The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis.

BACKGROUND: Direct-acting anti-viral therapy (DAA) has transformed hepatitis C virus (HCV) care, particularly in patients with decompensated cirrhosis. However, their impact on hepatocellular carcinoma (HCC) remains unclear. AIM: To use a national registry of patients with advanced liver disease to explore the relationship between DAA therapy and HCC. METHODS: All patients with de novo HCC post DAA therapy were frequency matched with patients who did not develop HCC. Demographic, clinical and laboratory data were obtained. Cross-sectional imaging and multidisciplinary team reports were reviewed for dates of HCC diagnosis and HCC progression. Patients were categorised by treatment outcome and time of HCC development. Data were examined by multivariable analysis and Kaplan-Meier estimation. RESULTS: Eighty patients with HCC were compared with 165 patients without HCC, treated between June 2014 and September 2015. Mean follow-up from start of DAA therapy was 32.4 months. Twenty-eight patients were diagnosed with early HCC (within 6 months of therapy) and 52 presented late. Baseline nonmalignant lesions (HR: 1.99), thrombocytopaenia (HR: 1.59) and diabetes (HR: 1.68) increased likelihood of HCC. Response to therapy was reduced in patients who developed liver cancer (SVR in patients with HCC = 54/80 (68%), SVR in patients without HCC = 143/165 (87%), P < 0.001, OR: 3.13, 95% CI: 1.64-5.99). We found no difference between tumour size, progression or survival between viraemic and nonviraemic patients. CONCLUSION: There is no alteration in prognosis or cancer progression following HCC development after HCV treatment. However, baseline nonmalignant liver lesions, diabetes and thrombocytopaenia increase the risk of HCC, and HCC is associated with a decreased SVR rate.

Chemical synapses without synaptic vesicles: Purinergic neurotransmission through a CALHM1 channel-mitochondrial signaling complex.

Conventional chemical synapses in the nervous system involve a presynaptic accumulation of neurotransmitter-containing vesicles, which fuse with the plasma membrane to release neurotransmitters that activate postsynaptic receptors. In taste buds, type II receptor cells do not have conventional synaptic features but nonetheless show regulated release of their afferent neurotransmitter, ATP, through a large-pore, voltage-gated channel, CALHM1. Immunohistochemistry revealed that CALHM1 was localized to points of contact between the receptor cells and sensory nerve fibers. Ultrastructural and super-resolution light microscopy showed that the CALHM1 channels were consistently associated with distinctive, large (1- to 2-µm) mitochondria spaced 20 to 40 nm from the presynaptic membrane. Pharmacological disruption of the mitochondrial respiratory chain limited the ability of taste cells to release ATP, suggesting that the immediate source of released ATP was the mitochondrion rather than a cytoplasmic pool of ATP. These large mitochondria may serve as both a reservoir of releasable ATP and the site of synthesis. The juxtaposition of the large mitochondria to areas of membrane displaying CALHM1 also defines a restricted compartment that limits the influx of Ca2+ upon opening of the nonselective CALHM1 channels. These findings reveal a distinctive organelle signature and functional organization for regulated, focal release of purinergic signals in the absence of synaptic vesicles.

The natural history of hepatitis C with severe hepatic fibrosis.

BACKGROUND/AIMS: To examine the morbidity and mortality of patients with severe fibrosis secondary to HCV infection, within a population unbiased by tertiary referral. METHODS: One hundred and fifty HCV infected patients were identified from the Trent HCV study with a liver biopsy taken before 2002 demonstrating severe fibrosis (Ishak stage > or =4). Follow-up data were extracted from the database and hospital records. RESULTS: Median follow-up was 51 months. Of the 131 patients with no prior history of decompensation, 33 (25%) died (n=25) or were transplanted (n=8), after a median interval of 42 months. The probability of survival without liver transplantation was 97%, 88%, and 78% at 1, 3, and 5 years, respectively. Hepatocellular carcinoma and/or decompensation was diagnosed in 33 (25%), after a median interval of 41 months. In multivariate analysis, combination antiviral therapy was associated with improved survival. Prognosis was not affected by the Ishak stage at index biopsy. There was a worse prognosis for the 19 patients with previous decompensation; 17 (89%) having either died (n=15) or been transplanted (n=2). CONCLUSIONS: This study demonstrates that severe liver fibrosis (Ishak stage > or = 4) secondary to hepatitis C is associated with a poor prognosis, that may be improved following combination antiviral treatment.