Review of gastrointestinal symptoms for Fabry disease. Review of impact from Fabry disease. Review of differential diagnosis for Fabry disease. Explanation of GI study for Fabry disease.

1. Gastrointestinal
Manifestations of Fabry
Disease
Mariana Almeida
February 10, 2018

2. Disclosure
• I am involved in a Genzyme supported ISS examining GI dysfunction
in Fabry disease
• I have no other financial disclosures
2

3. Topics
• What do we know about gastrointestinal
symptoms?
– Type and cause
• What are treatment options?
– ERT
– GI medications
• Fabry study on gastrointestinal symptoms
at Massachusetts General Hospital
3

4. Prominent Symptoms
• Abdominal Pain
– Most common symptom
– Cramping, mid-abdominal
– Worsened with food intake or stress
• Increased metabolic demand
• Diarrhea
– Increased urgency and frequency
– Some exclusively intake-associated
• Fatty foods, lactose
– No blood or mucous
• Constipation
– Almost twice as common in females1
1. Buda et al, Curr Pharm Des, 20134

5. Other symptoms
• Nausea, vomiting, early satiety
– Slow in stomach emptying
• BMI
– Conflicting finding, some lower Body-Mass Index
(BMI) vs. normal
• Severe and rare:
– Perforation
– Colostomy
– Fistulas
5

6. Quality of Life
• Gastrointestinal symptoms severe impact on quality of life
• Adult patients with gastrointestinal symptoms had lower
quality of life score than patients without gastrointestinal
symptoms
• Pediatric Fabry patients have lower quality of life scores as
compared to age-matched children in the general US
population
• Anecdotally
– School and work absence
– Social isolation due to discomfort and embarrassment
6

7. Suspected Pathophysiology1
Symptoms
Inflammation
&
Immunology
Neuropathy
Vasculopathy
7

8. Differential Diagnosis
• Irritable Bowel Syndrome-Diarrhea
• Gastroesophageal reflux
• Inflammatory Bowel Disease
• Celiac Disease
• Scleroderma
• Mitochondrial disease
• Dermatomyositis
• Appendicitis
• Other lysosomal and glycogen storage diseases
• Delay in diagnosis of up to 10 years as symptoms
nonspecific
8

9. Treatment: Enzyme
Replacement Therapy
• Shown to reduce glycolipid accumulation in tissue
– Effective in stabilizing and sometimes reversing skin,
renal and cardiac disease1
– Variable effects on the GI symptoms
• Hoffman et al, 2007 studied 342 patients adult and
pediatric2
– Reduce overall prevalence gastrointestinal at 24 month
post initiation
– Improved quality of life (0.63 to 0.71)
– 2/3 patients continued to have gastrointestinal
symptoms

10. Evaluation & Management
Persistence of gastrointestinal symptoms even in
the setting of prolonged ERT
Role for more targeted therapeutic intervention
Fabry
Symptoms
Abdominal
Pain
Diarrhea Gastric
10

11. Summary
• Gastrointestinal symptoms can be severe and lead to a
significant decrease in quality of life
• Little known about exact mechanism, but thought to be
due to similar mechanism of dysfunction seen in other
systems
– Suspected to be a motility disorder
• Enzyme replacement therapy can improve some
symptoms, however gastrointestinal symptoms continue
to be a significant source of problems among Fabry
patients.
• There is much that can and should be done in the
management of this aspect of the disease
11

12. Fabry GI Research Study

13. Goals & Objectives
• There is limited information about the underlying causes of
the gastrointestinal diseases in patients with Fabry
disease
– Muscle abnormalities
– Vessel Abnormalities
– Nerve Abnormalities
• Gastrointestinal symptoms frequently persist even when
being treated with enzyme replacement therapy.
• Much can be learned by examining the GI tract in order to
provide improved management and care for these types of
symptoms in Fabry disease
13

14. Study Goals
• Dysmotility
– Examine how the GI tract moves
– Evaluate the types of abnormalities in the movement of the
gut, including changes in the muscles and the nerves, to
better understand the underlying GI dysfunction
• Histology
– Analysis of the tissue of the GI tract under a microscope to
study the cell changes
– Examine the cells to assess the amount of accumulation of
glycolipid in the GI tract
14

15. Study Design
A. Validated Questionnaires
– GI symptoms
• Stool frequency
• Stool types
• Abdominal pain
• Depression/Anxiety
• Upper GI symptoms (nausea, vomit)
– Quality of life
15

16. Study Design
• B. Motility
– SmartPill, 5 day assessment:
• Whole-gut transit
• pH
• Contractility
– Ingest SmartPill, receiver kept close
– Pass pill in stool and return receiver
16

17. Study Design
• C. Histology
– Clinically warranted sigmoidoscopy (Diarrhea,
abdominal pain)
– Endoscopic mucosal resection taken during
sigmoidoscopy
• Tissue examined under microscope
– Light microscopy
– Electron microscopy
– Cellular changes (swelling, damage)
• Count amount of glycolipid accumulation
17

18. Outcomes
• SmartPill
– Abnormalities of movement (slow or fast passage)
• Histology
– Cellular changes
– Glycolipid accumulation
• Psychosocial
– Depression/Anxiety
• Quality of life
– Quality of life scale
• Medical Care Use
– Doctor’s visits, ER visits
• GI Symptom Protocol
– Intention of creating a protocol to aid in evaluation of Fabry-related
gastrointestinal issues
18

19. How to get involved?
• Do you meet criteria?
– SmartPill &Questionnaires
• Fabry disease
• GI symptoms, any severity
• 18-70 years old
• Do not have other GI diseases
– Biopsy/Sigmoidoscopy section:
• Meet criteria for above
• AND ERT naïve or < 6 months
19

20. How to get involved?
• Study being conducted in Boston, MA
– Dr. Braden Kuo (GI)
– Dr. Claire Zar-Kessler (GI)
– Dr. Amel Kaara (Genetics)
• Patient needs to travel to Massachusetts General Hospital
– Typically 2 day study, stay overnight
– Travel and lodging for the night covered by study
– Compensation provided for participation in the study
20

21. Interested?
Contact me!
Mariana Almeida
Email: mnalmeida@mgh.harvard.edu
Phone: 617-724-0480
21