Sunday, December 30, 2012

IBD Blood Tests for Diagnosis


IBD Blood Diagnostics


Crohn’s disease and Ulcerative colitis are the abnormal inflammation of the intestinal wall, resulting in ulcerations, that is not related to an otherwise identified reason (e.g. colon cancer).  Crohn’s disease can occur in bands and can be anywhere in the intestinal tract, whereas UC occurs exclusively in the large intestine* in a defined region.  Additionally, Crohns is a full thickness disease – it impacts all layers of the intestinal wall while UC impacts the surface layer.

Diagnosing IBD is generally a multi-stage process.  First, a detailed patient history is examined for symptoms consistent with IBD, including, but not limited to, chronic diarrhea, abdominal pain, blood in the stool, weight loss, and fatigue.  If the patient presents with possible IBD, the doctor may order imaging tests, ranging from barium swallow MRI tests to CT scans.  Next, direct observation of the suspected area through endoscopy, sigmoidoscopy, or colonoscopy is performed.  Finally, tissue samples of the affected area are biopsied.

What role does blood testing play in the diagnosis of IBD?  Blood testing is relatively harmless and can be used to identify signs of IBD initially and as an ongoing monitor of health in already diagnosed patients.  Blood tests look for a few things – markers of inflammation (such as C-Reactive Protein), vitamin and mineral levels (to look for things line iron deficiencies indicative of bleeding or vitamin deficiencies that may pinpoint disease areas), and other functional markers (such as liver function).

What about blood tests like the Prometheus IBD Serology 7 (now in the 4th generation with the IBD sgi Diagnostic)?  Prometheus, to its credit, identifies the test as aiding, not making the diagnosis, but more than a few doctors have misunderstood this claim:

The new Prometheus IBD sgi Diagnostic is the 4th-generation IBD diagnostic test and the first and only test to combine serologic, genetic, and inflammation markers in the proprietary Smart Diagnostic Algorithm for added diagnostic clairty. This test will aid healthcare providers in differentiating IBD vs non-IBD, and CD vs UC, in one comprehensive blood test. (1)

While including other factors (including inflammation and genetics), the serum marker test Prometheus Labs does is a probabilistic test, but the sensitivity and specificity are fairly low to be saying it diagnoses IBD well.  For example, if we look at one of the larger preliminary reviews of the serological component, we will see that there is a sensitivity of 65% and a specificity of 94% on the primary components of the test.(2)  In a more recent and larger study, the sensitivity and specificity of the Prometheus IBD testing was 80% and 61.5%, respectively.  What does that mean?

Sensitivity is the percentage of sick people who are correctly identified as having the condition. Specificity is the percentage of healthy people who are correctly identified as not having the condition.  80% sounds a lot better than chance, right?  The problems come when you do the math related to prevalence.  The positive prediction value and negative prediction value are what the patient is really interested in.  Looking at the second article’s raw numbers we get the following:

True Positive:  23
True Negative:  45
False Positive:   7
False Negative:  19

Positive Prediction Value = True Positive/(True Positive + False Positive) = 23/(23+7)= 77%
Negative Prediction Value = True Negative/(True Negative + False Negative) = 45/(45+19) = 70%

In non-mathematical terms, this means that 23% of the people who are diagnosed with Crohn’s disease by the test don’t actually have, and 30% of the people that are diagnosed as not having Crohn’s disease do have it.  The test has other uses – including differentiation of Crohn’s and UC, but the numbers above don’t show tremendous diagnostic ability.  The numbers above also represent a sample of individuals that already presented with the symptoms of IBD – if more fringe cases are tested, the numbers would be expected to get worse.  Although not marketed this way, if this test were presented to the US population as a whole, based on expected prevalence of IBD, we’d get the following results:

Positive Predictive Value = (Sensitivity)(Prevalence)/((Sensitivity)(Prevalence) + (1-Specificity)(1-Prevalence)) = (.8)(.005)/((.8)(.005) + (.385)(.995)) = 1%
Negative Predictive Value = (Specificity)(1-Prevalence)/((Specificity)(1-Prevalence)+(1-Sensitivity)(Prevalence)) = (.615)(.995)/((.615)(.995)+(.2)(.005)) = 99.8%

This means the test falls victim to the base rate fallacy – because IBD is rare enough, the test gets skewed based on the prevalence.  While no one is advocating mass screenings using this blood test, overzealous physicians may (and have) misused it with individuals that don’t meet the other diagnostic criteria (e.g. sending everyone with repeated boughts of diarrhea for IBD serological testing), leading to misdiagnoses in both directions.

The folks at Prometheus are doing great work in identifying markers of IBD, and hopefully they will keep it up and continue refining their tests.  Right now, their tests can provide probabilistic differentiation, but are not, in of themselves, a diagnosis.

Note:  I welcome anyone to check my math - lots of numbers in the probability calculations and I wouldn't object to a confirmation or correction!

* The terminal ileum can be impacted in rare cases.

Bottom Line:

  • Serological testing can be an adjunct to traditional diagnostics and assist in differentiating IBD.
  • Serological tests, including the Prometheus Serum 7 and Prometheus IBD sgi Diagnostic cannot be used exclusively to diagnosis IBD.




  1. http://www.prometheuspatients.com/Products_Diagnostics.asp, retrieved 12/24/2012. 
  2. Anna Zholudev MPH, David Zurakowski PhD, Wes Young BA, Alan Leichtner MD and Athos Bousvaros MD, MPHSerologic Testing with ANCA, ASCA, and Anti-OmpC in Children and Young Adults with Crohn's Disease and Ulcerative Colitis: Diagnostic Value and Correlation with Disease Phenotype.  The American Journal of Gastroenterology, 2004. 
  3. F. Rashid, M.L. Bechtold, S.R. Puli, J.D. Bragg: Utility of IBD Serology Tests: Experience of an Academic Center. The Internet Journal of Gastroenterology. 2011.

Sunday, December 23, 2012

IBD and Genetics


Will my relatives get IBD?


Genetics is believed to play a definitive role in the risk of developing Crohn’s Disease and Ulcerative Colitis.  One of the most common questions in IBD from the relatives of those diagnoses is what their likelihood of developing the disease is going to be.  Risk can be either vertical (the risk of children of IBD sufferers contracting the disease) or horizontal (the risk of siblings developing the disease).  Both vertical and horizontal risks have been shown to be higher than the general population risk.

Determining the role of genetics and inheritance in the likelihood of developing a particular disease generally involves twin studies.  Identical twins, who share the same genetics*, are compared to fraternal twins, who share the same parents but come from different eggs.  Because twins are generally raised in the same circumstances and exposed to the same environmental factors, differences in the rate of occurrence between identical and fraternal twins can show the degree of genetic influence on disease development.  In the rare cases where twins are separated and raised in different environments, further confirmation or disconfirmation of a genetic link can be made.  If twins living in different locations and raised by different parents have the same predisposition to developing a particular disease as twins raised together, the genetic link is that much stronger.  Because of the rarity of IBD, twin studies are difficult to perform, especially separated twin studies.

The largest twin study to-date on Crohn’s and UC was done in Sweden in the 1980’s.  The study found a stark difference between the two diseases.  When one twin has UC, the other twin is not significantly more likely than the general population to develop UC.  When a twin has Crohn’s, however, the other twin is twice as likely as the general population to develop the disease.  Additionally, if an identical twin has Crohn’s, the other twin has a greater than 50% chance of developing Crohn’s, showing a strong genetic link.  In a follow-up study fifteen years later, additional UC diagnosis showed an 18% chance of a second twin developing UC if the first twin had it.  (1), (2)

What about the non-twin factors in inheritance?  Familial incidence is the single biggest risk factor identified in the likelihood of being diagnosed with IBD.  In a study of 1,000 patients, 87 were found to have first degree relatives with Crohn’s disease – primarily siblings.(3)  The likelihood of a sibling developing IBD if another sibling is diagnosed is between 10 and 20%, significantly higher than the population as a whole. (4).  The evidence additionally suggests a stronger maternal influence on whether or not IBD is developed in children.  (5)

What if you are looking to have kids?  The risk of a child developing IBD is 3–10% when one parent has IBD and 30–50% if both parents have the IBD.  Predictive genetic testing is, unfortunately, still in its infancy and not an accurate predictor (alone) of developing IBD.  (6,7)

Despite the definitive role of genetics in IBD, research is currently trying to understand what specific genetic markers are predictive.  Additionally, there is almost certainly a non-genetic environmental factor or factors at play that has yet to be identified (though there are several well-grounded possibilities).

Bottom Line

  • IBD has a definite genetic component (but it is not believed to be exclusively genetic). 
  • Siblings of those with IBD have a 10 – 20% chance of developing the disease.
  • Children of parents with IBD have a 3 – 10% chance of developing the disease.  If both parents have IBD, the risk rises to 30-50%. 


* Technically, genetic mutations can occur even with identical twins.  Additionally, epigenetic factors can strongly influence identical twin development.  That said, identical twins still share a genetic makeup that is substantially more alike than other categories of relatives.

1.       C Tysk, E Lindberg, G Järnerot, and B Flodérus-Myrhed.  Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking.  Gut, 1988.
2.       Halfvarson J, Bodin L, Tysk C, Lindberg E, Järnerot G.  Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics.  Gut, 2003.
3.       Freeman, Hugh J. M.D.  Familial Crohn's Disease in Single or Multiple First-Degree Relatives. Journal of Clinical Gastroenterology.  2002. 
4.       R.K Russell, MBChB, MRCP(Ed), MRCPCH, J Satsangi, BSc, MBBS, Dphil, FRCP(Ed).  IBD: a family affair.  Best Practice and Research:  Clinical Gastroenterology.  2004.
5.       Zuzana Zelinkova, Pieter C. Stokkers, Klaas van der Linde, Ernst J. Kuipers, Maikel P. Peppelenbosch, Christine P.J. van der Woude.  Maternal imprinting and female predominance in familial Crohn's disease.  Journal of Crohn’s and Colitis.  2011.
6.       Satsangi, J., Grootscholten, C., Holt, H., & Jewell, D. P.. Clinical patterns of Familial Inflammatory Bowel Disease. Gut, 1996.
7.       Shelly A. Cummings  and David T. Rubin.  The Complexity and Challenges of Genetic Counseling and Testing for Inflammatory Bowel Disease.  Journal of Genetic Counseling, 2006.

Sunday, December 16, 2012

Caffeine and IBD


Caffeine, Crohn's, and Ulcerative Colitis



Caffeine is a naturally occurring stimulant drug and is commonly found in coffee, tea, chocolate, cola, and other products.  Caffeine is one of the most commonly ingested drugs, and is one of the most studied.  Caffeine use for IBD patients has historically been contraindicated, however the contraindication is not well supported by clinical research.

Negative effects of caffeine consumption are highly individual dependent and are due in part to the regularity of caffeine consumption.  Like many drugs, individuals who regularly consume caffeine develop a tolerance, and both the stimulant and side effects are generally reduced over time.  Additionally, caffeine is an addictive substance.  When caffeine intake is curtailed, withdrawal can occur resulting in headaches, irritability, difficulty sleeping, and abdominal pain.  Symptoms can persist for up to a week following the last intake of caffeine. 

The primary negative effects of caffeine are related to its function as a central nervous system stimulant.  Consuming more than 250mg of caffeine in one day can lead to nervousness, irritability, restlessness, difficulty sleeping, headaches, and heart arrhythmias.  Side effects are less when consuming small amounts of caffeine.

Caffeine has the positive effects of a stimulant as well.  Consuming products with caffeine can reduce drowsiness and increase alertness for short periods.  Caffeine has been included in some headache medicines as an adjunct treatment, and consumption has been shown to have a positive reduction in the incidence of certain cancers.

For those with IBD, the primary concerns behind consumption of caffeine are increases in inflammation and the diuretic effect of the drug.  For inflammation, there is currently no good evidence linking caffeine consumption to C-Reactive Protein levels, a common inflammation marker in IBD testing.(1)  Additionally, caffeine consumption has been shown to suppress tumor necrosis factor alpha (TNF-α) production. (2) TNF-α has been directly linked to inflammation related to IBD and suppression of TNF-α is the focus of several drugs, including Remicade, Cimzia, Enbrel, and Humira. 

While caffeine has been shown to have a small diuretic effect when first consumed, regular consumers have shown no incident increase in the diuretic properties against placebo.  Specifically, the risk of dehydration due to increased urination from caffeine is small but present for those who don’t regularly drink it, but the effect quickly goes away.  Because of this, caffeine should not be avoided exclusively because of IBD – it has not been shown to worsen symptoms.  Consumption of caffeine for IBD sufferers should be an educated, personal choice based on the side effects and positive properties unrelated to IBD. (3)

Caffeine levels for many commonly consumed products like coffee and tea vary greatly depending on the agricultural source and preparation.  A good baseline for non-excessive daily caffeine consumption is 8 to 16 ounces of coffee.  The average caffeine content of common foods and beverages is shown below.
 
Product
Serving Size
Amount of Caffeine (in mg)
Espresso
4 oz
254
Rockstar Energy Drink
16 oz
160
Coffee
8 oz
95
Red Bull
8.5 oz
80
Coffee, instant
8 oz
65
Tea, black
8 oz
47
Diet Coke
12 oz
45
Coca Cola Classic
12 oz
34
Hershey chocolate bar
1 bar
9
Lipton BRISK iced tea
12 oz
7
Coffee, decaffeinated
8 oz
2

 The information above is for the caffeine itself.  Specific drinks, such as coffee or soda, have multiple ingredients that can exacerbate the effects of caffeine or, alternatively, have pallative effects.  As such, caffeine should not be the only consideration in choosing what to eat or drink for those with IBD.

Bottom Line

  • Small amounts of caffeine (the equivalent of one cup of coffee a day) are not generally associated with negative side effects.
  • Large amounts of caffeine can exacerbate general health problems, though not specifically those related to IBD.
  • Caffeine reactions are highly dependent on the tolerance of the individual consuming it.

(1)  Rodrigues, I. M., & Klein, L. C. Boiled or Filtered Coffee?: Effects of Coffee and Caffeine on Cholesterol, Fibrinogen and C-Reactive Protein. Toxicological Reviews.  2006.

(2)  Horrigan, L. A., Kelly, J. P., & Connor, T. J.  Caffeine suppresses TNF-α production via activation of the cyclic AMP/protein kinase A pathway. International Immunopharmacology, 2004.

(3)  Maughan, R. J., & Griffin, J. Caffeine ingestion and fluid balance: a review. Journal of Human Nutrition and Dietetics, 2003.



Sunday, December 9, 2012

IBD By The Numbers, Part 2


Crohns and Ulcerative Colitis, by the Numbers

There are several areas of statistical interest in Crohns.  In another look at the numbers, I've highlighted areas where questions arise on three brief topics below - the diseases that are co-morbid with IBD, the age of diagnosis, and the number of bowel movements a day. I'll be throwing in a few cornucopia posts like this every few weeks to address a few simpler questions, intersperced with more in-depth posts.

Co-morbid Diseases with IBD


I previously noted the association between IBD and depression.  What about other diseases that are frequently co-morbid with IBD?  The specific diseases are different between UC and Crohns.  As expected, UC has more involvement with diseases of the large intestine like Hirschprung’s disease, whereas Crohns has impacts on bone-related diseases like osteoporosis (due partly to malabsorption).  Both have impacts on kidney and liver functions.  Interestingly, there is a higher likelihood of schizophrenia with UC.  All forms of IBD have higher comorbidity with other autoimmune disorders, such as psoriasis and rheumatoid arthritis.
The table below shows the proportional morbidity ratio (PMR) for the various diseases.  The PMR is equal to the number of individuals with the disease who have the condition divided by the number of people from the general population in the same sample size who have the condition.  A PMR of 1 would mean there is no higher likelihood than an average person.  Higher PMRs mean a much higher correlation between having IBD and the disease in particular. (1,2)

Condition
Crohns
Ulcerative Colitis
Osteoporosis
3.2
X
Ankylosing spondylitis
33.2
X
Cirrhosis of liver without mention of alcohol
1.7
X
Sequela of chronic liver disease
1.6
X
Cholangitis
5.9
16
Amyloidosis
6.6
X
Acute renal failure unspecified
2.3
3.1
Acute renal failure with lesion of tubular necrosis
X
9.9
Uremia NOS
2
X
Calculus of kidney
8.5
X
DIC, afibrinogenemia, fibrinolysis pathologies
4.7
4.6
Coagulation defect other unspecified
3.8
X
Pulmonary embolism
2.3
2.2
Hirschsprung’s disease
X
246.1
Schizophrenia
X
4.6
Asthma
1.43
1.66
Bronchitis
1.86
2.1
Arthritis
1.24
1.44
Multiple Sclerosis
X
1.9
Psoriasis
1.59
1.65
Pericarditis
3.07
3.33

Age of Onset


When do we get diagnosed with IBD?  Crohn’s disease tends to be an earlier diagnosis than Ulcerative Colitis, but only by 2 or 3 years.  Generally, the average age of diagnosis is 26, with a standard deviation of 12 years, (14-38 year of age being the expected age of diagnosis).  This doesn’t necessarily correlate to the onset of the disease itself – individuals can be misdiagnosed with irritable bowel syndrome (IBS), gastroenteritis, or other conditions for years before finalizing the diagnosis.  Nor does the distribution guarantee that it will occur during this period – it has been diagnosed in infants and retirees.  (3)

Number of Bowel Movements


What about normal bowel habits?  Most of us count the number of times we need to go every day as a measure of health.  The exact number of times we should be expecting to use the bathroom is based on diet, genetics, medications and a host of other factors not necessarily related to the underlying IBD (try eating $10 worth of Taco Bell, with or without IBD, and see what that does…)  Once a day is the median number of times to go, but there is actually a range of what is “normal”.  95% of the population (bowel-typical?) goes between three times a week and three times a day. (4)

Bottom Line

  •  IBD is generally diagnosed between the ages of 14 and 35.
  • The average person uses the bathroom between 3 times a week and 3 times a day, with 1 time a day being the median.
  • Crohns and IBD are both comorbid with other diseases, including autoimmune diseases and those effecting the liver and kidneys. 


(1)    Claudia Cucino, M.D., Amnon Sonnenberg, M.D., (M.Sc.).  The comorbid occurrence of other diagnoses in patients with ulcerative colitis and Crohn’s disease.  American Journal of Gastroenterology, 2001.
(2)    Charles N. Bernstein, Andre Wajda,  and James F. Blanchard.  The Clustering of Other Chronic Inflammatory Diseases in Inflammatory Bowel Disease: A Population-Based Study.  Gastroenterology, 2005.
(3)    JM Polito 2nd, B Childs, ED Mellits, AZ Tokayer, ML Harris, TM Bayless.  Crohn's disease: Influence of age at diagnosis on site and clinical type of disease.  Gastroenterology, 1996.
(4)    S. Walter, O. Hallböök, R. Gotthard, M. Bergmark and R. A Population-based Study on Bowel Habits in a Swedish Community: Prevalence of Faecal Incontinence and Constipation.  Scandinavian Journal of Gastroenterology, 2002.   

Sunday, December 2, 2012

Exercise and IBD


Crohn's, Ulcerative Colitis, and Calisthenics 


Exercise is generally one of the pillars of a healthy lifestyle.  By doing both cardio and weight training, an individual can increase their overall fitness level, lower their risk of heart issues, improve their mood, increase their overall energy, and improve their ability to stave off illness.  Additionally, exercise is fun – you can find an activity that fits your interests and lifestyle, from walks in the park to parkour, and it is a chance to be social.  There are concerns with exercise and its impact on IBD, though, ranging from the short-term issues from the exercise itself to the long term impact due to exercise-related inflammation. 

Inflammation


Inflammation is the general response of the body’s tissue to an unwanted stimulus.  Chronic inflammation is a serious concern with IBD sufferers.  IBD itself causes both local inflammation (in the digestive system) and remote inflammation (in the case of co-morbid diseases like Rheumatoid Arthritis and Psoriasis).  Overall inflammation is measured indirectly by looking at specific markers.  The three most common markers are:

IL-6.  Interleukin-6 is a cytokine (a molecule that sends signals to cells) that is released during muscle contraction.  IL-6 can cause inflammation, but also inhibits another inflammatory marker, TNF-alpha.

CRP.  C-Reactive Protein is the most common marker tested for in IBD.  It is an indirect measure of overall body inflammation, and a low CRP number is always desirable.

TNF-alpha.  Tumor necrosis factor alpha is another cytokine associated with all of the signs of inflammation.  TNF-alpha inhibitors such as Humira, Remicade, and Cimzia are now the cornerstones of IBD treatment.

Exercise is linked to inflammation in two ways – acute and chronic.  Acute inflammation occurs immediately after exercising (at least intense exercising).  Chronic inflammation is the overall level of inflammatory markers present while not exercising.  Because inflammation is also associated with obesity, smoking, poor diet, and other factors that are correlated with people that don’t exercise, it can be difficult to determine the impact of just exercise on inflammation.  That said, there have been a few studies that have isolated the impact of exercise.

The easiest effects for IBD sufferers to recognize and associate with are the acute effects of exercise.  Light (briskly walking a couple of miles) to moderate (swimming for 30 minutes) exercise tends to have minimal effect.  Strenuous exercise (running a marathon) does tend to have an effect – namely the provocation of heartburn, fecal incontinence and diarrhea.  Individuals running triathlons, even those without underlying IBD, have experienced GI symptoms (between 30 and 81% have reported this).  This is believed to be due to reduced blood flow to the GI tract, the mechanical impact of bouncing, and the overall acute inflammatory increase.  CRP, IL-6, and TNF-alpha markers tend to elevated immediately following a period of intense exercise(1,2)  At the most intense side, ischemic colitis, the lack of adequate blood flow to the large intestine can occur in endurance athletes.  Ischemic colitis is a serious, acute condition that requires immediate medical intervention, and is the result of numerous emergency room visits following marathons each year.  (3)

The long term impact of exercise is exactly the opposite.  Increased bone density, reduced stress levels, and overall lower at-rest levels of all three major inflammatory markers are present.  The impact was found to happen after even light exercise over a 12-week period, and is proportional (though with diminishing returns) to the intensity of the exercise.  Because the overall health impact of both muscle-building anaerobic exercise and aerobic conditioning are both important, two times a week each for strength training and aerobic workouts have been proven beneficial.  As a side benefit, regular exercise has been correlated with a 50% reduction in the risk for developing colon cancer.  (2,4,5)

Special Cases

IBD sufferers have special needs, depending on where they are with their disease.  Anyone who has had a recent IBD surgery (within the past 8 weeks) needs to discuss any psychical activity beyond walking or similar light impact activities with their physician.  Additionally, when flaring, the overall level of activity may need to be toned down – the impact of the flare on general body fatigue and the acute impact on already inflamed tissue may be detrimental.  This is an area where the research is spotty, and additional data is needed.

While fatigue is a general issue for those with IBD, individuals that have had extensive bowel resectioning  (30%+) have an even greater level of fatigue.  Because of this, most cannot tolerate the energy requirements of rigorous exercise.  (6)  

Bottom Line

·         Light to moderate exercise to the level tolerated is excellent for those with IBD that have not had recent surgery.
·         2-3 times a week of aerobic exercise (walking, jogging, swimming, biking) and twice a week of strength training have overall positive impacts on inflammation and quality of life, with generally no negative impact on the underlying disease.
·         Strenuous endurance exercise should be discussed with your doctor before starting a regime.

(1)    H P F Peters, W R De Vries.  Potential benefits and hazards of physical activity and exercise on the gastrointestinal tract.  Gut, 2001.
(2)    Neeraj Narula, BSc and Richard N Fedorak, MD.  Exercise and inflammatory bowel disease.  Canadian Journal of Gastroenterology, 2008.
(3)    I Leon D. Sanchez, MD, MPH , Jason A. Tracy, MD, David Berkoff, MD, Ivan Pedrosa, MD.  Ischemiccolitis in marathon runners: A case-based review.  Emergency Medicine, 2006.
(4)    Christos Kasapis, MD, Paul D. Thompson, MD (FACC).   The Effects of Physical Activity on Serum C-Reactive Protein and Inflammatory Markers: A Systematic Review.  Journal of the American College of Cardiology, 2005.
(5)    Ford, Earl S.  Does Exercise Reduce Inflammation? Physical Activity and C-Reactive Protein Among U.S. Adults.  Epidemiology, 2002.
(6)    Brevinge H, Berglund B, Bosaeus I, Tolli J, Nordgren S, Lundholm K. Exercise capacity in patients undergoing proctocolectomy and small bowel resection for Crohn’s disease. British Journal of Surgery. 1995;