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Elisabetta Cocconcelli

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.

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Elisabetta Cocconcelli

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  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

  2. Key Prioritiesof 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) Image courtesy of Giovanni Della Casa T. E. King Jr. A. Pardo, M. Selman. Idiopathic Pulmonary Fibrosis. Lancet 2011 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

  4. PATHOGENESIS OF IPFAbnormal wound healing model Selman M., Ann Intern Med 2001; 134:136.

  5. The CLINICAL DIAGNOSIS OF IPFrequires Suspected IPF • Exclusionof other known causes of ILD and • The presence of a UIP pattern on HRCT or • Specific combinations of HRCT and surgical lung biopsypattern Yes IdentificablecausesofILDs? No HRCT Not UIP Possible UIP Inconsistent w/ UIP UIP SurgicalLungBiopsy UIP Probable UIP/ possible UIP Non-classificablefibrosis MDD IPF IPF/ Not IPF Not IPF ATS/ERS/JRS/ALAT Guidelines; AJRCCM 2011.

  6. EPIDEMIOLOGY OF IPF and RISK FACTORS • Prevalence: 13 - 20 /100,000 individuals • M:F = 1.5 to 1.7:1 • Olderage: VI-VII decades • Mediansurvivaltime 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 Sporadicforms Familialforms 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 • Dyspnea • Dry cough • Bibasilar dry ‘velcro’-crackles • Finger clubbing (50%) STABLE SLOW PROGRESSION DISEASE PROGRESSION RAPID PROGRESSION TIME 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 • Biopsy • METAVIR • F0: no fibrosis • F1: portalfibrosis alone • F2: portalfibrosiswith rare septae • F3: portalfibrosiswithmanyseptae • F4: cirrhosis • NON-INVASIVE TESTS: • APRI 1.5 : significantfibrosis • APRI < 0.5 :significantfibrosisexcluded TRANSIENT ELASTOGRAPHY Alterations in the normally balanced process of extracellular matrix (ECM) production and degradation develop hepatic fibrosis

  12. TRANSIENT ELASTOGRAPHY (FibroScan) Castera L., Forns X., Alberti A. Journal of Hepatology 48. 2008; 835-847. Transient elastography (TE, FibroScan) is a non-invasive method for the assessment of hepatic fibrosis and steatosis, by measuring liver stiffness. Results are immediatelyavailable (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.

  13. TRANSIENT ELASTOGRAPHY (FibroScan) Castera L., Forns X., Alberti A. Journal of Hepatology 48. 2008; 835-847. • 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.

  14. TRANSIENT ELASTOGRAPHY (FibroScan) 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 • Results are expressed in kPa and correspond to the median of 10 validated measurements. Liver stiffness valuesrange 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.

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

  16. 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. 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. dyskeratosiscongenita, where both pulmonary and liver fibrosis display anticipation.

  17. 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. 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 detectabletelomerase 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.

  18. IgG4-RELATED SCLEROSIS DISEASE (ISD) Ryu JH, Sekiguchi H, Yi ES,Eur Respir J. 2012 Jan;39(1):180-6. Epub 2011 Jun 30. 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.

  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 > 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 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.

  23. FIBROSCAN RESULTS • 12 pts (22%) were excluded because of BMI > 29. • A certaindegree of liver fibrosis was documented in 14 pts (33%).

  24. RESULTS

  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 > 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 Society’s International Conference 2014 San Diego, May 16 - May 21

  29. Thank you

  30. 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

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