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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%