Tuesday, July 22, 2008

Index of Suspicion

There is an age old adage in medicine "You miss 100% of all disease X that you don't look for" It is stolen from an old golf adage that you miss 100% of all putts that you leave short. Big surprise, doctors stealing golf lines.

But I maintain, it is the same reason why we have been missing genetic causes of disease for the last 30 years. Yes, my friends in the Ivory Towers will tell you that they have a healthy index of suspicion for Every disease. I have worked in a community hospital and 2 Ivory Towers. I am here to tell you, that you miss 100% of a disease which you have never heard of or have never been taught about.

It's just that simple. Even more simple is that by thinking common things happen commonly only reinforces the lack of detection of genetic diseases which could actually be much more common than we know of.

I know that is a lot of jargon. But look at it this way. If you never test to detect a disease, you will never know how common it is. By not testing, you only reinforce your false belief of how "uncommon" a disease is. This is the case with things like the "Autism" epidemic. We are now looking for autism and are very good at detecting this multifactorial disease. Therefore prevalence goes up, and we look for it more often now......Sometimes, OVERDIAGNOSING it.

Why do I ramble about this today? Well, because a colleague of mine and I are having a debate. I think that Tony Snow's cancer is clearly heritable. In a very monogenic sense. The other physician thinks it is due to his other contributing multifactorial/genetic disease.

You see Tony Snow had Ulcerative Colitis(UC) at for 26 years prior to developing colorectal cancer(CRC). The risk of CRC in UC is pretty high. And often, the GI doctors invoke this "Inflammatory God" instead of keeping the index of suspicion of genetic causes, higher on the list. According to a nice review from MedScape

the cumulative probability of developing CRC is significantly higher in chronic ulcerative colitis than in the general population. Data from a comprehensive meta-analysis suggest that this probability is 2% after 10 years of disease, 8% after 20 years of disease, and 18% at 30 years after a diagnosis of chronic ulcerative colitis.[2] By comparison, the lifetime cumulative probability of developing CRC for the general population in the United States is approximately 5%.[2,3] Described in terms of relative risk, chronic ulcerative colitis increases the relative risk of CRC 5.7-fold compared with the general population.[3,4] The risk of developing CRC increases as a greater proportion of the colon is involved by inflammation.[5]

It is interesting to note that some populations of chronic ulcerative colitis patients do not have an increased risk of CRC compared with the background population. Data from these populations suggest that the risk of CRC in chronic ulcerative colitis can be modified. A Danish population-based cohort reported the cumulative probability of CRC was 0.4% after 10 years, 1.1% after 20 years, and 2.1% at 30 years after a chronic ulcerative colitis diagnosis.[6] These probabilities are comparable to those of a US population-based cohort, where the cumulative probability of CRC was 0% at 5 years, 0.4% at 15 years, and 2.0% at 25 years after a chronic ulcerative colitis diagnosis.[7]

2.0%, that is not inordinately high!

Why am I talking about this? Because, I put out to the world that NOT checking for a single gene risk and instead ascribing his CRC to UC would be a huge miss. In Fact, I still hold this opinion. Why? Tony Snow's mother DIED at 38 years of age from........you guessed it......CRC! To be fair, family history of CRC does increase risk of CRC in UC.....but in my mind that is likely due to defective DNA repair genes anyways.....

So, in my mind. The likelihood of her having UC AND CRC is pretty damn unlikely. In addition, UC is genetic....but there are 30 some genes ascribed to IBD......and none of these single genes cause the disease all on their own. For this to be autosomal dominant transmission of UC with a predisposing risk to CRC is a pretty big stretch.

Now to firmly believe the opposite of this and NOT test for HNPCC through pathology testing of Tony's original tumor is a big miss. I don't agree with anyone who says it isn't. Why?

What is the likelihood that Snow's mother passed a single gene on to him that increased his risk for CRC? Well, if she had the gene....50%.
What is the likelihood she had the gene?
Well from another great MedScape review approximately 24% of CRCs at 35 years of age or younger were germline positive (i.e. had Lynch Syndrome, the genetic cause I am suspicious caused Tony's cancer). So 3 years is a stretch, but let's just say the same data applies to a 38 year old....who likely had the cancer initially at 35 maybe 36. So what is 50% of 24%? 12%, a much higher incidence than that 2.0% in the cohort presented earlier. But not higher than the meta-analysis which included poorly controlled individuals. Which I am certain Tony was not.

So I ask you once again..........Was a lack of suspicion appropriate? I submit to you, it was completely inappropriate. In fact, I repeat. Not testing Tony's tumor for HNPCC was a HUGE miss, If in fact they did not do MSI and IHC testing. If they did, good for them!

Why is this important? Tony has a family that could benefit from identifying their risks for HNPCC. Why? Cancer prevention. Plain and Simple...

The Sherpa Says:

Index of suspicion is a funny thing. If you don't maintain it, then you miss a lot of bad things. If you have too much, you over diagnose and over test. I ask you. Now that Mr Snow has passed, which would you rather have? I vote for a high Index of Suspicion when it comes to an underdiagnosed condition like Lynch Syndrome! And when death is on the line!

References From Medscape
1. Clevers H, Colon cancer--understanding how NSAIDs work. N Engl J Med. 2006;354:761-763.
2. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526-535.
3. Canavan C, Abrams KR, Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease. Aliment Pharmacol Ther. 2006;23:1097-1104.
4. Jess T, Gamborg M, Matzen P, Munkholm P, Sorensen T. Increased risk of intestinal cancer in Crohn's disease: a meta-analysis of population-based cohort studies. Am J Gastroenterol. 2005;100:2724-2729.
5. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990;323:1228-1233.
6. Winther KV, Jess T, Langholz E, Munkholm P, Binder V. Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County. Clin Gastroenterol Hepatol. 2004;2:1088-1095.
7. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Gastroenterology. 2006;130:1039-1046.


Anonymous said...

I know this isn't related, but I wanted to share it anyways.


Steve Murphy MD said...

Isnt' related?????
Of course it is. Thank you so much.