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idiopathic pulmonary fibrosis

Monday 23 August 2004

cryptogenic fibrosing alveolitis

Definition: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease characterized by lung scarring and abnormal gas exchange. The disease is rare in children and typically affects individuals age 50 or more, with the incidence increasing with advanced age.

The UIP pattern is the underlying pathology in patients with the clinical diagnosis of "idiopathic pulmonary fibrosis" (IPF), also known as "cryptogenic fibrosing alveolitis" (CFA).

Idiopathic pulmonary fibrosis (IPF) is a distinctive clinicopathologic entity and the most common form of progressive diffuse lung scarring in older adults.

Idiopathic pulmonary fibrosis manifests histopathologically as the usual interstitial pneumonia (UIP) pattern.

The usual interstitial pneumonia pattern is distinguished by geographically and temporally heterogeneous fibrosis that is peripherally accentuated, often with honeycombing and traction bronchiectasis.

Idiopathic pulmonary fibrosis is not the only disease that leads to end-stage lung fibrosis, however, and several other entities may also cause advanced fibrosis.


The prevalence is 4 per 100 000 in adults aged 18–34 years but increases to over 227 per 100 000 among those 75 years and older. The disease is more common in men and in smokers. There are approximately 89 000 persons diagnosed with IPF in the United States, with about 34 000 new cases diagnosed each year. IPF is always fatal with no spontaneous remission. The median life span after diagnosis is usually between 2.5 and 3.5 years.

Clinical presentation

The clinical presentation of IPF is similar to that of all the "scarring lung diseases", collectively called "interstitial lung diseases", which lead to pulmonary fibrosis and symptoms of a chronic cough and shortness of breath.

Patients with IPF have abnormal pulmonary function tests (PFTs) reflecting a restrictive respiratory pattern coupled with evidence of lung scarring, characteristically involving the periphery of the lower lobes of the lung.


The UIP pattern is the underlying pathology in patients with the clinical diagnosis of "idiopathic pulmonary fibrosis" (IPF), also known as "cryptogenic fibrosing alveolitis" (CFA).

The diagnosis of IPF is supported by thorascopic lung biopsy, which reveals a histological pattern of ‘usual interstitial pneumonia’ (UIP), with fibroblastic foci at the interface between normal and scarred lung.

In the absence of a surgical lung biopsy, IPF can be diagnosed after other known causes of PF are excluded and certain clinical criteria have been met using spirometry to assess lung function, high resolution computed tomography (CT) of the chest to assess lung morphology, and a transbronchial lung biopsy or bronchoalveolar fluid (BAL) to rule out alternative diagnoses.

Differential diagnosis

Over one hundred different clinical interstitial lung diseases are associated with PF, including connective tissue diseases, occupational exposures, drug toxicities and other primary diseases of the lung.

If no culprit can be identified, the "interstitial lung disease" may represent a class of lung disease called "idiopathic interstitial pneumonias" (IIP).

These have been further classified to assist with predicting clinical course and outcome.

IPF is the most common of all the IIPs and also the most deadly, with no definitive medical treatments. Lung transplantation is an option for younger patients.


Idiopathic pulmonary fibrosis (IPF) is a poorly understood immunomediated disorder that is characterized by three major features; influx of inflammatory cells into the lower respiratory tract, alveolar epithelial or capillary cell injury, and release of cytokines that stimulate proliferation of fibroblasts and type II pneumocytes along with deposition of extracellular matrix proteins, notably collagen.

In the past few years interest in the pathogenetic mechanisms taking place in IPF has focused on immune effector cells that are involved in pulmonary inflammatory pathways, cell-specific injury, and fibroblast activation.

In particular, accumulating evidence indicates that a complex relationship exists between the macrophage/lymphocyte/neutrophil cellular axis and the local network of cytokines that, through paracrine and autocrine interactions, coordinate inflammation and fibrogenesis in the respiratory tract.

Familial IPF

A small subset of patients with IPF has a familial form of the disease. The first large collection of familial IPF families was reported just 7 years ago by Marshall and his colleagues who identified 25 families (including 67 cases).

They estimated that familial cases account for 0.5–2.2% of all cases of IPF, with a prevalence of 1.3 cases per million. The familial form of IPF accounts for 3.3–3.7% of all cases in Finland with geographic clustering of the familial cases suggesting a founder effect.

In cohorts of patients with early onset disease, such as those referred for lung transplantation, the incidence of the familial form of the disease has been reported to be much higher, up to 14–19% (80,81). The pattern of inheritance in most families is consistent with an autosomal dominant pattern with incomplete penetrance.

The clinical presentation of familial IPF in the United Kingdom appears to be indistinguishable from sporadic IPF except that the age of onset tends to be younger.

The mean age at diagnosis is 55.5 years for familial IPF compared to 67.4–69.8 years in sporadic IPF. In familial IPF, males outnumber females, with a ratio of 1.75:1.

Half of the cases in families are smokers. In another collection of over 100 families with IPF, older age, male sex and smoking cigarettes were strongly associated with the development of the disease.

An autosomal dominant pattern of inheritance was seen in 20% of these families.

Within the families, affected individuals have radiographic and/or histopathologic features consistent with two or even three different types of IIP, suggesting that the inherited genetic factor(s) confer an increased risk for the development of pulmonary fibrosis in response to injury, but not an absolute risk for one particular histologic subtype of IIP.

Telomere dysfunction

A clue to the molecular basis of familial IPF emerged from studies performed simultaneously by two groups using different approaches: Armanios and her colleagues at Johns Hopkins used a candidate gene approach while our group used a non-biased whole genome mapping approach.

Armanios had previously described a family with autosomal dominant DKC with haploinsufficiency of telomerase due to a missense mutation in the reverse transcriptase domain of TERT in which four of the seven affected individuals were diagnosed with idiopathic pulmonary fibrosis between 21 and 63 years of age. She and her colleagues subsequently sequenced TERT in probands of a collection of 73 kindreds with familial IPF.

They identified six probands (8%) with mutations; five were heterozygous for mutations in TERT and one was heterozygous for a mutation in TERC. The telomere lengths in lymphocytes from these affected individuals were all less than the 10th percentile when compared to age-matched controls.

Taking an unbiased genetic approach, we performed a whole genome linkage scan in two large families with familial IPF. We found evidence of linkage to the short arm of chromosome 5 in a small region that contained the TERT gene. Since a mutation in this gene had been previously found in a DKC family in which many of the affected individuals had pulmonary fibrosis, we considered this to be an excellent candidate gene.

Heterozygous mutations in TERC or TERT are seen in 12% of our cohort of families; TERT mutations were found not only in the two large families used for the linkage analysis but also in four other kindreds with familial pulmonary fibrosis, and a TERC mutation was found in an additional family.

The mutations in TERT segregated not only with individuals that met the strict diagnosis of IPF, but also several with pulmonary fibrosis favoring the upper lobes of the lung and others with unclassified pulmonary disease.

Several family members of these kindreds with no self-reported lung problems were identified to be heterozygous for a mutant TERT allele; thus, the pulmonary disease was not completely penetrant.

Almost 70% of telomerase mutation carriers over the age of 40 have pulmonary disease of some kind. More than one-third has osteoporosis or osteopenia affecting the axial skeleton.

While this condition may have been exacerbated by corticosteroid treatment that is frequently given to patients with pulmonary fibrosis, in half the cases this diagnosis either preceded steroid treatment or occurred independently of a diagnosis of pulmonary fibrosis.

A mild to moderate anemia (hematocrit of 23–32%) and several cancers (lymphoma, breast, skin) were occasionally found among the telomerase mutations carriers in the kindreds with familial pulmonary fibrosis.

Thus, our preliminary findings indicate that the clinical phenotypes of anemia and osteoporosis may provide additional clinical indices of disease in IPF families due to telomerase mutations.

The mutations in TERT found in kindreds with familial IPF are different from those previously found in patients with DKC or bone marrow failure (Figure 2B). Three identified mutations are nucleotide deletions that are predicted to create frameshifts and truncated proteins.

As predicted, the V747fs frameshift mutations missing half the reverse transcriptase domain had undetectable in vitro telomerase activity. Co-translation of different ratios of plasmids encoding the V747fs protein and the wild-type TERT protein did not negatively affect the activity of the wild-type protein, suggesting a mechanism of haploinsufficiency.

The other two identified deletion mutants, P122fs and E1116fs, are predicted to delete most of the protein or just the terminal 17 amino acids of the protein containing the conserved E-IV domain, respectively. The latter mutation has almost undetectable in vitro telomerase activity.

The other identified mutations in TERT in patients with familial pulmonary fibrosis are missense and splice site mutations. The missense mutations demonstrate a range of 30–100% wild-type telomerase activity in conventional rabbit reticulocyte in vitro assays.

The missense mutations span all the different functional domains of the protein. There is a cluster of three independent mutations in the motif C region of the reverse transcriptase domain. We found the R865H mutation in motif C that segregated in one of the large families used in the original linkage scan.

Sequencing TERT in 44 individuals with sporadic IIPs identified one individual with a mutation involving the same amino acid residue, R866C.

Armanios et al. also identified a mutation that results in selective skipping of exon 10, which encodes motif C. These three independent mutations in motif C in IPF patients suggest a potential genotype–phenotype relationship.

Only two different mutations in TERC have been described in kindreds with familial IPF. One mutation, 37a > g, affecting the terminal residue of the P1b helix that functions in the hTR template boundary definition, was previously identified in a patient with DKC and severe aplastic anemia who is a compound heterozygote for mutations in TERC. It was not reported whether family members with the same mutation had any signs or symptoms of pulmonary fibrosis. A second mutation in TERC was found in a family with pulmonary fibrosis and aplastic anemia. Mutations in TERC thus appear more likely associated with DKC and bone marrow failure syndromes than familial pulmonary fibrosis.

When compared with age-matched normal controls, individuals heterozygous for all the identified mutations in TERT or TERC had shorter telomere lengths of circulating white blood cells.

When these lengths were compared between individuals belonging to the same large family with the R865H mutation in TERT, the younger heterozygous mutation carriers had telomere lengths similar to age-matched controls.

In contrast, many of the mutation carriers older than 40 had telomeres with a shorter mean length and an increased proportion of short telomeres. Haploinsufficiency of telomerase due to TERT mutations may lead to the clinical phenotype of pulmonary fibrosis only after sufficient time has elapsed and after multiple rounds of cell division have occurred to shorten telomeres to critical lengths.

This may explain why individuals present with this disease later in life, as adults.

IPF is an age-related disease, with markedly increased prevalence with advanced age, especially after the fifth decade of life. Some fraction of sporadic cases is likely due to telomere attrition from age and environmental insults independent of specific genetic mutations.

See also

- fibrotic lung diseases
- pulmonary fibrosis


- Raghu G, Collard HR, Egan JJ, et al. American Thoracic Society Documents. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824. [21471066]

- Allam JS, Limper AH. Idiopathic pulmonary fibrosis: is it a familial disease? Curr Opin Pulm Med. 2006 Sep;12(5):312-7. PMID: 16926644

- Nogee LM. Genetics of pediatric interstitial lung disease. Curr Opin Pediatr. 2006 Jun;18(3):287-92. PMID: 16721150

- Agostini C, Siviero M, Semenzato G. Immune effector cells in idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 1997 Sep;3(5):348-55. PMID: 9331536