1. Leonard Weinstock, MD, FACG Specialists in Gastroenterology
Postural Orthostatic Tachycardia & Mast Cell Activation Syndromes What GI’s Should Know
Leonard Weinstock, MD, FACG
Specialists in Gastroenterology

2. Disclosures
Speakers bureau: Salix

3. POTS & MCAS New great masqueraders Blind men & the elephant
Overlap syndromes
New treatment

4. Old Great Masqueraders
Syphilis
Tuberculosis Celiac
Munchausen and Factitious

5. You have IBS and pelvic floor dysfunction
POTS, MCAS, EDS
You have chronic fatigue and migraine
You have dehydration and tachycardia
You have IBS and pelvic floor dysfunction
You have idiopathic vertigo and tinnitus
You have allergies and asthma
You have fibromyalgia (….and it does not exist)
Blind men and
the elephant

6. 19
MD’s
Pederson CL, Brook JB. Health-related quality of life and suicide risk in postural tachycardia syndrome. Clin Auton Res Feb 6. doi: /s [Epub ahead of print]
PURPOSE: Postural tachycardia syndrome (POTS) is a disorder featured by orthostatic intolerance. The purpose of this study was to investigate the severity of quality of life issues in POTS patients. METHODS: Online surveys for health related quality of life, sleep quality, fatigue, pain, and suicidal ideation were completed by 624 POTS patients and 139 controls. RESULTS: People with POTS have significantly more days of poor physical health (p < 0.001), fewer days with good energy (p < 0.001), and significantly more days with activity limitations (p < 0.001) than controls. Pain severity was significantly higher for those with POTS (p < 0.001) while feelings of control over life was lower than controls (p < 0.001). Sleep quality and daytime fatigue were also significantly worse for those with POTS than controls (p < 0.001). Finally, those with POTS have a significantly higher risk of suicide compared with controls (p < 0.001). INTERPRETATION: The myriad of symptoms from which many POTS patients suffer is associated with a decreased quality of life. Nearly half of our sample with POTS was at high risk for suicide. More work needs to be done to determine the underlying issues surrounding suicide in POTS so that an appropriate treatment regimen can be developed.
Sick for 25 yrs

7. Age 18 – Trigger-induced flushing, rash, nausea
Age 20 - Bloating, constipation, bad gas
Ages Weak, painful dependent edema,
ortho. lightheaded & tachy, syncope, body pain, stopped sweating
Ages Sx: above + fatigue, brain fog, HA, vertigo, tinnitus, dry mouth, vision prob., nocturia, pressure-induced urticaria, cyanosis, early satiety, pelvic floor dysfx, …
No sleep/rest, liquid diet, syncope with straining, unable to tolerate warmth
Mayo… Dx .. but failed 12 POTS & MCAS meds, thyroid Rx, salt, and stockings
Pederson CL, Brook JB. Health-related quality of life and suicide risk in postural tachycardia syndrome. Clin Auton Res Feb 6. doi: /s [Epub ahead of print]
PURPOSE: Postural tachycardia syndrome (POTS) is a disorder featured by orthostatic intolerance. The purpose of this study was to investigate the severity of quality of life issues in POTS patients. METHODS: Online surveys for health related quality of life, sleep quality, fatigue, pain, and suicidal ideation were completed by 624 POTS patients and 139 controls. RESULTS: People with POTS have significantly more days of poor physical health (p < 0.001), fewer days with good energy (p < 0.001), and significantly more days with activity limitations (p < 0.001) than controls. Pain severity was significantly higher for those with POTS (p < 0.001) while feelings of control over life was lower than controls (p < 0.001). Sleep quality and daytime fatigue were also significantly worse for those with POTS than controls (p < 0.001). Finally, those with POTS have a significantly higher risk of suicide compared with controls (p < 0.001). INTERPRETATION: The myriad of symptoms from which many POTS patients suffer is associated with a decreased quality of life. Nearly half of our sample with POTS was at high risk for suicide. More work needs to be done to determine the underlying issues surrounding suicide in POTS so that an appropriate treatment regimen can be developed.

8. Thinking Inside Our Own GI Box
…tempting to think separate sx =
separate GI diseases plus weird sx
Nausea
Constipation
Bloating
Flatulence
Early satiety
Anal outlet disorder
… remarkable ROS Dx

9. My Own Blindness
34 y.o. WF w 17 yrs abd pain, GERD, diarrhea, >250 ER visits; 5 universities
W/U and Rx – every known test, +LBT & SOD: failed CCK, 9 ERCPs, and all IBS and GERD Rx
Tachycardia w/u: + tilt table
New Medical Therapy
– no GI Sx for 14 mo…

10. Postural Orthostatic Tachycardia Syndrome
Sympathetic nervous system activation syndrome - resulting in postural tachycardia without hypotension
GI Sx – mimics GI disorders and syndromes
Deb 2015, Li 2014, Vernino 2016

11. POTS: Clinical & Dx 1 to 3 million; 85% F; 20-40 yo
(vs. 1.6 for Crohn’s)
Tilt table test (vs. screen w ortho vital signs)
Increase in 30 bpm w/i 10 min
Norepinephrine increases
Additional testing
Quantitative sudomotor axon reflex test (56%)
Biopsy for small fiber neuropathy
Pederson CL, Brook JB. Health-related quality of life and suicide risk in postural tachycardia syndrome. Clin Auton Res Feb 6. doi: /s [Epub ahead of print]
PURPOSE: Postural tachycardia syndrome (POTS) is a disorder featured by orthostatic intolerance. The purpose of this study was to investigate the severity of quality of life issues in POTS patients. METHODS: Online surveys for health related quality of life, sleep quality, fatigue, pain, and suicidal ideation were completed by 624 POTS patients and 139 controls. RESULTS: People with POTS have significantly more days of poor physical health (p < 0.001), fewer days with good energy (p < 0.001), and significantly more days with activity limitations (p < 0.001) than controls. Pain severity was significantly higher for those with POTS (p < 0.001) while feelings of control over life was lower than controls (p < 0.001). Sleep quality and daytime fatigue were also significantly worse for those with POTS than controls (p < 0.001). Finally, those with POTS have a significantly higher risk of suicide compared with controls (p < 0.001). INTERPRETATION: The myriad of symptoms from which many POTS patients suffer is associated with a decreased quality of life. Nearly half of our sample with POTS was at high risk for suicide. More work needs to be done to determine the underlying issues surrounding suicide in POTS so that an appropriate treatment regimen can be developed.
Schondorf. Low. Neurology
Peltier. Clin Aut Res

12. POTS: Systemic Syndrome
Esophagus – GERD, dysphagia
Stomach – abnl gastric emptying
Intestinal and sphincter - dysmotility
CNS – migraines/HA, brain fog, anxiety, depres.
Urinary tract - inability to empty the bladder
Ocular – inability to accommodate
Salivary glands – dry mouth
Skin – flushing, rashes, swelling
Extremities – pain, swelling, vasospasm
Benarroch. Mayo Clin Proc 2012

13. POTS Sx (50% percentile)
Postural lightheadedness (orthostatic intolerance – not O.H.)
Palpitations
Pre-syncope/Syncope
Headache
Blurry vision
Memory problems
Many complain only of GI sx & fatigue
postural lightheadedness, palpitations, morning symptom exacerbation, syncope, headache, blurry vision, and memory problems are experienced by ≥50% patients 
Deb. 2015

14. POTS - Pathophysiology
Mast Cell Activation
Partial Autonomic Neuropathy
Leg Blood Flow Abnormalities
Hypovolemia
Hyperadrenergic
Increased Release
Decreased Clearance
Autoantibodies
Shannon. NEJM 2000.
Lambert. Circ Arrhythm Electrophysiol 2008,
Green. JAHA 2014.

15. POTS: Established Causes
Traumatic brain injury
Electrical injury
Lyme disease
HPV vaccine
Pregnancy
Median arcuate ligament syndrome ***
Kanjwal -09,10,11, Blitshteyn 2014, Brinth 2015
Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Autonomic dysfunction presenting as postural tachycardia syndrome following traumatic brain injury. Cardiol J. 2010;17(5):482-7.
Autonomic dysregulation (also called diencephalic epilepsy) has been reported following traumatic brain injuries (TBI). However, until now, postural tachycardia syndrome (POTS) has not been reported as a long-term complication in patients who have suffered a TBI. We report on a series of patients who developed POTS after suffering TBI. METHODS: eight patients who were referred to our center had suffered TBI and developed features of orthostatic intolerance following head trauma. The patients' neurological, neurosurgical and autonomic data (charts and/or physician letters) were then carefully reviewed for demographic characteristics, comorbid conditions, symptoms of orthostatic intolerance, medications and response to medication. These patients were diagnosed as having POTS, primarily based on their clinical features and findings from the head-up tilt test (HUTT). The data presented is observational and descriptive (percentages or means).RESULTS: Eight patients (seven of them women) aged years had suffered from TBI and had developed features of POTS. All had been normal with no symptoms prior to their TBI. All patients experienced orthostatic dizziness, fatigue, palpitations and near syncope. Six patients suffered from frank syncope. Six patients developed significant cognitive dysfunction, and three developed a chronic pain syndrome following trauma. All of the patients reported severe limitations to their daily activities and had been unable to keep their jobs, and two were housebound. Six patients demonstrated a good response to therapy with various combinations of medication. The symptoms of orthostatic intolerance and syncope improved with the initiation of medical therapy, as well as their reported quality of life. Two patients failed to show any improvement with various combinations of medications and tilt training, and continued to experience orthostatic difficulties.CONCLUSIONS: Postural tachycardia syndrome may, in some cases, be a late complication of traumatic brain injury.
Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Postural orthostatic tachycardia syndrome following Lyme disease. Cardiol J. 2011;18(1):63-6.
BACKGROUND: A subgroup of patients suffering from Lyme disease (LD) may initially respond to antibiotics only to later develop a syndrome of fatigue, joint pain and cognitive dysfunction referred to as 'post treatment LD syndrome'. We report on a series of patients who developed autonomic dysfunction in the form of postural orthostatic tachycardia syndrome (POTS). METHODS: All of the patients in this report had suffered from LD in the past and were successfully treated with antibiotics. All patients were apparently well, until years later when they presented with fatigue, cognitive dysfunction and orthostatic intolerance. These patients were diagnosed with POTS on the basis of clinical features and results of the tilt table (HUTT) testing. RESULTS: Five patients (all women), aged years, were identified for inclusion in this study. These patients developed symptoms of fatigue, cognitive dysfunction, orthostatic palpitations and either near syncope or frank syncope. The debilitating nature of these symptoms had resulted in lost of the employment or inability to attend school. Three patients were also suffering from migraine, two from anxiety and depression and one from hypertension. All patients demonstrated a good response to the employed treatment. Four of the five were able to engage in their activities of daily living and either resumed employment or returned to school. CONCLUSIONS: In an appropriate clinical setting, evaluation for POTS in patients suffering from post LD syndrome may lead to early recognition and treatment, with subsequent improvement in symptoms of orthostatic intolerance.

16. Active POTS Auto-antibodies
Alpha-1, beta-1 and -2 adrenergic and acetylcholine autoantibodies
Muscarinic 1, 2 acetylcholine autoantibodies
Li. J Am Heart Assoc
Duby, Vernino. Abstract

17. POTS & GI Sx Nausea 39% Bloating 24% Diarrhea 18% Abd. Pain 15%
N = 163 patients, 87% female
Nausea
39%
Bloating
24%
Diarrhea
18%
Abd. Pain
15%
Constipation
Loavenbruck. Neurogastroenterol Motil

18. POTS & UGI 2/3rds had abnormal gastric motility Delayed in 21%
Rapid in 46%
- why fast?
Loavenbruck A, Iturrino J, Singer W, et al. Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome. Neurogastroenterol Motil. 2015;27:92–98.
BACKGROUND: Gastrointestinal symptoms are common in the postural orthostatic tachycardia syndrome (POTS). However, few studies have evaluated gastrointestinal transit in POTS. Our primary objectives were to evaluate gastrointestinal emptying and the relationship with autonomic dysfunctions in POTS. METHODS: We reviewed the complete medical records of all patients aged 18 years and older with POTS diagnosed by a standardized autonomic reflex screen who also had a scintigraphic assessment of gastrointestinal transit at Mayo Clinic Rochester between 1998 and Associations between specific gastric emptying and autonomic (i.e., cardiovagal, adrenergic, and sudomotor) disturbances were evaluated. KEY RESULTS: Among 163 patients (140 women, mean [± SEM] age 30 [± 1] years), 55 (34%) had normal, 30 (18%) had delayed, and 78 (48%) had rapid gastric emptying. Fifty-eight patients (36%) had clinical features of physical deconditioning, which was associated (p = 0.02) with rapid gastric emptying. Associations with delayed gastric emptying included vomiting, which was more common (p < 0.003), and anxiety or depression, which was less common (p = 0.02). The tilt-associated increase in heart rate and reduction in systolic BP at 1 min was associated (p < 0.05), being greater in patients with delayed gastric emptying. CONCLUSIONS & INFERENCES: Two-thirds of patients with POTS and GI symptoms had abnormal, most frequently rapid gastric emptying. Except for more severe adrenergic impairment in patients with delayed gastric emptying, the pattern of autonomic dysfunction did not discriminate among gastric emptying groups. Further studies are necessary to ascertain whether extravascular volume depletion and/or deconditioning contribute to POTS in patients with gastrointestinal symptoms.
Loavenbruck. Neurogastroenterol Motil

19. POTS & LGI N = 12 80% delayed colonic transit 86% had abnormal ARM
Huang et al. Dig Dis Sci

20. POTS & “IBS” In review articles IBS stated to be common
Visceral sensitivity is mediated by sensory afferent nerves - not autonomic
Consider SIBO & MC disease

21. POTS & Small Bowel SB imaging – 7/12 dilated loops & A/F levels
(potential risk for SIBO)
Huang et al. Dig Dis Sci

22. Ehlers-Danlos Syndrome
Point each for:
Palms to floor - 1
Thumbs to wrist - 2
Pinky back 90o - 2
Elbows hyperextend - 2
Knees hyperextend - 2
Positive if ≥ 4

23. POTS: Incidence of EDS N = 3389 POTS pts EDS in 30% EDS pts
More likely for life-long POTS-like Sx (p<0.001)
Raj. Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017

24. GI Sx in POTS: high frequency
EDS
No EDS
p=0.003
p<0.001
Raj. Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017

25. Ehlers-Danlos Syndrome & MCAS
Increased frequency of MCAS in EDS pts
Increased MC in uninvolved skin
J Neurol Sci May 15;340(1-2): doi: /j.jns Epub 2014 Mar 11.
Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: a relationship study.
Wallman D1, Weinberg J2, Hohler AD3.
Author information
1Boston University School of Medicine, 72 East Concord St, A-302, Boston, MA 02118, USA. Electronic address: of Biostatistics, Boston University School of Public Health, Boston University Medical Campus, 801 Massachusetts Avenue, 3rd Floor, Boston, MA 02118, USA. Electronic address: University School of Medicine/BMC, 725 Albany Street, 7th Floor, Boston, MA 02118, USA. Electronic address:
Abstract
OBJECTIVE:
This study examines a possible relationship between Ehlers-Danlos Syndrome (EDS) and Postural Tachycardia Syndrome (POTS).
DESIGN/METHODS:
We retrospectively reviewed 109 medical records of patients suffering from autonomic dysfunction exhibiting at least one POTS symptom from one urban clinic for EDS and POTS diagnoses between 2006 and The presence of EDS within the POTS and non-POTS populations was calculated and compared to that of the general population.
RESULTS:
The review revealed 39 (36F:3M) patients with POTS (mean ± SD age, 32.5 ± 11.8 years) with 7 cases of EDS yielding a prevalence of 18% (95% exact CI: 8%, 34%), a statistically significant difference from the suggested prevalence of EDS in the general population of 0.02% (p<0.0001). 70 patients (53F:17M) without POTS (mean ± SD age, 51.1 ± 14.7 years) contained 3 cases of EDS, yielding a prevalence of 4% (95% exact CI: 1%, 12%), a statistically significant difference from the general population (p<0.0001). The prevalence of EDS was significantly higher in the POTS group compared to the non-POTS group (p=0.0329). The odds ratio comparing the odds of EDS for POTS versus non-POTS patients is 4.9 (95% CI: 1.2, 20.1).
CONCLUSION:
The presence of EDS may be significantly higher in patients with POTS than that of the general population and in autonomic patients without POTS. We suspect an additional underlying mechanism of POTS caused by EDS.
Biomed Res Int. 2017;2017: doi: /2017/ Epub 2017 Feb 12.
Orthostatic Intolerance and Postural Orthostatic Tachycardia Syndrome in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type: Neurovegetative Dysregulation or Autonomic Failure?
Celletti C1, Camerota F1, Castori M2, Censi F3, Gioffrè L4, Calcagnini G3, Strano S4.
1Physical Medicine and Rehabilitation, Umberto I Hospital, Rome, Italy.2Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Rome, Italy.3Department of Cardiovascular, Dysmetabolic and Aging-Associated Diseases, Italian Institute of Health, Rome, Italy.4Department of Heart and Great Vessels "A. Reale", Sapienza University of Rome, Rome, Italy.
Background. Joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT), is a hereditary connective tissue disorder mainly characterized by generalized joint hypermobility, skin texture abnormalities, and visceral and vascular dysfunctions, also comprising symptoms of autonomic dysfunction. This study aims to further evaluate cardiovascular autonomic involvement in JHS/EDS-HT by a battery of functional tests. Methods. The response to cardiovascular reflex tests comprising deep breathing, Valsalva maneuver, 30/15 ratio, handgrip test, and head-up tilt test was studied in 35 JHS/EDS-HT adults. Heart rate and blood pressure variability was also investigated by spectral analysis in comparison to age and sex healthy matched group. Results. Valsalva ratio was normal in all patients, but 37.2% of them were not able to finish the test. At tilt, 48.6% patients showed postural orthostatic tachycardia, 31.4% orthostatic intolerance, 20% normal results. Only one patient had orthostatic hypotension. Spectral analysis showed significant higher baroreflex sensitivity values at rest compared to controls. Conclusions. This study confirms the abnormal cardiovascular autonomic profile in adults with JHS/EDS-HT and found the higher baroreflex sensitivity as a potential disease marker and clue for future research.
Luzgina
Sevenviratne

26. Normal Mast Cells Biology: Produced in marrow Immature form circulate
Migrates to sites of inflam. & T-cell activity
Lives in mucosa and by vessels/nerves
Functions:
Wound healing
Angiogenesis
Immune tolerance
Defense against pathogens
Blood–brain barrier function

27. MCAS vs. Mastocytosis
We act bad
We are
clones

28. Mast Cell Activation Syndrome
T-cell cytokines & microgranules
IgE and IgG
MC w mutations in GI, skin, & BM
Etiology: T-cell interaction? Abnl microbiome?
Antigens
Mediators
Many receptor types
Shefler. J Immunol
Afrin. Clin Ther

29. MCAS: Mediators 200 mediators Histamine Heparin Typtase
Pro-inflammatory cytokines (TNF-α…)
Proteases
Vascular permeability/dilators
Leukotrienes
Platelet aggregation factor …

30. Microbiome & MC Activity
Theory: dysbiosis and/or SIBO leads to MC activation and effector memory T and B cells
SCFA (butyrate) and other microbial factors inhibits MC degran. & TNF-α … dysbiosis alters this
Stressed rats develop MC hyperplasia in GI tract possibly due to incr. intestinal permeability
Mycoplasma and Strep. pneumoniae induced MC degranulation
Antibiotic induced dysbiosis reduce genes in the intestine reducing adenosine monophosphate expression which causes increased MC protease.
Afrin, Khoruts. Clin Ther

31. MCAS: prevalence
1% – 17%
Misconception re: serum typtase imprt in SM; limited in MCAS
Increased in only 15% of MCAS
Better during attack
Afrin. Am J Med Sci

32. Proposed Criteria for MCAS
Dx MCAS made by either:
1) major criterion plus one minor criteria or
2) three minor criteria
and rule out other diagnoses
Molderings , Afrin 2014.

33. LW: its a syndrome with supporting evidence
MCAS: Major Criteria
Constellation of complaints attributable to pathologically increased MC activity
≥2 organ systems w typical disorders: skin, CVS,
resp, GI, nasal, ocular, and/or anaphylaxis
LW: its a syndrome with supporting evidence
Molderings , Afrin 2014.

34. MCAS: Minor Criteria Evidence of increased MC mediators
Response to MC therapy
Evidence of increased MC mediators
Focal or disseminated increased MC in GI tract and/or marrow (CD117-, tryptase-, & CD25-MC express CD2 and/or CD25)
Spindle-shaped morphology in >25% of MC
Molderings, Afrin 2014

35. MCAS: W/U PE Lab Biopsy Orthostatic VS Skin Dermatographism
Joint hypermobility
Lab
50% yield:
Chromogranin A
Histamine - plasma
Heparin - plasma
LFT and cholesterol
Urine prostaglandin D2
Urine N-methylhistamine
15% yield:
Tryptase
Biopsy
GI – 20 MC/HPF
Skin
Marrow: exclude SM

36. Is the MC the ‘Missing Link’ for Hyper-Nociception?
GI “functional” pain, CRPS, CPPS, EDS, FMS

37. MC Activation: Alternative Brain-Gut & Gut-Brain Theories
Visceral hypersensitivity d/t inflammation
MC live near nerves in mucosa & serosa
Proteinase-activated receptors triggered by histamine, tryptase & prostaglandins
Stress triggers cortisol releasing factor … triggers MC-infiltration & degranulation
W.U. heresy !!

38. MC IL-1,6,8,13,17,32 Monocyte chemotactic protein-1 Prostaglandin D2
CNS-originated MC-activation Triggers
Intestine-derived MC-activation Triggers
Adenylate cyclase, Activating peptide, Calcitonin gene-related peptide, Corticotrophin releasing hormone, Myelin basic protein, Nerve growth factor, Neurotensin, Substance P
IL-1, IL-33, LPS, VIP, Butyrophillin,
neurotensin, caselin, glialdin, gluten, histamine, reactive O2, C. diff toxins, rotavirus MC
Inflamm. & Neurotoxic
Mediators
IL-1,6,8,13,17,32
Monocyte chemotactic
protein-1
Prostaglandin D2
Serotonin
Tryptase
TNF-α
Vasoactive Mediators
Histamine
Bradykinin
Endothelin
IL-6, IL-8
Nitric oxide
Serotonin
Tryptase
Urocortin
Vasoactive GF
VIP

39. MCAS: Systemic Syndrome
Esophagus – GERD, dysphagia, chest pain
Stomach – gastritis, dyspepsia, nausea
Colon – diarrhea, constipation
Liver – increased enzymes
CNS – migraines/HA, brain fog, panic attacks, anxiety, depression
CVS - tachycardia
Urinary tract – interstitial cystitis
Ocular – conjunctivitis
Salivary glands – swelling
Skin – flushing, rashes, swelling
Extremities – pain, swelling, vasospasm
Constitutional – fatigue, fever, wt. loss, obesity
Afrin. Am J Med Sci Divoux. J Clin Endocrinol Metab

40. MCAS Sx (50% percentile) Fatigue Nausea Muscle pain Chills
Pre-syncope or syncope
Headaches
Itching
Urticaria
Nausea
Chills
Edema
Eye irritation
Dyspnea
Heartburn
postural lightheadedness, palpitations, morning symptom exacerbation, syncope, headache, blurry vision, and memory problems are experienced by ≥50% patients 
Afrin. Am J Med Sci

41. MCAS GI Sx – 413 pts Nausea w/ or w/o vomiting - 57% Heartburn - 50%
Abdominal pain %
Chest pain %
Alternating D and C %
Dysphagia %
Oral irritation/sores %
Diarrhea %
Constipation %
fatigue, muscle pain, pre-syncope/syncope, headache, itching/urticaria, paresthesias, nausea, chills, edema, eye irritation, dyspnea, and heartburn
Afrin. Am J Med Sci

42. MC & UGI Esophagus Pain and dysphagia: 2 recent case reports Heartburn
C/P & increased distal pressure – MC seen
C/P & dysphagia - MC seen - responded to MC Rx
Heartburn
Histamine-induced hyperacidity
LES changes by different mediators?
Lee. Gut Liver
Parks. Dis Esophagus
Benedicte. BBA

43. MC & UGI Stomach Ulcers - histamine-induced hyperacidity
Dyspepsia - mediator-induced nociception
Tryptase and histamine …release MC neuropeptides (Sub P…)
Sub P activates MC – viscous circle
Anti-histamines help GI sx
Gastroparesis
1.2% of 413 pts
Aich. Int J Mol Sci
Seneviratne. Am J Med Gen
Afrin. Am J Med Sci

44. MC & IBS: Colon Bx Pain severity 44 IBS – ½ D, ½ C
Control IBS pts
Pain severity
44 IBS – ½ D, ½ C
77% pts had MC (3x control)
AP severity correlated with MC distance from nerves
# of MC <5μm from nerves
Also elevated mucosal tryptase and histamine
Barbara. Gastroenterology

45. MC & LGI: Pain Proximity to nerves (2 human studies)
Incr. intraluminal tryptase (2 human studies)
Incr. visceral hypersensitivity - IBS pts mucosal mediators increased rat mesenteric nerve firing & Ca++ in dorsal root ganglia neurons
Incr. proteases - IBS pt mucosal mediators led to incr. somatic and visceral pain in mice
Incr. visceral hypersensitivity assoc. w fungal dysbiosis (animal study)
Guilarte. Gut Cenec. J Clin Invest Benedicte. BBA Barbara. Gastroenterology and 2007.

46. MC & Refractory IBS-D: Clinical
N=20 refractory IBS-D
Sx of MCAS in 19 pts
Coag. & fibrinolysis factors detected in 11/12 tested
N = 3 refractory IBS-D
Omalizumab (Xolair) - reduces IgE-induced MC activity led to complete remission in all
MC stabilizer Rx:
Cromolyn - 67% of 200 pts improved
Ketotifen - RTC 60 pts: less pain
Frieling. Z Gastro 2011, Stefanini. Scand J Gastro 1995, Magen W J Gastro 2016, Klooker. Gut 2010.

47. MC & Constipation 
Full-thickness Bx w surgery for slow transit constipation (n=29) vs. controls
Constipated pts – sig. higher # MC
Degranulated MC close to enteric glial cells and filaments in pts
Related to impaired propulsive activity in these pts vs. part of pathophysiology?
Bassotti. Aliment Pharmacol Ther

48. MCAS & Liver N=413 AST, ALT, AP – incr. in 40% N=40
Incr. chol in 75% & LFT in 40%
Down-regulated chitotriosidase expression in MC
Afrin. Am J Med Sci
Alfter. Liver Int

49. MC Detection & Activation
H&E: MC granules only at 100x under oil
CD117 stain required (>20/HPF)
Labs may not detect GI MC activation
Jakate. Arch Path Lab Med

50. Usual POTS Rx
Cardiovascular Rx
Anal PT
Bennoch. Mayo Clin Proc

51. Usual MCAS Rx
Mediator effectors & MC receptor blockers: H1/H2 blockers, vit C, montelukast, zileuton, ASA Mast cell stabilizers: quercetin, cromolyn, ketotifen Advanced Rx: amalizumab (Xolair), etoricoxib, hydroxyurea, tamoxifen, steroids, 6-MP, MTX, cyclosporine, initinib, sunitinib
Molderings. Naumyn S Ach Pharm

52. MCAS Rx: Diet Gluten, yeast, cow milk protein free
Gluten, yeast, cow milk protein free
Low histamine diet – MC has H-1, 2, 3, 4, 5 receptors
FODMAP-free – theoretically could help (decreases histamine and improves microbiome)
Molderings. Naum S Arch Pharm
Theoharides. Ann All Asth Immunol
McKintosh. Gut

53. IVIg for Autonomomic Neuropathy
2017 – 1st publ. of a POTS pt - remission
Approved for autonomic and autoimmune neurologic diseases
Online interviews : 9/13 improved: ranged from no help/terrible SE to miraculous, got my life back, life changing, sensational, huge improvement, magic, amazing
Not FDA-approved for POTS
Goodman. Am J Ther
Zivkovic. Acta Neurol Scan
Brooks, Weinstock. Manuscript under review

54. Immunotherapy for Autoimmune GI Dysmotility
N=23 w GI dysmotility by testing (6 hr nuclear scintigraphy, G-D manometry and Indium CL3 colon transit). Autonomic testing: abnl in 88%.
13 AB tested incl. nicotinic Ach, VGKC, GAD65
Serologic evidence (16/23) or personal/FHx autoimmune
3 had pos ANNA-1 - cancer was found
Slow transit – gastric 11, SB 12, colon 11
Flanagan. Neurogastroenterol Motil

55. Immunotherapy for Autoimmune GI Dysmotility (cont.)
Rx 6 – 12 wks: IVIG 0.4 gm/kg (16), methylprednisolone 1000 mg/d/3 then weekly (5) or both (2)
74% improved Sx & testing
21% Sx only
17% testing only
Flanagan. Neurogastroenterol Motil

56. Immunotherapy for Autoimmune Gastroparesis
Drug/pacer resistant GP w dysautonomia
11 females, GAD-65 pos., Rx 8-12 wks: ) IVIg, 2) mycophenolate mofetil (MM) + methylprednisolone, or 3) MM
Max imprv. w IVIg (67%)
55% imprv. V
45% imprv. N, AP, & Bloat
Soota .Results Immunol

57. Novel Rx for MCAS and POTS

58. Naltrexone (LDN), IVIG, and Rifaximin (R)
POTS
MCAS
SIBO

59. Novel Rx for MCAS & POTS LDN Rebound increase in endorphins
Reduce T and B cell production
Reduce cytokines and antibodies
Block TLR on microglia and MC
Decrease MC production via OGFr
IVIg
Bind Fc portion of antibodies…
Bind to mast cell IgG receptors
Antibiotic - SIBO and/or dysbiosis Rx
Weinstock, Myers, Brooks, Goodman. Manuscript submitted

60. POTS & SIBO Antibiotics helped: LDN helped:
N = 27 (26F, 27% MCAS, 42% EDS)
GI Sx – Pain 96%, Bloat 92%, Nausea 85%, Constipation 73%, Diarrhea 58%, GERD 58%
LBT abnl in 19/27 (69%)
Antibiotics helped:
GI Sx in 10/15
POTS Sx in 4/15
LDN helped:
GI Sx in 7/11
POTS/MCAS Sx in 5/11 (1 POTS, 2 both, 2 MCAS)

61. Summary Consider POTS & MCAS in complicated, Rx refractory pts
Common syndromes
Potential use for LDN, IVIg, immunomodulators, and antibiotics

63. Back up slides

64. External GI Nervous System
Brain → vagus nerves → esophageal plexus → gastric nerves
Vagus nerves/branches supply:
Esophagus through ⅔ transverse colon
Sympathetic innervation from spinal nerves
Parasympathetic innervation from spinal nerves
Hormonal influences
L and R vagal nerves combine to form esophageal plexus from which the gastric nerves arise which supply all abdominal organs and the gastrointestinal tract ending just before the splenic flexure.
Sympathetic – abdominopelvic splanchnics
Parasympthetic – pelvic splanchnics (sacral) innervates from splenic flexure through rectum

65. External Nerve Diseases: adrenergic
Sympathetic (adrenergic)
innervation dysfunction
Adrenergic imbalance in diabetic diarrhea – usually painless diarrhea
Neurogenic bowel
Gastroparesis
Intestinal dysmotility
Constipation
L and R vagal nerves combine to form esophageal plexus from which the gastric nerves arise which supply all abdominal organs and the gastrointestinal tract ending just before the splenic flexure.
Sympathetic – abdominopelvic splanchnics
Parasympthetic – pelvic splanchnics (sacral) innervates from splenic flexure through rectum

66. Internal GI Nervous System
Enteric nervous system
What is it?
What is in it?
More serotonin in ENS than in the brain
The connections between the ENS and CNS are carried by the vagus and pelvic nerves and sympathetic pathways.
The enteric nervous system (ENS) is considered to be an independent nervous system that controls and coordinates motility, blood flow and secretion to meet the digestive needs of the individual.
The ENS contains million neurons, distributed in many thousands of small ganglia, the great majority of which are found in two plexuses, the myenteric and submucosal plexuses, both of which are embedded in the wall of the digestive tract.
The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter. It is located between the longitudinal and circular layers of muscle and exerts control primarily over GI tract motility.
Submucosal plexus, as its name implies, is buried within the submucosa in the small and large intestines, but is sparse or absent within the stomach and esophagus. Its principal role is in sensing the environment within the lumen, regulating gastrointestinal blood flow and controlling epithelial cell function.
The ENS in the small intestine and colon contains full reflex circuits, including sensory neurons, interneurons and several classes of motor neuron, through which muscle activity, transmucosal fluid fluxes, local blood flow and other functions are controlled.

67. Opioid Receptors in GI Tract
Activation causes constipation by increased absorption and decreased secretion
Activation slows motility by continuous contraction

68. Endogenous Opioids Play role in fine tuning of digestion
Endogenous opioid peptides participate in neural control of peristalsis by dampening peristaltic performance via activation of mu and kappa receptors
Holzer, P. Regul Pept 2009; 155: 11–17

69. Endorphin Functions Regulate cell growth Decrease inflammation
Decrease vascular permeability
Stabilize Toll-like receptors
Decrease microglia activation (reduce pain)
Decrease cytokine release
Shift from TH2 to TH1 immunity
Motility effects – regulatory, prokinetic, MMC

70. Endorphin Control of the Gut
Opioid receptors
Endorphins act at the mu-receptor to slow the colon down
Endorphins may also act to regulate motility via fine tuning inhibition, thus helping forward peristalsis
Increases secretion into gut – helps peristalsis