Gender Matters: Characteristics of Hepatocellular Carcinoma in Women From a Large, Multicenter Study in the United States.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further. METHODS: Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS: Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031). DISCUSSION: The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).

A Single-Center Study of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Recurrence in Recipients of Liver Transplant for Treatment of Nonalcoholic Steatohepatitis Cirrhosis.

OBJECTIVES: Nonalcoholic steatohepatitis is a growing indication for liver transplant. We examined multiple granular elements to determine risk factors for recurrence of nonalcoholic steatohepatitis or recurrence of nonalcoholic fatty liver disease. MATERIALS AND METHODS: This is a retrospective, single-center study of patients who underwent liver transplant for nonalcoholic steatohepatitis. Demographic differences were assessed with the Wilcoxon and Pearson tests for continuous and discrete variables, respectively. We used a linear mixed effects model to estimate mean changes in body mass index and laboratory measurements. Time to graft loss was analyzed with the Cox proportional hazards model. RESULTS: From 1998 to 2017, there were 275 patients at our center who underwent liver transplant as treatment for nonalcoholic steatohepatitis cirrhosis. Of these patients, 31 (11%) were diagnosed with recurrent nonalcoholic steatohepatitis and 60 (22%) had recurrent nonalcoholic fatty liver disease. Patients with or without recurrence of either nonalcoholic steatohepatitis or nonalcoholic fatty liver disease were similar with regard to Model for End-Stage Liver Disease score, body mass index, sex, ethnicity, comorbidity, and donor characteristics, including donor macrosteatosis. Exposures to several medication classes were examined, but there was no association with recurrence of either nonalcoholic steatohepatitis or nonalcoholic fatty liver disease. Changes in aspartate aminotransferase and alanine aminotransferase levels over time were correlated with recurrence of either nonalcoholic steatohepatitis or nonalcoholic fatty liver disease versus levels observed in the groups with no recurrent disease. There was no difference in graft survival for the groups with recurrence of either nonalcoholic steatohepatitis or nonalcoholic fatty liver disease. CONCLUSIONS: Recurrence of nonalcoholic fatty liver disease and recurrence of nonalcoholic steatohepatitis were not associated with increased mortality after liver transplant. There were notable steady increases in body mass index after transplant for all patients who received liver transplant as treatment for nonalcoholic steatohepatitis.

An Anomalous Cause of Portal Hypertension.

Portal hypertension is a syndrome marked by an increase in the pressure of the portal vein. Portal hypertension can be diagnosed clinically or if the measurement of the hepatic venous pressure gradient is greater than 5 mm Hg. Cirrhosis is the most common etiology in Western countries, but there are other causes which lead to presinusoidal portal hypertension. We present a patient with a rare cause of portal hypertension.

Distinctive Features and Outcomes of Hepatocellular Carcinoma in Patients With Alcohol-Related Liver Disease: A US Multicenter Study.

INTRODUCTION: The burden of hepatocellular carcinoma (HCC) occurring in patients with alcoholic liver disease (ALD) is increasing at an alarming rate. The aims of this study were to compare the patient and tumor characteristics of HCC occurring in ALD-alone relative to and in addition to other chronic liver diseases. METHODS: Patients diagnosed with HCC between 2000 and 2014 were identified at 5 US clinical centers. The patients were categorized as ALD-alone, ALD plus viral hepatitis, or a non-ALD etiology. Clinical and tumor characteristics among the 3 groups were compared, and survival probability was estimated by the Kaplan-Meier method. The frequency of noncirrhotic HCC was compared across the 3 groups. RESULTS: A total of 5,327 patients with HCC were analyzed. Six hundred seventy (12.6%) developed HCC due to underlying ALD. Ninety-one percent of ALD-related HCC arose in men, in contrast to non-ALD etiologies where men accounted for 70% of HCCs cases (P < 0.001). Patients with ALD-alone-related HCC were older at diagnosis and had tumors less likely to be detected as part of routine surveillance. The ALD-alone cohort was least likely to be within the Milan criteria and to undergo liver transplantation. Overall survival in the ALD-alone HCC cohort was lower than the other 2 groups (1.07 vs 1.31 vs 1.41 years, P < 0.001). HCC in the noncirrhotic ALD cohorts occurred in only 3.5% of the patients compared with 15.7% in patients with non-ALD etiologies (P < 0.001). DISCUSSION: HCC occurring in patients with ALD occurred mostly in older men and almost exclusively in a cirrhotic background. They present with advanced tumors, and their survival is lower than HCCs occurring in non-ALD.

Hepatocellular Carcinoma in Hispanic Patients: Trends and Outcomes in a Large United States Cohort.

Hepatocellular carcinoma (HCC) has a strong racial and ethnic association, with Hispanic patients having a higher incidence and mortality. However, there are limited data regarding clinical features and outcomes. This study includes Hispanic and non-Hispanic White patients with HCC diagnosed between January 2000 and June 2014 from five United States academic medical centers. The chi-square test for categorical variables and analysis of variance for continuous variables were used for statistical analysis, with two-tailed P < 0.05 considered statistically significant. Of 5,327 patients, 4,217 met inclusion criteria, of whom 12.3% were Hispanic patients. Compared to their non-Hispanic White counterparts, Hispanic patients were older at age of diagnosis (mean ± SD, 64.2 ± 10.9 vs. 61.9 ± 10.5 years; P < 0.0001), with higher body mass index (29.6 ± 6.5 vs. 28.8 ± 5.9 kg/m2; P = 0.01), and were more likely to have diabetes and hypertension. Hispanic patients had significantly more nonalcoholic fatty liver disease and alcohol-related liver disease (both P < 0.0001). Hispanic patients presented with larger tumors, more advanced stage disease, and increased rates of macrovascular invasion and extrahepatic spread. HCCs in Hispanic patients were less likely to be within Milan criteria (26% vs. 38%; P < 0.0001) and were less likely to be treated with resection (9% vs. 13%; P = 0.03) or transplantation (8% vs. 19%; P < 0.0001). Hispanic patients had a median overall survival of 1.4 years (95% confidence interval [CI], 1.22-1.56), which was similar to that of non-Hispanic White patients (1.3 years; 95% CI, 1.26-1.41; P = 0.07). Conclusion: Hispanic patients with HCC were more likely to have metabolic risk factors for chronic liver disease, including obesity. Despite diagnosis at more advanced stages with less curative intervention than non-Hispanic White patients, median overall survival was similar between groups.

More than the heart: Hepatic, renal, and cardiac dysfunction in adult Fontan patients.

SETTING: Fontan-associated liver disease universally affects adults with single ventricle heart disease. Chronic kidney disease is also highly prevalent in adult Fontan patients. In this study, we evaluate the relationship of Fontan hemodynamics invasively and noninvasively with extra-cardiac dysfunction as measured by MELD and MELD-XI. OBJECTIVE: We hypothesize that invasive and noninvasive measures of Fontan circuit congestion and ventricular dysfunction are associated with increased MELD and MELD-XI scores. DESIGN: Single-center data from adults with Fontan palliation who had ongoing care, including cardiac catheterization, were retrospectively collected. Hemodynamic data from cardiac catheterization and echocardiographic assessment of ventricular and atrioventricular valve function were tested for association with serum creatinine, MELD, and MELD-XI. Linear regression was used to perform multivariable analysis in the echocardiogram cohort. RESULTS: Fifty-seven patients had congruent lab and catheterization data for analysis. Sixty-three and sixty-nine patients had congruent lab and echocardiogram data for MELD and MELD-XI, respectively. Of the hemodynamic variables analyzed, only decreased systemic oxygen saturation had significant correlation with elevated MELD and MELD-XI (P = .045). Patients with moderately or severely reduced ejection fraction by echocardiogram had significantly higher MELD and MELD-XI scores compared to those with normal or mildly depressed systolic ventricular function (P = .008 and P < .001 for MELD and MELD-XI, respectively). Significant differences in creatinine were also found among the ventricular dysfunction groups (P = .02). CONCLUSIONS: In adults following Fontan palliation, systolic ventricular dysfunction and decreased oxygen saturation were associated with hepatic and renal dysfunction as assessed by elevated serum creatinine, MELD, and MELD-XI scores.

Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study.

BACKGROUND: Limited data exist on the burden and features of non-cirrhotic hepatocellular carcinoma (HCC) in the United States. AIM: To evaluate characteristics, aetiologies, trends and outcomes of non-cirrhotic HCC from 2000 to 2014 at five large US centres METHODS: Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS: Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non-cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P < .001 for all). Among non-cirrhotic patients, non-alcoholic fatty liver disease (NAFLD) was the most common liver disease (26.3%), followed by hepatitis C virus (HCV) (12.1%) and hepatitis B virus (HBV) (10%) infections. As of 2014, there was increased percentage of cirrhotic HCC and a decline in non-cirrhotic HCC mainly due to significant annual increases in cirrhotic HCC due to HCV (0.96% [P < .0001]) and NAFLD (0.66% [P = .003]). Patients with non-cirrhotic HCC had larger tumours (8.9 vs 5.3 cm), were less frequently within Milan criteria (15% vs 39%), more frequently underwent resection (43.6% vs 8%) (P < .001 for all) and had better overall survival than cirrhotic HCC patients (median 1.8 vs 1.3 years, P = .004). CONCLUSIONS: Nearly 12% of HCCs occurred in patients without underlying cirrhosis. NAFLD was the most common liver disease in these patients. During the study, the frequency of non-cirrhotic HCC decreased, whereas that of cirrhotic HCC increased. Although non-cirrhotic patients presented with more advanced HCC, their survival was better.

COMPASS: A Pilot Trial of an Early Palliative Care Intervention for Patients With End-Stage Liver Disease.

CONTEXT: Palliative care interventions have shown promise in improving quality of life and reducing health-care utilization among patients with chronic organ failure. OBJECTIVES: To evaluate the effect of a palliative care intervention for adults with end-stage liver disease. METHODS: A randomized controlled trial of patients with end-stage liver disease admitted to the hepatology service at a tertiary referral center whose attending hepatologist indicated they would not be surprised if the patient died in the following year on a standardized questionnaire was performed. Control group patients received usual care. Intervention group patients received inpatient specialist palliative care consultations and outpatient phone follow-up by a palliative care nurse. The primary outcome was time until first readmission. Secondary outcomes included days alive outside the hospital, referral to hospice care, death, readmissions, patient quality of life, depression, anxiety, and quality of end-of-life care over 6 months. RESULTS: The trial stopped early because of difficulties in accruing patients. Of 293 eligible patients, only 63 patients were enrolled, 31 in the intervention group and 32 in the control group. This pace of enrollment was only 25% of what the study had planned, and so it was deemed infeasible to complete. Despite stopping early, intervention group patients had a lower hazard of readmission (hazard ratio: 0.36, 95% confidence interval: 0.16-0.83, P = 0.017) and greater odds of having more days alive outside the hospital than control group patients (odds ratio: 3.97, 95% confidence interval: 1.14-13.84, P = 0.030). No other statistically significant differences were observed. CONCLUSION: Logistical obstacles hindered completion of the trial as originally designed. Nevertheless, a preemptive palliative care intervention resulted in increased time to first readmission and more days alive outside the hospital in the first six months after study entry.

Risk factors for hepatocellular carcinoma in cirrhosis due to nonalcoholic fatty liver disease: A multicenter, case-control study.

AIM: To identify risk factors associated with hepatocellular carcinoma (HCC), describe tumor characteristics and treatments pursed for a cohort of individuals with nonalcoholic steatohepatitis (NASH) cirrhosis. METHODS: We conducted a retrospective case-control study of a well-characterized cohort of patients among five liver transplant centers with NASH cirrhosis with (cases) and without HCC (controls). RESULTS: Ninety-four cases and 150 controls were included. Cases were significantly more likely to be male than controls (67% vs 45%, P < 0.001) and of older age (61.9 years vs 58 years, P = 0.002). In addition, cases were more likely to have had complications of end stage liver disease (83% vs 71%, P = 0.032). On multivariate analysis, the strongest association with the presence of HCC were male gender (OR 4.3, 95%CI: 1.83-10.3, P = 0.001) and age (OR = 1.082, 95%CI: 1.03-1.13, P = 0.001). Hispanic ethnicity was associated with a decreased prevalence of HCC (OR = 0.3, 95%CI: 0.09-0.994, P = 0.048). HCC was predominantly in the form of a single lesion with regional lymph node(s) and distant metastasis in only 2.6% and 6.3%, respectively. Fifty-nine point three percent of individuals with HCC underwent locoregional therapy and 61.5% underwent liver transplantation for HCC. CONCLUSION: Male gender, increased age and non-Hispanic ethnicity are associated with HCC in NASH cirrhosis. NASH cirrhosis associated HCC in this cohort was characterized by early stage disease at diagnosis and treatment with locoregional therapy and transplant.

Docetaxel inhibits progression of human hepatoma cell line in vitro and is effective in advanced hepatocellular carcinoma.

BACKGROUND: Current chemotherapy for advanced hepatocellular carcinoma (HCC) is insufficient; only sorafenib has been proven to provide a modest survival benefit. A future direction of chemotherapy is to tailor treatment based on the chemosensitivity of each individual tumor. By doing so, only patients who stand to benefit from therapy will be exposed to potential side-effects and morbidity. Although the use of docetaxel (DTX) for the treatment of lung, breast and gastric cancer has been reported, there are few reports about its use in the setting of HCC. METHODS: To examine the efficacy of DTX for HCC, we established a human hepatoma cell line (TK cell) from the patient's malignant ascites from peritoneal carcinomatosis and treated it with DTX in vitro. RESULTS: After we confirmed the efficacy of DTX in vitro, we treated our patient with DTX with positive results. CONCLUSION: In this study, we present a therapeutic approach by using DTX that supports the potential usefulness of personalized medicine in vitro and demonstrates it clinically.

Management of biliary complications following orthotopic liver transplantation.

Biliary complications are a major cause of morbidity following orthotopic liver transplantation with an overall incidence between 11% and 25%. The most common complications are biliary leaks, strictures, and stones. These complications have an impact on graft survival, length of hospital stay, recovery, and overall cost of care. Therefore, knowledge of these complications and their management is important to the practicing gastroenterologist. Historically, biliary complications after liver transplantation have been managed surgically. However, with the growth of therapeutic endoscopic and percutaneous radiologic methods, most of these complications can now be managed less invasively. This article focuses on the incidence, timing, mechanism, and endoscopic management of biliary leak, strictures, stones, sludge, casts, and sphincter of Oddi dysfunction following liver transplantation.

DNase I-hypersensitive sites enhance alpha1(I) collagen gene expression in hepatic stellate cells.

Liver fibrosis is characterized by a dramatic increase in the expression of type I collagen. Several deoxyribonuclease (DNase) I-hypersensitive sites (HS) have been located in the distal 5'-flanking region of the alpha1(I) collagen gene that are specific to collagen-producing cells. To assess the role of the DNase I-HS in regulating alpha1(I) collagen gene expression in hepatic stellate cells (HSCs), 3 transgenic mouse lines expressing collagen-alpha1(I) reporter genes were used (Krempen et al. Gene Expr 1999;8:151-163). The pCol9GFP transgene contains the collagen gene promoter (-3122 to +111) linked to the green fluorescent protein (GFP) reporter gene. The pCol9GFP-HS4,5 transgene contains HS4,5 and pColGFP-HS8,9 contains HS8,9 positioned upstream of the collagen promoter in pCol9GFP. HSCs isolated from transgenic mice containing pCol9GFPHS4,5 and pColGFP-HS8,9 showed earlier and higher GFP expression patterns than HSCs isolated from pCol9GFP mice. HSCs from pCol9GFP-HS4,5 showed the highest levels of GFP expression and culture-induced expression correlated with induction of the endogenous alpha1(I) collagen gene. After CCl(4) administration, pCol9GFP-HS4,5 mice showed increased GFP expression compared with pCol9GFP mice in both whole liver extracts and isolated HSCs. Several sites for DNA-protein interactions in both HS4 and HS5 were identified that included a binding site for activator protein 1. In conclusion, DNase I-HS4,5 enhance expression of the alpha1(I) collagen gene promoter in HSCs both in vitro and in vivo after a fibrogenic stimulus. The collagen-GFP transgenic mice provide a convenient and reliable model system to investigate the molecular mechanisms controlling increased collagen expression during fibrosis.

The role of focal adhesion kinase-phosphatidylinositol 3-kinase-akt signaling in hepatic stellate cell proliferation and type I collagen expression.

Following a fibrogenic stimulus, the hepatic stellate cell (HSC) undergoes a complex activation process associated with increased cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, cell attachment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-beta, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-beta mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and alpha1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, cell attachment, and PDGF-induced cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.