The etiology of liver diseases has changed in recent years, but its impact on the comparative burden of liver cancer between males and females is unclear. We estimated sex differences in the burden ...of liver cancer across 204 countries and territories from 2010 to 2019.
We analyzed temporal trends in the burden of liver cancer using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of liver cancer incidence, death, and disability-adjusted life-years (DALYs) by sex, country, region, and etiology of liver disease. Globally in 2019, the frequency of incident cases, deaths, and DALYs due to liver cancer were 376,483, 333,672, and 9,048,723 in males, versus 157,881, 150,904, and 3,479,699 in females. From 2010 to 2019, the incidence ASRs in males increased while death and DALY ASRs remained stable; incidence, death, and DALY ASRs in females decreased. Death ASRs for both sexes increased only in the Americas and remained stable or declined in remaining regions. In 2019, hepatitis B was the leading cause of liver cancer death in males, and hepatitis C in females. From 2010 to 2019, NASH had the fastest growing death ASRs in males and females. The ratio of female-to-male death ASRs in 2019 was lowest in hepatitis B (0.2) and highest in NASH (0.9).
The overall burden of liver cancer is higher in males, although incidence and death ASRs from NASH-associated liver cancer in females approach that of males.
MicroRNA (miRNA) is a new class of small, noncoding RNA. The purpose of this study was to determine if miRNAs are differentially expressed in hepatocellular carcinoma (HCC).
More than 200 precursor ...and mature miRNAs were profiled by real-time PCR in 43 and 28 pairs of HCC and adjacent benign liver, respectively, and in normal liver specimens.
Several miRNAs including miR-199a, miR-21, and miR-301 were differentially expressed in the tumor compared with adjacent benign liver. A large number of mature and precursor miRNAs were up-regulated in the adjacent benign liver specimens that were both cirrhotic and hepatitis-positive compared with the uninfected, noncirrhotic specimens (P < 0.01). Interestingly, all of the miRNAs in this comparison had increased expression and none were decreased. The expression of 95 randomly selected mRNAs was not significantly altered in the cirrhotic and hepatitis-positive specimens, suggesting a preferential increase in the transcription of miRNA. Comparing the miRNA expression in the HCC tumors with patient's survival time revealed two groups of patients; those with predominantly lower miRNA expression and poor survival and those with predominantly higher miRNA expression and good survival (P < 0.05). A set of 19 miRNAs significantly correlated with disease outcome. A number of biological processes including cell division, mitosis, and G(1)-S transition were predicted to be targets of the 19 miRNAs in this group.
We show that a global increase in the transcription of miRNA genes occurs in cirrhotic and hepatitis-positive livers and that miRNA expression may prognosticate disease outcome in HCC.
Oxidative stress plays a critical role in liver tissue damage and in hepatocellular carcinoma (HCC) initiation and progression. However, the mechanisms that regulate autophagy and metabolic ...reprogramming during reactive oxygen species (ROS) generation, and how ROS promote tumorigenesis, still need to be fully understood. We show that protein kinase C (PKC) λ/ι loss in hepatocytes promotes autophagy and oxidative phosphorylation. This results in ROS generation, which through NRF2 drives HCC through cell-autonomous and non-autonomous mechanisms. Although PKCλ/ι promotes tumorigenesis in oncogene-driven cancer models, emerging evidence demonstrate that it is a tumor suppressor in more complex carcinogenic processes. Consistently, PKCλ/ι levels negatively correlate with HCC histological tumor grade, establishing this kinase as a tumor suppressor in liver cancer.
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•PKCλ/ι levels negatively correlate with HCC histological tumor grade•PKCλ/ι-deficient hepatocytes promote HCC linked to increased ROS and NRF2 activation•PKCλ/ι represses autophagy directly and inhibits OXPHOS to restrain ROS and NRF2•Increased ROS and NRF2 by PKCλ/ι deficiency accounts for increased HCC
Yotaro et al. define a tumor suppressor role for PKCλ/ι in hepatocellular carcinoma (HCC). PKCλ/ι loss induces oxidative phosphorylation, reactive oxygen species production, and autophagy. These events activate an NRF2 transcriptional program that supports HCC progression.
Liver masses present a relatively common clinical dilemma, particularly with the increasing use of various imaging modalities in the diagnosis of abdominal and other symptoms. The accurate and ...reliable determination of the nature of the liver mass is critical, not only to reassure individuals with benign lesions but also, and perhaps more importantly, to ensure that malignant lesions are diagnosed correctly. This avoids the devastating consequences of missed diagnosis and the delayed treatment of malignancy or the unnecessary treatment of benign lesions. With appropriate interpretation of the clinical history and physical examination, and the judicious use of laboratory and imaging studies, the majority of liver masses can be characterized noninvasively. Accurate characterization of liver masses by cross-sectional imaging is particularly dependent on an understanding of the unique phasic vascular perfusion of the liver and the characteristic behaviors of different lesions during multiphasic contrast imaging. When noninvasive characterization is indeterminate, a liver biopsy may be necessary for definitive diagnosis. Standard histologic examination usually is complemented by immunohistochemical analysis of protein biomarkers. Accurate diagnosis allows the appropriate selection of optimal management, which is frequently reassurance or intermittent follow-up evaluations for benign masses. For malignant lesions or those at risk of malignant transformation, management depends on the tumor staging, the functional status of the uninvolved liver, and technical surgical considerations. Unresectable metastatic masses require oncologic consultation and therapy. The efficient characterization and management of liver masses therefore requires a multidisciplinary collaboration between the gastroenterologist/hepatologist, radiologist, pathologist, hepatobiliary or transplant surgeon, and medical oncologist.
Background & Aims Pancreatobiliary cancer is detected by fluorescence in situ hybridization (FISH) of pancreatobiliary brush samples with UroVysion probes, originally designed to detect bladder ...cancer. We designed a set of new probes to detect pancreatobiliary cancer and compared its performance with that of UroVysion and routine cytology analysis. Methods We tested a set of FISH probes on tumor tissues (cholangiocarcinoma or pancreatic carcinoma) and non-tumor tissues from 29 patients. We identified 4 probes that had high specificity for tumor vs non-tumor tissues; we called this set of probes pancreatobiliary FISH. We performed a retrospective analysis of brush samples from 272 patients who underwent endoscopic retrograde cholangiopancreatography for evaluation of malignancy at the Mayo Clinic; results were available from routine cytology and FISH with UroVysion probes. Archived residual specimens were retrieved and used to evaluate the pancreatobiliary FISH probes. Cutoff values for FISH with the pancreatobiliary probes were determined using 89 samples and validated in the remaining 183 samples. Clinical and pathologic evidence of malignancy in the pancreatobiliary tract within 2 years of brush sample collection was used as the standard; samples from patients without malignancies were used as negative controls. The validation cohort included 85 patients with malignancies (46.4%) and 114 patients with primary sclerosing cholangitis (62.3%). Samples containing cells above the cutoff for polysomy (copy number gain of ≥2 probes) were classified as positive in FISH with the UroVysion and pancreatobiliary probes. Multivariable logistic regression was used to estimate associations between clinical and pathology findings and results from FISH. Results The combination of FISH probes 1q21, 7p12, 8q24, and 9p21 identified cancer cells with 93% sensitivity and 100% specificity in pancreatobiliary tissue samples and were therefore included in the pancreatobiliary probe set. In the validation cohort of brush samples, pancreatobiliary FISH identified samples from patients with malignancy with a significantly higher level of sensitivity (64.7%) than the UroVysion probes (45.9%) ( P < .001) or routine cytology analysis (18.8%) ( P < .001), but similar specificity (92.9%, 90.8%, and 100.0% respectively). Factors significantly associated with detection of carcinoma, in adjusted analyses, included detection of polysomy by pancreatobiliary FISH ( P < .001), a mass by cross-sectional imaging ( P < .001), cancer cells by routine cytology (overall P = .003), as well as absence of primary sclerosing cholangitis ( P = .011). Conclusions We identified a set of FISH probes that detects cancer cells in pancreatobiliary brush samples from patients with and without primary sclerosing cholangitis with higher levels of sensitivity than UroVysion probes. Cytologic brushing test results and clinical features were independently associated with detection of cancer and might be used to identify patients with pancreatobiliary cancers.
Biliary tract cancers (BTC) are malignancies that arise from the epithelium of the biliary system and comprise the second most common type of hepatobiliary cancer worldwide. BTC are sub-classified as ...intrahepatic cholangiocarcinoma (iCCA), perhilar/hilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA), and gallbladder carcinoma. Due to the differences in their etiologic risk factors, pathogenesis, and molecular and genetic characteristics, each of these subtypes is considered a separate biological entity. The geographic diversity of risk factors for the subtypes of biliary cancers results in profound differences in the worldwide incidence of each. In this article we provide a review of the current epidemiology of BTC and their associated risk factors. Further, we discuss the available evidence for genetic predisposition to BTC and anticipate the results of planned large-scale, genome-wide association studies (GWAS) exploring the inherited sequence variants conferring risk of BTC. These studies may also potentially of reveal important pathogenic mechanisms of the biliary tract cancer subtypes.
Liver-related diseases, including liver cirrhosis and hepatocellular carcinoma (HCC), are significant causes of mortality globally. Specific causes and predictors of liver-related mortality in low ...resource settings require assessment to help inform clinical decision making and develop strategies for improved survival. The objectives of this study were to determine the proportion of liver-related deaths associated with liver cirrhosis, HCC, and their known risk factors, and secondly to determine predictors of in-hospital mortality among cirrhosis and HCC patients in Ghana. We first performed a cross-sectional review of death register entries from 11 referral hospitals in Ghana to determine the proportion of liver-related deaths and the proportion of risk factors associated with these deaths. Secondly, we conducted a retrospective cohort review of 172 in-patient liver cirrhosis and HCC cases admitted to a tertiary referral centre and determined predictors of in-hospital mortality using binary logistic regression and Kaplan-Meier survival analysis. In total, 8.8% of deaths in Ghanaian adults were due to liver-related causes. The proportion of liver-related deaths attributed to HBV infection was 48.8% (95% CI: 45.95–51.76), HCV infection was 7.0% (95% CI: 5.58–8.45), HBV-HCV co-infection 0.5% (95% CI: 0.1–0.9) and alcohol was 10.0% (95% CI: 8.30–11.67). Of 172 cases of HCC and liver cirrhosis, the in-patient mortality rate was 54.1%. Predictors of in-patient mortality in cirrhotic patients were increasing WBC (OR = 1.14 95% CI: 1.00–1.30) and the revised model for end-stage liver disease with sodium (MELD-Na) score (OR = 1.24 95% CI: 1.01–1.54). For HCC patients, female sex (OR = 3.74 95% CI: 1.09–12.81) and hepatic encephalopathy (grade 1) were associated with higher mortality (OR = 5.66 95% CI: 1.10–29.2). In conclusion, HBV is linked to a high proportion of HCC-related deaths in Ghana, with high in-hospital mortality rates that require targeted policies to improve survival.
The risks and benefits of metformin use in patients with cirrhosis with diabetes are debated. Although data on a protective effect of metformin against liver cancer development have been reported, ...metformin is frequently discontinued once cirrhosis is diagnosed because of concerns about an increased risk of adverse effects of metformin in patients with liver impairment. This study investigated whether continuation of metformin after cirrhosis diagnosis improves survival of patients with diabetes. Diabetic patients diagnosed with cirrhosis between 2000 and 2010 who were on metformin at the time of cirrhosis diagnosis were identified (n = 250). Data were retrospectively ed from the medical record. Survival of patients who continued versus discontinued metformin after cirrhosis diagnosis was compared using the log‐rank test. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using Cox's proportional hazards analysis. Overall, 172 patients continued metformin whereas 78 discontinued metformin. Patients who continued metformin had a significantly longer median survival than those who discontinued metformin (11.8 vs. 5.6 years overall, P < 0.0001; 11.8 vs. 6.0 years for Child A patients, P = 0.006; and 7.7 vs. 3.5 years for Child B/C patients, P = 0.04, respectively). After adjusting for other variables, continuation of metformin remained an independent predictor of better survival, with an HR of 0.43 (95% CI: 0.24‐0.78; P = 0.005). No patients developed metformin‐associated lactic acidosis during follow‐up. Conclusion: Continuation of metformin after cirrhosis diagnosis reduced the risk of death by 57%. Metformin should therefore be continued in diabetic patients with cirrhosis if there is no specific contraindication. (Hepatology 2014;60:2007–2015)
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