gastrointestinal complications of ehlers-danlos...
TRANSCRIPT
Gastrointestinal Complications of Ehlers-Danlos Syndrome
EDNF Physicians Conference September 15, 2014 Heidi A Collins, MD
Presenter
Presentation Notes
My intention is to provide a presentation that can be appreciated even if viewed independently by persons not attending the EDNF 2014 Physicians 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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome
“All disease begins in the gut.”
“Bad digestion is the root of evil.”
“Death sits
in the bowels.”
- Hippocrates (c. 400 BC)
Presenter
Presentation Notes
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”.
Gastrointestinal Complications of Ehlers-Danlos Syndrome
Isn’t Ehlers-Danlos Syndrome (EDS) all about: • hypermobility? • musculoskeletal issues? • pain? • skin issues? • vascular issues?
What do gut functions have to do with EDS?
Presenter
Presentation Notes
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. (See: http://www.ncbi.nlm.nih.gov/books/NBK1494/)
Gastrointestinal Complications of Ehlers-Danlos Syndrome
Conditions / symptoms caused by gastrointestinal connective tissue abnormalities in EDS include:
• structural / anatomic issues. • dysmotility. • Functional Gastrointestinal Disorders. • dysbiosis. • inflammation. • increased permeability. • malabsorption (malnutrition). • gut-related immune dysregulation. • pain.
The autonomic nervous system abnormalities common in EDS may cause additional GI symptoms.
Presenter
Presentation Notes
further inflammation, allergies, autoimmune conditions may affect digestive tract and other organ systems
Gastrointestinal Complications of Ehlers-Danlos Syndrome
Gastrointestinal complications of EDS are: • common. • potentially disabling. • well-documented in existing literature. • under-appreciated by clinicians.
Presenter
Presentation Notes
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. (See: http://www.ncbi.nlm.nih.gov/books/NBK1279/) 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. (See: http://www.ncbi.nlm.nih.gov/pubmed/23295898, http://www.karger.com/Article/Pdf/346068) 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. (See: http://www.ncbi.nlm.nih.gov/pubmed/23295973, http://www.karger.com/Article/Pdf/345998) 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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Potentially Disabling
Teenager, 18, is fed through her heart via a drip after being diagnosed with life-threatening tissue disorder
By Larisa Brown PUBLISHED: 10:58 EST, 26 August 2012 | UPDATED: 12:16 EST, 26 August 2012
“Jodie, of Carlisle, Cumbria, has Ehlers-Danlos Syndrome Hypermobility Type III (EDS), a disorder that affects the collagen in the body and can also interfere with the way internal organs, nerves and muscles work.” “Jodie has severe complex intestinal failure, has had her large bowel removed and a permanent stoma bag fitted, her small intestine has stopped working, her stomach doesn't function and her bladder has failed. It was hoped she would be able to get a five-organ transplant but doctors have said she would not survive the surgery. As the teenager cannot tolerate food she has not eaten since 2009 and is fed intravenously into the heart by a Total Parental Nutrition tube (TPN), however, this comes with serious risks including septicaemia and liver disease.”
Presenter
Presentation Notes
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
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Presenter
Presentation Notes
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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Presenter
Presentation Notes
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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Program Nr: 362 from the 1999 ASHG Annual Meeting Gastroesophageal reflux and irritable bowel syndrome in classical and hypermobile Ehlers Danlos syndrome (EDS). H.P. Levy1, W. Mayoral2, K. Collier2, T.L. Tio2, C.A. Francomano1. 1) NHGRI, NIH, Bethesda, MD; 2) Georgetown University Medical Center, Washington, DC. Rupture of the GI tract is a known manifestation of vascular EDS (type IV), and diverticuli and hiatal hernia have been reported without specification of EDS subtype. However, the spectrum and frequency of GI complications in classical (types I and II) and hypermobile (type III) EDS have not been established. We reviewed the charts of 51 EDS patients for GI findings. 38 patients had classical, and 13 had hypermobile EDS. Age range was 8 to 78 years. Sex ratio was biased, with F:M=41:10 (30:8 classical and 11:2 hypermobile). Gastroesophageal reflux (GERD) was suspected clinically in 26 of 45 patients [58%] for whom data was available (17 of 32 classical [53%] and 9 of 13 hypermobile [69%]). Irritable bowel syndrome (IBS), defined as chronic intermittent diarrhea and/or constipation, with or without abdominal cramps, was reported by 24 of 43 patients (56%) for whom data was available (18 of 30 classical [60%] and 6 of 13 hypermobile [46%]. Also, 4 patients (2 classical, 2 hypermobile) had endoscopic diagnoses of non-specific inflammatory bowel disease (IBD); thus 28 of 47 informative patients [60%] had IBS or IBD. Overall, 34 of 47 patients [72%] had any combination of GERD, IBS & IBD. If all missing data was considered negative, the overall prevalence would be 26 of 51 [51%] for GERD and 28 of 51 [55%] for IBS/IBD. EDS patients may have chronic pain, leading to NSAID-induced gastritis mimicking GERD or narcotic-induced symptoms mimicking IBS. Alternatively, EDS may cause reduced lower esophageal sphincter tone, increased distensibility, and/or decreased GI motility, resulting in GERD and/or IBS. Autonomic dysfunction could cause both GERD and IBS. 10 patients had suspected or confirmed cardiovascular autonomic dysfunction; 9 also had GI complications. We conclude that GERD and IBS are common complications of classical and hypermobile EDS, and should be sought and treated in these patients.
Presenter
Presentation Notes
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].
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/15317957, http://rheumatology.oxfordjournals.org/content/43/9/1194.full.pdf)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Program Nr: 11076 from the 2007 ASHG Annual Meeting Gastrointestinal Disorders in Patients with Hypermobile or Classical Ehlers-Danlos Syndromes. A. Gustafson1, B.F. Griswold2, L. Sloper2, M. Lavallee4, C.A. Francomano3, N.B. McDonnell2 1) Brown Univ, Providence, RI; 2) LCI, NIA/NIH, Baltimore,MD; 3) GBMC,Baltimore, MD; 4) IUSM, South Bend, IN. Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue that are characterized by joint, skin, and vascular abnormalities. Most literature reports of gastrointestinal (GI) involvement in EDS have been limited to patients with vascular EDS. Patients with vascular EDS have abnormalities of type III collagen, a constituent of the bowel wall, and thus prone to GI complications and bowel rupture. Patients with other types of EDS, however, also report GI dysfunction. Complete physicals and medical histories were obtained from 90 patients with hypermobile or classical types of EDS enrolled in the National Institutes on Aging protocol 2003-086, “Clinical and Molecular Manifestations of Heredity Disorders of Connective Tissue. ” We found a high prevalence of GI manifestations in this cohort of patients, including severe chronic constipation (17%), irritable bowel syndrome (12%), acid reflux or gastroesophageal reflux disease (14%), and/or chronic abdominal pain (22%). Gastroparesis was noted in four subjects. The prevalence of each of these disorders was significantly higher in our cohort (P<.0001) compared with the general population. In our cohort, lack of tissue integrity may cause structural abnormalities, decreased blood vessel wall strength, and/or altered motility or absorption, which may all contribute to development of GI disorders.
Presenter
Presentation Notes
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
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Program Nr: 21352 from the 2007 ASHG Annual Meeting High prevalence of Food Allergies in Patients with Ehlers-Danlos Syndromes. H. Zhang1, B.F. Griswold1, L. Sloper1, M. Lavallee3, C.A. Francomano2, N.B. McDonnell2, A. Gustafson1 1) LCI, NIA/NIH, Baltimore, MD; 2) GBMC, Baltimore, MD; 3) IUSM, South Bend, IN. Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue that are characterized by joint, skin, and vascular abnormalities. Complete physicals and medical histories were obtained from 95 patients with hypermobile, classical, and vascular EDS enrolled in the National Institutes on Aging Protocol 2003-086, “Clinical and Molecular Manifestations of Heredity Disorders of Connective Tissue. ” We found a high prevalence of food allergies in patients with EDS (14%) when compared with the general population (P<.0001). We also found a significantly higher incidence of gastrointestinal manifestations in our cohort when compared with the general population (P<.0001). The presence of food allergies also seems to correlate with gastrointestinal dysfunction in some patients. Of the patients who reported constipation, irritable bowel syndrome, gastroesophageal reflux disease, and/or chronic abdominal pain, many also reported having a food allergy (40%, 42%, 17%, and 20%, respectively). Collagen abnormalities may cause mucosal lesions, altering tissue integrity and increasing the chance of larger proteins crossing the mucosal barrier and creating an immunogenic response. Multiple studies have correlated eosinophillic gastrointestinal disorders, allergic responses that fall in between IgE and TH2-type responses that are mediated by IL-5 and other eotaxins, with classic mast cell tissue degranulation, producing gastrointestinal disorders similar to those seen in our patients. Understanding the mechanisms associated with food allergies in patients with EDS may aid in development of effective treatments.
Presenter
Presentation Notes
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
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/20169104, http://downloads.hindawi.com/journals/grp/2009/924138.pdf)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Presenter
Presentation Notes
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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Well-documented in Existing Literature
Presenter
Presentation Notes
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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Under-appreciated by Clinicians
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/23227356, 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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Under-appreciated by Clinicians
Presenter
Presentation Notes
“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: 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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Under-appreciated by Clinicians
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Under-appreciated by Clinicians
Presenter
Presentation Notes
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. (See: http://www.ncbi.nlm.nih.gov/pubmed/22193218, http://link.springer.com/article/10.1007%2Fs00296-011-2275-2#page-1)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Under-appreciated by Clinicians
Presenter
Presentation Notes
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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome
Ehlers-Danlos Syndrome is NOT “just” hypermobility.
Ehlers-Danlos Syndrome affects the vital physiologic processes of digestion, nutrition, elimination, and
gut-related immune function.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Alimentary Canal
The Alimentary Canal
Presenter
Presentation Notes
Image: http://starklab.slu.edu/Physio/Alimentary.jpg
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Layers of the Alimentary Canal
• lumen: enteric microbiota • mucosa: serves as a barrier, allows absorption
– epithelium: absorption, secretion – lamina propria: connective tissue, lymphoid tissue,
mast cells, eosinophils – muscularis mucosae: smooth muscle
• submucosa: specialized structures – dense irregular connective tissue – lymphoid tissue – nerves (submucosal plexus) – blood vessels, glands
• muscularis: mixes, propels – nerves (myenteric plexus) – circular and longitudinal muscle
• serosa / adventitia: connective tissue
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Layers of the Alimentary Canal
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Gut-Related Immune Function
The alimentary canal encloses an environment considered to be external to the body.
• a very large surface area – about the area of a football field
• The mucosa of the gut is very analogous to skin. • gut immune defenses
– physical (e.g., intact mucosa, vomiting, diarrhea) – cellular (e.g., lymphoid cells, mast cells, eosinophils) – chemical (e.g., pH, antibodies)
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Gut-Related Immune Function
Leukocytes in Alimentary Tissues • Gut-Associated Lymphoid Tissue (GALT)
– T lymphocytes, B lymphocytes, Natural Killer cells lamina propria, submucosa esophagus, stomach, small intestine, large intestine tonsils, adenoids, appendix
• myeloid cells – e.g., mast cells, eosinophils
mucosa
Presenter
Presentation Notes
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
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Gut Microbiome
Over 100 trillion organisms occupy the human gut. • Over 1000 species identified so far.
– bacteria – archea – fungi – protozoa
Our microbiota have 150 times more genes than us. • 90% of the cells within our body are microbial. • https://commonfund.nih.gov/hmp/
The colonic microbiome is the most biodense natural ecosystem known.
• 1010-1012 cells/ml • Bacteria make up ~60% of the dry mass of feces.
Presenter
Presentation Notes
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. (See: http://www.ncbi.nlm.nih.gov/pubmed/22162969, 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/)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Gut Microbiome
Bacterial Benefits • ferment undigested carbohydrates
– provide short chain fatty acids as energy
• enhance lipid metabolism – fat-soluble vitamin A, D, E, and K absorption
• assist in absorption of minerals – e.g., calcium, magnesium, iron
• synthesize nutrients – e.g., B vitamins, vitamin K, folate, biotin
• metabolize bile acids, sterols, and xenobiotics • ferment non-digestible dietary residue and mucus • support / regulate epithelial and lymphoid function • affect the production of neurotransmitters by gut tissue
Presenter
Presentation Notes
Bacteria are not always harmful.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Gut Microbiome
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/16819463, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1500832/pdf/7400731.pdf)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Gut Microbiome and Immunomodulation
Presenter
Presentation Notes
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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Normobiosis vs. Dysbiosis
Normobiosis: A Balancing Act • believed to prevent:
– auto-immune disease – allergies – cancer – diabetes – obesity
Dysbiosis: Leads to Non-Specific Inflammation • An inflamed mucosa is a less effective barrier. • 2005 Nobel Prize in Physiology and Medicine • Bacteriotherapy may restore normobiosis.
– prebiotics and probiotics – fecal transplant
Presenter
Presentation Notes
“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. (See: http://www.ncbi.nlm.nih.gov/pubmed/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
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Normobiosis vs. Dysbiosis
Presenter
Presentation Notes
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. (See: http://www.ncbi.nlm.nih.gov/pubmed/19343057, http://www.stritch.luc.edu/lumen/meded/hostdef/Gut_Microbiota_Shapes_Intestinal.pdf)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Autonomic Nervous System
Autonomic Nervous System (ANS) • Sympathetic Nervous System (SNS)
– “Fight or Flight”
• Parasympathetic Nervous System (PNS) – “Rest and Digest”
Presenter
Presentation Notes
Images: http://www.myworkhorse.com/content/over-training-and-plateaus http://blogs.christianpost.com/health/natural-vs-traditional-medicine-for-heartburn-and-indigestion-4254/
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Autonomic Nervous System
Presenter
Presentation Notes
Image: http://www.uic.edu/classes/bios/bios100/lectures/ANS.jpg
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Autonomic Nervous System
Presenter
Presentation Notes
Image: http://www.highlands.edu/academics/divisions/scipe/biology/faculty/harnden/2121/images/nervousorg.jpg 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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Enteric Nervous System
The functions of the alimentary canal are locally regulated by the Enteric Nervous System (ENS).
Presenter
Presentation Notes
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
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Enteric Nervous System
The ENS is intrinsic to the alimentary canal, and it connects with the CNS via the SNS and PNS.
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Enteric Nervous System
The Enteric Nervous System: “The Second Brain” • can function autonomously
– after spinal cord injury – with stored programs (e.g., vomiting)
• regulated by SNS and PNS – “Fight or Flight” – “Rest and Digest”
• Part of the “Brain-Gut Axis”
Presenter
Presentation Notes
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. (See: http://www.ncbi.nlm.nih.gov/pubmed/15300595)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Autonomic Nervous System – The Brain-Gut Axis
Presenter
Presentation Notes
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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Autonomic Nervous System – Brain-Gut-Enteric Microbiota Axis
“Schematic representation of the pattern of bidirectional brain–gut–microbe interactions. The brain can modulate various functions of the gut, as well as the perception of gut stimuli, via a set of parallel outflow systems that are referred to as the EMS, which include the sympathetic and parasympathetic branches of the ANS, the HPA axis, and endogenous pain-modulation systems. Activation of the EMS can occur via interoceptive and exteroceptive stressors. The enteric microbiota are likely to interact with gut-based effector systems and with visceral afferent pathways, which establish a bidirectional brain–gut–enteric microbiota axis. Abbreviations: ANS, autonomic nervous system; CNS, central nervous system; EMS, emotional motor system; GI, gastrointestinal; HPA, hypothalamus–pituitary–adrenal.”
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/19404271, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817714/pdf/nihms-523421.pdf)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: The Autonomic Nervous System – Autonomic Dysfunction
Common Forms of Autonomic Dysfunction (Dysautonomia) • Postural Orthostatic Tachycardia Syndrome (POTS)
– tachycardia (very fast heart rate)
• Neurocardiogenic Syncope (NCS) – syncope (fainting or nearly fainting)
• Neurally Mediated Hypotension (NMH) – hypotension (low blood pressure)
• Orthostatic Intolerance (OI) – poor tolerance of:
upright positions rapidly changing positions
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Modifiable Factors
Diet • nutrient-dense vs. nutrient-poor • affects the health of the gut microbiome
– in turn, affects gut-related immune function
Exercise • Some conditions can be caused by inactivity.
– e.g., gall bladder disease, diverticulitis, constipation
• Activity may prevent inflammatory bowel disease. Medications
• prescription vs. non-prescription – “pharmaceutical” vs. “nutraceutical” – supplements, herbs, teas, etc.
• intended effects vs. side effects
Presenter
Presentation Notes
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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Putting it all Together
EDS is a disorder affecting the production, maintenance, or repair of connective tissues.
• The alimentary canal is rich in connective tissue. Gut-related immunity is part of alimentary health.
• Dysregulation of gut-related immunity is prevalent in EDS. Normobiosis is necessary for healthy alimentary function.
• Dysbiosis is prevalent in EDS. The autonomic nervous system affects whether the alimentary canal is “on” (“Rest and Digest”) or “off” (“Fight or Flight”).
• Autonomic Dysfunction is prevalent in EDS. Persons with EDS can either support or thwart alimentary functions through diet, exercise, and medicine or supplement use.
• Persons with EDS often have a sub-optimal diet, find it difficult to exercise, and are on numerous medications or supplements.
Presenter
Presentation Notes
Of course EDS affects digestion, nutrition, bowel function, and gut-related immune function!
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues, Dysmotility, and FGIDs
Connective tissue abnormalities in EDS may affect gastrointestinal physiology by causing:
• structural issues affecting the alimentary canal. – microscopic (may be inflammatory or non-inflammatory)
tissue biopsy – macroscopic
imaging direct inspection (e.g., endoscopy, colonoscopy, surgery)
– may vary with time
• gastrointestinal dysmotility. • Functional Gastrointestinal Disorders (FGIDs).
– FGIDs are those without a known underlying structural, biochemical, metabolic, or autoimmune cause.
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Teeth • dentin dysplasia • root dilaceration • hypodontia • ectopic eruption • delayed eruption • transmigration • fracture after minor stress • recurrent caries (i.e., tooth decay) • premature loss • difficulty with hemostasis after tooth extraction • difficulty achieving dental anesthesia
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/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 (See: http://www.ncbi.nlm.nih.gov/pubmed/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 (See: http://www.ncbi.nlm.nih.gov/pubmed/20140961, http://www.ehlersdanlos.it/Public/Dynamic/Documents/Document634103349567582849.pdf) “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).”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Oropharynx • Mucosa, Gingiva, and Alveolar Bone
– xerostomia – fragility – breakdown – odontogenic keratocysts
• Tongue – hypermobility (Gorlin’s Sign)
• Temporomandibular Joint (TMJ) – dysfunction – dislocation
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/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 (See: http://www.ncbi.nlm.nih.gov/pubmed/8931403, http://www.annabelleschallenge.org/app/download/3570409/GI+Manifestation+of+EDS.pdf) “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 (See: http://www.ncbi.nlm.nih.gov/pubmed/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 (See: http://www.ncbi.nlm.nih.gov/pubmed/20140961, http://www.ehlersdanlos.it/Public/Dynamic/Documents/Document634103349567582849.pdf) “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).”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Esophagus • dilation (e.g., megaesophagus) • diverticula (e.g., giant epiphrenic diverticula) • Gastroesophageal Reflux Disease (GERD)
– reduced lower esophageal sphincter tone – esophageal reflux – laryngopharyngeal reflux (“Silent Reflux”)
may cause excessive phlegm, cough, postnasal drip may mimic bronchitis, asthma, sinusitis, etc.
• hiatal hernia (very common) • rupture or perforation • arterial rupture
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Stomach • GERD • gastritis • peptic ulceration
– complications may be particularly severe in VEDS hematemesis melena very rarely: erosion of the aorta by a duodenal ulcer
• diverticula: nidus for perforation – comorbid gall bladder and small intestinal diverticula
• hiatal hernia (very common)
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Stomach (cont’d) • diaphragmatic eventration • gastric malrotation • volvulus • gastric infarction • visceroptosis
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Small Intestine • dilation
– e.g., megaduodenum, dilation of entire small bowel – has been linked to bacterial overgrowth, malabsorption
• diverticula: nidus for perforation • hernia • visceroptosis
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Small Intestine (cont’d) • perforation
– with or without diverticula – more common in VEDS – symptoms
pain emesis hematemesis peritonitis
– may be more prone to abscess formation inability to wall off infectious processes
– may require partial small bowel resection and anastomosis
• intramural hematomas – more common in VEDS – may be heralded by hematemesis – focal necrosis increases risk of perforation
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
Special Alimentary Structures • Liver, Gall Bladder, Pancreas
– may rupture
• Appendix – Appendicitis is likely less common in EDS than in the
general population.
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Large Intestine • dilation
– megacolon – dolichocolon
• diverticula: nidus for perforation • hernia • visceroptosis
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues – Visceroptosis
Presenter
Presentation Notes
References: Dordoni C, Ritelli M, Venturini M, Chiarelli N, Pezzani L, Vascellaro A, Calzavara-Pinton P, Colombi M. Recurring and generalised visceroptosis in Ehlers-Danlos syndrome hypermobility type. Am J Med Genet A. 2013 May;161A(5):1143-7. (See: http://www.ncbi.nlm.nih.gov/pubmed/23533212 ) 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. (See: http://www.ncbi.nlm.nih.gov/pubmed/22781752) Visceroptosis of the bowel in the hypermobility type of Ehlers-Danlos syndrome: presentation of a rare manifestation and review of the literature. Reinstein E, Pimentel M, Pariani M, Nemec S, Sokol T, Rimoin DL. Eur J Med Genet. 2012 Oct;55(10):548-51. doi: 10.1016/j.ejmg.2012.06.012. Epub 2012 Jul 7. Review. PMID: 22781752
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Large Intestine (cont’d) • spontaneous perforation(s)
– with or without diverticula – more common in VEDS – may have history of constipation, pain
diverticula intramural hematoma tear in seromuscular coat
– likelihood increases with age – more frequent in women – most common in sigmoid colon – may be multifocal – tend to recur
Colostomy is often recommended. Risk of colostomy stenosis is significant.
Colectomy with ileostomy is often needed. Ileoproctostomy can be considered.
– Perforation may be considered “inevitable”. Prophylactic colectomy may be advised.
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Structural Issues
The Rectum • traumatic perforation
– more common in VEDS – most likely to occur in rectum
Avoid enemas. Avoid manual disimpaction. Avoid colonoscopy.
• rectocele • prolapse
– often in infancy – less likely with increasing age
• hemorrhoids
Presenter
Presentation Notes
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.” 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/ 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.” 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) “5.8. 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 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysmotility – A Word on Gastroparesis
Gastroparesis (Delayed Gastric Emptying) • About 4% of the US population has gastroparesis. • About a third of all cases are idiopathic. • For the rest, an underlying cause is identifiable.
– commonly recognized causes include: autonomic neuropathy (e.g., Diabetes Mellitus) vagus nerve damage (e.g., after abdominal surgery) connective tissue abnormalities
heritable (e.g., EDS) acquired (e.g., Scleroderma)
Parkinson’s Disease mitochondrial disorders
– additional recognized causes include: Anorexia Nervosa and Bulimia Nervosa smoking
Presenter
Presentation Notes
Abell TL, Bernstein RK, Cutts T, Farrugia G, Forster J, Hasler WL, McCallum RW, Olden KW, Parkman HP, Parrish CR, Pasricha PJ, Prather CM, Soffer EE, Twillman R, Vinik AI: Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil 18:263 –283, 2006 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 (See: http://www.ncbi.nlm.nih.gov/pubmed/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 (See: http://www.ncbi.nlm.nih.gov/pubmed/23227356, http://downloads.hindawi.com/journals/isrn.dermatology/2012/751768.pdf) “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.” 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) “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”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysmotility
Gastrointestinal Dysmotility is well-documented in EDS. • esophageal dysmotility
– includes ineffective esophageal motility, nonspecific esophageal motility disorder
• gastric dysmotility – includes gastroparesis (delayed gastric emptying)
• small bowel dysmotility – includes pseudoobstruction
• colonic dysmotility – includes delayed colonic transit, constipation, Chronic
Intestial Pseudoobstruction (Ogilvie Syndrome), diarrhea, Irritable Bowel Syndrome
• rectal evacuatory dysfunction
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/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 (See: http://www.ncbi.nlm.nih.gov/pubmed/23227356, http://downloads.hindawi.com/journals/isrn.dermatology/2012/751768.pdf) “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.” 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) “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”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysmotility
Presenter
Presentation Notes
VERY Important References for EDS patients regarding CIPO:��"Chronic Intestinal Pseudo-obstruction: Assessment and Management"�http://faculty.vet.upenn.edu/gastro/documents/Gastroenterologypseudoobstruction.pdf �SEE TABLE 1 for specific mention of EDS.��"Chronic intestinal pseudo-obstruction"�http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712158/pdf/WJG-14-2953.pdf �SEE TABLE 1 and para 1 on p. 2954 for specific mention of EDS. Note that EDS is known to be responsible for neuronal and myogenic impairment in CIPO.�"...Ehlers-Danlos syndrome, jejunal diverticulosis and radiation enteritis can be responsible for both a neuronal and myogenic impairment."��"Chronic intestinal pseudo-obstruction: manifestations, natural history and management"�http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2982.2007.00902.x/pdf �SEE TABLE 1 for specific mention of EDS as an underlying disease causing secondary CIPO.��
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysmotility – Faces of the Disorder
Presenter
Presentation Notes
http://www.lucy-watts.co.uk/2014/05/ehlers-danlos-syndrome-are-you-aware.html http://helpme-minx.blogspot.com/p/photos.html http://jodiesjourney.wix.com/eds#!__jodies-story
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Functional Gastrointestinal Disorders
Functional Gastrointestinal Disorders (FGIDs) • Rome III Criteria
– http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf
• Documented in EDS – Functional Esophageal Disorders
e.g., Functional Dysphagia, Globus – Functional Abdominal Pain Syndrome – Irritable Bowel Syndrome – Functional Diarrhea – Functional Constipation
e.g., chronic (slow transit) constipation – Functional Fecal Incontinence – Functional Defecation Disorders
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Nutritional Deficiencies
EDS patients are recognized to suffer numerous nutritional deficiencies and related conditions.
• Nutritional deficiencies in EDS occur despite: – meeting recommended dietary intake goals. – diligent oral supplementation.
Formal research is lacking regarding the specific pathophysiology of how EDS affects nutritional status.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Nutritional Deficiencies
The most likely culprit causing EDS-related malnutrition is malabsorption due to:
• intrinsic connective tissue abnormalities. • inflammation (e.g., in the setting of dysbiosis). • dysautonomia (e.g., “Rest and Digest” is “off”).
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Nutritional Deficiencies
Acknowledged / Suspected Nutritional Deficiencies in EDS • minerals: e.g., magnesium, potassium, calcium, iron • vitamins: e.g., Vitamin C, Vitamin D, vitamin K
Associated conditions include: • osteopenia, osteoporosis, and osteomalacia. • anemia. • skin and small blood vessel fragility. • myriad musculoskeletal and neurologic symptoms.
Some deficiencies are only apparent clinically. • For example, magnesium deficiency is NOT always
accompanied by hypomagnesemia!
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Nutritional Deficiencies
Repletion of deficiencies should not be expected to bring immediate results, as the conditions they cause may require weeks, months or even years to improve. Repletion of deficiencies may not fully reverse developmental or chronic conditions. While National Guidelines are established for nutritional standards, without specific research, how these guidelines may need to be modified specifically for persons with EDS is presently unclear.
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Nutritional Deficiencies
Presenter
Presentation Notes
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.” 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – Should Persons with EDS Supplement with Collagen?
Not all forms of EDS are proven to be due to mutations in genes encoding collagen. • faulty collagen vs. faulty gene products regulating or interacting with collagen
Collagen Assembly • triple helix of coiled protein chains made of amino acids
– a high proportion of glycine, proline, and lysine • requires vitamin C for hydroxylation of procollagen molecules
– without hydroxylation, procollagen is degraded • ultrastructure: molecules are arranged together (e.g., fibrils, laminae)
Collagen Digestion • catabolized first into smaller peptide chains • ultimately catabolized into amino acids
– assembled into new peptide chains or catabolized via Krebs Cycle Bottom Line:
• No established research or clinical experience has proven that collagen supplementation is helpful for persons with EDS!
• Theoretically, a diet adequate in glycine, proline, lysine, and vitamin C (or supplementation) would support collagen biosynthesis.
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysregulation of Gut-Related Immune Function
Are persons with EDS more prone to: • food allergies or other forms of hypersensitivity? • inflammatory or autoimmune disorders of the
alimentary canal? (e.g., gluten sensitivity, Celiac Disease, Crohn’s Disease, ulcerative colitis, microcytic colitis, eosinophilic esophagitis)
• Mast Cell Activation Disorders? Available medical knowledge as well as ample patient experience indicates a connection between EDS and dysregulation of gut-related immune function.
• Formal research is lacking regarding the specific pathophysiology of how EDS affects gut-related immunity.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysregulation of Gut-Related Immune Function
The most likely culprits causing dysregulation of gut-related immune function in EDS are:
• intrinsic connective tissue abnormalities. • dysbiosis. • dysautonomia.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysregulation of Gut-Related Immune Function
Program Nr: 21352 from the 2007 ASHG Annual Meeting High prevalence of Food Allergies in Patients with Ehlers-Danlos Syndromes. H. Zhang1, B.F. Griswold1, L. Sloper1, M. Lavallee3, C.A. Francomano2, N.B. McDonnell2, A. Gustafson1 1) LCI, NIA/NIH, Baltimore, MD; 2) GBMC, Baltimore, MD; 3) IUSM, South Bend, IN.
“…Collagen abnormalities may cause mucosal lesions, altering tissue integrity and increasing the chance of larger proteins crossing the mucosal barrier and creating an immunogenic response. Multiple studies have correlated eosinophillic gastrointestinal disorders, allergic responses that fall in between IgE and TH2-type responses that are mediated by IL-5 and other eotaxins, with classic mast cell tissue degranulation, producing gastrointestinal disorders similar to those seen in our patients. Understanding the mechanisms associated with food allergies in patients with EDS may aid in development of effective treatments.”
Presenter
Presentation Notes
Reference: http://ashg.org/genetics/ashg07s/f21352.htm
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysregulation of Gut-Related Immune Function
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysregulation of Gut-Related Immune Function
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/23608731)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysregulation of Gut-Related Immune Function
Presenter
Presentation Notes
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) “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
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Gluten-sensitive Enteropathies
Gluten is a prolamin protein composed of gliadin and glutenin found in wheat and other grains (e.g. rye, barley) common in the Western diet. Some persons respond to gluten exposure with gluten-sensitive enteropathy.
• Celiac Disease • Gluten Sensitivity (Gluten Intolerance)
Presenter
Presentation Notes
Image: http://www.marilynglenville.com/tests/gluten-intolerance-test/
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Gluten-sensitive Enteropathies
Celiac Disease (Coeliac Disease, Sprue): • is an autoimmune disorder.
– anti-transglutaminase antibody positivity – HLA-DQ2, HLA-DQ8 positivity – Autoimmune comorbidities are common.
• involves “leaky” intestinal mucosa due to a combination of the innate inflammatory response and a maladapive immune response.
• causes multiple GI complaints (e.g., diarrhea, abdominal pain, bloating, mouth ulcers, lactose intolerance).
Malnutrition due to malabsorption Celiac Disease may be severe.
• weight loss, fatigue, anemia, coagulopathy, osteopenia and osteoporosis, neuropathy, psychiatric manifestations
Presenter
Presentation Notes
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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Gluten-sensitive Enteropathies
Gluten Sensitivity (Gluten Intolerance): • IS NOT an autoimmune disorder.
– may or may not be accompanied by anti-gliadin antibodies
• is due to an innate inflammatory response to gluten.
– part of the normal physiology of oxidative stress
• is similar to Celiac Disease. – may be accompanied by extreme pain and fatigue
• is usually less severe than Celiac Disease. • is a diagnosis of exclusion.
– rule out Celiac Disease – rule out true wheat allergy
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Gluten-sensitive Enteropathies
Presenter
Presentation Notes
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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Gluten-sensitive Enteropathies
Figure 1. Intestinal epithelial damage in celiac disease: role of “toxic” and “immunogenic” peptides.
Presenter
Presentation Notes
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) “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).”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Gluten-sensitive Enteropathies
A Potential “Nutrigenetic” Approach • In vitro nutrition research demonstrates protective
effects of certain nutrients against gluten cytotoxicity.
– phytonutrients (lycopene, quercitine, vitamin C, tyrosol) – DHA
• In vivo nutrition research is needed to determine whether additional specific nutrients bolster antioxidant defenses against gluten cytotoxicity.
– long chain unsaturated fatty acids – antioxidant vitamins – plant polyphenols – carotenoids
Presenter
Presentation Notes
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: 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) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Mast Cell Activation
Presenter
Presentation Notes
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).
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Mast Cell Activation
Mast cell activation is a NORMAL protective immune system response triggered by a pathogen.
• e.g., insect venom Mast Cell Activation Disorders (MCADs) include:
• overreaction to a valid trigger. • activation without any trigger.
Signs of Mast Cell Activation (“degranulation”) • skin: flushing, rash, itching, dermatographism • pulmonary: wheezing, shortness of breath • upper respiratory: congestion, throat swelling • cardiac: tachycardia, (near-)syncope • neurologic: poor memory, headache • GI: abdominal pain, diarrhea
Presenter
Presentation Notes
Image: http://homepage.ntlworld.com/bhandari/Imperial/Atenolol/The%20Future.htm See also: http://ainotes.wikispaces.com/Mast+Cell+Disorders
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Mast Cell Activation
Image: http://ainotes.wikispaces.com/Mast+Cell+Disorders (Original article not cited; Author: “Akdis”)
Previous management of suspected disorders of mast cell activation DID NOT recommend a trial of antimediator treatment when mast cell mediators are not elevated in serum when symptomatic.
Presenter
Presentation Notes
Image: http://ainotes.wikispaces.com/Mast+Cell+Disorders (Original article not cited; Author: “Akdis”)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Mast Cell Activation
With the recognition of nc-MCAS, the most recent thinking now mandates a trial of medications to block mast cell mediators REGARDLESS of whether mast cell mediators are elevated in serum when symptomatic.
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/23212667, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545645/pdf/nihms426735.pdf) See also: http://ainotes.wikispaces.com/Mast+Cell+Disorders
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Special Topic – A Few Words on Mast Cell Activation
Available medical knowledge as well as ample patient experience indicates a connection between EDS and dysregulation of gut-related immune function, including Mast Cell Activation Disorders. Formal research is lacking regarding the specific pathophysiology of how EDS affects Mast Cell Activation.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Autonomic Dysfunction – A Word on Gastrointestinal Symptoms
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/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 (See: http://www.ncbi.nlm.nih.gov/pubmed/11479407)
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Dysautonomia is Very Common in Ehlers-Danlos Syndrome
Presenter
Presentation Notes
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. (See: http://www.ncbi.nlm.nih.gov/pubmed/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 (See: http://www.ncbi.nlm.nih.gov/pubmed/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. (See: http://www.ncbi.nlm.nih.gov/pubmed/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. (See: http://www.ncbi.nlm.nih.gov/pubmed/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)
Gastrointestinal Complications of Ehlers-Danlos Syndrome
Clinical Recommendations
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Clinical Recommendations
Until specific research is available regarding the pathophysiology and effective diagnosis and treatment of gastrointestinal issues secondary to EDS, each recognized issue should each be addressed according to current standards in the hopes of improving the nutritional and immune status and thereby the overall health of affected EDS patients:
• structural / anatomic issues, dysmotility, or FGIDs • dysbiosis • malabsorption • gut-related immune dysregulation • dysautonomia
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Clinical Recommendations
Recognize structural disorders, gastrointestinal dysmotility, and FGIDs affecting digestion and address according to established clinical standards. Consider clearly and weigh carefully the recognized risks of rupture, abscess, stenosis, recurring perforation, hemorrhage, poor wound healing, etc., when considering surgery or invasive procedures (e.g. proctoscopy, flexible sigmoidoscopy, colonoscopy, manual disimpaction, and enemas), especially in CEDS and VEDS.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Clinical Recommendations
To address dysbiosis, consider: • using prebiotics.
– e.g., inulin, FOS, XOS, GOS, lactulose, chicory root, jerusalem artichoke, dandelion greens, garlic, leeks, onion, asparagus, bananas.
• using probiotics. – e.g. kefir, yogurt, miso, tempeh, kimchi, sauerkraut
• increasing intake of antioxidants and fiber. – fresh or raw greens and vegetables – ancient grains
buckwheat, amaranth, chia, millet, quinoa, sorghum, taro – beans, peas, chickpeas, lentils, nuts and almonds – certain fruits
• supplementing vitamin D and omega FAs. • In some cases, use of broad-spectrum antibiotics (e.g., Rifaximin) in
combination with multi-strain probiotics (e.g., VSL#3) is warranted. In the future, will profound or refractory dysbiosis in EDS be an accepted / approved clinical indication for fecal transplant?
Presenter
Presentation Notes
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 (See: http://www.bengmark.com/sites/default/files/110.%20Microbiota,%20immune%20%20....Pharmacological%20Research%202012.pdf) 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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Clinical Recommendations
To avoid dysbiosis, also consider: • avoiding refined carbohydrates. • limiting daily intake of fructose <25g/day. • eliminating sugar alcohols (e.g. xylitol, sorbitol). • eliminating artificial sweeteners (e.g., aspartame). • minimizing intake of saturated fats. • avoiding fried, grilled, and toasted food. • reducing intake of cured meat. • limiting alcohol consumption. • eliminating or minimizing casein, gluten, and zein. • eliminating polypharmacy where possible.
Presenter
Presentation Notes
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 (See: http://www.bengmark.com/sites/default/files/110.%20Microbiota,%20immune%20%20....Pharmacological%20Research%202012.pdf) 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.
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Clinical Recommendations
Determine and correct nutrient deficiencies caused by malabsorption.
• Consider specialized testing to identify deficits of micronutrients or deficits of nutrients not always accurately assessed with routine laboratory testing (e.g., magnesium).
Pursue parenteral repletion of nutrients for persons with EDS refractory to increased dietary intake or oral supplementation of deficient nutrients.
Presenter
Presentation Notes
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 (See: http://www.ncbi.nlm.nih.gov/pubmed/23227356, http://downloads.hindawi.com/journals/isrn.dermatology/2012/751768.pdf) “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.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Clinical Recommendations
Determine when patients will benefit from specialized diets. It is reasonable to advise persons with EDS who manifest symptoms concerning for gluten enteropathy to avoid gluten intake. It is reasonable to consider other exclusion diets, depending upon individual circumstances. For example:
• Dairy-free or Lactose-free • Low Fructose • Low Histamine or “Anti-Inflammatory” • No Nightshade Vegetables • Low FODMAP
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Clinical Recommendations
It is reasonable to offer a trial of mast cell mediator blocking agents to those persons with EDS who have symptoms concerning for nc-MCAS, regardless of whether they have elevated mediator levels on serum testing when symptomatic. Blocking agents include:
• quercetin – dietary intake vs. over-the-counter supplement
• type I and type II histamine blockers • cromolyn sodium and ketotifen • cysteinyl leukotriene receptor 1 blockers • 5-lipoxygenase inhibitor • aspirin • omalizumab • systemic or topical steroids
Presenter
Presentation Notes
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 carefully selected patients who tolerate NSAIDs and who have persistent flushing and elevated urinary 11a- 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]”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Clinical Recommendations
Strive to gain control over any dysautonomia so that a state of “Rest and Digest” is not continually suppressed by a state of “Fight or Flight.”
Gastrointestinal Complications of Ehlers-Danlos Syndrome: Sometimes Between a Rock and a Hard Place
Presenter
Presentation Notes
Image: http://cdn.trinixy.ru/pics2/20071108/podborka_192_59.jpg For those who feel they are between a rock and a hard place!
Gastrointestinal Complications of Ehlers-Danlos Syndrome
THE END
Presenter
Presentation Notes
Physiology: Digestion, nutrition, bowel function, and gut-related immune function are vital physiologic processes dependent upon the health of the alimentary canal.