Tumor Necrosis Is an Indicator of Poor Prognosis Among Hepatoma Patients Undergoing Resection.

INTRODUCTION: Tumor necrosis has been associated with poor prognosis in hepatocellular carcinoma (HCC) patients undergoing liver resection (LR). However, more evidence is needed to clarify this issue. METHODS: Patients who underwent upfront LR between 2010 and 2018 for newly diagnosed HCC without undergoing neoadjuvant therapy were enrolled in this retrospective study. Tumor necrosis was classified as present or absent according to retrospective examinations. The association between tumor necrosis, pathologic characteristics, overall survival (OS), and recurrence-free survival (RFS) were analyzed. RESULTS: Among 756 patients who underwent LR for HCC, tumor necrosis was present in 279 (36.9%) patients. Compared with patients without tumor necrosis, patients with tumor necrosis had higher proportions of tumors sized >5.0 cm (P < 0.001), multiple tumors (P < 0.001), microvascular or macrovascular invasion (P < 0.001), poorly differentiated or undifferentiated tumors (P < 0.001), and T stage 3 or 4 (P < 0.001) on pathological examination. The presence of tumor necrosis was associated with worse OS and RFS compared with the absence of tumor necrosis: 5-y OS was 56% versus 78% (P < 0.001); 5-y RFS was 42% versus 55% (P < 0.001). In multivariate analysis, the presence of tumor necrosis was an independent factor associated with worse OS (hazard ratio: 1.956; 95% confidence interval: 1.409-2.716; P < 0.001) and RFS (hazard ratio: 1.422; 95% confidence interval: 1.085-1.865; P = 0.011). CONCLUSIONS: Tumor necrosis was associated with worse OS and RFS among patients who underwent LR for HCC.

Overall survival among patients who undergo resection does not differ significantly between T1a and T1b hepatocellular carcinoma based on the 8th American Joint Commission on Cancer.

PURPOSE: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) has been used since 2018. However, whether any significant difference in overall survival (OS) exists between patients with T1a and T1b HCC who undergo resection has been controversial. We aim to clarify this issue. METHODS: We consecutively enrolled newly diagnosed HCC patients who underwent liver resection (LR) from 2010 to 2020 at our institution. OS was estimated using the Kaplan-Meier method and compared using log-rank tests. Prognostic factors for OS were identified by multivariate analysis. RESULTS: This study enrolled 1250 newly diagnosed HCC patients who underwent LR. No significant differences in OS were identified between patients with T1a and T1b tumors among all patients (p = 0.694), cirrhotic patients (p = 0.753), non-cirrhotic patients (p = 0.146), patients with alpha-fetoprotein (AFP) > 20 ng/ml (p = 0.562), patients with AFP ≤ 20 ng/ml (p = 0.967), patients with Edmondson grade 1 or 2 (p = 0.615), patients with Edmondson grade 3 or 4 (p = 0.825), patients positive for hepatitis B surface antigen (HBsAg; p = 0.308), in patients positive for anti-hepatitis C virus (HCV) antibody (p = 0.781), or patients negative for both HBsAg and anti-HCV antibody (p = 0.125). Using T1a as the reference, multivariate analysis showed that T1b is not a significant predictive factor for OS (hazard ratio (HR): 1.338; 95% confidence interval (CI):0.737-2.431; p = 0.339). CONCLUSION: No significant difference in OS was observed between patients who underwent LR to treat T1a and T1b HCC tumors.

Microscopic portal vein invasion is a powerful predictor of prognosis in patients with hepatocellular carcinoma who have undergone liver resection.

BACKGROUND AND OBJECTIVES: A recent study proposed simple classifications of microscopic vascular invasion (MVI): microscopic portal vein invasion (MPVI) and microvessel invasion (MI). We aim to validate these classifications of MVI. METHODS: This retrospective study consecutively enrolled 514 Barcelona Clinic Liver Cancer stage 0, A, and B naïve hepatocellular carcinoma patients who underwent liver resection in our institution from 2011 to 2017. RESULTS: Among these 514 patients, 240 patients were classified as having no MVI at all (designated as no vascular invasion, NVI), 157 patients were classified as having MI only, and 117 patients were classified as having MPVI. The 5-year overall survival (OS) rate in the MI-only group was 83.3%, which was not significantly different from that of the NVI group (87.2%), p = .20. Using NVI as a reference, multivariate analysis showed that MI-only is not an independent variable associated with OS. The 5-year OS in the MPVI group was 59.2%, which was significantly lower than those for MI-only (p < .001) and NVI groups (p < .001). Using NVI as a reference, multivariate analysis showed that MPVI is an independent variable associated with OS (HR, 3.12; 95% CI, 1.80-5.40; p < .001). CONCLUSIONS: The results of this study validate the simple MVI classifications to be clinically useful.

Clinical and novel application of FibroScan, FIB-4 and aspartate aminotransferase-to-platelet ratio index in liver fibrosis evaluation in patients with hepatocellular carcinoma and their roles in oesophageal variceal prediction.

BACKGROUND: Non-invasive techniques for liver fibrosis diagnosis are very important for clinician especially in high-risk patients for liver biopsy. We further explored the diagnostic accuracy of FibroScan, FIB-4 and aminotransferase-to-platelet ratio index (APRI) in identifying liver fibrosis and assess their predictive role for oesophageal varices in patients with hepatocellular carcinoma (HCC). METHODS: In total, 380 patients who underwent surgery for HCC were included based on retrospective study design. Liver fibrosis was pathologically diagnosed using the Ishak scoring system. Liver stiffness parameters were measured using FibroScan. APRI and FIB-4 were calculated. Among those, 121 patients who received oesophagogastroduodenoscopic examination underwent variceal evaluation. RESULTS: For liver cirrhosis diagnosis with FibroScan, the optimal cut-off values for the patients with HCC overall, left HCC and right HCC were 8.85, 11.75 and 8.70 kPa (the accuracy were 78.7%, 78.4% and 79.2%, respectively). They had high areas under the receiver operating characteristic curve of 0.84, 0.84 and 0.85. The combined FibroScan, APRI and FIB-4 had very high specificity (more than 92%) for cirrhosis diagnosis. The optimal cut-off liver stiffness values for the diagnosis of varices were all 11.2 kPa. For predicting varices, the optimal cut-off values of FIB-4 and APRI were 2.64 and 0.71, their accuracy were 64.3%-78.4%, 69.4% and 72.7%, respectively. CONCLUSIONS: FibroScan, FIB-4 and APRI have moderate accuracy for liver fibrosis diagnosis and oesophageal varices prediction in patients with hepatoma. This is a study of these non-invasive techniques applied in specific hepatoma patients and with inevitable limitations and need future more studies for validation.

Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study.

AIMS: Cellular senescence plays a role in tumour suppression and in the pathogenesis of various non-neoplastic diseases, including primary biliary cholangitis and other adult cholangiopathies. Less is known about the role of cellular senescence in cholangiopathies in children. With that in mind, we examined the expression of senescence-associated cell cycle regulators in biliary atresia, the most common form of paediatric obliterative cholangiopathy. METHODS AND RESULTS: The expression of senescence-associated cell cycle regulators (p16Ink4a and p21WAF1/Cip1 ) and a ductular reaction related marker (neural cell adhesion molecule: NCAM) was examined in bile ducts and bile ductules in liver samples taken from the patients with biliary atresia [n = 80; including 23 samples at the time of the Kasai procedure (KP) and 63 obtained from the explanted liver (LT) (six cases with samples at both surgical stages of disease)] and from appropriate controls (n = 17). The degree of ductular reaction and cholestasis was significantly more extensive in LT than KP (P < 0.01). The expression of p16INK4a and NCAM was significantly more extensive in bile ducts and bile ductules in ductular reaction in both KP and LT compared to controls and in LT compared to KP (P < 0.05). The expression of p21WAF1/Cip1 was significantly more extensive in bile ducts and bile ductules in KP compared to both LT and controls (P < 0.01). CONCLUSIONS: Cellular senescence may play a role in the progression of bile duct loss in biliary atresia in a manner similar to that of adult cholangiopathies.

The association between steatosis and diabetes with hepatocellular carcinoma in non-genotype 3 chronic hepatitis C patients.

BACKGROUND & AIMS: Diabetes mellitus (DM) has been found to be strongly associated with an increased risk of hepatocellular carcinoma (HCC) among chronic hepatitis C (CHC) patients. Several studies have also found an association between metabolic steatosis and the risk of HCC in CHC patients, whether this latter association has been accounted for by the known relationship between DM and HCC is still unknown. METHODS: A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC and treated with interferon and ribavirin was studied. Cumulative incidence and HCC risk were analysed using the Kaplan-Meier method and Cox proportional hazard analysis. RESULTS: Hepatocellular carcinoma developed in 140 subjects over a median follow-up period of 97.3 months, while 699 patients achieved sustained virological response (SVR). According to multivariate analyses, age ≥ 60 years, advanced fibrosis and genotype 1 were identified as independent factors significantly associated with HCC development in SVR patients. Furthermore, using the absence of steatosis and absence of DM as references, the presence of steatosis without DM (HR = 2.09, 95% CI = 1.12-3.9, P = .021), the presence of DM without steatosis (HR = 2.78, 95% CI = 1.3-5.92, P = .008) and the combined presence of steatosis and DM (HR = 3.25, 95% CI = 1.44-7.33, P = .004) were identified as independent factors significantly associated with HCC development in the SVR patients. In contrast, steatosis alone, DM alone and the combined presence of steatosis and DM were not associated with HCC development in non-SVR patients. CONCLUSIONS: Steatosis and DM may be associated with HCC development in non-genotype 3 CHC patients with SVR.

Rebound thymic hyperplasia after liver transplantation for a child with biliary atresia; a case report.

The thymus gland possesses the ability to regrow in children leading to a newly developed anterior mediastinal mass. This condition may represent a rebound phenomenon during recovery from a stressful event such as post-chemotherapy and hence was described as RTH. RTH after LT has not been well documented. We are reporting an infant with BA who underwent LT and presented with a symptomless anterior mediastinal mass, detected on follow-up imaging 6 months thereafter. Surgical partial excision was performed to rule out other differential diagnoses of a solid mass in the anterior mediastinum of an infant particularly lymphoma-that may arise as post-transplant lymphoproliferative disorder-and teratoma, as well as the other aggressive lesions such as thymoma and thymic carcinoma. The final pathological analysis revealed true thymic hyperplasia, consistent with RTH. The diagnosis of RTH should be considered for a child presenting by anterior mediastinal mass after LT.

Circulating microRNAs as biomarkers for diagnosis of early hepatocellular carcinoma associated with hepatitis B virus.

Hepatocarcinogenesis is a multistep process that evolves from cirrhosis or dysplastic nodule (DN), and eventually leads to overt hepatocellular carcinoma (HCC). Differentiation between early HCC and DN is an important issue in the clinical setting. This study aims to investigate the potential of circulating microRNA (miRNA) levels in the diagnosis of early HCC. RNA was extracted from sera of 30 chronic hepatitis B patients with pathologically proven DN and 120 age- and sex-matched patients with early HCC. Paired samples were collected from ten patients with DN who developed overt HCC in the follow-up. A panel of ten cancer-associated miRNAs was analyzed by quantitative real-time reverse-transcription polymerase chain reaction. Serum levels of miR-16, miR-122, miR-221, let-7b and miR-15b were significantly lower in patients with DN than in the HCC group. When DN progressed to overt HCC, serum miR-122, miR-let-7b and miR-15b levels increased significantly (p = 0.046, 0.043 and 0.044, respectively). As a single marker, α-fetoprotein (AFP) and miR-122 as well as let-7b had the similar performance for differentiate HCC from DN. As limited to subjects with normal AFP, let-7b resulted in a sensitivity of 84.8% and a specificity of 50% in separating HCC and DN with a cutoff value of 3.5 (p = 0.001). In conclusion, miR-122 and let-7b, which are upregulated in the serum of early-HCC patients, can be useful markers for differentiating early HCC from DN in chronic hepatitis B patients.

Surgical experience of adult primary hepatic sarcomas.

BACKGROUND: Primary hepatic sarcoma (PHS) is a rare primary liver malignancy. The histological types of PHS are diverse, and the clinical outcomes and management mainly depend on the histopathology. This study aims to evaluate the results of surgical intervention. METHODS: Between January 2003 and June 2009, 13 adult patients with pathologically proven PHS were identified by record review. The patients' demographic profile, tumor characteristics, treatment modalities, and outcomes were reviewed and analyzed. The end of follow-up was December 2014. RESULTS: Nine (69%) underwent curative liver resection and two underwent liver transplantation; the others received non-operative treatments. The pathologic findings were six (46%) angiosarcomas, four (30.7%) undifferentiated sarcomas, one (7.6%) leiomyosarcoma, one (7.6%) malignant mesenchymoma, and one (7.6%) hepatic epithelioid hemangioendothelioma. The median follow-up was 31.4 (2.8 ~ 142.5) months. The 1-, 2-, and 5-year survival of surgical patients were 72.7%, 63.6%, and 36.4%, respectively. Importantly, the 1-, 2-, and 5-year survival rates of non-angiosarcoma patients were superior to those of angiosarcoma (85.7% vs. 33.3%, 71.4% vs. 16.7%, and 57.1% vs. 0%, respectively, P = 0.023). CONCLUSIONS: Surgical intervention provides the possibility of long-term survival from PHS. Angiosarcoma is associated with a more dismal outcome than non-angiosarcoma.

Patients undergoing liver resection for non-alcoholic fatty liver disease-related hepatocellular carcinoma and those for viral hepatitis-related hepatocellular carcinoma have similar survival outcomes.

Numerous studies have compared outcomes of liver resection (LR) of patients with non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) to those of patients with non-NAFLD-related HCC. However, results have been inconsistent. We aim to clarify this issue. We enrolled 801 patients with hepatitis B virus (HBV)-related HCC, 433 patients with hepatitis C virus (HCV)-related HCC, and 128 patients with NAFLD-related HCC undergoing LR. Overall survival (OS) and disease-free survival (DFS) of patients with different etiologies of chronic liver disease was compared using the Kaplan-Meier estimator and log-rank test after propensity score matching (PSM). After PSM, 83 patients remained in each group. The groups did not differ significantly in age, sex, the proportion of patients with pathological American Joint Committee on Cancer stage 1, tumor size > 50 mm, receipt of major resection, alpha-fetoprotein (AFP) ≥ 20 ng/ml, presence of cirrhosis, model for end-stage liver disease (MELD) score, and American Society of Anesthesiologists (ASA) classification. The five-year OS of patients with HBV-, HCV-, and NAFLD-related HCC was 78%, 75%, and 78%, respectively (p = 0.789). The five-year DFS of the HBV, HCV, and NAFLD groups was 60%, 45%, and 54%, respectively (p = 0.159). Perioperative morbidity was noted in 17 (20.5%) in the HBV group, 22 (26.5%) in the HCV group, and 15 (18.1%) in the NAFLD group (p = 0.398). The five-year OS, DFS, and perioperative morbidity of patients undergoing LR for NAFLD-related HCC and those for viral hepatitis-related HCC was similar.

Ultrasonographic quantification of hepatic-renal echogenicity difference in hepatic steatosis diagnosis.

BACKGROUND AND AIM: Ultrasound (US) is recommended for hepatic steatosis screening. The purpose of this study was to determine the usefulness of US hepatic-renal echo-intensity (HR) difference in the quantitative assessment of hepatic steatosis. METHODS: Consecutive patients undergoing liver biopsy were prospectively enrolled. Using US histogram technique, the mean gray level of hepatic parenchyma and right renal parenchyma at selected regions of interest were evaluated on the same day of biopsy. With steatosis assessed by histology as the reference, the diagnostic performances of HR difference in predicting the degree of steatosis was analyzed. The optimal cut-off level, diagnostic validity and post-test probability were assessed. RESULTS: A total of 175 patients were enrolled (M/F, 103/72; mean age, 48.6 ± 11.7). There were 64 (36.5 %), 42 (24 %), 29 (16.6 %), 12 (6.9 %) and 28 (16 %) patients with steatosis of <5, 5-9, 10-19, 20-29 and ≥ 30 %, respectively. Multivariate analysis showed HR difference correlated with the severity of steatosis (R (2) = 0.425, p < 0.001) with positive correlation between HR difference and the severity of steatosis (r = 0.60, p < 0.001). The diagnostic performances were 0.927, 0.890, 0.816 and 0.760 for steatosis ≥ 30, ≥ 20, ≥ 10 and ≥ 5 %, respectively. The cut-off is 7 for diagnosing steatosis ≥ 30 %, with a negative predictive value of 97.6 %. The cut-off is 4 in predicting steatosis ≥ 5 %, with a positive predictive value of 79 %. The prevalence of steatosis influenced the post-test probability. CONCLUSIONS: Quantitative assessment of HR difference with US histogram technique is useful in excluding moderate to severe hepatic steatosis.

Fish omega-3 fatty acids induce liver fibrosis in the treatment of bile duct-ligated rats.

BACKGROUND: Biliary atresia-induced cholestasis increases hepatic oxidative stress with eventual progression to cirrhosis and liver failure. Omega-3 fatty acids play a possible role in the regulation of oxidative stress and the improvement of cholestasis. AIM: The goal of the present study is to investigate the role of dietary supplementation of fish omega-3 fatty acids in the reduction of hepatocellular damage by using a rat common bile duct ligation model. METHODS: Sprague-Dawley rats received either sham or bile duct ligation (BDL) and were divided into four study groups: Sham+saline (Sham+sal) group, Sham+Fish oil (Sham+FO) group, BDL+saline (BDL+sal) group, and BDL+Fish oil (BDL+FO) group. Rats from each group were assigned to receive, besides regular chow, once daily with either normal saline or fish omega-3 fatty acids (0.4 % of its own body weight) via gavage for 10 days. Samples of blood, liver tissue homogenates, and histological studies from different groups were analyzed at the end of the study. RESULTS: Rats from BDL+FO had significantly impaired liver function as compared to other study groups (p < 0.05 is of significant difference). Ishak scores and the TGF-b1 contents were significantly higher in rats that received BDL+FO, p < 0.05. Contrary to TGF-b1 liver content, rats from the BDL+FO group had the lowest glutathione levels among the study groups, p < 0.05. CONCLUSIONS: Fish omega-3 fatty acids supplementation, albeit increased tissue content of DHA, tended to increase liver fibrosis in BDL rats, decrease liver glutathione level, and compromise hepatic function; fish oil supplementation to subjects with biliary atresia might be of potential hazard and should be used with caution.

Tumor necrosis as a predictor of early tumor recurrence after resection in patients with hepatoma.

BACKGROUND: Tumor necrosis is a significant risk factor affecting patients' prognosis after liver resection (LR) for hepatocellular carcinoma (HCC). We aimed to develop a model with tumor necrosis as a variable to predict early tumor recurrence in HCC patients undergoing LR. MATERIALS AND METHODS: Patients who underwent LR between 2010 and 2018 for newly diagnosed HCC but did not receive neoadjuvant therapy were enrolled in this retrospective study. Six predictive factors based on pathological features-tumor size > 5 cm, multiple tumors, high-grade tumor differentiation, tumor necrosis, microvascular invasion, and cirrhosis-were chosen a priori based on clinical relevance to construct a multivariate logistic regression model. The variables were always retained in the model. The impact of each variable on early tumor recurrence within one year of LR was estimated and visualized using a nomogram. The nomogram's performance was evaluated using calibration plots with bootstrapping. RESULTS: Early tumor recurrence was observed in 161 (21.3%) patients. The concordance index of the proposed nomogram was 0.722. The calibration plots showed good agreement between nomogram predictions and actual observations of early recurrence. CONCLUSION: We developed a nomogram incorporating tumor necrosis to predict early recurrence of HCC after LR. Its predictive accuracy is satisfactory.

Characteristics and prognosis of patients with large well-differentiated hepatocellular carcinoma who have undergone resection.

BACKGROUND: Large well-differentiated hepatocellular carcinoma (HCC) ≥ 3 cm (defined as atypical HCC) is uncommon. We evaluated the characteristics and outcomes of atypical HCC patients underwent liver resection (LR). METHODS: This retrospective study enrolled patients who underwent LR for HCC from 2007 to 2017. Patient characteristics and overall survival (OS) were compared between patients with atypical HCC and patients with typical HCC (moderate-to-undifferentiated HCC ≥ 3 cm). RESULTS: Among 598 patients, 51 (8.5%) had atypical HCC. Patients with atypical HCC had higher rates of non-hepatitis B or C infections (p = 0.02) and American Joint Committee on Cancer T1 pathology (p < 0.001), a lower rate of alpha-fetoprotein >20 ng/ml (p < 0.001) and a longer OS (p < 0.001) than those with typical HCC. Multivariate analysis showed that atypical HCC was associated with OS (HR = 0.50, 95% CI = 0.27-0.91, p = 0.02). CONCLUSIONS: Patients with atypical HCC have a higher rate of non-hepatitis B or C infections and a lower rate of aggressive tumor biologic behavior. Atypical HCC is an independent predictor of OS.

Significant association between serum Wisteria floribunda agglutinin-positive Mac-2-binding protein and prognosis of hepatocellular carcinoma after surgical treatment.

Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) is a novel marker for evaluating fibrosis and predicting the development of hepatocellular carcinoma (HCC). However, the role of WFA+-M2BP in the prognosis of HCC patients after curative surgery remains unknown. In this study, we aimed to evaluate the prognostic role of serum WFA+-M2BP in HCC patients after curative resection and liver transplantation. We enrolled 460 HCC patients (357 resection and 103 transplantation) to analyze the risk factors for HCC recurrence and patient's survival. We employed time-to-event models using univariate and multivariable Cox proportional hazards regression analyses and calculated the hazard ratios (HRs) and adjusted HRs with their corresponding 95% confidence intervals (CIs). The levels of WFA+-M2BP were 0.19-14.51 COI (median 1.08) in patients of hepatectomy and 0.47-19.90 COI (median 6.0) in transplant patients. The levels of WFA+-M2BP in liver transplant patients is much higher than that of hepatectomy patients. Overall, liver fibrotic stage was positively correlated to WFA+-M2BP levels (P<0.0001). This study demonstrated that elevated WFA+-M2BP level (COI ≥0.75) was associated with a higher HCC recurrence rate in the resection group (P<0.001). Survival analysis showed that an elevated WFA+-M2BP level (COI ≥1.43) is associated with a higher mortality risk after surgical resection (P=0.0088) in the univariate analysis only. In liver transplant patients, WFA+-M2BP level (COI ≥3.81) did not predict HCC recurrence at all, but was associated poor survival after transplantation, with a borderline significance (P=0.0943). Serum WFA+-M2BP is a reliable marker for liver fibrosis in the present study. It is also reliable marker to predict prognosis of HCC after surgical resection. However, the prognostic role of WFA+-M2BP in HCC related transplants is equivocal, which is different from that of surgical resection.

Elevated neutrophil-to-lymphocyte ratio and predominance of intrahepatic cholangiocarcinoma prediction of poor hepatectomy outcomes in patients with combined hepatocellular-cholangiocarcinoma.

OBJECTIVES: Although elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with survival in some liver cancers, its prognostic relevance has not been studied in the context of combined hepatocellular cholangiocarcinoma CHCC-CC, a rare primary liver cancer. We investigated whether elevated NLR and a predominance of cholangiocarcinoma might predict poor prognosis in patients with resectable CHCC-CC. METHODS: We retrospectively reviewed the clinicopathologic data of forty-two patients with CHCC-CC receiving hepatectomies at our hospital. We used Kaplan-Meier and Cox regression to analyze survival. RESULTS: Two-year disease-free survival and five-year overall survival rates were 43.2% and 32.9%, respectively. Univariate analyses showed that patients with NLR ≥3 had significantly worse 2-year DFS and 5-year OS rates. Univariant Kaplan-Meier survival analysis also associated these rates with a predominance in intrahepatic cholangiocarcinoma, AJCC tumor stage, pathological T stage and lymph-vascular invasion. However, our multivariate analysis found NLR ≥3 to be the only independent predictor of disease recurrence and poorer survival. CONCLUSIONS: Neutrophil-to-lymphocyte ratio was the most important independent predictor of poorer survival in patients with resectable CHCC-CC. Predominance of intrahepatic cholangiocarcinoma, advanced AJCC tumor stage and pathological T stage, and lymph-vascular invasion also may affect poor prognosis in patients receiving complete tumor resections.

Early transcriptional deregulation of hepatic mitochondrial biogenesis and its consequent effects on murine cholestatic liver injury.

Mitochondria are known to be involved in cholestatic liver injury, but the damage and biogenesis of mitochondria in response to the early stage of cholestasis is unknown. A rat model of cholestasis was established by bile duct ligation (BDL), with simultaneous creation of the sham group receiving laparotomy without BDL. A significant decrease of liver peroxisome proliferators-activated receptor gamma coactivator-1alpha, mitochondrial transcriptional factor A (Tfam) and glutathione peroxidase (GPx) mRNA and Tfam protein from 6 to 72 h after BDL was found, which was associated with significant decrease of the glutathione, GPx and catalase activity at 72 h. At 72 h after BDL, mitochondrial DNA copy number reached the lowest level, while caspase 9 and 3 activity, but not caspase 8, Bax, Bcl(2), Fas L and Fas-Fas L complex, were upregulated significantly in the liver homogenates of BDL rats. The apoptotic liver cells appeared in large amounts in the rat liver by 72 h after BDL. Our results indicate that transcriptional regulation of the mitochondrial biogenesis is impaired within a few hours after complete bile duct obstruction, resulting in later mitochondrial dysfunction and consequent cholestatic liver injury via the intrinsic apoptosis pathway.

Computerized analyses of morphology and proliferative activity differentiate hepatoblastoma from paediatric hepatocellular carcinoma.

AIMS: To differentiate hepatoblastoma (HB) from hepatocellular carcinoma (HCC) by computerized image analysis. This is critical for treatment modalities and prognostic stratification but is usually difficult in small biopsy specimens. METHODS AND RESULTS: Computerized image-processing technology was used to calculate the nuclear-cytoplasmic ratio (N/C), cellularity (CEL) and other cellular and nuclear parameters in HB (n = 18) and paediatric HCC (pHCC, n = 11). The proliferation index (PI) and apoptotic index (AI) were also measured. Fetal type HB (FHB) compared with pHCC had more uniform nuclei (P < or = 0.014), lower PI (P = 0.028) and AI (P = 0.009), whereas the embryonal type HB (EHB) had a higher N/C (P < 0.001), higher CEL (P = 0.043), smaller cells (P = 0.043) and higher PI (P = 0.020) than pHCC. Moreover, EHB had a higher N/C (P < 0.001), higher CEL (P = 0.021), smaller cells (P = 0.021), more nuclear pleomorphism (P < or = 0.036) and higher PI (P < 0.001) than FHB. Multivariate analysis showed that FHB, EHB and pHCC could be classified accurately by a regression model. This logistic model further correctly stratified four additional test cases from biopsy specimens. CONCLUSIONS: These results indicate that computerized morphometric analysis can yield useful criteria to distinguish HB from pHCC in small biopsy specimens, and, compared with FHB, the poorer prognosis of EHB may result from its more undifferentiated (immature) and proliferative phenotype.

Diabetes is associated with advanced fibrosis and fibrosis progression in non-genotype 3 chronic hepatitis C patients.

BACKGROUND: Diabetes is a risk factor of fibrosis progression in chronic hepatitis C (CHC). However, only one longitudinal study exploring whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in CHC patients has been conducted. AIMS: We investigated whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients. METHODS: A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC was studied. After excluding patients with biopsy-proven or ultrasound-identified cirrhosis, there were 684 patients without cirrhosis. All 684 patients underwent hepatocellular carcinoma surveillance using ultrasound every 6 months, with a median duration of follow-up evaluation of 102.4 months. During the follow-up period, 60 patients developed cirrhosis according to ultrasound findings. RESULTS: For the subgroup of 684 patients without cirrhosis, Kaplan-Meier survival analyses showed no significantly different cumulative incidences of cirrhosis (log-rank test; P = 0.71) among the patients with diabetes as compared to those without. However, after making adjustments for age, gender, fibrosis, steatosis, sustained virological response status, and obesity using Cox's proportional hazard model, diabetes was found to be an independent predictor for cirrhosis (HR = 1.9; 95% CI = 1.05-3.43, P = 0.03). CONCLUSIONS: Diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients.

Ultrasound is highly specific in diagnosing compensated cirrhosis in chronic hepatitis C patients in real world clinical practice.

Ultrasound is routinely used during the evaluation of liver cirrhosis. Inter-observer variability is considered a major drawback. This retrospective study investigated the accuracy of ultrasound in diagnosing compensated cirrhosis (i.e., modified Knodell F3, F4) in chronic hepatitis C (CHC) patients in real world clinical practice. Consecutive treatment-naive CHC patients who underwent liver biopsy (LB) prior to interferon therapy from 1997 to 2010 were enrolled. Ultrasound was performed by 30 hepatologists prior to LB. Ultrasound-identified cirrhosis was defined as small liver size, nodular liver surface and coarse liver parenchyma. LB was used as a reference, and the diagnostic accuracy of ultrasound was assessed and compared. Fibrosis was scored according to the modified Knodell classification. A cohort comprising 1738 patients, including 922 men and 816 women with a mean age of 52.5 years, was analyzed in the present study. The distribution of the patients' modified Knodell scores was F0 = 336, F1 = 489, F2 = 165, F3 = 315, F4 = 433. Ultrasound-identified cirrhosis was noted in 283 patients. Using ultrasound-identified cirrhosis to predict compensated cirrhosis, the sensitivity was 34.0%, the specificity was 97.1%, the positive predictive value was 89.8%, the negative predictive value was 66.1%, the positive likelihood ratio was 11.6, and the negative likelihood ratio was 0.68. The area under the ROC curve (AUROC) was 0.66.Despite being affected by inter-observer variability, ultrasound is highly specific in diagnosing compensated cirrhosis in CHC patients in real world clinical practice. However, the sensitivity is low.