Validation of a Congestive Hepatic Fibrosis Scoring System.

Congestive hepatopathy is a complication of right heart failure and chronically elevated right heart pressure. Histologic findings include sinusoidal dilatation, centrilobular hepatocellular plate atrophy, and fibrosis. We performed a validation study of a recently proposed scoring system (0 to 4 scale) for congestive hepatic fibrosis on 38 liver biopsies. Glutamine synthetase immunohistochemistry was also performed, and loss of centrizonal immunoreactivity correlated with increasing fibrosis score (P<0.01). Interobserver concordance for congestive hepatic fibrosis score based on Masson trichrome stain was initially fair (Fleiss κ=0.28, weighted concordance coefficient=0.60) and significantly improved (κ=0.40, weighted concordance coefficient=0.66) following a multiheaded microscope training session and inclusion of glutamine synthetase immunohistochemistry. Average congestive hepatic fibrosis score correlated with significantly higher right atrial pressure, severity of right atrial dilation, presence of right ventricular dilation, elevated serum alanine aminotransferase, platelet counts, prothrombin time, and model for end-stage liver disease score. In conclusion, the congestive hepatic fibrosis scoring system is reproducible among pathologists and correlates with clinical and laboratory markers of congestive hepatopathy.

Segmental Yttrium-90 Radioembolization versus Segmental Chemoembolization for Localized Hepatocellular Carcinoma: Results of a Single-Center, Retrospective, Propensity Score-Matched Study.

PURPOSE: To compare segmental radioembolization with segmental chemoembolization for localized, unresectable hepatocellular carcinoma (HCC) not amenable to ablation. MATERIALS AND METHODS: In a single-center, retrospective study (2010-2015), 101 patients with 132 tumors underwent segmental radioembolization, and 77 patients with 103 tumors underwent segmental doxorubicin-based drug-eluting embolic or conventional chemoembolization. Patients receiving chemoembolization had worse performance status (Eastern Cooperative Oncology Group 0, 76% vs 56%; P = .003) and Child-Pugh class (class A, 65% vs 52%; P = .053); patients receiving radioembolization had larger tumors (32 mm vs 26 mm; P < .001), more infiltrative tumors (23% vs 9%; P = .01), and more vascular invasion (18% vs 1%; P < .001). Toxicity, tumor response, tumor progression, and survival were compared. Analyses were weighted using a propensity score (PS). RESULTS: Toxicity rates were low, without significant differences. Index and overall complete response rates were 92% and 84% for radioembolization and 74% and 58% for chemoembolization (P = .001 and P < .001). Index tumor progression at 1 and 2 years was 8% and 15% in the radioembolization group and 30% and 42% in the chemoembolization group (P < .001). Median progression-free and overall survival were 564 days and 1,198 days in the radioembolization group and 271 days and 1,043 days in the chemoembolization group (PS-adjusted P = .002 and P = .35; censored by transplant PS-adjusted P < .001 and P = .064). CONCLUSIONS: Segmental radioembolization demonstrates higher complete response rates and local tumor control compared with segmental chemoembolization for HCC, with similar toxicity profiles. Superior progression-free survival was achieved.

Irreversible Electroporation Can Effectively Ablate Hepatocellular Carcinoma to Complete Pathologic Necrosis.

PURPOSE: To describe full explant pathology and radiographic correlation in patients with hepatocellular carcinoma (HCC) treated with irreversible electroporation (IRE) who subsequently underwent liver transplant. MATERIALS AND METHODS: In a retrospective study, 6 patients who had undergone IRE for HCC and subsequent orthotopic liver transplant during the period 2011-2013 were evaluated. Of the 6 patients, 4 had Child-Pugh class A cirrhosis, and 2 had class B cirrhosis. Irreversible electroporation was performed for a single focal HCC with median tumor diameter of 22 mm (range, 6-26 mm). After IRE, follow-up multiphasic cross-sectional imaging was performed at 1 month and every 3 months thereafter until liver transplant. Mean time between IRE and transplant was 10 months (range, 3-17 mo). Assessment of imaging response was based on modified Response Evaluation Criteria In Solid Tumors. Liver explants were evaluated for necrosis and viable carcinoma in IRE-treated tumors. RESULTS: After IRE, all tumors showed a complete response on follow-up imaging. Five tumors showed complete pathologic necrosis without any viable carcinoma, sharply demarcated from the surrounding hepatic parenchyma. Bile ducts within the treatment area were preserved. A single tumor treated with a bipolar IRE probe had < 5% viable carcinoma cells at the periphery. CONCLUSIONS: This study demonstrates the efficacy of IRE for HCC based on pathologic evaluation and correlation to radiologic findings.

Multidisciplinary perspective of hepatocellular carcinoma: A Pacific Northwest experience.

Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer in the United States. HCC is a highly malignant cancer, accounting for at least 14000 deaths in the United States annually, and it ranks third as a cause of cancer mortality in men. One major difficulty is that most patients with HCC are diagnosed when the disease is already at an advanced stage, and the cancer cannot be surgically removed. Furthermore, because almost all patients have cirrhosis, neither chemotherapy nor major resections are well tolerated. Clearly there is need of a multidisciplinary approach for the management of HCC. For example, there is a need for better understanding of the fundamental etiologic mechanisms that are involved in hepatocarcinogenesis, which could lead to the development of successful preventive and therapeutic modalities. It is also essential to define the cellular and molecular bases for malignant transformation of hepatocytes. Such knowledge would: (1) greatly facilitate the identification of patients at risk; (2) prompt efforts to decrease risk factors; and (3) improve surveillance and early diagnosis through diagnostic imaging modalities. Possible benefits extend also to the clinical management of this disease. Because there are many factors involved in pathogenesis of HCC, this paper reviews a multidisciplinary perspective of recent advances in basic and clinical understanding of HCC that include: molecular hepatocarcinogenesis, non-invasive diagnostics modalities, diagnostic pathology, surgical modality, transplantation, local therapy and oncological/target therapeutics.

Outcomes of Locoregional Tumor Therapy for Patients with Hepatocellular Carcinoma and Transjugular Intrahepatic Portosystemic Shunts.

PURPOSE: Locoregional therapy for hepatocellular carcinoma (HCC) can be challenging in patients with a transjugular intrahepatic portosystemic shunt (TIPS). This study compares safety and imaging response of ablation, chemoembolization, radioembolization, and supportive care in patients with both TIPS and HCC. METHODS: This retrospective study included 48 patients who had both a TIPS and a diagnosis of HCC. Twenty-nine of 48 (60%) underwent treatment for HCC, and 19/48 (40%) received best supportive care (i.e., symptomatic management only). While etiology of cirrhosis and indication for TIPS were similar between the two groups, treated patients had better baseline liver function (34 vs. 67% Child-Pugh class C). Tumor characteristics were similar between the two groups. A total of 39 ablations, 17 chemoembolizations, and 10 yttrium-90 radioembolizations were performed on 29 patients. RESULTS: Ablation procedures resulted in low rates of hepatotoxicity and clinical toxicity. Post-embolization/ablation syndrome occurred more frequently in patients undergoing chemoembolization than ablation (47 vs. 15%). Significant hepatic dysfunction occurred more frequently in the chemoembolization group than the ablation group. Follow-up imaging response showed objective response in 100% of ablation procedures, 67% of radioembolization procedures, and 50% of chemoembolization procedures (p = 0.001). When censored for OLT, patients undergoing treatment survived longer than patients receiving supportive care (2273 v. 439 days, p = 0.001). CONCLUSIONS: Ablation appears to be safe and efficacious for HCC in patients with TIPS. Catheter-based approaches are associated with potential increased toxicity in this patient population. Chemoembolization appears to be associated with increased toxicity compared to radioembolization.

Impact of locoregional therapy and alpha-fetoprotein on outcomes in transplantation for liver cancer: a UNOS Region 6 pooled analysis.

Liver transplantation (LT) provides optimal long-term disease-free survival for hepatocellular carcinoma (HCC). High pre-LT alpha-fetoprotein (AFP) has been associated with HCC recurrence, but it is unclear whether a drop in AFP or locoregional therapy impacts survival/recurrence after LT. LT-recipients transplanted for HCC in three centers (UNOS Region 6) were reviewed (2006-2009) for demographics, tumor characteristics, locoregional therapy, AFP, recurrence, and survival. Among 211 LT recipients (mean age 56.4 yr, 83% male, mean MELD 12.2), 94% met Milan criteria and 61% received locoregional therapy. Mean disease-free survival (DFS) was 1549.7 d, and 84% are currently alive. Factors affecting DFS included recurrence (RR, 0.074; 95% CI, 0.038-0.14), normal peak AFP (29.6, 95% CI, 2.96-296.3), peak AFP >400 (RR, 0.15; 95% CI, 0.03-0.73) and AFP at LT >400 (RR, 15.5; 95% CI, 2.4-100.5). Twenty-one patients had recurrence and were more likely beyond Milan criteria (5/23(21%) vs. 8/220 (4%), p = 0.0038), with peak AFP >400 and AFP at LT >400 (p = 0.001). Locoregional therapy did not affect mean DFS (1458.0 vs. 1603.8 d, p = 0.05) or recurrence (12.5% vs. 6%). Predictors of recurrence were similar to previous studies, including high AFP and tumor outside Milan criteria. While locoregional therapy itself did not affect DFS/recurrence, a decrease in AFP pre-transplant appears to positively influence outcomes in those who received locoregional therapy.

Proteome and computational analyses reveal new insights into the mechanisms of hepatitis C virus-mediated liver disease posttransplantation.

UNLABELLED: Liver transplant tissues offer the unique opportunity to model the longitudinal protein abundance changes occurring during hepatitis C virus (HCV)-associated liver disease progression in vivo. In this study, our goal was to identify molecular signatures, and potential key regulatory proteins, representative of the processes influencing early progression to fibrosis. We performed global protein profiling analyses on 24 liver biopsy specimens obtained from 15 HCV(+) liver transplant recipients at 6 and/or 12 months posttransplantation. Differentially regulated proteins associated with early progression to fibrosis were identified by analysis of the area under the receiver operating characteristic curve. Analysis of serum metabolites was performed on samples obtained from an independent cohort of 60 HCV(+) liver transplant patients. Computational modeling approaches were applied to identify potential key regulatory proteins of liver fibrogenesis. Among 4,324 proteins identified, 250 exhibited significant differential regulation in patients with rapidly progressive fibrosis. Patients with rapid fibrosis progression exhibited enrichment in differentially regulated proteins associated with various immune, hepatoprotective, and fibrogenic processes. The observed increase in proinflammatory activity and impairment in antioxidant defenses suggests that patients who develop significant liver injury experience elevated oxidative stresses. This was supported by an independent study demonstrating the altered abundance of oxidative stress-associated serum metabolites in patients who develop severe liver injury. Computational modeling approaches further highlight a potentially important link between HCV-associated oxidative stress and epigenetic regulatory mechanisms impacting on liver fibrogenesis. CONCLUSION: Our proteome and metabolome analyses provide new insights into the role for increased oxidative stress in the rapid fibrosis progression observed in HCV(+) liver transplant recipients. These findings may prove useful in prognostic applications for predicting early progression to fibrosis.

HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis.

UNLABELLED: Previous studies examining the relationship between HFE mutations and severity of nonalcoholic steatohepatitis (NASH) have been limited by small sample size or ascertainment bias. The aim of this study was to examine the relationship between HFE mutations and histological severity in a large North American multicenter cohort with NASH. Data from 126 NASH patients were collected from 6 North American centers. Liver biopsy and genotyping for the C282Y and H63D HFE mutations were performed in all subjects. Serum transferrin-iron saturation and ferritin levels as well as hepatic iron content were recorded whenever available. Univariate and multivariate logistic regression analyses were performed to identify factors associated with advanced hepatic fibrosis. The prevalence of heterozygous C282Y and H63D HFE mutations was 14.3% and 21.4%, respectively, in the overall cohort. Among Caucasians, C282Y heterozygotes were more likely to have bridging fibrosis or cirrhosis (44% versus 21% [P = 0.05]) and stainable hepatic iron (50% versus 16% [P = 0.011]) compared with patients with other genotypes. Diabetes mellitus was the only independent predictor of advanced hepatic fibrosis (OR 4.37, 95% CI 1.41-13.54 [P = 0.010]) using multiple logistic regression analysis adjusting for age, sex, ethnicity, body mass index, and HFE genotype status. CONCLUSION: The HFE C282Y heterozygous mutation is associated with advanced fibrosis among Caucasians with NASH. Additional studies are warranted to examine the possible mechanisms for this relationship.

Hepatitis C and alcohol: interactions, outcomes, and implications.

BACKGROUND: Alcoholism and chronic hepatitis C (HCV) infection are common causes of liver disease worldwide. Hepatitis C virus and alcohol use frequently coexist, and together lead to more rapid progression of liver disease. GOALS: To critically review the literature pertaining to the combined effects of alcohol and HCV, focusing primarily on how alcohol influences the natural history, pathogenesis, and treatment of HCV liver disease. STUDY: A thorough review of the English literature was conducted, using a MEDLINE-based computerized literature search and review of cited references. RESULTS: Hepatitis C virus is prevalent in unselected alcoholic populations (14-36%) and in alcoholic individuals with liver disease (< or =51%). Hepatitis C virus-infected individuals who drink alcohol in excess have more severe histologic injury, more rapid disease progression, and a higher frequency of cirrhosis and hepatocellular carcinoma. Alcohol use also appears to decrease response rates to interferon therapy. The mechanisms of interaction between alcohol and HCV are not fully understood, but they likely include the effects of alcohol on the host immune system and the virus and on other factors possibly related to HCV liver disease and hepatic carcinogenesis. CONCLUSIONS: Alcohol use and HCV infection frequently coexist. Although there is ample evidence that alcohol use adversely affects the natural history of HCV liver disease, how the two interact is not well understood. Patients with chronic HCV should be encouraged to avoid alcohol; however, the threshold above which alcohol results in accelerated liver disease remains to be determined.

Liver involvement in patients with solid tumors of nonhepatic origin.

Metastatic disease represents the most common hepatic neoplasm in the Western world. The most common primary malignancies to spread to the liver are those that originate in the gastrointestinal tract. Of non-gastrointestinal malignancies, breast, lung, and melanoma malignancies are most likely to develop hepatic metastases. Some solid tumors, such as renal cell carcinoma, may cause liver-related abnormalities in the absence of hepatic metastases, presumably by way of cytokine-mediated mechanisms. Physical examination, laboratory testing, histologic evaluation, and various radiographic studies are useful in the detection and diagnosis of liver metastases. Multiple treatment modalities are available, including hepatic resection, hepatic arterial chemotherapy, systemic chemotherapy, chemoembolization, cryotherapy, ethanol injection, and radiofrequency ablation.