coeliac disease: the current role of pathology (ii ... · pdf filecoeliac disease: the current...
TRANSCRIPT
Coeliac disease: the current role of pathology (II) Refractory coeliac disease
Luigi Terracciano
What is Refractory coeliac disease ?
Refractory sprue or refractory coeliac disease (RCD) is defined by:
persistent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet (GFD) for 6 -12 months
Refractory coeliac disease
An high rate of progression to lymphoma (> EATL)
Unique biochemical and immunologic features
Heterogeneous group whereas collagenous sprue accounts for 30-50% of cases
Most patients with collagenous sprue die from disease or require corticosteroids, other immunsuppressive agents or total parenteral nutrition to survive
High prevalence of autoimmune conditions (2-12 fold
> than coeliac disease)
Prevalence of refractory sprue among patients with coeliac disease
The real prevalence of RCD is unknown but is probably rare
0.7% - 1.5% of patients with Coeliac Disease (non-referral population-based cohorts)
More common in women
Most cases diagnosed after age 50
West J. Celiac Disease and Its Complications: A Time Traveller’s Perspective Gastroenterology 2009 136: 32-4
Rubio-Tapia A, Murray JA. Classification and management of refractory coeliac disease
Gut 2010 59: 547-557
Presentation of Refractory Sprue/Refractory Coeliac Disease
Persistent diarrhoea, abdominal pain, and involuntary weight loss
Multiple vitamin deficiencies
Anaemia, fatigue, malaise
Refractory Coeliac Disease Patients
The majority of patients with RCD experience initial clinical improvement on a GFD, but, after a period of remission, develop disease refractory to gluten abstinence (‘secondary RCD’)
Patients who have no initial response to a GFD (‘primary RCD’ or ‘unclassified sprue’)
The first step in the diagnosis of RCD is to confirm the initial diagnosis of CD
Confirm gluten abstinence
Rule out other causes of villous atrophy
Response to GFD
Clinically - a marked symptomatic improvement may occur within several days of starting GFD
Mucosal improvement may continue for 2 years or more
Causes of Villous Atrophy Coeliac disease
Tropical sprue
Giardiasis
Infectious enteritis
Small bowel bacterial overgrowth
Microscopic colitis
Eosinophilic gastroenteritis
Graft-versus-host disease
Cow's milk and soy protein enteropathy
Abetalipoproteinaemia
Small bowel ischaemia
Intestinal lymphoma
Tuberculosis
Crohn's disease
Parasitic infestation
Severe malnutrition
Adult onset autoimmune enteropathy
Common Variable Immunodeficiency
HIV enteropathy
Chemotherapy and radiation enteritis
Pathology work-up Abnormal Intraepithelial Lymphocyte Detection
Double CD3/CD8 immunohistochemistry
T cell receptor clonal rearrangement by PCR
Immunophenotyping using flow cytometry
Refractory Coeliac Disease
Clonal intraepithelial lymphocytes? >50% IELs with abnormal immunophenotype (CD3+ CD8-) by IHC > 20% ‘aberrant’ IELS (express cytoplasmic CD3ε, but lack surface expression CD3, CD4 and CD8) by flow cytometry Clonal T cell receptor gene rearrangement by molecular analysis
Refractory Coeliac
Disease Type 1
Refractory Coeliac
Disease Type 2
No Yes
CD3 CD8
From Cellier C et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet. 2000;356:203
CD3 CD8
NORMAL
ABNORMAL
Gut, 2007; 56: 1373 - 1378.
Five-year survival was higher in the type 1 group (96 vs 58 %).
Most deaths (half) were due to development of T-cell lymphoma
No patient with type 1 disease developed type 2 disease
Treatment Options
RCD type 1 - prednisone, budesonide or combination of prednisone and azathioprine are beneficial
No established treatments for RCD type 2
Chemotherapeutic drugs alone or high-dose chemo followed by autologous stem cell transplantation for selected patients with RCD type 2
Future novel therapies, such as interleukin 15 blockade ?
Al-Toma A, Goerres MS, Meijer JW, et al. Cladribine therapy in refractory celiac disease with aberrant T cells. Clin
Gastroenterol Hepatol 2006;4:1322e7; quiz 1300.
Al-toma A, Visser OJ, van Roessel HM, et al. Autologous hematopoietic stem cell transplantation in refractory celiac disease
with aberrant T cells. Blood 2007;109:2243-9
Al-Toma A, Verbeek WH, Visser OJ, et al. Disappointing outcome of autologous stem cell transplantation for enteropathy-
associated T-cell lymphoma. Dig Liver Dis 2007;39:634-41
Yokoyamaa S, Watanabea, Satob N et al. Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in
transgenic mice that overexpress IL-15 in enterocytes. PNAS 2009:106:15849–15854
Common Variable Immune Deficiency
CVID can display features similar to those of coeliac disease
Villous atrophy in 24% to 53% of duodenal samples from patients
Increased IELs (53%).
CVID patients often show markedly decreased to absent plasma cells (CD 138 useful)
Daniels JA et al. Gastrointestinal Tract Pathology in Patients with Common Variable Immune Deficiency (CVID) – A Clinicopathologic Study and Systematic Review Am J Surg Pathol 2007;31:1800–1812
Autoimmune Enteropathy
Rare cause of intractable diarrhoea associated with circulating gut autoantibodies and a predisposition to autoimmunity.
Adults and children
Histologically similar to coeliac disease with increased IELs and villous blunting
IgA and IgG anti-enterocyte antibodies
Other organ-specific autoantibodies
No coeliac-related autoantibodies
Steroid responsive
From: Akram S, Murray JA, Pardi DS et al. Adult Autoimmune Enteropathy: Mayo Clinic Rochester Experience. Clin Gastroenterol Hepatol 2007;5:1282–1290
Collagenous sprue
Rare form of small bowel enteropathy.
Pathologic lesion consists of subepithelial collagen deposition associated with variable alterations in villous architecture.
Characterised clinically by chronic diarrhoea and progressive malabsorption.
It has traditionally been associated with significant morbidity
- 7 cases of collagenous sprue.
- Clonal TCR gamma configurations were found in 5/6
- 3 of these patients died from malnutrition.
- 5 new cases of collagenous sprue and extensive literature review
- 13/30 patients known to have died from complications of disease
AJSP 24(5):676-687, May 2000
The Lancet - Vol. 356, Issue 9225, 15 July
2000, P 203-208
12 cases (4 males), 41-84 yrs
6 patients improved clinically with combination of GFD and immunosuppressant drugs; histologic improvement in 3/6.
1 patient died of another illness, 2 died of CS complications. No lymphoma.
4 had CD
AJSP 2009;33:1440–1449
Collagenous sprue
Coeliac sprue
• Flat or nearly flat mucosa with crypt
hyperplasia and increased
intraepithelial lymphocytes (IELs)
CD3+ CD8+
• Positive serologic tests : tTG,
antiendomisial, antigliadin abs
• DQw2 and DQ8
• Clinical, biochemical and
morphologic response to a gluten-
free diet regimen
Collagenous sprue
• Flat or nearly flat mucosa with mild
or absent crypt hyperplasia and
increased intraepithelial
lymphocytes (IELs) CD3+ CD8 +/-
• Collagen band
• > Serologic test negative
• no DQw2
• Incomplete or absent response to a
gluten-free diet regimen (refractory
sprue)
Masson’s Trichrome
Lamina propria cells and capillaries entrapped in collagen
Varying degrees of villous atrophy
Sirius Red _ subepithelial collagen deposition
Sirius Red _ subepithelial collagen deposition
CD3
CD8
CD8
IgH-FR3 TCRg Rearrangement IgH-FR1
Beta-Globin= QC
100
Size (bp)
139
150
160
200
247
300
339
350
400
450
Almost no B-cells Polyclonal TCR-g rearrangement
Seminested multiplex-PCR for B- and T-cell rearrangement
Collagenous sprue
Histology • Layer of subepithelial collagen thicker than 12mm into the lamina propria
• Entrapment of cellular elements is a mandatory diagnostic criterion
• Crypt atrophy more frequent than crypt hyperplasia
• Intraepithelial lymphocytosis may be absent (>25 IELs per 100 epithelial cells)
• Hyperchromasia of the crypt epithelium
• Subcrypt inflammation and even crypt abscesses
• If collagen deposits are found in ther small bowel, similar deposity may be
concomitantly present in colonic (ie, collagenous colitis) and/or gastric
mucosa: further endoscopic assessment and biopsy elsewhere in GI tract
Zhao X, Arch Pathol Lab Med, 2011
Small bowel histology Gastric histology (4/7 bx) Colonic histology (7/9 bx)
Collagenous sprue Collagenous gastritis Collagenous colitis
Lymphocytic colitis
Collagenous sprue Chronic gastritis No biopsy
Collagenous sprue Lymphocytic gastritis Normal colonic biopsy
Collagenous sprue No biopsy Normal colonic biopsy
Collagenous sprue Collagenous gastritis Collagenous colitis
Collagenous sprue Normal antral biopsy No biopsy
Collagenous sprue No biopsy Collagenous colitis
Collagenous sprue No biopsy Collagenous colitis
Collagenous sprue No biopsy Collagenous colitis
Collagenous sprue Collagenous gastritis Collagenous colitis
Collagenous sprue Reactive gastropathy Collagenous colitis
Collagenous sprue
Ulcerative jejuno-ileitis
No biopsy No biopsy
TAKE HOME When patients fail to respond to GFD revisit and confirm initial diagnosis
of CD
Confirm adherence to GFD
Rare causes of villous atrophy should also be considered and ruled out.
• Recognition of RCD, and discrimination between RCD type 1 and 2, is important for prognosis and treatment.
• RCD is a potentially treatable condition, particularly type 1 variant.
• RCD type 2 is associated with a poorer prognosis and patients have a high risk of developing EATL.
Collagenous sprue:
• may be a histological pattern associated with several different immune-mediated GI diseases, most commonly CD
• may be associated with collagen deposition in other parts of GIT
• Most patients respond to a combination of GFD and immunosuppressive drugs
TEMPLATE REPORT
CLINICAL DETAILS
SITE & NO. OF BIOPSIES
COMMENT ON ORIENTATION
VILLOUS/CRYPT RATIO – NORMAL (type 1)/PARTIAL OR SUBTOTAL (type 2) / OR TOTAL (type 3)
INCREASED IELS –NORMAL/INCREASED (>25)
PRESENCE OF NEUTROPHILS, EOSINIPHILS, SUBEPITHELIAL COLLAGEN (> 10-20 micron and measure)
References
1. Zhao X, Johnson RL, Collagenous sprue: a rare, severe small-bowel malabsorptive
disorder Arch Pathol Lab Med. 2011 Jun;135(6):803-9
2. WeinsteinWM, Saunders DR, Tytgat GN, et al. Collagenous sprue—an
unrecognized type of malabsorption. N Engl J Med 1970;283:1297-301.
1. Vakiani E, Arguelles-Grande C, Mansukhani MM, et al. Collagenous sprue is not
always associated with dismal outcomes: a clinicopathological study of 19
patients. Mod Pathol. 2010;23(1):12–26.
2. Bagdi E, Diss TC, Munson P, Isaacson PG. Mucosal intra-epithelial lymphocytes in
enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac
disease constitute a neoplastic population. Blood. 1999; 94(1):260–264.
3. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and
enteropathy-associated T-cell lymphoma. Lancet. 2000;356(9225):203–208.
CD8 Phenotype in Refractory sprue
IEL phenotype is considered abnormal when the number of CD8+ IEL /
100 epithelial cells is less than 50% of CD3+ IEL / 100 epithelial cells
Cellier C, Lancet, 2000
23 complicated CD
18 Refractory Sprue: CD3+ CD8+ in 12/18 (67%)
CD3+ CD8- in 6/18 (33%)
5 EATL CD3+ CD8- in 3/5 (60%)
de Mascarel A, Am J Surg Pathol, 2008
CD8- 6/6 RCD Patey-Mariaud de Serre N, Histopathology, 2000
15/15 RCD Verkarre V, Gut, 2003
17/20 RCD Bagdi E, Blood, 1999
CD8 Phenotype in Refractory sprue
Refractory Sprue
Type 1 CD3+ CD8+
Type 2 CD3+ CD8- with clonal intestinal TCR g rearrangements and
clonal dissemination into the blood. Worse prognosis and strong
indicator for the development of overt T-cell lymphoma (cryptic T-cell
lymphoma, Green PH, N Engl J Med, 2007 )