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Ultrasuoni versus Breath Test:
Pro e Contro nella valutazione del danno epatico
13C-Breath Tests in epatologia
Edoardo G. Giannini
Cattedra di Gastroenterologia,Dipartimento di Medicina Interna,Università di Genova.
Corso SIGE: “Test Non-Invasivi” – Roma, 19 giugno 2015
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Agenda
- What is liver function?
- Why should we assess liver function?
- Use of BTs to assess liver function(s)
- Conclusions
13C-Breath Tests in chronic liver disease
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Quantitation of Intrinsic Drug-Metabolizing
Capacity: The Intact-Hepatocyte Theory
“…the changes within the liver can be considered to be due to reduced mass of
cells which function relatively normally and are normally perfused.”
What is liver function?
Branch RA. Hepatology 1982; 2: 97-105.
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Two reasons for decreased hepatic function in
chronic liver disease:
What is liver function?
1. Alteration of blood flow
2. Impairment of the intrinsic metabolic activity
Decreased hepatocellular functioning massDecreased hepatocellular functioning mass
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- The “liver biopsy paradigm”
- The complexity of liver functions and the
derangement of hepatic physiology in liver disease
- To score or to measure: that’s the question!
- Patients prognosis alias going beyond fibrosis
Why should we assess liver function?
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Can 13C-Breath Tests be considered surrogate markers
of liver fibrosis?
The complexity of liver functions…
Is liver fibrosis a surrogate marker for liver function?
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Histological
Clinical
Instrumental
Assessing disease stage and liver function
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F1 F2 F3 F4
“…grading and staging…are not measurements…A grade of 2 for a particular
feature…is not exactly half way between 1 and 3; it is merely in the opinion of the
pathologist…more than 1 and less than 3. It follows that the number generated must
not be manipulated as if they were exact measurements”
P. Scheuer
???? ???? ????Liver function
The “liver biopsy paradigm”
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To score or to measure: that’s the question!
5-6 7-9 10-15
Child-Pugh score
0 1 2 3 4
METAVIR fibrosis score
MELD score
• Equal transition between stages
• Variables weight
• Variables subjectivity/’manipulation’
• Assay variability (INR)
• Not comprehensive of CLD spectrum
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Patients prognosis alias going beyond fibrosis
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Liver BTs: Principles
Chronic Liver Disease
• Distortion of vascular architecture
• Shunting of hepatic blood flow
Decreased hepatocellular functioning mass
Giannini EG, et al. Eur Rev Med Pharmacol Sci 2004; 8: 51-4.
Inflammation Necrosis Fibrosis Regeneration
Disease stage and patients prognosis
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Liver BTs: Principles
Time
13C
O2
tota
l am
ount
Normal
Cirrhosis
13C-Substrate
Metabolite
13CO2
Rate-limiting step
Discrete versus Continuous
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Liver BTs: Principles
•Aminopyrine Microsomal P450s
•Methacetin Microsomal CYP1A2
Probe Hepatic function Enzyme studied
•Galactose Cytosolic Galactokinase
•Phenylalanine Cytosolic Hydroxylase•-Ketoisocaproic acid Mitochondrial ketoacid dehydrogenase complex
Blood flow dependent:
•13C-MBT
•13C-GBT
Blood flow independent:
•13C-ABT
•13C-GBT
•13C-PBT
•13C-KICABT
Armuzzi A, et al. Aliment Pharmacol Ther 2002; 16: 1977-96.
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Liver BTs: Principles
Branch RA. Hepatology 1982; 2: 97-105.
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Liver BTs: Results interpretation
Giannini E, et al. Aliment Pharmacol Ther 2002; 16: 717-25.
AB
T %
cum
/hr
PeakShape
AUC
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Am I sick?1. To detect disease
How bad is my disease?
2. To assess disease severity
How long will I live?
44. To establish prognosis
Will this drug be good for me?
33. To evaluate the effects of treatment
Why should we assess liver function?
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1. To detect disease
Giannini E, et al. Aliment Pharmacol Ther 2002; 16: 717-25.
0
1
2
3
4
5
6
7
8
9
10
0 30 60 90 120
Sampling time (min)
AB
T %
cum
dos
e
Normal subjects
Ishak stage 0-2
Ishak stage >2
P=0.001
•13C-Aminopyrine BT •HCV patients
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1. To detect disease
Lalazar G, et al. J Viral Hep 2008; 15: 716-28.
•13C-Methacetin BT
•HCV patients
•PNAL
•Continuous breath sampling device
•Fibrosis score>2
•AUROC=0.915
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1. To detect disease
Portincasa P, et al. Clin Sci 2006; III: 135-43.
•13C-Ketoisocaproic acid BT •NASH patients
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2. To stage disease
Mion F, et al. Eur J Clin Invest 1999; 29: 624-9.
•13C-Aminopyrine BT •HCV patients
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Giannini EG, et al. Clin Gastroenterol Hepatol 2005; 3: 279-85.
2. To stage disease
0
1
2
3
4
5
6
7
8
0 30 60 90 120 150 180Sampling time (min)
GB
T %
dose
/hr
Chronic Hepatitis
Child-Pugh class Acirrhosis
p<0.001
•13C-Galactose BT •Mixed aetiology
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2. To stage disease
Forestier J, et al. Eur J Gastroenterol Hepatol 2010; 22: 532-40.
AUC (95% CI)
- Fibroscan 0.93 (0.90-0.96)
- 13C-ABT 0.82 (0.77-0.87)
- APRI 0.81 (0.76-0.86)
Cirrhosis
P<0.0001
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3. To evaluate the effect of treatment
Ocker M, et al. World J Gastroenterol 2005; 11: 5521-4.
•13C-Aminopyrine BT • Chronic HCV infection on IFN
P<0.05
P<0.05
Week 12
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• 13C-Aminopyrine BT
• Chronic, untreated HCV infection
Rocco A, et al. J Hepatol 2012; 56: 782-7.
4. To establish prognosis
Basal fibrosis stage
2.7±0.8 (NP) versus 3.1±0.9 (Progr.)
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4. To establish prognosis
Giannini EG, et al. Dig Dis Sci 2013; 58: 3024-8.
•13C-Aminopyrine BT: 1-year survival in cirrhosis
•13C-ABT %dose/h30-MELD score: r= -0.414; P=0.004
0 50 100 150 200 250 300 350 400
Time
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
Surv
ival
pro
babi
lity
13C-ABT %dose/h30 2.0
13C-ABT %dose/h30 >2.0
P=0.001
(days)
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4. To establish prognosis
Degré D, et al. Transpl Int 2004; 17: 31-8.
AUROC:
• ABT 0.858
• CTP score 0.726
• MELD 0.704
•
•13C-Aminopyrine BT
•Mixed aetiology (42% ETOH)
•90-day survival on OLT wating list
P=0.07
P=0.02
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4. To establish prognosis
•OLT and MELD
Ecohard Y, et al. Clin Transplant 2011; 25: 755-65.
•13C-Aminopyrine BT
Dose/hr >2% Dose/hr 1-2% Dose/hr <1%
90-day survival = 78%
90-day survival = 51%
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Why should we use liver BTs?
Afolabi P, et al. Dig Dis Sci 2013; 58: 33-41.
Clinical assessment using 13C Breath Tests in patients with liver disease
Diagnostic utility Prognostic utility Monitoring liver function
Recognition/exclusion of liver disease in a target population
Prediction at an early stage of the severity and possible
outcome of disease
Determining the course of disease and the impact of clinical management on
patients outcome
- Various substrates with ≠ accuracy
- Better accuracy in advanced stages
-/+
++
- Possible use alone
- Helpful in fine-tuning prognosis in association with other scores
+/-
++
- Serial determinations (prognosis; therapeutic outcome)
+++
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Limitations
- Dedicated equipment, experienced physiciansDedicated equipment, experienced physicians
- Factors affecting results variability (CYP Factors affecting results variability (CYP
polymorphisms; gender, age; co-medications; polymorphisms; gender, age; co-medications;
comorbid illnesses)comorbid illnesses)
- Competing techniques (elastography, ARFI, etc.)Competing techniques (elastography, ARFI, etc.)
- CostsCosts
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Conclusions
- 13C-Liver Breath Tests can provide useful information
that goes beyond simple evaluation of fibrosis
- BTs can be used to detect disease, stage its
severity, and foresee patients’ prognosis
- They should not substitute the common tools used in
the clinical work-up of the patients but their use may
be complementary
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Jean Siméon Chardin (1699-1779)
La bulle de savon (1734))