Sunday, May 26, 2013

Crohn's, Ulcerative Colitis, and Ayurveda


Ayurvedic “Medicine” and IBD


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 healing.(1)

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) 

Bottom Line


·         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.

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1.       Patwardhan, 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.
2.       Holtmeier, Wolfgang, Stefan Zeuzem, Jan Preiβ, Wolfgang Kruis, Stephan Böhm, Christian Maaser, Andreas Raedler et al. "Randomized, placebocontrolled, doubleblind 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.
3.       Sugimoto, Ken, 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.
4.       Taylor, 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.
5.       Saper, Robert 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.
6.       Singh, Ram Harsh. "Exploring larger evidence-base for contemporary Ayurveda." International Journal of Ayurveda Research 1, no. 2 (2010): 65.

Sunday, May 19, 2013

Research Update

IBD Research Briefs



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 (22.5%)

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)

Bottom Line


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

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1.       Sandborn, W. 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.
2.       Dewint, 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).
3.       Ananthakrishnan, 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).
4.       Chiodini, 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).

Sunday, May 12, 2013

Andrew Wakefield and Crohns Disease


Andrew Wakefield and IBD


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.

Bottom Line

·         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.

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1.       Wakefield, 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.
2.       Taylor, Brent, 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.
3.       Deer, Brian. "How the case against the MMR vaccine was fixed." BMJ 342 (2011).
4.       Godlee, Fiona, 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 - [2007] All ER (D) 30 (Jun).
7.       Wakefield, A. 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.
9.       Wakefield, 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.

Sunday, May 5, 2013

Malabsorption and IBD


Intestinal Absorption


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. 

Small Intestine


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

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

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 Ilieum

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.

Large Intestine


 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 potential accidents.

Bottom Line


·         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 treatments.

*Other areas can absorb smaller amounts of nutrients – only the primary absorption areas are noted.

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1.       Heizer, William D. "Normal and abnormal intestinal absorption by humans."Environmental health perspectives 33 (1979): 101.
2.       Langman, J. M., and R. Rowland. "Activity of duodenal disaccharidases in relation to normal and abnormal mucosal morphology." Journal of clinical pathology 43, no. 7 (1990): 537-540.