Ehab Abd-El-Atty Hepatitis-2015 Orlando, USA July 20 - 22 2015

Ehab Abd-El-Atty

Hepatitis-2015Orlando, USA

July 20 - 22 2015

HCC risk factors and how to prevent?

Prof, Ehab Abd-El-AttyProfessor of Internal Medicine &

Gastroenterology & Hepatology & Endoscopy

Faculty of Medicine, Menoufia University

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)

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

Risk factors of HCC

Non-Modified Modified(Non-correctable) (Correctable)

Non-Modified risk factorsAging (male >40, female > 50)Male genderFamily history of HCCPBCAlpha-1-antitrypsin deficiency

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

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 >40, female > 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

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. (N’Kontchou et al, 2006)

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

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)

Risk factors of HCC recurrence after resection

Age >60 yearsTumor size >5 cm (Hung et al., Am

J Gastroenterol 2008)

Microvascular invasion. (Chen et al., World J Gastroenterol 2011)

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 >104 copies/mL) and hepatic inflammatory activity. (Wu et al, 2009) Therefore, antiviral treatment after surgical resection is highly recommended. (Jang et al., Cancer 2007)

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.

Prevalence and Risk Factors of Hepatocellular Carcinoma in Egyptian

Cirrhotic patients

Comparison between HCC group and cirrhotic patients without HCC:

  HCC cases(n = 302)

Cirrhotic patients without HCC

(n = 1212)

P value

Age (years) 60.9±9.8 56.4±8.8 0.01*Sex (male %) 89.1% (n=269) 85.1% (n=1032) 0.09 Family history of HCC 3.3% (n=10) 2% (n=24) 0.2Schistosomiasis 30.1% (n=91) 25% (n=303) 0.08Smoking 83.4% (n=252) 50.5% (n=612) 0.0001*DM 37.4% (n=113) 38.6% (n=468) 0.7HCV Ab +ve 87.1% (n=263) 77.7% (n=942) 0.01*HBS Ag +ve 12.9% (n=39) 5.9% (n=72) 0.01*Serum albumin (gm/dl) 2.8±0.5 2.9±0.5 0.02*Total bilirubin (mg/dl) 2.9±1.1 2.1±1.7 0.01*PT (%) 52.5±12.1 57.9±18.1 0.02*Child-Pugh score 9.6±2.7 9.2±2.96 0.02*AFP (ng/ml) 295.9±154.2 8.7±5.1 0.0001*

Multivariate regression analysis for risk factors of HCC

Risk factor P value Odds Ratio

95% CI

Age 0.4 1.58 0.7-4.11Smoking 0.001* 4.42 1.7-11.5HB s Ag 0.02* 3.5 1.3-9.7HCVAb 0.02* 3.4 1.4-9.1Child-Pugh score

0.2 1.76 0.69-4.47

HCC risk factors synergismWe 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.

Risk factors

P value

Odds Ratio

95% CI Lower Upper

Family history of HCC

0.002* 4.4 1.70 11.51

DM 0.22 1.8 0.69 4.47Smoking 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

Multivariate regression analysis for risk factors of HCC:

Interaction among different risk factors of HCC

Risk factors P value Odds RatioDM+Smoking 0.0001 5.7( 2.4 – 13.7)

HBV+Smoking 0.0001 4.9( 2.0 – 11.9)

HCV+Smoking 0.0001 8.2( 3.4 – 19.6)

HBV+DM 0.0001 4.1( 1.7 – 9.3)

HCV+DM 0.0001 9.2( 3.7 – 22.9)

HCV+HBV 0.0001 18.9 (6.7 – 50.2)

HBV+HCV+Smoking 0.0001 19.6 (6.9 – 59.1)

HBV+HCV+DM 0.0001 35.3 (11.8 – 105.4)

Best e-poster award European Gastro Update

Vienna – Austria 2014

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).

Occult Hepatitis B Virus infection in Egyptian Hepatitis C Virus positive patients: Prevalence and impact on

Hepatocellular Carcinoma development

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

  OBI/HCV dual infection (n=16)

HCV monoinfection

(n=84)

P-value

Age (years) 51.5±8.9 52.5±7.9 0.6Gender (male %) 69% (n=11) 55% (n=46) 0.4GIT bleeding (%) 69% (n=11) 52% (n=44) 0.3HCC (%) 31%(n=5) 7%(n=6) 0.01*AST (U/L) 82±36 58±19 0.01*ALT (U/L) 66±20 55±16 0.03*Serum albumin(gm/dl)

2.66±0.47 2.65±0.45 0.8

PT (%) 41.4±7.3 49.3±10.9 0.03*AST/platelet ratio 3.61±5.59 1.64±2.21 0.03*Child-Pugh score 10.6±2.3 10±1.8 0.3AFP (ng/ml) 88.4±166.5 30.3±77.8 0.2

Comparison between HCV patients with and without HCC:  HCV patients with

HCC(n=11)

HCV patients without HCC

(n=89)

P-value

Age (years) 57.4±9.4 51.6±7.6 0.02*Gender (male %) 56% (n=6) 57% (n=51) 1Encephalopathy (%) 100% (n=11) 52% (n=46) 0.002*Shrunken liver (%) 100%(n=11) 58%(n=52) 0.0001*Spleen size (cm) 16.5±1.3 14.2±1.9 0.0001*GIT bleeding (%) 100%(n=11) 49%(n=44) 0.0001*Occult HBV (%) 45%(n=5) 12%(n=11) 0.01*Platelet count (×103) 66.8±15. 6 79.8±17.3 0.01*AST (U/L) 87±30.4 59.2±21.5 0.003*ALT (U/L) 71.9±15.1 54.7±16.9 0.002*albumin(gm/dl) 2.46±0.45 2.68±0.45 0.1Total bilirubin(mg/dl) 2.87±1.1 2.39±0.84 0.1PT (%) 40.7±7.2 48.7±10.5 0.03*Child-Pugh score 11.5±2.2 9.9±1.7 0.03*AFP (ng/ml) 251.5±199.4 13.4±11.2 0.0001*

Multivariate regression analysis for risk factors of HCC in HCV+ve patients

Risk factors P-value RAge 0.3 0.001Shrunken liver 0.03* 0.33

Splenic size 0.5 0.001Occult HBV 0.04* 0.32PT% 0.3 0.001Child-Pugh score 0.8 0.001

Prevention of HCC

Early detection of HCC

Treatment of modified risk factors

Early detection of HCCDeterioration 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-β1, HGF, micro RNA, alpha-1-fucosidase

Contrast-enhanced ultrasonography (Levovist, Sonazoid)

Triphasic CT

Treatment of modified risk factorsInterferon 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

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 smokingStop Alcohol drinking Proper control of DMPrevention of NASH

Treatment of NASH Obesity

Moderate weight reduction (weight loss 10% over 6 months) ExercisePharmacologic (Orlistat)Endoscopic (Gastric balloon)Surgical treatment (bypass & sleeve surgery)

Control of DMModerate 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

Dyslipidemia (Statin, Fibrates, Omega-3 fatty acids)

Pro-inflammatory cytokines Pentoxifylline (Anti-tumor necrosis factor

agents)Atorvastatin (used in NASH patients who

have hyperlipidemia)

ApoptosisCytoprotective agents (Ursodeoxycholic

acid)ACE inhibitors/ARBs (Losartan)

Take home massage

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 (HCV&HBV), smoking and DM for HCC development.

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.

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

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

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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