Pulmonary Fibrosis Linked to Genetic Susceptibility and Smoking

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Smoking and Pulmonary Fibrosis

Because genetic susceptibility plays a significant role in the development of pulmonary fibrosis, physicians should maintain a high degree of suspicion when examining any patient who has a family history of this fatal disease, especially smokers, according to a new study published in the first issue of the November 2005 American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

Mark P. Steele, M.D., of the Duke University Medical Center, Durham, North Carolina, along with 12 associates, identified 111 families with members who had familial interstitial pneumonia (one of several lung diseases generally described as pulmonary fibrosis). Among this group, 309 individuals were affected by the illness, while 360 were unaffected. Other than genetic susceptibility, the researchers associated three additional traits with development of the disease: older age (over 68), male sex and a history of smoking cigarettes.

"Our findings suggest that familial interstitial pneumonia may be caused by an interaction between a specific environmental exposure and a gene or genes that predisposes to the development of several subtypes of interstitial pneumonia," said Dr. Steele.

In the 111 families involved in the study, 231 persons had probable familial interstitial pneumonia, while 78 were definitely diagnosed with the disease. The researchers found that those "definite" individuals were significantly younger at diagnosis than those with probable illness. Overall, the age range at onset of the disease varied greatly, from slightly over 30 years to over 95.

"Subjects with definite familial interstitial pneumonia died at a younger age, had higher mortality and had a shorter time to death from their age at diagnosis," said Dr. Steele.

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The authors also noted that cigarette smoking may lead to the development of pulmonary fibrosis in individuals who are genetically prone to the problem, since lung injury can interact with genetic susceptibility and substantially contribute to illness.

Although the investigators strongly associated smoking with the development of the disease, they conclude that genetic susceptibility plays a more significant etiologic role, even among smokers.

Utilizing a "two-hit" hypothesis, the investigators also raised the possibility that affected persons have an intrinsic inability to adequately repair injured lung parenchyma (the functional part of the lung). This problem could be the fundamental biological defect that ultimately results in fibrosis and the collapse of lung units. However, this approach requires a second "hit" from lung injury, such as that from smoking, to develop the illness.

"Regardless of pathogenesis, our findings clearly indicate a delicate balance between injury to the lung and genetic susceptibility to the development of idiopathic interstitial pneumonia," Dr. Steele wrote.

In an editorial on the study in the same issue of the journal, Kevin Flaherty, M.D., M.S., of the University of Michigan, Ann Arbor, and Gary Hunninghake, M.D., of the University of Iowa, Iowa City, highlight one of the study's surprising conclusions: forty-five percent of the families involved had more than one type of interstitial pneumonia, a statistic that may help clarify the genetic mechanisms of the disease.

They wrote: "The presence of multiple genes, interacting with each other, could explain why varying clinical phenotypes can be seen within families where the genetics would be expected to be similar and in families where only a single genetic mutation, such as surfactant protein C was identified."

"A practical point for our day-to-day practice is the need for heightened suspicion for idiopathic interstitial pneumonia in patients with a positive family history. Approximately 8 percent of the subjects participating in this survey who reported their clinical status as 'unaffected' had definite or probable interstitial pneumonia when they were evaluated. Although there is currently no effective therapy for idiopathic pulmonary fibrosis, many therapeutic trials are underway and others are in the design phase. Most investigators believe these interventions are more likely to work in patients with mild to moderate disease. Maintaining a high level of suspicion for interstitial pneumonia, especially in patients with pertinent family history, should help identify patients with an early stage disease who could be eligible for participation in research trials."

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