Elisabetta Cocconcelli
Prevalence of liver fibrosis among patients with definite diagnosis of
Idiopathic Pulmonary Fibrosis
Azienda Ospedaliero - Universitaria Policlinico di Modena
Clinica di Malattie dell’Apparato RespiratorioDirettore L.M. Fabbri
Ospedale Privato Accreditato Villa PinetaU.O. di Pneumologia e Riabilitazione Respiratoria
Direttore E. M. Clini
Pavullo n/F (MO), 4 Luglio 2014
Fibrosis Across Organ System Symposium, March 8th, 2012 - March 11th, 2012 Denver, CO
Key Priorities of Meeting:
1.Set Priorities for Research: Identify the scientific priorities for future investigations in single organ and cross-organ fibrotic disease 2.Assess Existing Models: Assess the currently available experimental models and their relevance to human health and disease (identify new models, if needed) 3.Identify Fibrosis Therapies: Identify potential promising therapies for pathologic tissue fibrosis
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
PATHOGENESIS OF IPFAbnormal wound healing model
Selman M., Ann Intern Med 2001; 134:136.
The CLINICAL DIAGNOSIS OF IPFrequires
Exclusion of other known causes of ILDand
The presence of a UIP pattern on HRCTor
Specific combinations of HRCT and surgical lung biopsy pattern
ATS/ERS/JRS/ALAT Guidelines; AJRCCM 2011.
Suspected IPFSuspected IPF
MDDMDD
Surgical Lung BiopsySurgical Lung Biopsy
HRCTHRCT
Identificable causes of ILDs?Identificable causes of ILDs?
Not IPFNot IPFIPF/ Not IPFIPF/ Not IPFIPFIPF
No
Possible UIPInconsistent w/ UIP
UIPNot UIP
Yes
UIPProbable UIP/ possible UIPNon-classificable fibrosis
EPIDEMIOLOGY OF IPF and RISK FACTORS
Prevalence: 13 - 20 /100,000 individuals
M:F = 1.5 to 1.7:1
Older age: VI-VII decades Median survival time 3 yrs
Despite the uncertain cause, some potential risk factors might be:History of cigarette smokingEnvironmental exposureMicrobial agentsGastroesophageal reflux AgeingGenetic 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
AJRCCM 2011; 183: 788-824 (modified)
Clinical features and NATURAL HISTORY of IPF
RAPID PROGRESSION
STABLE
DIS
EASE
PRO
GRE
SSIO
N
TIME
SLOW PROGRESSION
Bibasilar dry ‘velcro’-crackles Finger clubbing (50%)
Dyspnea Dry cough
TREATMENT OF IPF
MECHANISMS OF FIBROSIS
Wynn TA & Ramalingam TR, Nature Medicine 2012; 18(7): 1028-40.
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.
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 fibrosisAPRI < 0.5 :significant fibrosis excluded
Biopsy METAVIR
F0: no fibrosisF1: portal fibrosis aloneF2: portal fibrosis with rare septaeF3: portal fibrosis with many septaeF4: cirrhosis
TRANSIENT ELASTOGRAPHY
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.
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.
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 > 29) or in those with narrow intercostal space -Not feasible in patients with ascites
Existing models for multi-organ fibroticinvolvement
Telomeres shortening and telomere syndrome
IgG4-related sclerosis disease
TELOMERE SHORTENINGShort 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; 356:1317-26.Calado RT, et al. Hepatology 2011; 53:1600-1607.
TELOMERE SHORTENINGShort 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; 356:1317-26.Calado RT, et al. Hepatology 2011; 53:1600-1607.
IgG4-RELATED SCLEROSIS DISEASE (ISD)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.
Ryu JH, Sekiguchi H, Yi ES, Eur Respir J. 2012 Jan;39(1):180-6. Epub 2011 Jun 30.
AIM of the studyRESEARCH QUESTION
What is the prevalence of subclinical liver fibrosis among patients with a definite
diagnosis of IPF?
Answer is unknown
METHODSInclusion 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.
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
DEMOGRAPHICS
Characteristics Results (N=55)
Patients, M:F 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, FVC=forced vital capacity, DLCO-SB= diffusing capacity for carbon monoxide, single breath, G=gender, A=age, P= lung pulmonary variables.
FIBROSCAN RESULTSFibroScan – METAVIR scale Results (N=43) 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 > 29.
• A certain degree of liver fibrosis was documented in 14 pts (33%).
RESULTS F0-F1 F1-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
γ 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
RESULTSData 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.
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?
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?
American Thoracic Society’s International Conference 2014 San Diego, May 16 - May 21
Thank you
Elisabetta Cocconcelli
Prevalence of liver fibrosis among patients with definite diagnosis of
Idiopathic Pulmonary Fibrosis
Azienda Ospedaliero - Universitaria Policlinico di Modena
Clinica di Malattie dell’Apparato RespiratorioDirettore L.M. Fabbri
Ospedale Privato Accreditato Villa PinetaU.O. di Pneumologia e Riabilitazione Respiratoria
Direttore E. M. Clini
Pavullo n/F (MO), 4 Luglio 2014