Elisabetta Cocconcelli

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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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• 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
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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
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PATHOGENESIS OF IPFAbnormal wound healing model
Selman M., Ann Intern Med 2001 134136.
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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.
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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
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Clinical features and NATURAL HISTORY of IPF

• Bibasilar dry velcro-crackles
• Finger clubbing (50)

• Dyspnea
• Dry cough

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

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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
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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.
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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.
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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

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Existing models for multi-organ
fibroticinvolvement

• Telomeres shortening and telomere syndrome
• IgG4-related sclerosis disease

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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.
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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.
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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.
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AIM of the studyRESEARCH QUESTION

• What is the prevalence of subclinical liver
  fibrosis among patients with a definite diagnosis
  of IPF?
• Answer is unknown

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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.

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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

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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.
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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).

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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
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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.

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• 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?

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• 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?

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

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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