Idiopathic pulmonary fibrosis (IPF) refers to a pulmonary disorder of unknown etiology that is characterized by patchy, progressive bilateral interstitial fibrosis. Because its etiology is unknown, it is also known as cryptogenic fibrosing alveolitis. Males are affected more often than females, and it is a disease of aging, virtually never occurring before 50 years of age. The radiologic and histologic pattern of fibrosis is referred to as usual interstitial pneumonia (UIP), which is required for the diagnosis of IPF. Of note, similar pathologic changes in the lung may be present in entities such as asbestosis, collagen vascular diseases, and other conditions. Therefore, IPF is a diagnosis of exclusion.
The interstitial fibrosis that characterizes IPF is believed to result from repeated injury and defective repair of alveolar epithelium, often in a genetically predisposed individual (
Fig. 13.13 ). The cause of the injury is obscure, and a variety of sources have been proposed, including chronic gastroesophageal reflux. However, only a small fraction of individuals suffering from reflux or exposed to other proposed environmental triggers develop IPF; thus, other factors must have a predominant role. The clearest etiologic clues come from genetic studies. Germ line mutations leading to loss of telomerase are associated with increased risk, suggesting that cellular senescence contributes to a profibrotic phenotype. The link to cellular aging also is in line with the observation that IPF is a disorder of older adults, rarely occurring before the age of 55 years. Other genetic associations also point to the primary defect residing in epithelial cells. Specifically, approximately 35% of affected individuals have a genetic variant in the MUC5B gene that alters the production of mucin, while a smaller number of affected patients have germ line mutations in surfactant genes. These genes are only expressed in lung epithelial cells, indicating that epithelial cell abnormalities can be the primary initiators of IPF. It is hypothesized that abnormal epithelial repair at the sites of chronic injury and inflammation gives rise to exuberant fibroblastic or myofibroblastic proliferation, leading to the characteristic fibroblastic foci. Although the mechanisms of fibrosis are incompletely understood, recent data point to excessive activation of profibrotic factors such as TGF-β.
MORPHOLOGYGrossly,thepleuralsurfacesofthelungarecobblestonedduetoretractionofscarsalongtheinterlobularsepta.Thecutsurfaceshowsfirm,rubberywhiteareasoffibrosis,whichoccurspreferentiallywithinthelowerlobe,thesubpleuralregions,andalongtheinterlobularsepta.Histologically,thehallmarkispatchy interstitial fibrosis, whichvariesinintensity(
Fig.13.14
Environmental factors:
Other irritants, toxins
At risk epithelium:
Genetics:
FibrosisProliferation, collagen production
Fig. 13.13 Proposedpathogenicmechanismsinidiopathicpulmonaryfibrosis.Seetextfordetails.
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Fig. 13.14 Usualinterstitialpneumonia.Thefibrosis,whichvariesininten-sity,ismorepronouncedinthesubpleuralregion.
worsenswithtime.Theearliestlesionsdemonstrateexuberantfibroblasticproliferation(fibroblastic foci)(