Familial Pulmonary Fibrosis: Hope and Hand Wringing for a Difficult Disease. Charlene D Fell Division of Respiratory Medicine University of Calgary

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1 Familial Pulmonary Fibrosis: Hope and Hand Wringing for a Difficult Disease Charlene D Fell Division of Respiratory Medicine University of Calgary

2 Disclosures Speakers Fees: GlaxoSmithKline, AstaZeneca, Boehringer- Ingelheim, Pfizer Scientific Advisory Board: Actelion

3 50 year old woman with possible Familial Pulmonary Fibrosis Referred by Dr. Loyd at Vanderbilt University Part of a large family with fibrotic lung disease MRC I dyspnea, habitual throat clearing PMHx: Migraines, mild intermittent asthma No medications/allergies Exam: normal PFTs: FVC 94%; DL CO 92% May 2008

4 50 year old woman with possible Familial Pulmonary Fibrosis

5 50 year old woman with possible Familial Pulmonary Fibrosis

6 Familial Pulmonary Fibrosis (FPF) FPF occurs when two or more members of a family have idiopathic interstitial pneumonia. Idiopathic Pulmonary Fibrosis Non-specific Interstitial Pneumonia Over 100 families have been described. Prevalence is estimated at 2-3%. Individuals within families may have different forms of IIP. WE Lawson & JE Loyd. Proc Am Thorac Soc. 2006

7 What is Idiopathic Pulmonary Fibrosis? Chronic, progressive fibrotic pulmonary disease No known cause No effective therapies currently available Mean survival after diagnosis is 3 years May 2005 Nov 2005 Apr 2006

8 Selman M, King TE, Pardo A. Ann Intern Med. 2001

9 Is pulmonary fibrosis a genetic disease? Not all patients exposed to fibrogenic dusts develop pulmonary fibrosis; Pulmonary fibrosis occurs in a number of genetic disorders: Tuberous sclerosis, Hermansky-Pudlak syndrome, Niemann-Pick disease, Gaucher disease, neurofibromatosis, and adult hypercalciuric hypercalcemia; Familial clustering of pulmonary fibrosis has been observed, including individuals raised in different environments.

10 Is FPF a genetic disease? Surfactant proteins A1, A2, B, C, and D Telomerase reverse transcriptase (TERT) Interleukin-1 Receptor Antagonist (IL-1RN) TNF-α Erythrocyte complement receptor 1 (CR1) TGF-β1 Angiotensin converting enzyme (ACE)

11 Is FPF a genetic disease? Surfactant proteins A1, A2, B, C, and D Telomerase reverse transcriptase (TERT) Interleukin-1 Receptor Antagonist (IL-1RN) TNF-α Erythrocyte complement receptor 1 (CR1) TGF-β1 Angiotensin converting enzyme (ACE)

12 Surfactant

13 Surfactant Protein C and FPF SFTPC gene mutation was associated with DIP in a mother and NSIP in her infant. The mutation resulted in a defective pro-sp-c protein. Several other infants with ILD have been found to have different mutations in the SFTPC gene. Absence of SP-C on BAL was associated with ILD in a mother and two daughters. Is surfactant protein C important in the pathogenesis of IPF?

14 Surfactant Protein C and FPF Thomas, AQ et al. AJRCCM. 2002

15 Surfactant Protein C and FPF T A transversion in exon 5 of the SFTP-C gene Thomas, AQ et al. AJRCCM. 2002

16 Surfactant Protein C and FPF Thomas, AQ et al. AJRCCM. 2002

17 Surfactant Protein C and FPF Normal Affected Thomas, AQ et al. AJRCCM. 2002

18 Surfactant Protein C and FPF Thomas, AQ et al. AJRCCM. 2002

19 SP-C and FPF Chibbar, R et al. Modern Pathology. 2004

20 SP-C and FPF Chibbar, R et al. Modern Pathology. 2004

21 SP-C and FPF patient V:4 Chibbar, R et al. Modern Pathology. 2004

22 Surfactant Protein C and FPF Transversion of T A in exon 5 of SFTP-C gene Leu 188 to Gln 188 in the carboxy-terminal of the pr-sp-c protein Improper folding and processing of pro-sp-c protein Accumulation of pro-spc in the cytoplasm of alvelolar type II pneumocytes Leads to alveolar type II injury Autosomal dominant with variable expression L188Q mutation + unknown environmental factors form the basis for the UIP and NSIP phenotypes in this family Thomas, AQ et al. AJRCCM Chibbar, R et al. Modern Pathology. 2004

23 Back to the patient.

24 50 year old woman with FPF

25 50 year old woman with FPF Thomas, AQ et al. AJRCCM. 2002

26 50 year old woman with FPF: 2 years later.. Daily morning cough MRC I dyspnea Exam: fine crackles at R base PFTs: FVC 79%; DL CO 71% March 2010 (FVC 94%; DL CO 92%) May 2008

27 50 year old woman with FPF August 2008 August 2009

28 Some challenges with FPF For this patient HRCT does not meet ATS/ERS criteria for UIP; she does not want a lung biopsy No effective treatments for this disease

29 Some challenges with FPF Should we screen asymptomatic family members? How should we follow SFTP-C mutationpositive patients who do not have clinical signs of disease? What is different between the adults in this family (UIP) and the infants (NSIP)?

30 Summary FPF: IIP in two or more members of a family Exon T A mutation in the gene encoding SFTPC has been associated with FPF There are many other potential genetic mutations associated with FPF Many challenges face FPF families and their clinicians!

31 Thank you

32 FPF: An Exploratory Study Anecdotal evidence suggests that the prevalence of FPF may be as high as 20% Objectives: Determine if we could identify FPF among the IPF patients seen in the University of Calgary ILD Clinic Hypothesis: The prevalence of FPF is greater than 3%

33 FPF: An Exploratory Study 44 Patients 24 Excluded: 1 Hypersensitivity Pneumonitis 1 LIP 4 CTD-ILD 4 Other diagnoses* 14 Unknown: unable or unwilling to have a lung biopsy 20 Included 2 FPF 1 Possible FPF 17 No FPF

34 FPF: An Exploratory Study Patient FPF # Relatives Relationship Diagnosis Quality of Data 1 Yes 3 Father Sister Sister IPF Symptoms UIP IPF Hearsay Autopsy Hearsay 2 Yes 3 Father Brother Brother Pulmonary Fibrosis Pulmonary Fibrosis Pulmonary Fibrosis Hearsay Hearsay Hearsay 3 Possible 1 Grandmother Pulmonary Fibrosis Hearsay

35 FPF: An Exploratory Study Prevalence of FPF was 10% in this sample. Quality of the information on family members was poor. A more extensive study at the U of C is not likely to result in reliable data.

36 Is FPF a genetic disease? Surfactant proteins A1, A2, B, C, and D Telomerase reverse transcriptase (TERT) Interleukin-1 Receptor Antagonist (IL-1RN) TNF-α Erythrocyte complement receptor 1 (CR1) TGF-β1 Angiotensin converting enzyme (ACE)

37 What is a telomere? (a refresher on DNA replication) Start telomere

38 What are telomeres and telomerases? Calado, RT & Young, NS. NEJM. 2009

39 Consequences of telomere shortening Dyskeratosis congenita Aplastic anemia, myelodysplasia and AML Pulmonary fibrosis Cirrhosis and nodular regenerative hyperplasia Risk of cancer? Calado, RT and Young, NS. NEJM. 2009

40 Telomeres and FPF Tsakiri KD et al. PNAS

41 Telomeres and FPF Tsakiri KD et al. PNAS

42 Telomeres and IPF Alder J K et al. PNAS

43 Telomeres and IPF Short telomeres are associated with both sporadic IPF and FPF. Several mutations in the gene encoding telomerase have been identified. FPF is attributable to these mutations in some families. Development of pulmonary fibrosis in these patients may be due to a loss of regenerative capacity. Telomere length may be considered a risk factor for IPF in the future.

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