8-OHdG) was suggested as an inhibitor of Rac1 and NADPH oxidase (NOX). The aim of this study was to evaluate the effects of the exogenous 8-OHdG on hepatic fibrogenesis in vitro and in vivo model of liver fibrosis. METHODS: Adult Sprague-Dawley rats were allocated to sham-operated rats (n = 7), rats that underwent bile duct ligation (BDL) (n = 6), and BDL rats treated with 8-OHdG (60 mg/kg/day by gavage, n = 6). All rats were sacrificed on day 21. Double immunofluorescence staining between either NOX1 or NOX2 and α-smooth muscle actin (SMA) in liver was performed. Hepatic fibrotic contents were assessed by hydroxyproline assay and quantified by Sirius red staining. In vitro, hepatic stellate cell (HSC) line LX-2 and HHSteC cells were stimulated by angiotensin II (10 µM). The reactive oxygen species (ROS) production was measured by confocal microscopy. The expressions of NOX1, NOX2, α-SMA, transforming growth factor (TGF)-ß1, and collagen Iα were analyzed by quantitative real-time polymerase chain reaction or immunoblotting. RESULTS: The 8-OHdG treatment in BDL rats reduced the NOX1 and NOX2 protein expression, which overlapped with α-SMA compared with BDL rats. The 8-OHdG treatment in BDL rats significantly decreased the mRNA expression of NOX1, NOX2, α-SMA, TGF-ß1, and collagen Iα, and fibrotic contents. Increases of ROS production, Rac1 activation, NOX1, NOX2, and fibronectin expression induced by angiotensin II in HSCs were attenuated by 8-OHdG. CONCLUSIONS: Rac1 activation and NOX-derived ROS are implicated to liver fibrosis. The 8-OHdG ameliorates liver fibrosis through the inhibition of Rac1 activation and NOX-derived ROS.

Durability of Sustained Virologic Response and Improvement of Fibrosis Markers after Daclatasvir and Asunaprevir Treatment in Genotype 1b Hepatitis C Virus-Infected Patients: a Real Life and Multicenter Study.

BACKGROUND: The long-term data with direct acting antiviral agents were rare. This study investigated the durability of a sustained virologic response (SVR) and the improvement of fibrosis after daclatasvir and asunaprevir (DCV/ASV) treatment in genotype 1b (GT1b) hepatitis C virus (HCV)-infected patients. METHODS: A total of 288 HCV GT1b patients without baseline non-structural 5A (NS5A) resistance-associated substitution (RAS) treated with DCV/ASV were enrolled. Virologic response was measured at 12 weeks and 1 year after treatment completion. In cirrhotic patients, liver function, aspartate transaminase to platelet ratio index (APRI), FIB-4 index, fibrosis index (FI), and liver stiffness measurement (LSM) at baseline and 1 year after treatment completion were evaluated. RESULTS: SVR12 was obtained in 278 patients (96.5%). Six patients who checked NS5A RAS after treatment failure were RAS positive. Only one patient showed no durability of SVR. In cirrhotic patients who achieved SVR12 (n = 59), the changes of albumin (3.8 [2.2-4.7] to 4.3 [2.4-4.9] g/dL; P < 0.001), platelet count (99 [40-329] to 118 [40-399] × 10³/mm³; P < 0.001), APRI (1.8 [0.1-14.8] to 0.6 [0.1-4.8]; P < 0.001), FIB-4 index (5.45 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), FI (5.5 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), and LSM (17.2 [5.3-48.0] to 11.2 [3.7-28.1] kPa; P = 0.001) between baseline and 1 year after treatment completion were observed. CONCLUSION: DCV/ASV treatment for HCV GT1b infected patients without RAS achieved high SVR rates and showed durable SVR. Cirrhotic patients who achieved SVR12 showed the improvement of liver function and fibrosis markers.

Rapid Alanine Aminotransferase Normalization with Entecavir and Hepatocellular Carcinoma in Hepatitis B Virus-Associated Cirrhosis.

BACKGROUND: Sustained abnormal serum alanine aminotransferase (ALT) levels can increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. AIM: This study is aimed to confirm the impact of rapid ALT normalization (≤30 IU/L) on HCC risk in patients with hepatitis B virus (HBV)-associated cirrhosis after entecavir (ETV) commencement. METHODS: A total of 578 treatment-naïve patients with HBV-associated cirrhosis (mean age 51 ± 9 years, male sex 63.3%) were treated with ETV for more than 1 year. Serum ALT and HBV DNA levels were measured at three time points (baseline, 6, and 12 months after ETV commencement) and subjected to risk factor analysis. RESULTS: Median follow-up after ETV commencement was 43 (12-98) months. Cumulative incidences of HCC at 1, 3, 5, and 7 years were 0.3, 8.5, 19.5, and 30.6%, respectively. Univariate Cox regression analysis showed that older age, abnormal ALT at 6 months or 12 months, and lower platelet count were significant risk factors for HCC. However, gender, HBeAg positivity, abnormal ALT levels or HBV DNA levels at baseline, and detectable HBV DNA at 6 or 12 months were not risk factors. Multivariate analysis showed that older age (P < 0.001), abnormal ALT at 12 months (P = 0.006), and lower platelet count (P = 0.034) were the risk factors for HCC. CONCLUSIONS: Abnormal serum ALT levels after ETV commencement are significant risk factor for HCC. Therefore, ALT should be rapidly normalized to minimize the risk of HCC development in patients with HBV-associated cirrhosis.

Improvement of liver function and non-invasive fibrosis markers in hepatitis B virus-associated cirrhosis: 2 years of entecavir treatment.

BACKGROUND AND AIM: Entecavir (ETV) induces biochemical and histologic improvement of the liver in patients with chronic hepatitis B. This study aimed to confirm that 2 years of ETV treatment improves liver function and non-invasive fibrosis markers in patients with hepatitis B virus (HBV)-associated cirrhosis. METHODS: A total 472 naïve patients with HBV-associated cirrhosis was treated with ETV for at least 2 years, between March 2007 and December 2012. Model for end-stage liver disease and Child-Pugh (CP) score were used to evaluate the improvement of liver function. Aspartate transaminase to platelet ratio index, FIB-4 index, and fibrosis index were used to evaluate the improvement of fibrosis. RESULTS: The final 370 of 472 patients with HBV-associated cirrhosis were enrolled. Mean age was 51 ± 10 years, and 240 patients (64.9%) were men. The distribution of CP class was 71.1% in A, 24.6% in B, and 4.3% in C. Mean end-stage liver disease and CP score changed over the study period from 8.5 ± 4.6 to 6.2 ± 4.2 (P < 0.001) and from 6.2 ± 1.6 to 5.6 ± 0.9 (P < 0.001), respectively. Aspartate transaminase to platelet ratio index, FIB-4 index, and fibrosis index changed from 3.6 ± 4.5 to 1.5 ± 1.5 (P < 0.001), from 7.0 ± 6.2 to 3.9 ± 2.8 (P < 0.001), and from 3.3 ± 0.9 to 2.5 ± 1.1 (P < 0.001), respectively. CONCLUSIONS: After 2 years of treatment, ETV improves liver function and non-invasive fibrosis markers in patients with HBV-associated cirrhosis.

A Composite Blood Biomarker Including AKR1B10 and Cytokeratin 18 for Progressive Types of Nonalcoholic Fatty Liver Disease.

Background: We aimed to evaluate whether composite blood biomarkers including aldo-keto reductase family 1 member B10 (AKR1B10) and cytokeratin 18 (CK-18; a nonalcoholic steatohepatitis [NASH] marker) have clinically applicable performance for the diagnosis of NASH, advanced liver fibrosis, and high-risk NASH (NASH+significant fibrosis). Methods: A total of 116 subjects including healthy control subjects and patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were analyzed to assess composite blood-based and imaging-based biomarkers either singly or in combination. Results: A composite blood biomarker comprised of AKR1B10, CK-18, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) showed excellent performance for the diagnosis of, NASH, advanced fibrosis, and high-risk NASH, with area under the receiver operating characteristic curve values of 0.934 (95% confidence interval [CI], 0.888 to 0.981), 0.902 (95% CI, 0.832 to 0.971), and 0.918 (95% CI, 0.862 to 0.974), respectively. However, the performance of this blood composite biomarker was inferior to that various magnetic resonance (MR)-based composite biomarkers, such as proton density fat fraction/MR elastography- liver stiffness measurement (MRE-LSM)/ALT/AST for NASH, MRE-LSM+fibrosis-4 index for advanced fibrosis, and the known MR imaging-AST (MAST) score for high-risk NASH. Conclusion: Our blood composite biomarker can be useful to distinguish progressive forms of NAFLD as an initial noninvasive test when MR-based tools are not available.

Surgery versus radiofrequency ablation in patients with Child- Pugh class-A/single small (≤3 cm) hepatocellular carcinoma.

BACKGROUND/AIMS: We compared the post-treatment overall survival (OS) and recurrence-free survival (RFS) between patients with Child-Turcotte-Pugh (CTP) class-A and single small (≤3 cm) hepatocellular carcinoma (HCC) treated by surgical resection (SR) and radiofrequency ablation (RFA). METHODS: We retrospectively analyzed 391 HCC patients with CTP class-A who underwent SR (n=232) or RFA (n=159) as first-line therapy for single small (≤3 cm) HCC. Survival was compared according to the tumor size (≤2 cm/2-3 cm) and the presence of cirrhosis. Inverse probability of treatment weighting (IPW) method was used to estimate the average causal effect of treatment. RESULTS: The median follow-up period was 64.8 months (interquartile range, 0.1-162.6). After IPW, the estimated OS was similar in the SR and RFA groups (P=0.215), and even in patients with HCC of ≤2 cm (P=0.816) and without cirrhosis (P=0.195). The estimated RFS was better in the SR group than in the RFA groups (P=0.005), also in patients without cirrhosis (P<0.001), but not in those with HCC of ≤2 cm (P=0.234). The weighted Cox proportional hazards model with IPW provided adjusted hazard ratios (95% confidence interval) for OS, and the RFS after RFA versus SR were 0.698 (0.396-1.232) (P=0.215) and 1.698 (1.777-2.448) (P=0.005), respectively. CONCLUSION: SR was similar for OS compared to RFA, but was better for RFS in patients with CTP class-A and single small (≤3 cm) HCC. The RFS was determined by the presence or absence of cirrhosis. Hence, SR rather than RFA should be considered in patients without cirrhosis to prolong the RFS, although there is no OS difference.

Long-Term Prediction Model for Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Receiving Antiviral Therapy: Based on Data from Korean Patients.

Predicting the development of hepatocellular carcinoma (HCC) is a key clinical issue in patients with chronic hepatitis B (CHB). The aim of this study was to develop a precise and simple HCC risk score for up to 10 years. A total of 1895 CHB patients treated with entecavir or tenofovir disoproxil fumarate were retrospectively recruited and randomized into derivation (n = 1239) and validation cohorts (n = 656). Variables proven to be independent risk factors for HCC in the derivation cohort were used to develop the prediction model. The ACCESS-HCC model included five variables (age, cirrhosis, consumption of ethanol, liver stiffness, and serum alanine aminotransferase). Areas under curves were 0.798, 0.762, and 0.883 for HCC risk at 3, 5, and 10 years, respectively, which were higher than those of other prediction models. The scores were categorized according to significantly different HCC incidences: 0-4, low; 5-8, intermediate; and 9-14, high-risk. The annual incidence rates were 0.5%, 3.2%, and 11.3%, respectively. The performance of this model was validated in an independent cohort. The ACCESS-HCC model shows improved long-term prediction and provides three distinct risk categories for HCC in CHB patients receiving antiviral therapy. Further research is needed for external validation using larger cohorts.

Partial Virological Response after 2 Years of Entecavir Therapy Increases the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Virus-Associated Cirrhosis.

Background/Aims: : The clinical significance of partial virological response (PVR) in patients undergoing antiviral therapy is not well known. This study investigated whether PVR after 2 years of entecavir (ETV) therapy is associated with hepatocellular carcinoma (HCC) development in cirrhotic patients. Methods: A total of 472 naïve patients with hepatitis B virus (HBV)-associated cirrhosis who were treated with ETV for at least 2 years were retrospectively enrolled. Clinical characteristics, laboratory data, PVR, and noninvasive fibrosis markers (aspartate aminotransferase to platelet ratio and FIB-4 index) at 2 years after ETV commencement were analyzed for HCC risk. Results: After excluding those who developed HCC within 2 years of ETV therapy, 359 patients (mean age, 51±10 years; male 64.3%) were examined. During a median follow-up of 82 months, 80 patients developed HCC. In the univariate analysis, older age (hazard ratio [HR], 1.056; p<0.001), PVR (HR, 2.536; p=0.002), higher aspartate aminotransferase (HR, 1.018; p=0.005), lower albumin level (HR, 0.463; p<0.001), lower platelet count (HR, 0.993; p=0.01), and higher FIB-4 index (HR, 1.141; p<0.001) at 2 years after ETV commencement were risk factors for HCC. In the multivariate analysis, older age (HR, 1.046; 95% confidence interval [CI], 1.022 to 1.072; p<0.001), PVR (HR, 2.358; 95% CI, 1.310 to 4.245; p=0.004), and higher FIB-4 index (HR, 1.103; 95% CI, 1.035 to 1.177; p=0.003) were independent risk factors. Conclusions: PVR and higher FIB-4 index after 2 years of ETV therapy were independent risk factors for HCC. Therefore, efforts to accomplish a complete virological response and reduce the FIB-4 index should be made.

Magnetic Resonance-Based Assessments Better Capture Pathophysiologic Profiles and Progression in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Several noninvasive tools are available for the assessment of nonalcoholic fatty liver disease (NAFLD) including clinical and blood biomarkers, transient elastography (TE), and magnetic resonance imaging (MRI) techniques, such as proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE). In the present study, we aimed to evaluate whether magnetic resonance (MR)-based examinations better discriminate the pathophysiologic features and fibrosis progression in NAFLD than other noninvasive methods. METHODS: A total of 133 subjects (31 healthy volunteers and 102 patients with NAFLD) were subjected to clinical and noninvasive NAFLD evaluation, with additional liver biopsy in some patients (n=54). RESULTS: MRI-PDFF correlated far better with hepatic fat measured by MR spectroscopy (r=0.978, P<0.001) than with the TE controlled attenuation parameter (CAP) (r=0.727, P<0.001). In addition, MRI-PDFF showed stronger correlations with various pathophysiologic parameters for cellular injury, glucose and lipid metabolism, and inflammation, than the TE-CAP. The MRI-PDFF and TE-CAP cutoff levels associated with abnormal elevation of serum alanine aminotransferase were 9.9% and 270 dB/m, respectively. The MRE liver stiffness measurement (LSM) showed stronger correlations with liver enzymes, platelets, complement component 3, several clinical fibrosis scores, and the enhanced liver fibrosis (ELF) score than the TE-LSM. In an analysis of only biopsied patients, MRE performed better in discriminating advanced fibrosis with a cutoff value of 3.9 kPa than the TE (cutoff 8.1 kPa) and ELF test (cutoff 9.2 kPa). CONCLUSION: Our results suggest that MRI-based assessment of NAFLD is the best non-invasive tool that captures the histologic, pathophysiologic and metabolic features of the disease.

The Role of Urinary N-Acetyl-ß-d-glucosaminidase in Cirrhotic Patients with Acute Kidney Injury: Multicenter, Prospective Cohort Study.

BACKGROUND AND AIMS: Currently, it is difficult to predict the reversibility of renal function and to discriminate renal parenchymal injury in cirrhotic patients with acute kidney injury (AKI). The aim of this study is to evaluate whether urine N-acetyl-ß-d-Glucosaminidase (NAG) can predict the survival and response to terlipressin in cirrhotic patients with AKI. METHODS: Two hundred sixty-two cirrhotic consecutive patients who developed AKI were prospectively enrolled from 11 tertiary medical centers in Korea between 2016 to 2019. AKI was defined as an increase in serum Cr (SCr) of 0.3 mg/dL or a 50% increase in baseline SCr. Patients diagnosed with hepatorenal syndrome (HRS-AKI) were treated with terlipressin plus albumin. RESULTS: The patients were 58.8 ± 12.9 years old on average and were predominantly male (72.5%). The mean MELD score was 25.3 ± 9.1. When classified according to the AKI phenotype, there were 119 pre-renal, 52 acute tubular necrosis, 18 miscellaneous, and 73 HRS-AKI patients. However, the urine NAG was not effective at discriminating AKI phenotypes, except for HRS-AKI. The baseline urine NAG increased as the baseline AKI stage increased (p < 0.001). In addition, within the same AKI stage, the urine NAG values were significantly lower in the AKI-resolved group than in the unresolved group. The urine NAG level was significantly lower in living patients compared with those who died or who underwent a liver transplant within 3 months (p = 0.005). In the multivariate analysis, the increased urine NAG was a significant risk factor for the 3-month transplant-free survival (TFS) rate, especially in patients with Child-Pugh class ≤ B or MELD < 24. The urine NAG did not predict the response to terlipressin treatment in patients with HRS. CONCLUSIONS: Urine NAG is strongly associated with the severity of AKI in patients with liver cirrhosis and is useful for predicting the 3-month TFS.

Seroreversion and Acute Decompensation in Chronic Hepatitis B after Discontinuation of Oral Nucleotide Analog in the Patients Achieving HBsAg Loss.

Although rare patients with chronic hepatitis B can achieve HBsAg loss on oral nucleos(t)ide analog (NA), the optimal timing of stopping oral NAs safely has been considered when HBsAg and HBV DNA are negative in the serum because HBsAg loss induced by nucleos(t)ide analogs (NAs) appears to be durable if immunosuppressive therapy or chemotherapy are not done. On the other hand, the author experienced a case of HBsAg seroreversion and acute decompensation after the discontinuation of NA in a patient with HBsAg loss. This rare case highlights the need for the close monitoring of patients who achieved HBsAg loss and stopped NA.

Systematic Review with Meta-Analysis: Low-Level Alcohol Consumption and the Risk of Liver Cancer.

Background/Aims: Multiple meta-analyses and observational studies have reported that alcohol is a risk factor for liver cancer. However, whether there is a safe level of alcohol consumption remains unclear. We performed a systematic review and meta-analysis of the correlation between low-level alcohol consumption and the risk of liver cancer. Methods: Nested case-control studies and cohort studies involving the general population published prior to July 2019 were searched. In total, 28 publications (31 cohorts) with 4,899 incident cases and 10,859 liver cancer-related deaths were included. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: Compared with those with low levels of alcohol consumption, moderate and heavy drinkers (≥1 drink/day for females and ≥2 drinks/day for males) had pooled ORs of 1.418 (95% CI, 1.192 to 1.687; p<0.001) for liver cancer incidence and 1.167 (95% CI, 1.056 to 1.290; p=0.003) for liver cancer mortality. The pooled OR for liver disease-related mortality for those with more than low levels of alcohol consumption was 3.220 (95% CI, 2.116 to 4.898; p<0.001) and that for all-cause mortality was 1.166 (95% CI, 1.065 to 1.278; p=0.001). The sensitivity analysis showed that none of the studies had a strong effect on the pooled OR. The Egger test, Begg rank correlation test, and the funnel plot showed no overt indication of publication bias. Conclusions: Continuous consumption of more than a low-level of alcohol (≥1 drink/day for females and ≥2 drinks/ day for males) is related to a higher risk of liver cancer.

Characteristics of contrast-enhanced ultrasound in distinguishing small (≤3 cm) hepatocellular carcinoma from intrahepatic cholangiocarcinoma.

Contrast-enhanced ultrasound (CEUS) is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to verify the characteristics of CEUS in distinguishing small (≤3 cm) hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC).A total of 65 patients with a liver nodule (HCC, n = 58; ICC, n = 7) smaller than 3 cm who underwent liver CEUS and pathologic confirmation were retrospectively reviewed. CEUS findings were compared with histopathologic and clinical data.Arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS were observed in 77.6% (45/58) of HCCs and 85.7% (6/7) of ICCs. Time of arterial-phase hyperenhancement (11 seconds [6-20] vs 16 seconds [14-19], P = .008), time of portal-delayed-phase wash-out (65 seconds (15-260) vs 35 secconds (27-54), P = .002), and time interval between arterial-phase hyperenhancement and portal-delayed-phase wash-out (50 seconds [5-249] vs 19 seconds [13-35], P < .001) on CEUS were significantly different between HCCs and ICCs showing arterial-phase hyperenhancement and portal-delayed-phase wash-out. The sensitivity, specificity, positive predictive value, and negative predictive value of time interval more than 25 seconds between arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS for the differentiation of HCCs and ICCs were 91.1%, 83.3%, 97.6%, and 55.6%, respectively.The time interval between arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS was the most sensitive indicator in distinguishing small HCC from ICC showing arterial-phase hyperenhancement and portal-delayed-phase wash-out.

[Spontaneously Resolving of Huge Simple Hepatic Cyst].

Simple hepatic cysts are common benign liver lesions that usually have no malignant capability. They are generally asymptomatic and are often found incidentally by abdominal imaging procedures. Treatment becomes necessary, however, when huge hepatic cysts cause symptoms and develop complications, such as hemorrhage, adjacent organ damage, and infection. Several therapeutic options have been performed for symptomatic and huge cysts, including the aspiration of cystic fluid, infusion of various sclerosing agents, and surgical intervention. The optimal management of huge hepatic cysts is controversial and each option has its complications and limitations. This paper reports a case of a 66-year-old woman diagnosed with a simple hepatic cyst 2 years earlier, who was referred to hospital due to abdominal pain. The diagnosis was a huge hepatic cyst with symptoms by abdominal imaging studies. During the follow-up period, the huge cysts resolved spontaneously without treatment.