Sahil Mittal

Epidemiology of hepatocellular carcinoma: consider the population.

Hepatocellular carcinoma (HCC) is increasing in incidence and has a very high fatality rate. Cirrhosis due to chronic hepatitis B or hepatitis C is the leading risk factor for HCC. Global epidemiology of HCC is determined by the prevalence of dominant viral hepatitis and the age it is acquired in the underlying population. Upcoming risk factors include obesity, diabetes, and related nonalcoholic fatty liver disease. This review discusses the latest trends of HCC globally and in the United States. It also provides an evidence-based commentary on the risk factors and lists some of the preventive measures to reduce the incidence of HCC.

Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMSnHepatocellular carcinoma (HCC) can develop in individuals without cirrhosis. We investigated risk factors for development of HCC in the absence of cirrhosis in a U.S.nnnMETHODSnWe identified a national cohort of 1500 patients with verified HCC during 2005 to 2010 in the U.S. Veterans Administration (VA) and reviewed their full VA medical records for evidence of cirrhosis and risk factors for HCC. Patients without cirrhosis were assigned to categories of level 1 evidence for no cirrhosis (very high probability) or level 2 evidence for no cirrhosis (high probability), which were based on findings from histologic analyses, laboratory test results, markers of fibrosis from noninvasive tests, and imaging features.nnnRESULTSnA total of 43 of the 1500 patients with HCC (2.9%) had level 1 evidence for no cirrhosis, and 151 (10.1%) had level 2 evidence for no cirrhosis; the remaining 1203 patients (80.1%) had confirmed cirrhosis. Compared with patients with HCC in presence of cirrhosis, greater proportions of patients with HCC without evidence of cirrhosis had metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), or no identifiable risk factors. Patients with HCC without evidence of cirrhosis were less likely to have abused alcohol or have hepatitis C virus infection than patients with cirrhosis. Patients with HCC and NAFLD (unadjusted odds ratio, 5.4; 95% confidence interval, 3.4-8.5) or metabolic syndrome (unadjusted odds ratio, 5.0; 95% confidence interval, 3.1-7.8) had more than 5-fold risk of having HCC in the absence of cirrhosis, compared with patients with HCV-related HCC.nnnCONCLUSIONSnApproximately 13% of patients with HCC in the VA system do not appear to have cirrhosis. NAFLD and metabolic syndrome are the main risk factors for HCC in the absence of cirrhosis.

Temporal Trends of Nonalcoholic Fatty Liver Disease–Related Hepatocellular Carcinoma in the Veteran Affairs Population

BACKGROUND & AIMSnNonalcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, no systemic studies from the United States have examined temporal trends, HCC surveillance practices, and outcomes of NAFLD-related HCC.nnnMETHODSnWe identified a national cohort of 1500 patients who developed HCC from 2005 through 2010 from Veterans Administration (VA) hospitals. We reviewed patients full VA medical records; NAFLD was diagnosed based on histologic evidence for, or the presence of, the metabolic syndrome in the absence of hepatitis C virus (HCV) infection, hepatitis B, or alcoholic liver disease. We compared annual prevalence values for the main risk factors (NAFLD, alcohol abuse, and HCV), as well a HCC surveillance and outcomes, among HCC patients.nnnRESULTSnNAFLD was the underlying risk factor for HCC in 120 patients (8.0%); the annual proportion of NAFLD-related HCC remained relatively stable (7.5%-12.0%). In contrast, the proportion of HCC cases associated with HCV increased from 61.0% in 2005 (95% confidence interval, 53.1%-68.9%) to 74.9% in 2010 (95% confidence interval, 69.0%-80.7%). The proportion of HCC cases associated with only alcohol abuse decreased from 21.9% in 2005 to 15.7% in 2010, and the annual proportion of HCC cases associated with hepatitis B remained relatively stable (1.4%-3.5%). A significantly lower proportion of patients with NAFLD-related HCC had cirrhosis (58.3%) compared with patients with alcohol- or HCV-related HCC (72.4% and 85.6%, respectively; P < .05). A significantly higher percentage of patients with NAFLD-related HCC did not receive HCC surveillance in the 3 years before their HCC diagnosis, compared with patients with alcohol- or HCV-associated HCC. A lower proportion of patients with NAFLD-related HCC received HCC-specific treatment (61.5%) than patients with HCV-related HCC (77.5%; P < .01). However, the 1-year survival rate did not differ among patients with HCC related to different risk factors.nnnCONCLUSIONSnNAFLD is the third most common risk factor for HCC in the VA population. The proportion of NAFLD-related HCC was relatively stable from 2005 through 2010. Although patients with NAFLD-related HCC received less HCC surveillance and treatment, a similar proportion survive for 1 year, compared with patients with alcohol-related or HCV-related HCC.

Effectiveness of surveillance for hepatocellular carcinoma in clinical practice: A United States cohort

BACKGROUND & AIMSnThe effectiveness of surveillance for hepatocellular carcinoma (HCC) in reducing cancer related mortality among patients with cirrhosis is largely unknown. The objective of this study was to study the effectiveness of HCC surveillance in the national Veterans Administration (VA) clinical practice.nnnMETHODSnWe conducted a retrospective cohort study of patients with HCC during 2005-2010 by reviewing patients medical records to determine receipt of HCC surveillance in the 2years prior to HCC diagnosis. We determined association of HCC surveillance with overall mortality adjusting for age, risk factors, model for end-stage liver disease (MELD) score, comorbidity index, alpha-fetoprotein levels, healthcare utilization, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment. We accounted for lead and length time biases.nnnRESULTSnOf 887 patients with HCC, only 412 (46.5%) received any surveillance prior to HCC diagnosis. Patients who received surveillance were significantly more likely to have early stage disease HCC (BCLC stage 0/A 27.2% vs. 11.6%) and receive potentially curative (20.9% vs. 11.6%) or palliative (59.2% vs. 45.5%) treatments compared to those without HCC surveillance. Receipt of HCC surveillance was associated with 38% reduction in mortality risk (unadjusted hazard ratios (HR) 0.62, 95% confidence intervals (CI) 0.54-0.71) that declined to 20% (HR 0.80, 95% CI 0.69-0.94) after adjusting for HCC stage and treatment, compared to those without HCC surveillance.nnnCONCLUSIONSnAmong patients with HCC, pre-diagnosis HCC surveillance is associated with a significant 38% reduction in overall mortality. The reduction in mortality risk with surveillance is mediated via stage migration and receipt of HCC specific treatment.nnnLAY SUMMARYnSurveillance for liver cancer leads to earlier detection of cancer and increases chances of getting curative treatment. This ultimately leads to increased longevity in patients with liver cancer.

Cirrhosis is under-recognised in patients subsequently diagnosed with hepatocellular cancer.

Most clinical practice guidelines recommend screening for HCC in patients with cirrhosis. However, patients with compensated cirrhosis are often asymptomatic and may remain unrecognised for years.

Natural History of Untreated Hepatocellular Carcinoma in a US Cohort and the Role of Cancer Surveillance

BACKGROUND & AIMS: Determining the natural history and predictors of survival in patients with untreated hepatocellular carcinoma (HCC) in the United States is useful to test existing tumor classifications, identify subgroups of patients likely to benefit from treatment, and estimate lead time related to HCC surveillance. METHODS: We identified a national cohort of 518 veterans diagnosed with HCC from 2004 through 2011, with follow‐up ending in 2014, who received no palliative or curative treatment. We examined the association between postdiagnosis survival and patient factors, tumor characteristics, and prediagnosis surveillance. RESULTS: The mean age at HCC diagnosis was 65.7 years and most patients had hepatitis C (60.6%). Almost all patients (99%) died within the observation period; the median overall survival time was 3.6 months and survival times were 13.4, 9.5, 3.4, and 1.6 months for patients of Barcelona Clinic Liver Cancer stages 0/A, B, C, and D, respectively. In addition, model for end‐stage liver disease and levels of &agr;‐fetoprotein were predictive of survival. Nearly 28% received prediagnosis HCC surveillance, which was associated with detection of disease at an earlier stage (Barcelona Clinic Liver Cancer 0/A/B; 26.4% vs 14.4%; P = .0006) and slightly longer survival than patients with no surveillance overall (5.2 months vs 3.4 months; P = .021); there was no difference in survival times of patients with 0/A stage who did versus did not receive surveillance (10.3 months vs 10.5 months). CONCLUSIONS: Patients with HCCs, including those detected through surveillance, survived for short time periods in the absence of treatment, irrespective of their initial stage at diagnosis. Model for end‐stage liver disease scores and levels of &agr;‐fetoprotein were prognostic factors, independent of Barcelona Clinic Liver Cancer stage. The lead time related to detection by surveillance was modest (<2 months) and therefore unlikely to explain the survival benefit associated with surveillance in previous studies.

Hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis B virus infection

BACKGROUND & AIMSnCirrhosis related to chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma (HCC). The extent to which HCC occurs in U.S. in the absence of cirrhosis in CHB remains unclear.nnnMETHODSnWe identified CHB patients who were diagnosed with HCC in the national Veterans Administration (VA) between 2001 and 2013. We defined presence and absence of cirrhosis at the time of HCC diagnosis using explicit histological, radiological, endoscopic, and laboratory criteria. We used multivariable regression analysis to identify demographic and clinical characteristics associated with CHB-related HCC in the absence of cirrhosis. We also examined liver transplant-free survival in CHB-HCC patients with and without cirrhosis.nnnRESULTSnAmong 8539 CHB patients, 317 developed HCC of whom 30 (9.5%) did not have any evidence of cirrhosis at the time of HCC diagnosis. Compared to HCC patients with cirrhosis, HCC patients without cirrhosis were more likely to be non-white (African American, OR=6.78; 95% CI 2.05-22.4; Asian, OR 11.6, 95% CI 2.63-50.8), have a family history of HCC (OR 32.9, 95% CI 3.76-288), and hypertension (OR 3.15, 95% CI 1.02-9.75). There was no significant difference in the transplant-free survival between CHB-HCC patients with and without cirrhosis (hazard ratio 0.68, 95% CI 0.43-1.09).nnnCONCLUSIONSnFewer than 10% of U.S. based CHB-related HCC patients did not have cirrhosis. Race and family history of HCC were the main risk factors for HCC in the absence of cirrhosis in CHB. These factors may help guide the decision to initiate HCC surveillance in CHB patients without cirrhosis.nnnLAY SUMMARYnPatients with chronic hepatitis B who are African American, or Asian, older than 40years of age with family members with liver cancer or high blood pressure are at a higher risk of developing liver cancer in the absence of cirrhosis. These patients should be included in the screening program for liver cancer.

Hepatocellular Carcinoma Screening Associated with Early Tumor Detection and Improved Survival Among Patients with Cirrhosis in the US

BACKGROUNDnProfessional societies recommend hepatocellular carcinoma screening in patients with cirrhosis, but high-quality data evaluating its effectiveness to improve early tumor detection and survival in real world clinical practice are needed. We aim to characterize the association between hepatocellular carcinoma screening and early tumor detection, curative treatment, and overall survival among patients with cirrhosis.nnnMETHODSnWe performed a retrospective cohort study of patients diagnosed with hepatocellular carcinoma between June 2012 and May 2013 at 4 health systems in the US. Patients were categorized in the screening group if hepatocellular carcinoma was detected by imaging performed for screening purposes. Generalized linear models and multivariate Cox regression with frailty adjustment were used to compare early detection, curative treatment, and survival between screen-detected and non-screen-detected patients.nnnRESULTSnAmong 374 hepatocellular carcinoma patients, 42% (nxa0= 157) were detected by screening. Screen-detected patients had a significantly higher proportion of early tumors (Barcelona Clinic Liver Cancer stage A 63.1% vs 36.4%, P <.001) and were more likely to undergo curative treatment (31% vs 13%, Pxa0= .02). Hepatocellular carcinoma screening was significantly associated with improved survival in multivariate analysis (hazards ratio 0.41; 95% confidence interval, 0.26-0.65) after adjusting for patient demographics, Child-Pugh class, and performance status. Median survival of screen-detected patients was 14.6 months, compared with 6.0 months for non-screen-detected patients, with the difference remaining significant after adjusting for lead-time bias (hazards ratio 0.59, 95% confidence interval, 0.37-0.93).nnnCONCLUSIONnHepatocellular carcinoma screening is associated with increased early tumor detection and improved survival; however, a minority of hepatocellular carcinoma patients are detected by screening. Interventions to increase screening use in patients with cirrhosis may help curb hepatocellular carcinoma mortality rates.

Limited Life Expectancy Among a Subgroup of Medicare Beneficiaries Receiving Screening Colonoscopies

BACKGROUND & AIMSnLife expectancy is an important consideration when assessing appropriateness of preventive programs for older individuals. Most studies on this subject have used age cutoffs as a proxy for life expectancy. We analyzed patterns of utilization of screening colonoscopy in Medicare enrollees by using estimated life expectancy.nnnMETHODSnWe used a 5% random national sample of Medicare claims data to identify average-risk patients who underwent screening colonoscopies from 2008 to 2010. Colonoscopies were considered to be screening colonoscopies in the absence of diagnoses for nonscreening indications, which were based on either colonoscopies or any claims in the preceding 3 months. We estimated life expectancies by using a model that combined age, sex, and comorbidity. Among patients who underwent screening colonoscopies, we calculated the percentage of those with life expectancies <10 years.nnnRESULTSnAmong the 57,597 Medicare beneficiaries 66 years old or older who received at least 1 screening colonoscopy, 24.8% had an estimated life expectancy of <10 years. There was a significant positive association between total Medicare per capita costs in hospital referral regions and the proportion of patients with limited life expectancies (<10 years) at the time of screening colonoscopy (R = 0.25; P < .001, Pearson correlation test). In a multivariable analysis, men were substantially more likely than women to have limited life expectancy at the time of screening colonoscopy (odds ratio, 2.25; 95% confidence interval, 2.16-2.34).nnnCONCLUSIONSnNearly 25% of Medicare beneficiaries, especially men, had life expectancies <10 years at the time of screening colonoscopies. Life expectancy should therefore be incorporated in decision-making for preventive services.

Everolimus with early withdrawal or reduced-dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta-analysis

Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal‐sparing effect. We conducted a systematic review and meta‐analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30 mL/min who received EVR with CNI minimization or withdrawal were included. Four RCTs (EVR n=465, control n=428) were included. In three RCTs, EVR was initiated 4 weeks following LT; these studies were used to assess the primary outcome. All four studies were used to assess the secondary outcomes. Based on this study, EVR use with CNI minimization in LT recipients is associated with improved renal function at 12 months by GFR of 10.2 mL/min (95% CI: 2.75‐17.8). EVR use was not associated with an increased risk of biopsy‐proven acute rejection (RR 0.68, 95% CI: 0.31‐1.46), graft loss (RR 1.60, 95% CI: 0.51‐5.00), or mortality (RR 1.34, 95% CI 0.62‐2.90). However, it was associated with an increased risk of overall infections (RR 1.45, 95% CI: 1.10‐1.91).