1. Diverticular Disease Genetics and correlation to cancer
Tryggvi Stefánsson
Centrallasarettet in Västerås
and
Landspítali University Hospital
Reykjavík/Iceland

2. Diverticular disease Non-Symptomatic diverticular disease
= Diverticulosis
Symptomatic diverticular disease
= Diverticulosis +
Diverticulitis
Hemorrage
Motility disorders

3. Diverticular disease and CRC
Many similarities.
Cancer and diverticulosis:
No known association.
Cancer and symptomatic diverticular disease: Association.

4. Diverticulosis and CRC
Prevalence for diverticulosis and for CRC increases as age increases and is the same in men and women.

5. Diverticulosis and CRC
Low prevalens of Diverticulosis in populations with low risk for CRC and Polyps.
Lack of fiber in the diet causes diverticulosis.
Painter and Burkitt, BMJ,1971
Fiber in the diet decreases the risk for colon cancer Howe GR et al, J Nat Ca Inst, 1992
Potter JD, Ca Causes and Control 1996

6. Diverticulosis and CRC
Diverticulosis increases in migrating populations when moving from low risk areas to high risk areas.
Painter and Burkitt, BMJ,1971
Stemmermann GN, Cancer, 1973
CRC increases in migrating populations when moving from low risk areas to high risk areas.
Stazewski J, J Nat Ca Inst, 1965
Haenszel W, J Nat Ca Inst, 1968

7. Diverticulosis and CRC
One small study on the association between non-symptomatic diverticular disease and CRC
119 cases with CRC
40% of men had diverticulosis
39% of women had diverticulosis
119 age-matched controls without CRC
50% of men had diverticulosis
36% of women had diverticulosis
There was no significant difference in number of patients with diverticulosis in the two groups
Mc Callum et al, Scand J Gastro, 1988

8. Symptomatic Diverticular Disease and CRC
Physical activity lowers the risk of symptomatic diverticular disease in men WH Aldoori et al, Gut, 1995
Physical activity lowers the risk of CRC.
Garabrant DH et al, Am J Epid, 1984
Vena JE et al, Am J Epid, 1985
Gerhardson M, Int J Epid, 1988

9. Symptomatic Diverticular Disease and CRC
High intake of fat and low intake of fiber is associated with increased risk of Symptomatic Diverticular Disease
Aldoori WH et al, Am J Clin Nutr, 1994
High intake of fat is associated with increased risk of CRC
Howe et al, Ca Causes and Control, 1997

10. Symptomatic Diverticular Disease and CRC
High intake of red meat and low intake of fiber is associated with increased risk of Symptomatic Diverticular Disease.
Aldoori WH et al, Am J Clin Nutr, 1994
High intake of red meat is associated with increased risk of CRC
Potter JD, J Natl Ca Inst, 1999

11. Symptomatic Diverticular Disease and CRC
Uppsala Health Care Region
Total 7159 patients with diverticular disease
Men 2478
Women 4681
<60 years 1410
60-69 years 1665
>70 years 4084

12. First year after the diagnosis Diverticular Disease
Site Obs SIR 95% CI
Colon
Pancreas
Prostate
Stomach
Blood
Rectum
Liver
Ovary
Lung
Stefánsson T et al, Eur J Surg, 1995

13. First year after the diagnosis Diverticular Disease
All Colon Right Colon Left Colon
obs SIR CI obs SIR CI obs SIR CI
(6.5-11) ( ) (8-14.1)
During 2 years after the diagnosis symptomatic DD there were 75 colon cancers among 7159 Sympt DD patients 1/100
FOBT screening in average risk>50 years 1/300
Stefánsson T et al, Eur J Surg, 1995

14. Symptomatic Diverticular Disease and CRC
7159 patients with symptomatic diverticular disease Followed up untill The first two years excluded.
Obs= Observed numbers of CRC.
obs SIR 95%CI
All Colon ( )
Right and Transv ( )
Desc and Sigm ( )
Rectum ( )
Stefansson T et al, Gut, 1993

15. Symptomatic Diverticular Disease and CRC
7159 patients with symptomatic diverticular disease Followed up untill The first two years excluded.
A nested case control study
64 cases of colon cancer x 123 controls,
matched by age, sex and year of discharge
Patients with sigmoid diverticulitis had four-fold risk of colon cancer compared to those with only diverticulosis
OR= 4.2 (95% CI )
Stefánsson T et al, Scand J Gastroenterol, 2004

16. Summary Diverticulosis and Colon cancer
Many things in common. No known association
Diverticular Disease and Colon Cancer
The first year after diagnosis RR= 18 in left colon
The first two years excluded RR=1.8 in left colon
Diverticulitis and Colon Cancer
The first two years excluded OR=4 in left colon

17. Conclusion Many similarities. Cancer and diverticulosis:
No known association.
Cancer and Diverticulitis
Association.

18. Genetics and Diverticular Diseasex

19. Diverticulosis In European and US populations Distal Colon
90% with sigmoidal involvement
15% in right colon
Parks TG, Clin Gastroenterol, 1975
Hughes LE, Gut, 1969
In Asian populations
Right sided involvement of Diverticula
Lee YS, Dis Colon Rectum, 1986
Chia JG, Dis Colon Rectum, 1991

20. Diverticulosis Prevalence is high in Europe, USA and Australia
but low in rural Africa and Asia.
Painter NS and Burkitt DP, BMJ, 1971

21. Diverticulosis
The incidence of diverticula can vary in ethnic groups within a given country.
Singapore:
Chinese : 1,4/100000/year
Europeans: 54,1/100000/year
Kyle J et al, Scand J Gastroent, 1967
Israel
Ashkenazy Jews 16,2% 17,3%
Sephardi Jews 3,8% 12,9%
Arabs 0,7% 5,4%
Levy N, Dis Colon Rectum, 1985

22. Diverticulosis Smooth Muscle Abnormality Elastin Depositions
Taenia Coli Appear thick with a cartilagenous consistency
The circular musle is thick
Corrugated concertina like appearance
Morson BC, Proceedings of the Royal Society of Medicine 1963
Elastin Depositions
The diverticular colonic wall contains normal muscle cells, but muscle cells in the taenia coli contains 200% more elastin compared with those without diverticula.
Whiteway J, Morson BC, Gut, 1985

23. Diverticulosis Increase in type III collagen synthesis
Bode MK, Scand J Gastroenterol, 2000
Stumpf M, Int J Colorectal Dis, 2001

24. Diverticulosis
Increased Diverticulosis in Marfans and Ehler Danlos syndromes
Simpson J, Br J Surg, 2002

25. Diverticulosis
Interstitial cells of Cajal and Glial cells are significantly reduced in Colonic Diverticular Disease.
Bassotti G et al, Journal of Clinical Pathology, 2005

26. Genetics of Diverticular Disease
Discharged from hospital in Iceland with the diagnosis Diverticular disease.
Genealogy register at deCode in Reykjavík containing all Icelanders living in Iceland from the settlement of the island.
RR of relatives, mates and relatives of mates of being in the discharged group.

27. Genetics of Diverticular Disease
All
Operated 488
Not Operated 2577

28. 1°rel-5°rel All Operated Not-op RR (95% CI) RR (95% CI) RR (95% CI)
1°relatives 1.77( ) ( ) 1.54( )
2°relatives 1.17( ) ( ) 1.09( )
3°relatives 1.17( ) ( ) 1.17( )
4°relatives 1.14( ) ( ) 1.18( )
5°relatives 1.05( ) ( ) 1.43( )

29. All Grandparents 1.48 (0.97-2.10) Aunts & uncles 1.22 (1.09-1.37)
1.12( )
parents
2.20( )
Parents
1.33( )
Cousin
1.18 ( )
Cousin
1.15( )
Siblings
1.60 ( )
Index
3065
Mates
1.42( )
Siblings
0.99( )
Nephews & nieces
1.14 ( )
Children
1.81 ( )
Children
1.66( )
Nephews & nieces
1.06( )

30. Not Operated Grandparents 1.45 (0.82-2.26) Aunts & uncles
1.13 ( )
Aunts & uncles
1.14( )
parents
1.96( )
Parents
1.41( )
Cousin
1.20 ( )
Cousin
1.17( )
Siblings
1.41 ( )
Index
2577
Mates
1.42( )
Siblings
1.07( )
Nephews & nieces
1.05 ( )
Children
1.56 ( )
Children
1.45( )
Nephews & nieces
1.09( )

31. Operated Grandparents 4.45 (1.45-9.08) Aunts & uncles 1.34 (0.64-2.28)
1.02( )
parents
3.26( )
Parents
0.61( )
Cousin
1.39 ( )
Cousin
0.99( )
Siblings
6.28 ( )
Index
488
Mates
0.00( )
Siblings
0.52( )
Nephews & nieces
1.29 ( )
Children
2.94 ( )
Children
2.39( )
Nephews & nieces
1.49( )

32. Discussion Diverticular Disease both genetic and environmental.
Diverticulosis more environmental ?
Complicated diverticular disease more genetic ?