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