Screening is associated with a lower risk of hepatocellular carcinoma-related mortality in patients with chronic hepatitis B.

BACKGROUND & AIMS: Patients with chronic hepatitis B (CHB) infection routinely undergo screening for hepatocellular carcinoma (HCC), but the efficacy of screening remains unclear. We aimed to evaluate the impact of screening with ultrasound and/or serum alpha-fetoprotein (AFP) on HCC-related mortality in patients with CHB. METHODS: We performed a matched case-control study of patients with CHB receiving care through the Veterans Affairs (VA) health administration. Cases were patients who died of HCC between 01/01/2004 and 12/31/2017, while controls were patients with CHB who did not die of HCC. Cases were matched to controls by CHB diagnosis date, age, sex, race/ethnicity, cirrhosis, antiviral therapy exposure, hepatitis B e antigen status, and viral load. We identified screening ultrasound and AFPs obtained in the 4 years preceding HCC diagnosis in cases and the equivalent index date in controls. Using conditional logistic regression, we compared cases and controls with respect to receipt of screening. A lower likelihood of screening in cases corresponds to an association between screening and reduced risk of HCC-related mortality. RESULTS: We identified 169 cases, matched to 169 controls. Fewer cases than controls underwent screening with either screening modality (33.7% vs. 58.6%) or both modalities (19.5% vs. 34.4%). In multivariable conditional logistic regression, screening with either modality was associated with a lower risk of HCC-related mortality (adjusted odds ratio [aOR] 0.21, 95% CI 0.09-0.50), as was screening with both modalities (aOR of 0.13; 95% CI 0.04-0.43). CONCLUSIONS: HCC screening was associated with a substantial reduction in HCC-related mortality in VA patients with CHB. LAY SUMMARY: Patients with hepatitis B infection have a high risk of developing liver cancer. It is therefore recommended that they undergo frequent screening for liver cancer, but whether this leads to a lower risk of dying from liver cancer is not clear. In this study, we show that liver cancer screening is associated with a reduction in the mortality from liver cancer in patients with hepatitis B infection.

Cholesterol Crystals in Hepatocyte Lipid Droplets Are Strongly Associated With Human Nonalcoholic Steatohepatitis.

It is unclear what drives the development of fibrosing nonalcoholic steatohepatitis (NASH). We aimed to determine whether cholesterol crystallization within hepatocyte lipid droplets (LDs) distinguishes patients with fibrosing NASH from patients with isolated hepatic steatosis and to study pathways leading to cholesterol accumulation in hepatocyte LDs. Patients with fibrosing NASH (n = 16) were compared to patients with isolated steatosis (n = 14). Almost all patients with fibrosing NASH had free cholesterol staining by filipin (16/16) and cholesterol crystals (15/16) in hepatocyte LDs, mostly in association with the LD membrane, compared to only 3/14 with cholesterol crystals and 3/14 with faint filipin staining in patients with isolated steatosis (P < 0.05). We were unable to identify significant differences in the expression of genes in liver tissue related to cholesterol homeostasis or LD proteins between patients with fibrosing NASH and isolated steatosis. Human hepatoma cell line (HepG2) cells were supplemented with low-density lipoprotein (LDL)-cholesterol and oleic acid to develop large LDs, similar to those observed in patients with NASH. Fluorescent markers were used to track the uptake and intracellular trafficking of LDL-cholesterol. LDL-cholesterol was taken up by HepG2 cells and transported through the endosomal-lysosomal compartment directly to LDs, suggesting direct contact sites between late endosomes and LDs. Exposure of HepG2 cells to LDL-cholesterol resulted in a high concentration of cholesterol and cholesterol crystallization in LDs. Conclusion: Excess cholesterol is stored in the liver primarily within hepatocyte LDs where it can crystallize. Our findings are best explained by direct transport of cholesterol from late endosomes/lysosomes to LDs in hepatocytes. We found a strong association between the presence of LD cholesterol crystals and the development of fibrosing NASH in humans, suggesting a causal relationship.

No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients With Cirrhosis.

BACKGROUND & AIMS: Screening patients with cirrhosis for hepatocellular carcinoma (HCC) has been recommended. We conducted a matched case-control study within the US Veterans Affairs (VA) health care system to determine whether screening by abdominal ultrasonography (USS) and/or by measuring serum level of α-fetoprotein (AFP) was associated with decreased cancer-related mortality in patients with cirrhosis. METHODS: We defined cases (n = 238) as patients with cirrhosis who died of HCC from January 1, 2013 through August 31, 2015 and had been in VA care with a diagnosis of cirrhosis for at least 4 years before the diagnosis of HCC. We matched each case to 1 control (n = 238), defined as a patient with cirrhosis who did not die of HCC and had been in VA care for at least 4 years before the date of the matched case's HCC diagnosis. Controls were matched to cases by year of cirrhosis diagnosis, race and ethnicity, age, sex, etiology of cirrhosis, Model for End-Stage Liver Disease score, and VA medical center. We identified all USS and serum AFP tests performed within 4 years before the date of HCC diagnosis in cases or the equivalent index date in controls and determined by chart extraction (blinded to case or control status) whether these tests were performed for screening. RESULTS: There were no significant differences between cases and controls in the proportions of patients who underwent screening USS (52.9% vs 54.2%), screening measurement of serum AFP (74.8% vs 73.5%), screening USS or measurement of serum AFP (81.1% vs 79.4%), or screening USS and measurement of serum AFP (46.6% vs 48.3%) within 4 years before the index date, with or without adjusting for potential confounders. There also was no difference in receipt of these screening tests within 1, 2, or 3 years before the index date. CONCLUSIONS: In a matched case-control study of the VA health care system, we found that screening patients with cirrhosis for HCC by USS, measurement of serum AFP, either test, or both tests was not associated with decreased HCC-related mortality. We encourage additional case-control studies to evaluate the efficacy of screening for HCC in other health care systems, in which available records are sufficiently detailed to enable identification of the indication for USS and AFP tests.