Mast cells in the GI tract: How many is too many? (Part Two)

As I mentioned in the previous post, a 2006 paper counted mast cells in the duodenum (part of the small intestine) and colon of patients with treatment resistant chronic diarrhea and compared these counts to patients with known inflammatory GI diseases and to asymptomatic healthy controls.  This paper posited that cell counts over 20 mast cells/hpf represented a distinct phenomenon called mastocytic enterocolitis.  The author felt that mastocytic enterocolitis was distinct from inflammation caused by other GI diseases, such as Crohn’s colitis, ulcerative colitis and celiac disease.

In this paper, the counts for asymptomatic controls ranged from 3-20 cells/hpf and the counts for known inflammatory GI disease ranged from 2-18 mast cells/hpf.  Patients with chronic diarrhea that resisted treatment demonstrated counts ranging from 13-35 mast cells/hpf.  Mast cells were identified by using an antibody to tryptase.

70% of patients with chronic diarrhea without a known cause had over 20 mast cells/hpf. Cells were counted in 10 hpf and averaged.  Counting in multiple fields and averaging generally gives more representative counts. Based upon this study, it was reasonable to assume that mast cells over 20/hpf was higher than normal. See Table 4 for details.

Table 4: Mast cell counts in duodenum and colon of chronic diarrhea patients (Jakate 2006)
Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase (IHC)
Sample type Study group: Intractible chronic diarrhea Control group A: Inflammatory GI disease that causes chronic diarrhea (ie. Crohn’s colitis, ulcerative colitis, gluten sensitive enteropathy) Control group B: Asymptomatic, healthy controls
Duodenum and colon (counts averaged) Average Range Average Range Average Range
25.7 mast cells/hpf 13-35 mast cells/hpf 12.4 mast cells/hpf 2-18 mast cells/hpf 13.3 mast cells/hpf 3-20 mast cells/hpf

 

In a 2012 paper by Akhavein, the stomach, small intestine and colon of patients with a history of atopic/allergic disease were biopsied.  Mast cells were identified using an antibody to CD117, the CKIT receptor found on the surface of all mast cells. The cells were counted in only 1 hpf.

This paper found that the average mast cell count for biopsies from all organs was 37/hpf.  The author posited that given that these patients had a history of allergic conditions, that a count of over 40/hpf described a phenomenon called allergic mastocytic gastroenteritis that was distinct from the previous described mastocytic enterocolitis.  Cells were scattered and not clustered. There was no control group in this study.  See Table 5 and Table 6 for details.

Table 5: Mast cell count in small intestine of patients with GI pain and dysmotility and a history of allergic disease
Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.
Microscopy method: Magnification not explicitly stated, assumed 400x, mast cells counted in 1 hpf
Visualization: CD117 (IHC)
Sample type Study group: atopic/allergic history with abdominal pain and GI dysmotility Control group A:

No control group

Control group B:

No control group

Small intestine Average Range Average Range Average Range
57 mast cells/hpf 30-90 mast cells/hpf N/A N/A N/A N/A
Diffuse scattered cells, no clusters.

 

Table 6: Mast cell count in colon of patients with GI pain and dysmotility and a history of allergic disease
Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.
Microscopy method: Magnification not explicitly stated, assumed 400x, mast cells counted in 1 hpf
Visualization: CD117 (IHC)
Sample type Study group: Diarrhea predominant IBS Control group A:

Healthy controls

Control group B:

No control group

Colon Average Range Average Range Average Range
37 mast cells/hpf 1-69 mast cells/hpf N/A N/A N/A N/A
Diffuse scattered cells, no clusters.

 

A 2013 paper quantified mast cells in patients with diarrhea predominant irritable bowel syndrome and compared to healthy controls. The patients averaged 26.2 mast cells/hpf in the jejunum, part of the small intestine, while the controls averaged 17.2. Mast cells were identified using an antibody to CD117, the CKIT receptor found on the surface of all mast cells. The cells were likely counted in only 1 hpf as it was not explicitly stated. Distribution of mast cells was not described. See table 7 for details.

 

Table 7: Mast cell count in small intestine of patients diarrhea predominant irritable bowel syndrome
Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168.
Microscopy method: Magnification not explicitly stated, assumed 400x, number of hpf not explicitly stated, assumed mast cells counted in 1 hpf
Visualization: CD117 (IHC)
Sample type Study group: Diarrhea predominant IBS Control group A:

Healthy controls

Control group B:

No control group

Jejunum Average Range Average Range Average Range
26.2 ± 11.1 mast cells/hpf N/A 17.2 ± 8.8 mast cells/hpf N/A N/A N/A
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

 

Mast cells in the GI tract: How many is too many? (Part One)

Let’s have a chat about the idea that 20 mast cells/hpf (high powered field) in gastrointestinal biopsy is higher than normal.

First, let’s review a few things.

The WHO diagnostic criteria for systemic mastocytosis are as follows:

Table 1: World Health Organization Criteria for Systemic Mastocytosis (2008)
  • Systemic mastocytosis is diagnosed in the presence of: 1 major and 1 minor criterion; or 3 minor criteria.
  • Biopsy specimens can be from any non-cutaneous organ (any organ that is not the skin).
Major criterion:
Multifocal, dense aggregates of mast cells (15 or more) detected in sections of bone marrow and confirmed by tryptase immunohistochemistry or other special stains:
Minor criterion:
1.       In biopsy section, more than 25% of mast cells in the infiltrate have atypical morphology, or, of all the mast cells in the smear, more than 25% are immature or atypical. (25% of the mast cells are shaped wrong.)
2.       Mast cells co-express CD117 with CD25 and/or CD2. (Mast cells show markers CD25 or CD2 on their outsides.)
3.       Detection of KIT point mutation at codon 816 in bone marrow, blood or other extracutaneous organs. (Positive for the CKIT D816V mutation.)
4.       Serum total tryptase persistently >20 ng/ml (not a valid criteria in cases of systemic mastocytosis with associated clonal non-hematologic mast-cell lineage disease). (Baseline serum tryptase over 20 ng/ml – baseline, not reaction.)

 

There are several different diagnostic algorithms floating around for mast cell activation syndrome (MCAS).  They are summarized here:

Table 2: Diagnostic algorithms for  mast cell activation syndrome (MCAS, also called mast cell activation disorder, MCAD)
  • Biopsy specimens can be from any non-cutaneous organ (any organ that is not the skin).
Molderings, Afrin 2011 Akin, Valent, Metcalfe 2010 Valent, Akin, Castells, Escribano, Metcalfe et al 2012
MCAD (mast cell activation disease, an  umbrella term including both MCAS and SM) is diagnosed if both major criteria, or one major criterion and one minor criterion, are present; following bone marrow biopsy, diagnosis is narrowed down to either SM or MCAS MCAS diagnosed if all criteria are met MCAS diagnosed if all criteria are met
Major Criteria
Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained) Episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems evidenced as follows:

  • Skin: urticaria, angioedema, flushing
  • Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping
  • Cardiovascular: hypotensive syncope or near syncope, tachycardia
  • Respiratory: wheezing
  • Naso-ocular: conjunctival injection, pruritus, nasal stuffiness
Typical clinical symptoms
Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom) A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1– and H2-histamine receptor inverse agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizers (cromolyn sodium) Increase in serum total tryptase by at least 20% above baseline plus 2 ng/ml during or within 4 h after a symptomatic period
  Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on ≥2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-β-prostaglandin F2. Response of clinical symptoms to histamine receptor blockers or MC-targeting agents e.g. cromolyn
  Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities
Minor Criteria
Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies
Mast cells in bone marrow express CD2 and/or CD25
Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved
Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

  • Tryptase in blood
  • N-methylhistamine in urine
  • Heparin in blood
  • Chromogranin A in blood
  • Other mast cell specific mediators (leukotrienes, PGD2)

 

Additionally, a questionnaire (found here: http://www.wjgnet.com/2218-6204/abstract/v3/i1/1.htm) designed to assess the likelihood of mast cell activation disease (MCAS or SM) in a patient was published in 2014 by Lawrence Afrin.  It assigns numerical values to various findings, such as mediator elevation, symptoms, clinical findings, and biopsy features.

The criteria for systemic mastocytosis can be met with a gastrointestinal biopsy showing the features listed above in Table 1.  So if you have gastrointestinal scopes and your biopsy shows mast cells with the features listed in Table 1, then that contributes to receiving a diagnosis of SM.  If you meet some of the criteria but not all of them, with a GI biopsy or otherwise, then you receive a diagnosis of monoclonal mast cell activation syndrome (MMAS), which is like a pre-SM.

A common adage in the mast cell community is that having 20 or more mast cells in a high powered field (hpf, what you see when you look through a microscope with high magnification) is diagnostic for mast cell activation syndrome.

In 2006, a paper was published called “Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.” This paper detailed a study that quantified the mast cells in biopsies of duodenum (small intestine) and colon in patients with chronic diarrhea that resisted treatment. These counts were then compared to patients who had other conditions that caused chronic diarrhea, and to some control subjects that had no GI symptoms.

Table 3: Average mast cell count per hpf in colon and duodenum (Jakate 2006)
Group Average mast cell count in colon and duodenum
Healthy control group 13.3 ± 3.5
Inflammatory GI disease control group 12.4 ± 2.3
Intractible chronic diarrhea group 25.7 ± 4.5

 

The average mast cell count in the healthy control group was 13.3/hpf.  (See Table 3 for details.) Two standard deviations from this value is approximately 20/hpf.  Two standard deviations (SD) is a statistical mechanism that allows for variation in the patient, sample or test procedure.  It is common to round to an even number.

The patients in this group were not evaluated for typical mast cell symptoms.  No information is provided regarding history of allergic or atopic disease. This paper is the origin of the idea that more than 20 mast cells/hpf in the gastrointestinal tract is considered higher than normal.

 

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

 

 

 

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Five)

HEDS patients showed overactivity of sympathetic nervous system (part of autonomic nervous system) at risk.  Conversely, when presented with a trigger that should activate the sympathetic nervous system, they show a lower response than they should.  In response to Valsalva maneuvers, their blood pressure dropped more than it should. In tilt table testing, the diastolic blood pressure increases less than it should.  Hypermobility was associated with worsened dysautonomic symptoms.  POTS is the most common subtype of dysautonomia found in HEDS patients.

Dysfunction of sympathetic nervous system is common in HEDS.  Laxity of connective tissue and use of medications that affect blood vessels aggrevate dysautonomia. Autonomic dysfunction in HEDS patients is associated with poor disease prognosis, decreased quality of life, unstable blood pressure, increased risk of cardiac disease and death as a result of it, particularly under anesthesia.

Deconditioning has a complicated relationship to orthostatic intolerance and dysautonomia.  Deconditioning lowers blood volume and alters response to adrenalin, contributing to orthostatic symptoms.

However, a study on the relationship between HEDS and dysautonomia found that decreased physical activity was not linked to worsened orthostatic symptoms.  As a result, it is thought that deconditioning in this group is probably not the primary cause of orthostatic intolerance, but a secondary contributor.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Four)

The relationship between Ehlers Danlos Syndrome and dysautonomia, the dysfunction of autonomic nervous system, is currently being elucidated.  There is a correlation between hypermobility and autonomic symptoms. One study found that in patients with autonomic dysfunction, 18% had EDS, compared to the control group, in which only 4% had EDS.

Ehlers Danlos Syndrome alters collagen structure throughout the body. In HEDS, this usually affects the skin less than in other types of EDS.  In the cardiovascular system, this contributes to vascular laxity, which allows excessive dilation of the blood vessels, causing orthostatic intolerance. Importantly, you do not see the spontaneous rupture of blood vessels seen in VEDS.

In HEDS, connective tissue defects in the GI tract lead to dysfunctional peristalsis (contraction of GI tract to move food through it), excessive stretching or swelling, dysregulation of intestinal permeability and damage to the epithelial cells of the GI tract. Without proper connective tissue support, the bladder can become distended or impinge on other structures, as in cystocele.  HEDS frequently causes weakness in the pelvic floor and can lead to prolapse of pelvic organs.

Pain and fatigue are often attributed to dysautonomia in EDS patients, but it could also be caused by HEDS. Peripheral neuropathy is prevalent in HEDS and can drive pain in this population.  Many HEDS patients have sensory pain, such as tingling, pins and needles, numbness, radiating or burning pain. If the autonomic nervous system is responsible for the pain signals, it could provide a link between dysautonomia and pain. Chronic pain and inflammation can change the structure and behavior of the nervous system, making it easier to transmit pain signals.  Orthostatic intolerance can activate the sympathetic nervous system, part of the autonomic nervous system, contributing to these types of symptoms.

By contrast, many HEDS patients are known to frequently have anxiety, palpitations, dizziness, shortness of breath and high affective distress.  Rather than being from HEDS directly, these are likely from dysautonomia.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Three)

Autonomic dysfunction can present in many ways.  Patients complained of orthostatic symptoms like fatigue, difficulty concentrating, brain fog, chest pain, palpitations, headache, visual disturbances, shortness of breath and feeling “absent.” Common GI symptoms were early satiety, bloating, nausea and vomiting (particularly after a meal), colonic spasms, constipation and diarrhea.  Sweating too much or too little and dry eyes and mouth were reported.  Raynaud’s phenomenon and purple limbs upon standing affected many HEDS patients.  Sensitivity to light and difficulty focusing vision occurred due to dysregulation of pupils. Urine retention, failure to empty bladder while urinating, and incontinence of urine were also common.

Some symptoms were strongly associated with others.  Fatigue and difficulty in concentrating was most often seen in association with symptoms that affected blood vessels changing size, symptoms that affected secretion by glands, and GI or sleep symptoms.  An overall large burden of autonomic symptoms was also seen in patients with fatigue and difficulty concentration.  Greater concentration difficulties also correlated with worse orthostatic symptoms, bladder symptoms, gastroparesis, dysregulation of pupil motion and an overall large burden of autonomic symptoms.

Many autonomic symptoms (but not those affecting motion of blood vessels or fainting) were correlated to neuropathic pain.  Orthostatic, GI, bladder, pupil and gland secretion symptoms, sleep dysfunction, and overall high autonomic burden were linked to pain severity. Tachycardia when upright and dysautonomia generally were related to severity of pain.

Dysautonomia symptoms were often seen in HEDS, particularly orthostatic and GI symptoms.  Dysautonomia symptoms greatly impacted quality of life and were associated with more fatigue and pain. Dysautonomia was much worse in HEDS than in CEDS, VEDS or fibromyalgia. In particular, orthostatic intolerance dramatically affected quality f life.  The physical limitations observed in POTS patients, the most common form of orthostatic intolerance for HEDS patients, were comparable to those seen in people with congestive heart failure or COPD.  These symptoms contribute to the lower quality of life seen in HEDS patients when compared to other EDS patients.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Two)

The Autonomic Symptom Profile (ASP) is a questionnaire that assesses symptoms in functional areas controlled by the autonomic nervous system.  The autonomic nervous system regulates many involuntary functions, such as heart rate, blood pressure, urination and digestion.  Dysfunction of the autonomic nervous system can affect many organ systems.

One study evaluated Ehlers Danlos patients for autonomic symptoms using the ASP.  The patients in this study had classic Ehlers Danlos (cEDS), vascular Ehlers Danlos (vEDS) or hypermobility type Ehlers Danlos (HEDS).  Symptom burden was compared among these different presentations of EDS and to healthy controls.

Patients with HEDS had the highest total burden of autonomic symptoms among EDS patients.  All EDS patients had more autonomic symptoms than healthy controls.  HEDS caused more orthostatic symptoms (symptoms that happen when standing up) than in other EDS forms.  94% of HEDS patients had orthostatic symptoms, including lightheadedness, dizziness, palpitations, nausea, blurred vision and anxiety.  Though many patients said they often “felt faint”, true fainting was not common.  These symptoms could be provoked or worsened with physical activity, heat, meals, or change in position.

Patients with HEDS also had the highest burden of GI symptoms compared to other types of EDS.  73% had gastroparesis, 66% had chronic constipation, and 64% had regular diarrhea.  Diarrhea was found to be the most impairing GI symptom.

HEDS patients had a larger impact of orthostatic symptoms and bladder dysfunction than either CEDS or VEDS.  Compared to just CEDS, HEDS showed more GI, secretomotor (release of fluid by glands) and pupillomotor (motion of pupil) symptoms.  Compared to just VEDS, HEDS patients had more vasomotor burden (symptoms related to the dilation of blood vessels).  HEDS autonomic burden was similar to those seen in fibromyalgia patients, with more bladder dysfunction and less sleep dysfunction.

Higher autonomic symptom burden was associated with more physical impairment, pain and decreased vitality.  More hypermobility was associated with higher burden of orthostatic symptoms, GI symptoms generally, gastroparesis, diarrhea, vasomotor symptoms and overall autonomic symptom burden.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part One)

Ehlers Danlos Syndrome (EDS) is a heritable connective tissue disease with six major subtypes. EDS occurs in approximately 1/5000 births.  Classical EDS (cEDS) and hypermobility type EDS (HEDS or ht-EDS) are the most common forms, with approximately 90% of patients having one of these types.  Vascular EDS (vEDS) affects about 5% of EDS patients.  The remaining types are rare. Generally, EDS patients demonstrate hypermobility of joints, excessive stretchiness of the skin (hyperextensibility) and fragility of soft tissues.

Ehlers Danlos is diagnosed by clinical evaluation and diagnostic testing.  Mutations affecting structure of collagen, a key component of connective tissue, have been identified for cEDS and vEDS.  For hypermobility type EDS, no consistent genetic anomality has been found.  As a result, diagnosis of this subtype relies upon patient history and clinical examination.

The Beighton scale is a nine point scale for evaluating hypermobility.  One point is granted for each: elbow hyperextended more than 10°, knee hyperextended more than 10°, thumb that can be touched to the forearm, and fifth finger that can be passively bent back more than 90°.  One further point is granted for being able to place the palms flat on the floor with knees fully extended.  A score of 5 points or more is suggestive of joint hypermobility, a major criterion for diagnosis of HEDS.

In addition to an appropriate Beighton score, soft skin with normal or slight hyperextensibility and absence of significant soft tissue abnormalities are also important for HEDS diagnosis.  Excessive skin hyperextensibility and serious fragility of connective tissue could be indicative of other forms of EDS.

Hypermobility type EDS was regarded for many years as a benign laxity of the joints.  In recent years, this position has been debunked, though this belief still persists for many medical providers. Hypermobility and musculoskeletal pain were previously recognized as the dominant manifestations, but we now know that HEDS can cause cardiovascular, gastrointestinal, genitourinary and neurologic symptoms, among others.  In fact, the aspects of this disease that aren’t musculoskeletal are the most disabling and are correlated with lower quality of life

Symptoms arising from dysfunction of the autonomic nervous system have serious impact on quality of life as demonstrated in a number of conditions, including chronic fatigue syndrome and fibromyalgia.  Autonomic dysfunction can be assessed with an Autonomic Symptom Profile (ASP), a questionnaire of 169 questions that evaluates symptoms in eight broad categories: orthostatic (upright posture), secretomotor (secretion of substances by glands), urinary, GI, pupillomotor (movement of the pupil), vasomotor (changing diameter of blood vessels), reflex syncope (dysfunction of blood pressure and heart rate) and sleep function. These functions are all controlled by the autonomic nervous system.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Explain the tests: Complete blood count (CBC) – Red cell indices (Part 4)

A number of red blood cell tests are performed together in a complete blood count (CBC).  These tests  (called red cell indices) are assessed together to point to specific causes of red blood cell dysfunction.  These tests include:

Red blood count: The count of all red blood cells in a volume of blood

  • Adult women: 3.9-5.0 million cells/µL
  • Adult men: 4.3-5.7 million cells/µL
  • Please refer to previous posts for detailed discussion of causes of low and high RBC.

Hemoglobin (Hb): The amount of hemoglobin in a volume of blood

  • Adult women: 12.0-15.5 grams/dL
  • Adult men: 12.5-17.5 grams/dL
  • Hemoglobin constitutes about 95% of the mass of a red blood cell.
  • Hemoglobin binds oxygen so that red cells can carry them through the blood into the tissues.
  • Common causes of low hemoglobin include vitamin or mineral deficiency, chronic inflammation, autoimmune disease, hemoglobinopathies, thalassemia, GI bleeding, surgery and blood loss.
  • Common causes of high hemoglobin include lung disease, neoplastic conditions including cancers, and dehydration.
  • If red blood cell count and hematocrit are low, usually hemoglobin is low, too. If red blood cell count and hematocrit are high, usually hemoglobin is high, too.
  • Even if red blood cell count is normal, low hemoglobin will cause symptomatic anemia.
  • Anemia is a decreased ability to carry oxygen from lungs to tissues.

Hematocrit (HCT): The portion of a volume of blood that is red blood cells

  • Adult women: 34.0-44.5%
  • Adult men: 38.8-50.0%
  • Equal to (red blood cell count)/(volume of blood measured)
  • Used to assess severity of blood loss.
  • Common causes of low hemoglobin include vitamin or mineral deficiency, chronic inflammation, autoimmune disease, hemoglobinopathies, thalassemia, GI bleeding, surgery and blood loss.
  • Common causes of high hemoglobin include lung disease, neoplastic conditions including cancers, and dehydration.
  • If red blood cell count and hemoglobin are low, usually hematocrit is low, too. If red blood cell count and hemoglobin are high, usually hematocrit is high, too.

Definitions:

  • Microcytic anemia: low MCV
  • Normocytic anemia: normal MCV
  • Macrocytic anemia: high MCV
  • Hypochromic anemia: low MCH
  • Normochromic anemia: normal MCH
  • Hyperchromic anemia: high MCH

Mean corpuscular volume (MCV): Identifies if red cells are the right size

  • 80-96 fL/cell
  • Equal to (hematocrit)/(red blood cell count)
  • The size of red cells tells you what causes anemia.
  • Low MCV with low red cell count and low hemoglobin indicates microcytic anemia.
  • Common causes of microcytic anemia (low MCV) include iron deficiency, blood loss, anemia of chronic inflammation, sideroblastic anemia, thalassemia, pyridoxine deficiency and lead poisoning.
  • High MCV with low red cell count and low hemoglobin indicates macrocytic anemia.
  • Common causes of macrocytic anemia (high MCV) include megaloblastic anemia, alcoholism, COPD, hypothyroidism, MDS, liver disease and deficiency of vitamin B12 and/or folate.

Mean corpuscular hemoglobin (MCH): The average hemoglobin in a red blood cell in a volume of blood

  • 5-33.2 pg/cell
  • Equal to (hemoglobin)/(red blood cell count)
  • MCH usually mirrors MCV. If MCV is low, MCH is usually low.  If MCV is high, MCH is usually high.
  • Common causes of low MCH include iron deficiency, blood loss, anemia of chronic inflammation, sideroblastic anemia, thalassemia, pyridoxine deficiency and lead poisoning.
  • Common causes of high MCH include megaloblastic anemia, alcoholism, COPD, hypothyroidism, MDS, liver disease and deficiency of vitamin B12 and/or folate.

Mean corpuscular hemoglobin concentration (MCHC): Determines size of red cells

  • 4-35.5 g/dL
  • Equal to (hemoglobin)/(hematocrit)
  • Low MCHC is associated with hypochromic (“too little color”) anemia. Cells with less hemoglobin have less intense red color.  Patients with hypochromic anemia often have a green tinge to their skin.
  • MCHC is usually low in microcytic anemia.
  • MCHC is sometimes normal in some macrocytic anemias. This is called normochromic anemia (“normal color”).
  • Common causes of low MCHC include thalassemia, vitamin B6 deficiency, lead poisoning, Faber’s syndrome, GI bleeding and iron deficiency.
  • Common causes of normal MCHC in the presence of anemia (normocytic anemia) include anemia of chronic inflammation, aplastic anemia, blood loss, hemolysis, and deficiency of vitamins B2 or B6.
  • High MCHC is associated with hyperchromic (“too much color”) anemia.
  • Common causes of high MCHC include sickle cell disease, hereditary spherocytosis, autoimmune hemolytic anemia and hemoglobin C disease.

Red blood cell distribution width (RDW): The amount of variation in the size of red cells

  • 5-14.5%
  • RDW is normal or high. A “low” RDW should be read as normal.
  • RDW helps to identify the cause of anemia.
  • A high RDW indicates that there are large amounts of both new and mature red cells.
  • Variation in size of red cells is called anisocytosis.
  • Common causes of high RDW include

Reticulocyte count: The amount of new red cells in a volume of blood

  • 5-1.5%
  • Elevated reticulocyte count is called reticulocytosis.
  • Common causes of reticulocytosis include hemolytic anemia, pernicious anemia, deficiency of iron, vitamin B12 or folate, anemia of chronic inflammation, cancers affecting bone marrow and chemotherapy.

In conditions with low RBC, low hemoglobin and/or low hematocrit:

  • Low MCV with high RDW: Iron deficiency anemia
  • High MCV with high RDW: Vitamin B12 and/or folate deficiency
  • Variable MCV (low, high or normal) with high RDW: Mixed deficiency (iron and B12 or folate)
  • Normal MCV with high RDW: Large blood loss (hemorrhage)
  • Normal MCV with normal MCH: chronic illness, aplastic anemia, prosthetic heart valves, sepsis or kidney failure
  • Low MCV with low MCH: iron deficiency, thalassemia, lead poisoning, long term inflammation
  • High MCV with normal or high MCH: deficiency of B12 or folate

Explain the tests: Complete blood count (CBC) – High red cell count (Part 3)

A number of conditions can cause high red blood cell count.  This is called polycythemia.  Red cells are responsible for bringing oxygen from the lungs to the tissues. If the blood is getting less oxygen than normal, the bone marrow will produce more red cells to compensate.  Excessive release of erythropoietin, a molecule that triggers red cell production, can also cause high red blood cell count.  Additionally, changes in amount of fluid in the blood stream can artificially alter red blood cell and hemoglobin levels.

Normal range for red blood count:

  • Adult women: 3.9-5.0 million cells/µL
  • Adult men: 4.3-5.7 million cells/µL

Reasons for making too many red blood cells:

  • High levels of erythropoietin, a molecule that tells the bone marrow to make red cells
  • Lower levels of oxygen in blood stream
  • Neoplastic conditions
  • Relative polycythemia, in which reduction of blood volume causes an artificial increase in red blood cells

Some conditions that cause lower oxygenation of the blood, triggering polycythemia:

  • Lung diseases, such as COPD, sleep apnea and pulmonary fibrosis.
  • Heart conditions, such as congestive heart failure.
  • Carbon monoxide poisoning.
  • Hemoglobin defects, such as 2,3-BPG deficiency, which causes hemoglobin to hold onto oxygen too tightly.
  • Lengthy stays at high altitude.

Some conditions that cause elevated erythropoietin:

  • Poor blood flow to the kidney, such as in narrowing of the renal artery, hydronephrosis and kidney cysts. The body interprets as low oxygenation.
  • Chuvash polycythemia, which causes overactivity of the erythropoietin gene.

Some neoplastic conditions that cause excessive proliferation of red cells:

  • Polycythemia vera. This myeloproliferative disorder (MPN) is strongly associated with the JAK2 V617F mutation.
  • Cancers such as renal cell carcinoma and adenocarcinoma.

Situations that cause artificially high red blood cell count:

  • Hypovolemia, from dehydration, alcoholism, obesity, smoking or third spacing.
  • Use of some diuretics.

Some medications that cause secondary polycythemia:

  • Anabolic steroids
  • Testosterone

 

Special notes on high red cell count for mast cell patients:

  • Polycythemia vera is a myeloproliferative neoplasm like systemic mastocytosis. It is a common comorbidity for patients with SM-AHNMD.  Some SM patients are positive for the JAK2 V617F mutation without having polycythemia vera.
  • Third spacing (fluid from the blood stream becoming trapped in the tissues) occurs in many mast cell patients as a regular symptom, as well as during anaphylaxis. This can cause the red cell count to appear artificially high.

Reading list: Papers to better understand mast cells and mast cell disease (Part 5)

Relationship of diabetes, steroids and allergic diseases

  • Carvalho V.F, et al. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int. J. Exp. Path. (2009), 90, 148–155.
  • Carvalho V.F, et al. Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers. Int Arch Allergy Immunol 2008;147:246–254.
  • Carvalho V.F., Barreto E.O., Cordeiro R.S. et al. (2005) Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem. Inst. Oswaldo Cruz 100(Suppl. 1), 121–125.
  • Carvalho V.F., Barreto E.O., Diaz B.L. et al. (2003) Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur. J. Pharmacol. 472, 221–227.
  • Carvalho VF, Barreto EO, Diaz BL, Serra MF, Azevedo V, Cordeiro RS, et al: Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur J Pharmacol 2003; 472: 221–227.
  • Cavalher-Machado SC, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004; 24: 552–558.
  • Foreman JC, Jordan CC, Piotrowski W. Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. Br J Pharmacol. 1982 Nov;77(3):531-9.
  • Kjaer A, et al. Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons. Endocrinology. 1993 May;132(5):2213-20.
  • Meng, Fanyin, et al. Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice. The American Journal of Pathology, Volume 184, Issue 3, March 2014, Pages 662–673
  • Theoharides TC et al. Mast cells and inflammation. Biochimica et Biophysica Acta 1822 (2012) 21–33.
  • Theoharides, T., et al. A probable case report of stress-induced anaphylaxis. Ann Allergy Asthma Immunol xxx (2013) 1e2