1. Iron and Liver Cancer
Prof. Mohandas Mallath, M.D.
Convener, GI-Oncology Disease Management Group
Tata Memorial Hospital
Director, Centre for Cancer Epidemiology
Tata Memorial Centre Mumbai
mohandaskm@gmail.com

3. The role of iron in tumour cell proliferation.
Steegmann Olmedillas JL. Clin Transl Oncol 2011;13:71-6
• Iron can be considered a double-edged weapon;
– Iron has a pivotal role in homeostasis and participates in virtually
all of the body's oxidation-reduction processes.
– Iron excess may increase the risk of developing cancer,
presumably by the generation of reactive oxygen species, and its
participation in cell proliferation.
• Thus, iron might as well be considered a cofactor in
tumour cell proliferation.
– In certain pathological conditions, such as hemochromatosis,
hepatitis B and C virus infection, asbestosis and endometriosis
iron overload may increase the risk of cancer.
– By contrast, iron depletion could be considered a useful adjunct
in antitumor therapy.

4. The real issues are
• Does the high iron/ ferritin reflect:
– Cause or effect (confounding)
– Can iron reduction alter the natural history

7. Prevalence of hepatic iron overload and association
with HCC in end stage liver disease: results from the
national hemochromatosis transplant registry.
Ko C et al. Liver International 2007;27:1394–1401
• 5224 patients undergoing liver transplantation
– Pathological diagnosis, HCC and degree of iron staining.
– HCC most common in patients with HBV (16.7%)
– Hepatitis C (15.1%)
– Hereditary Hemochromatosis (14.9%).
• Iron overload was significantly associated with
HCC (P=0.001), after adjusting for etiology of
cirrhosis

8. Iron levels in hepatocytes and portal tract
cells predict progression and outcomes of
patients with advanced chronic hepatitis C.
Lambrecht RW et al Gastroenterology 2011;140:1490-500.
• Significantly higher baseline scores for stainable iron in
hepatocytes and in portal tract cells in participants who
developed clinical outcomes [CTP > 7, ascites,
encephalopathy, variceal bleeding, SBP, HCC, death] than
those without.
• HFE genetic variations did not correlate with outcomes,
including development of hepatocellular carcinoma.
• Iron in triads at baseline increased risk of outcomes (HR =
1.35, P = 0.02).

10. Lab studies in HCC cell lines and HFE knockout mice
TSC24 a potent iron chelator that suppresses human HCC
tumor growth by disrupting iron homeostasis, reducing
available iron and triggering cell-cycle arrest and apoptosis
With out host toxicity at effective doses.

11. HCC incidence in men and women
ASR per 100,000

12. GI cancer trends in Mumbai
Cancer registry (ASR-W)
PERIOD ESO STM ILE COL RECT LIV GALL PAN
1964-66 13.0 10.0 0.2 4.1 4.3 0.5 0.6 2.0
1968-72 15.2 9.3 0.2 4.6 4.4 1.4 0.7 1.8
1973.75 15.7 9.7 0.1 3.5 4.5 2.7 0.5 2.0
1978.82 14.7 8.9 0.2 3.4 4.5 4.9 0.9 2.1
1983.87 11.4 7.3 0.3 3.2 3.2 3.4 1.0 2.5
1988.92 10.8 7.7 0.4 3.7 3.9 3.9 1.8 2.3
1993.97 8.4 6.3 0.3 3.4 3.2 3.9 1.7 2.5
12
1998.02 6.7 4.6 0.2 3.0 2.9 4.5 1.6 2.2

13. Iron Metabolism & Iron Deficiency in India
• Most Indians experience iron deficiency at the
beginning of life, childhood years, adolescent life,
…….. Till end of life.
– 87% pregnant females
– 75% children <5yrs of age
– 50-75% adult females
– 25-55% adult males
• WHO survey on iron stores in over 2000 liver
specimens showed that minimum content of iron
was in Indians and Indians from south Africa
Venkatachalam PS, Am J Clin Nutrition; 1968;21:1156-1161.

14. Hepatic iron in different populations
Charlton RW, et al. AJCN 1970;23:358-71
Hepatic iron
Population Pts HCC(#)
Median
Indians(Delhi) 203 16 93-142
UK 182 28 111-204
USA 229 32 173-277
Bantu 403 25 189-946

15. Hypothesis: Rampant dietary iron deficiency
offers protection against the development of
HCC in CLD of viral etiology in Indians.
Primary aim: To find the association of Serum
Ferritin levels and HCC in patients with CLD
of viral etiology

16. Our study designs
• Hospital based case-control study
– TMH and KEMH, Mumbai
• Prospective observational cohort study
– ACT clinic, TMH
• Intramural funding from TMH in October 2008
• IRB approval obtained from TMH/ KEMH
• Recruitment July 2009-Nov 2011

17. Patient recruitment
283 cases with HCC 334 controls with chronic
screened liver disease screened
47 (14%) were seronegative
126 (44.5%) seronegative 21 (6.2%) low platelet counts
13 (4.6%) low platelets 17 (5%) not fit age criteria
12 (4.2%) not fit age criteria 15 (4.5%) refused consent
15 (5.3%) refused consent 23 (6.8%) transfused or on
hematinics
116 (40.9%) enrolled 201 (60%) enrolled
Recruitment period: July 2009- Nov 2011

18. Multivariate analysis 116 cases, 201 controls
Term Odds 95% C.I. P-Value
Ratio
Coffee drinks (Ever vs. Never) 0.4693 0.2467 - 0.8928 0.0211
Alanine aminotransferase U/L 1.0069 1.0014 - 1.0124 0.0142
Age in years 1.0877 1.0611 - 1.1150 0.0000
Haemoglobin G/dl 1.2307 1.0669 - 1.4197 0.0044
Socioeconomic group -High vs. Others 1.7611 0.9777 - 3.1722 0.0595
Tobacco use (Ever vs. Never) 1.9879 1.0826 - 3.6505 0.0267
Sex (Male vs. Female) 3.2316 1.3731 - 7.6059 0.0072
Alcohol (Ever vs. Never) 3.2321 1.6522 - 6.3230 0.0006
Low normal Ferritin vs. Low Ferritin* 4.0383 0.7319 - 22.2814 0.1092
High normal Ferritin vs. Low Ferritin* 13.1354 2.3353 - 73.8827 0.0035
High Ferritin vs. Low Ferritin* 42.8561 7.3750 - 249.0353 0.0000
Not published yet

19. Yamasaki et al. N Engl J Med. 2011;365(6):576-8
• 10 patients with advanced HCC not responding to hepatic
arterial infusion chemotherapy
• Treated with deferoxamine infusions
• 2 had PR, 3 had SD and 5 had PD
• 20% overall response rate (Higher than sorafenib)
• 20% 1-year cumulative survival rate
• Acceptable toxicity
• ? New treatment

21. Serum ferritin concentration predicts
mortality in patients awaiting liver
transplantation. Walker et al. Hepatology 2010;51:1683
• 191 consecutive adults with cirrhosis Australian Liver
Transplant Service [Jan 2000 -Jun 2006]
• Validation cohort: 131 pts - UCLA Transplant Center.
• Ferritin > 200 micro g/L at start was an independent
predictor of higher 180-day & 1-year waiting list
mortality.
• Was independent of age, sex, model for end-stage
liver disease (MELD), and HCC

23. Potential applications
• Reducing iron overload to prevent HCC in CLD
– Avoiding iron supplements
– Avoiding foods rich in iron
– Avoiding foods fortified with iron
• Iron chelation therapy
– Control of ongoing liver cell damage to prevent HCC
– Adjuvant therapy along with anti HCC treatment
• Ferritin as a prognostic biomarker for HCC
– Deciding on transplantation wait list
– Screening protocol and intervals

24. Are you vaccinated against Hepatitis
B?
mohandaskm@gmail.com