Transcript Diapositiva 1

Azienda Ospedaliero - Universitaria Policlinico di Modena
Clinica di Malattie dell’Apparato Respiratorio
Direttore L.M. Fabbri
Ospedale Privato Accreditato Villa Pineta
U.O. di Pneumologia e Riabilitazione Respiratoria
Direttore E. M. Clini
Pavullo n/F (MO), 4 Luglio 2014
Prevalence of liver fibrosis among
patients with definite diagnosis of
Idiopathic Pulmonary Fibrosis
Elisabetta Cocconcelli
Key Priorities of Meeting:
1. Set Priorities for Research: Identify the scientific priorities for future
investigations in single organ and cross-organ fibrotic disease
2. Assess Existing Models: Assess the currently available experimental models
and their relevance to human health and disease (identify new models, if
needed)
3. Identify Fibrosis Therapies: Identify potential promising therapies for
pathologic tissue fibrosis
Fibrosis Across Organ System Symposium, March 8th, 2012 - March 11th, 2012 Denver, CO
Idiopathic Pulmonary Fibrosis (IPF)
IPF is defined as a specific form of chronic, progressive fibrosing
interstitial pneumonia of unknown cause, occurring primarily in
elderly male adults, limited to the lungs, and associated with the
histopathologic and/or radiologic pattern of UIP
Image courtesy of Giovanni Della Casa
T. E. King Jr. A. Pardo, M. Selman. Idiopathic Pulmonary Fibrosis. Lancet 2011
PATHOGENESIS OF IPF
Abnormal wound healing model
Selman M., Ann Intern Med 2001; 134:136.
The CLINICAL DIAGNOSIS OF IPF
requires
 Exclusion of other
known causes of ILD
and
 The presence of a UIP
pattern on HRCT
or
 Specific combinations
of HRCT and surgical
lung biopsy pattern
Suspected IPF
Yes
Identificable causes of ILDs?
No
HRCT
UIP
Not UIP
Surgical Lung Biopsy
UIP
Probable UIP/ possible UIP
Non-classificable fibrosis
MDD
IPF
ATS/ERS/JRS/ALAT Guidelines; AJRCCM 2011.
Possible UIP
Inconsistent w/ UIP
IPF/ Not IPF
Not IPF
EPIDEMIOLOGY OF IPF and
RISK FACTORS
 Prevalence: 13 - 20 /100,000
individuals
 M:F = 1.5 to 1.7:1
 Older age: VI-VII decades
 Median survival time 3 yrs
Despite the uncertain cause, some potential risk factors might be:
 History of cigarette smoking
 Environmental exposure
 Microbial agents
 Gastroesophageal reflux
 Ageing
 Genetic factors
Sporadic forms
Familial forms
Raghu G, Collard HR, Egan J. et al. Am J Respir Crit Care Med. 2011.
T. E. King Jr. A. Pardo, M. Selman. Idiopathic Pulmonary Fibrosis. Lancet 2011
Clinical features and NATURAL HISTORY of IPF
 Dyspnea
 Dry cough
 Bibasilar dry ‘velcro’-crackles
 Finger clubbing (50%)
DISEASE PROGRESSION
STABLE
SLOW
PROGRESSION
RAPID
PROGRESSION
TIME
AJRCCM 2011; 183: 788-824 (modified)
TREATMENT OF IPF
MECHANISMS OF FIBROSIS
Wynn TA & Ramalingam TR, Nature Medicine 2012; 18(7): 1028-40.
Chronic liver disease and Cirrhosis
Chronic hepatitis is characterized by a combination of
hepatocyte necrosis and inflammation, persisting
from more than 6 months and associated with a
variable degree of fibrosis.
Cirrhosis is the final common histologic pathway for a wide
variety of chronic liver diseases. Mean features are: hepatic
fibrosis and regenerative nodules.
HEPATIC FIBROSIS
Clinical evaluations
Alterations in the normally balanced process of
extracellular matrix (ECM) production and
degradation develop hepatic fibrosis
 Biopsy
METAVIR
 NON-INVASIVE TESTS:
F0: no fibrosis
F1: portal fibrosis alone
F2: portal fibrosis with rare
septae
F3: portal fibrosis with many
septae
F4: cirrhosis
APRI 1.5 : significant fibrosis
APRI < 0.5 :significant fibrosis excluded
TRANSIENT ELASTOGRAPHY
TRANSIENT ELASTOGRAPHY (FibroScan)
Transient elastography (TE, FibroScan) is a non-invasive method for the assessment of
hepatic fibrosis and steatosis, by measuring liver stiffness. Results are immediately
available (5-7min) and operator-independent
Principles
 An ultrasound transducer probe is mounted on the axis of a vibrator.
 Vibrations of mild amplitude and low frequency (50 Hz) are
transmitted by the transducer, inducing an elastic shear wave that
propagates through the underlying tissues.
 Pulse-echo ultrasound acquisition is used to follow the propagation
of the shear wave and to measure its velocity, which is directly
related to tissue stiffness: the stiffer the tissue, the faster the shear
wave propagates.
Castera L., Forns X., Alberti A. Journal of Hepatology 48. 2008; 835-847.
TRANSIENT ELASTOGRAPHY (FibroScan)
 TE measures liver stiffness in a volume that approximates a cylinder 1
cm wide and 4 cm long, between 25 mm and 65 mm below the skin
surface
volume 100 times bigger than a biopsy sample
 The tip of the probe transducer is placed on the skin between the rib
bones at the level of the right lobe of the liver where liver biopsy
would be performed.
 The software determines whether each measurement is successful or
not. When a shot is unsuccessful, the machine does not give any
reading.
Castera L., Forns X., Alberti A. Journal of Hepatology 48. 2008; 835-847.
TRANSIENT ELASTOGRAPHY (FibroScan)
 Results are expressed in kPa and correspond to the median of 10 validated
measurements. Liver stiffness values range from 2.5 to 75 kPa.
 Use of ranges of values rather than a single cut-off value
Combining TE results with serum markers increases diagnostic accuracy and liver
biopsy can be avoided.
Limitations:
- Failure in ≈5% of cases, mainly in obese patients (BMI > 29) or in those with narrow
intercostal space
- Not feasible in patients with ascites
Existing models for multi-organ fibrotic
involvement
 Telomeres shortening and telomere syndrome
 IgG4-related sclerosis disease
TELOMERE SHORTENING
Short telomeres limit tissue renewal capacity and
ultimately lead to organ failure.
 Involved in degenerative age-related disease.
 In a subset of patients with familiar (8-15%) or sporadic (1-3%)
IPF, germ-line mutations in telomerase components (hTERT and
hTR) have been described.
 Telomere shortening has been described in sporadic cirrhosis.
 Mutations in telomerase have heterogeneous manifestations
(telomere syndromes), e.g. dyskeratosis congenita, where both
pulmonary and liver fibrosis display anticipation.
Diaz de Leon A, et al. PLoS ONE 2010; 5(5):e10680.
Armanios MY, et al. NEJM 2007; 356:1317-26.
Calado RT, et al. Hepatology 2011; 53:1600-1607.
TELOMERE SHORTENING
Short telomeres limit tissue renewal capacity and
ultimately lead to organ failure.
 It has been identified a cluster of individuals (3%) with
concomitant IPF and cryptogenic liver cirrhosis. They had
telomeres in the lowest percentiles.
 None of these patients had detectable telomerase mutations,
although they had telomeres in the lowest percentiles.
 Therefore, telomere length, rather than telomerase mutations,
might predict disease onset in syndromes of telomere
shortening.
Diaz de Leon A, et al. PLoS ONE 2010; 5(5):e10680.
Armanios MY, et al. NEJM 2007; 356:1317-26.
Calado RT, et al. Hepatology 2011; 53:1600-1607.
IgG4-RELATED SCLEROSIS DISEASE (ISD)
ISD is a fibroinflammatory disease associated with elevated circulating
levels of IgG4 (> 140 mg/dL), occurring primarly in males with median
age of 60-65 years.
• The characteristic lesions of dense lymphoplasmocytic infiltrates
containing IgG4-positive plasma cells have been documented in many
organs, including bile duct, liver (IgG4-hepatopathy), kidney,
retroperitoneum, as well as the lung.
• The disease can either be localized or systemic. Lesions in different organs
can present simultaneously or metachronously.
• Intrathoracic manifestations are heterogeneous, involving lung
parenchyma, intrathoracic lymph nodes, pleura, as well as the
mediastinum.
Ryu JH, Sekiguchi H, Yi ES, Eur Respir J. 2012 Jan;39(1):180-6. Epub 2011 Jun 30.
AIM of the study
RESEARCH QUESTION
What is the prevalence of subclinical liver
fibrosis among patients with a definite
diagnosis of IPF?
Answer is unknown
METHODS
Inclusion criteria
• Patients with a diagnosis of IPF according to 2011
ATS/ERS/JRS/ALAT Guidelines
Exclusion criteria
• BMI > 29
• Previous history of chronic liver disease
Approved by the local Ethics Committee.
METHODS
Enrolled patients undergo FibroScan to detect
any degree of liver fibrosis.
Patients with FibroScan results suggesting
liver fibrosis underwent:
• additional testing for markers of liver injury
• extensive screening for possible secondary causes of liver fibrosis
DEMOGRAPHICS
Characteristics
Results (N=55)
Patients, M:F
41 : 14
Mean age years ± SD
69 ± 10
Diagnosis HRCT vs. SLB
41 vs. 14
Mean FVC, % pred.
Mean DLCO-SB, % pred.
73,4 % (range 22-120%)
40 % (range 11-102%)
GAP score
• Stage I
36%
• Stage II
43%
• Stage III
21%
Definition of abbreviations: HRCT= high resolution computed tomography, SLB= surgical lung biopsy, FVC=forced
vital capacity, DLCO-SB= diffusing capacity for carbon monoxide, single breath, G=gender, A=age, P= lung
pulmonary variables.
FIBROSCAN RESULTS
Results (N=43)
Mean Stiffness ±SD
18 (42%)
3.72 ±0.7 kPa
1
6.60 kPa
F1-F2, n (%)
4 (9%)
6.78 ±0,74 kPa
F2, n (%)
6 (14%)
7.87 ±0.43 kPa
F2-F3, n
1
9.5 kPa
F4, n
1
14.3 kPa
Probable fibrosis
1
40.3 kPa
FibroScan – METAVIR scale
F0-F1, n (%)
F1, n (%)
Not reliable/Low quality
11 (25%)
• 12 pts (22%) were excluded
because of BMI > 29.
• A certain degree of liver fibrosis
was documented in 14 pts (33%).
distribution on fibroscan results
Not reliable
33%
F0-F1
25%
42%
Liver Fibrosis
RESULTS
F0-F1
F1-F2
≥ F2
n 25°
median
75°n 25°
median
75°n 25°
median
75°
kPa
18 3,05
3,65
4,28 5 6,20
6,60
7,20 9 7,60
8,40
9,50
APRI
17 0,19
0,23
0,31 3 0,20
0,22
0,40 9 0,17
0,24
0,29
AST
18 19
20
24,75 4 15,50
17,50
ALT
18 10,25
14
17,50 4 10,25
12
γ GT
17 15
21
30 4 15,75
Bilirubin 15 0,37
IgG4
12 43
MCV
16 87,68
18,50
23,25 9 14
25
27
26 9 17
29
32
21,50 9 15
58
120
0,41
0,45 3 0,38
0,51
0,65 7 0,44
0,59
0,73
52
146,50 2 42,00
60
78 5 32
126
419
91,85
95,83 3 94,85
97
101,15 8 90,43
91,75
94,83
RESULTS
Data show that about one third (33%) of patients with IPF has a
concomitant fibrosing process in the liver.
 Minor impairment of markers of liver injury was found in a
minority of patients with liver fibrosis.
 Secondary causes of liver fibrosis were excluded in all patients.
 IgG4 levels were measured in 19 patients and isolated
increased levels were found in 5 patients.
 One patient with F4 fibrosis on FibroScan and elevated IgG4,
underwent liver biopsy showing a chronic non-alcoholic liver
disease. No evidence of IgG4 on liver histology.
Limitations and problems
 Sample size
 In patients with BMI > 29, results are not reliable
 Is the incidence of liver fibrosis in IPF patients really
higher than in age-matched controls?
Future directions
 Investigate the possibility of final common pathways
leading to fibrosis both in the lung and in the liver
 Increase the sample size
 Possibly enroll an age-matched control population
 More analysis of telomerase mutations and telomere
length should be performed
 Assess the presence of pulmonary fibrosis among
patients with cryptogenic liver fibrosis
Unanswered question
 What is the effect of any degree of liver fibrosis on the
biological response to IPF treatments?
American Thoracic Society’s International Conference 2014 San Diego, May 16 - May 21
Thank you
Azienda Ospedaliero - Universitaria Policlinico di Modena
Clinica di Malattie dell’Apparato Respiratorio
Direttore L.M. Fabbri
Ospedale Privato Accreditato Villa Pineta
U.O. di Pneumologia e Riabilitazione Respiratoria
Direttore E. M. Clini
Pavullo n/F (MO), 4 Luglio 2014
Prevalence of liver fibrosis among
patients with definite diagnosis of
Idiopathic Pulmonary Fibrosis
Elisabetta Cocconcelli