Postural Orthostatic Tachycardia Mast Cell Activation Syndromes What

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

Disclosures • Speakers bureau: Salix

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

Old Great Masqueraders Syphilis Tuberculosis Celiac Munchausen and Factitious

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

19 MD’s Sick for 25 yrs

Age 18 – Trigger-induced flushing, rash, nausea Age 20 - Bloating, constipation, bad gas Ages 23 -43 - Weak, painful dependent edema, ortho. lightheaded & tachy, syncope, body pain, stopped sweating Ages 37 -43 - 45 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

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

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…

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

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 Schondorf. Low. Neurology. 1993. Peltier. Clin Aut Res. 2010.

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

POTS Sx (50% percentile) • Postural lightheadedness (orthostatic intolerance – not O. H. ) • Palpitations • Pre-syncope/Syncope • Headache • Blurry vision • Memory problems Deb. 2015 Many complain only of GI sx & fatigue

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.

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

Active POTS Auto -antibodies Alpha-1, beta-1 and -2 adrenergic and acetylcholine autoantibodies Muscarinic 1, 2 acetylcholine autoantibodies Li. J Am Heart Assoc. 2014. Duby, Vernino. Abstract. 2016.

POTS & GI Sx • N = 163 patients, 87% female Nausea 39% Bloating 24% Diarrhea 18% Abd. Pain 15% Constipation 15% Loavenbruck. Neurogastroenterol Motil. 2015.

POTS & UGI • 2/3 rds had abnormal gastric motility • Delayed in 21% • Rapid in 46% –- why fast? Loavenbruck. Neurogastroenterol Motil. 2015.

POTS & LGI • N = 12 – 80% delayed colonic transit – 86% had abnormal ARM Huang et al. Dig Dis Sci. 2013.

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

POTS & Small Bowel • SB imaging – 7/12 dilated loops & A/F levels (potential risk for SIBO) Huang et al. Dig Dis Sci. 2013.

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

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

GI Sx in POTS: high frequency No EDS p<0. 001 p=0. 003 p<0. 001 Raj. Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017

Ehlers-Danlos Syndrome & MCAS Increased frequency of MCAS in EDS pts Increased MC in uninvolved skin Luzgina. 2011. Sevenviratne. 2017.

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

MCAS vs. Mastocytosis We act bad We are clones

Mast Cell Activation Syndrome Ig. E and Ig. G T-cell cytokines & microgranules Antigens Mediators MC w mutations in GI, skin, & BM Etiology: T-cell interaction? Abnl microbiome? Many receptor types Shefler. J Immunol. 2010. Afrin. Clin Ther. 2015.

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

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. 2015.

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. 2017.

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.

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.

MCAS: Minor Criteria � Response to MC therapy � Evidence of increased MC mediators � Focal or disseminated increased MC in GI tract and/or marrow (CD 117 -, tryptase-, & CD 25 -MC express CD 2 and/or CD 25) � Spindle-shaped morphology in >25% of MC Molderings, Afrin 2014

MCAS: W/U • PE – Orthostatic VS – Skin – Dermatographism – Joint hypermobility • Biopsy • GI – 20 MC/HPF • Skin • Marrow: exclude SM • Lab 50% yield: – Chromogranin A – Histamine - plasma – Heparin - plasma – LFT and cholesterol – Urine prostaglandin D 2 – Urine N-methylhistamine 15% yield: – Tryptase

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

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 !!

Intestine-derived MC-activation Triggers CNS-originated MC-activation Triggers Adenylate cyclase, Activating peptide, Calcitonin gene-related peptide, Corticotrophin releasing hormone, Myelin basic protein, Nerve growth factor, Neurotensin, Substance P MC IL-1, IL-33, LPS, VIP, Butyrophillin, neurotensin, caselin, glialdin, gluten, histamine, reactive O 2, C. diff toxins, rotavirus Inflamm. & Neurotoxic Mediators IL-1, 6, 8, 13, 17, 32 Monocyte chemotactic protein-1 Prostaglandin D 2 Serotonin Tryptase TNF-α Vasoactive Mediators Histamine Bradykinin Endothelin IL-6, IL-8 Nitric oxide Serotonin Tryptase Urocortin Vasoactive GF VIP

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. 2017. Divoux. J Clin Endocrinol Metab. 2012.

MCAS Sx (50% percentile) • Fatigue • Nausea • Muscle pain • Chills • Pre-syncope or syncope • Edema • Headaches • Dyspnea • Itching • Urticaria • Eye irritation • Heartburn Afrin. Am J Med Sci. 2017.

MCAS GI Sx – 413 pts • • • Nausea w/ or w/o vomiting - 57% Heartburn - 50% Abdominal pain - 48% Chest pain - 40% Alternating D and C - 36% Dysphagia - 35% Oral irritation/sores - 30% Diarrhea - 27% Constipation - 14% Afrin. Am J Med Sci. 2017.

MC & UGI Esophagus • Pain and dysphagia: 2 recent case reports Pain and dysphagia – 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. 2016. Parks. Dis Esophagus. 2015. Benedicte. BBA. 2012.

MC & UGI Stomach • Ulcers - histamine-induced hyperacidity Ulcers • Dyspepsia - mediator-induced nociception Dyspepsia • 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. 2015. Seneviratne. Am J Med Gen. 2017. Afrin. Am J Med Sci. 2017.

MC & IBS: Colon Bx Control IBS pts Pain severity • 44 IBS – ½ D, ½ C • 77% pts had MC (3 x control) • AP severity correlated with MC distance from nerves # of MC <5μm from nerves Also elevated mucosal tryptase and histamine Barbara. Gastroenterology. 2004.

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. 2007. Cenec. J Clin Invest. 2007. Benedicte. BBA. 2012. Barbara. Gastroenterology. 2004 and 2007.

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 Ig. E-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.

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. 2017.

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. 2017. Alfter. Liver Int. 2009.

MC Detection & Activation • H&E: MC granules only at 100 x under oil • CD 117 stain required (>20/HPF) • Labs may not detect GI MC activation Jakate. Arch Path Lab Med. 2006.

Usual POTS Rx • Cardiovascular Rx • Anal PT

Usual MCAS Rx Mediator effectors & MC receptor blockers: H 1/H 2 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. 2016.

MCAS Rx: Diet 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. 2016. Theoharides. Ann All Asth Immunol. 2004. Mc. Kintosh. Gut. 2017.

IVIg for Autonomomic Neuropathy • 2017 – 1 st 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. 2017. Zivkovic. Acta Neurol Scan. 2015. Brooks, Weinstock. Manuscript under review. 2017.

Immunotherapy for Autoimmune GI Dysmotility • N=23 w GI dysmotility by testing (6 hr nuclear scintigraphy, G-D manometry and Indium CL 3 colon transit). Autonomic testing: abnl in 88%. • 13 AB tested incl. nicotinic Ach, VGKC, GAD 65 • 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. 2014.

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. 2014.

Immunotherapy for Autoimmune Gastroparesis • Drug/pacer resistant GP w dysautonomia • 11 females, GAD-65 pos. , Rx 8 -12 wks: 1) 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. 2016.

Novel Rx for MCAS and POTS

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

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 Ig. G receptors • Antibiotic - SIBO and/or dysbiosis Rx Weinstock, Myers, Brooks, Goodman. Manuscript submitted. 2017.

POTS & SIBO N = 27 (26 F, 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)

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

Back up slides

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

External Nerve Diseases: adrenergic • Sympathetic (adrenergic) innervation dysfunction – Adrenergic imbalance in diabetic diarrhea – usually painless diarrhea – Neurogenic bowel – Gastroparesis – Intestinal dysmotility – Constipation

Internal GI Nervous System • Enteric nervous system – What is it? – What is in it? – More serotonin in ENS than in the brain

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

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

Endorphin Functions • • Regulate cell growth Decrease inflammation Decrease vascular permeability Stabilize Toll-like receptors – Decrease microglia activation (reduce pain) – Decrease cytokine release • Shift from TH 2 to TH 1 immunity • Motility effects – regulatory, prokinetic, MMC

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