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

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

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.

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

- 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?

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?

Histological

Clinical

Instrumental

Assessing disease stage and liver function

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”

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

Patients prognosis alias going beyond fibrosis

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

Liver BTs: Principles

Time

13C

O2

tota

l am

ount

Normal

Cirrhosis

13C-Substrate

Metabolite

13CO2

Rate-limiting step

Discrete versus Continuous

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.

Liver BTs: Principles

Branch RA. Hepatology 1982; 2: 97-105.

Liver BTs: Results interpretation

Giannini E, et al. Aliment Pharmacol Ther 2002; 16: 717-25.

AB

T %

cum

/hr

PeakShape

AUC

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?

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

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

1. To detect disease

Portincasa P, et al. Clin Sci 2006; III: 135-43.

•13C-Ketoisocaproic acid BT •NASH patients

2. To stage disease

Mion F, et al. Eur J Clin Invest 1999; 29: 624-9.

•13C-Aminopyrine BT •HCV patients

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

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

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

• 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.)

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)

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

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%

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)

+++

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

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

Jean Siméon Chardin (1699-1779)

La bulle de savon (1734))