A Cautionary Tale

1
A Cautionary Tale

• Hesham M. Elgouhari, M.D., FACP
• Assistant Professor of Medicine
• Hepatologist Medical Director
• Avera Center For Liver Disease
• Avera McKennan Hospital University Health
  Center
• Sioux Falls, South Dakota

2
The Case-History

• A 76 YOM presented with progressive fatigue and
  SOB for 3 weeks
• No Hematemesis/Melena/BRBPR
• Abdominal discomfort. No progressive distention
• No Jaundice or Pruritus
• New noticing of confusion per Family
• History of PUD S/P Partial Gastrectomy in 1976
• Colonoscopy recently revealed small rectal polyp
• Biopsy-proven cirrhosis in 2008 locally

3
The CaseHistory

• Drinks 1-2 beer per day for the last few years
  but more prior
• No DM, HTN, or HPL
• Has Psoriasis and gout
• Prostate Cancer S/P resection

4
The CasePE

• Elderly Male with mild respiratory distress
• VS BP 108/67, P 85, RR 20, Temp 98, BMI 38
• HEENT Temporal wasting, No Jaundice
• Cardiopulmonary No significant findings
• Abdomen Slightly distended, No tenderness
• Ext 1 edema bilaterally
• Neuro Has asterixis. No focal signs
• Skin Spider Angiomatosis and Palmar erythema

5
The Case Investigations

• CBC Hb 5.8, Plat 270 K, WBC 9800
• CMP Creat 1.5, T Bili 2.7, Alb 2.6, AST 56, ALT
  38, AP 92, INR 1.5
• AFP 13
• HBV and HCV serology Unremarkable
• AIH markers High IgG with negative ANA SMA
• A1ATP Normal
• U/S Hepatic steatosis/No focal mass, Patent BVs
• EGD EV-I, Patent Billroth II GJ

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• Questions
• Thoughts.

7
Dhjghghhghg
8
Dhjghghhghg
9
Dhjghghhghg
10

• Now What should we do??

11

• Diagnosis
• 1-Decompensated Cirrhosis
• 2-HCC (NO BIOPSY)
• 3-Mild Ascites
• 4-Portal HTN
• 5-Mild HE

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The Case Management

• CT Chest and Bone Scan Negative for mets
• TACE in April and July 2011
• Does not want Evaluation for LT
• Stable

13

• Hepatocellular Carcinoma (HCC)

14
HCC and The Globe
HCC Epidemiology

• HCC is the most common primary liver cancer
• The incidence is increasing worldwide
• Among men, HCC is the 5th most common cancer
• It is the 3rd lethal cancer worldwide
• 711,000 Cases of HCC in 2007
• Every year, 694,000 deaths from liver cancer

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Age-Adjusted Rates of Death for HCC Per 100,000
population
HCC Epidemiology
H. El Serag and A. Mason, NEJM, 1999 Kiyosawa K,
Jpn. J. Inf. Dis., 55, 69-77, 2002
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Age-Adjusted Incidence Rates For HCC in The
United States (1976-2002)
HCC Epidemiology
3.5
3.3
3.1
3
2.7
2.5
2.3
Rate per 100,000
2.0
2
1.8
1.6
1.4
1.4
1.5
1
0.5
0
76-78
79-81
82-84
85-87
88-90
91-93
94-96
97-99
2000-02
Year
El-Serag HB, Mason A, N Engl J Med 1999 El-Serag
HB et al, Ann Intern Med 2003
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HCC is One of the Fastest Rising Cancers in
Middle Age White Men
HCC Epidemiology
Incidence rate per 100,000
El-Serag HB et al, Ann Intern Med 2003
18
More recently
HCC Epidemiology

• HCC is the fastest growing cause of
  cancer-related death in men
• Expected to continue to
• increase until 2015-2020

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Why HCC is Rising?
HCC Epidemiology
Why HCC incidence is Rising?
Increasing prevalence of patients with cirrhosis

• Rising incidence of cirrhosis
• HCV (main reason)
• HBV
• Other (?NAFLD/insulin resistance)
• Improved survival of patients with cirrhosis

El-Serag HB, Gastroenterology 2004
20
Future Trends in HCC Incidence
HCC Epidemiology
Future Trends in HCC Incidence

• Distribution of risk factors among HCC cases
• HCV 24 to 60
• NASH/NAFLD 13 up to 50
• Prevalence of risk factors in the general
  population
• HCV 2
• Obesity 30, overweight 60
• HBV 0.4

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Prevalence of HCV
HCC Epidemiology
Worldwide 170 million (3)
United States Anti-HCV positive 3.9 million
(1.8) HCV RNA positive 2.7 million (1.4)
Alter MJ et al, New Engl J Med 1999 Lavanchy D
McMahon B, In Liang TJ Hoofnagle JH
(eds.) Hepatitis C. New York Academic Press,
2000
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HCV to HCC Pyramid
HCC Epidemiology

HCC
Cirrhosis
Chronic Hepatitis
HCV Infection
Goodgame B, et al., Am J Gastroenterol 2003
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HCC After IFN Therapy for HCV
HCC Epidemiology
30
25
20
No Response
Cumulative Incidence of HCC ()
15
10
Relapse
5
Sustained Response
0
0
1
2
3
4
5
6
7
Follow-up (yr)
Imai Y, et al, Ann Intern Med 1998
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Clinical Outcome of Chronic Hepatitis B
HCC Epidemiology
Chronic HBV Infection
Inactive Carrier State
Chronic Hepatitis
Cirrhosis
HCC
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Impact of HBV Vaccine on Incidence of HCC in
Children
HCC Epidemiology
8
6
Annual Incidence of HCC (per 1,000,000)
4
2
0
?
1981-1986
1986-1990
1990-1994
Universal Vaccination of Newborns
Chang MH, N Engl J Med 1997
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NAFLD Spectrum of Hepatic Pathology
HCC Epidemiology
Steatohepatitis
Steatosis
Cirrhosis
Hepatocellular carcinoma
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Coffee and Hepatocellular Carcinoma
HCC Epidemiology

• A source of antioxidants
• Animal experiments inhibitory effects against
  chemical carcinogenesis in liver tissue
• Epidemiologic studies coffee consumption is
  inversely related to
• serum liver enzyme activity
• liver cirrhosis
• HCC

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Definitions
Definitions
HCC Surveillance

• Screening
• Screening is a public health service in which
  members of a defined population are offered a
  test to identify those individuals who are more
  likely to be helped than harmed by further tests
  or treatment to reduce the risk of a disease or
  its complications.
• Surveillance
• The continuous monitoring of disease occurrence
  (using the screening test) within an at-risk
  population to achieve the same goals as screening
• For HCC, surveillance is recommended

Meissner Hi, et al, Cancer 2004 Sherman M, et al,
Hepatology 1998
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Patients for Whom HCC Surveillance Is Recommended
HCC Surveillance

• Asian males HBV carriers older than 40 yrs of age
• Asian female HBV carriers older than 50 yrs of
  age
• HBV carrier with HCC family history
• African/N American blacks with HBV
• Cirrhotic HBV carriers
• Hepatitis C with cirrhosis
• Stage 4 primary biliary cirrhosis
• Genetic hemochromatosis and cirrhosis
• Alpha-1 antitrypsin deficiency and cirrhosis
• Other cirrhosis
• 80 of patients with HCC have underlying cirrhosis

Bruix J, et al. AASLD HCC guidelines. July 2010.
Simonetti RS, et al. Dig Dis Sci.
199136962-972.
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Screening for HCC AASLD Recommendations
HCC Surveillance
Screening for HCCAASLD Recommendations

• Population in which screening should be done
• Cirrhosis (any etiology)
• HBV older, family history, cirrhosis
• Surveillance for HCC should be performed with
  ultrasonography
• AFP alone should not be used for surveillance
  unless ultrasonography is not available
• Screening should occur every 6 months

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Ultrasound Surveillance in Early HCC Systematic
Review
HCC Surveillance
Ultrasound Surveillance in Early HCC Systematic
Review
0 1.0
Singal A, et al. APT 2009
32
Performance Characteristicsof AFP Based on
Cutoff Level
HCC Surveillance
Sensitivity
Specificity
100
80

60
40
Cutoff 10-11 17-21 50 gt
100 Studies 4 7 4 5
ng/ml
Colli A, et al, Am J Gastro 2005
33
Surveillance for HCC Improves MortalityA
Randomized Controlled Trial
HCC Surveillance

• A study of hepatitis B carriers in China
• 18,816 randomized to surveillance with AFP
  US biannual vs. no surveillance
• Adherence to surveillance was 58

Zhang BH, et al, J Cancer Res Clin Oncol 2004
34
Surveillance for HCC Improves MortalityA
Randomized Controlled Trial
HCC Surveillance

Screened group
Control group Person-years in study 38,444 41,07
7 HCC occurrence Cases 86 67 Total incidence
(per 100,000) 223.7 163.1 Rate ratio (95
CI) 1.37 (0.99, 1.89) Deaths from
HCC Deaths 32 54 Total mortality (per
100,000) 83.2 131.5 Rate ratio (95 CI) 0.63
(0.41, 0.98)
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Surveillance for HCC Reduces MortalityA
Randomized Controlled Trial
HCC Surveillance
.8
Control
Screening
.6
Survival Probability ()
.4
.2
0
0
1
2
3
4
5
Time (Years)
Zhang BH, et al, J Cancer Res Clin Oncol 2004
36
Effect of Surveillance on Outcomes
HCC Surveillance

• Retrospective analysis of patients with cirrhosis
  and HCC (N 269)
• Standard-of-care surveillance (n  172)
• Ultrasound or other abdominal imaging 1
  time/year
• Substandard surveillance (n  48)
• Lack of abdominal imaging within 1 year of cancer
  diagnosis
• Absence of surveillance (n  59)

Outcomes, Standard-of-Care Surveillance (n  172) Substandard Surveillance (n  48) Absence of Surveillance (n  59) P Value
HCC diagnosis at stages 1/2 69 35 18 lt .001
Liver transplantation 32 13 7 lt .05
Mean 3-year survival from HCC diagnosis 40 27 13 lt .005
37
Surveillance Recommendations
HCC Surveillance
Surveillance Recommendations

• The target population for surveillance are those
  with liver cirrhosis (and HBV-infected patients)
• AFP and US are the recommended screening tests
  for HCC in patients at the highest risk
• Based on tumor doubling time and studies, the
  recommended interval for surveillance is every 6
  months in patients with cirrhosis
• Screening increases likelihood of HCC diagnosis
• Small and potentially treatable
• May reduce mortality

38
HCC Surveillance

• Review records of patients gt 65 YO diagnosed with
  HCC between 1994-2002
• Number of cirrhotic patients with HCC was 1,873
• Only 17 received regular surveillance

39
HCC Surveillance

• Those seen by Gastroentrologist/Hepatologist or
  by a Doctor with an academic affiliation were
  more likely to have regular surveillance by 4.5
  fold and 2.8 fold respectively than those seen by
  PCPs only
• Getting Better Regular surveillance increased
  from 9 in 1994-1996 to 21 in 2000-2002

40
Dual Blood Supply of Liver
HCC Diagnosis

• The vascular supply of HCC arises from the
  hepatic artery through neovascularization.
• Imaging of the liver has to be performed in a
  triple phase manner to account for the early
  arterial phase followed by the portal venous
  phase and the delayed phases

Yu JS, et al, Am J Roentgenol 1999
41
Triple Phase Imaging of Hepatocellular Carcinoma
HCC Diagnosis
Arterial Phase
Pre-contrast
Portal Venous Phase
5-min Delayed
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Guidelines for Diagnosis of HCC
HCC Diagnosis
Ultrasound findings
lt 1 cm 1-2 cm gt 2 cm
Repeat US every 3-6 mo Dynamic CT, contrast US or MRI 2 tests Typical HCC Atypical biopsy Dynamic CT, contrast US or MRI 1 test Typical HCC Atypical biopsy
Typical features of HCC vascular nodule on
arterial phase with washout in delayed
phases
Bruix J, et al, Hepatology 2005
43
Patient Survival Comparing Detection of HCC by
Surveillance vs Presentation With Symptoms
HCC Prognosis
100
80
Symptoms
Surveillance
60
Survival,
40
20
P lt .001
0
0
12
24
36
48
60
72
96
84
Months Follow up
Tong MJ et al. J Clin Gastroenterol. Sept 9, 2009
44
Barcelona Clinic Liver Cancer Staging
Classification (BCLC)
HCC Treatment
Barcelona Clinic Liver CancerStaging
Classification (BCLC)
Llovet JM et al. Lancet. 2003 3621907
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Liver Transplantation for HCCMilan Criteria
HCC Treatment
OR
Single tumor, not gt 5 cm
Up to 3 tumors, none gt 3 cm
Extra MELD Points
Absence of macroscopic vascular
invasion, absence of extrahepatic spread

• 5-yr survival with transplantation 70
• 5-yr recurrent rates lt 15

Mazzaferro V, et al. N Engl J Med.
1996334693-699. Llovet JM. J Gastroenterol
Hepatol. 200217(suppl 3)S428-S433.
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Multidisciplinary HCC Management
HCC Treatment

• HCC is the intersection of 2 diseases
• Liver disease and cancer
• Skilled Radiologists pathologists needed for
  diagnosis
• Specialists required to deliver treatment options
• Surgeons for resection or transplantation
• Radiologists for ablation and chemoembolization
• Hepatologists and oncologists follow treatment
  strategy and labs

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Management of Hepatocellular Carcinoma Requires a
Multidisciplinary Approach
HCC Treatment
Hepatobiliary Surgery
Oncology
Hepatology
Pathology
Radiology
Liver Transplant Program
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Thank you