An evidence-based look at Crohns Disease and Ulcerative Colitis. This blog explores various aspects of inflammatory bowel disease, including nutrition, treatment, and lifestyle based on clinical evidence.
Ayurveda is a form of alternative medicine in India (the
term refers to medicine in general, but it has come to be associated with a
particular form in Western parlance).
Ayurveda’s principles were established around the transition from BCE to
CE, and include many of the same concepts that were popular in early Greek
medicine – the concept of three humors, or fluids, present in the body (linked
to the elements fire, earth, water, and air) and the concept of “channels” present
in the body that need to be aligned.
While knowledge of basic anatomy grew in other parts of
Eurasia and North Africa, showing how the body functioned through dissection
and observation, the Ayurvedic system continued in India through to the
present. While India has some of the
world’s foremost physicians, they are differentiated from Ayurvedic
practitioners by training and the application of evidence to their techniques.
Ayurveda’s treatment modalities are broken along 8
paths. The two most prominent
modalities, hygiene and herbal medicine, are the most well-known. Other paths include surgical, diet, and meditation-based
The key Ayurvedic medicine associated with IBD is Boswellia serrate, more commonly known
as frankincense. Given in oral dosing, Boswellia has been shown to have a
similar efficacy to 5-ASA drugs in maintaining remission in early studies, but
the comparison to placebo in a recent double blind study showed no increased
efficacy. Overall, the safety profile of
Boswellia is good, but it does not
appear to have a clinically significant effect.(2)
Turmeric (Curcumin) has also been postulated as a treatment
for IBD. A common cooking ingredient,
Curcumin showed efficacy as an anti-inflammatory in induced colitis in mouse
studies.(3) To date, there have been two
human studies using curcumin to treat IBD.
Both were open-label pilots, though, and the subjects remained on
existing medications. Because there were
no controls or blinding (and the studies were small), there isn’t really data
to support its medicinal use to treat Crohn’s and IBD, though better double
blind studies are a possibility. That
said, it is a tasty edition to many Southeast Asian dishes, and makes a nice
addition to curry!(4)
Unfortunately, even if the Curcumin studies show positive
results, it would not be recommended that patients purchase them from ayurvedic
suppliers. Not controlled or monitored
as drugs, ayuverdic medicines have shown toxic levels of lead, arsenic, and
other heavy metals when properly assayed.(5)
Ayurvedic medicine does not have a solid theoretical basis,
but there are some practitioners that have proposed the discipline adopt a true
evidence-based approach. If these
proponents have their way, we may see true evidence to support (or refute) the
ayurvedic approaches. If the treatments
turn out to have a positive effect and quality control can be ensured, there is
some promise in ayurvedic treatments, especially the herbal possibilities.(6)
·Ayurveda’s theoretical basis is founded on long
disproven theories of body function.
·Some of the modalities (such as practicing good hygiene)
are not unique to ayuverda and are general good life skills.
·Other modalities (the herbal supplements) are
unregulated and dangerous.
·Current studies have failed to show efficacy of
ayurvedic techniques to treat IBD, but turmeric is a low risk possibility as an
anti-inflammatory and warrants further investigation.
Bhushan, Dnyaneshwar Warude, P. Pushpangadan, and Narendra Bhatt.
"Ayurveda and traditional Chinese medicine: a comparative overview."Evidence-Based Complementary
and Alternative Medicine 2, no.
4 (2005): 465-473.
Wolfgang, Stefan Zeuzem, Jan Preiβ, Wolfgang Kruis, Stephan Böhm, Christian
Maaser, Andreas Raedler et al. "Randomized, placebo‐controlled, double‐blind trial of Boswellia serrata in maintaining
remission of Crohn's disease: Good safety profile but lack of efficacy."Inflammatory bowel diseases 17, no. 2 (2011): 573-582.
Hiroyuki Hanai, Kotaro Tozawa, Taiki Aoshi, Masato Uchijima, Toshi Nagata, and
Yukio Koide. "Curcumin prevents and ameliorates trinitrobenzene sulfonic
acid–induced colitis in mice."Gastroenterology 123, no. 6 (2002): 1912-1922.
Rebecca A., and Mandy C. Leonard. "Curcumin for inflammatory bowel
disease: a review of human studies."Alternative medicine review: a
journal of clinical therapeutic 16,
no. 2 (2011): 152.
B., Russell S. Phillips, Anusha Sehgal, Nadia Khouri, Roger B. Davis, Janet
Paquin, Venkatesh Thuppil, and Stefanos N. Kales. "Lead, mercury, and
arsenic in US-and Indian-manufactured Ayurvedic medicines sold via the
Internet."JAMA: the journal of the
American Medical Association 300,
no. 8 (2008): 915-923.
Harsh. "Exploring larger evidence-base for contemporary Ayurveda."International Journal of Ayurveda Research 1, no. 2 (2010): 65.
Instead of a major update on a single topic, this week I’ll
cover a few interesting pieces of research related to IBD in the past 6 months
or so. The research presented is not
comprehensive, nor are the studies individually conclusive (though some may be
replications confirming earlier work). I
have tried, however, to choose works that may have an impact in another 12
months on the overall treatment/understanding/etc. of IBD.
Double-dose Humira (adalimumab)
This one has a personal resonance with me – I’m one of the
individuals who are on a weekly (as opposed to every other week) dose of
Humira, which is an off-label usage. I
moved to this regimen after my Crohn’s stopped responding to the every other
week (EOW) injections on the advice of my GI doctor. Now, there is evidence for a dose-response
increase in using weekly Humira injections for those with moderate-to-severe
Crohn’s disease and elevated CRP numbers.
In a double-blind study with placebo control, Sandborn et al found that
both weekly and EOW Humira doses outperformed placebo in a year-long remission
study. Further, in those with high CRP
levels, they found:
[R]emission rate with weekly dosing
(46.9%) was statistically significantly greater compared with eow dosing
The results show a lot of promise for weekly dosing in the
most severe cases. The other side of the
coin, the safety of doubling the dose, is still an unknown, and would support
the use of weekly dosing only in severe cases until further information on dose-related side effects can
be found. (1)
Humira, Antibiotics, and Fistulae
In a not unexpected result, but confirming what is a common
and widespread regimen, a new double-blind study showed that using Cipro in
combination with Humira was more effective than Humira alone in closing
fistulae. There are still unanswered
questions – does Flagyl work better in combination, or does the trifecta of
Humira, Flagyl, and Cipro work better than the others? Right now, you can’t go wrong with the
recommended Humira/Cipro one-two punch, but it will be interesting to see if we
can improve even more on this.(2)
Crohn’s, Ulcerative Colitis, and Sleeping
An interesting study by Ananthakrishnan et al looked at both
Crohn’s and Ulcerative Colitis in relation to sleep disturbances. They found that, at enrollment, “Disease
activity, depression, female sex, smoking, and use of corticosteroids or
narcotics” were associated with increased sleep disturbance. Interestingly, they found that sleep
disturbances to be predictive of an increased risk of flares in Crohn’s disease
(2x as likely) but not in Ulcerative Colitis (1.1x as likely). This is an unusual look at IBD, but may be
supportive of good sleep management practices (if causal) or monitoring of
sleep practices for prediction of flares (if only correlated).(3)
Could Crohn’s Disease be Multiple Diseases?
The idea that Crohn’s isn’t a single disease, but a variety
of diseases that are closely related isn’t new.
This study adds another drop in the bucket toward this hypothesis. Specifically, a study of the genes present in
the submucosal layers in patients showed that Mycobacterium were present in
approximately 50% of patients, and 43% of patients showed the presences of
genes from an unrelated bacteria family.
The most interesting aspect of the study was the exclusivity – there was
no overlap between the two families of genes in the same patient. The study was small, but could be very
important if the results hold up in larger studies, potentially resulting in
better targeted treatments.(4)
Preliminary Research Shows:
·Weekly use of Humira vice every-other-week is
more effective in treating severe Crohn’s
·Use of an antibiotic with a TNF-alpha drug
closes fistulae better than monotreatments
·Sleep disturbances are related to increased
Crohn’s activity, but not increased UC activity
·A small study on the sub mucosal layers in Crohn’s
patients showed two distinct and non-overlapping bacterial profiles
J., J. F. Colombel, G. D'Haens, S. E. Plevy, J. Panés, A. M. Robinson, P. F.
Pollack, Q. Zhou, M. Castillo, and R. B. Thakkar. "Association of Baseline
C-Reactive Protein and Prior Anti-TNF Therapy with Need for Weekly Dosing
During Maintenance Therapy with Adalimumab in Patients with Moderate to Severe
Crohn's Disease."Current Medical Research &
Opinion 0 (2013): 1-34.
Pieter, Bettina E. Hansen, Elke Verhey, Bas Oldenburg, Daniel W. Hommes,
Marieke Pierik, Cyriel IJ Ponsioen et al. "Adalimumab combined with ciprofloxacin
is superior to adalimumab monotherapy in perianal fistula closure in Crohn's
disease: a randomised, double-blind, placebo controlled trial (ADAFI)."Gut (2013).
Ashwin N., Millie D. Long, Christopher F. Martin, Robert S. Sandler, and
Michael D. Kappelman. "Sleep Disturbance and Risk of Active Disease in
Patients with Crohn's Disease and Ulcerative Colitis."Clinical Gastroenterology and Hepatology (2013).
Rodrick J., Scot E. Dowd, Brian Davis, Susan Galandiuk, William M. Chamberlin,
John Todd Kuenstner, Richard W. McCallum, and Jun Zhang. "Crohn's Disease
May Be Differentiated Into 2 Distinct Biotypes Based on the Detection of
Bacterial Genomic Sequences and Virulence Genes Within Submucosal
Tissues."Journal of clinical gastroenterology (2013).
Andrew Wakefield, a former physician at the center of the
anti-vaccination controversy, had a fairly prolific publishing and research
history before his fall from grace.
While Wakefield’s infamous vaccination paper made the headlines, many
don’t realize that his previous work was as a researcher into Crohn’s
disease. What happened in the
controversy, and how should we now view Wakefield’s work on Crohn’s disease?
Wakefield is a former physician came to infamy with his
paper that linked autism and vaccinations in 1998. Published in the Lancet (and now retracted),
the paper looked at a small number of autistic children and claimed to link
their autism to recent vaccinations with the measles, mumps, and rubella (MMR)
vaccine. According to Wakefield’s paper,
12 children developed autism shortly after being vaccination, with the MMR
vaccine noted as a proximal cause of the autism. The paper stated that the children had
previously never exhibited symptoms of an autism spectrum disorder diagnosis,
and the immediate proximity to the vaccine led to the conclusion that there was
a causal relationship.(1)
The studies presented by Wakefield were alarming, and
elevated him to the status of a legend within the anti-vaccination
community. His work was cited as
evidence that the mercury contained in vaccines (through the preservative
Thimerosal) was the reason behind the increase in autism in the recent past. Wakefield’s celebrity was short-lived,
however, when other doctors in larger, better controlled studies failed to
replicate his results.(2)
Wakefield’s work could have been a simple preliminary study
with non-representative results, which are fairly common in medicine, but the
increased publicity led to an investigation of the paper itself. Wakefield’s co-authors voluntarily withdrew
their names from the study, and Wakefield was left to defend it. Led
primarily by Brian Deer, funded by the Sunday Times of London, and published in
the British Medical Journal, Wakefield’s work was found to be not only wrong
but fraudulent.(3,4) A few key points
from the findings include:
·Wakefield engaged the 12 subjects in preparation
for a lawsuit he was involved in. (5)
·Multiple children enrolled in the study had
pre-existing cases of autism, before taking the MMR vaccine.
·The funding for the individuals enrolled in the
study came from the planned litigation.
·All 12 of the cited cases were misrepresented on
multiple factors, from the time of diagnosis to the diagnosis itself (not all
of the subjects were even diagnosed properly).(3)
Following Deer’s work, the Lancet retracted the article, but
not until 12 years of damage had been done by its alleged findings. In 2010, the UK’s General Medical Council
revoked Wakefield’s right to practice medicine in that country, citing his
fraudulent behavior, and finding, as summarized by the Guardian:
[T]he GMC said he had failed in the care of vulnerable children and was
guilty of "irresponsible and misleading reporting of research findings
potentially having such major implications for public health".(6)
The decline in MMR vaccination rates has led to a resurgence
in cases of the three diseases, and the impact in human suffering due to
Wakefield’s actions make take decades to sort out. While this alone would be an
interesting cautionary tale about non-evidence based medicine, there is a big
link to IBD in this tale – Wakefield published numerous papers on Crohn’s
disease, and believed the link between autism and MMR involved an IBD-like
intestinal disorder called autistic enterocolitis. While Wakefield’s MMR work has been
thoroughly discredited, how do we treat his earlier Crohn’s publications?
Wakefield’s earlier work on the histopathology of Crohn’s included
a highly cited paper “Pathogenesis of Crohn's disease: multifocal
gastrointestinal infarction”, which characterized intestinal regions with
active disease.(7) Wakefield did work
with both Ulcerative Colitis and Crohn’s segments in other forums as well,
including well respected publications like Gut.(8) Wakefield’s work rapidly moved into the
territory of linking Crohn’s with the measles virus, and this became a focal
point for his work until the controversial Lancet article.(9) Because the articles all had multiple authors,
it is difficult to dismiss all of their contents directly. That said, other articles have since been
retracted, including one from the American Journal of Gastroenterology that
included the same patients as above.(10)
Despite his unethical behavior, Wakefield’s early work
(before linking to the measles virus) appears to have been based on stronger
evidence. That said, there have been
numerous follow-on works since that point which have further elaborated or
replicated pieces of the results he put together. As such, it is not necessary to cite any of
Wakefied’s work directly. To sidestep
risk, any of the key points that have since been validated in other studies can
be cited standalone.
Wakefield’s story show the value of evidence based medicine
in taking to task behaviors that were found to be fraudulent. While he committed fraud in that event, and
we certainly need to revalidate his earlier works, the opposite of the appeal
to authority consideration needs to be part of the skeptical evaluation. Individuals like Linus Pauling went from
brilliant scientist to evangelical and misguided outside his field of
expertise. While Wakefield is no Linus
Pauling (and Pauling never committed fraud), the principle still applies – his earlier
work should be judged on its repeatability in controlled studies, not on the
integrity of the original source – that’s one of the beauties of science.
·Wakefield was an IBD researcher that turned to
the dark side and committed fraud to promote an anti-vaccine agenda.
·The current research has repeatedly shown no
link between vaccines and autism.
·Wakefield did some important work prior to his
fraud, and that work has been repeated and validated. The later studies are better citations due to
the issues surrounding the later Lancet work.
Andrew J., Simon H. Murch, Andrew Anthony, John Linnell, D. M. Casson, Mohsin
Malik, Mark Berelowitz et al. "Ileal-lymphoid-nodular hyperplasia,
non-specific colitis, and pervasive developmental disorder in children."Lancet 351,
no. 9103 (1998): 637-641.
Elizabeth Miller, Raghu Lingam, Nick Andrews, Andrea Simmons, and Julia Stowe.
"Measles, mumps, and rubella vaccination and bowel problems or
developmental regression in children with autism: population study."Bmj 324,
no. 7334 (2002): 393-396.
"How the case against the MMR vaccine was fixed."BMJ 342
Jane Smith, and Harvey Marcovitch. "Wakefield’s article linking MMR
vaccine and autism was fraudulent."BMJ 342 (2011).
5.MMR and MR Vaccine Litigation
Sayers and others v Smithkline Beecham plc and others -  All ER (D) 30
J., A. P. Dhillon, P. M. Rowles, A. M. Sawyerr, R. M. Pittilo, A. A. M. Lewis,
and R. E. Pounder. "Pathogenesis of Crohn's disease: multifocal
gastrointestinal infarction."The Lancet 334, no. 8671 (1989): 1057-1062.
8.Sankey, E. A.,
A. P. Dhillon, A. Anthony, A. J. Wakefield, R. Sim, L. More, M. Hudson, A. M.
Sawyerr, and R. E. Pounder. "Early mucosal changes in Crohn's
disease."Gut 34, no. 3 (1993): 375-381.
Andrew J., Anders Ekbom, Amar P. Dhillon, R. Michael Pittilo, and Roy E.
Pounder. "Crohn's disease: pathogenesis and persistent measles virus
infection."Gastroenterology 108, no. 3 (1995): 911-916.
The intestines are the entry point for most of the body’s
nutrients. Because of the damage caused
by Crohns Disease and Ulcerative Colitis, that absorption is negatively
impacted, resulting in malabsorption.
What specific nutrients are malabsorped (and may require
supplementation) depends greatly on what areas the IBD has damaged. What specific areas of the intestines, therefore,
are primarily* responsible for absorbing specific nutrients?(1)
The intestines are broken up into two halves – the small
intestine and the large intestine (or colon).
Each have different patterns of nutrient absorption, and are further
delineated into subregions.
The small intestine extends from the pyloric sphincter
(marking the end of the stomach) to the ileocecal valve (marking the beginning
of the large intestine). It is further
broken up into three separate regions – the duodenum, the jejunum, and the
ileum (in order from the stomach).
The duodenum isn’t directly involved in absorption, but it
is the processing center for breaking down nutrients for absorption later in
the intestines. Chyme (the liquefied contents
that are the results of the stomach breaking down food) release is regulated by
the duodenum, so the speed of gastric emptying can be impacted by damage
here. Additionally, the duodenum’s cells
signal the pancreas, liver, and gall bladder to release digestive enzymes. Damage to or excitation of the receptors can
result in too little (poor breakdown of nutrients) or too much (depends on the
enzyme). Duodenal damage can sometimes
be detected by color changes in the stool, ranging from whitish color (potential
liver disease or gallbladder issues) to yellow stool (potential bile issues),
but any sustained change in color could also be the result of secondary
infection and warrants a visit to the GI.
Finally, the proximal duodenum is primarily associated with iron
absorption and constant anemia may be a result of duodenal damage (though it
can also result from bleeding anywhere in the GI tract).
The jejunum is the area responsible for the absorption of
most nutrients in the intestines. The
villi are larger there, and the surface area is greater than the duodenum. Once the broken down nutrients pass through
the duodenum, the enterocytes, or absorption cells, take in vitamins, sugars,
amino acids, and water. They then enter
the bloodstream via the liver. Blood
tests showing low vitamin levels may be indicative of active disease or damage
to the jejunum. While the jejunum does
secrete some lactase, lactose intolerance is more often, but not exclusively,
associated with duodenal damage.(2)
The ileum digests everything that is left after the
jejunum. Carbohydrate and protein
digestion are completed through protease and carbohydrase enzyme activity. Additionally, vitamin B-12 is primarily absorbed
in the ileum, and ileum damage may show up as lower B-12 levels on blood tests
(and require booster shots). Finally,
bile salts are absorbed in the ileum and damage may result in bile acid being
passed along into the large intestine and causing rectal discomfort. Rectal pain after eating fatty foods may
indicate ileum-based disease. While
duodenal and jejunal damage are related to Crohn’s Disease, both Crohn’s and
Ulcerative Colitis can impact the ileum.
The large intestine
is broken up into the cecum, the rectum, and the anal canal. It has a smaller role in absorption than the
small intestine, and is much shorter (though of a larger diameter) than it’s digestive
predecessor. Because of this,
individuals can survive the removal of their large intestine (as a final treatment
of ulcerative colitis) through an ileostomy.
Because ileostomies are fairly well understood, the symptoms
of those with ileostomies mimic those with severe large intestinal damage. The two primary absorptions of the colon are
water and electrolytes, principally sodium and potassium. Damage to the large intestine may result in
watery stools and diarrhea, or in systemic electrolyte imbalances.
While not primarily involved in asbsorption, rectal damage
can cause increased urgency. The flow of
stool to the rectum triggers the need to defecate. If the need is suppressed in normal guts, the
stool is generally moved back into the cecum.
In those with damaged rectal tissue, the urgency may not subside and may
actually force the anal canal to open, resulting in unpleasant feelings and
·Damage to different areas of the intestines due
to inflammatory bowel disease causes different malabsorption issues.
·Blood tests, stool color and consistency, and related
symptoms can help pinpoint areas of active disease and assist in targeted
*Other areas can absorb smaller amounts of nutrients – only
the primary absorption areas are noted.