Ja Kyung Kim

A Liver Stiffness Measurement-Based, Noninvasive Prediction Model for High-Risk Esophageal Varices in B-Viral Liver Cirrhosis

OBJECTIVES:Periodic endoscopic screening for esophageal varices (EVs) and prophylactic treatment for high-risk EVs ((HEVs); (1) medium/large EVs and (2) small EVs with red sign or decompensated cirrhosis) are currently recommended for all cirrhotic patients. However, if a simple, noninvasive test is available, many low-risk patients may safely avoid endoscopy. We developed and validated a new liver stiffness measurement (LSM)-based prediction model for HEVs.METHODS:We prospectively enrolled 280 consecutive B-viral cirrhosis patients from 2005 to 2007 (training set) and 121 from 2007 to 2008 (validation set). All underwent laboratory workups, endoscopy, LSM, and ultrasonography. For detection of HEVs, univariate and multivariate analysis were performed, using χ2-test/t-test and logistic regression, respectively. A prediction model was derived from multivariate predictors.RESULTS:In the training set, 90 had HEVs, and multivariate analysis showed significant differences in LSM, spleen diameter, and platelet count between patients with and without HEVs. We developed LSM-spleen diameter to platelet ratio score (LSPS): LSM × spleen diameter/platelet count. The area under the receiver-operating characteristic curve (AUROC) in the training set was 0.954. At LSPS<3.5, 94.0% negative predictive value (NPV) was provided (184 patients), whereas 94.2% positive predictive value (PPV) was achieved (69 patients) at LSPS>5.5. Overall, the likelihood of HEVs was correctly diagnosed in 253 patients (90.3%). Its predictive values were maintained at similar accuracy in subsequent validation set (AUROC=0.953; 94.7% NPV/93.3% PPV at cutoff 3.5/5.5, respectively).CONCLUSIONS:LSPS is a reliable, noninvasive method for detection of HEVs. Patients with LSPS<3.5 may avoid endoscopy safely, whereas those with LSPS>5.5 should be considered for appropriate prophylactic treatments.

Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma with portal vein thrombosis

Patients with advanced hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have a particularly grave prognosis. In the current study, an attempt was made to localize chemoradiation therapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) in patients with locally advanced HCC with PVT and good reserve liver function. The objective of the current study was to evaluate the therapeutic effect of localized CCRT followed by HAIC as a new treatment modality for these patients.

Validation of FIB‐4 and comparison with other simple noninvasive indices for predicting liver fibrosis and cirrhosis in hepatitis B virus‐infected patients

Backgrounds: To optimize management and predict long‐term clinical courses in patients with chronic hepatitis B (CHB), noninvasive tests to determine the degree of hepatic fibrosis have been developed.

Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection

Background: Elevated serum hepatitis B virus (HBV) DNA increases the development of hepatocellular carcinoma (HCC). Rather than instantaneous DNA level, the duration of persistent HBV replication is more important in carcinogenesis. Nevertheless, most investigators evaluated the DNA level at study entry. We assessed the effects of persistently detectable serum HBV DNA on HCC recurrence.

How can we enhance the performance of liver stiffness measurement using fibroscan in diagnosing liver cirrhosis in patients with chronic hepatitis B

Goal This study aimed to enhance the diagnostic accuracy by defining different cutoff liver stiffness measurement (LSM) values according to alanine aminotransferase (ALT) level and combining LSM with noninvasive models in patients with chronic hepatitis B (CHB). Background Several studies have indicated that ALT influences LSM using FibroScan. Study The study prospectively enrolled 200 patients (143 men, mean age 45.4 y) between June 2007 and November 2008 who had been diagnosed with CHB and underwent both liver biopsy and LSM on the same day. Results The area under the receiver operating characteristic curves (AUROC) of LSM for predicting cirrhosis in patients with ALT ≤upper limit of normal (ULN) was higher than that of all patients or those with ALT >ULN and ≤2× ULN (AUROC=0.884 vs. 0.849 and 0.867). The cutoff LSM values for ≥F2, ≥F3, and F4 were 6.0, 7.5, and 10.1 kPa, respectively, in patients with ALT ≤ULN, whereas they were 8.9, 11.0, and 15.5 kPa, respectively, in those with ALT >ULN and ≤2× ULN. The combination of LSM and the age-spleen-platelet ratio index performed the best at predicting cirrhosis, regardless of ALT level (AUROC=0.917 in patients with ALT ≤ULN, 0.909 in those with ALT ≤2× ULN, and 0.894 in all patients). Conclusions Different cutoff LSM values according to ALT level and combination with age-spleen-platelet ratio index can enhance the performance of LSM in CHB, regardless of ALT level.

Role of 18F-Fluorodeoxyglucose Positron Emission Tomography in Detecting Extrahepatic Metastasis in Pretreatment Staging of Hepatocellular Carcinoma

Objectives:18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is useful for differentiating benign from malignant lesions, evaluating tumor stage, monitoring the response to therapy and detecting tumor recurrence in a variety of malignancies. Nevertheless, its use in patients with hepatocellular carcinoma (HCC) is still uncertain. We evaluated whether FDG-PET has a role in detecting extrahepatic metastasis in pretreatment tumor staging of HCC and the characteristics of patients with extrahepatic metastasis that benefit from FDG-PET. Methods: Eighty-seven patients with HCC underwent computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and chest X-ray to evaluate pretreatment tumor staging. FDG-PET was then performed to detect extrahepatic metastasis. The power of FDG-PET to detect extrahepatic metastasis was compared with that of conventional images. In addition, we evaluated whether the detection of extrahepatic metastasis using FDG-PET changed the TNM stage. Moreover, we investigated the clinical and tumor characteristics of patients with extrahepatic HCC metastasis. Results: Extrahepatic metastases were identified in 24 of 87 patients. The location and frequency of metastases were lung 12, lymph nodes 19 and bone 11. All of the extrahepatic metastases were detected by FDG-PET. In addition, FDG-PET identified 4 lymph node metastases and 6 bone metastases that were not found using conventional methods. The initial TNM stage based on the conventional staging workup was changed in 4 cases after FDG-PET. Extrahepatic metastasis was significantly more frequent in patients with intrahepatic tumor >5 cm in size (p = 0.045). Conclusions: FDG-PET is a useful imaging modality for identifying extrahepatic metastases which may lead to accurate staging and proper management of patients with possible extrahepatic metastases.

Autologous bone marrow infusion activates the progenitor cell compartment in patients with advanced liver cirrhosis.

Several clinical trials of bone marrow cell infusion in patients with liver cirrhosis (LC) have shown clinical improvement, despite conflicting results from animal models. We investigated serial pathological features and the clinical impact after autologous bone marrow infusion (ABMI) in patients with advanced LC. Ten patients with advanced LC due to chronic hepatitis B virus infection underwent ABMI. Serological tests, MRI, and liver biopsies were performed, and quality of life was assessed by a questionnaire. Median serum albumin and hemoglobin levels increased significantly after ABMI. All patients showed an improvement in quality of life, with no serious adverse events. Liver volume, measured by MRI, increased in 80% of the patients, and ascites decreased after ABMI. Child-Pugh scores were also significantly improved at 6 months after ABMI. In the serially biopsied livers, a gradually increasing activation of the hepatic progenitor cell (HPC) compartment, including HPC activation (ductular reaction) and HPC differentiation (intermediate hepatocyte), reached a peak after 3 months, with continued proliferation of hepatocytes, and returned to baseline levels after 6 months. There was no significant change in grade or stage of liver fibrosis or stellate cell activation after ABMI. ABMI is suggested to improve liver function and to activate the progenitor cell compartment. Although clinical improvement was sustained for more than 6 months, histological changes in the liver returned to baseline 6 months after ABMI. Further comparative studies are warranted.

Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice

Activation of innate immunity (natural killer [NK] cell/interferon‐γ [IFN‐γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2‐week or a 10‐week carbon tetrachloride (CCl4) challenge, respectively. Injection of polyinosinic‐polycytidylic acid (poly I:C) or IFN‐γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2‐week CCl4 model. Such activation was diminished in the 10‐week CCl4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN‐γ on liver fibrosis was markedly reduced in the 10‐week versus the 2‐week CCl4 model. In vitro coculture experiments demonstrated that 4‐day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid–induced early gene 1–dependent mechanism. Such activation was reduced when cocultured with 8‐day cultured (intermediately activated) HSCs due to the production of transforming growth factor‐β (TGF‐β) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN‐γ–mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN‐γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN‐γ signaling and functioning, whereas production of TGF‐β by HSCs inhibited NK cell function and cytotoxicity against HSCs. Conclusion: The antifibrogenic effects of NK cell/IFN‐γ are suppressed during advanced liver injury, which is likely due to increased production of TGF‐β and expression of SOCS1 in intermediately activated HSCs. (HEPATOLOGY 2011;)

PIVKA-II Is a Useful Tumor Marker for Recurrent Hepatocellular Carcinoma after Surgical Resection

Objectives: The aim of this study is to assess the usefulness of prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) in monitoring of recurrent hepatocellular carcinoma (HCC) after curative resection. Methods: From April 2001 to March 2004, a total of 245 patients with histologically proven HCC and 267 non-HCC patients were recruited. Serial follow-up measurements of both alpha-fetoprotein (AFP) and PIVKA-II were performed in 27 patients who had recurrent HCC after resection. Results: In the initial HCC diagnosis, the sensitivity of AFP and PIVKA-II was 48.6% (119/245) and 75.1% (184/245), respectively, at the cutoff of 20 ng/ml for AFP and 40 mAU/ml for PIVKA-II (p < 0.01). The specificity was 81.3% (217/267) and 94.8% (253/267), respectively. When AFP and PIVKA-II were combined, the sensitivity and specificity was 83.3% (204/245) and 77.2% (206/267), respectively. In 27 patients developing recurrent HCC after curative surgical resection, the sensitivity of AFP and PIVKA-II was 40.7% (11/27) and 74.1% (20/27), respectively. Several fluctuating patterns of AFP and PIVKA-II were observed from initial diagnosis to recurrence. Conclusion: Our data suggest that PIVKA-II is a useful tumor marker for HCC, complementary to AFP. Serial measurements of both markers after resection might be helpful for early diagnosis of tumor recurrence.

Risk assessment of esophageal variceal bleeding in B-viral liver cirrhosis by a liver stiffness measurement-based model

OBJECTIVES:Periodic endoscopic screening for esophageal varices (EVs) and prophylactic treatment for high-risk EVs (HEVs; (i) medium/large EVs and (ii) small EVs with red sign or decompensated cirrhosis) are recommended for cirrhotic patients. We assessed cumulative risks of future EV bleeding (EVB) using the liver stiffness measurement (LSM)-based model, LSM–spleen diameter to platelet ratio score (LSPS=LSM×spleen diameter/platelet count).METHODS:We prospectively enrolled 577 consecutive B-viral cirrhosis patients from 2005 to 2009, none of whom experienced EVB. All underwent laboratory workups, endoscopy, LSM, and ultrasonography. Those with HEVs took nonselective β-blockers as prophylaxis for EVB after diagnosis, if not contraindicated. The major end point was the first EVB event, examined using Kaplan–Meier and Cox-regression methods.RESULTS:Among whole population, 95.9% negative- /93.5% positive-predictive value by LSPS<3.5/LSPS≥5.5 were provided for predicting the presence of HEV at enrollment, respectively. Among patients with HEV (n=150), 25 experienced their first EVBs during follow-up (median, 29 months). To differentiate EVB risk, we divided them into subgroup 1 (LSPS<6.5) and 2 (LSPS≥6.5) according to LSPS 6.5, a point with maximum sum of sensitivity and specificity from time-dependent receiver-operating characteristic (ROC) curves (area under ROC curve=0.929). EVB risk was higher in subgroup 2 than subgroup 1 (P<0.001). Multivariate analysis found higher LSPS (P=0.003) a significant predictor, alongside large variceal sizes (P=0.004) and Child-Pugh classifications B/C (P=0.001). Notably, EVB risk of subgroup 1 was as low as that of low-risk EVs (P=0.507).CONCLUSIONS:LSPS is a reliable predictor for EVB risk. According to risk stratification, different prophylactic treatments should be considered for subgroups with LSPS≥6.5.