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Transcript
A Practical Tribute to the Career of
Donald Antonioli, MD
• Opening Remarks
• Evaluation of the “Flat” Small-Intestinal Mucosal
Biopsy: Contributions of Dr. Antonioli to SI
Mucosal biopsy analysis
– Rhonda Yantiss, MD
• Donald Antonioli and Eosinophilic/Allergic
Esophagitis
– Jeff Goldsmith, MD
Dr. Donald Antonioli
Education/Training/Appointments
• BSC, MD
Tufts University
1964
• Internal medicine intern
Tufts University
1965
• Pathology
Beth Israel Hospital
1969
• Assistant/Associate/Full Professor
HMS
1974/1980/1997
• Associate Chief, Dept Path
BIH
1987-1996
• Head Anatomic Path
BIH
1988-1990
• Director Residency Program
BIH/BIDMC
1992-1996
• Associate Director Graduate
BIDMC
2002
Medical Education
Dr. Donald Antonioli
Notable Research Contributions
• Vaginal adenosis: characterization and neoplastic
1970’s
complications
• Early description of dysplasia in colitis
1977
• Post BII (bile reflux) gastric polyps
1978
• Esophageal squamous papillomas
1978
• DES associated dysplasia
1978
• Classification of intestinal ischemia/infarction
1981
• Upper GI (and non GI) manifestations of Crohn’s
70’s-80’s
• Changing patterns/classification gastric cancer
1980’s
• Liver Cancer post Hep C
1983
• Esophageal eosinophilia (GERD/EOE)
1986-2000
Dr. Donald Antonioli
Notable Research Contributions, cont.
• EM properties of Barrett’s precursors
1980’s-2000
• Observer variability Barrett’s dysplasia
• Morphology of microscopic colitis, specificity
1988
1988-2000
• Characterization of allergic colitis
1990
•“Lymphocytic” esophagitis (“squiggly cells”)
1992
• Morphologic patterns of disease in treated colitis
1993
• Pediatric H. pylori gastritis
1990’s
•“Short Segment” Barrett’s
1994
• UGI involvement in Celiac Disease
1996
• Dysplasia/DALMs in colitis and Barrett’s
• Reflux/H. pylori carditis
1990’s-2000
2000’s
Dr. Donald Antonioli
General reviews/Editorials/Textbooks
• Mucosal biopsies of the upper and lower GI tract
• Contemporary aspects of gastric carcinoma
• Association of Hep C with liver cancer
• Chronic gastritis: a classification
• Editor, GI section Sternbergs Diagnostic Surgical
Human Path
1981
NEJM
1984
NEJM
1991
Bayliss
1994
1989,
1991,1999
Pathology
• Gastric carcinoma and its precursors
• Pathology of incipient neoplasia
IAP Mono
1990
Major Prob
Pathology
1993,2001
Dr. Donald Antonioli
National/International Committees/Courses
• Education committee GIPS
• NIH study section on gastric cancer
• Education committee USCAP
• NIH review committee colon/pancreas cancer
• NIH review committee Barrett’s
• Nominating committee USCAP
• >25 HMS steering/course committees
• >15 Hospital committees
• Associate director graduate medical education
• Co-chair director graduate medical education
1979
1985
1993
1993
2001
2004
70’s-2000
2002
2003
• >20 Post grad courses
• >15 Editorial boards Path/Gyn/GI journals
1980’s-2000’s
Antonioli/Goldman
GI Fellows
Beth Israel Deaconess Medical Center
<1990
1990-91
Yogeshwar Dayal
Larry Brown
Helen Wang
Formerly at Tufts
BIDMC
BIDMC
Charles (Buddy) Andrews ? Georgia
Robert Odze
BWH
1991
Colleen Powell
Ronnie Ray
Delaware
-------------
1992
Rita Addison
Sigfus Nikulasson
Boston
Iceland
1993
David Hurlbut
Cristian Robiou
Kingston, Canada
Texas
1994
Nada Alsaigh
Lilliane Yacoub
Connecticut
North Shore
1995
Franz Fogt
Jennifer Lipman
Philadelphia
-----------------
Antonioli/Goldman
GI Fellows Cont.
1996
Surendra Singh
Ohio
1997
Shaun Walsh
Scotland
1998
Amy Becker
Northwest
1999
Gamze Ayata
U. Mass
2000
Rhonda Yantiss
Cornell
2001
Heather Crowley
Jeremy Ditelberg
John Hunt
North Shore
Worcester
Springfield
2002
Joseph Grossman
S. Carolina
2003
Maria Botero
Barcelona, Spain
2004
Atoussa Goldar-Najaifi
Lahey Clinic
2005
Tracy Challies
BIDMC
2006
Saryn Doucette
Providence, Rhode Island
2007
Matthew Turner
U. Mass (July 1)
Thoughts about Donald
“Kind and thoughtful”
“Love of life and people”
“Gentleman scholar”
“Mature, calm, sound judgment”
“Generous, supportive, a laugh riot”
“True gentleman, (except for the dirty jokes)”
“Funny, kind”
“Wonderful colleague, mentor, friend”
“A practical tribute to the career of Donald Antonioli M.D.”
Case #1
Rhonda Yantiss, MD
Weill Cornell Medical College, New York, NY
Clinical History
A 66-year old male patient presented to the gastroenterologist with a four-month history of
progressive watery diarrhea and 8-10 bowel movements/day. He was hospitalized twice during a
6-week period for dehydration and suffered a 40-pound weight loss. Stool studies demonstrated
abundant fecal fat and negative cultures, and a C. difficile toxin assay was negative. Other
laboratory results included a polyclonal hypergammaglobulinemeia, normal IgA, mildly elevated
celiac markers (IgA and IgG gliadin, tTG) with negative HLA DQ2/8 haplotype, and normal
serum chromogranin, gastrin, serotonin, and VIP levels. Mild thickening of the ileal wall was
noted on abdominal imaging, but no other abnormalities were observed. Pertinent past medical
history included pancreatic insufficiency requiring enzyme supplementation and mild
hypothyroidism.
Microscopic Examination
Mucosal biopsy samples obtained from the duodenum and jejunum demonstrated complete
villous shortening and crypt hyperplasia in association with marked lymphoplasmacytic
inflammation in the lamina propria and relatively mild intraepithelial lymphocytosis (see figures
1 and 2). Paneth cells and goblet cells were entirely lacking in both the jejunum and duodenum,
and endocrine cells were markedly diminished. The ileal mucosal biopsy samples similarly
showed villous shortening as well as increased lamina propria inflammation, apoptotic crypt
epithelial cells, a paucity of Paneth cells and goblet cells, and intraepithelial inflammation. Mild
active colitis and gastritis were also present.
Figure 1.
Mucosal biopsy
sample of the
jejunum with
complete villous
shortening and
marked mucosal
inflammation.
1
Figure 2.
The jejunum is
infiltrated with a
mononuclear cellrich inflammatory
infiltrate that
contains numerous
plasma cells.
Intraepithelial
inflammation is
not striking. The
crypts show a
paucity of Paneth
cells and goblet
cells.
Diagnosis
Adult-onset autoimmune enteropathy
Clinical Features
The term “autoimmune enteropathy” was first proposed by Unsworth and Walker-Smith to
describe a disorder characterized by severe protracted diarrhea, extra-intestinal autoimmune
disorders, and autoantibodies directed against enteric epithelial cells26,32. Since that time,
slightly more than 100 cases have been reported in the literature. This disease most commonly
occurs in young children (<1 year of age), either sporadically, or in association with a familial
autoimmune disorder termed the Immunodysregulation, Polyendocrinopathy, and Enteropathy,
X-linked (IDEX) syndrome23,27. Most affected children are males and harbor a spectrum of
autoantibodies (anti-enterocyte, anti-goblet cell, anti-nuclear, anti-mitochondrial, antiendoplasmic reticulin, anti-parietal, anti-DNA, anti-smooth muscle, anti-gliadin, anti-tubular
basement membrane, anti-islet cells). However, the detection of specific subtypes of
autoantibody does not necessarily correlate with the presence of extra-intestinal immunemediated injury (i.e. patients with anti-tubular basement membrane antibodies may, or may not,
have concomitant renal disease)20,24,26.
Adult-onset autoimmune enteropathy is quite uncommon and fewer than thirty cases have been
reported in the literature9,18. In contrast to pediatric patients, adult males and females are
affected equally and may lack detectable anti-enterocyte antibodies in 10-15% of cases. Akram
et al. comprehensively described a series of 15 patients with autoimmune enteropathy in the
largest series of adult patients to date1. They found that most patients were older (mean age: 55
years), predominantly Caucasian, and often (87%) suffered from other autoimmune diseases.
Interestingly, 33% had elevated tTG antibodies and biopsy findings that suggested concomitant
gluten sensitive enteropathy.
2
Associated Diseases
A wide variety of extra-intestinal immune-mediated diseases may be associated with
autoimmune enteropathy, including pancreatic, renal, hepatic, and thyroid insufficiency,
hemolytic anemia, thrombocytopenia, eczema, arthritis, and vasculitis11,15. Among these,
insulin-dependent diabetes mellitus is most common and may precede the onset of diarrheal
symptoms6,14. Patients with autoimmune enteropathy may also suffer from renal disorders, such
as nephrotic syndrome, hematuria, membranous glomerulopathy or interstitial nephritis. These
individuals often show granular IgG deposits in glomeruli or along the tubular basement
membrane and have autoantibodies against the tubular epithelial brush border.
Pathologic Features
Biopsy samples from the small bowel demonstrate partial or complete villous shortening, crypt
hyperplasia, a paucity of Paneth cells, and increased stromal mononuclear cell inflammation,
with relatively little intra-epithelial inflammation2. Many cases, particularly those associated
with high levels of circulating anti-goblet cell antibodies, show marked goblet cell depletion and
apoptotic epithelial cell debris within the crypts. Diminished numbers of chromogranin-positive
endocrine cells are also frequently noted. Immunohistochemical stains demonstrate that the
inflammatory infiltrate largely consists of CD3 and CD4-positive T cells with the αβ receptor
phenotype5. Intestinal epithelial cells may express aberrant HLA-DR and ICAM-1, and the
lamina propria contains increase IL-2 receptor-positive cells5,12. Many patients also have
concomitant mononuclear cell-predominant colitis and gastritis.
Autoantibodies and Pathogenesis
The presence of anti-enterocyte antibodies may be demonstrated by indirect immunofluorescence
using serial dilutions of the patient’s serum applied to frozen tissue sections of normal human
small bowel followed by incubating with fluorochrome-conjugated anti-human
immunoglobulins. The tissue reaction is generally a linear pattern of fluorescence along the apex
of the enterocyte brush border with less staining along the basolateral membrane10. Most
antibodies are of the IgG subtype, but IgA and IgM have also been described7,19,28.
Although autoantibodies are often present in the sera of patients with autoimmune enteropathy,
they may disappear after the onset of treatment or clinical remission and it is not clear whether
they are pathogenetic or merely represent an epiphenomenon related to an unidentified etiologic
factor. Some investigators have shown that patients with IPEX syndrome have autoimmunity to a
75 kD protein expressed on renal tubular epithelium and enterocytes, which is encoded by a 21
exon region on chromosome 11p14.3. Recent studies have also shown that this disorder results
from a mutation in the FOXP3 locus on gene Xp11.23-Xq13.313. FOXP3 is a member of the
forkhead/winged-helix family of transcriptional regulators and encodes scurfin, a powerful
transcriptional suppressor and modulator of T cell function expressed on CD4+/CD25+
regulatory T cells. Loss of FOXP3 presumably results in hyperimmune activity and immune
dysregulation25 31.
Differential Diagnosis
The differential diagnosis of autoimmune enteropathy includes other forms of chronic enteritis
that show villous shortening and increased mononuclear cell inflammation, particularly gluten
sensitive enteropathy. Autoimmune enteropathy may be distinguished from celiac disease
3
because the former shows a paucity, or absence, of Paneth, goblet, and endocrine cells, but
relatively few surface intraepithelial lymphocytes. In contrast, although the surface epithelium
may show features of injury, such as attenuation of the cytoplasm, gluten sensitive enteropathy
does not result in a profound decrease in the number of specialized epithelial cells. In addition,
many of the intraepithelial T cells in gluten sensitive enteropathy express the γδ receptor, rather
than the αβ receptor. Common variable immunodeficiency may be considered in the differential
diagnosis as well, but this entity typically shows decreased numbers of plasma cells within the
lamina propria. However, as demonstrated by Akram et al., adult onset autoimmune enteropathy
may coexist with either gluten sensitive enteropathy or common variable immunodeficiency and
thus, show overlapping features with each of these entities1.
Treatment and Outcome
Autoimmune enteropathy has been historically associated with a high mortality, although the
increasing use of immunosuppression in the management of this disorder has been met with
increasing success14,21. Approximately one-third of patients may respond, at least initially, to
dietary modification alone, but nearly half ultimately require additional therapy6,12,19,28.
Monotherapy with corticosteroids has minimal utility, whereas the combined use of this agent
with azathioprine and/or cyclophosphamide achieves better results6,8,12,22,26,28. Cyclosporine,
sirolimus and tacrolimus have been reported to successfully induce and maintain remission of
symptoms in patients who have failed other immunosuppressive agents4,29. Bone marrow or cord
blood stem cell transplantation is usually reserved for individuals with IPEX syndrome who fail
other treatment modalities3,16,17,30.
References
1.
2.
3.
4.
5.
6.
7.
Akram S, Murray JA, Pardi DS, et al.: Adult Autoimmune Enteropathy: Mayo Clinic
Rochester Experience. Clin Gastroenterol Hepatol 2007
Al Khalidi H, Kandel G, Streutker CJ: Enteropathy with loss of enteroendocrine and
paneth cells in a patient with immune dysregulation: a case of adult autoimmune
enteropathy. Hum Pathol 2006, 37:373-6
Baud O, Goulet O, Canioni D, et al.: Treatment of the immune dysregulation,
polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow
transplantation. N Engl J Med 2001, 344:1758-62
Bindl L, Torgerson T, Perroni L, et al.: Successful use of the new immune-suppressor
sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked
syndrome). J Pediatr 2005, 147:256-9
Brousse N, Canioni D, Rambaud C, et al.: [Intractable infantile diarrhea. A framework to
subdivide]. Ann Pathol 1994, 14:333-8
Catassi C, Mirakian R, Natalini G, et al.: Unresponsive enteropathy associated with
circulating enterocyte autoantibodies in a boy with common variable
hypogammaglobulinemia and type I diabetes. J Pediatr Gastroenterol Nutr 1988, 7:60813
Charritat JL, Polonovski C: [Pediatric autoimmune enteropathies with anti-cytoplasmic
enterocytic auto-antibodies]. Ann Pediatr (Paris) 1987, 34:195-203
4
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Colletti RB, Guillot AP, Rosen S, et al.: Autoimmune enteropathy and nephropathy with
circulating anti-epithelial cell antibodies. J Pediatr 1991, 118:858-64
Corazza GR, Biagi F, Volta U, et al.: Autoimmune enteropathy and villous atrophy in
adults. Lancet 1997, 350:106-9
Cutz E, Sherman PM, Davidson GP: Enteropathies associated with protracted diarrhea
of infancy: clinicopathological features, cellular and molecular mechanisms. Pediatr
Pathol Lab Med 1997, 17:335-68
Habib R, Beziau A, Goulet O, et al.: [Renal involvement in autoimmune enteropathies].
Ann Pediatr (Paris) 1993, 40:103-7
Hill SM, Milla PJ, Bottazzo GF, et al.: Autoimmune enteropathy and colitis: is there a
generalised autoimmune gut disorder? Gut 1991, 32:36-42
Kobayashi I, Imamura K, Kubota M, et al.: Identification of an autoimmune enteropathyrelated 75-kilodalton antigen. Gastroenterology 1999, 117:823-30
Lachaux A: [Autoimmune enteropathy]. Arch Pediatr 1996, 3:261-6
Lachaux A, Bouvier R, Cozzani E, et al.: Familial autoimmune enteropathy with
circulating anti-bullous pemphigoid antibodies and chronic autoimmune hepatitis. J
Pediatr 1994, 125:858-62
Lucas KG, Ungar D, Comito M, et al.: Submyeloablative cord blood transplantation
corrects clinical defects seen in IPEX syndrome. Bone Marrow Transplant 2007, 39:55-6
Mazzolari E, Forino C, Fontana M, et al.: A new case of IPEX receiving bone marrow
transplantation. Bone Marrow Transplant 2005, 35:1033-4
Mirakian R, Collins P, Bottazzo GF: Autoimmune enteropathy in adults. Lancet 1997,
350:959-60
Mirakian R, Richardson A, Milla PJ, et al.: Protracted diarrhoea of infancy: evidence in
support of an autoimmune variant. Br Med J (Clin Res Ed) 1986, 293:1132-6
Moore L, Xu X, Davidson G, et al.: Autoimmune enteropathy with anti-goblet cell
antibodies. Hum Pathol 1995, 26:1162-8
Ochs HD, Torgerson TR: Immune dysregulation, polyendocrinopathy, enteropathy, Xlinked inheritance: model for autoaggression. Adv Exp Med Biol 2007, 601:27-36
Pearson RD, Swenson I, Schenk EA, et al.: Fatal multisystem disease with immune
enteropathy heralded by juvenile rheumatoid arthritis. J Pediatr Gastroenterol Nutr 1989,
8:259-65
Powell BR, Buist NR, Stenzel P: An X-linked syndrome of diarrhea, polyendocrinopathy,
and fatal infection in infancy. J Pediatr 1982, 100:731-7
Rogahn D, Smith CP, Thomas A: Autoimmune enteropathy with goblet-cell antibodies. J
R Soc Med 1999, 92:311-2
Ruemmele FM, Brousse N, Goulet O: Autoimmune enteropathy: molecular concepts.
Curr Opin Gastroenterol 2004, 20:587-91
Russo P, Alvarez F: Autoimmune enteropathy: a review. Clinical and Applied
Immunology Reviews 2002, 2:203-16
Satake N, Nakanishi M, Okano M, et al.: A Japanese family of X-linked auto-immune
enteropathy with haemolytic anaemia and polyendocrinopathy. Eur J Pediatr 1993,
152:313-5
Savage MO, Mirakian R, Wozniak ER, et al.: Specific autoantibodies to gut epithelium in
two infants with severe protracted diarrhoea. J Pediatr Gastroenterol Nutr 1985, 4:18795
5
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Seidman EG, Lacaille F, Russo P, et al.: Successful treatment of autoimmune enteropathy
with cyclosporine. J Pediatr 1990, 117:929-32
Smyk-Pearson SK, Bakke AC, Held PK, et al.: Rescue of the autoimmune scurfy mouse
by partial bone marrow transplantation or by injection with T-enriched splenocytes. Clin
Exp Immunol 2003, 133:193-9
Torgerson TR, Ochs HD: Immune dysregulation, polyendocrinopathy, enteropathy, Xlinked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin
Immunol 2007, 120:744-50; quiz 51-2
Unsworth J, Hutchins P, Mitchell J, et al.: Flat small intestinal mucosa and
autoantibodies against the gut epithelium. J Pediatr Gastroenterol Nutr 1982, 1:503-13
Case #2
Jeffrey Goldsmith
Beth Israel Deaconess Medical Center, Boston, MA
Case History:
A 13 year old male presented to his family practice physician with a 3-4 month history of
difficulty swallowing. The patient reported an intermittent history of associated epigastric pain
after eating which sometimes radiated to his back. Most recently, the patient had the feeling that
food was ‘stuck in his throat’ while eating a steak dinner. The patient’s past medical history
was significant for asthma since age 5. His asthma was well controlled.
Due to the history of meat impaction, his primary care physician referred him to a
gastroenterologist who was similarly concerned. An upper endoscopy was performed. The
duodenum and stomach were grossly normal. However, the esophageal mucosa appeared pale
with red streaks and areas of transverse mucosal folds (aka ‘feline esophagus’). These findings
were most prominent in the distal 5 cm; however, the findings were present to lesser degree in
the proximal esophagus. The endoscopist took multiple mucosal biopsies throughout the
esophagus.
Biopsies of the distal esophagus (37 cm), and proximal esophagus (22 cm) showed
similar findings (see pictures below). The squamous epithelium exhibited marked regenerative
changes; the epithelial cells displayed increased nuclear to cytoplasmic ratio throughout the
entire thickness of the epithelium. Examination at higher power showed markedly increased
numbers of intraepithelial eosinophils with up to 50 per high power field. Additionally, there
were aggregates of 3-5 eosinophils in the superficial epithelium (termed ‘eosinophilic
microabscesses’), extensive eosinophilic degranulation, and increased density of eosinophils in
6
the superficial epithelium compared with the basal epithelial cells. Focally, there was a crust
adherent to the epithelium that was composed of fibrin with numerous admixed eosinophils and
eosinophilic debris.
7
Based on these findings the following diagnoses were rendered:
A. Esophagus, 38 cm, biopsy:
Moderately active esophagitis; see note.
B. Esophagus, 20 cm, biopsy:
Moderately active esophagitis; see note.
Note: The biopsy findings suggest allergic / eosinophilic esophagitis. However, severe reflux
esophagitis cannot be entirely excluded. Clinical correlation is required to make this distinction.
The patient was started in high-dose proton pump inhibitors. Despite three months of therapy,
the patient’s symptoms persisted.
The patient was given a presumptive diagnosis of
allergic/eosinophilic esophagitis, and was started on topical corticosteroid therapy. Within one
month of instituting this treatment, his symptoms significantly improved.
Background & Pathogenesis:
In a recent comprehensive review and consensus recommendation statement, Furuta et
al., defined allergic / eosinophilic esophagitis (EE) as “a clinicopathologic disorder of the
esophagus characterized by esophageal and/or upper gastrointestinal tract symptoms in
association with esophageal mucosal biopsy specimens containing more than or equal to 15
intraepithelial eosinophils / high power field (HPF) in one or more biopsy specimens and
absence of pathologic gastroesophageal reflux disease (GERD) as evidenced by a normal pH
monitoring study of the distal esophagus or lack of response to high-dose proton pump inhibitor
(PPI) medication1.”
The epidemiologic characteristics of EE remain somewhat unknown. However, it is clear
that EE more often affects males in both the pediatric and adult populations with up to 75% of
EE patients being male2-7. Few studies have been performed that addressed the incidence and/or
prevalence of disease; however, in a study performed on the population in Hamilton County,
Ohio, the incidence of EE was up to 1.7 / 10,000 persons and the prevalence of disease was up to
3 / 10,000 people8; in longitudinal studies, the prevalence of disease has been noted to be
increasing7. This is likely due to increasing recognition of disease; additionally, since EE is not
associated with mortality, the prevalence of disease is expected to increase with time. It seems
8
that there is significant ethnic variation in the distribution of EE with a majority of cases reported
in Caucasians; however this topic has not been extensively studied.
Unlike long-standing GERD, which has an association with the development of Barrett’s
esophagus, dysplasia, and adenocarcinoma, a long history of EE predisposes patients to
esophageal mural fibrosis that results in stricture formation7,9. These patients with strictures are
more likely to suffer from dysphagia and food impaction. To date, an association with neoplasia
has not been observed.
The pathogenesis of EE remains relatively unclear. However, it is relatively certain that
EE is an allergic disease since most patients have a history of environmental hypersensitivity as
evidenced by positive radioallergosorbent (RAST) testing and/or positive skin prick testing10.
Additionally, changes identical to EE can be reproduced in mouse models by exposing the
animals to various allergens after sensitization11. It also seems that EE is associated with
cytokines secreted by TH2 lymphocytes that directly act on and recruit eosinophils. These
cytokines include IL-4, IL-5, and IL-13 and their secretion may act to recruit eosinophils to the
squamous epithelium via the secretion of eosinophil-specific chemokines, the eotaxins, in
appropriately stimulated hosts12,13. Additionally, there has been an association with a single
nucleotide polymorphism of the eotaxin-3 gene12. However, this genetic mutation has not been
causally associated with the development of EE, and may predispose patients to the development
of EE.
Diagnosis of Eosinophilic / Allergic Esophagitis:
Clinical Findings & Laboratory Studies:
Classically, symptoms of EE closely mimic GERD, with substernal chest pain and
referred pain to the back being common symptoms in both children and adults. However,
dysphagia is the most frequent symptom in patients with EE in adults. Food impaction is also
closely associated with EE, and was seen in 50% of patients in one case series of adult patients5.
In children, feeding intolerance, failure to thrive, and vomiting can also be seen14.
Intraesophageal pH probe monitoring is considered the gold standard for the diagnosis of
acid reflux. In the early studies of EE, pH probe studies were performed to exclude GERD, and
are negative in up to 80% of adult and pediatric patients with EE15-17. However, the current
9
standard of care is to give patients a trial of proton-pump inhibitors to exclude GERD. If patients
respond to this treatment, GERD is the presumed diagnosis9.
Endoscopic findings:
Endoscopically, a host of abnormal findings can be seen which include pale mucosa,
white exudates, longitudinal furrows, strictures, and ‘crepe paper esophagus’. The presence of
multiple, transient mucosal rings, termed ‘feline esophagus,’ has also been reported in EE. Of
these findings, the presence of longitudinal furrows and ‘crepe paper’ changes, in which the
esophageal mucosa becomes pale and fragile-appearing, are most suggestive of EE15,18.
However, none of these findings are diagnostic.
Histologic findings:
In general, biopsy findings in patients with EE include reactive squamous epithelium,
increased length of the submucosal papillae, and significant numbers of intraepithelial
eosinophils. The intraepithelial eosinophils number in excess of 15 eosinophils per high-power
field, and are typically distributed preferentially toward the luminal ½ or 1/3 of the squamous
epithelium19,20. Additionally, extensive eosinophilc degranulation6 and collections of over 4
eosinophils, typically present in the superficial epithelium, termed ‘eosinophilic microabscesses,’
can be seen in EE16. Perhaps the most specific finding of EE is the presence of a superficial
exudate of fibrin, eosinophils, and eosinophilic debris that is adherent to the epithelial surface;
however, this finding is uncommonly seen. The distribution of eosinophilic inflammation along
the esophageal length is typically uniform with similar numbers of intraepithelial eosinophils in
both proximal and distal esophageal biopsies16. Lamina propria, when present, may show
increased fibrosis21.
Differential Diagnosis
Gastroesophageal reflux disease
Gastroesophageal reflux disease can closely mimic EE. The histologic overlap between
GERD and EE is sufficient such that a definitive pathologic diagnosis of EE or GERD should
never be made when over 15 intraepithelial eosinophils per hpf are seen22. Rather, a description
of the histologic findings should be given and an appropriate differential diagnosis should be
10
given (see index case above). In general, however, the following histologic findings help to
separate EE from GERD:
1.
Numbers of intraepithelial eosinophils: EE generally has over 15-20 intraepithelial
eosinophils per high-power field, whereas biopsies of GERD typically have
substantially less than this number. When using this criterion, one should report the
maximal number of eosinophils seen in a particular biopsy, not the average.
2.
Distribution of eosinophils along the esophagus: When well-informed clinicians
suspect EE based on clinical findings or the endoscopic appearance, they usually
take biopsies from both the distal and proximal esophagus. In cases of GERD, the
intraepithelial eosinophilia is most often exclusively present in the distal biopsy. If
eosinophils are present in proximal biopsies, there are significantly reduced in
number when compared to the distal biopsy. In cases of EE, the numbers of
intraepithelial eosinophils remains relatively constant throughout the entire length
of the esophagus.
3.
Distribution of eosinophils throughout the epithelial thickness: In EE, the
eosinophils show increased density towards the luminal aspect of the epithelium.
Whereas, in GERD eosinphils are distributed evenly thought the epithelium.
4.
Eosinophilic microabscesses: Aggregates of more than 4 intraepithelial eosinophils
within the superficial epithelium are more highly associated with EE.
5.
Eosinophilic degranulation: Typically, biopsies of patients with EE show,
sometimes extensive, eosinophilic degranulation. This is much less commonly seen
in GERD. There is some recent evidence, however, that artifactual eosinophilic
degranulation may be induced by biopsy procurement and/or manipulation of the
biopsy specimen at the grossing bench23,24.
6.
“Eosinophilic Exudate”: The presence of an adherent exudate composed of
eosinophils, eosinophilic debris, and fibrin seems to be the most specific finding for
the diagnosis of EE. However, this assertion requires further study. Sadly,
however, this seems to be a specific, but not sensitive criterion.
11
Other Mimics of EE
Although GERD is the most common mimic of EE, other esophagitides also enter the
differential diagnosis. Other inflammatory conditions that may induce an eosinophilic response
include the following:
1.
Infections: While the inflammatory infiltrate in infectious esophagitis typically is
composed of neutrophils, eosinophils can sometimes predominate. In these cases,
the finding of the infectious organism, most commonly Candida pseudohyphae,
would obviously help to arrive at the correct diagnosis. Other infectious organisms
that might induce an inflammatory infiltrate composed partly of eosinophils include
herpes simplex virus, and, less commonly, cytomegalovirus. Again, the finding of
neutrophils within the inflammatory infiltrate should prompt a thorough search for
an infectious etiology25. It is important to note that Candida esophagitis and EE can
be coincident, since the main treatment for EE is topical steroid therapy which
predisposes patients to esophageal candidiasis.
2.
Crohn’s Disease: Crohn’s disease uncommonly involves the esophagus. Biopsies
of esophageal involvement by Crohn’s disease typically show ulceration with a
brisk lymphocytic infiltrate; non-necrotizing granulomas are rarely seen. In a
minority of cases, eosinophils may be a minor constituent of the infiltrate26.
3.
Other diseases: For completeness sake, other diseases, such as chemical induced
esophagitis, radiation damage, drugs, graft-versus-host disease, and various
connective tissue diseases may cause eosinophilic inflammation in the esophagus.
In these rare cases, the eosinophilic infiltrate is typically found in combination with
other findings that lead to the correct diagnosis. For example, in radiation-induced
esophagitis, the epithelium may contain a polymorphic infiltrate, including
eosinophils. However, the submucosal tissue would contain the vascular changes,
and atypical stromal cells typical of radiation-induced esophagitis.
Treatment
Eosinophilic/allergic esophgitis is typically treated with topical steroid therapy. Patients
orally instill topical steroids from a metered dose inhaler. Instead of inhaling this preparation,
patients swallow it. This action coats the esophageal mucosa with steroids which decreases
12
intraepithelial inflammation. Little of this swallowed steroid is absorbed systemically. Using
this therapy, all patients studied to date have had a significant decrease in their symptoms, and
about 75% of patients had complete symptomatic resolution27-29. Other treatments include
systemic corticosteroids and dietary therapy. Systemic corticosteroids are not typically used due
to long-term systemic side effects. However, if patients present with severe symptoms of EE,
systemic corticosteroids may be used on a short-term basis to relieve acute symptoms.
Institution of a food elimination diet has had variable success in the treatment of EE. However,
the use of an amino acid-based diet is quite effective in treating EE with up to 98% of patients
responding to this treatment modality30. However, this treatment is quite expensive and often
requires installation through a nasogastric or percutaneous gastrostomy tube because the aminoacid based diet is unpalatable.
References
1.
Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, Bonis P,
Hassall E, Straumann A, Rothenberg ME: Eosinophilic esophagitis in children and
adults: a systematic review and consensus recommendations for diagnosis and treatment.
Gastroenterology 2007, 133:1342-1363
2.
Attwood SE, Smyrk TC, Demeester TR, Jones JB: Esophageal eosinophilia with
dysphagia. A distinct clinicopathologic syndrome. Dig Dis Sci 1993, 38:109-116.
3.
Baxi S, Gupta SK, Swigonski N, Fitzgerald JF: Clinical presentation of patients with
eosinophilic inflammation of the esophagus. Gastrointest Endosc 2006, 64:473-478
4.
Croese J, Fairley SK, Masson JW, Chong AK, Whitaker DA, Kanowski PA, Walker NI:
Clinical and endoscopic features of eosinophilic esophagitis in adults. Gastrointest
Endosc 2003, 58:516-522.
5.
Desai TK, Stecevic V, Chang CH, Goldstein NS, Badizadegan K, Furuta GT: Association
of eosinophilic inflammation with esophageal food impaction in adults. Gastrointest
Endosc 2005, 61:795-801
6.
Parfitt JR, Gregor JC, Suskin NG, Jawa HA, Driman DK: Eosinophilic esophagitis in
adults: distinguishing features from gastroesophageal reflux disease: a study of 41
patients. Mod Pathol 2006, 19:90-96
13
7.
Straumann A, Spichtin HP, Grize L, Bucher KA, Beglinger C, Simon HU: Natural
history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5
years. Gastroenterology 2003, 125:1660-1669.
8.
Noel RJ, Putnam PE, Rothenberg ME: Eosinophilic esophagitis. N Engl J Med 2004,
351:940-941.
9.
Liacouras CA, Wenner WJ, Brown K, Ruchelli E: Primary eosinophilic esophagitis in
children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr
1998, 26:380-385.
10.
Fox VL, Nurko S, Furuta GT: Eosinophilic esophagitis: it's not just kid's stuff.
Gastrointest Endosc 2002, 56:260-270.
11.
Mishra A, Hogan SP, Brandt EB, Rothenberg ME: An etiological role for aeroallergens
and eosinophils in experimental esophagitis. J Clin Invest 2001, 107:83-90
12.
Blanchard C, Wang N, Stringer KF, Mishra A, Fulkerson PC, Abonia JP, Jameson SC,
Kirby C, Konikoff MR, Collins MH, Cohen MB, Akers R, Hogan SP, Assa'ad AH,
Putnam PE, Aronow BJ, Rothenberg ME: Eotaxin-3 and a uniquely conserved geneexpression profile in eosinophilic esophagitis. J Clin Invest 2006, 116:536-547
13.
Straumann A, Bauer M, Fischer B, Blaser K, Simon HU: Idiopathic eosinophilic
esophagitis is associated with a T(H)2-type allergic inflammatory response. J Allergy
Clin Immunol 2001, 108:954-961
14.
Sant'Anna AM, Rolland S, Fournet JC, Yazbeck S, Drouin E: Eosinophilic esophagitis in
children: symptoms, histology and pH probe results. J Pediatr Gastroenterol Nutr 2004,
39:373-377
15.
Remedios M, Campbell C, Jones DM, Kerlin P: Eosinophilic esophagitis in adults:
clinical, endoscopic, histologic findings, and response to treatment with fluticasone
propionate. Gastrointest Endosc 2006, 63:3-12
16.
Walsh SV, Antonioli DA, Goldman H, Fox VL, Bousvaros A, Leichtner AM, Furuta GT:
Allergic esophagitis in children: a clinicopathological entity. Am J Surg Pathol 1999,
23:390-396.
17.
Steiner SJ, Gupta SK, Croffie JM, Fitzgerald JF: Correlation between number of
eosinophils and reflux index on same day esophageal biopsy and 24 hour esophageal pH
monitoring. Am J Gastroenterol 2004, 99:801-805.
14
18.
Kaplan M, Mutlu EA, Jakate S, Bruninga K, Losurdo J, Keshavarzian A: Endoscopy in
eosinophilic esophagitis: "feline" esophagus and perforation risk. Clin Gastroenterol
Hepatol 2003, 1:433-437.
19.
Furuta GT, Straumann A: Review article: the pathogenesis and management of
eosinophilic oesophagitis. Aliment Pharmacol Ther 2006, 24:173-182
20.
Potter JW, Saeian K, Staff D, Massey BT, Komorowski RA, Shaker R, Hogan WJ:
Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features.
Gastrointest Endosc 2004, 59:355-361.
21.
Straumann A, Rossi L, Simon HU, Heer P, Spichtin HP, Beglinger C: Fragility of the
esophageal mucosa: a pathognomonic endoscopic sign of primary eosinophilic
esophagitis? Gastrointest Endosc 2003, 57:407-412.
22.
Ngo P, Furuta GT, Antonioli DA, Fox VL: Eosinophils in the esophagus--peptic or
allergic eosinophilic esophagitis? Case series of three patients with esophageal
eosinophilia. Am J Gastroenterol 2006, 101:1666-1670
23.
DeBrosse CW, Case JW, Putnam PE, Collins MH, Rothenberg ME: Quantity and
distribution of eosinophils in the gastrointestinal tract of children. Pediatr Dev Pathol
2006, 9:210-218
24.
Kato M, Kephart GM, Morikawa A, Gleich GJ: Eosinophil infiltration and degranulation
in normal human tissues: evidence for eosinophil degranulation in normal gastrointestinal
tract. Int Arch Allergy Immunol 2001, 125 Suppl 1:55-58
25.
Fenoglio-Preiser CM (editor): Gastrointestinal Pathology. Philadelphia, Lippincott-Raven
Publishers, 1999
26.
Ruuska T, Vaajalahti P, Arajarvi P, Maki M: Prospective evaluation of upper
gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn's disease. J
Pediatr Gastroenterol Nutr 1994, 19:181-186
27.
Arora AS, Perrault J, Smyrk TC: Topical corticosteroid treatment of dysphagia due to
eosinophilic esophagitis in adults. Mayo Clin Proc 2003, 78:830-835
28.
Teitelbaum JE, Fox VL, Twarog FJ, Nurko S, Antonioli D, Gleich G, Badizadegan K,
Furuta GT: Eosinophilic esophagitis in children: immunopathological analysis and
response to fluticasone propionate. Gastroenterology 2002, 122:1216-1225.
15
29.
Noel RJ, Putnam PE, Collins MH, Assa'ad AH, Guajardo JR, Jameson SC, Rothenberg
ME: Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic
esophagitis. Clin Gastroenterol Hepatol 2004, 2:568-575.
30.
Markowitz JE, Spergel JM, Ruchelli E, Liacouras CA: Elemental diet is an effective
treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol
2003, 98:777-782
16
Evaluation of the “Flat”
Small-Intestinal Mucosal Biopsy
Contributions of Dr. Donald A. Antonioli to
Small-Intestinal Mucosal Biopsy Analysis
Rhonda K. Yantiss, MD
Department of Pathology and Laboratory Medicine
Weill Cornell Medical College
New York, NY
Case Presentation
ƒ
Clinical history
– 66 year old male with hypothyroidism and pancreatic insufficiency
– 8-10 episodes of watery diarrhea/day
– Approximately 40 pound weight loss over 4 months
ƒ
Radiology
– Small bowel follow through and CT imaging
ƒ
ƒ
Multifocal ileal thickening without ulceration or fistulae
Laboratory studies
– Normal serum chromogranin, gastrin, serotonin, VIP
– Polyclonal hypergammaglobulinemia
– Mildly elevated celiac markers (IgA and IgG gliadin, tTG) with
negative HLA-DQ2 and HLA-DQ8 haplotypes
– Abundant fecal fat
Differential Diagnosis
Injury of proximal small bowel
and extra-intestinal inflammation
Chronic enteritis with villous
shortening and crypt hyperplasia
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
Inflammatory bowel disease
Celiac disease
Autoimmune enteropathy
Common variable immunodeficiency
Refractory sprue
Infection
Tropical sprue
Bacterial overgrowth
Microvillous inclusion disease
Protein intolerance
Nutritional deficiency
Medications
ƒ
ƒ
ƒ
ƒ
ƒ
Inflammatory bowel disease
Celiac disease
Autoimmune enteropathy
Common variable immunodeficiency
Refractory sprue
Overlapping Features of Immune-Mediated Small-Intestinal Diseases
Autoimmune
Enteropathy
Common Variable
Immunodeficiency
Crohn’s
Disease
Celiac
Disease
Pediatric and adult patients
+
+
+
+
Malabsorption/diarrhea
+
+
+
+
Weight loss/failure to thrive
+
+
+
+
Other autoimmune disorders
+
+
+
+
FOXP3
(IPEX syndrome)
TACI, BAFF,
APRIL
Dysregulation
of T cells
Abnormal B cell
maturation
Clinical Features
Pathogenesis
Molecular predisposition
Mechanism
NOD2,
TLR4
HLA-DQ2,
HLA-DQ8
Defective immune response to
environmental antigens
Serologic Markers
Anti-tissue transglutaminase
<5%
+
30%
unreliable
Anti-endomysial IgA antibody
+/-
+
+/-
unreliable
Anti-gliadin IgG antibody
+/-
+
+/-
unreliable
30%
+/-
unreliable
50-90%
+/-
Anti-Saccharomyces cerevisiae
Anti-enterocyte antibody
40-90%
Crohn’s Disease
Autoimmune Enteropathy
Celiac Disease
Common Variable Immunodeficiency
“Lymphocytic Gastritis” May Reflect
Immune-Mediated Gastrointestinal Injury
Gastric Intraepithelial Lymphocytes in
Pediatric Celiac Disease
ƒ
33 pediatric biopsies evaluated for gastric intraepithelial
lymphocytes (IELs)
–
–
–
23 patients with celiac disease
10 normal controls
Assessed for IELs/100 epithelial cells
Gluten Sensitivity
Mean IELs (range)
21 (4-50)
Controls
P Value
3 (1-8)
<0.01
– 70% of celiac disease cases had >8 IELs/100 epithelial cells
– Re-biopsy after gluten withdrawal showed decreased
gastric lymphocytosis (mean: 20 versus 4, n=4)
ƒ
Lymphocytic gastritis present in
– 4% of patients with Helicobacter pylori infection
– 33% of patients with celiac disease
Alsaigh N, Odze R, Goldman H, Antonioli DA, Ott MJ, Leichtner A. Am J Surg Pathol 1996; 20: 865-870.
Wu, T, Hamilton, S. Am J Surg Pathol 1999; 23(2): 153-158.
Immune-Mediated Disorders May Manifest
as Lymphocytic Colitis
Ileal Lymphocytosis Occurs in “Microscopic” Colitis
Mean
Lymphocytic
Colitis
Collagenous
Colitis
Controls
p Value
11.8+1.8
10.3+1.9
2.2+0.2
<0.01
Sapp H, Ithamukkala S, Brien TP, Ayata G, Shaz B, Dorfman DM, Wang HH, Antonioli DA,
Farraye FA, Odze RD. Am J Surg Pathol 2002; 26:1484-1492.
Manifestations of Immune-Mediated Diseases in the GI Tract
Crohn’s
Disease
Celiac
Disease
Autoimmune
Enteropathy
Common Variable
Immunodeficiency
Chronic non-specific inflammation
+
+
+
+
Chronic active gastritis, severe
+
-
+
+
Lymphocytic gastritis
-
+
+
+
Non-specific colitis
+
-
+
+
Lymphocytic colitis
+
+
+
+
Chronic colitis
+
-
+
+
+
+
+
+
Stomach
Colon
Duodenum/jejunum
Chronic enteritis with villous shortening
Specific Interrelationships
Celiac disease
0.85%
Crohn’s disease
Common variable immunodeficiency
Jevremovic, D, et al. Am J Surg Pathol. 2006; 30 (11): 1412-1419.
Leeds, JS, et al. Scand J Gastroenterol. 2007;42(10):1214-1220.
Akram, S, et al. Clin Gastroenterol Hepatol. 2007; 4(11): 1282-90.
Daniels, J, et al. Am J Surg Pathol. 2007;31(12):1800-12.
13%
1.7%
13%
Evaluation of Small-Intestinal Mucosal Biopsies
ƒ
Checklist
– Architecture
– Distribution (diffuse or patchy)
– Location of inflammation
ƒ
ƒ
Superficial or deep lamina propria
Surface, crypts or both
– Nature of inflammation
ƒ
ƒ
Lymphocyte predominant
Neutrophilic cryptitis
– Other abnormal features
ƒ
ƒ
Apoptosis
Infection (CMV)
– Presence of normal elements
ƒ
ƒ
Plasma cells
Goblet, Paneth, endocrine cells
Crohn’s Disease of the Proximal Small Bowel
Bousvaros, A, Antonioli, DA, Colletti, RB, Dubinsky, MC, Glickman, JN, Gold, BD, Griffiths, AM, Jevon, GP, Higuchi, LM, Hyams, JS,
Kirschner, BS, Kugathasan, S., Baldassano, RN, Russ, PA. J Pediatr Gastroenterol Nutr. 2007;44:653-674.
Antonioli, DA. Pediatr Dev Pathol. 2005;8:2-19.
Crohn’s Disease of the Proximal Small Bowel
Histologic Features of Celiac Disease
Antonioli, DA. Mod Pathol 2003; 16(4):342-346.
Celiac Disease
Autoimmune Enteropathy
Autoimmune Enteropathy
Common Variable Immunodeficiency
Common Variable Immunodeficiency
Common Variable Immunodeficiency
Classification of Chronic Enteritis
Crohn’s disease
Mixed inflammation
Multifocal neutrophilic cryptitis
Granulomas
Celiac disease
Surface and crypt lymphocytosis
No neutrophilic cryptitis
Chronic enteritis with villous shortening and crypt hyperplasia
Associated gastric and/or colonic injury
Relative sparing of surface epithelium
Crypt neutrophils
Apoptosis
Loss of goblet, endocrine, and Paneth cells
Autoimmune
enteropathy
Relative sparing of surface epithelium
Crypt neutrophils
Apoptosis
Lymphoid aggregates
Decreased plasma cells
Associated Giardia and/or CMV infection
Common variable
immunodeficiency
Case
Case
Autoimmune
Enteropathy
Summary and Conclusions
Contributions of Dr. Donald A. Antonioli
ƒ
The diagnostician
– Methodical approach to mucosal biopsy analysis
Villous architecture
ƒ Distribution of disease
ƒ Location of inflammation
ƒ Nature of inflammation
ƒ
Presence of other features
- Apoptosis or infection
ƒ Presence of normal elements
- Paneth, goblet, and plasma cells
ƒ
– Interpretation in combination with clinical features
ƒ
The educator
– More than 100 lectures
– 9 USCAP courses
ƒ
The academician
– More than 100 original articles
– More than 30 reviews and book chapters
Many thanks to our teacher, colleague and friend
&
&
Jeffrey D Goldsmith MD
Beth Israel Deaconess Medical Center
Children’s Hospital Boston
Harvard Medical School
Boston, MA
“PubMed = (“Allergic” or “Eosinophilic”) + “Esophagitis”
120
80
"Allergic"
"Eosinophilic"
60
40
20
07
20
06
20
05
20
04
20
03
20
02
20
01
20
00
20
99
19
98
0
19
Number of Manuscripts
100
Histology of GERD v EE
GERD
EE
pH Probe
Testing
PPI Therapy