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Elisabetta Cocconcelli

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Title: Elisabetta Cocconcelli


1
Prevalence 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
  • Elisabetta Cocconcelli

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
3
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
4
PATHOGENESIS OF IPFAbnormal wound healing model
Selman M., Ann Intern Med 2001 134136.
5
The 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.
6
EPIDEMIOLOGY 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
7
Clinical features and NATURAL HISTORY of IPF
  • Bibasilar dry velcro-crackles
  • Finger clubbing (50)
  • Dyspnea
  • Dry cough

AJRCCM 2011 183 788-824 (modified)
8
TREATMENT OF IPF
9
MECHANISMS OF FIBROSIS
Wynn TA Ramalingam TR, Nature Medicine 2012
18(7) 1028-40.
10
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.

11
HEPATIC 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
12
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.
13
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.
14
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 gt 29) or in those with narrow intercostal
    space
  • Not feasible in patients with ascites

15
Existing models for multi-organ
fibroticinvolvement
  • Telomeres shortening and telomere syndrome
  • IgG4-related sclerosis disease

16
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
3561317-26. Calado RT, et al. Hepatology 2011
531600-1607.
17
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
3561317-26. Calado RT, et al. Hepatology 2011
531600-1607.
18
IgG4-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.
19
AIM of the studyRESEARCH QUESTION
  • What is the prevalence of subclinical liver
    fibrosis among patients with a definite diagnosis
    of IPF?
  • Answer is unknown

20
METHODS
  • 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.

21
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

22
DEMOGRAPHICS
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.
23
FIBROSCAN 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).

24
RESULTS
  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
25
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.

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?

28
American Thoracic Societys International
Conference 2014 San Diego, May 16 - May 21
29
  • Thank you

30
Prevalence 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
  • Elisabetta Cocconcelli
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