presentazione di powerpoint · • significant intra-individual biological variations • watery...
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Gianluca Ianiro, Giovanni Cammarota
Internal Medicine, Gastroenterology and Liver Unit ‘A. Gemelli’ University Hospital - Catholic University of Rome, Italy
Email: [email protected] Twitter: @gianluca1aniro
Accuracy of biomarkers
of past and present inflammation
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Do we need biomarkers to manage
diverticular disease?
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COMPLICATED UNCOMPLICATED
DIVERTICULITIS HAEMORRHAGE
ABSCESS
PERFORATION
STENOSIS
FISTULA
UNCOMPLICATED COMPLICATED
~20%
~80%
~95% ~5%
DIVERTICULOSIS
ASYMPTOMATIC SYMPTOMATIC
(“DIVERTICULAR DISEASE”)
~20%
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COMPLICATED UNCOMPLICATED
DIVERTICULITIS HAEMORRHAGE
ABSCESS
PERFORATION
STENOSIS
FISTULA
UNCOMPLICATED COMPLICATED
~20%
~80%
~95% ~5%
DIVERTICULOSIS
ASYMPTOMATIC SYMPTOMATIC
(“DIVERTICULAR DISEASE”)
~20%
We need to monitor patients with
diverticular disease
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• Assessment of disease activity
• Evaluation of response to therapy
• Prediction and prevention of clinical relapse
• Prediction and prevention of surgery
Which aspects of diverticular disease
should we monitor?
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CLINICAL SIGNS AND SYMPTOMS
Symptomatic DD
•Nonspecific ‘colicky’ or steady abd pain
•Abdominal tenderness
•Bloating
•Changes in bowel habits
Acute diverticulitis
Additional symptoms as:
• nausea, vomiting
• fever
• occasionally, urinary problems
It is enough?
How to monitor patients with
diverticular disease?
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Pro • Gold standard in diagnosing acute diverticulitis
Cons • Expensive
• X-ray exposure
ABDOMEN CT-SCAN
How to monitor patients with
diverticular disease?
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How to monitor patients with
diverticular disease?
Pro • Monitoring and diagnosis of acute diverticulitis
• Rules out other diseases (IBD, cancer, etc)
Cons • Expensive
• Invasive
• Potentially harmful (especially in
acute diverticulitis)
COLONOSCOPY
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Do we need biomarkers to manage
diverticular disease?
Of course!
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Official NIH definition of a biomarker:
A characteristic that is objectively measured and evaluated as an
indicator of:
• Normal biologic processes
• Pathogenic processes
• Pharmacologic responses to a therapeutic intervention
Biomarkers Definitions Working Group. Clin Pharmacol Ther 2001
WHAT IS A BIOMARKER?
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FEATURES OF A BIOMARKER
• Accurate
• Reproducible
• Acceptable
• Easy to be interpreted
• High sensitivity
• High specificity
• Low cost
Biomarkers Definitions Working Group. Clin Pharmacol Ther 2001
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Do we have biomarkers to manage
diverticular disease?
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Mimura T. DCR 2004;47: 371-8; Tursi A. DDS 2008;53:2474-9; Simpson J. NGM 2009;21: 847-58; Ridgway PF. CRD 2009;11: 941-6; Tursi A. IJCD 2009;24:
49-55; Tursi A. JCG 2010;; Laméris W. DCR 2010;53: 896-904; Käser SA. WJS 2010;34: 2717-22; Elli L. DDS 2011;56: 2098-103; Andeweg CS. AS 2011
SEROLOGICAL BIOMARKERS
Acute phase
reactants
• Erithrocyte sedimentation rate (ESR)
• C-reactive protein
• Bilirubin, alkaline phosphatase,
• α1-acid glycoprotein (orosomucoid)
• Platelet count, fibrinogen
Cytokines • Interleukins (IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13)
• Interleukin receptors (IL-1 and IL-2)
• IFN-γ,TGF-β, TNF-α, tTG-2, caspase 9
Other
biomarkers
• PGP9.5, SP, NPK, PACAP, VIP, galanin
• Metalloproteinase (MMP-1 and MMP-2)/M. inhibitors (TIMPs)
FECAL BIOMARKERS
Fecal excretion of cells
and leucocytes products
• Fecal calprotectin
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INCREASE OF SEROLOGICAL MARKERS
Acute uncomplicated diverticulitis
• 21 pts with acute uncomplicated diverticulitis
Tursi et al – JCG 2010
19.4%
57.1%
61.9%
23.8%
28.6%
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INCREASE OF SEROLOGICAL MARKERS
Uncomplicated VS complicated diverticulitis
Tursi et al – Dig Dis Sci 2008
Uncomplicated Diverticulitis
(39 pts)
Complicated
Diverticulitis (11 pts)
WBC*
[range 4000-9000 mm3]
8700
(range 5000-12.000)
12.500
(range 10000-18.000)
ESR*
[range 0 - <10 mm/h]
28 (range 18 – 40) 78 (range 56 – 104)
CRP*
[range 0.0-0.50 mg/dl]
2.50 (range 1.0- 3.50) 20.50 (range 15.0 - 33.50)
Fibrinogen*
[range 200-400 mg/dl]
490 (range 420-550) 730 (range 640 – 890)
β2-globulin*
[range 2.50 – 6.50%]
5.40 (range 3.8 – 7.2) 11.20 (range 8.5 – 14.90)
α1-acid glycoprotein*
[range 47-120 mg/dl]
118 (range 68 – 129) 156 (range 138 – 179)
*Statistically significant difference
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BLOOD VS TISSUE Biomarkers predict histologic damage in AUD
Tursi et al – JCG 2010
Diagnostic accuracy of different biomarkers in predicting
neutrophilic infiltrate in AUD
Sensitivity Specificity PPV NPV
CRP 86% 86% 0.92 0.75
ESR 90% 70% 0.76 0.87
α1-acid glycoprotein 85% 42% 0.42 0.85
Fibrinogen 88% 46% 0.48 0.84
WBC 66% 22% 0.12 0.80
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Biomarkers correlate with resolution of
symptoms in acute diverticulitis
Ridgway PF. Colorectal Dis 2009
a
b
c
Correlation between serological markers
and resolution of symptoms after treatment
• CRP: r = 0.40; p<0.01
• WBC: r = 0.396; P<0.01
• ESR: r = 0.27; P<0.01
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MULTIVARIATE LOGISTIC REGRESSION
•CRP≥50 is an independent predictor of ALCD (Adj OR 5.18 – 95% CI 2.11–
12.76)
SEROLOGICAL BIOMARKERS C-Reactive Protein and acute diverticulitis
VARIABLE ALCD + (n=124) ALCD- (n=163) OR (95% IC)
WBCC (x N9/L) •<10 •10–12 •13–15
•>15
35
31
29
29
77
27
26
33
1
2.53 (1.32–4.85)
2.45 (1.26–4.76)
1.93 (1.02–3.66)
CRP (mg/dl) •≤10
•10-49
•≥50
14
26
84
46
44
73
1
1.94 (0.90–4.19)
3.78 (1.92–7.43)
• 287 pts with acute abd pain - Acute left-sided diverticulitis in 43% of them (124)
UNIVARIATE LOGISTIC REGRESSION
Andeweg CS. Ann Surg 2011
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C-reactive protein predicts perforation in
acute sigmoid diverticulitis
Retrospective cohort of 247pts with acute sigmoid diverticulitis (86 with perforation)
Andeweg CS. Ann Surg 2011
• CRP<50 mg/l = perforation unlikely
• CRP>200 mg/l= strong indicator of perforation
• Higher CRP levels correspond to higher Hinchey grades
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FECAL BIOMARKERS
Fecal calprotectin
Tursi – Dig Dis 2012
• 50–60% of neutrophilic cytosolic protein
• Released from cells during cell activation or death.
• Stable in feces for several days after excretion
• Easily measured in stool by commercially available ELISAs
• Able to differentiate between IBS and IBD
• Sensitive marker of activity in CD
• Good correlation with endoscopic/histological activity in UC
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Increase of fecal calprotectin is able to
distinguish patients with IBS and DD
Tursi – Int J Colorectal Dis 2009
• PTS: 16 asympt diverticulosis, 16 SUDD, 16 AUD, 16 IBS and 16 HC
• FC assessment at baseline and, in SUDD & AUD, after treatment (rifa+mesalazine)
• No significant difference in FC levels
between AD, HC, IBS
• Higher FC values in AUD (p<0.0005)
and SUDD (p<0.005) VS HC and IBS
• FC decreased after treatment to normal
values in both AUD (p<0.0005) and
SUDD (p<0.005)
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Tursi – Dig Dis 2012
• Prospective cohort study of 54 pts with acute uncomplicated diverticulitis
• FC monitoring after remission and during follow-up
• Increased FC was found
in 87.5 % of pts which
experienced recurrence
of diverticulitis
Increase of fecal calprotectin predicts
recurrence of diverticulitis
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• Bleedings>100 ml (e.g. menstrual bleeding) might increase calprotectin
levels
• Significant intra-individual biological variations
• Watery feces may reduce sensitivity of the rapid test
• NSAIDs might cause an increase in calprotectin levels due to NSAIDs-
induced enteropathy
• Specificity is not as high as desired because calprotectin increases in
any condition that causes neutrophil migration to gut (neoplasm and
infection)
Turkay C. Clinics 2010; Vestergaard TA. Scand J Clin Lab Invest 2007
FECAL CALPROTECTIN
Not all that shines is gold
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(Some) biomarkers are good and cheap tools for the management of diverticular disease
TAKE-HOME MESSAGES
• Both CRP and fecal calprotectin are reliable markers of disease activity and therapeutic response
• Fecal calprotectin is a reliable tool to distinguish IBS from diverticular disease