diagnosi difficili ed errori diagnostici - celiachia · università di pavia diagnosi difficili ed...
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Gino Roberto Corazza
I Clinica Medica
Fondazione IRCCS Policlinico San Matteo
Università di Pavia
DIAGNOSI DIFFICILI ED
ERRORI DIAGNOSTICI
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COELIAC DISEASE IN ITALY. THE SIZE OF THE PROBLEM
Italian population
Diagnosed patients
True figure
Undiagnosed patients
61.000.000
175.000
610.000 (1:100)
435.000
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MISDIAGNOSIS AND DIAGNOSTIC DELAY IN CD
Pts previously
misdiagnosed
(n=196)
J Clin Gastroenterol 1996
Pts with no previous
misdiagnosis
(n=223)
p
12.9 12.9 8.0 12.5 < 0.005
Pts with major
presentation
(n=129)
Pts with minor
presentation
(n=67)
p
14.0 13.8 9.7 9.2 < 0.05
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KNOWLEDGE LEVEL OF COELIAC DISEASE
AMONG 91 FULL PROFESSORS OF GASTROENTEROLOGY
? CD & Gallbladder and Pancreatic Dysfunction ?
? CD & Diabetes Mellitus ?
? CD & Psychiatric Illness ?
20
15
10
5
0
Group 1 Group 2
NS
Mann & Leung, Internat Med J 2006
Sc
ore
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PROTOCOLLO PER LA DIAGNOSI ED IL
FOLLOW-UP DELLA MALATTIA CELIACA
ADULTO
BAMBINO
Gazzetta Ufficiale n. 191; 15.08.2015
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THE SEQUENTIAL PROCESS OF MAKING DIAGNOSIS
Bowen, NEJM 2006
Data Acquisition Illness Scripts Testing Diagnosis
history taking
abstraction of problems
further oriented questioning
focused clinical examination
characterizing defining /
discriminating features
prioritizing features
finding a prototype
from clinical memory
generating hypotheses
ordering with a
specific intent
so optimizing
resource utilization
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Eva, Med Educ 2004
ANALYTIC vs NON-ANALYTIC PROCESSES IN CLINICAL REASONING
ANALYTIC NON-ANALYTIC
Presenting Clinical
Features
Diagnostic Hypotheses
Posterior Probability
A
B
C
Dx1
Dx2
Dx3
Pr(Dx1)
Pr(Dx2)
Pr(Dx3)
Presenting Clinical
Features
Diagnostic Hypotheses
Filter through prior
Episodes
A
B
C
D
A B D F
B D G R
C F G H
Pr(Dx1)
Pr(Dx2)
Pr(Dx3)
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ANALYTIC VS NON ANALYTIC PROCESSES IN DIARRHOEA
ANALYTIC NON - ANALYTIC
Diarrhoea
Acute (self–limiting)
Chronic ( > 4 wks)
Variable duration
> 300 – 400 g / 24 h Pain may be present Blood may be present May be nocturnal Systemic involvement Weight loss Stress–unrelated
< 300 – 400 g 24 / h Pain ↓ by evacuation Blood absent No special pattern
No systemic involvement
No weight loss Stress related
Duration > 6 mo
Organic Functional
Large volume Few movements No urgency
No mucus No blood
Small volume Frequency Urgency Tenesmus No tenesmus Mucus Blood
Right-sided Left-sided
Osmotic Secretory
Inflammatory
Blood / mucus
↑ white cells
↑ calprotectin
Watery
Anionic gap<50
↓ at fasting
Anionic gap>50
↓pH/steatorrhea
Diarrhoea + Delayed Menarche + ID anemia
Diarrhoea + Previous Arthralgias + Lymphadenopathy
Diarrhoea + Retinitis Pigmentosa + Friedreich Ataxia
Diarrhoea + Erithema Nodosum + RLoQ cramps
Diarrhoea + Predisposing Conditions + ↓ B12
COELIAC
DISEASE
WHIPPLE’S
DISEASE
A-β LIPO-
PROTEINEMIA
CROHN’S
DISEASE
BACTERIAL
OVERGROWTH
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DIAGNOSTIC REASONING STRATEGIES AND DIAGNOSTIC SUCCESS
20 experts & 20 novices – 12 gastroenterological questions
Coderre et al, Med Educ 2003
Dia
gn
osti
c S
uccess
(Od
ds R
ati
o)
10
5
0
- 5
15
5
0
10
Pattern Recognition vs Hypothetico-Deductive
Fre
uen
cy o
f u
se (
%)
of
Patt
ern
Reco
gn
itio
n v
s
Hyp
oth
eti
co
-Ded
ucti
ve
Experts Novices
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IS COELIAC DISEASE MIS/OVERDIAGNOSED?
RESULTS OF 605 CONSECUTIVE CASES REFERRED
TO UNIVERSITY OF PAVIA (1999/2005)
605
187-24
52+27
False Predictors
Clinical diagnosis
Unconventional tests
Poor sample quality
Marsh 1/2 lesions
tTG false-positivity
questioned
refused
Can J Gastroenterol 2009
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FLAT MUCOSA IN COELIAC DISEASE
OM DM
SEM
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SOURCE OF MISINTERPRETATION IN ASSESSING SMALL INTESTINAL BIOPSY
TANGENTIAL ARTIFACT
BRUNNER ARTIFACT
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SMALL INTESTINAL BIOPSY. PROPER HANDLING AND PROCESSING
Orientation
Sectioning
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Mars
h
cla
ssif
icati
on
O
berh
ub
er
cla
ssif
icati
on
C
ora
zza
cla
ssif
icati
on
1 2 3 4
1 2 3a 3b 3c 4
A B1 B2
Infiltrative Hyperplastic Atrophic Hypoplastic
Serra & Jani, J Clin Pathol 2006
AN APPROACH TO DUODENAL BIOPSIES IN CD
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A NEW CLASSIFICATION FOR THE DIAGNOSIS OF COELIAC DISEASE
Marsh-Oberhuber New Classification
Grade A
Grade B1
Grade B2
Deleted
Type 1
Type 2
Type 3a
Type 3b
Type 3c
Type 4
J Clin Pathol 2005
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0
10
20
30
40
Dis
trib
uti
on
(%
)
Kappa values
Marsh-Oberhuber System New Grading System
DISTRIBUTION (%) OF K VALUES COMPUTED USING 2 DIFFERENT GRADING SYSTEMS IN COELIAC DISEASE
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
Clin Gastroenterol Hepatol 2007
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PATHOLOGIST AGREEMENT WITHIN M-H CLASSIFICATION
Categories K Values
M–H type 0
M–H type 1
M–H type 2
M–H type 3a
M–H type 3b
M–H type 3c
0.46
0.23
0.04
0.19
0.24
0.64
Arguelles-Grande et al, J Clin Pathol 2012
0.58
0.03
0.05
0.30
0.18
0.50
Corazza et al, Clin Gastroenterol Hepatol 2007
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A REBUTTAL OF OBERHUBER'S SUBDIVISION OF MARSH III
it is surprising that their conclusions have been followed
and adopted so widely without logical and critical evaluation
pathologists, when classifying coeliac mucosa, since they
add nothing either of diagnostic nor prognostic value,
should resist these subcategories
we strongly disagree with the conclusions of Oberhuber et
al and do not believe that they offer a sound basis for "a
standardised report scheme for pathologists"
Marsh et al, Gastroenterol Hepatol 2015
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IS COELIAC DISEASE MIS/OVERDIAGNOSED?
RESULTS OF 605 CONSECUTIVE CASES REFERRED
TO UNIVERSITY OF PAVIA (1999/2005)
605
187-24
52+27
False Predictors
Clinical diagnosis
Unconventional tests
Poor sample quality
Marsh 1/2 lesions
tTG false-positivity
questioned
refused
Can J Gastroenterol 2009
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most of the studies performed in centres with a specific interest in CD most of the results obtained from stored serum samples comparisons between new and old ABs untenable lack of real prospective studies (even in risk groups [expected prevalence ~ 5-10%] 500/1000 new upper GI endoscopies needed to collect 50 new true positives !)
THE "BIASABLE" SEROLOGY IN CD
the real screening power of coeliac ABs is at best questionable!
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VILLOUS ATROPHY WITHOUT COELIAC
ANTIBODIES AT PAVIA UNIVERSITY (2000-2015)
274 pts with villous atrophy
260 pts with established CD (age 35±12 yrs; F 178, M 82; 4 deaths)
14 pts EMA-ve (age 49±16; F 2, M 12; 4 deaths)
5 CVID (2 nonCD, 3 ??)
2 IgA def + CD
3 DH
2 EATL
1 Olmesartan ETP
1 CD
Biagi et al, in press
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persistency (primary) or recurrency (secondary) of villous atrophy and malabsorptive symptoms despite strict adherence to a 12 mo GFD in the absence of overt malignancy
REFRACTORY COELIAC DISEASE (RCD)
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ʺFALSEʺ REFRACTORY CD
• dietary non-compliance or inadvertent gluten intake
• misinterpretation of the original biopsy
poor sample quality non-coeliac flat mucosa
• slow histological recovery after diet
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PITFALLS IN DIAGNOSING CD
Tangential artifact Proper orientation
Subtotal villous atrophy Normal mucosa
Six patients referred with a diagnosis of refractory CD
Failure to respond to a GFD should always
raise doubt regarding the initial diagnosis
Shidrawi et al, J Clin Pathol 1994
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CAUSES OF FLAT MUCOSA OTHER THAN CD
Autoimmune enteropathy
Common variable ID
Collagenous sprue
Giardiasis
Graft-versus-host disease
Tropical sprue
Whipple's disease
HIV enteropathy
Crohn's disease
Bacterial overgrowth
Eosinophilic gastroenteritis
Cow's milk enteropathy
Soy protein enteropathy
Chemotherapy
Radiation damage
Protein energy malnutrition
Lancet 2009
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AUTOIMMUNE ENTEROPATHY IN ADULTS
Mayo Clinic Series Case 1 Case 2
Lancet 1997 Clin Gastroenterol Hepatol 2007
● May 2001- June 2006
● 15 pts (47% Fe, age 55 yr)
● 15/15 severe malabsorbers
● 13/14 E/GoAb+
● 80% associated AI
● 60% clinical improvement
after immunosuppressants
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Pts. Sex Age (yrs)
Histological
response to a
GFD
Positive coeliac
antibodies HLA
1 M 47 Yes EMA IgG DQ2+
2 F 27 Yes EMA IgA-IgG DQ2+
3 M 42 Yes EMA IgG DQ8+
4 M 28 No EMA IgG DQ2/8-
5 M 46 No None DQ2/8-
6 M 35 No None DQ2/8-
7 M 53 No None DQ2+
8 M 46† No EMA IgG DQ2+
9 M 44 No EMA IgG DQ2+
10 F 59 No None DQ8+
11 F 52 No None DQ2+
Am J Clin Pathol 2012
FLAT DUODENAL MUCOSA IN PATIENTS WITH CVID
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DUODENAL MUCOSA IN PATIENTS WITH CVID
PC DEPLETION PMN INFILTRATE GVHD-like LESIONS
10/11 5/10 3/5
only in pts in whom CD not confirmed (#4-11)
Am J Clin Pathol 2012
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FLAT MUCOSA IN GIARDIASIS
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A 56 yr-old PHISYCIAN WITH BLOOD HYPERTENSION
& TYPE 2 DIABETES
2012
• RCD I diagnosis
• steroides added to GFD
• only mild clinical improvement
• BX partial villous atrophy
2011
• diarrhoea (10mov/d)
• weight loss (10kg/3mo)
• ve-
coeliac ABs
• BX complete villous atrophy
2013
• olmesartan withdrawal
• BX villous regrowth
• symptom resolution
• marked weight gain
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HISTOLOGIC FINDINGS IN 22 PTS WITH SPRUE-LIKE ENTHEROPATHY ASSOCIATED WITH OLMESARTAN
AUGUST 2012
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REG3α - A PANETH CELL-DERIVED ANTIMICROBIAL PROTEIN
Alim Pharmacol Therap 2014
Reg
3α
(n
g/m
L)
UTCD RCD CVID Crohn’s IBS
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ULCERATIVE JEJUNOILEITIS IN CD
Lancet 1998
A 53 yr-old woman with recurrence of abdominal pain, fever, diarrhoea and weight loss after a large intestinal resection for Crohn’s disease