Outline

Background

List of Related Symptoms/Syndromes

Nutritional Supplementation for HSDs and EDS

2005 List of Recommended Supplements (Mantle et al)

2015 List of Recommended Supplements (Castori et al)

Dr. Heidi Collins “EDS – You are NOT what you eat”

Functional Gastrointestinal Disorder Involvement

Hemorrhoids and Collagen – A Possible Connection

Background

In March 2017, in conjunction with the revised nosology relating to the Ehlers-Danlos syndromes (EDS) and Hypermobility Spectrum Disorders (HSD), the International Consortium published a paper on the relationship between EDS and gastrointestinal issues, “Gastrointestinal Involvement in the Ehlers-Danlos Syndromes,” by Fikree et al. This seems like a good place to start!

“Current literature suggests an association between all subtypes of EDS and GI symptoms. This association is common and has hitherto been underestimated. The group observed that evidence for GI symptoms to be included as a major diagnostic criteria is compelling. However, a causative relationship between abnormalities in connective tissue and GI symptoms has not yet been established.” (Fikree et al, 2017)

Gastrointestinal issues are a frequent part of EDS manifestations, but this side of the disease was not well recognized until recently. But, because they have not yet been able to prove the underlying cause of the various symptoms, they decided not to make them part of the new diagnostic criteria. In the abstract they highlight a few of the conditions specifically:

“Patients with EDS can present with both structural problems such as hiatus hernias, visceroptosis, rectoceles, and rectal prolapse as well as functional problems such as disordered gut motility. It has recently been demonstrated that patients with hypermobile EDS (hEDS) present with GI symptoms related to the fore and hind-gut and these patients frequently meet the criteria for functional gastrointestinal disorders such as functional dyspepsia an irritable bowel syndrome.” (Fikree et al, 2017)

It’s also worth mentioning that all the studies discussed in the article were performed using the OLD diagnostic criteria. This limits the applicability of the findings to the new EDS and hypermobility categories, on a basic statistical level, as the populations are now quite different. Patients who met the diagnostic criteria for joint hypermobility syndrome (JHS)/Ehlers-Danlos Hypermobility Type (EDS-HT) and therefore were included in the previous studies, may very well no longer meet to the criteria for hEDS, and consequently wouldn’t be included if the same studies were conducted today (see “Hypermobility – A History“). Therefore we can’t say that these issues don’t also apply to the newly defined HSD populations, or even otherwise asymptomatic patients with generalized joint hypermobility (GJH). Hopefully new studies will include various groups of patients, controls and asymptomatic JH, HSD, and EDS patients, stratified, to see how all of these issues affect patients across the entire hypermobility spectrum, not just the ones doctors view as the most extreme manifestation.

Fikree et al discuss the current research related to GI issues and EDS, and in the course of the article, they mention many related symptoms, which I list here.

  • Functional Gastrointestinal Disorders (FGID), including Irritable Bowel Syndrome (IBS)
  • bleeding or perforation
  • diverticulosis, diverticulitis, diverticular disease
  • rectoceles
  • prolapse
  • constipation
  • rectal evacuatory dysfunction
  • megacolon
  • hiatus hernia
  • lower urinary tract dysfunction
  • visceroptosis of the bowel
  • abnormal colonic transit
  • abnormal gastric emptying
  • nausea
  • diarrhea
  • abdominal pain
  • dyspepsia
  • gastroesophageal reflux disease (GERD)
  • alternating constipation and diarrhea
  • dysphagia, trouble swallowing
  • globus (lump in the throat feeling)
  • inflammatory bowel disease, celiac disease, ulcerative colitis
  • small bowel dysmotility
  • surgical complications and ruptures, particularly in vascular EDS

Unfortunately, just what to do in the presence of the symptoms in an EDS setting is not established.

“Specific evidence based management guidelines for the management of of GI symptoms in EDS patients do not exist and these patients are often treated symptomatically… Future studies are required to identify the mechanisms that lead to GI symptoms in patients with EDS and more specific treatment guidelines are required.” (Fikree et al, 2017)

“There are currently no well validated national or international management and care guidelines for the management of EDS-related GI symptoms. GI symptoms are normally managed using best practice models and evidence.” (Fikree et al, 2017)

This means that the symptoms need to be managed individually, with a team of specialized doctors, following the best practices for each symptoms. I discuss many of the associated conditions and recommendations in more detail below, but please keep in mind that this is not medical advice and if you suffer from any of the conditions, you should seek care from a qualified professional.

Nutritional Supplementation for HSDs and EDS

The 2017 article by Fikree et al references two earlier articles regarding nutritional supplementation in the setting of Ehlers-Danlos syndrome and Hypermobility Spectrum Disorders:

The general hypothesis from the first article is as follows:

“The novel aspect of this proposal is based on three principles: (i) the increasing scientific evidence that nutrition may be a major factor in the pathogenesis of many disorders once thought to result from the effects of defective genes alone; (ii) the recognition that many symptoms associated with Ehlers–Danlos syndrome are also characteristic of nutritional deficiencies; and (iii) the synergistic action within the body of appropriate combinations of nutritional supplements in promoting normal tissue function. We therefore hypothesize that the symptoms associated with Ehlers–Danlos syndrome outlined above may be successfully alleviated using a combination of specific (and potentially synergistic) nutritional supplements (in appropriate dosages)”

The rest of the article goes on to describe a variety of symptoms experienced by Ehlers-Danlos patients and the supplements that are known to help treat those particular symptoms. The supplements are charted by symptom in Table 1 of the article, shown below:

Table 1 Proposed treatment of Ehlers–Danlos syndrome symptoms with nutritional supplements 
Table 1 Proposed treatment of Ehlers-Danlos symptoms with traditional supplements

I list them here by supplement:

  • Glucosamine: 1500 mg/day
  • Vitamin C: 750 mg/day
  • MSM/silica: 1500 mg/3 mg/day
  • Calcium/vitamin K: 500 mg/35 µg/day
  • Magnesium: 200 mg/day
  • Carnitine: 250 mg/day
  • Coenzyme Q10: 100 mg/day
  • Pycnogenol: 80 mg/day
  • ϒ-linolenic acid: 240 mg/day

The second article, “Gastrointestinal and Nutritional Issues in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type,” is a much longer article about GI issues associated with EDS in general, but they discuss nutritional supplements in some detail. They focus on five areas where supplements may have come benefit: osteoarticular features, musculoskeletal pain, poor sleep quality and fatigue, skin and mucosal manifestations, and gastrointestinal manifestations. Their Table V is a list of recommended supplements, which I copy here:

Supplementation Quantity per dose No. doses/day Note
Prevention
Eicosapentaenoic and decosahexaenoic acid 3 g 1 Prevention of osteoarthritis and epithelial fragility
Glucosamine/ chodroitin/ hyaluronan 2 mg(/kg)/ 1.2 mg/ 75 mg 1 Prevention of osteoarthritis
Phytoflavonoids/ polyphenols 750 mg 2 Prevention of osteoarthritis and epithelial fragility
S-adenosylmethionine 500 mg 1 Prevention of osteoarthritis
Selenium/ manganese/ boron/ zinc 300 mcg/ 10 mg/ 8 mg/ 50 mg 1 Prevention of osteoarthritis
Undenatured collagen II 40 mg 1 Prevention of osteoarthritis
Vitamin C 250 mg 2 Prevention of osteoarthritis, and capillary and epithelial fragility
Vitamin D3 400-800 IU 1 Prevention of osteoarthritis and reduced bone mass
Vitamin E 200 IU 1 Prevention of osteoarthritis and epithelial fragility
Vitamin K2 1 mg 1 Prevention of osteoarthritis
ϒ-linolenic acid 1 g 1 Prevention of osteoarthritis
Treatment
Acetyl-L-carnitin 250 mg 1 Treatment of chronic fatigue; treatment of xerophthalmia
Co-enzyme Q10 100-400 mg 1 Treatment of chronic fatigue
Isotonic liquids 2-2.5 L – Treatment of fatigue; treatment of xerophthalmia
Magnesium oxide/ gluconate 400 mg/ 100 mg 1 Treatment of chronic/ neurogenic/ neuropathic pain
Melatonin 3–5 mg 1 (bedtime) Sleep regularization
Membrane phospholipids 2,000 mg 1 Treatment of chronic fatigue
NADH 35 mg 1 Treatment of chronic fatigue
Palmitoylethanolamide 300-600 mg 2 Treatment of chronic/ neuropathic pain
Probiotics 1–6 billion CFU 1 Treatment of irritable bowel syndrome (optimal pros vs. cons evaluation)
Thiamine/ pyridoxine/ cyanocobalamin 100 mg/ 100 mg/ 5 mg 1 Treatment of chronic/ neuropathic pain (i.e., improvement of analgesic effect of painkillers)
Vitamin A 0.8 mg 1 Treatment of dry eye (after careful clinical investigations, and exclusion of pregnancy status and planning)
Vitamin C 500–3,000 mg 1 Treatment of skin/ capillary/ mucosal fragility
Vitamin D3 880 IU 1 Treatment of reduced bone mass
α-ketoglucaric acid 880 IU 1 Treatment of reduced bone mass

But it is very important to recognize the limitations of these articles and of supplements themselves, and of course to never start a supplement regimen without consulting your doctor. As Castori et al note,

“All the following considerations should be considered low-level recommendations exclusively based on the authors’ experience and speculations.”

“Some dietary supplements are optimal for prevention of osteoarthritis and a few additional features, while others are best suitable for treatment of specific complaints, mostly including pain, fatigue and epithelial/vascular fragility. Listed dosages and recommendations may be used in the practice, but their applications need caution. All reported dosages are extracted from previous experimental works carried out within a discrete time window or from expert reviews. Therefore, all prescriptions should be always personalized considering patient’s age and co-morbidities, and their efficacy (and possible side-effects) should be periodically monitored by close follow-ups.”

There haven’t yet been any clinical trials reporting the how effective the proposed treatments are. To prove anything, Fikree et al (2017) note that,

“Further controlled studies are required to determine efficacy of the diet based interventions in patients with GI symptoms associated with hEDS.”

Supplement themselves have their own limitations. In the USA, many do not fall under the regulation of the FDA, so quality standards are limited. Not all supplements contain forms of the vitamins and minerals recommended that the body can easily process, digest, and put into use. Iron supplements are one known example. It may turn out that supplementing with pills isn’t the most effective treatment, but rather finding a diet which meets the recommendations is the best option, similar to the low FODMAP diet for irritable bowel syndrome. As yet, however, no such option exists. There is no “connective tissue diet.”

For more information about diets (including the low FODMAP diet) and supplements, I recommend a free online course offered through FutureLearn.com called Food as Medicine. I took the course in the spring of 2017 and found it quite informative. At this time, they run several courses per year. The course was developed by Monash University in Australia and has been certified by the Association for Nutrition and endorsed by the British Dietetic Association.

I also recommend watching Dr. Heidi Collins’ presentation “Diet and Supplementation for Persons with EDS” from the 2017 EDS Global Learning Conference, or you can check out the slides here: EDS – You are NOT what you eat.

Functional Gastrointestinal Involvement

The topic has 3 sections. First I address what function gastrointestinal disorders (FGIDs) are, second I discuss the medical literature relating FGIDs to hypermobility, and finally I discuss some treatment options recommended for FGIDs, particularly irritable bowel syndrome (IBS).

Functional Gastrointestinal Disorders – What are they?

The UNC Center for Functional GI & Motility Disorders offers an excellent summary of “What is a Function GI disorder?”

“Functional gastrointestinal disorders (FGIDs) are common disorders that are characterized by persistent and recurring GI symptoms. These occur as a result of abnormal functioning of the GI tract. They are not caused by structural (tumors or masses) or biochemical abnormalities. As a result, many routine medical tests attempting to diagnose an FGID — such as x-rays, CT scans, blood tests and endoscopic exams — can have essentially normal/negative (non-disease) results. More than 20 functional GI disorders have been identified. They can affect any part of the GI tract, including the esophagus, stomach, bile duct and/or intestines. The most common and best researched FGID is Irritable Bowel Syndrome (IBS) – abdominal pain associated with altered bowel habits of diarrhea, constipation or alternating between both. Other common FGIDs include functional dyspepsia (pain or discomfort in the upper abdominal area, feeling of fullness, bloating or nausea), functional vomiting, functional abdominal pain, and functional constipation or diarrhea.“

FGIDs are distinct from other gastrointestinal disorders and diseases, such as inflammatory bowel disease (IBD), Crohn’s disease, ulcerative colitis (UC), and celiac disease, all of which have other distinct causes that can be identified by clinical tests.

FGIDs and Hypermobility – A look at the medical literature

There are several medical journal articles outlining the relationship between hypermobility and functional gastrointestinal disorders.

The first worth examining is “Unexplained gastrointestinal symptoms and joint hypermobility: Is connective tissue the missing link?” by Zarate et al, published in 2009. For this study, they examined patients who were referred to a GI clinic and discovered that many exhibited signs of joint hypermobility.

“Almost half of the patients described had clinical evidence of JHM orBJHS and these tended to be those with thus far unidentified aetiology. This is in contrast to the general population JHM prevalence of 10–30%. It is of interest to note that many of the patients who were referred to our clinic were unaware of their hypermobile features. The patients in this series had a variety of symptoms (heartburn, vomiting, abdominal bloating and change in bowel habit, most frequently constipation) that may be suggestive of ‘sluggish’ GI tract biodynamics. Many had impaired propulsion of con-tents demonstrable on GI physiological investigations.”

Given the high rate of joint hypermobility in their FGID patients, they postulate that the nature of FGID might be related to connective tissue disorders and call for further research.

The next is an article published in April of 2015, which I could only find for free as an abstract, “Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study,” by Fikree et al. They found that “JHS is significantly associated with FGID, and this subgroup of patients have increased comorbidity and decreased QOL.”

The final article is a much longer article, “Gastrointestinal and Nutritional Issues in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type” by Castori et al, also published in 2015. In this article they do reviewed the literature related to EDS and gastrointestinal involvement, and have a very detailed tables explaining the results of those studies. Related to functional manifestations in JHS/EDS-HT, they write,

“(1) Collectively, the rate of functional GI symptoms is high, increases with age and ranges from 1/3 to 3/4 of the patients. Although GI manifestations are still not included in the available clinical criteria for JHS/EDS-HT, their frequency and related impact on quality of life suggest consideration of GI involvement as a major feature of this condition.

“2) In JHS/EDS-HT, functional GI features span from mouth to anus and mainly includes dysphagia, gastroesophageal reflux, dyspepsia, irritable bowel disease, and chronic constipation. The typical adult patient presents with multiple, variably combined symptoms, while (isolated) chronic constipation is the most common manifestation in children.

“3) Functional tests, including esophageal manometry, 24 hr pH-me-try, gastric emptying study, small bowel manometry, and colorectal transity study, often lead to positive results but should be considered second-line investigations and performed in highly specialized settings, preferably by professionals with experience on JHS/EDS-HT. Swallowing studies could be also considered in patients with upper GI complaints but evidence is still lacking.

“4) First-line investigations, such as upper GI endoscopy, could be performed safely, but usually lead to negative or inconsistent results. Colonoscopy should be performed with care due to a possibly increased risk of mucosal bleeding. Colonic redundancy, ptosis and/or hypermobility may be further limitations to colonoscopy.

“5) Treatment of functional GI complaints in JHS/EDS-HT is problematic due to the absence of tailored strategies and an apparent resistance to pharmacologic treatments at standard dosages/regimens. The exclusion of common co-morbidities, such as celiac disease, lactose intolerance, and Helico-bacter pylori infection, is reasonable at first examination.

“6) Due to the lack of efficacious treatments and the absence of known precipitating triggers (perhaps, except for inadequate surgical treatment of internal and pelvic organ prolapse(s) as well as traumatic deliveries), patients’ education, also comprising diet and nutritional advice, seems at the moment the most effective management tool.”

Which brings us nicely to the next section, managing FGIDS.

FGIDs – Treatments

As mentioned earlier in the page, there aren’t any management protocols established specifically for EDS patients, but symptoms can be managed individually based on the best known practices for each. As the practices relate to EDS, a good place to start is back in “Gastrointestinal Involvement in the Ehlers-Danlos Syndromes,” by Fikree et al.

“In the author’s own clinical practice, low FODMAP (Fructose, Oligosaccharides, Disaccharides, Monoamines, and Polyols) diet is frequently used to good effect for abdominal bloating, pain, and diarrhea, these features often overlap with irritable bowel syndrome (IBS) where the efficacy of this diet is now well established.”

The low FODMAP diet was developed by Monash University Department of Gastroenterology to

“control gastrointestinal symptoms associated with IBS/FGID focusing on a group of carbohydrates called FODMAPs. Current research strongly suggests that this group of carbohydrates contributes to IBS/FGID symptoms.”

For more information about the diet, it’s best to go to their website and read their materials directly. They have even developed an app with lots of information about FODMAPs, which foods to avoid, recipes, and so on. The app is not free, but it does have a lot of information, and I feel like I’ve gotten my money’s worth. What’s really important to keep in mind, though, is that they strongly recommend not just trying to diet on your own, but doing it with the help of a doctor/dietician. They emphasize that if you are experiencing these symptoms it is important not to self diagnose, in case your symptoms are being caused by something more life-threatening.

Another approach for treating FGID could be through the use of pre- and probiotics. In the article “Gastrointestinal and Nutritional Issues in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type” by Castori et al, they write,

“Among the various dietary supplementations with potential effects, probiotics and prebiotics are the sole for which experimental studies have been published, mostly in irritable bowel syndrome. Recent reviews of the literature [e.g., Whelan, 2011; Whelan and Quigley, 2013] indicate that, in irritable bowel syndrome, probiotics result effective in not all studies and that its effectiveness is mostly related to single symptoms rather than the entire GI phenotype.

“In addition, variability in the outcome is influenced by many factors, including microbiological characteristics of probiotics and “quality”of the industrial product used in the study. Therefore, the level of evidence for the efficacy of probiotics in functional GI disorders is still low and needs further refinement.

“In consideration of the presumed beneficial effect of probiotics on joint health (see above), after careful assessment of the GI status—Especially in symptomatic patients -, regular intake of prebiotics and probiotics (e.g., 1–6 billion CFU/day) may be considered in JHS/EDS-HT.”

Essentially, not all prebiotics and probiotics are created equal, but they have been shown to relieve symptoms in some cases. For more information on the limitations of nutritional supplements, please refer to the Nutritional Supplementation for HSDs and EDS section.

Hemorrhoids and Collagen – A Possible Connection

Not mentioned in any of the 2017 literature, at least, not where I could find, was the potential connection between hemorrhoids and the Ehlers-Danlos syndromes and possibly Hypermobility Spectrum Disorders as well.

The earliest reference I can find that potentially links hemorrhoids and connective tissue dysfunction is an article from 2010 called Haemorrhoids – a collagen disease? by Willis et al. I haven’t been able to find the full article for free anywhere, but the abstract contains a lot of information:

“Epidemiological data and histopathological findings support the hypothesis that reduced connective stability is associate with the incidence of haemorrhoids… Patients with haemorrhoids had a significantly reduced collagen/protein ration… and a significantly reduced collagen I/III ratio… There is a fundamental disorder of collagen metabolism in patients with haemorrhoidal disease.” (Willis et al)

The next relevant article I could find was case study published in 2014, Ehlers-Danlos Syndrome – Hypermobility Type and Hemorrhoids by Plackett et al. They write,

“Ehlers-Danlos syndrome (EDS) is a heterogenous group of connective tissue disorders caused by a deficiency in collagen synthesis and processing… Although hemorrhoids have not been thought of as one of the traditional gastrointestinal manifestations, we present a case that suggests it should be considered as one.” (Plackett et al)

This makes sense, because if hemorrhoids are caused by errant collagen, and EDS is also due to errant collagen, it seems likely that they would have some sort of relationship. We should also keep in mind when reading this article that it was written before the nosological reform in 2017:

“Rheumatology found the patient to meet the criteria for both benign joint hypermobility syndrome and EDS-HT.” (Plackett et al)

Based on the information given and symptoms described in the article, it is impossible to know if the case patient would even meet the new stricter criteria for hEDS or whether she would fall into the HSD category instead. The conclude,

“An association between EDS and anorectal prolapse has also been previously described. In particular there is an association between EDS and rectal prolapse which has been described in a few small cases series and case reports. We believe hemorrhoids may be another associated condition with EDS.“

They call for further research to understand the links between the two, and caution that  connective tissue disorder complications (such as tissue fragility) should be taken into consideration when treating hemorrhoids surgically.

The final related article is Abnormalities in collagen composition may contribute to the pathogenesis of hemorrhoids: morphometric analysis, by Nasseri et al, published later in 2014. They don’t focus on Ehlers-Danlos specifically, although the potential links to connective tissue disorders are mentioned, but I include it in this discussion because I thought they did a nice job discussion what collagen is:

“Collagen is the major insoluble fibrous protein in the extracellular matrix and connective tissue and is the single most abundant protein in the animal kingdom. While there are at least 16 types of collagen, 80-90% of the collagen in the body consists of types I, II, and III. Type I collagen fibers have immense tensile strength and can withstand enormous forces, while type III collagen are thinner and more immature. The strength and quality of connective tissue is primarily determined by the amount and ratio of collagens Type I and III. Decreased Type I to III collagen ratio translates into decreased amount of cross-linking and hence, reduced mechanical stability of connective tissue.” (Nasseri et al)

They write that,

“Our data clearly indicated a decrease in Type I/III collagen ratio in patients with hemorrhoidal disease as compare to normal studies.” (Naserri et al)

This means something is absolutely going on in the collagen of patients with hemorrhoids. Two separate studies demonstrate it. It doesn’t mean they’ve found the exact cause of and cure for hemorrhoids, but it adds to the body of knowledge.

Finally, in relation to connective tissue disorders, they say,

“The previously held belief that connective tissue disease directly correlates with hernias and genitourinary prolapse may also hold true with hemorrhoidal disease… These findings support our hypothesis that genetic and hereditary factors may lead to reduced quality collagen and thus an earlier onset of hemorrhoidal disease. Within this study, we did not focus on collagen-vascular disorders such as Ehlers-Danlos or osteogenesis imperfecta and the belief that these disorders have a higher propensity to develop hemorrhoidal disease remains a subject of future investigation.”

They definitely think there is a link between hemorrhoids and connective tissue disorders then, but stop short of making any definitive claims regarding particular connective tissue syndromes.

Sources

Castori M, Morlino S, Pascolini G, Blundo C, Grammatico P. 2015. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type. Am J Med Genet Part C 169C:54–75.

Fikree, A., Aktar, R., Grahame, R., Hakim, A. J., Morris, J. K., Knowles, C. H. and Aziz, Q. (2015), Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case–control study. Neurogastroenterol. Motil., 27: 569–579. doi:10.1111/nmo.12535

Fikree A, Chelimsky G, Collins H, Kovacic K, Aziz Q. 2017. Gastrointestinal involvement in the Ehlers–Danlos syndromes. Am J Med Genet Part C Semin Med Genet 175C:181–187.

Mantle D, Wilkins RM, Preedy V. A novel therapeutic strategy for Ehlers-Dantos syndrome based on nutritional supplements. Medical Hypotheses 64(2): 279-83. February 2005. DOI: 10.1016/j.mehy.2004.07.023.

Nasseri YY, Krott E, Van Groningen KM, et al. Abnormalities in collagen composition may contribute to the pathogenesis of hemorrhoids: morphometric analysis. Techniques in Coloproctology. 2015;19:83-87. doi:10.1007/s10151-014-1238-5.

Plackett TP, Kwon E, Gagliano RA, Oh RC. Ehlers-Danlos Syndrome—Hypermobility Type and Hemorrhoids. Case Reports in Surgery. 2014;2014:171803. doi:10.1155/2014/171803.

Willis S, Junge K, Ebrahimi R, Prescher A, Schumpelick V. Haemorrhoids – a collagen disease? Colorectal Dis. 2010 Dec;12(12):1249-53. doi: 10.1111/j.1463-1318.2009.02010.x.

Zarate N, Farmer AD, Grahame R, MohammedSD, Knowles CH, Scott SM, Aziz Q. 2009. Unexplained gastrointestinal symptoms and joint hypermobility: Is connective tissue the missing link? Neurogastroenterol Motil 22:e78.