Gino Roberto Corazza

I Clinica Medica

Fondazione IRCCS Policlinico San Matteo

Università di Pavia

DIAGNOSI DIFFICILI ED

ERRORI DIAGNOSTICI

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

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

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

PROTOCOLLO PER LA DIAGNOSI ED IL

FOLLOW-UP DELLA MALATTIA CELIACA

ADULTO

BAMBINO

Gazzetta Ufficiale n. 191; 15.08.2015

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

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)

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

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

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

FLAT MUCOSA IN COELIAC DISEASE

OM DM

SEM

SOURCE OF MISINTERPRETATION IN ASSESSING SMALL INTESTINAL BIOPSY

TANGENTIAL ARTIFACT

BRUNNER ARTIFACT

SMALL INTESTINAL BIOPSY. PROPER HANDLING AND PROCESSING

Orientation

Sectioning

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

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

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

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

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

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

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!

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

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)

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

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

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

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

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

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

FLAT MUCOSA IN GIARDIASIS

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

HISTOLOGIC FINDINGS IN 22 PTS WITH SPRUE-LIKE ENTHEROPATHY ASSOCIATED WITH OLMESARTAN

AUGUST 2012

REG3α - A PANETH CELL-DERIVED ANTIMICROBIAL PROTEIN

Alim Pharmacol Therap 2014

Reg

3α

(n

g/m

L)

UTCD RCD CVID Crohn’s IBS

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