Ehab Abd-El-Atty

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Hepatitis-2015Orlando, USAJuly 20 - 22 2015

• Ehab Abd-El-Atty

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HCC risk factors and how to prevent? Prof, Ehab
Abd-El-AttyProfessor of Internal Medicine
Gastroenterology Hepatology EndoscopyFaculty
of Medicine, Menoufia University
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• HCC is one of the most common cancers worldwide.
  The incidence rate is 10.8 per 100,000 person
  years (16.0 for males and 6.0 for females)
• HCC accounts for 85-90 of primary liver cancers
• It represents the third leading cause of cancer
  death in males and the fourth in females with
  more than half a million deaths per year. (Kirk
  et al., Carcinogenesis 2006)

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• The burden of HCC has been increasing in Egypt in
  the past 10 years.
• In Egypt, HCC was reported to account for about
  4.7 of chronic liver disease patients.
  (El-Zayadi et al., Hepatol Res 2001)
• The risk of developing HCC is 1 to 4 per year
  for a patient with HCV-related cirrhosis
• The carcinogenesis risk for HBV-infected persons
  is 200 times higher than for those non-infected

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• Risk factors of HCC
• Non-Modified Modified
• (Non-correctable) (Correctable)

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• Non-Modified risk factors
• Aging (male gt40, female gt 50)
• Male gender
• Family history of HCC
• PBC
• Alpha-1-antitrypsin deficiency

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• Modified risk factors
• Liver cirrhosis (80-90 of HCC)
• HBV (active, carrier, occult)
• HCV
• NASH
• Alcohol (excess intake)
• Obesity
• DM
• Smoking
• Aflatoxin
• Oral contraception (long-term)
• High-dose anabolic steroids

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• Risk factors for the development of HCV
  associated HCC
• More than 60 of all HCC cases are attributed to
  HCV infection alone. (Hassan et al., J Clin
  Gastroenterol 2008.(
• Age of patients (male gt40, female gt 50), rather
  than the duration of HCV infection, is more
  significant for HCC development in patients with
  HCV (Yatsuji et al., 2009).
• Gender (male)
• Cirrhosis (irregular regeneration of hepatocytes)
  
• HCV genotype (1, 2)
• High viral load

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• Hepatic steatosis (Ohata et al, 2003)
• Co-infection with HBV and HCV is associated with
  a higher risk for developing HCC than either
  infection alone.
• Total alcohol intake (80 mL of ethanol/day)
• Overweight and DM are associated with an
  increased risk of HCC occurrence in patients with
  HCV- or alcohol-related cirrhosis. (NKontchou et
  al, 2006)

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• Risk factors for the development of HBV
  associated HCC
• AflatoxinB1 increases the risk of HCC in chronic
  HBV carriers.
• Alcohol drinking. (Liao et al, 2012)
• Family history of HCC (Hassan et al., J Hepatol
  2009)
• Male gender
• increasing age
• Cirrhosis (Wong et al., J Clin Oncol 2010)
• Low albumin high bilirubin

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• High viral load 104 copies/mL (Yin et al., Am J
  Gastroenterol 2011)
• Genotype C cause liver cirrhosis and HCC. (Yin et
  al., World J Gastroenterol 2010)
• Genotype B (B2) is associated with HCC in
  non-cirrhotics and relapse of HCC. (Yin et al.,
  Carcinogenesis 2008)
• HBV mutations (preS, precore, core promoter
  region) combined rather than single mutations
  might accumulate before the diagnosis of HCC and
  predict the occurrence of HCC. (Zhu et al.,
  Cancer Epidemiol Biomarkers Prev 2010)

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• Risk factors of HCC recurrence after resection
• Age gt60 years
• Tumor size gt5 cm (Hung et al., Am J Gastroenterol
  2008)
• Microvascular invasion. (Chen et al., World J
  Gastroenterol 2011)

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• High serum AFP concentration ( 400 ng/mL) tends
  to have greater tumor size, bilobar involvement,
  massive or diffuse type of recurrence, portal
  vein thrombosis. (Watanabe et al., J
  Gastroenterol (2008
• High viral loads (HCV) (HBV gt104 copies/mL) and
  hepatic inflammatory activity. (Wu et al, 2009)
  Therefore, antiviral treatment after surgical
  resection is highly recommended. (Jang et al.,
  Cancer 2007)

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Prevalence and Risk Factors of Hepatocellular
Carcinoma in Egyptian Cirrhotic patients

• The study included 1514 patients with liver
  cirrhosis from Menoufia University Hospitals
  during 2014. They were 1301 males and 312 females
  ranged between 31-89 years old. Abdominal
  ultrasonography was done for all patients. HCC is
  further confirmed by triphasic CT of the liver.
• Results Out of the 1514 examined cirrhotic
  patients, 302 patients (19.9) had HCC.

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• Comparison between HCC group and cirrhotic
  patients without HCC

  HCC cases (n 302) Cirrhotic patients without HCC (n 1212) P value
Age (years) 60.99.8 56.48.8 0.01
Sex (male ) 89.1 (n269) 85.1 (n1032) 0.09
Family history of HCC 3.3 (n10) 2 (n24) 0.2
Schistosomiasis 30.1 (n91) 25 (n303) 0.08
Smoking 83.4 (n252) 50.5 (n612) 0.0001
DM 37.4 (n113) 38.6 (n468) 0.7
HCV Ab ve 87.1 (n263) 77.7 (n942) 0.01
HBS Ag ve 12.9 (n39) 5.9 (n72) 0.01
Serum albumin (gm/dl) 2.80.5 2.90.5 0.02
Total bilirubin (mg/dl) 2.91.1 2.11.7 0.01
PT () 52.512.1 57.918.1 0.02
Child-Pugh score 9.62.7 9.22.96 0.02
AFP (ng/ml) 295.9154.2 8.75.1 0.0001
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Multivariate regression analysis for risk factors
of HCC
Risk factor P value Odds Ratio 95 CI
Age 0.4 1.58 0.7-4.11
Smoking 0.001 4.42 1.7-11.5
HB s Ag 0.02 3.5 1.3-9.7
HCVAb 0.02 3.4 1.4-9.1
Child-Pugh score 0.2 1.76 0.69-4.47
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• HCC risk factors synergism
• We do a retrospective study of the different risk
  factors of HCC in 300 HCC patients and 50
  patients with chronic liver diseases of different
  etiologies without HCC (control group).
• The aim of this study
• is to detect the effect of synergism of two or
  more risk factors on the development of HCC.

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Multivariate regression analysis for risk factors
of HCC
Risk factors P value Odds Ratio 95 CI 95 CI
Risk factors P value Odds Ratio Lower Upper
Family history of HCC 0.002 4.4 1.70 11.51
DM 0.22 1.8 0.69 4.47
Smoking 0.35 1.6 0.60 4.13
HB s Ag 0.02 3.4 1.21 9.55
HCV Ab 0.02 3.3 1.20 9.02
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• Interaction among different risk factors of HCC

Odds Ratio P value Risk factors
5.7 (2.4 13.7) 0.0001 DMSmoking
4.9 (2.0 11.9) 0.0001 HBVSmoking
8.2 (3.4 19.6) 0.0001 HCVSmoking
4.1 (1.7 9.3) 0.0001 HBVDM
9.2 (3.7 22.9) 0.0001 HCVDM
18.9 (6.7 50.2) 0.0001 HCVHBV
19.6 (6.9 59.1) 0.0001 HBVHCVSmoking
35.3 (11.8 105.4) 0.0001 HBVHCVDM
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Best e-poster award European Gastro Update
Vienna Austria 2014
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Occult Hepatitis B Virus infection in Egyptian
Hepatitis C Virus positive patients Prevalence
and impact on Hepatocellular Carcinoma development

• The study included 100 chronic HCV positive
  patients. There were 57 male and 43 females
  ranged between 41-77 years old. Diagnosis was
  done clinically, by abdominal ultrasonography and
  by assessing viral markers (HBsAg, HBsAb, HBcAb
  and qualitative PCR for HBV-DNA). HCC lesions
  were further confirmed by triphasic CT of the
  liver and AFP.
• Results Out of the 100 examined chronic HCV
  patients, only 16 patients (16) had occult
  Hepatitis B (OBI).

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• Comparison between (occult HBV/HCV dual
  infection) and (HCV monoinfection)

P-value HCV monoinfection (n84) OBI/HCV dual infection (n16)  
0.6 52.57.9 51.58.9 Age (years)
0.4 55 (n46) 69 (n11) Gender (male )
0.3 52 (n44) 69 (n11) GIT bleeding ()
0.01 7(n6) 31(n5) HCC ()
0.01 5819 8236 AST (U/L)
0.03 5516 6620 ALT (U/L)
0.8 2.650.45 2.660.47 Serum albumin(gm/dl)
0.03 49.310.9 41.47.3 PT ()
0.03 1.642.21 3.615.59 AST/platelet ratio
0.3 101.8 10.62.3 Child-Pugh score
0.2 30.377.8 88.4166.5 AFP (ng/ml)
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Comparison between HCV patients with and without
HCC
P-value HCV patients without HCC (n89) HCV patients with HCC (n11)  
0.02 51.67.6 57.49.4 Age (years)
1 57 (n51) 56 (n6) Gender (male )
0.002 52 (n46) 100 (n11) Encephalopathy ()
0.0001 58(n52) 100(n11) Shrunken liver ()
0.0001 14.21.9 16.51.3 Spleen size (cm)
0.0001 49(n44) 100(n11) GIT bleeding ()
0.01 12(n11) 45(n5) Occult HBV ()
0.01 79.817.3 66.815. 6 Platelet count (103)
0.003 59.221.5 8730.4 AST (U/L)
0.002 54.716.9 71.915.1 ALT (U/L)
0.1 2.680.45 2.460.45 albumin(gm/dl)
0.1 2.390.84 2.871.1 Total bilirubin(mg/dl)
0.03 48.710.5 40.77.2 PT ()
0.03 9.91.7 11.52.2 Child-Pugh score
0.0001 13.411.2 251.5199.4 AFP (ng/ml)
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Multivariate regression analysis for risk factors
of HCC in HCVve patients
Risk factors P-value R
Age 0.3 0.001
Shrunken liver 0.03 0.33
Splenic size 0.5 0.001
Occult HBV 0.04 0.32
PT 0.3 0.001
Child-Pugh score 0.8 0.001
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• Prevention of HCC
• Early detection of HCC
• Treatment of modified risk factors

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• Early detection of HCC
• Deterioration of hepatic synthetic function of
  cirrhotic patients
• Combined ultrasonography AFP
• (6 month in high-risk population).
• AFP-L3. glypican-3, descarboxy prothrombin and
  human telomerase reverse transcriptase, TGF-ß1,
  HGF, micro RNA, alpha-1-fucosidase
• Contrast-enhanced ultrasonography (Levovist,
  Sonazoid)
• Triphasic CT

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• Treatment of modified risk factors
• Interferon therapy or DAA for HCV infection can
  reduce the incidence of HCC.
• Interferon therapy reduces the degree of
  cirrhosis in HCV-infected patients, even without
  viral clearance or normalisation of liver
  enzymes, lowers the risk of HCC development and
  improves long-term prognosis

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• Pre- and post-operative antiviral therapy in HCV
  HBV reduces late recurrence of HCC. (Wu et al,
  2009)
• Standard HBV vaccination dramatically decreases
  HCC prevalence. (Chang et al., J Natl Cancer Inst
  2009)
• Stop smoking
• Stop Alcohol drinking
• Proper control of DM
• Prevention of NASH

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• Treatment of NASH
• Obesity
• Moderate weight reduction (weight loss 10 over 6
  months)
• Exercise
• Pharmacologic (Orlistat)
• Endoscopic (Gastric balloon)
• Surgical treatment (bypass sleeve surgery)

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• Control of DM
• Moderate weight reduction
• Exercise
• Pharmacologic (Thiazolidinediones Metformin)
• Oxidative stress(Antioxidants)
• Vitamin E (inhibits activity of transforming
  growth factor beta1)
• N-Acetyl-cysteine increases hepatic glutathione,
  which decreases oxidative stress

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• Dyslipidemia (Statin, Fibrates, Omega-3 fatty
  acids)
• Pro-inflammatory cytokines
• Pentoxifylline (Anti-tumor necrosis factor
  agents)
• Atorvastatin (used in NASH patients who have
  hyperlipidemia)
• Apoptosis
• Cytoprotective agents (Ursodeoxycholic acid)
• ACE inhibitors/ARBs (Losartan)

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Take home massage
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• Egypt has a high incidence of HCC about 20 in
  cirrhotic Egyptian patients.
• Chronic HCV, HBV, NASH, alcohol consumption,
  smoking and DM are significant risk factors for
  HCC development.
• Significant synergy among hepatitis virus
  infection (HCVHBV), smoking and DM for HCC
  development.

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• Occult HBV infection may influence the outcome of
  HCV infection leading to more hepatic fibrosis
  and development of HCC.
• The persistent HBV infection may have a critical
  role in the development of HCC in HBsAg-negative
  patients.
• Occult HBV should be considered and evaluated by
  more sensitive PCR among HCV-infected patients.

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• An active prevention and surveillance programs
  for patients with chronic hepatitis are the most
  important steps to reduce the risk of HCC.
• Vaccination against HBV in infancy is the most
  effective approach to prevent HBV-related HCC
• Prevention program against HCV infection by
  changing personal behavioral and cultural habits

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• Tailoring suitable treatment options like
  antiviral treatment to improve the survival,
  interrupt or delay progression to HCC or postpone
  recurrence of HCV or HBV-related HCC.
• Patients at high risk of HCC should undergo
  closer follow-up (6 month).
• Development of early detection markers is a vital
  missing component in strategies to reduce HCC
  mortality

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• Serum AFP level may represent a marker for either
  tumor bulk or aggressive tumor biology, such as
  tumor cell proliferation and spread.

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Thank you
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atHepatitis-2016Dubai, UAEOctober 17 - 19,
2016

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