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Hepatitis and Hepatocellular Carcinoma
Prof. Shad Salim AkhtarMBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA)
Consultant Medical Oncologist & Medical DirectorPrince Faisal Oncology Center, KFSHProfessor of Clinical MedicineQassim Medical University, Buraidah, Al-Qassim
6th most common cancer (2002 Globocan)626,000 new cases95% mort (598,000)3-5% SurvivalM:F ratio 1.3-3.6Increasing incid in some countries
Parkin DM Ca Cancer J Clin 2005;55:74HCC
AAIR(Number)
AAMR(Number)
Industrialized countries
Men 8.71(73,270)
8.07(68,992)
Women 2.86(33,680)
3.01(36,657)
Non industrialized
Men 17.43(325,108)
16.86(314,611)
Women 6.77(132,298)
6.57(128,305)
New Cases and MortalityNew Cases and Mortality
Bosch FX et al: Clin Liver Dis 2005; 9:191
Risk Factors for HCCRisk Factors for HCC
• Other risk factors– Alcohol intake– Aflatoxins*– Hemochromatosis– Other metabolic disorders
• α 1 antitrypsin deficiency• Porphyrias
– NASH– Diabetes
• Older age• Male gender• First degree relative with
HCC*
• Cirrhosis– A common denominator in
most cases– West 80-90% pts – KSA 50-60% pts– Africa 60-70% pts in
• HBV 50-55%• HCV 25-30%
Fattovich G: Int Hepat Conf; 2004:Paris Bosch FX et al: Clin Liver Dis 2005; 9:191
Nomenclature and Features of Nomenclature and Features of Hepatitis VirusesHepatitis Viruses
Type Virus particle Genome
A 27 nm 7.5 kb RNA, linear, ss, +
B 42 nm 3.2 kb DNA, circular, ss/ds
C 40-60 nm 9.4 kb RNA, linear, ss, +
D 35-37 nm 1.7 kb RNA, circular, ss,-
E 32-34 nm 7.6 kb RNA, linear, ss,+
Link Between HCC and HBV/HCVLink Between HCC and HBV/HCV
• Strong association in epidemiological studies– Parallelism between HBsAg carrier rate and
HCV infection and incidence of HCC– High rate of positivity of HBV/HCV in HCC
• 90% HCC pts in Taiwan + HBsAg• High rates of HCV in HCC pts in Japan
• 61.9% + HBV in KSA
• HBV/HCV molecules present in HCC
HCC Risk FactorsHCC Risk Factors
HCV HBV Alcohol OtherEurope 60-70% 10-15% 20% 10%
North Am 50-60% 20% 20% 10%
Japan 70% 10-20% 10% <10%
Asia & Africa
20% 70% 10% <10%*Aflatoxins co factor with HBV
Llovet JM et al: The Lancet 2003; 362:1907
Geographic Distribution of Chronic HBV Infection
HBsAg Prevalence
≥8% - High
2-7% - Intermediate
<2% - Low
450 million infected
Bosch FX et al: Clin Liver Dis 2005; 9:191
100 million infected
HCC in Saudi ArabiaHCC in Saudi Arabia
Site (Number)~
Qassim Riyadh Gizan Madina Riyadh Abha Al Baha
NHL (64)
11.53 8.50 NA NA 12.72 9.6 10.4
Liver (51)
9.17 14.48 18.72 9.4 5.50 11.0 6.5
Esophagus (45)
8.09 2.98 1.83 6.6 5.72 3.0 2.7
Stomach (44)
7.91 7.35 3.28 7.5 4.54 8.0 11.3
Skin (41)
7.38 2.75 12.51 8.8 3.97 14.6 15.2
Hodgk Dis(36)
6.47 3.90 NA NA 4.96 NA NA
Prostate (31)
5.57 6.20 4.20 3.2 1.87 2.3 4.2
Bladder (28)
5.03 4.82 8.58 5.1 3.52 9.4 7.5
Lip, oral cav (24)
4.31 NA 13.24 1.8 5.45 NA 4.5
Akhtar SS et al Ann Saudi Med 1997
1
1.9
2
2.8
3.2
3.4
3.9
4
5
5.9
6.6
10.5
15.2
0 2 4 6 8 10 12 14 16
Riyadh
Najran
Madinah
Qassim
Makkah
East
Jazan
Baha
Hail
Asir
North
Tabuk
Jouf
HCC ASR KSA (Males)- NCR -2000HCC ASR KSA (Males)- NCR -2000
Males Females
ASR 6.5 2.6
Mean Age 64 58
Hepatitis B Virus
Acute Hepatitis B Virus Infection with RecoveryTypical Serologic Course
Weeks after Exposure
Titer
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBsHBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Progression to Chronic Hepatitis B Virus InfectionTypical Serologic Course
Weeks after Exposure
Titer
IgM anti-HBc
Total anti-HBc
HBsAg
Acute(6 months)
HBeAg
Chronic(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
Outcome of Hepatitis B Virus Infectionby Age at Infection
Symptomatic Infection
Chronic Infection
Age at Infection
Ch
ron
ic I
nfe
ctio
n (
%)
Sym
pto
mat
ic I
nfe
ctio
n (
%)
Birth 1-6 months 7-12 months 1-4 years Older Childrenand Adults
0
20
40
60
80
100100
80
60
40
20
0
Lok A: NEJM 2002; 346:1683
Closed Circular DNA
Viral replication
Persists for life time? during Ch infection
Random integration into the host genome
Immortalized cells
Malignant phenotype
Genetic alteration
Inactivates p53, Free radical & superoxide prduction, induces genomic instability
Activates cellular oncogenes
Incidence of HCC during Follow Up Incidence of HCC during Follow Up of HBVof HBV
Yang HI: NEJM 2002; 347:168
Yang HI: NEJM 2002; 347:168
Cumulative incidence of HCC during Follow Up in Taiwan
Relative Risk compared to normal
HBsAg +ve only 9.6 (CI 6.0-15.2)
+HBeAg +ve also 60.2 (CI 35.5-102.1)
Genotypes B & C related to HCC
In HCV Cirrhosis annual HCC risk = 1-7%
Zhu AX: ASCO 2004
HCC & Chronic Viral Hepatitis HCC & Chronic Viral Hepatitis • Chronic HBV
– 9.6 X RR for HBsAg +– 60 X RR for HBsAg + & HBe Ag +– 0.3% annual risk in carriers– 4.2-6.6% risk in cirrhotic
• Chronic HCV– 17 X RR– Cirrhosis a prerequisite– 1-7% annual risk in cirrhotic
Donato et al: Int J Cancer 1998; 75:347
HCC What to do?HCC What to do?• You know the well defined risk factors
• Catch them young
• No definite screening program has been prospectively validated by RCT and not possible any more
• Most commonly used tools– AFP 6 monthly
– Ultrasound 6 monthly
HCC Screening AFPHCC Screening AFP• >400 ng/ml rare in benign disease• >1000 ng/ml suggestive of HCC• Positivity rate in established HCC
– 80-90% in Orient
– 60-70% in West
– App 80% in KSA
• Poor test for small tumors• ? Use of AFP L3 fraction• Other serological tests
– Desgammacarboxyprothrombin (DGCP) activity– Alpha-fucosidase
HCC USG AdvantagesHCC USG Advantages
• Sensitivity 81%
• Easily available
• Operator dependant
• Cheap
• New generation machines have better quality doppler
• Used in combination with AFP
HCC -Whom Shall We ScreenHCC -Whom Shall We Screen
Hep B Carriers Cirrhosis secondary toAsian males >40 yrs Chronic Hep C
Asian female >50 yrs Genetic hemochromatosis
Asian any age +ve F/His Alpha 1 antitrypsin def
Any pt with cirrhosis Alcoholic liver disease
Africans >20 yrs
Sherman M et al: Gastroenterol Clin N Am 2004; 33:671
Surveillance should continue even after anti viral therapy in cirrhotic!
Ryder SD: Gut 2003; 52(Siii):iii1
HCC Surveillance HCC Surveillance
• Lesions <1 cm reliable diagnosis difficult
• Close follow up required
• Nodules 1-2 cm in size false negative rate– 30-40%
• Helical CT and MRI (Contrast enhanced)– >80% accuracy
– MRI superior to CT
• PET no encouraging results yet
Liovet JM et al: The Lancet 2003; 362:1907
EASLD Surveillance StrategyEASLD Surveillance Strategy
Bruix J et al: J Hepatol 2001; 35:421
* HBsAg + pts
EASLD Diagnostic Criteria for HCCEASLD Diagnostic Criteria for HCC
1. Cytohistopathological diagnosis
2. >2 cm arterial hypervascular lesion detected by two coincident imaging techniques or
3. >2 cm arterial hypervascular lesion detected by one imaging technique with AFP >400 ng/ml (2 and 3 only in the setting of cirrhosis)
HCC Can We Prevent It?HCC Can We Prevent It?
• Well defined risk factors
• Poor treatment outcomes make it a must
• No established benefit of vigorous screening
• Increased understanding of hepatocarcinogenesis
• New drugs available
Craxi A et al: Clin Liver Dis 2005; 9:329
Education
Vigorous blood product screening
Aflatoxin prevention as in Sudan
Vaccination-Taiwan ExperienceVaccination-Taiwan Experience• Nation wide HBV vaccination program
– Initiated 1984
• HBsAg carrier state in children– Pre vaccination 10%– Post vaccination 10 yrs <1%
• Annual incidence of HCC (per 100,000) in children 6-14 yrs– 1981-86 0.70– 1986-90 0.57– 1990-94 0.36
Chang MH et al: NEJM 1997; 336:1855
HCC Presentation- SymptomsHCC Presentation- Symptoms
79.50%
69.50%
56%
50%
30%
0.00% 20.00% 40.00% 60.00% 80.00%
Anorexia
Jaundice
Malaise/Fever
Mass
Pain Up Abdo
Shobokshi O et al Hepatocellular Ca Technical Report 1409 AH
HCC TreatmentHCC Treatment
• Surgical resection
• Liver transplantation
• Local regional therapy
• Systemic therapy
• New targeted agents
Hayashi PH et al: Med Clin N Am 2005; 89:345
HCC Surgical resectionHCC Surgical resection
• Treatment of choice for non cirrhotic
• Single lesion preserved liver function
• 5 year surv 50-70%
• Tumour recurrence 60-100%– De-novo– True recurrences
• May be followed by transplantation
Hayashi PH et al: Med Clin N Am 2005; 89:345
HCC TransplantationHCC Transplantation
• Transplantation potentially curative therapy
• Milan Criteria generally followed– Solitary tumor <= 5 cm diameter– Multifocal
• <=3 nodules• <=3 cm
• No vascular invasion
Ryder SdD Gut 2003; 52 (Siii); iii1Burroughs A et al: Lancet Oncol 2004; 5:409
HCC Local Ablative TherapiesHCC Local Ablative Therapies• Chemical ablation
– Ethanol injection– Acetic acid injection– Hot saline injection
• Thermal ablation– Radiofrequency ablation– Microwave ablation– Laser ablation
• TACE
Lencioni R et al: Clin Liver Dis 2005; 9:301
HCC Percutaneous Ethanol InjectionHCC Percutaneous Ethanol Injection
• 1-10 ml ethanol through small bore needle– Real time observation possible (alcohol
hyperechoeic)
• Response rate 50-100%– Size is the determining factor
• Best response smaller lesions (<2 cm)
• Well tolerated• Multiple sessions needed• Selected candidates with <3 cm tumours
– 50% 5 yr survival– Almost similar to resection group
Hayashi PH et al: Med Clin N Am 2005; 89:345
HCC Radiofrequency AblationHCC Radiofrequency Ablation
• Thermal injury from electromagnetic energy by radio frequency probes
• Larger needle size
• USG guidance required
• Can be done– Percutaneously– Laparoscopically– Laparotomy
HCC RFAHCC RFA• More patient discomfort• Complication rate 8.9%
– Mortality 0.5%
• Advantages– Fewer sessions– Better response rates
• Survival similar to PEI (lesions <3 cms)• Local recurrence lesser• Becoming popular local ablative therapy• Need a RCT with resection
Hayashi PH et al: Med Clin N Am 2005; 89:345
HCC TACEHCC TACE• Most widely used therapy for uresectable HCC• Higher efficacy with larger tumours
– Not indicated in early stage disease
• Selective catherization of the feeding artery to the segment or subsegment
• Drug injected – No single drug or combination is better
– Doxorubicin, cisplatin commonly used
• Lipoidol used to increase chemotherapy contact time• Gelatin or polyvinly alcohol particles used to
embolise the vessel
HCC TACEHCC TACE
• Best candidates– Preserved liver function– Normal functional status
• Better for smaller tumours (<4-5cm)
• Meta-analysis confirms survival benefit of TACE compared to conservative therapy
Llovet JM et al: Hepatology 2003; 37: 429
HCC Systemic TherapyHCC Systemic Therapy• Few effective drugs
– Responses to Cisplatin+5FU therapy?
• As neoadjuvant?• Anti angiogenesis agents• EGFR inhibitors• Signal transduction inhibitors• Telomerase inhibitors• Immune therapy• Gene therapy• Nanoparticle therapy
Burroughs A et al: Lancet Oncol 2004; 5:409
Hayashi PH et al: Med Clin N Am 2005; 89:345
HCC TreatmentHCC TreatmentLarge HCC >5 cm Small HCC < 5cm
Resectable Resectable
Systemic chemo TACE
Unresectable
Local ablative therapy
TransplantationDefinitive resection
Unresectable
Leung T: ASCO 2005 Orlando Fl
HCC StagingHCC Staging
• UICC Staging• Tx-T4
• Nx-N1
• Mx-M1
• Vascular invasion T1-T3
• Single/multiple T1/T2,T3
HCC Staging OkudaHCC Staging OkudaTumor size
Ascites Bilirubin Albumin
>50%=+ <50%=-
+ or -
>3g/dl=+ <3g/dl=-
<3g/dl=+ >3g/dl=-
Stage I=all - Stage II=1 or 2 +
Stage III=3 or 4 +
HCC Radiologic Investig HCC Radiologic Investig USGUSG
• Vascular invasion sensitivity 17%
• Operator dependant
• 62 yrs M
• Rt hypoch pain
• Clinically ? Ac. Cholecystitis
• USG normal
• Rept CT scan & USG HCC
HCC DiagnosisHCC Diagnosis
• Biopsy
• USG/CT guided biopsy
• FNAC
• Special stains
HCC StagingHCC Staging
• UICC Staging• Tx-T4
• Nx-N1
• Mx-M1
• Vascular invasion T1-T3
• Single/multiple T1/T2,T3
HCC ManagementHCC Management
• Untreated 3/22 alive at 3 yrs even with small tumours
• Median survival 8.3 months (Stage I)
• Surgical
• Chemotherapy
• Radiation therapy
• Biological response modifiers
HCC ResectionHCC Resection
• 30-50% Survival
• <2 cms 85% 5 yr survival
• 4 cms 60% 5 yr survival
• 80% without cirrhosis
• 35% with cirrhosis
HCC Etiology HBV/AflatoxinsHCC Etiology HBV/Aflatoxins
• High level and prevalence of exposure to aflatoxins in West Africa, Mozambique, some regios of China
• High prevalence of 249ser p53 mutation in these countries
• HCC from low aflatoxin exposure countries low prevalence of mutation
Montesano R et al Hepatocellular Ca JNCI 1997;1844
HCC Etiology HBV/AflatoxinsHCC Etiology HBV/Aflatoxins
• p53 mutaion occurs early
• Perinatal aflatoxin exposure
• HBV infection alters aflatoxin metabolism
• ?Recurrent liver cell proliferation in HBV carriers favors selective clonal development of aflatoxin mutated cells
Montesano R et al JNCI 1997;89:1844
