GI amyloidosis presensation

1. GI amyloidosis
Presentor – Dr Aadhar
Moderator – Dr A S Puri
1

2. Outlines
History
Introduction
Etiology
Nature of amyloidosis
Classification
Pathophysiology
Clinical features
Diagnostic approach
Management
Prognosis
Summary
2

3.  History
• First describe by Rokitansky in 1842
• Term first used by Rudolf Virchow in 1854 based on the color
after staining it with crude iodine staining techniques.
• Later recognized as protein by Friedrich and Kekule 5 yrs later.
• Latin word amylum , amylon in Greek means cellulose or starch
like
3

4.  Introduction
• Abnormal deposition of insoluble polymeric protein fibrils in tissue and organs
• Extracellular tissue deposition of fibrils
• The subunit proteins forming amyloid deposits are derived from soluble precursors which have
undergone conformational changes that lead to the adoption of a predominantly antiparallel beta-
pleated sheet configuration
• These fibrils can be identified on biopsy specimens both by their characteristic appearance on
electron microscopy and by their ability to bind Congo red (leading to green birefringence under
polarized light) and thioflavine T (producing an intense yellow-green fluorescence)
Nordling E, Abraham-Nordling M. Colonic amyloidosis, . Comput Biol Chem 2012; 39:29
4

5.  Epidemiology
• AL amyloidosis - incidence of 1 case per 100000 person-years in Western
countries
• United States approximately 1275 to 3200 new cases are reported every year
• Systemic amyloidosis is more common than localized amyloidosis
• Annual portion of new cases with primary systemic amyloidosis (AL) is 78%
5
Bustamante JG et al https://www.ncbi.nlm

6. Epidemiology
• Secondary systemic amyloidosis (AA) represents only 6% of these cases every
year in US
• Males > females
• Elderly males (40-70yrs)
• In the united states amyloidosis-related mortality from 1.77 to 3.96 per million
between 1979 and 2015.
• Highest mortality rates noted in the african-american population
6
Bustamante JG et al https://www.ncbi.nlm.nih.

7. Epidemiology
• Single center retrospective cohort study
• 2008 to 2017
• n= 583
7
T. Yen et al 2017
Colonoscopy/
UGI E
Biopsy proven
GI amyloidosis
Absent og
amyloidosis
82 37(45%) 45(55%)

8. Epidemiology
Retrospective study
n=2337
13-year period
Boston University Amyloid Treatment and Research Program database
Reported biopsy proven GI Amyloidosis in only 76 (3.3%) of the patients.
8
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

9.  Nature of amyloidosis
Main components of amyloidosis
9
A fibrillary protein 95%
Amyloid P component 5%
A glycosoamynoglycan

10. Amyloid protein
10
Fibrillary amyloid protein Non fibrillar amyloid proteins
AL AP (amyloid P component )
SAA Apo E
A2M - HD Sulfated GAGs
αβ amyloid
ATTR amyloid

11.  Classifications
Systemic (Generalized ) Localised amyloidosis
AL Senile cerebral
AA Alzheimer’s disease
Ab2M Medullary carcinoma of the
thyroid (endocrine)
ATTR Isolated atrial amyloidosis
11
Based on cause –primary and secondary
Extend of amyloid deposit –systemic & localized

12. Systemic amyloidosis with organ involvement
Type of systemic
amyloidosis
Causative protein Organ involvement
Primary systemic
amyloidosis
Monoclonal light chain (AL) Heart, Kidneys, Liver,
PNS, ANS,GIT
Senile Wild-type transthyretin (ATTR) Heart
Hereditary systemic
amyloidosis
Mutant (ATTR);
Apolipoprotein 1 (AApoA1);
Mutant fibrinogen A alpha (AFib);
Lysozyme (ALys)
Heart; Heart, Kidneys, Liver, Peripheral nervous
system
Isolated Atrial Systemic Atrial natriuretic factor (AANF) Heart
Secondary Systemic
Amyloidosis
Serum amyloid A (AA)
Kidneys, Heart, and Gastrointestinal tract
Dialysis-Related Systemic
Amyloidosis
β2-microglobulin (Aβ2M) Osteoarticular tissue, Circulatory system,
and
Gastrointestinal tract
Finnish-type Systemic
Amyloidosis
Gelsolin (AGel) Lattice dystrophy of cornea, and Corneal
neuropathy
12
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

13. Differences in systemic and localized gastrointestinal amyloidosis
Systemic GI amyloidosis Localized GI amyloidosis
Type More common subtype
Amyloid production at a remote location with subsequent
deposition in the GI tract
in the GI tract with subsequent deposition
locally
amyloid precursor proteins in the blood present Absent
Associated Plasma cell dyscrasia
Chronic inflammatory conditions
Dialysis
Hereditary conditions
Not associated with an underlying disease
pathology
Amyloid precursor protein deposited
include
AL, AA, Aβ2M and ATTR AL
Management consists of symptomatic management and treatment of
the underlying etiology
observation or surgical excision of the
localised deposition
Prognosis Depends on the type and amount of amyloid
deposition
Good prognosis.
No transition to systemic type
13
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

14.  GI amyloid Pathophysiology
 Infiltration of extracellular
misfolded proteins can be seen in
the different layers of the GI tract
 Amyloid fibrils can infiltrate the
mucosal lining , muscles, nerves or
arteries that supply the gi tract
14

15. Amyloid deposits in GI
tract
Mucosal lining
Muscles along the GI tract
Nerves along the GI tract
Arteries that supply the GI tract
15

16. o Mucosal infiltration
• Duodenum, followed by the stomach, colorectum and the esophagus
• –
16
AL amyloid
deposition
• MM,SM,MP often leading to the formation of
protrusions-
AA amyloid
deposition
• mucosa, which may lead to increased
friability and erosions ---
β2-
macroglobuli
n deposition
• a/c hemodialysis -
• blood vessels of the GI tract, mucosa,
submucosa, and muscularis propria-
symptoms of bowel obstruction
diarrhea and clinical
features of malabsorption
features of mucosal
ulceration

17. o Neuromuscular infiltration
17
Deposition of the amyloid proteins in the neuromuscular layer of the GI tract
Affect the intrinsic nerve plexus (myenteric or submucosal nerve plexus) and
muscularis externa (longitudinal and circular muscles)
Abnormal peristalsis,
Abnormal GI transit times and
Dysmotility

18.  Clinical manifestations of GI amyloidosis
Malabsorption
Protein-losing gastroenteropathy
Chronic gastrointestinal dysmotility (stasis syndrome)
Gastrointestinal bleeding
Hepatic amyloidosis
18
Uncommon symptoms
www.arci.org

19. Clinical manifestations of GI amyloidosis
19
T. Yen et al 2017

20. o Malabsorption
Mucosal infiltration
Pancreatic insufficiency
Bacterial overgrowth
Diarrhea
Weight loss
Steatorrhea
Anorexia
Dizziness
20
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

21. o Protein-losing gastroenteropathy
Mucosal lesions which may lead to abnormal protein loss from the GI tract
Diarrhea
Edema
Ascites
21
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

22. o Chronic gastrointestinal dysmotility (Stasis syndrome)
Dysmotility can be secondary to myopathic and neuropathic dysfunction
Nausea ,vomiting,
Dysphagia
Gastroparesis
Gastro-oesophagealreflux
Loss of appetite
Constipation
Abdominal pain, bloating
Clinical features of chronic intestinal pseudo-obstruction
Persistent diarrhea due to rapid transit times secondary to dysmotility, intestinal inflammationand
bacterial overgrowth
22
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

23. o Hepatic amyloidosis
Hepatomegaly and mild elevations in alkaline phosphatase (ALP)
Weight loss (72%),
Fatigue (60%),
Abdominal discomfort (53%)
Anorexia (26%)
Elevated direct serum bilirubin levels (> 2 mg/dL) - poor
prognosis
23
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

24. o Uncommon symptoms
Cholangitis,
Pneumatosis
Intestinalis (gas pockets within the bowel wall), or
Bowel perforation
24
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

25.  Physical examination
Macroglossia
Hepatosplenomegaly
Ascites
Restrictive
cardiomyopathy
,
Neuropathy
Unexplained
edema
Unexplained
facial or neck
purpura
Carpal tunnel
syndrome
25

26.  Establishing diagnosis of GI amyloidosis
GI
amyloidosis
Non-specific GI symptoms
Past medical history of disorders commonly associated with amyloidosis (PCD,
CKD on MHD)
Chronic inflammatory conditions (RA,IBD)
positive family history
of amyloidosis
Radiological investigations
in GI amyloidosis
Laboratory investigations-
Anaemia,
elevations in ALP levels,
Elevations of CRP,ESR
Deficiencies from
malabsorption
26
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

27. Diagnostic modality
Imaging
Endoscopy or colonoscopy
Manometry
Wireless motility capsule
Sitz marker study
Breath tests
©2022 Amyloidosis Research Consortium

28. Radiological investigations
in GI amyloidosis on CT/MRI
28
Diffuse or nodular wall thickening of the involved bowel segment
Dilatation depending upon the degree of hypomotility
Attenuation due to cluster of calcifications ormucosal ulcerations
Presence of polyploid protrusions or masses mimicking cancer
Loss of haustrations
Mesenteric thickening or adenopathy
Mesenteric thickening or adenopathy
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

29. Imaging
29
GI amyloidosis with plasma cell dyscrasia presented as CIPO
Early phase Delayed phase

30. Colonic transit study
30
GI amyloidosis with plasma cell dyscrasia presented as CIPO
11th july 23 17th july 23

31. Imaging
31
Nonspecific dilatation of small bowel loops (arrow) with a stricture in the
duodenal loop (arrowhead) in a patient with secondary amyloidosis.
Camilleri M et al , Manometric Diagnosis of Gastrointestinal Motility
Disorders. Thieme Medical Publishers, New York 1986.

32.  Establishing the diagnosis
Gold standard test tissue biopsy followed by CR staining and visualization under
polarized light microscopy
• EGD or colonoscopy should be performed to obtain the biopsy specimen
Digitally reinforced hematoxylin-eosin polarization (DRHEP)
• newly introduced technique which uses both routine light microscopy and
digital photography, can detect weak birefringence which is not recognized
through the microscope objective
• DRHEP is currently limited to kidney biopsies, its role for GI amyloidosis is
currently under investigation
32
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

33. Diagnosis
Diagnosis
of
gastrointestinal
amyloid
Tissue biopsy
Endoscopy
Histology
Positive staining of amyloid by congo
red
The presence of amyloid fibrils on
electron microscopy
33
Camilleri M et al , Manometric Diagnosis of Gastrointestinal Motility Disorders. Thieme Medical Publishers, New York
1986.

34. o Tissue biopsy
• Duodenum, followed by the stomach, colorectum and the esophagus
• –
34
Endoscopy
• Fine granular appearance
• Polypoid protrusions
• Erosions, ulcerations, friability
• Thickening of the wall
Histology
• Hematoxylin and eosin stained-amyloid appears as a pink,
amorphous, waxy substance with a characteristic 'cracking' artifact
• In the gastrointestinal tract, amyloid deposite in mucosa and
submucosa and are best identified in the wall of blood vessels
Camilleri M et al , Manometric Diagnosis of Gastrointestinal Motility Disorders. Thieme Medical Publishers, New York 1986.

35. Endoscopic finding
35
Colonoscopy- superficial colonic ulcers and spontaneous haemorrhages
UGIE -polypoid protrusions and thickened folds at second portionof the duodenum and pinkish plaque-like amyloid infiltration
2008 The Authors, Aliment Pharmacol Ther 27

36. 36
Duodenal epithelium stained with hematoxylin and eosin. Duodenal mucosa stained with Congo red.
Blood vessels (a) and lamina propria (b) using hematoxylin and eosin stain
Camilleri M et al , Manometric Diagnosis of Gastrointestinal Motility Disorders. Thieme Medical Publishers, New York 1986.

37. Congo-red staining of amyloid in lamina propria and submucosa of the lower GI tract
37
Reddish brown appearance under the white light
Apple green birefringence under polarized light
2008 The Authors, Aliment Pharmacol Ther 27

38. Managed
conservatively
?RA
MTx
HCQS
2016 2018-2019 27 april
2023
Timeline
Ovarian
cyst
resection
4 april
2023
Weight loss of 22 kg
Improved ,
medication
stopped
2022
CTS
feb 2023
Exploratory
laprotomy &
adhesinolysis
?SAIO
Recurrence
of Vomiting
Medanta
improving
clinically
Discharge
3 may
2023
Re-admission
10th july
2023
1 august
2023
PCD AL-
amyloid
CIPO
treatment
started

39. Amyloid ileum
H&E stain
Eosinophilic, amorphous, extracellular material in the lamina propria Congo- Red stain showing apple green birefringence

40. Plethora of Plasma Cells Plasma cells with eccentric cart wheel nucleus
BM Imprint
Bone Marrow
H&E

41. Bone Marrow IHC
CD138 Marker for Plasma cells CD56: Marker of NK cells

42. 42

43. 43
Gastrointestinal manometric tracing during fasting primary amyloidosis.
Low amplitude contractions at all levels
Camilleri M et al , Manometric Diagnosis of Gastrointestinal Motility
Disorders. Thieme Medical Publishers, New York 1986.
Manometry

44. List of investigations required for work up of amyloidosis
• Target organ or surrogate site (abdominal fat pad) biopsy
• H & E and Congo red stain
• IHC/Immunoelectron microscopy/proteomic study for
amyloid typing SPEP, IFE, (sFLC) for evidence of monoclonal
plasma cell proliferation
• Bone marrow aspirate and biopsy for clonal plasma cells
• Mutation studies for various hereditary amyloidosis
• Work up for rheumatoid arthritis, tuberculosis and other
inflammatory conditions associated with AA amyloidosis
Diagnosis
and typing
44
Richa Juneja et al Indian J Hematol Blood Transfus (Apr-June
2020)

45. List of investigations required for work up of amyloidosis
• Renal function test
• 24 h urine protein/albumin
• MRI/ECHO for cardiac involvement
• Pro NT-beta natriuretic peptide
• ECG
• USG/CT scan for liver span
• Alkaline phosphatase
• X ray or CT scan of lung
• GIT biopsy with evidence of amyloid
• SAP scintigraphy/technetium scintigraphy
• Coagulation screen
For confirming
systemic
involvement,
assess distribution
and complications
45
Richa Juneja et al Indian J Hematol Blood Transfus (Apr-June
2020)

46. 46
Hasib Sidiqi and Gertz Blood Cancer Journal (2021)

47. Aproach
https://www.ascopost.com/search
47

48.  Management of GI amyloidosis
Symptomatic management
Treatment of the underlying condition for systemic amyloidosis
48

49. o Symptomatic management
Symptoms
of
dysmotility
(stasis
syndrome)
Dietary modifications-
frequent, small-volume
liquid or
homogenized foods with
low soluble fibre
Adequate
hydration
pro-kinetic and
anti-emetic agent -
Metoclopramide
Erythromycin
Domperidone
Severe cases of
chronic
GI dysmotility
Parenteral nutrition
Dysphagia
successfully treated with balloon
dilation
49
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

50. o Symptomatic management
Diarrhea or bloating
anti-diarrheal agent -
loperamide should be initiated
Diarrhea and
suspected bacterial
overgrowth
Empiric antibiotic
therapy
Severe
Diarrhea
associated with
protein-losing
enteropathy
GI bleeding
good response
to corticosteroid and octreotide therapy
supportive measures, volume resuscitation if needed,
and source control through ligation of the bleeding
blood vessel
50
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

51. o Symptomatic management
Cases of severe obstruction
Uncontrolled GI hemorrhage
Bowel ischemia
Surgical intervention
Macroglossia causing
airway obstruction or
obstructive
sleep apnea
Partial resection of the tongue to
alleviate symptoms
51
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

52. o Treatment of the underlying condition for systemic amyloidosis
52
Gastrointestinal
amyloidosis
AL amyloidosis AA amyloidosis Hereditary
amyloidosis
Dialysis-related
Amyloidosis
• No specific
treatment
protocols
• Depends cause
and type of amyloid
protein
Systemic:
Eligible: (ASCT) for
plasma cell
dyscrasias.
Non-eligible:
No standard
protocol
combination
of Bortezomib,
Melphalan and
Dexamethasone
Localized:
Observation or
localized surgical
Excision
Chronic inflammatory
conditions:
Biologics and
immunosuppressants.
Familial
mediterranean fever:
Colchicine.
Liver production of
transthyretin:
Orthotopic liver
transplantation (OLT)
Disease
modifying therapy:
Transthyretin
stabilizers-
Tafamidis
Diflunisal
Doxycycline
Patisiran
Inotersen
Prevention:
Removal
of plasmatic β2-
microglobulin (Aβ2M)
through hemodialysis
or peritoneal dialysis.
Early renal transplant
Dahiya DS et al Gastrointestinal amyloidosis: A focused review. World J Gastrointest Endosc 2021; 13(1):

53. Reducing the supply of fibril precursors in systemic amyloidosis
53
Emerging therapies for amyloidosis. Nat Clin Pract Nephrol 2006; 2:263

54. 54

55. 55
Clujul Medical Vol. 91, No. 4, 2018

56. 56
friable, polypoid protrusion of the duodenal mucosa.
Histopatology duodenal amyloidosis
Severe erythematous duodenopathy
apple-green birefringence under polarized light microscopy

57.  What is the Prognosis of Gastrointestinal Amyloidosis?
(Outcomes/Resolutions)
• The prognosis for gastrointestinal amyloidosis is determined by a number of factors, such as the extent
of the condition, overall health of the affected individual, and his/her response to treatment
• Although the gastrointestinal complications can result in significant morbidity, they are not usually the cause of
death
• The presence of hepatic manifestations has a poor prognosis as it likely reflects relatively severe systemic
disease
• Independent predictors of shortened survival include-
Heart failure,
Total bilirubin >2 mg/dl
Platelet count>500,000/microl.
57

58. Summary
• Characterized by extracellular deposition of fibrillar proteins, which can disrupt tissue structure and
function.
• The most causes of systemic amyloid deposition are
AL amyloid - plasma cell dyscrasia
AA amyloidosis- ongoing or recurring inflammation from chronic disease
• On electron microscopy, amyloid fibrils are approximately 10 nm in diameter, and on polarized light
microscopy after staining with Congo red (CR) dye, they have the characteristic apple green-birefringence
appearance
• Patients with GI amyloidosis commonly present with fatigue, lightheadedness, anorexia, weight loss, GI
bleeding, features of malabsorption, protein losing enteropathy, or chronic GI dysmotility.
58

59. Summary
• Jaundice with liver involvement (elevated direct bilirubin levels > 2mg/dl) is associated with
a poor prognosis
• Radiological investigations are usually non-specific, and a definitive diagnosis is established
with a tissue biopsy followed by CR-staining
• Characteristic apple-green birefringence of the CR-stained deposits under polarized light is
diagnostic
• Localized GI amyloidosis- observation or localized surgical excision
• Systemic GI amyloidosis, therapy is directed towards the underlying disease pathology
• overall survival outcome depends on the extent of involvement of the GI tract, the
quantity, and type of amyloid deposition
59

60. Thank you
60