Title: Elisabetta Cocconcelli
1Prevalence of liver fibrosis among patients with
definite diagnosis of Idiopathic Pulmonary
Fibrosis
Azienda Ospedaliero - Universitaria Policlinico
di Modena Clinica di Malattie dellApparato
Respiratorio Direttore L.M. Fabbri Ospedale
Privato Accreditato Villa Pineta U.O. di
Pneumologia e Riabilitazione Respiratoria Direttor
e E. M. Clini Pavullo n/F (MO), 4 Luglio 2014
2- Key Priorities of Meeting
- Set Priorities for Research Identify the
scientific priorities for future investigations
in single organ and cross-organ fibrotic disease - Assess Existing Models Assess the currently
available experimental models and their relevance
to human health and disease (identify new models,
if needed) - Identify Fibrosis Therapies Identify potential
promising therapies for pathologic tissue
fibrosis
Fibrosis Across Organ System Symposium, March
8th, 2012 - March 11th, 2012 Denver, CO
3Idiopathic 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
4PATHOGENESIS OF IPFAbnormal wound healing model
Selman M., Ann Intern Med 2001 134136.
5The CLINICAL DIAGNOSIS OF IPFrequires
- 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
ATS/ERS/JRS/ALAT Guidelines AJRCCM 2011.
6EPIDEMIOLOGY OF IPF and RISK FACTORS
- Prevalence 13 - 20 /100,000 individuals
- MF 1.5 to 1.71
- 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
7Clinical features and NATURAL HISTORY of IPF
- Bibasilar dry velcro-crackles
- Finger clubbing (50)
AJRCCM 2011 183 788-824 (modified)
8TREATMENT OF IPF
9MECHANISMS OF FIBROSIS
Wynn TA Ramalingam TR, Nature Medicine 2012
18(7) 1028-40.
10Chronic 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.
11HEPATIC FIBROSISClinical evaluations
- Alterations in the normally balanced process of
extracellular matrix (ECM) production and
degradation develop hepatic fibrosis
- NON-INVASIVE TESTS
- APRI? 1.5 significant fibrosis
- APRI lt 0.5 significant fibrosis excluded
- Biopsy
- METAVIR
- F0 no fibrosis
- F1 portal fibrosis alone
- F2 portal fibrosis with rare septae
- F3 portal fibrosis with many septae
- F4 cirrhosis
TRANSIENT ELASTOGRAPHY
12TRANSIENT 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.
13TRANSIENT 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.
14TRANSIENT 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 gt 29) or in those with narrow intercostal
space - Not feasible in patients with ascites
15Existing models for multi-organ
fibroticinvolvement
- Telomeres shortening and telomere syndrome
- IgG4-related sclerosis disease
16TELOMERE 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
3561317-26. Calado RT, et al. Hepatology 2011
531600-1607.
17TELOMERE 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
3561317-26. Calado RT, et al. Hepatology 2011
531600-1607.
18IgG4-RELATED SCLEROSIS DISEASE (ISD)
- ISD is a fibroinflammatory disease associated
with elevated circulating levels of IgG4 (gt 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
Jan39(1)180-6. Epub 2011 Jun 30.
19AIM of the studyRESEARCH QUESTION
- What is the prevalence of subclinical liver
fibrosis among patients with a definite diagnosis
of IPF? - Answer is unknown
-
20METHODS
- Inclusion criteria
- Patients with a diagnosis of IPF according to
2011 ATS/ERS/JRS/ALAT Guidelines - Exclusion criteria
- BMI gt 29
- Previous history of chronic liver disease
- Approved by the local Ethics Committee.
21METHODS
- 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
22DEMOGRAPHICS
Characteristics Results (N55)
Patients, MF 41 14
Mean age years SD 69 10
Diagnosis HRCT vs. SLB 41 vs. 14
Mean FVC, pred. 73,4 (range 22-120)
Mean DLCO-SB, pred. 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, FVCforced vital capacity, DLCO-SB
diffusing capacity for carbon monoxide, single
breath, Ggender, Aage, P lung pulmonary
variables.
23FIBROSCAN RESULTS
FibroScan METAVIR scale Results (N43) Mean Stiffness SD
F0-F1, n () 18 (42) 3.72 0.7 kPa
F1, n () 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
Not reliable/Low quality 11 (25)
- 12 pts (22) were excluded because of BMI gt 29.
- A certain degree of liver fibrosis was documented
in 14 pts (33).
24RESULTS
 F0-F1 F0-F1 F0-F1 F0-F1 F1-F2 F1-F2 F1-F2 F1-F2 F2 F2 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 23,25 9 14 25 27
ALT 18 10,25 14 17,50 4 10,25 12 26 9 17 29 32
? GT 17 15 21 30 4 15,75 18,50 21,50 9 15 58 120
Bilirubin 15 0,37 0,41 0,45 3 0,38 0,51 0,65 7 0,44 0,59 0,73
IgG4 12 43 52 146,50 2 42,00 60 78 5 32 126 419
MCV 16 87,68 91,85 95,83 3 94,85 97 101,15 8 90,43 91,75 94,83
25RESULTS
- 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.
26- Limitations and problems
- Sample size
- In patients with BMI gt 29, results are not
reliable - Is the incidence of liver fibrosis in IPF
patients really higher than in age-matched
controls?
27- 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?
28American Thoracic Societys International
Conference 2014 San Diego, May 16 - May 21
29 30Prevalence of liver fibrosis among patients with
definite diagnosis of Idiopathic Pulmonary
Fibrosis
Azienda Ospedaliero - Universitaria Policlinico
di Modena Clinica di Malattie dellApparato
Respiratorio Direttore L.M. Fabbri Ospedale
Privato Accreditato Villa Pineta U.O. di
Pneumologia e Riabilitazione Respiratoria Direttor
e E. M. Clini Pavullo n/F (MO), 4 Luglio 2014