Gianluca Ianiro, Giovanni Cammarota

Internal Medicine, Gastroenterology and Liver Unit ‘A. Gemelli’ University Hospital - Catholic University of Rome, Italy

Email: gianluca.ianiro@hotmail.it Twitter: @gianluca1aniro

Accuracy of biomarkers

of past and present inflammation

Do we need biomarkers to manage

diverticular disease?

COMPLICATED UNCOMPLICATED

DIVERTICULITIS HAEMORRHAGE

ABSCESS

PERFORATION

STENOSIS

FISTULA

UNCOMPLICATED COMPLICATED

~20%

~80%

~95% ~5%

DIVERTICULOSIS

ASYMPTOMATIC SYMPTOMATIC

(“DIVERTICULAR DISEASE”)

~20%

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

• 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?

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?

Pro • Gold standard in diagnosing acute diverticulitis

Cons • Expensive

• X-ray exposure

ABDOMEN CT-SCAN

How to monitor patients with

diverticular disease?

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

Do we need biomarkers to manage

diverticular disease?

Of course!

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?

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

Do we have biomarkers to manage

diverticular disease?

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

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%

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

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

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

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

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

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

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)

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

• 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

(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