Hepatitis & Hepatocellular Carcinoma

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Information about Hepatitis & Hepatocellular Carcinoma

Published on December 16, 2016

Author: DrShadSalimAkhterAkh

Source: slideshare.net

1. Hepatitis and Hepatocellular Carcinoma Prof. Shad Salim Akhtar MBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA) Consultant Medical Oncologist & Medical Director Prince Faisal Oncology Center, KFSH Professor of Clinical Medicine Qassim Medical University, Buraidah, Al-Qassim

2. 6th most common cancer (2002 Globocan) 626,000 new cases 95% mort (598,000) 3-5% Survival M:F ratio 1.3-3.6 Increasing incid in some countries Parkin DM Ca Cancer J Clin 2005;55:74 HCC

3. 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

4. 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

5. Nomenclature and Features ofNomenclature 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,+

6. 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

7. HCC Risk FactorsHCC Risk Factors HCV HBV Alcohol Other Europe 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

8. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ≥8% - High 2-7% - Intermediate <2% - Low 450 million infected

9. Bosch FX et al: Clin Liver Dis 2005; 9:191

10. 100 million infected

11. 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

12. 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

13. Hepatitis B Virus

14. Acute Hepatitis B Virus Infection with Recovery Typical 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

15. Progression to Chronic Hepatitis B Virus Infection Typical 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

16. Outcome of Hepatitis B Virus Infection by Age at Infection Symptomatic Infection Chronic Infection Age at Infection ChronicInfection(%) SymptomaticInfection(%) Birth 1-6 months 7-12 months 1-4 years Older Children and Adults 0 20 40 60 80 100100 80 60 40 20 0

17. Lok A: NEJM 2002; 346:1683

18. 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

19. Incidence of HCC during Follow UpIncidence of HCC during Follow Up of HBVof HBV Yang HI: NEJM 2002; 347:168

20. 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

21. In HCV Cirrhosis annual HCC risk = 1-7% Zhu AX: ASCO 2004

22. HCC & Chronic Viral HepatitisHCC & 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

23. 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

24. 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

25. HCC USG AdvantagesHCC USG Advantages • Sensitivity 81% • Easily available • Operator dependant • Cheap • New generation machines have better quality doppler • Used in combination with AFP

26. HCC -Whom Shall We ScreenHCC -Whom Shall We Screen Hep B Carriers Cirrhosis secondary to Asian 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

27. HCC SurveillanceHCC 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

28. EASLD Surveillance StrategyEASLD Surveillance Strategy Bruix J et al: J Hepatol 2001; 35:421 * HBsAg + pts

29. 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)

30. 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

31. Craxi A et al: Clin Liver Dis 2005; 9:329 Education Vigorous blood product screening Aflatoxin prevention as in Sudan

32. 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

33. 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

34. 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

35. 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

36. 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); iii1 Burroughs A et al: Lancet Oncol 2004; 5:409

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. Hayashi PH et al: Med Clin N Am 2005; 89:345

45. HCC TreatmentHCC Treatment Large HCC >5 cm Small HCC < 5cm Resectable Resectable Systemic chemo TACE Unresectable Local ablative therapy TransplantationDefinitive resection Unresectable Leung T: ASCO 2005 Orlando Fl

46. HCC StagingHCC Staging • UICC Staging • Tx-T4 • Nx-N1 • Mx-M1 • Vascular invasion T1-T3 • Single/multiple T1/T2,T3

47. HCC Staging OkudaHCC Staging Okuda Tumor 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 +

48. HCC Radiologic InvestigHCC 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

49. HCC DiagnosisHCC Diagnosis • Biopsy • USG/CT guided biopsy • FNAC • Special stains

50. HCC StagingHCC Staging • UICC Staging • Tx-T4 • Nx-N1 • Mx-M1 • Vascular invasion T1-T3 • Single/multiple T1/T2,T3

51. 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

52. HCC ResectionHCC Resection • 30-50% Survival • <2 cms 85% 5 yr survival • 4 cms 60% 5 yr survival • 80% without cirrhosis • 35% with cirrhosis

53. 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

54. 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

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