How EDS Affects GI (Heidi Collins, MD)

My intention is to provide a presentation that can be appreciated even if viewed independently by

persons not attending the EDNF 2013 Learning Conference.

Due to time constraints, some of the many slides in this presentation will not be discussed in great

detail during the scheduled sessions, so I encourage members of the audience to refer to the presenter

notes.

This presentation is authored with thoroughly cited presenter notes, including links to full-text articles

and resources when available.

1

Image:

http://www.springerimages.com/img/Images/BMC/VOL=2009.4/ISU=1/ART=129/MediaObjects/LARGE

_13013_2009_Article_129_Fig12_HTML.jpg

In addition to his statements regarding the gut, Hippocrates has been credited with perhaps being the

first to recognize Ehlers-Danlos Syndrome when he wrote about laxity in Scythian warriors in his text,

“On Airs, Waters, Places”.

2

Why this topic?

The minor diagnostic criteria for Classic EDS (CEDS) include manifestations of tissue extensibility and

fragility (e.g., hiatal hernia, rectal prolapse).

The diagnostic criteria for Vascular EDS (VEDS) include complications including rupture or perforation

of hollow organs such as the bowel.

The official clinical criteria for CEDS, Hypermobile EDS (HEDS), and VEDS Types otherwise do not

mention digestion, nutrition, bowel function, or gut-related immunity.

References:

Malfait F, Wenstrup R, De Paepe A. Ehlers-Danlos Syndrome, Classic Type. 2007 May 29 [updated

2011 Aug 18]. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors.

GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.

(See: http://www.ncbi.nlm.nih.gov/books/NBK1244/,

http://www.nature.com/gim/journal/v12/n10/pdf/gim2010100a.pdf)

Levy HP. Ehlers-Danlos Syndrome, Hypermobility Type. 2004 Oct 22 [updated 2012 Sep 13]. In:

Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet].

Seattle (WA): University of Washington, Seattle; 1993-2013.

(See: http://www.ncbi.nlm.nih.gov/books/NBK1279/)

Pepin MG, Byers PH. Ehlers-Danlos Syndrome Type IV. 1999 Sep 02 [updated 2011 May 03]. In:

Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet].

Seattle (WA): University of Washington, Seattle; 1993-2013.


3

GI complications of EDS are:

…common: a majority of persons with EDS suffer gastrointestinal complications – 50% to 85% depending on the specific complication(s) (see references below).

…potentially disabling: Of course, gut rupture or perforation associated with VEDS is potentially fatal. However, many persons with suspected or confirmed EDS types other than VEDS will attest to the often disabling gut- or immune-related symptoms with which they suffer.

…under-appreciated: Surgeons are typically aware of GI complications related to VEDS, such as rupture. However, there is widespread under-appreciation of myriad GI complications beyond those well-documented for persons with VEDS.

…well-documented: These issues have long been recognized and documented, despite the fairly ubiquitous patient experience of lack of recognition or acknowledgement of their connection to EDS by their involved MDs.

References (a selected bibliography):

Levy HP. Ehlers-Danlos Syndrome, Hypermobility Type. 2004 Oct 22 [updated 2012 Sep 13]. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.


Burcharth J, Rosenberg J. Gastrointestinal surgery and related complications in patients with Ehlers-Danlos syndrome: a systematic review. Dig Surg. 2012;29(4):349-57. doi: 10.1159/000343738. Epub 2012 Oct 22. Review. PubMed PMID: 23095510.

(See: http://www.ncbi.nlm.nih.gov/pubmed/23095510, http://www.karger.com/Article/Pdf/343738)

Castori M, Camerota F, Celletti C, Danese C, Santilli V, Saraceni VM, Grammatico P. Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A. 2010 Mar;152A(3):556-64. doi: 10.1002/ajmg.a.33231. PubMed PMID: 20140961.

(See: http://www.ncbi.nlm.nih.gov/pubmed/23095510, http://www.ehlersdanlos.it/Public/Dynamic/Documents/Document634103349567582849.pdf)

Castori M. Surgical recommendations in Ehlers-Danlos syndrome(s) need patient classification: the example of Ehlers-Danlos syndrome hypermobility type (a.k.a. joint hypermobility syndrome). Dig Surg. 2012;29(6):453-5. doi: 10.1159/000346068. Epub 2013 Jan 7. PubMed PMID: 23295898.


Burcharth J, Rosenberg J. Surgical recommendations in Ehlers-Danlos syndrome(s) need patient classification: the example of Ehlers-Danlos syndrome hypermobility type (a.k.a. joint hypermobility syndrome)---reply. Dig Surg. 2012;29(6):456. doi: 10.1159/000345998. Epub 2013 Jan 7. PubMed PMID: 23295973.


Reinstein E, Pimentel M, Pariani M, Nemec S, Sokol T, Rimoin DL. Visceroptosis of the bowel in the hypermobility type of Ehlers-Danlos syndrome: presentation of a rare manifestation and review of the literature. Eur J Med Genet. 2012 Oct;55(10):548-51. doi: 10.1016/j.ejmg.2012.06.012. Epub 2012 Jul 7. Review. PubMed PMID: 22781752; PubMed Central PMCID: PMC3568682.

(See: http://www.ncbi.nlm.nih.gov/pubmed/22781752, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568682/pdf/nihms392200.pdf)

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Gastrointestinal complications of are potentially disabling, even in HEDS.

Reference:

http://www.dailymail.co.uk/news/article-2193857/Ehlers-Danlos-Syndrome-Jodie-Vasquez-fed-heart-

drip-diagnosed-disorder.html

6

Gastrointestinal complications of EDS are well-documented in existing literature. References span

more than 5 decades.

1969

EDS patients should recognize in particular one of the authors: Peter Beighton.

Note that both “lethal” and “non-lethal” gastrointestinal complications are acknowledged.

Reference:

Beighton PH, Murdoch JL, Votteler T. Gastrointestinal complications of the Ehlers-Danlos syndrome.

Gut. 1969 Dec;10(12):1004-8.PubMed [citation] PMID: 5308459, PMCID: PMC1553023

(See: http://www.ncbi.nlm.nih.gov/pubmed/5308459, http://gut.bmj.com/content/10/12/1004.full.pdf)

7

1996

The authors indicate within the article, “the phenotypical variance that characterizes this syndrome

often makes its recognition difficult.”

Note: At the time this article was published, CEDS (as Types I and II – gravis and mitis) were thought

to constitute 80% of EDS cases, and HEDS (as Type III) was thought to constitute 10% of EDS cases.

This underscores the under-recognition of the disorder as a whole, with particular lack of recognition of

HEDS.

Reference:

Solomon JA, Abrams L, Lichtenstein GR. GI manifestations of Ehlers-Danlos syndrome. Am J

Gastroenterol. 1996 Nov;91(11):2282-8. Review. PubMed [citation] PMID: 8931403

(See: http://www.ncbi.nlm.nih.gov/pubmed/8931403,

http://www.annabelleschallenge.org/app/download/3570409/GI+Manifestation+of+EDS.pdf)

8

1999

The abstract mentions not only the possibility of gut rupture and herniation, but also concludes that

GERD, Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) are common

complications in Classical and Hypermobile EDS Types as a result of medication effects, structural or

functional abnormalities, and autonomic dysfunction.

Reference:

http://www.ashg.org/genetics/abstracts/abs99/f362.htm

See also:

Levy HP, Mayoral W, Collier K, Tio TL, Francomano CA. 1999. Gastroesophageal reflux and irritable

bowel syndrome in classical and hypermobile Ehlers–Danlos syndrome (EDS). Am J Hum Genet

65:A69 [Abstract].

9

2004

This article notes the interconnectedness of EDS, autonomic dysfunction, and gastrointestinal

complaints.

Reference:

Hakim AJ, Grahame R. Non-musculoskeletal symptoms in joint hypermobility syndrome. Indirect

evidence for autonomic dysfunction? Rheumatology (Oxford). 2004 Sep;43(9):1194-5. No abstract

available. PubMed [citation] PMID: 15317957


http://rheumatology.oxfordjournals.org/content/43/9/1194.full.pdf)

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2007

This program presented at the 2007 American Society of Human Genetics suggests that lack of tissue

integrity may be the cause of GI disorders. More specifically, tissue abnormalities are believed to

cause structural abnormalities, decreased blood vessel wall strength, and/or altered motility or

absorption.

Reference:

http://www.ashg.org/genetics/ashg07s/f11076.htm

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2007

This program presented at the 2007 American Society of Human Genetics suggests that altered tissue

integrity due to collagen abnormalities could lead to increased immunogenicity, specifically causing

humoral (immunoglubulin) and cellular (lymphoid, eosinophil and mastocyte) responses leading to

gastrointestinal problems for persons with EDS.

Reference:

http://www.ashg.org/genetics/ashg07s/f21352.htm

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2009

Again, researchers recognize the possibility that connective tissue abnormalities play into autoimmune

and inflammatory GI processes.

Reference:

Vounotrypidis P, Efremidou E, Zezos P, Pitiakoudis M, Maltezos E, Lyratzopoulos N, Kouklakis G.

Prevalence of joint hypermobility and patterns of articular

manifestations in patients with inflammatory bowel disease. Gastroenterol Res Pract.

2009;2009:924138. doi: 10.1155/2009/924138. Epub 2010 Feb 11. PubMed [citation] PMID: 20169104,

PMCID: PMC2821781


http://downloads.hindawi.com/journals/grp/2009/924138.pdf)

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2010

Stresses connective tissue abnormalities as a pathophysiological link between joint hypermobility (such

as that seen in EDS) and unexplained GI symptoms.

Rather than studying a population of patients with joint hypermobility in order to see whether

gastrointestinal symptoms were prevalent among them, this study focused upon a population of

patients with gastrointestinal complaints to see whether joint hypermobility was prevalent among them.

Reference:

Zarate N, Farmer AD, Grahame R, Mohammed SD, Knowles CH, Scott SM, Aziz Q. Unexplained

gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link?

Neurogastroenterol Motil. 2010 Mar;22(3):252-e78. doi: 10.1111/j.1365-2982.2009.01421.x. Epub 2009

Oct 15.PubMed [citation] PMID: 19840271

(See: http://www.ncbi.nlm.nih.gov/pubmed/19840271, http://onlinelibrary.wiley.com/doi/10.1111/j.1365-

2982.2009.01421.x/pdf)

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2013

This review indicates that Joint Hypermobility Syndrome and EDS are essentially identical and that

EDS is common and frequently overlooked.

Additionally, this review stresses that EDS is a multisystem disorder with significant GI manifestations.

Reference:

Fikree A, Aziz Q, Grahame R. Joint hypermobility syndrome. Rheum Dis Clin North Am. 2013

May;39(2):419-30. doi: 10.1016/j.rdc.2013.03.003. PubMed [citation] PMID: 23597972

(See: http://www.ncbi.nlm.nih.gov/pubmed/23597972)

15

2012

This comprehensive review stressing underdiagnosis and multisystem involvement underscores that

EDS is NOT just joint hypermobility!

Importantly, this study suggests EDS is far more prevalent than published numbers suggest, likely a

frequency as high as 1:50 (2%) in Africans to 1:167 (0.6%) in Europeans and Americans.

Reference:

Castori M. Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective

tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN Dermatol.

2012;2012:751768. doi: 10.5402/2012/751768. Epub 2012 Nov 22.PubMed [citation] PMID: 23227356,

PMCID: PMC3512326


http://downloads.hindawi.com/journals/isrn.dermatology/2012/751768.pdf)

“The early literature fixed to 1/5,000 the frequency of EDS as a whole, with EDS-HT accounting for

approximately half of all registered cases. However, as JHS/EDS-HT is a neglected HCTD, its

frequency is likely underestimated. Accordingly, based on registered data on the frequency of

generalized JHM in various populations and the assumption of an ∼10% chance of developing

symptoms according to the Brighton criteria for “double-jointed” people, a presumed frequency of 0.75–

2% has been proposed for JHS. As general JHM is rarer among Caucasians compared to other

populations such as Africans, a frequency of 0.2–0.6%, with the lowest value better fitting for men and

the highest for females, appears more realistic in Europe and USA. However, no systematic study

accurately investigating the real incidence of JHS/EDS-HT has been performed to date.”

16

“Figure 6: Schematic representation of extra-articular manifestations of Ehlers-Danlos syndrome,

hypermobility type (alternatively termed joint hypermobility syndrome). The dark grey circle symbolizes

the phenotypic spectrum of this condition, which includes a series of functional somatic syndromes and

tissue/organspecific dysfunctions (i.e., the white triangles, whose tips are indeed comprised within the

dark circle). Outside the clinical spectrum of Ehlers-Danlos syndrome, hypermobility type, the single

phenotypic components may be observed in isolation or, perhaps, in incomplete associations within the

general population (the larger and light grey circle). It is expected that, in the future, the study of

heritable dysfunctions of the connective tissue will move from the dark gray circle to the light gray one,

as a prominent field of interest. 1Mostly including fibromyalgia, myofascial pain and complex regional

pain syndromes. 2Comprising xerophthalmia, xerostomia, vaginal dryness, and abnormal sweating.

3Asthma, atopy, gluten sensitivity, inflammatory bowel disease, and recurrent cystitis are all possible

manifestations of an underlying immune system dysregulation.”

Reference:




PMCID: PMC3512326



17

Ehlers Danlos Syndrome is NOT just joint hypermobility!

Unfortunately, physicians acknowledging the possibility of EDS in a patient often do so only because

they recognize joint hypermobility.

Many physicians literally refuse to acknowledge EDS as a multisystem disorder.

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Few members of the medical community are aware and understand the multisystem nature of EDS.

A physician may recognize discrete issues experienced by persons with EDS but fail to consider them

interconnected.

Multiple physicians may become involved, each seeing only the discrete issue for which they are

consulted.

See Also:

Castori M, Celletti C, Camerota F. Ehlers-Danlos syndrome hypermobility type: a possible unifying

concept for various functional somatic syndromes. Rheumatol Int. 2013 Mar;33(3):819-21. doi:

10.1007/s00296-011-2275-2. Epub 2011 Dec 23.


http://link.springer.com/article/10.1007%2Fs00296-011-2275-2#page-1)

19

Image:

http://livingwithautism-brian.blogspot.com/2009_10_01_archive.html

Reference:

Riordan, James. "Six Blind Men and An Elephant." An Illustrated Treasury of Fairy and Folk Tales (1986): 30-33.

“A long time ago, in the valley of Brahmaputra in India there lived six men who were much inclined to boast of their wit and lore. Though they were no longer young and had all been blind since birth, they would compete with each other to see who could tell the tallest story. One day, however, they fell to arguing. The object of their dispute was the elephant. Now, since each was blind, none had ever seen that mighty beast of whom so many tales are told. So, to satisfy their minds and settle the dispute, they decided to go and seek out an elephant. Having hired a young guide, Dookiram by name, they set out early one morning in single file along the forest track, each placing his hands on the back of the man in front. It was not long before they came to a forest clearing where a huge bull elephant, quite tame, was standing contemplating his menu for the day. The six blind men became quite excited; at last they would satisfy their minds. Thus it was that the men took turns to investigate the elephant's shape and form. As all six men were blind, neither of them could see the whole elephant and approached the elephant from different directions. After encountering the elephant, each man proclaimed in turn: 'O my brothers,' the first man at once cried out, 'it is as sure as I am wise that this elephant is like a great mud wall baked hard in the sun.' 'Now, my brothers,' the second man exclaimed with a cry of dawning recognition, 'I can tell you what shape this elephant is - he is exactly like a spear.' The others smiled in disbelief. 'Why, dear brothers, do you not see,' said the third man -- 'this elephant is very much like a rope,' he shouted. 'Ha, I thought as much,' the fourth man declared excitedly, 'This elephant much resembles a serpent.' The others snorted their contempt. 'Good gracious, brothers,' the fifth man called out, 'even a blind man can see what shape the elephant resembles most. Why he's mightily like a fan.' At last, it was the turn of the sixth old fellow and he proclaimed, 'This sturdy pillar, brothers' mine, feels exactly like the trunk of a great areca palm tree.' Of course, no one believed him. Their curiosity satisfied, they all linked hands and followed the guide, Dookiram, back to the village. Once there, seated beneath a waving palm, the six blind men began disputing loud and long. Each now had his own opinion, firmly based on his own experience, of what an elephant is really like. For after all, each had felt the elephant for himself and knew that he was right! And so indeed he was. For depending on how the elephant is seen, each blind man was partly right, though all were in the wrong.”

See Also:

Castori M, Celletti C, Camerota F. Ehlers-Danlos syndrome hypermobility type: a possible unifying concept for various functional somatic syndromes. Rheumatol Int. 2013 Mar;33(3):819-21. doi: 10.1007/s00296-011-2275-2. Epub 2011 Dec 23.

(See: http://www.ncbi.nlm.nih.gov/pubmed/22193218, http://link.springer.com/article/10.1007%2Fs00296-011-2275-2#page-1)

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Digestion, nutrition, bowel function, and gut-related immune function are vital physiologic processes.

If digestion did not occur, whatever enters the mouth would leave the rectum untouched.

Nutrition includes oral (enteral) intake, digestion, absorption and metabolism of nutrients. Nutrients

may also enter the body via parenteral (e.g., IV, transdermal) routes.

Elimination includes excretion of wastes via the bladder and bowel, as well as processes such as

sweating and respiration. (Vomiting may be considered an unintended form of elimination, with loss of

unabsorbed nutrients, etc.)

The gut has to be able to protect the body from “foreign invaders” (e.g., bacteria, viruses, fungi,

protozoa, foreign antigens, toxins, etc.).

21

Image:

http://starklab.slu.edu/Physio/Alimentary.jpg

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Image:


24

Image:


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Note in particular the presence of connective tissue, lymphoid tissue, mast cells, eosinophils, and

nerve tissue.

Connective tissue (including collagen) is also plentiful in the special structures (teeth, gums, TMJ, liver,

gall bladder, pancreas, sphincters) and in vascular walls and healed or scarred tissues after injury or

procedure.

26

Image:

http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/2020/2020%20Exam%20Reviews

/Exam%203/CH23%20General%20Digestive%20Histology.htm

Concentric tissue layers are present throughout the upper GI and lower GI tract.

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Image:

http://en.wikipedia.org/wiki/File:Hematopoiesis_simple.svg

The immune cells residing in the gut migrate there from elsewhere in the body.

Lymphoid tissues in the gut include:

• tonsils (Waldeyer's ring)

• adenoids (pharyngeal tonsils)

• small lymphoid aggregates in the esophagus

• lymphoid tissue accumulating with age in the stomach

• Peyer's patches

• lymphoid tissue in the appendix and large intestine

• diffusely distributed lymphoid cells and plasma cells in the lamina propria of the gut

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References:

Grenham S, Clarke G, Cryan JF, Dinan TG. Brain-gut-microbe communication in health and disease.

Front Physiol. 2011;2:94. doi: 10.3389/fphys.2011.00094. Epub 2011 Dec 7. PubMed PMID:

22162969; PubMed Central PMCID: PMC3232439.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232439/pdf/fphys-02-00094.pdf)

Coyle, MD, Walter J. "The Human Microbiome: The Undiscovered Country".

(See: http://www.acponline.org/about_acp/chapters/ca/microbiome.pptx)

The Human Microbiome Project

(See: https://commonfund.nih.gov/hmp/)

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Bacteria are not always harmful.

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The gut microbiome acts much as an internal organ, with protective, structural, and metabolic

functions, and a key role in immune system development.

“In addition to playing an important role in barrier defence, probiotics have an ever-unfolding role to

play in the modulation of mucosal immunity. Probiotic bacteria can modulate the activity of many cells

of the immune system, including innate system NKs, DCs, macrophages, epithelial cells and

granulocytes, as well as adaptive system Th1, Th2, Th17, Treg, Tc and B cells. Thus, probiotic

bacteria have the potential to modulate any part of the immune system in the context of acute

responses to intracellular or extracellular pathogens or chronic responses observed in dysregulated

immunopathological conditions such as IBD, colorectal cancer and hypersensitivity. Modulation of

immunopathology to the advantage of the human host can only realistically occur upon a full

knowledge of the modulatory capabilities of the probiotic and a full appreciation of the mechanisms

underpinning the pathology. Probiotic bacterial strains can be generalised to exert immune-activation, -

deviation or -regulation/suppression responses. Thus, selection of probiotic strains, and indeed

combinations of probiotics, will be formulated upon careful consideration of the disease mechanisms

and the desired immunomodulatory effect. Finally, the growing body of evidence for the suitability of

prebiotics in immunomodulation and formulation with probiotic strains, as synbiotics, represents a

realistic approach in disease modification. The probiotic species acting as a quick-fix

immunomodulatory “plaster” and the prebiotic facilitating commensal organisms, modulating the

dysbiosis in the gut microbiota and further modifying the immune system to our benefit—healing from

within!!”

Reference:

O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006 Jul;7(7):688-93.

Review. PubMed [citation] PMID: 16819463, PMCID: PMC1500832


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1500832/pdf/7400731.pdf)

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A “Brain-Gut-Enteric Microbiota Axis” is recognized.

Reference:

Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric

microbiota axis. Nat Rev Gastroenterol Hepatol. 2009 May;6(5):306-14. doi: 10.1038/nrgastro.2009.35.

Review. PubMed [citation] PMID: 19404271


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817714/pdf/nihms-523421.pdf)

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“A healthy microbiota contains a balanced composition of many classes of bacteria. Symbionts are

organisms with known health promoting functions. Commensals are permanent residents of this

complex ecosystem and provide no benefit or detriment to the host (at least to our knowledge).

Pathobionts are also permanent residents of the microbiota and have the potential to induce pathology.

In conditions of dysbiosis there is an unnatural shift in the composition of the microbiota, which results

in either a reduction in the numbers of symbionts and/or an increase in the numbers of pathobionts.

The causes for this are not entirely clear, but are likely to include recent societal advances in

developed countries. The result is non-specific inflammation, which may predispose certain genetically

susceptible people to inflammatory disease and may be caused by pathogens, which are opportunistic

organisms that cause acute inflammation.”

References:

Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and

disease. Nat Rev Immunol. 2009 May;9(5):313-23. doi: 10.1038/nri2515. Review. Erratum in: Nat Rev

Immunol. 2009 Aug;9(8):600. PubMed PMID: 19343057.


http://www.stritch.luc.edu/lumen/meded/hostdef/Gut_Microbiota_Shapes_Intestinal.pdf)

Zimmer, Carl. "How microbes defend and define us." New York Times 17 (2010).

(See: http://www.nytimes.com/2010/07/13/science/13micro.html)

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2005/press.html

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Our Western diet is thought to promote development of a proinflammatory gut microbiome.

Additional medical practices, such as the use of proton pump inhibitors and anti-hypertensives are

increasingly recognized to adversely affect immune development and functions because of the way

they affect microbiota.

Examples of Conditions in which Th Cell Activity is Increased:

• Delayed Type Hypersensitivity (e.g., autoimmune disorders such as Celiac Disease): Th1-

Related Pathology

• Crohn’s Disease: Th1/Th17-Dominant Pathology

• Allergy and Type I Hypersensitivity: Th2-Related Pathology

• Ulcerative Colitis: Th2-Dominant Pathology

Reference:

Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and

disease. Nat Rev Immunol. 2009 May;9(5):313-23. doi: 10.1038/nri2515. Review. Erratum in: Nat Rev

Immunol. 2009 Aug;9(8):600. PubMed PMID: 19343057.


http://www.stritch.luc.edu/lumen/meded/hostdef/Gut_Microbiota_Shapes_Intestinal.pdf)

34

Images:

http://www.myworkhorse.com/content/over-training-and-plateaus

http://www.tokresource.org/tok_classes/biobiobio/biomenu/options_folder/E5_human_brain/index.htm

http://blogs.christianpost.com/health/natural-vs-traditional-medicine-for-heartburn-and-indigestion-

4254/

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Image:

http://www.uic.edu/classes/bios/bios100/lectures/ANS.jpg

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Image:

http://www.highlands.edu/academics/divisions/scipe/biology/faculty/harnden/2121/images/nervousorg.j

pg

The sensory division of the peripheral nervous system includes autonomic sensory afferents carrying

signals from visceral sensory receptors monitoring internal organs to the spinal cord and brain.

The motor division of the peripheral nervous system includes autonomic motor efferents carrying

signals from the brain and spinal cord to effectors – target organs (e.g. smooth muscle, cardiac

muscle, glands, adipose tissue) whose activities change in response to neural commands.

37

Image:

http://quizlet.com/5132557/vphys-digestive-system-flash-cards/

See also:

Costa M, Glise H, Sjodahl R. The enteric nervous system in health and disease. Gut. 2000

Dec;47(Suppl 4):iv1. No abstract available. PMID: 18668961 [PubMed]

(See: http://www.ncbi.nlm.nih.gov/pubmed/18668961, http://gut.bmj.com/content/47/suppl_4)

http://www.scholarpedia.org/article/Enteric_nervous_system

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Images:

http://universe-review.ca/I10-51-enteric02.jpg

http://ajpgi.physiology.org/content/277/5/G922.full.pdf

Reference:

Furness JB, Kunze WA, Clerc N. Nutrient tasting and signaling mechanisms in the gut. II. The intestine as a sensory organ: neural, endocrine, and immune responses. Am J Physiol. 1999 Nov;277(5 Pt 1):G922-8. Review. PubMed PMID: 10564096.

(See: http://www.ncbi.nlm.nih.gov/pubmed/10564096, http://ajpgi.physiology.org/content/277/5/G922.full.pdf)

“Fig. 2. Simplified diagram to illustrate the arrangement of primary afferent neurons of the intestine. See text for a more complete description. Intestinal primary afferent neurons include IPANs, vagal and spinal primary afferent neurons, and intestinofugal neurons. IPANs are multipolar, and their terminals are confined within the wall of the intestine. Vagal and spinal primary afferent neurons are pseudounipolar and have collaterals that run to enteric ganglia (e.g., arrows). Subgroups of these that respond to specific modalities may have specific patterns of ending in the gut wall (not shown). Vagal primary afferent neurons have cell bodies in the nodose ganglia, and their outputs are via terminals in the nucleus tractus solitarius within the brain stem. Cell bodies of spinal primary afferent neurons are in dorsal root ganglia, their central processes end in the dorsal horns of the spinal cord, and their peripheral axons pass through sympathetic ganglia to innervate the intestine. In many cases, primary afferent neurons are excited by hormones released by gut endocrine cells. Intestinofugal neurons are part of the afferent limb of intestinointestinal reflexes that pass through sympathetic ganglia. LM, longitudinal muscle; CM, circular muscle; MP, myenteric plexus; SM, submucosa; Muc, mucosa.”

See also:

http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/2020/2020%20Exam%20Reviews/Exam%203/CH23%20General%20Digestive%20Histology.htm

neural plexus - The interlacing networks of nerve fibers which originate from certain cranial nerves, e.g., the Vagus (X) and the ventral rami of spinal nerves in which individual autonomic nerve processes from the brain stem and individual spinal segments become redistributed to that (1) each resulting branch of the plexus contains fibers from several cranial and spinal nerves and (2) fibers from each ventral ramus travel to the peripheral tissues of the body by several routes; this arrangement permits portion of the digestive tube to be innervated by autonomic motor (afferent) fibers from more than one spinal segment -- as a result, an injury to a single spinal segment or spinal motor (ventral) root cannot completely paralyze any organ.

submucosal plexus - The interlacing networks of unmyelinated nerve fibers derived chiefly from the superior mesenteric plexus which is located within the submucosa of the gastrointestinal tract, especially in the intestines; it consists chiefly of visceral sensory fibers and postganglionic autonomic motor fibers; it is concerned with the control of functions within the inner walls of each gut segment, i.e., local absorption, secretion, and contraction.

myenteric plexus - The interlacing networks of unmyelinated nerve fibers derived chiefly from the superior mesenteric plexus which is located within the muscularis of the gastrointestinal tract (between the inner circular and outer longitudinal layers); it consists chiefly of postganglionic autonomic motor fibers; it is concerned with the control of smooth muscle tone, peristalsis, and the relaxation of the pyloric and ileocecal sphincters.

39

Image:

http://alexpicotannand.com/2011/03/24/the-anxiety-solution-part-2-2/

References:

Gershon M. The Second Brain: the Scientific Basis of Gut Instinct and a Groundbreaking New

Understanding of Nervous Disorders of the Stomach and Intestines. New York: Harper; 1998

http://www.scientificamerican.com/article.cfm?id=gut-second-brain

See Also:

Wood JD. Enteric neuroimmunophysiology and pathophysiology. Gastroenterology. 2004

Aug;127(2):635-57. Review. PubMed PMID: 15300595.


40

Reference:

Wilhelmsen I. Brain-gut axis as an example of the bio-psycho-social model. Gut. 2000 Dec;47 Suppl

4:iv5-7; discussion iv10. Review. PubMed PMID: 11076893; PubMed Central PMCID: PMC1766804.

(See: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1766804/,

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1766804/pdf/v047p00iv5.pdf)

“The brain-gut axis is a good example of a circular relationship between different factors, and illustrates

that research on interrelationship and interaction is necessary to understand the whole picture (fig 1).

Chronic functional gastrointestinal symptoms can be seen as a result of dysregulation of intestinal

motor, sensory, and CNS activity.”

41

Reference:

Mathias CJ, Low DA, Iodice V, Owens A, Kirbis M, Grahame R. Postural tachycardia syndrome - current experience and concepts. Nat Rev Neurol. 2011 Dec 6;8(1):22-34.

(See: http://www.ncbi.nlm.nih.gov/pubmed/22143364, http://ukpotsies.org.uk/wp-content/uploads/2013/01/nrneurol.2011.187.pdf)

See Also:

Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP. Comparative Clinical Profile of Postural Orthostatic Tachycardia Patients With and Without Joint Hypermobility Syndrome. Indian Pacing and Electrophysiology Journal. 10(4): 173-178 PMC [article] PMCID: PMC2847867, PMID: 20376184

(See: http://www.ncbi.nlm.nih.gov/pubmed/20376184, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847867/pdf/ipej100173-00.pdf)

Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med. 2003 Jul;115(1):33-40. PubMed PMID: 12867232.


Fikree A, Aziz Q, Grahame R. Joint hypermobility syndrome. Rheum Dis Clin North Am. 2013 May;39(2):419-30. doi: 10.1016/j.rdc.2013.03.003.PubMed [citation] PMID: 23597972


“Autonomic dysfunction is a frequently occurring feature of JHS. In one series it was identified (by the Brighton criteria) in 78% of patients with JHS compared with 21% of controls. The most common type of dysautonomia seen in JHS is postural tachycardia syndrome (PoTS), defined as an increase in heart rate of greater than or equal to 30 beats per minute on 60 head-up tilt table or on rising from the lying to the erect posture. Symptoms include palpitations, orthostatic intolerance (dizziness, presyncope, or syncope on standing), headache, impaired concentration, forgetfulness, irritability, fatigue, and heat intolerance.”

Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr. 1999 Oct;135(4):494-9. PubMed PMID: 10518084.


Thieben MJ, Sandroni P, Sletten DM, Benrud-Larson LM, Fealey RD, Vernino S, Lennon VA, Shen WK, Low PA. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc. 2007 Mar;82(3):308-13. PubMed PMID: 17352367.


Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc. 2012 Dec;87(12):1214-25. doi: 10.1016/j.mayocp.2012.08.013. Epub 2012 Nov 1. Review. PubMed PMID: 23122672; PubMed Central PMCID: PMC3547546.

(See: http://www.ncbi.nlm.nih.gov/pubmed/23122672, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547546/pdf/main.pdf)

43

Physiology: Digestion, nutrition, bowel function, and gut-related immune function are vital physiologic

processes dependent upon the health of the alimentary canal.

44

Image: http://starklab.slu.edu/Physio/Alimentary.jpg

OROPHARYNX (Mouth and Pharynx)

Mechanical

• mastication: biting and chewing

• lubrication and softening: mixing with saliva

• bolus formation and transport

– from mouth to esophagus

– avoid trachea

o epiglottis

Chemical

• secretion (saliva)

• breakdown (catabolism)

– salivary amylase (complex carbohydrates: starch)

• absorption

Biting and chewing breaks foods into smaller pieces with greater exposed surface area. Some direct absorption through mucosa occurs, and alivary amylase begins digestion of starch. The ultimate goal of the oropharyngeal phase of digestion is the formation of a softened bolus that the rest of the alimentary canal can process. Of course, oropharyngeal digestion may be bypassed (e.g. enteral feeding, swallowing whole pills).

ESOPHAGUS AND STOMACH

Mechanical

• transport

– peristaltic movement toward stomach

– avoid regurgitation

• storage

• mixing and grinding (chyme)

Chemical

• secretion (hydrochloric acid, pepsin, electrolytes)


– hydrochloric acid, pepsin (proteins)

• absorption

The Upper GI phase of digestion involves transport of boluses by the esophagus to the stomach so that the stomach can prepare a soupy mixture called chyme for the intestines. Breakdown of proteins begins in the stomach, and minimal absorption (generally via passive transport) occurs in the esophagus and stomach.

LIVER, GALL BLADDER, AND PANCREAS

Liver

• digestive chemical production and secretion

– bile (fats)

Gall Bladder

• bile storage and secretion

Pancreas

• digestive enzyme production and secretion

– protease (proteins)

– nuclease (nucleic acids)

– lipase (lipids)

– sucrase, lactase, etc. (simple carbohydrates: sugars)

– amylase (complex carbohydrates: starch, glycogen)

The liver and pancreas make and secrete chemicals aiding digestion (exocrine function). The gall bladder stores bile. These specialized structures secrete digestive chemicals into the small intestine via a system of ducts. Of note, the liver and pancreas also play a role in nutrition, and both secrete chemicals relating to nutrition in to the bloodstream (endocrine function).

SMALL INTESTINE

Mechanical

• transport

• mixing

Chemical

• secretion (bicarbonate, water, electrolytes)


– bile, enzymes

• absorption

– 95% of nutrient absorption occurs here!

The small intestine is responsible for almost all nutrient absorption. Bicarbonate neutralizes hydrochloric acid.

LOWER GI (Large Intestine, Rectum, Anus)

Mechanical

• waste storage prior to elimination

– continence

Chemical

• secretion

• absorption

– water

– electrolytes

– some nutrients

Although some specialized absorption occurs distal to (beyond) the small intestine, the large intestine, rectum, and anus are primarily responsible for waste storage and, ultimately, timely and discreet elimination of stool.

46

In the most basic sense: digestion allows us to extract energy from the food we eat.

Food is broken down from “bites” or “pieces” so that nutrients can be absorbed from the alimentary

canal and used by the cells of the body.

Mechanical digestion doesn’t change the molecules – just makes smaller pieces of food to work with,

mixes food with the contents of alimentary canal, and moves the contents along the alimentary canal.

(For example, surface area is increased.)

Chemical digestion breaks down larger molecules into smaller molecules or recombines molecules so

that they can successfully pass through the intestinal mucosa, enter the bloodstream and ultimately get

to where we need them.

47

http://www.health.gov/dietaryguidelines/2010.asp

49

As an aside, in an analagous fashion, the respiratory system also encloses an environment considered

external to the body with about the surface area of a tennis court.

50

There is an irrefutable connection between the microbiome and gut-related immune function.

Reference:

Hardy H, Harris J, Lyon E, Beal J, Foey AD.Probiotics, prebiotics and immunomodulation of gut mucosal defences: homeostasis and immunopathology. Nutrients. 2013 May 29;5(6):1869-912. doi: 10.3390/nu5061869.PubMed [citation] PMID: 23760057, PMCID: PMC3725482

(See: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725482/pdf/nutrients-05-01869.pdf)

“This review will focus on the immunomodulatory role of probiotics and prebiotics on the cells, molecules and immune responses in the gut mucosae, from epithelial barrier to priming of adaptive responses by antigen presenting cells: immune fate decision—tolerance or activation?

“Figure 1. Probiotic and prebiotic modulation of intestinal barrier and immune responses. Prebiotics and probiotics exert a range of effects on mucosal barrier function and the responses of the underlying immune tissue of the GALT. Probiotic and commensal microbes (light blue rectangles), assisted by prebiotics (light blue strings), out-compete pathogenic organisms (red rectangles) for nutrients and binding sites on the epithelial cell surface (1). This barrier function is enforced by the ability of probiotics to influence mucin expression and mucus secretion from the goblet cells (GoC, 2) and by pathogen neutralisation by IgA in the mucus layer, facilitated by pIgR-mediated transcytosis of sIgA through the epithelial cell (3). Probiotic bacteria can induce anti-microbial peptides against pathogens either directly, as bacteriocins (4) or activation of epithelial cells to secrete defensins (5). Luminal gut contents are tasted by three mechanisms: directly via DCs extending dendrites through the tight junction and into the lumen (6), epithelial cell pinocytosis of microbiota (7) or by selective transfer of luminal contents via specialised epithelial cells, microfold (M) cells (8). Interspersed between epithelial cells, intraepithelial lymphocytes (IELs—predominantly CD8+) contribute to the cytotoxic, killing response of the epithelial barrier (9). The innate killing response can be activated in NK cells via APC production of IL-12 and the production of IL-15 by epithelial cells (10). Immunity to extracellular parasites is elicited through B cell class switching to IgE production and the sensitisation of mast cells/granulocytes, which upon secondary exposure, release primary amines such as histamine (type I hypersensitivity) (11). Finally, the adaptive response elicited is dependent of the presentation responses of 6, 7 & 8. If these APCs present safe commensal/probiotic (blue) peptides, then tolerogenic mechanisms driven by TGFβ, IL-10 and retinoic acid are initated—resulting in suppression of T effector responses (Th1, Th2, Th17, Tc) and IgA production. If APCs present pathogenic peptides (red), then the default setting of tolerance is bypassed and as a result of the immune stimulatory cytokine environment, effector responses are initiated: Th1—CMI to intracellular pathogens, Th17—CMI to fungal infection and Th2—humoral responses to extracellular pathogens (12). Probiotics modulate this on/off switch of the mucosal immune system in a strain-dependant manner. Inappropriate modulation by probiotics or pathogenic subversion of mucosal immunity can result in immunopathology: allergy, inflammatory bowel disease and cancer.

“Dysbiosis in the human gut is not only seen in gastrointestinal tract pathology but is also associated with disease at distal sites such as the airways of the lungs [201] and the skin [202,203]. Cross-talk between the microbiota and immune cells located in the mucosa and lamina propria not only primes and tolerises cells locally, but may initiate migration away from the gut towards the mesenteric lymph nodes and other lymphoid tissues inducing systemic immunomodulatory effects [204].”

See also:

Bengmark S, Gut microbiota, immune development and function, Pharmacological Research (2010), doi:10.1016/j.phrs.2012.09.002

(See: http://www.bengmark.com/sites/default/files/110.%20Microbiota,%20immune%20%20....Pharmacological%20Research%202012.pdf)

51

Diet, exercise, and medication use are modifiable factors.

Reference:

Booth FW, Roberts CK, Laye MJ.Lack of exercise is a major cause of chronic diseases.Compr Physiol.

2012 Apr 1;2(2):1143-211. doi: 10.1002/cphy.c110025.PubMed [citation] PMID: 23798298

(See:

http://www.researchgate.net/publication/242018403_Lack_of_Exercise_Is_a_Major_Cause_of_Chronic

_Diseases/file/32bfe50e5e5ec2d5c9.pdf)

“Observational studies suggest that diverticulitis, constipation, and gallbladder disease can be caused

by physical inactivity and primarily prevented by increased activity. Physical activity may reduce the

risk of gastrointestinal hemorrhage and inflammatory bowel disease although this cannot be

substantiated firmly.”

52

Of course EDS affects digestion, nutrition, bowel function, and gut-related immune function!

53

Note that EDS can affect the gastrointestinal system both anatomically and functionally.

• Many GI functions depend upon tissue elasticity.

– gut motility (stretch, relax, and contract)

– visceral sensors monitor tissue tension

http://www.iffgd.org/site/gi-disorders/functional-gi-disorders/

Reference:

Drossman DA, et al. Rome III, the functional gastrointestinal disorders. Gastroenterology. April 2006

Volume 130 Number 5.

http://www.jgld.ro/2006/3/5.pdf

http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf

The Rome criteria is a system developed to classify the functional gastrointestinal disorders (FGIDs),

disorders of the digestive system in which symptoms cannot be explained by the presence of structural

or tissue abnormality, based on clinical symptoms. Some examples of FGIDs include irritable bowel

syndrome, functional dyspepsia, functional constipation, and functional heartburn. The most recent

revision of the criteria, the Rome III criteria, were published in 2006 in book form, and in a shorter

journal supplement in Gastroenterology.

55

Definitions:

• dentin dysplasia: dentin and pulp abnormalities

• root dilaceration: curve or sharp angulation in root(s)

• hypodontia: failure of teeth to develop

• ectopic eruption: teeth occur where they should not

• delayed eruption: teeth are slow to come in

• transmigration: teeth move out of place

References:

Castori M. Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN Dermatol. 2012;2012:751768. doi: 10.5402/2012/751768. Epub 2012 Nov 22.PubMed [citation] PMID: 23227356, PMCID: PMC3512326

(See: http://www.ncbi.nlm.nih.gov/pubmed/23227356, http://downloads.hindawi.com/journals/isrn.dermatology/2012/751768.pdf)

“5.2.Mucosal and Oropharyngeal Features (Figure 2). Mucosal involvement is common in JHS/EDS-HT. Xerostomia, xerophthalmia, and vaginal dryness are frequent accompanying complaints. Together with hypohidrosis, mucosal xerosis could be a remote consequence of autonomic dysregulation [65, 66]. Blue sclerae are overrepresented among JHS/EDSHT patients and are likely caused by more visible uveal blood vessels through thinner sclerae [65]. Focal blue purple discolorations of the oral mucosa are not uncommon in JHS/EDS-HT, and their origin may parallel blue sclerae. Minor pigmentation anomalies of the enamel can be observed in JHS/EDS-HT, also in the absence of environmental causes (e.g., smoking). Increased mucosal fragility can lead to spontaneous epistaxis and, more commonly, gingival bleeding, which is often elicited by teeth brushing. Repeated gingival damage due to increasedmucosal fragility may progressively cause recurrent gingival inflammations/infections, gingival retractions, and, eventually (although rarely), true parodontopathy with premature tooth loss [67]. Impaired oral cleanliness related to increased gingival bleeding and restraint of wrist and finger mobility may be the cause of the higher rate of caries in JHS/EDS-HT [67].

“In the last decade, attention has been posed on the absence of the lingual and inferior labial frenulum in EDSs [68]. Subsequent reports offered contrasting results [69–72]. More recently, a functional origin for the apparent agenesis/absence of the lingual frenulumin JHS/EDS-HT has been emphasized. In fact, this feature is likely the results of multiple contributors, such as primitive (developmental) hypoplasia of the frenulum and uncoordinated tongue movements due to concomitant orofacial dyspraxia [73]. Although still unsupported by evidence-based investigations, oropharyngeal dysphagia seems common in JHS/EDS-HT and, in rare instances, may impede feeding with consequent excessive weight loss, exacerbation of fatigue, and, in children, failure to thrive.

“Temporomandibular joint (TMJ) dysfunction is reported in >70% of JHS/EDS-HT patients [74, 75]. It is partly determined by TMJ hypermobility, as documented by increased mouth opening (i.e., mandibular depression over 50mm in adults) and voluntary subluxations in asymptomatic subjects. Over the years, TMJ hypermobility becomes complicated by clicks, arthralgias, myofascial pain, masticatory dysfunction, and, eventually, articular locks. Similarly to other joints, it is likely that a primary lack of coordination (dyspraxia) of the masticatory muscles may cooperate with JHM in determining dysfunction.”

Richmon JD, Wang-Rodriguez J, Thekdi AA. Ehlers-Danlos syndrome presenting as dysphonia and manifesting as tongue hypermobility: Report of 2 cases. Ear Nose Throat J. 2009 Feb;88(2):E8-12.PubMed [citation] PMID: 19224471


“Ehlers-Danlos syndrome (EDS) comprises a group of related hereditary connective tissue diseases. EDS manifests as joint hypermobility, tissue elasticity, and easy bruising. Although affected patients typically present to primary care physicians, orthopedists, and rheumatologists, some head and neck symptoms (e.g., dysphonia, dysphagia, and/or temporomandibular joint complaints) may direct some to an otolaryngologist. We describe the cases of 2 patients who presented to our otolaryngology clinic for evaluation of dysphonia. On physical examination, both exhibited tongue hypermobility, and both were subsequently diagnosed with EDS. We also review the results of our comprehensive literature search, in which we found only 3 articles that specifically described tongue hypermobility; in each case, the hypermobility was related to EDS. Finally, we discuss presentations of EDS that otolaryngologists might encounter.”

Akinbami BO. Evaluation of the mechanism and principles of management of temporomandibular joint dislocation. Systematic review of literature and a proposed new classification of temporomandibular joint dislocation. Head Face Med. 2011 Jun 15;7:10. doi: 10.1186/1746-160X-7-10. Review.PubMed [citation] PMID: 21676208, PMCID: PMC3127760

(See: http://www.ncbi.nlm.nih.gov/pubmed/21676208, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127760/pdf/1746-160X-7-10.pdf)

Solomon JA, Abrams L, Lichtenstein GR. GI manifestations of Ehlers-Danlos syndrome. Am J Gastroenterol. 1996 Nov;91(11):2282-8. Review.PubMed [citation] PMID: 8931403

“Management should focus not only on effective hemostasis and patient education, but more so on the recognition of these manifestations as symptoms of a systemic disease with the need to correctly classify the individual and monitor for more serious complications.”

(See: http://www.ncbi.nlm.nih.gov/pubmed/8931403, http://www.annabelleschallenge.org/app/download/3570409/GI+Manifestation+of+EDS.pdf)

Yassin OM, Rihani FB. Multiple developmental dental anomalies and hypermobility type Ehlers-Danlos syndrome. J Clin Pediatr Dent. 2006 Summer;30(4):337-41.PubMed [citation] PMID: 16937863


“Concurrent existence of multiple developmental dental anomalies: hypodontia of permanent mandibular incisors, dentin dysplasia, transmigration, root dilaceration, ectopic eruption and delayed eruption combined with systemic abnormalities including joint hyperlaxity and skin hyperextensibility aided in diagnosis of a sporadic case of hypermobility type of Ehlers-Danlos syndrome in a Jordanian Arab male. In dental practice the presence of multiple developmental dental anomalies expressing simultaneous defects in different stages of tooth development should raise suspicion of possible of manifestation of an underlying systemic abnormality.”

Castori M, Camerota F, Celletti C, Danese C, Santilli V, Saraceni VM, Grammatico P. Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A. 2010 Mar;152A(3):556-64. doi: 10.1002/ajmg.a.33231.PubMed [citation] PMID: 20140961


“Gingival fragility with recurrent toothbrush-induced or, more rarely, spontaneous hemorrhages (52.4%) and recurrent caries (57.1%) were reported consistently. Gingival retractions and alveolar bone reabsorption with secondary tooth loss (parodontitis) were registered in three patients (no.s 7, 12, and 21; Fig. 2b).”

56

http://www.ncbi.nlm.nih.gov/pubmed/16937863

References:



“5.2.Mucosal and Oropharyngeal Features (Figure 2). Mucosal involvement is common in JHS/EDS-HT. Xerostomia, xerophthalmia, and vaginal dryness are frequent accompanying complaints. Together with hypohidrosis, mucosal xerosis could be a remote consequence of autonomic dysregulation [65, 66]. Blue sclerae are overrepresented among JHS/EDSHT patients and are likely caused by more visible uveal blood vessels through thinner sclerae [65]. Focal blue purple discolorations of the oral mucosa are not uncommon in JHS/EDS-HT, and their origin may parallel blue sclerae. Minor pigmentation anomalies of the enamel can be observed in JHS/EDS-HT, also in the absence of environmental causes (e.g., smoking). Increased mucosal fragility can lead to spontaneous epistaxis and, more commonly, gingival bleeding, which is often elicited by teeth brushing. Repeated gingival damage due to increasedmucosal fragility may progressively cause recurrent gingival inflammations/infections, gingival retractions, and, eventually (although rarely), true parodontopathy with premature tooth loss [67]. Impaired oral cleanliness related to increased gingival bleeding and restraint of wrist and finger mobility may be the cause of the higher rate of caries in JHS/EDS-HT [67].

“In the last decade, attention has been posed on the absence of the lingual and inferior labial frenulum in EDSs [68]. Subsequent reports offered contrasting results [69–72]. More recently, a functional origin for the apparent agenesis/absence of the lingual frenulumin JHS/EDS-HT has been emphasized. In fact, this feature is likely the results of multiple contributors, such as primitive (developmental) hypoplasia of the frenulum and uncoordinated tongue movements due to concomitant orofacial dyspraxia [73]. Although still unsupported by evidence-based investigations, oropharyngeal dysphagia seems common in JHS/EDS-HT and, in rare instances, may impede feeding with consequent excessive weight loss, exacerbation of fatigue, and, in children, failure to thrive.

“Temporomandibular joint (TMJ) dysfunction is reported in >70% of JHS/EDS-HT patients [74, 75]. It is partly determined by TMJ hypermobility, as documented by increased mouth opening (i.e., mandibular depression over 50mm in adults) and voluntary subluxations in asymptomatic subjects. Over the years, TMJ hypermobility becomes complicated by clicks, arthralgias, myofascial pain, masticatory dysfunction, and, eventually, articular locks. Similarly to other joints, it is likely that a primary lack of coordination (dyspraxia) of the masticatory muscles may cooperate with JHM in determining dysfunction.”

Richmon JD, Wang-Rodriguez J, Thekdi AA. Ehlers-Danlos syndrome presenting as dysphonia and manifesting as tongue hypermobility: Report of 2 cases. Ear Nose Throat J. 2009 Feb;88(2):E8-12.PubMed [citation] PMID: 19224471


“Ehlers-Danlos syndrome (EDS) comprises a group of related hereditary connective tissue diseases. EDS manifests as joint hypermobility, tissue elasticity, and easy bruising. Although affected patients typically present to primary care physicians, orthopedists, and rheumatologists, some head and neck symptoms (e.g., dysphonia, dysphagia, and/or temporomandibular joint complaints) may direct some to an otolaryngologist. We describe the cases of 2 patients who presented to our otolaryngology clinic for evaluation of dysphonia. On physical examination, both exhibited tongue hypermobility, and both were subsequently diagnosed with EDS. We also review the results of our comprehensive literature search, in which we found only 3 articles that specifically described tongue hypermobility; in each case, the hypermobility was related to EDS. Finally, we discuss presentations of EDS that otolaryngologists might encounter.”

Akinbami BO. Evaluation of the mechanism and principles of management of temporomandibular joint dislocation. Systematic review of literature and a proposed new classification of temporomandibular joint dislocation. Head Face Med. 2011 Jun 15;7:10. doi: 10.1186/1746-160X-7-10. Review. PubMed [citation] PMID: 21676208, PMCID: PMC3127760

(See: http://www.ncbi.nlm.nih.gov/pubmed/21676208, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127760/pdf/1746-160X-7-10.pdf)

Solomon JA, Abrams L, Lichtenstein GR. GI manifestations of Ehlers-Danlos syndrome. Am J Gastroenterol. 1996 Nov;91(11):2282-8. Review. PubMed [citation] PMID: 8931403


“Management should focus not only on effective hemostasis and patient education, but more so on the recognition of these manifestations as symptoms of a systemic disease with the need to correctly classify the individual and monitor for more serious complications.”

Yassin OM, Rihani FB. Multiple developmental dental anomalies and hypermobility type Ehlers-Danlos syndrome.J Clin Pediatr Dent. 2006 Summer;30(4):337-41.PubMed [citation] PMID: 16937863


“Concurrent existence of multiple developmental dental anomalies: hypodontia of permanent mandibular incisors, dentin dysplasia, transmigration, root dilaceration, ectopic eruption and delayed eruption combined with systemic abnormalities including joint hyperlaxity and skin hyperextensibility aided in diagnosis of a sporadic case of hypermobility type of Ehlers-Danlos syndrome in a Jordanian Arab male. In dental practice the presence of multiple developmental dental anomalies expressing simultaneous defects in different stages of tooth development should raise suspicion of possible of manifestation of an underlying systemic abnormality.”

Castori M, Camerota F, Celletti C, Danese C, Santilli V, Saraceni VM, Grammatico P. Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A. 2010 Mar;152A(3):556-64. doi: 10.1002/ajmg.a.33231.PubMed [citation] PMID: 20140961


“Gingival fragility with recurrent toothbrush-induced or, more rarely, spontaneous hemorrhages (52.4%) and recurrent caries (57.1%) were reported consistently. Gingival retractions and alveolar bone reabsorption with secondary tooth loss (parodontitis) were registered in three patients (no.s 7, 12, and 21; Fig. 2b).”

57

References:

Malfait F, Wenstrup R, De Paepe A. Ehlers-Danlos Syndrome, Classic Type. 2007 May 29 [updated 2011 Aug 18]. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.

(See: http://www.ncbi.nlm.nih.gov/books/NBK1244/, http://www.nature.com/gim/journal/v12/n10/pdf/gim2010100a.pdf)

“Manifestations of tissue fragility: Manifestations of generalized tissue extensibility and fragility may be observed in multiple organs. Patients with classic EDS often suffer from repetitive hernia, such as inguinal, umbilical, hiatal, or incisional hernia. In early childhood, recurrent rectal prolapse may be observed.”


(See: http://www.ncbi.nlm.nih.gov/books/NBK1279/ PubMed PMID: 20301456.)

“Gastrointestinal. Functional bowel disorders are common and underrecognized, affecting up to 50% of individuals with EDS, hypermobility and classic types [Levy et al 1999]. Gastroesophageal reflux and gastritis may be symptomatic despite maximal doses of proton pump inhibitors with additional H2-blockers and acid-neutralizing medications. Early satiety and delayed gastric emptying may occur and may be exacerbated by opioid (and other) medications. Irritable bowel syndrome may manifest with diarrhea and/or constipation, associated with abdominal cramping and rectal mucus.”



“5.8. Gastrointestinal Features. Although not included in the Villefranche and Brighton criteria, gastrointestinal involvement is common in JHS/EDS-HT. Indirect evidence comes from several studies demonstrating a high incidence of JHS or (generalized) JHM among patients suffering from chronic (slow transit) constipation [41–43], hiatus hernia [58], Crohn’s disease [48], faecal incontinence [50], rectal evacuatory dysfunction [63], and functional gastrointestinal disorder [56]. Typical gastrointestinal features include gastroesophageal reflux (74%) with or without hiatus hernia, chronic/recurrent gastritis (48%), symptoms of delayed gastric emptying, recurrent abdominal pain (68%), and constipation/diarrhea (72%) [19]. However, the range of bowel involvement may extend much beyond to include a wide variety of functional gastrointestinal disorders according to the Rome III classification [128]. The mechanisms underlying such a severe visceral involvement are obscure. Possible contributing factors may comprise (i) reduced fixation to adjacent structures causing visceroptosis and hernias, (ii) gut hypotonia/hypomotility, and (iii) structural anomalies (e.g., dolichocolon). A recent study demonstrating an increased rate of celiac disease in JHS/EDS-HT [129] adds complexity to the study of connections between connective tissue and bowel function, which appear also mediated by an abnormally functioning immune system. The apparent underdiagnosis of visceroptosis in JHS/EDS-HT has been recently pointed out [130]. Accordingly, while literature data concerning such a disease manifestation is scarce, clinical practice often reveals abnormal downward displacement of the gastrointestinal tract and kidneys (Figure 4). The impact of such anatomic features, as well as gut motility and length, in symptom development needs further clarification.”

Feldman, Mark, Lawrence S. Friedman, and Lawrence J. Brandt. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management, Expert Consult Premium Edition-Enhanced Online Features. Vol. 1. Elsevier Health Sciences, 2010.

(From: CHAPTER 35 Gastrointestinal and Hepatic Manifestations of Systemic Diseases by Rajeev Jain and Dwain L. Thiele; See: Table 35-1 and p. 563.)

“MARFAN’S AND EHLERS-DANLOS SYNDROMES: Owing to defective collagen synthesis, patients with Marfan’s or Ehlers-Danlos syndrome develop skin fragility, megaesophagus, small intestine hypomotility, giant jejunal diverticula, bacterial overgrowth, and megacolon.[160] Mesenteric arterial rupture and intestinal perforation also can occur.[161]”

[160] McLean AM, Paul RE Jr, Kritzman J, Farthing MJ. Malabsorption in Marfan (Ehlers-Danlos) syndrome. J Clin Gastroenterol. 1985 Aug;7(4):304-8. PMID: 4045174

[161] Stillman AE, Painter R, Hollister DW. Ehlers-Danlos syndrome type IV: diagnosis and therapy of associated bowel perforation. Am J Gastroenterol 1991 Mar;86(3):360-2. PMID: 1998319



“Structural defects are commonly seen. Giant epiphrenic diverticula and megaesophagus have been reported but are far less frequent than hiatal hernias, which are a common abnormality. Patients present with mild symptoms of epigastric discomfort and can be successfully managed with conservative treatment. The hyperextensibility of certain types of EDS is thought to decrease somewhat with age, therefore surgery is usually deferred when possible to help minimize the rate of surgical complications. If a life-threatening situation such as hemorrhage, incarceration, or strangulation develops, however, urgent surgery is appropriate. One of the most severe complications is that of esophageal rupture requiring urgent surgery, which has been reported after forceful vomiting.”

“Factors other than dilation, such as altered motility, may also play a role in malabsorptive states in these patients.”

“The presence of a perforation in a young patient, without a predisposing factor such as neoplasm, diverticulitis, colitis, steroid use, or inflammatory bowel disease, mandates the consideration on EDS.”

58

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59

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60

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61

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62

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63

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64

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65

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66

Symptoms of gastroparesis include palpitations, heartburn, abdominal pain, abdominal bleeding erratic blood glucose levels, lack of appetitie, GERD, and spasms of stomach wall.

References:

Chelimsky G, Boyle JT, Tusing L, Chelimsky TC. Autonomic abnormalities in children with functional abdominal pain: coincidence or etiology? J Pediatr Gastroenterol Nutr. 2001 Jul;33(1):47-53.PubMed [citation] PMID: 11479407


Castori M. Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations.ISRN Dermatol. 2012;2012:751768. doi: 10.5402/2012/751768. Epub 2012 Nov 22.PubMed [citation] PMID: 23227356, PMCID: PMC3512326



Fikree A, Aziz Q, Grahame R. Joint hypermobility syndrome. Rheum Dis Clin North Am. 2013 May;39(2):419-30. doi: 10.1016/j.rdc.2013.03.003. PubMed [citation] PMID: 23597972


“Hypermobility and FGID: The only direct evidence for an association between FGID and hypermobility comes from a single retrospective observational study in the tertiary gastroenterology setting.11 In this study, the validated 5-point hypermobility questionnaire was used to screen for JH in 129 consecutive patients attending a neurogastroenterology clinic. The prevalence of JH in these patients was 49%, 3 times higher than the prevalence in healthy controls (17%). Those with JH were more likely to have GI symptoms without a known underlying structural, biochemical, metabolic, or autoimmune cause compared with those without JH (ie, the symptoms were more likely to be unexplained). A subgroup of these patients were assessed further by a rheumatologist and found to have JHS. These patients with JHS tended to have motility problems in their gut on physiologic testing, such as small bowel dysmotility, delayed gastric emptying, and delayed colonic transit. This study confirmed that, in a tertiary neurogastroenterology setting, JH was strongly associated with unexplained GI symptoms or FGID. It also showed that GI dysmotility is common in patients with GI symptoms and JHS, suggesting that these patients may have a neuromuscular basis for their symptoms. The cause of the dysmotility and the GI symptoms is as yet unknown but research is ongoing to determine whether this is a direct consequence of abnormal connective tissue in the gut, or of associated dysautonomia.

“Although no large observational studies have been published that confirm an association between JHS and FGID, smaller studies have shown not only that IBS symptoms are common in JHS30,31,35 but that patients with JHS with GI symptoms often have a preexisting diagnosis of IBS.26,31

“Further support for the association between JHS and FGID comes from both disorders sharing several features, in particular an association with several medically unexplained disorders, also known as functional somatic syndromes (Table 2). There is speculation that the same underlying process, involving a combination of somatic hypersensitivity, chronic pain, and dysautonomia, underlies all the functional somatic syndromes and that JHS is the common link (Fig. 3).36”

67

References:

Chelimsky G, Boyle JT, Tusing L, Chelimsky TC. Autonomic abnormalities in children with functional abdominal pain: coincidence or etiology? J Pediatr Gastroenterol Nutr. 2001 Jul;33(1):47-53.PubMed [citation] PMID: 11479407





Fikree A, Aziz Q, Grahame R. Joint hypermobility syndrome. Rheum Dis Clin North Am. 2013 May;39(2):419-30. doi: 10.1016/j.rdc.2013.03.003. PubMed [citation] PMID: 23597972


“Hypermobility and FGID: The only direct evidence for an association between FGID and hypermobility comes from a single retrospective observational study in the tertiary gastroenterology setting.11 In this study, the validated 5-point hypermobility questionnaire was used to screen for JH in 129 consecutive patients attending a neurogastroenterology clinic. The prevalence of JH in these patients was 49%, 3 times higher than the prevalence in healthy controls (17%). Those with JH were more likely to have GI symptoms without a known underlying structural, biochemical, metabolic, or autoimmune cause compared with those without JH (ie, the symptoms were more likely to be unexplained). A subgroup of these patients were assessed further by a rheumatologist and found to have JHS. These patients with JHS tended to have motility problems in their gut on physiologic testing, such as small bowel dysmotility, delayed gastric emptying, and delayed colonic transit. This study confirmed that, in a tertiary neurogastroenterology setting, JH was strongly associated with unexplained GI symptoms or FGID. It also showed that GI dysmotility is common in patients with GI symptoms and JHS, suggesting that these patients may have a neuromuscular basis for their symptoms. The cause of the dysmotility and the GI symptoms is as yet unknown but research is ongoing to determine whether this is a direct consequence of abnormal connective tissue in the gut, or of associated dysautonomia.

“Although no large observational studies have been published that confirm an association between JHS and FGID, smaller studies have shown not only that IBS symptoms are common in JHS30,31,35 but that patients with JHS with GI symptoms often have a preexisting diagnosis of IBS.26,31

“Further support for the association between JHS and FGID comes from both disorders sharing several features, in particular an association with several medically unexplained disorders, also known as functional somatic syndromes (Table 2). There is speculation that the same underlying process, involving a combination of somatic hypersensitivity, chronic pain, and dysautonomia, underlies all the functional somatic syndromes and that JHS is the common link (Fig. 3).36”

68

FGIDs are those without a known underlying structural, biochemical, metabolic, or autoimmune cause.

http://www.iffgd.org/site/gi-disorders/functional-gi-disorders/

Reference:

Drossman DA, et al. Rome III, the functional gastrointestinal disorders. Gastroenterology. April 2006

Volume 130 Number 5.

http://www.jgld.ro/2006/3/5.pdf

http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf

The Rome criteria is a system developed to classify the functional gastrointestinal disorders (FGIDs),

disorders of the digestive system in which symptoms cannot be explained by the presence of structural

or tissue abnormality, based on clinical symptoms. Some examples of FGIDs include irritable bowel

syndrome, functional dyspepsia, functional constipation, and functional heartburn. The most recent

revision of the criteria, the Rome III criteria, were published in 2006 in book form, and in a shorter

journal supplement in Gastroenterology.

Rome III Criteria are the accepted standards for clinical diagnosis.

69

References:

Chelimsky G, Hupertz VF, Chelimsky TC. Abdominal pain as the presenting symptom of autonomic

dysfunction in a child. Clin Pediatr (Phila). 1999 Dec;38(12):725-9. No abstract available. PubMed

[citation] PMID: 10618765


Chelimsky G, Boyle JT, Tusing L, Chelimsky TC. Autonomic abnormalities in children with functional

abdominal pain: coincidence or etiology? J Pediatr Gastroenterol Nutr. 2001 Jul;33(1):47-53.PubMed

[citation] PMID: 11479407


70

Nutrition is of life-long importance – while in utero, through childhood, and into adulthood.

Lifelong negative impacts of poor nutrition that have affected health developmentally or chronically can

not be easily reversed.

74

Research is needed to determine appropriate nutritional recommendations in EDS.

Available literature is in general outdated or hypothetical.

References:

Mantle D, Wilkins RM, Preedy V. A novel therapeutic strategy for Ehlers-Danlos syndrome based on nutritional supplements. Med Hypotheses. 2005;64(2):279-83.PubMed [citation] PMID: 15607555

(See: http://www.ncbi.nlm.nih.gov/pubmed/15607555, http://www.eds-nyc.com/wp-content/uploads/2013/06/EDSnutritionalSupplements.pdf)

“In principal, adequate amounts of essential nutrients required by the body should be available from a normal balanced diet. However, in practice many individuals do not have an adequate intake of many essential nutrients, because of a reliance on highly processed convenience foods that may be substantially depleted in these substances (for example vitamin C, which is readily destroyed by cooking or food processing).

“In addition, a recent report [2] has indicated fruit and vegetables may have become increasingly depleted in the levels of essential nutrients between 1940 and 1991; examples include depletions in zinc (57%), calcium (46%), and magnesium (24%). Essential nutrient levels are also reduced by stress and illness.

“The best evidence that disorders thought to result entirely from the effects of defective genes may also have a nutritional component is based on studies involving identical twins. There have been several reports of identical twins with inherited disorders of connective tissue metabolism, with widely differing severity of symptoms, indicating that disease progression can be modulated by environmental factors, the most likely of which is nutrition.”



“In addition to behavior modifications, adequate nutritional supplementations may be of some help in preventing/treating some features of JHS/EDS-HT. Although specific studies are still lacking, suggestions have been recently proposed [62, 162, 163]. In particular, dysautonomia-related fatigue may be partly managed by (i) generous daily water/liquid intake (2–2.5 lts) preferring isotonic solutions, (ii) high salt intake (to avoid in case of arterial hypertension), and (iii) daily assumption of carnitine (250 mg) and/or coenzyme Q10 (100 mg). Capillary/small vessels fragility may be improved by daily assumption of ascorbic acid, a cofactor of prolyl and lysyl hydroxylases, which are enzymes involved in the biogenesis of collagens. Approximately 8–50 times the 60 mg recommended daily intake for adults is indicated as the dose for maximal improvement of such biological functions. In case of osteopenia, daily intake of therapeutic doses of vitamin D (usually 880 IU/day in adults) and calcium (usually 1,000 mg/day in adults) is indicated for lowering the risk of fracture. Vitamin D is present in a few foods, and many people, especially in USA and Europe, may not get enough sunlight, which is essential for endogenous production of vitamin D from cholesterol. Therefore, a daily supplementation of 200 mg or 400 mg vitamin D, for adults and children, respectively, may be recommended also in the nonosteopenic individual. A 1–5mg daily intake of melatonin is considered a resource for improving sleepiness in various functional somatic syndromes, such as fibromyalgia. Similarly, melatonin may be effective in JHS/EDS-HT. Other nutraceuticals which have been thought beneficial, though still without evidence, in JHS/EDS-HT comprise vitamin E, vitamin B complex, vitamin K, glucosamine, chondroitin, γ-linolenic acid, pycnogenol,magnesium, zinc,methyl sulfonyl methane and silica.”

75

From my comment on a post to a Facebook group regarding use collagen supplements. "Why I Won't Waste My Money on Collagen Supplements" First... In very, VERY basic terms... Collagen Biosynthesis: A single collagen molecule is actually made of 3 coiled chains wound around each other to make a triple helix. The chains are proteins, made of amino acids. There is more than one type of collagen. The unique properties (tensile strength, elasticity, etc) of each type of collagen are due to differences in segments of the individual chains that don't fit well in the triple helix and cause the types of collagen molecules to fold differently. Each type of collagen differs according to its ultrastructure in tissues (how individual collagen molecules are arranged together - e.g. fibrils, laminae, etc.), the tissues in which it is found, and the other proteins and extracellular components with which it associates. Note that Vitamin C is mandatory for hydroxylation of procollagen molecules in order to form stable triple helices and stable fibrils. Without hydroxylation, procollagen molecules are degraded within cells, before they are sent outside of cells (via exocytosis) and modified to become the final collagen molecules. This is why Vitamin C is often a recommended supplement in patients with collagen or connective tissue disorder. For more detail - search the Web on "collagen biosynthesis". (For example, try http://www.ncbi.nlm.nih.gov/books/NBK21582/) Now... Regarding EDS and collagen... Although EDS is widely referred to as a collagen vascular disease, strictly speaking, it is a connective tissue disorder, and not all forms of the disorder are proven to be due to mutations in genes encoding collagen. (See: http://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome) That means that some of us with EDS have genes that encode faulty collagen, while others of us with EDS instead have genes that encode faulty proteins responsible for regulating or interacting with collagen. For those of us in the latter group, collagen is not technically the problem - some other gene product is. (Think of it this way - for those in the latter group, collagen is guilty not because it is defective, but instead because it is mismanaged!) To date, no research has proven that consumption of any collagen supplement helps EDS patients in any significant way. This would make sense, given the basic knowledge about collagen biosynthesis and the known pathology in EDS. Collagen is NOT a nutrient molecule absorbed whole or even in part and incorporated into tissues or metabolic reactions during normal human physiology. As above, it is synthesized from tiny amino acid building blocks in specific cells and assembled with special modifications specific to collagen type. If we eat collagen, we do as we would with any protein: break it down (digest it) in our gut into smaller and smaller peptides which are ultimately catabolized into amino acids. Within the body, amino acids are recycled and reassembled into peptide chains and proteins, or amino acids are further catabolized via the Krebs cycle (for a picture of metabolism of amino acids: http://www.wikipathways.org/index.php/Pathway:WP1847). One may argue that a potential benefit of eating collagen would theoretically be the supplementation of a higher proportion of hydoxyproline (an amino acid abundant in collagen) than from other protein sources. However, simply getting hydroxyproline and other amino acids needed to make collagen into the body does not mean the body will use them to make collagen effectively, especially if there is a faulty gene encoding collagen or encoding a protein regulating collagen production or interaction. Additionally, commercial collagen supplements are irreversibly hydrolyzed and thus quite different from the collagen existing in our tissues. Truthfully - the only peer-reviewed or evidence-based literature found after an exhaustive search regarding collagen supplementation in EDS refers to the use of exogenous collagen applied in vitro to fibroblasts. In vitro is NOT the same as in vivo! Perhaps research will eventually validate the use of collagen supplements in EDS. To date, there is no established validity for its use. Although it is not likely to be harmful, it is not likely to be any more helpful than a healthy, balanced diet including adequate protein (and Vitamin C). ***** FYI - A few documents regarding known molecular pathology relating to collagen biosynthesis and regulation in EDS

(see: http://www.ncbi.nlm.nih.gov/sites/myncbi/collections/public/1ze2UxiTYiPJvSTu5isFBXwkj/) 1: Hermanns-Lê T, Reginster MA, Piérard-Franchimont C, Delvenne P, Piérard GE, Manicourt D. Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome. J Biomed Biotechnol. 2012;2012:878107. doi: 10.1155/2012/878107. Epub 2012 Oct 3. PubMed PMID: 23091361; PubMed Central PMCID: PMC3471064. 2: Zoppi N, Ritelli M, Colombi M. Type III and V collagens modulate the expression and assembly of EDA(+) fibronectin in the extracellular matrix of defective Ehlers-Danlos syndrome fibroblasts. Biochim Biophys Acta. 2012 Oct;1820(10):1576-87. doi: 10.1016/j.bbagen.2012.06.004. Epub 2012 Jun 15. PubMed PMID: 22705941. 3: Guenova E, Schaller M. Residents' corner November 2011. (Carpe)DIEM - dermatological indications for electron microscopy: Ehlers Danlos syndrome. Eur J Dermatol. 2011 Nov-Dec;21(6):1030. doi: 10.1684/ejd.2011.1607. PubMed PMID: 22231911. 4: Bicca Ede B, Almeida FB, Pinto GM, Castro LA, Almeida Jr HL. Classical Ehlers-Danlos syndrome: clinical, Histological and ultrastructural aspects. An Bras Dermatol. 2011 Jul-Aug;86(4 Suppl 1):S164-7. PubMed PMID: 22068801. 5: Viglio S, Zoppi N, Sangalli A, Gallanti A, Barlati S, Mottes M, Colombi M, Valli M. Rescue of migratory defects of Ehlers-Danlos syndrome fibroblasts in vitro by type V collagen but not insulin-like binding protein-1. J Invest Dermatol. 2008 Aug;128(8):1915-9. doi: 10.1038/jid.2008.33. Epub 2008 Feb 28. PubMed PMID: 18305566. 6: Hermanns-Lê T, Piérard GE. Ultrastructural alterations of elastic fibers and other dermal components in ehlers-danlos syndrome of the hypermobile type. Am J Dermatopathol. 2007 Aug;29(4):370-3. PubMed PMID: 17667170. 7: Hermanns-Lê T, Piérard GE. Collagen fibril arabesques in connective tissue disorders. Am J Clin Dermatol. 2006;7(5):323-6. PubMed PMID: 17007543. 8: Bristow J, Carey W, Egging D, Schalkwijk J. Tenascin-X, collagen, elastin, and the Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2005 Nov 15;139C(1):24-30. Review. PubMed PMID: 16278880. 9: Zweers MC, Dean WB, van Kuppevelt TH, Bristow J, Schalkwijk J. Elastic fiber abnormalities in hypermobility type Ehlers-Danlos syndrome patients with tenascin-X mutations. Clin Genet. 2005 Apr;67(4):330-4. PubMed PMID: 15733269. 10: Kobayasi T. Abnormality of dermal collagen fibrils in Ehlers Danlos syndrome. Anticipation of the abnormality for the inherited hypermobile disorders. Eur J Dermatol. 2004 Jul-Aug;14(4):221-9. PubMed PMID: 15319154. 11: Zweers MC, van Vlijmen-Willems IM, van Kuppevelt TH, Mecham RP, Steijlen PM, Bristow J, Schalkwijk J. Deficiency of tenascin-X causes abnormalities in dermal elastic fiber morphology. J Invest Dermatol. 2004 Apr;122(4):885-91. PubMed PMID: 15102077. 12: Zoppi N, Gardella R, De Paepe A, Barlati S, Colombi M. Human fibroblasts with mutations in COL5A1 and COL3A1 genes do not organize collagens and fibronectin in the extracellular matrix, down-regulate alpha2beta1 integrin, and recruit alphavbeta3 Instead of alpha5beta1 integrin. J Biol Chem. 2004 Apr 30;279(18):18157-68. Epub 2004 Feb 17. PubMed PMID: 14970208. 13: Corsi A, Xu T, Chen XD, Boyde A, Liang J, Mankani M, Sommer B, Iozzo RV, Eichstetter I, Robey PG, Bianco P, Young MF. Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos-like changes in bone and other connective tissues. J Bone Miner Res. 2002 Jul;17(7):1180-9. PubMed PMID: 12102052. 14: Iurassich S, Rocco D, Aurilia A. Type III Ehlers-Danlos syndrome: correlations among clinical signs, ultrasound, and histologic findings in a study of 35 cases. Int J Dermatol. 2001 Mar;40(3):175-8. PubMed PMID: 11422519. 15: de Moraes AM, Cintra ML, Sampaio S de A, Sotto MN, Sesso A. The ultrastructural and histophotometric study of elastic and collagen fibers in type II Ehlers-Danlos syndrome and subclinical forms. Ultrastruct Pathol. 2000 May-Jun;24(3):129-34. PubMed PMID: 10914423. 16: Zoppi N, Ghinelli A, Gardella R, Barlati S, Colombi M. Effect of dexamethasone on the assembly of the matrix of fibronectin and on its receptors organization in Ehlers-Danlos syndrome skin fibroblasts. Cell Biol Int. 1998;22(7-8):499-508. PubMed PMID: 10452818. 17: Moro L, Colombi M, Zoppi N, Ghinelli A, Barlati S. Correction of the defective extracellular matrix of Ehlers-Danlos syndrome skin fibroblasts by dexamethasone. Cell Biol Int. 1994 Jan;18(1):29-37. PubMed PMID: 8186768. 18: Kurata S, Senoo H, Hata R. Transcriptional activation of type I collagen genes by ascorbic acid 2-phosphate in human skin fibroblasts and its failure in cells from a patient with alpha 2(I)-chain-defective Ehlers-Danlos syndrome. Exp Cell Res. 1993 May;206(1):63-71. PubMed PMID: 8482361. 19: Meyer E, Ludatscher RM, Zonis S. Collagen fibril abnormalities in the extraocular muscles in Ehlers-Danlos syndrome. J Pediatr Ophthalmol Strabismus. 1988 Mar-Apr;25(2):67-72. PubMed PMID: 3357129.

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Reference:

http://ashg.org/genetics/ashg07s/f21352.htm

79

Reference:

Cutts, R. M., Meyer, R., Thapar, N., Rigby, K., Schwarz, C., Mailliard, S., & Shah, N. (2012).

Gastrointestinal food allergies in children with Ehlers Danlos type 3 syndrome. Journal of Allergy and

Clinical Immunology, 129(2), AB34.

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Reference:

Abonia JP, Wen T, Stucke EM, Grotjan T, Griffith MS, Kemme KA, Collins MH, Putnam PE, Franciosi

JP, von Tiehl KF, Tinkle BT, Marsolo KA, Martin LJ, Ware SM, Rothenberg ME. High prevalence of

eosinophilic esophagitis in patients with inherited connective tissue disorders. J Allergy Clin Immunol.

2013 Apr 19. doi:pii: S0091-6749(13)00361-8. 10.1016/j.jaci.2013.02.030. [Epub ahead of

print]PubMed [citation] PMID: 23608731


81

Reference:

Fikree A, Aziz Q, Grahame R. Joint hypermobility syndrome. Rheum Dis Clin North Am. 2013

May;39(2):419-30. doi: 10.1016/j.rdc.2013.03.003. PubMed [citation] PMID: 23597972


“JHS and Organic GI Disorders: Only 2 published studies exist that show a possible association

between hypermobility and organic disorders. The first compared 69 patients with IBD with 67 age-

matched and sex-matched controls. A significantly higher prevalence of JH was found in patients with

Crohn’s disease (70%) compared with controls (25%) and with patients with ulcerative colitis

(36%),[33] suggesting a possible association between JH and Crohn’s disease, although this has not

yet been replicated. In addition, only JH was assessed, so it is questionable whether the findings can

be generalized to JHS. The other study assessed 31 patients with JHS for celiac disease. Five (16%)

had a confirmed diagnosis based on both serologic and histologic testing,[34] which was significantly

higher than the estimated population prevalence (1%). However, the patients were a highly selected

group, attending specialist genetics clinics, and so may not represent most patients with JHS, most of

whom remain undiagnosed and do not present to clinics.”

[33] Vounotrypidis P, Efremidou E, Zezos P, Pitiakoudis M, Maltezos E, Lyratzopoulos N, Kouklakis G.

Prevalence of joint hypermobility and patterns of articular manifestations in patients with inflammatory

bowel disease. Gastroenterol Res Pract. 2009;2009:924138. doi: 10.1155/2009/924138. Epub 2010

Feb 11.PubMed [citation] PMID: 20169104, PMCID: PMC2821781

[34] Danese C, Castori M, Celletti C, Amato S, Lo Russo C, Grammatico P, Camerota F. Screening for

celiac disease in the joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type. Am J

Med Genet A. 2011 Sep;155A(9):2314-6. doi: 10.1002/ajmg.a.34134. Epub 2011 Aug 3. No abstract

available. PubMed [citation] PMID: 21815256

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Image:

http://www.marilynglenville.com/tests/gluten-intolerance-test/

83

Celiac Disease is the manifestation of both an innate inflammatory response and a maladaptive

autoimmune response.

Disruption of tight junctions between intestinal cells allows peptides larger than three amino acids to

enter circulation, prompting a maladaptive immune hypersensitivity response.

84

Reference:

Ferretti G, Bacchetti T, Masciangelo S, Saturni L. Celiac disease, inflammation and oxidative damage:

a nutrigenetic approach. Nutrients. 2012 Apr;4(4):243-57. doi: 10.3390/nu4040243. Epub 2012 Mar 27.

Review.PubMed [citation] PMID: 22606367, PMCID: PMC3347005

(See: http://www.ncbi.nlm.nih.gov/pubmed/22606367, http://www.mdpi.com/2072-6643/4/4/243/pdf)

“Celiac disease (CD), a common heritable chronic inflammatory condition of the small intestine caused

by permanent intolerance to gluten/gliadin (prolamin), is characterized by a complex interplay between

genetic and environmental factors. The prolamin fractions in cereal grains (gliadin in wheat and similar

alcohol-soluble proteins in other cereals, secalin in rye, hordein in barley) are the environmental stimuli

responsible for the development of intestinal damage associated with CD. The classical presentation of

CD as a pediatric predominant disorder, is characterized by small-intestinal villous atrophy and crypt

hyperplasia. However especially in adult-onset patients, a preserved mucosal architecture

characterized by dense lymphocytic infiltration, with no villous atrophy or crypt hyperplasia can also be

observed.

“Several dietary components exert anti-inflammatory and antioxidant roles and have a protective effect

on intestinal epithelium, therefore their adoption could contribute to preserving intestinal barrier

integrity and play a protective role against the toxicity of gliadin peptides in CD subjects.

“Nutrigenetics refers to genetically determined differences in reactivity of individuals to specific foods,

while Nutrigenomics refers to the functional interactions of food with the genome.”

86

Reference:





“Cytotoxic vs. Immunogenic Effects of Gluten

“Figure 1. Intestinal epithelial damage in celiac disease: role of “toxic” and “immunogenic” peptides.

“Toxic” peptides in intestinal cells induce tight junction (TJ) dysfunctions and several cytotoxic effects

such as apoptosis and altered cell differentiation. Most of these effects are mediated by increased

oxidative stress induced by gluten peptides in enterocytes. These alterations reflect in an impairment of

the epithelial barrier and increased permeability. As a consequence, both “toxic” and “immunogenic”

peptides of gliadin pass through the enterocytes leading to activation of the immune response (native

and adaptive) contributing to cell damage and villous atrophy in celiac disease (CD) subjects. LPMC,

lamina propria mononuclear cells; tTG, Tissue transglutaminase.

“Different gluten peptides are involved in the CD process. Computer modeling studies have

demonstrated that two groups of biologically-active peptides derive from α-gliadin. The serine-

containing group of peptides appears to be essentially cytotoxic, whilst the tyrosine-containing group

has the capacity to trigger immunological reactions in CD patients. Both types of activity in celiac

disease are possible if there is defective digestion of the active peptides.

“Imunomodulatory Effects of Gluten Peptides: The immunogenic peptides such as P57–68, P57–89,

and P63–76 cause an adaptive response that proceeds through their binding to HLA-DQ2 or -DQ8 of

antigen presenting cells and the subsequent stimulation of T-cells (Figure 1).”

87

Here is the key: EDS-related research needs to focus upon whether (how) EDS patients are

predisposed to chronic inflammatory conditions in the gut.

If the manner in which EDS affects digestion and nutrition predisposes EDS patients to Gluten

Intolerance and Celiac Disease (for example through bacterial overgrowth, leaky gut, etc.), such

research would apply EDS patients.

Reference:





“Conclusions: Celiac disease is characterized by a complex interaction between genetic and

environmental factors. The mucosal damage in celiac patients is considered to be induced by an

interplay between innate and adaptive immune responses to ingested gluten. Developments in

proteomics have provided an important contribution to the understanding of the biochemical and

immunological aspects and the mechanisms involved in toxicity of prolamins. “Inflammation and

oxidative stress due to an increase of reactive oxygen species and a decrease of antioxidant defenses

are involved in the molecular mechanisms of celiac disease. This in turn leads to uncontrolled

activation of the redox-sensitive, pro-inflammatory transcription factors NF-κB, continued production of

ROS and RNS and support of chronic inflammation.

“Previous studies have demonstrated that several nutrients exert antioxidant effects and influence gene

expression, therefore they represent a useful approach for nutritional intervention in CD subjects, as

corroborated by recent in vitro studies that have demonstrated that phytonutrients (lycopene,

quercitine, vitamin C and tyrosol) protect against the cytotoxic effect of gliadin. A protective effect has

also been exerted by DHA.

“To realize the usefulness of nutritional genomics as a tool for targeted medical nutrition therapy,

further basic research, extensive epidemiological studies and controlled intervention trials are needed

to investigate whether long chain unsaturated fatty acids , antioxidant vitamins , plant polyphenols and

carotenoids modulate in vivo predisposition of chronic inflammatory conditions and thus have a role in

the therapy of celiac disease.”

88

Since POTS is connected to EDS, and POTS is connected to MCADs, a logical connection may exist

between EDS and MCADs via POTS (or dysautonomia in general).

89

Image:

http://homepage.ntlworld.com/bhandari/Imperial/Atenolol/The%20Future.htm

See also:

http://ainotes.wikispaces.com/Mast+Cell+Disorders

90

Image:

http://ainotes.wikispaces.com/Mast+Cell+Disorders (Original article not cited; Author: “Akdis”)

91

Reference:

Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell

activation syndrome. Curr Allergy Asthma Rep. 2013 Feb;13(1):10-8. doi: 10.1007/s11882-012-0326-8.



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545645/pdf/nihms426735.pdf)

See also:

http://ainotes.wikispaces.com/Mast+Cell+Disorders

92

Reference:

Bengmark S. Gut microbiota, immune development and function. Pharmacol Res. 2013 Mar;69(1):87-113. doi: 10.1016/j.phrs.2012.09.002. Epub 2012 Sep 16.PubMed [citation] PMID: 22989504


An individual who wants to live in line with the present knowledge obtained from extensive research in recent years might want, in addition regular physical exercise, good sleep and spiritual harmony to consider:

1. Minimizing intake of insulinogenic foods such as refined carbohydrates; cereals, bread, sweats, cookies, rice, pasta, cooked tubers incl. potatoes, foods, which are absorbed high in the small intestine and of minimal benefit to microbiota.

2. Keeping a daily intake of fructose below 25 gram a day.

3. Minimizing their intake of dairy products especially butter, cheese and milk powder, rich in

saturated fats, hormones and growth factors such as IGF1, and to reduce meat intake, especially inflammation-inducing processed and cured meat such as bacon and sausages, this far though only fat demonstrated to being detrimental to microbiota.

4. Dramatically increasing the intake of fresh and raw greens, fresh spices and vegetables, rich in antioxidants, fibers, minerals and nutrients, but also inflammation-controlling factors such as curcumin, resveratrol - some of which most likely are of great importance for diversity, replication, growth and functions of the microbiota and for immune development and immune functions of the body.

5. Minimizing intake of foods, which are heated above 100o C known to be rich in the inflammation-inducing molecules AGEs and ALEs, foods heated above 130 Co, which with increase in temperature becomes increasingly rich in pro-inflammatory and carcinogenic substances such acrylamide and heterocyclic amines. This means avoiding fried and grilled foods but also toasted and high-temperature baked breads.

6. Minimizing exposure to microbe-derived highly inflammation-inducing endotoxin, especially rich in meat hung for several days, hard cheeses, pork and ice-creams.

7. Eliminating/minimizing intake of foods rich in proteotoxins such as casein, gluten and zein.

8. Seeking out and consuming ancient anti-oxidant-rich, high fiber, low-calorie containing grains

such as buckwheat, amaranth, chia, lupin, millet, quinoa, sorghum, taro, teff etc, and also increasing the intake of beans, peas, chickpeas, lentils, nuts and almonds - all extraordinary rich in nutrients and minerals - all prepared for eating by low-temperature cooking - all most likely of importance for maintenance of a rich microbiota.

9. Restricting intake of chemicals including pharmaceutical drugs to only what is absolutely nessessary as most likely most chemicals are detrimental to microbiota.

10. Supplement of large doses of vitamin D and omega fatty acids, both important in control of inflammation and for function of microbiota.

98

Reference:

Bengmark S. Gut microbiota, immune development and function. Pharmacol Res. 2013 Mar;69(1):87-113. doi: 10.1016/j.phrs.2012.09.002. Epub 2012 Sep 16.PubMed [citation] PMID: 22989504


An individual who wants to live in line with the present knowledge obtained from extensive research in recent years might want, in addition regular physical exercise, good sleep and spiritual harmony to consider:

1. Minimizing intake of insulinogenic foods such as refined carbohydrates; cereals, bread, sweats, cookies, rice, pasta, cooked tubers incl. potatoes, foods, which are absorbed high in the small intestine and of minimal benefit to microbiota.

2. Keeping a daily intake of fructose below 25 gram a day.

3. Minimizing their intake of dairy products especially butter, cheese and milk powder, rich in

saturated fats, hormones and growth factors such as IGF1, and to reduce meat intake, especially inflammation-inducing processed and cured meat such as bacon and sausages, this far though only fat demonstrated to being detrimental to microbiota.

4. Dramatically increasing the intake of fresh and raw greens, fresh spices and vegetables, rich in antioxidants, fibers, minerals and nutrients, but also inflammation-controlling factors such as curcumin, resveratrol - some of which most likely are of great importance for diversity, replication, growth and functions of the microbiota and for immune development and immune functions of the body.

5. Minimizing intake of foods, which are heated above 100o C known to be rich in the inflammation-inducing molecules AGEs and ALEs, foods heated above 130 Co, which with increase in temperature becomes increasingly rich in pro-inflammatory and carcinogenic substances such acrylamide and heterocyclic amines. This means avoiding fried and grilled foods but also toasted and high-temperature baked breads.

6. Minimizing exposure to microbe-derived highly inflammation-inducing endotoxin, especially rich in meat hung for several days, hard cheeses, pork and ice-creams.

7. Eliminating/minimizing intake of foods rich in proteotoxins such as casein, gluten and zein.

8. Seeking out and consuming ancient anti-oxidant-rich, high fiber, low-calorie containing grains

such as buckwheat, amaranth, chia, lupin, millet, quinoa, sorghum, taro, teff etc, and also increasing the intake of beans, peas, chickpeas, lentils, nuts and almonds - all extraordinary rich in nutrients and minerals - all prepared for eating by low-temperature cooking - all most likely of importance for maintenance of a rich microbiota.

9. Restricting intake of chemicals including pharmaceutical drugs to only what is absolutely nessessary as most likely most chemicals are detrimental to microbiota.

10. Supplement of large doses of vitamin D and omega fatty acids, both important in control of inflammation and for function of microbiota.

99

Reference:




PMCID: PMC3512326



“In addition to behavior modifications, adequate nutritional supplementations may be of some help in

preventing/treating some features of JHS/EDS-HT. Although specific studies are still lacking,

suggestions have been recently proposed [62, 162, 163]. In particular, dysautonomia-related fatigue

may be partly managed by (i) generous daily water/liquid intake (2–2.5 lts) preferring isotonic solutions,

(ii) high salt intake (to avoid in case of arterial hypertension), and (iii) daily assumption of carnitine (250

mg) and/or coenzyme Q10 (100 mg). Capillary/small vessels fragility may be improved by daily

assumption of ascorbic acid, a cofactor of prolyl and lysyl hydroxylases, which are enzymes involved in

the biogenesis of collagens. Approximately 8–50 times the 60 mg recommended daily intake for adults

is indicated as the dose for maximal improvement of such biological functions. In case of osteopenia,

daily intake of therapeutic doses of vitamin D (usually 880 IU/day in adults) and calcium (usually 1,000

mg/day in adults) is indicated for lowering the risk of fracture. Vitamin D is present in a few foods, and

many people, especially in USA and Europe, may not get enough sunlight, which is essential for

endogenous production of vitamin D from cholesterol. Therefore, a daily supplementation of 200 mg or

400 mg vitamin D, for adults and children, respectively, may be recommended also in the

nonosteopenic individual. A 1–5mg daily intake of melatonin is considered a resource for improving

sleepiness in various functional somatic syndromes, such as fibromyalgia. Similarly, melatonin may be

effective in JHS/EDS-HT. Other nutraceuticals which have been thought beneficial, though still without

evidence, in JHS/EDS-HT comprise vitamin E, vitamin B complex, vitamin K, glucosamine, chondroitin,

γ-linolenic acid, pycnogenol,magnesium, zinc,methyl sulfonyl methane and silica.”

100

Reference:

Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep. 2013 Feb;13(1):10-8. doi: 10.1007/s11882-012-0326-8. Review.PubMed [citation] PMID: 23212667, PMCID: PMC3545645

(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545645/pdf/nihms426735.pdf)

“The final useful piece of information to support the diagnosis of nc-MCAS is the patient response to medications that block mast cell mediators. When nc-MCAS is strongly suspected with laboratory evidence of mast cell mediator release, medical treatment using a standard stepwise approach can have excellent results [6] (Table 1). Standard and proven therapy includes use of type I and II histamine blockers and mast cell membrane-stabilizing agents (such as Cromolyn sodium and Ketotifen) [55]. Cysteinyl leukotriene receptor 1 blockers and 5-lipoxygenase inhibitors may be considered in patients with symptoms refractory to the above medications, particularly those with pulmonary symptoms. Aspirin therapy may be especially useful in

- prostaglandin F2 levels [31]. Case reports and case series have suggested that omalizumab may be helpful in controlling refractory symptoms (particularly anaphylaxis) in both patients with nc-MCAS and with systemic mastocytosis, with and without atopic sensitization [56–59]. Systemic or topical steroids, in addition to other immunosuppressants and immunomodulators, may be considered for more refractory or aggressive symptoms, although experience is limited with non-steroid immunosuppressants. Medications that treat pain pathways may be a useful adjunctive therapy. The most important treatment of all, however, may be avoidance of known triggers, so it is important for patients to understand their mast cell-related symptoms and to keep track of provoking factors. Special attention should also be directed towards the patient’s nutritional and mental state.

“Patients who may have attendant prominent mast cell activation symptoms in addition to syncope and near syncope may be categorized as nc-MCAS with IA, and future diagnostic algorithms should take this subtlety in to account. With this in mind, it is important to recognize that patients with nc-MCAS may be at higher risk for invasive procedures, particularly those requiring general anesthesia.

“Stepwise approach to the treatment of MCAS (comments are partly based on clinical observation and experience. (Adapted from Castells et al. [72].)

• Avoidance of known triggers

• Second generation H1 blockers (e.g. loratidine, cetirizine): Second generation H1 blockers are preferred due to less sedation, and may be used on a

• scheduled basis once or twice daily.

• First generation H1 blockers (e.g. diphenhydramine, hydroxyzine): May be used as needed for breakthrough symptoms, and before or during invasive procedures or radiology studies.

• H2 blockers (e.g. ranitidine, famotidine): Can be scheduled once or twice daily.

• Cromolyn sodium (oral formulation): Useful for abdominal bloating and diarrhea. Benefit may extend beyond GI symptoms and target also skin and neuropsychiatric manifestations. Divided dosing and weekly titration to reach target daily dose is advised to avoid side effects and improve adherence with regimen.

• H1 blocker/mast cell stabilizer (Ketotifen): Now available as a generic formulation in compounding pharmacies in the USA.

• Aspirin: Useful for flushing in select patients with elevated urinary 11β-PGF2a. Contraindicated in those with allergic or adverse reactions to NSAIDs. Clinical improvement may require dosing increases up to 650mg twice daily if tolerated.

• Steroid taper (prednisone, prednisolone): May be useful in patients with refractory signs or symptoms. Initial oral dosage of 0.5mg/kg/

• day followed by a slow taper over 1–3 months.

• Omalizumab: May be useful in patients with recalcitrant symptoms or resistance to therapy, including anaphylaxis.

• Montelukast (or other cysteinyl-leukotriene receptor 1 blockers): May be useful in patients with wheezing.

• Zileuton: May be useful in patients with wheezing.

“[72] Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. American journal of clinical dermatology. 2011 Aug 1;12(4):259–270. PubMed PMID: 21668033. [PubMed: 21668033]”

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Image:

http://cdn.trinixy.ru/pics2/20071108/podborka_192_59.jpg

For those who feel they are between a rock and a hard place!

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Are we really zebras?

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Persons with EDS are like the elephant, surrounded by the blind men.

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EDS is NOT just joint hypermobility.

106

The medical community needs to be able to recognize EDS. The relevance of this talk is that

gastroenterologists, immunologists, and other specialists who deal with FGID and immune

dysregulation need to take off their blindfolds.

Reference:




PMCID: PMC3512326



107

What else belongs in the EDS circle?

• sleep disorders

• neuropsychologic conditions

• developmental conditions

• etc.

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The overall numbers for prevalence and incidence are changing.

EDS is now understood to be far more prevalent than previously reported.

Some EDS Types may be considered “rare” or “orphan”, but, taken as a whole, EDS is not so rare.

The herd is gathering its strength in numbers!

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How EDS Affects GI (Heidi Collins, MD)

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