Mast Cell Activation

Syndrome and LDN

Leonard Weinstock, MD, FACG

Associate Professor of Clinical Medicine

Washington University School of Medicine

President, Specialists in Gastroenterology

Creve Coeur, Missouri

LDN

Disclosures

• Off label use of naltrexone is reviewed

• LDN is not currently FDA approved for

inflammation

• There are no FDA approved meds for

MCAS

Conflicts of interests

• No financial conflicts

• Partial research funding from Missouri

Baptist Healthcare Foundation

My path

Motility

IBS

IBS-SIBO

SIBO

Extra-intestinal syndromes

LDN

POTS

MCAS

POTS-SIBO

MCAS-SIBO

LDN

MCAS GI Sx – 413 pts

Afrin. Am J Med Sci. 2017.

• 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%

Case of Cyclic Nausea

• Duodenum Bx

– 20-30 MC/hpf

• PGD2 p

– 203 (nl<115)

• Rx– H1/H2

– Quercetin

– Vitamin C

– LDN

• Outcome– resolved N/V

• 28 y.o. WF w 9 mo Hx:

N/V usually preceded

by cramps q 3 wks

• 12 hrs vomiting

• Alcohol occ. trigger

• GI ROS – GERD,

tension HA, 2 migraines

• Referred for EGD by PA

2nd OV: list of life time sxFatigue

Brain fog

Jumbled words

Memory loss

Migraine

Heightened smell

Smell and light sensitivity

Shake my feet lying down

Severe anxiety

Bloat

Acid reflux

Belching

Stomach burning

Stomach pain

Nausea

Chest pains

Bruising

Rash/redness when drinking wine or beer

Reaction to cinnamon scented spray

Headache

Itchy eyes, nose, throat

Seasonal allergies

Small rash when dog

lays on arm

Acne on chin

Sensitive skin to

lotions

ADHD

Hereditary

Degenerative bone

disease

Dry eyes

Hand cramps

Back pain

Shoulder pain

Hip pain

Leg pain

Stiffness

Hip pain/“dislocation”

Pain during

intercourse

Lower pelvic pain

Jaw pain

Rapid heart beat

Near faint standing,

Fainting in HS

MCAS & Esophagus

• Pain and dysphagia: 2 recent case reports

– 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?

• Lessons from EoE mediators on esophagus

– LE D4, PG F2α, & thromboxane B2 contract muscles

– IL (6, 8) relax muscles

– TGF-β, IL (8, 13), & VGEF fibroses

Lee. Gut Liver. 2016.

Parks. Dis Esoph. 2015.

Benedicte. BBA. 2012.

Spechler. Am J G. 2018.

MC & 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 ptsAich. Int J Mol Sci. 2015.

Seneviratne. Am J Med Gen. 2017.

Afrin. Am J Med Sci. 2017.

MCAS & Small Bowel

MCAS: SIBO Testing

(CH4 in 33% of 134 tests)

0.0%20.0%40.0%60.0%

MC & IBS: Colon Bx

• 44 IBS – ½ D, ½ C

• 77% pts had MC (3x control)

• AP severity correlated with

MC distance from nerves

Barbara. Gastroenterology. 2004.

Control IBS pts

Also elevated mucosal

tryptase and histamine

# of MC <5μm from nerves

Pain severity

MC & Abdominal Pain

– MC near nerves (2 human studies)

– Intraluminal tryptase (2 human studies)

– Visceral hypersensitivity - IBS pt’s mucosal

mediators increased rat mesenteric nerve firing

& Ca++ in dorsal root ganglia neurons

– Proteases from an IBS pt’s mucosal mediators

led to somatic and visceral pain in mice

– Visceral hypersensitivity and fungal dysbiosis

(animal study)

Guilarte. Gut. 2007. Cenec. J Clin Invest. 2007. Benedicte. BBA. 2012.

Barbara. Gastroenterology. 2004 and 2007.

Epiploic Appendagitis

40 y.o. WF w 1 yr sharp pain – migratory esp RLQ, lasted days, worse

w palpation & movement

GI PMH: IBS-m, SIBO, GERD, nausea

Pain worsened – led to surgery. BRBPR soon after … “MCAS ROS”

positive for 11/11 systems. Positive ileal bx and CD117 staining of EA

MCAS PMH and ROS: Tick bite age 18 with ring. Lyme in co-campers

Over 20 yrs - 18 admissions: migraine with dysarthria & hemiplegia (5),

syncope (2), dyspnea (2), vomiting (2)

Fatigue, brain fog, muscle pain, pelvic floor dysfunction, RLS,

Bechet's, Raynaud’s, morbid obesity, and infections: adult cystic acne,

tonsillitis, sinusitis, cellulitis w insect bite, and herpes zoster x3

Final Dx: MCAS, POTS, EDS, Adrenal Insufficiency

EA - ring next to the sigmoid colon

EA Case: Take Home Messages

• MCAS can cause chronic and acute

peritoneal pain

• Add MCAS to DDx of EA

• Risk factor: obesity

• 208 cases:

• Torsion or inflammation (73%)

• Hernia incarceration (18%)

• Intestinal obstruction (8%)

[Thomas 1974]

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

Bassotti. Aliment Pharmacol Ther. 2017.

EA Case: Pathology

Patient:

EA surface – 60 MC/HPF

Control patient:

EA surface – 2 MC/HPF

Patient colonoscopy:

ileum 80 MC/HPF

SIBO – To Test or Not to Test?

To Test: IBS and SIBO by BT

Author Substrate N Prevalence (%)

McCallum, 2005 Glucose 143 38.5

Lupascu, 2005 Glucose 65 30.7

Nucera, 2005 Lactulose 98 65

Nucera, 2004 Lactulose 200 75

Pimentel, 2000-3 Lactulose 313 57, 76, 84

Weinstock, 2006 Lactulose 254 63

LBT Interpretation: Basics

SIBO criteria

Rise of >20 ppm for either gas from

baseline ≤ 90 minutes

Methane significance

≥ 3 ppm; associated with constipation

≥ 10 ppm; significant value as per ACG

LBT Interpretation:Controversial patterns

Plateau pattern

Production of gas from colon

and possibly the small intestine

Too much fermentable material in colon

Flat line

H2 ≤ 3 ppm & no CH4 w 3 hr study

Suggests H2S (sulfur, rotten egg smell)

DDx: gastroparesis or bad test tubes

Lactulose Breath Testing:Controversial Issues

Poor specificity

• Hard to know when bulk of lactulose reaches the colon

• Distal ileum has large amount of bacteria

• Expect sudden rise in last gas sample

“Test & treat” vs. treat empirically

• Either is “acceptable”

• Interpret the test and treat accordingly

IBS: SIBO Test and Treat• IBS-D with abnl LBT predicts higher likelihood of

response vs. neg LBT: 59.9% vs. 25.8% (P=0.002) (Rezaie. 2017.)

POTS: Test and Treat

N=876 chart review

– 67 (7.7%) had LBT d/t N, V, bloat

Positive test in 39/67 (58.2%)

14/39 given low doses of “antibiotics”

4/14 had follow up data

– 2 better

Rehman. Clin Auton Res. 2018;28:490[A].

POTS: Test and Treat

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 given in 15/19 and these helped:

• GI Sx in 10/15

• POTS Sx in 4/15Weinstock. Br J Med Case Reports. 2018.

Abx for

SIBO Rx in

MCAS

N = 79

Improved: 69.6%

Partial help: 5.0%

No help: 22.8%

AE DC: 7.6%

Abx for

SIBO

Rx in

MCAS

Gas: 7

Diarrhea: 13

Constip: 4

RLS: 1

Bloat: 15

Belch: 1

Abd pain: 14

Nausea: 3Fatigue: 2

Tinnitus: 1

Reflux: 4

Weight loss

stopped: 2

Number of

symptoms

improved in

55 patients

Treat Underlying Cause First?

PRO: Consider SIBO EtiologyWhat can be treated must be treated

Anatomic stasis and disorders

Immune deficiency

Maldigestion Achlorhydria

Neuromuscular

Etiology of SIBOTreatable disorders

Immune deficiency

Maldigestion Achlorhydria

Neuromuscular

Anatomic stasis and disordersGastric bypass, peptic ulcer surgery, jejunal

diverticulosis, IC valve resection, IC

incompetence, strictures/obstruction (radiation,

Crohn’s disease, tumor), adhesions, hEDS

Etiology of SIBO

Anatomic stasis and disorders

Immune deficiency

Achlorhydria

Neuromuscular

MaldigestionCeliac, sucrase

def., pancreatic

insufficiency

Etiology of SIBO

Anatomic stasis and disorders

Immune deficiency

Maldigestion

Neuromuscular

AchlorhydriaPernicious

anemia, aging,

surgery

Etiology of SIBO

Anatomic stasis and disorders

Immune deficiency

CLL, IgA & IgG def, chemotherapy

Achlorhydria

Neuromuscular

Maldigestion

NM SIBO Disorders

Anatomic stasis and disorders

Immune deficiency

Maldigestion Achlorhydria

Neuromuscular disorders

Occasional

• Autoimmune

• Cirrhosis

• Diabetes

• Ehlers Danlos(and mech. stasis)

• Scleroderma

Rare

• Acromegaly

• Amyloidosis

• Cystic fibrosis

• Familial GUCY2C

• Mitochondrial dz.

• Muscular dystrophy

• Pseudo-obstruction

• Short bowel synd.

Common

• Anti-vinculin

• Hypothyroid

• MCAS

• NASH

• Parkinson’s

• POTS

Comprehensive Rx

Treat SIBO and gut permeability which lead to

MC activation and memory T & B effector cells

• Treat SIBO to decrease T-cell & cytokines

• Rx for tight junctions

• FODMAP to increase SCFA (butyrate)

• Balance microbiome to reduce MC

degranulation – probiotics after Rx

• Treat candida

Afrin, Khoruts. Clin Ther. 2015.

Improve Gut Permeability

General

• Treat underlying disease

• Diets

Specific Rx

• SBI

• Zinc

• Glutamine

• Curcumin

• Probiotics

• LDN Sanz Fernandez. Animal. 2014.

Wang, Am J Physiol Cell Physiol. 2017.

Rapin. Clinics (Sao Paulo). 2010.

Lopeuso. Eur Rev Med Pharmacol Sci. 2015.

LDN for

MCAS

Rx

N = 116

Improved: 60.3%

No help: 28.5%

AE DC: 21.6%

LDN for

MCAS

Rx

Fatigue: 11

Headache: 4

Dizziness: 1

Autism: 1

Pain:

Joint: 11

Muscle: 9

Nerve: 2

RLS: 5

Diarrhea: 6

Constip: 5

Bloating: 4

Weight: 2

Abd pain: 15

Edema: 1

Erythromelalgia: 1

Hives: 2

Rash: 2

Itch: 1

Number of

symptoms

improved in

70 patients

Depression: 4

Brain fog: 3

Anxiety: 2

Nausea: 2

Insomnia: 2

MC flares: 4

Allergies: 1

Dyspnea: 1

Erythromelalgia and LDN

LDN for MCAS

• LDN

• Rebound increase in endorphins

• Reduce T & B cell production

• Less cytokines & antibodies

• Shift from Th1 to Th2

• Block TLR on microglia

• Block TLR on MC

• Decrease MC production via OGFr

LDN AE: MCAS pts

25/116 (21.5%)

– Fatigue

– Anxiety

– Edema (lip)

– Nausea

– Sweats

Weinstock et al. Manuscript in preparation. 2019.

LDN AE: neurologic (IBS pts)

– Anxiety: 15.7%

– Drowsiness: 11.6%

– Headache: 11.6%

– Insomnia: 8.3%

– Muscle pain: 8.3%

– Vivid dreams: 5.0%

– Mood change: 3.3%

– Brain fog: 1.7%

Ploesser J, Weinstock LB, Thomas E. Internat J Pharm Compound. 2010.

LDN AE: others (IBS)

– Nausea: 12.4%

– Abd. pain: 11.6%

– Diarrhea: 8.3%

– Anorexia: 8.3%

– Rash: 0.1%

– Hot flashes: 0.1%

– Weight gain: 0.1%