nafld and liver tumors · nafld and liver tumors eli zuckerman, m.d. liver unit, carmel medical...
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NAFLD and Liver Tumors
Eli Zuckerman, M.D. Liver Unit, Carmel Medical Center,
Technion Faculty of Medicine, Haifa, Israel
Disclosures
• Advisory boards (international): Gilead, Abbvie, Merck, Janssen, BMS
• Consultant: Janssen, Gilead, Merck, Roche, Neopharm, Abbvie, GSK
• Advisory committees or review panels: Merck, Gilead, Janssen, BMS, Abbvie
• Speaker: Merck, Janssen, Roche, Novartis, BMS, Neopharm, GSK, Abbvie, Gilead
NAFLD and Liver Tumors
• Intra-hepatic cholangiocarcinoma (ICC)
• Hepatic adenoma (inflammatory)
• HCC
J Gastrointest Surg 2013, Semin Liver Dis 2015
NAFLD and Liver Tumors
• Intra-hepatic cholangiocarcinoma (ICC)
• Hepatic adenoma (inflammatory)
• HCC
J Gastrointest Surg 2013, Semin Liver Dis 2015
NAFLD and HCC
• Epidemiology
• Pathogenesis
• Presentation
• Curative treatment and outcomes
• Survival
NAFLD and HCC
• Epidemiology
• Pathogenesis
• Presentation
• Curative treatment and outcomes
• Survival
8
Liver Cancer Incidence: Sixth Most Common Cancer Worldwide1
• HCC is the most common primary liver malignancy in adults2
1. Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed March 20, 2008.
2. Perz JF, et al. J Hepatol. 2006;45:529-538.
196,298
226,787
230,555
200,774
314,256
330,963
529,283
559,094
711,128
782,647
1,066,543
1,167,020
1,301,867
1,549,121
0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000
Non-Hodgkin's Lymphoma
Corpus Uteri
Ovary
Oral Cavity
Bladder
Leukemia
Esophagus
Cervix Uteri
Liver
Prostate
Stomach
Colon/Rectal
Breast
Lung
9
Liver Cancer: Estimated Mortality
1,351,034
800,230
679,871 602,967
Lung and
bronchus
Stomach Liver Colon and
rectum
Nu
mb
er
of
es
tim
ate
d d
ea
ths
• Liver cancer is the third most common cause of cancer-related death
Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed August, 2008.
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
From 2012 HCC is the 2nd most
common cause of cancer-related death
world wide with overall 5-year survival
of 16%
NAFLD and HCC -Epidemiology
• Annual incidence in the US : 6.2:100,000 (SEER 18 database)
• While overall rate of cancer-related death has declined , mortality from HCC has increased.
• NAFLD-HCC is becoming a leading cause of HCC incidence and mortality
• The cumulative incidence of HCC from NAFLD-cirrhosis: 2.4-12.8% (FU 3.2-7.2 years)
Njei B,Hepatology 2015, Ryerson AB, Cancer 2016
HCC Prevalence in NAFLD Cohorts
Metabolism 2016
Prevalence: 0.5-17%
HCC Annual Incidence
Metabolism 2016
Annual incidence 0-10%
HCC patients (n=250) Clinical Characteristics
67.6±11 Age
(81%) Sex (male)
129 (52%) HCV
53 (21.4%) NASH
36 (14.5%) HBV
25 (12.3%) Other
Hadassah-Ichilov database: Etiology-250 HCC Patients
UK NAFLD associated HCC over time
Dyson J, et al. J Hepatol. 2014;60(1):110-7
Affected 66.1%
Prevalence of metabolic syndrome risk factors: Obesity, Diabetes, low HDL….
35%
Welzel TM, et al. Am J Gastroenterol. 2013 Aug;108(8):1314-21.
USA Population-attributable fractions of risk factors for HCC
6991 cases with HCC from the SEER–Medicare databases from 1994-2007
OR 39.89
OR 11.17
OR 4.06 OR 2.47
NAFLD and HCC
• HCC is associated with obesity and diabetes
Margini, Liver international 2016
NAFLD and HCC
• Epidemiology
• Pathogenesis
• Presentation
• Curative treatment and outcomes
• Survival
NAFLD-HCC pathogenesis
HCC
Hyperinsulinemia
and cellular mechanism
NAFLD-HCC pathogenesis
Hyperinsulinemia and cellular mechanisms
• Uninhibited and dysregulated cell growth
(IGF1 ,IRS-1 , M6P/IGF2R ) (cell proliferation and inhibition of apoptosis)
• Activation of STAT-3
(oncogenic transcription factor) by TNF-alpha and IL-6
• Activation of JNK-1
(phosphorylates IRS-1 and promotes development and proliferation of HCC
through epigenetic mechanisms, repression of suppressor genes)
• Decreased adiponectin.
(anti-iflammatory polypeptide), negative regulator of angiogenesis and
enhances apoptosis)
Wong, WJG 2016, Starley, Hepatology 2010, Yamada T, Proc Natl Acad Sci USA 1997, Park EJ, Cell 2010)
NAFLD-HCC pathogenesis
Hyperinsulinemia and cellular mechanisms
• Induction of Hedghog signalling
mobilization of liver progenitor cell, impaired repair and
dysregulated proliferation of hepatocyte
• Loss of PTEN
(Suppressor gene, inhibits insulin signalling via PI3K/AKT/mTOR
• PPARs and FXR
Inflammation, cell survival and differentiation
• Impaired autophagy
Impaired elimination of damaged cellular components through lysosomal
degradation by steatosis and impaired programmed cell death.
(Experimental models)
Wong, WJG 2016, Starley, Hepatology 2010, Yamada T, Proc Natl Acad Sci USA 1997, Park EJ, Cell 2010)
Autophagy in HCC
Dash, Hepatic Medicine: Evidence and Research 2016
NAFLD-HCC pathogenesis
HCC
Hyperinsulinemia
and cellular mechanism
Inflammation, oxidative
stress and lipotoxicity
NAFLD-HCC pathogenesis Inflammation, oxidative stress and lipotoxicity
• Accelerated production of TNF-α, IL-6 and leptin
Chronic cycle of hepatocyte injury and compensatory proliferation
Activation of STAT3, upregulation of telomerase reverse
transcriptase (leptin) leading to decreased apoptosis
• NF-κB signaling pathway
Inflammation and dysregulation of apoptosis
• Adaptive immune response
Activation of intrahepatic CD8+ T-lymphocytes and NK cells
(inflammatory response, cell damage and enhanced
carcinogenesis), selective depletion of CD4+.
• ROS
Dysregulation of cell cycle, cell injury, apoptosis,
enhance mutations and cancer cell growth
Wong, WJG 2016, Starley, Hepatology 2010, Yamada T, Proc Natl Acad Sci USA 1997, Park EJ, Cell 2010)
NAFLD-HCC pathogenesis
HCC
Hyperinsulinemia
and cellular mechanism
Inflammation, oxidative
stress and lipotoxicity
Microbiome
NAFLD-HCC and microbiome
• Altered microbiota in NAFLD/NASH
• Role of TLRs
• Decreased IL-18 (inflammatory cytokine), increased IL-6 (apoptosis )
• Deleterious effect on HSC
Brenner D, Gastroenterol 2014)
NAFLD-HCC pathogenesis
HCC
Hyperinsulinemia
and cellular mechanism
Inflammation, oxidative
stress and lipotoxicity Genetic polymorphism
Microbiome
Liu YL, J Hepatology 2014
• PNPLA3 rs738409 polymorphism (encodes the I148M variant protein) is associated with NAFLD HCC
• Carriers of minor allele G: increased risk for HCC over CC genotype: OR 2.26 • Homozygous for GG allele, compared with the general UK population: OR 12.19
Pathogenesis of HCC in NAFLD
Annu Rev Med 2016
Hyperinsulinemia
IRS-1, IGF1 M6P/IGFR2
WJG 2015, Scand J Gastro 2013, Am J Gastro 2013
Meta-analysis (8 studies): 22650 cases of HCC in 334307
patients with T2DM: 50% risk reduction in HCC incidence
NAFLD and HCC
• Epidemiology
• Pathogenesis
• Presentation
• Curative treatment and outcomes
• Survival
Sanyal AJ, et al. Hepatology 2006;43(4):682-9
152 patients with cirrhosis due to NASH , 150 matched patients with cirrhosis due to HCV 10 years follow up
Non-cirrhotic NAFLD and HCC
• Up to 50% of incidence of NAFLD-HCC in non-cirrhotics
• Patients with NAFLD had the greater odds to developing
HCC in the absence of cirrhosis in comparison to HBV,
HCV, ALD and other etiologies
• VA study: Non-cirrhotic NAFLD-HCC : OR 2.5 compared
with HCV and ALD.
Rinella , JAMA 2015, Piscaglia, Hepatology 2016, Mitall S, Clin Gastroenterol ,Hepatology 2015, J Hepatology 2012, JAMA
2015,, Clin Gastroenterolo Hepatol 2016, J Gastroentero Hepatol 2013
HCC in non-cirrhotic NAFLD
HCC in cirrhotic and non-cirrhotic patients with NAFLD
Liver Int 2016
NAFLD-HCC : Clinical presentation
• Delayed diagnosis with suboptimal surveillance (cirrhosis) and no
surveillance among non-cirrhotics.
• Technical difficulties (US)
• Fewer cases of NAFL-HCC are diagnosed in early stage (BCLC A)
compared with HCV-HCC: 5.8% vs 16.1% (VA cohort).
• Higher proportion of NAFLD-HCC are presented in advanced stage :
33% vs 24% compared with HCV-HCC
• Fewer patients with NAFLD-HCC had surveillance before HCC
detection (43%) compared with HCV (60%) and ALD (87%)
(p=0.001)
WJG 2016, J Hepatology 2012, JAMA 2015, Hepatology 2016, Clin Gastroenterolo Hepatol 2016, J Gastroentero Hepatol 2013
Hepatology 2016
NAFLD-HCC (145) HCV-HCC (611) p-value
Liver disease stage
NAFLD and HCC
• Epidemiology
• Pathogenesis
• Presentation
• Curative treatment and outcomes
• Survival
Wong RJ, et al. Hepatology. 2014 Jun;59(6):2188-95
Trends in HCC Liver Transplantation by Etiology of Liver Disease
HCV
NASH
NAFLD-HCC : Curative treatment and outcome
MittalS, Clin Gastroenterol Hepatol 2015, Hepatology 2016, Younoss, Hepatology 2015 , J Gastroenterol Hepatol 2011
Study HCV-HCC NAFLD-HCC
VA cohort 21.9% 10.8% Curative treatment
Italian cohort 11% 19% Resection
SEER data 11.3% 5.7% OLT
European cohort None (n=45)
VA cohort 61.5% 77.5% No treatment
• No significant difference in outcome between NAFLD-HCC and other etiologies • At early stage: lower recurrence rate and higher 5YS Than HCV (local ablation)
NAFLD and HCC
• Epidemiology
• Pathogenesis
• Presentation
• Curative treatment and outcomes
• Survival
NAFLD-HCC : Survival
• Patients with NAFLD-HCC are recognized to have worse prognosis
and lower eligibility for curative treatment .
(advanced stage of HCC at presentation)
• SEER (2015): 1YS 50% vs 61% (viral HCC)
• Italian cohort: survival 25.5m NAFLD-HCC vs 33.7m (HCV)
(survival difference disappeared after matching)
• US cohort (Reddy SK): Patients with NAFLD-HCC had less liver dysfunction at baseline and longer overall survival (vs HCV/ALD)
• NAFLD-HCC patients can have favorable survival if diagnosed at early stage of HCC and receive curative treatment
Mittal S, Clin Gastroenterol Hepatol 2015, Hepatology 2016, Younoss, Hepatology 2015 , J Gastroenterol Hepatol 2011 ,
Reddy, Hepatology 2012
Summary (1)
• The proportion of patients with HCC due to NAFLD is increasing. NAFLD becoming the leading cause of HCC
• HCC in NAFLD is associated with obesity and Diabetes
• HCC can occur in NAFLD non-cirrhotic however, the risk should be
better stratified
• The pathogenesis of NAFLD-HCC is multifactorial
(including hyperinsulinemia, cellular mechanisms, innate and
adaptive immune response, inflammation, oxidative stress,
intestinal microbiota and genetic polymorphism)
Summary (2)
• Patients with NAFLD-HCC are often presented with advanced tumor
stage, however if detected at early stage, the prognosis may be
favorable.
• Patients with non-cirrhotic NAFLD and MetS (obesity, DM) are at
risk and should undergo surveillance for HCC
Future: Identify high-risk groups (genetic polymorphism?) for HCC
surveillance
Thank You