idiopathic%20pulmonary%20fibrosis
IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis is the progressive parenchymal scarring & loss of pulmonary function due to unidentifiable cause of lung injury.

It is a specific form of chronic fibrosing interstitial pneumonia with the histopathologic characteristics of usual interstitial pneumonia.

Approximately 5% of patients are asymptomatic. Common signs and symptoms are exertional dyspnea, nonproductive cough, finger clubbing and bilateral inspiratory crackles.

Introduction

  • The most common type of idiopathic interstitial pneumonia (IIP)
  • The most common interstitial lung disease among referrals & 2nd most common diagnosis or frequent disease for lung transplantation

Definition

  • A specific form of chronic, progressive fibrosing interstitial pneumonia that occurs spontaneously & is limited to the lungs, associated with a pattern of usual interstitial pneumonia (UIP) both on high-resolution computed tomography (HRCT) or lung biopsy
  • Also known as cryptogenic fibrosing alveolitis (CFA)

Etiology

  • Exposure to agents like smoke, environmental pollutants & dust, viral infections, gastroesophageal reflux disease (GERD) & chronic aspiration may lead to initial alveolar epithelial damage especially in susceptible hosts
  • Familial pulmonary fibrosis (FPF)
    • Account for <5% of the total number of patients with idiopathic pulmonary fibrosis
    • May affect ≥2 family members of the same primary biological family
    • May be caused by a genetic mutation in serum surfactant protein C or A2 (SFTPA2)
    • Also associated with the gene encoding mucin 5B (MUC5B) & mutant human telomerase RNA
  • Respiratory viruses
    • Common cause of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF)

Signs and Symptoms

  • Exertional dyspnea
  • Nonproductive cough
  • Finger clubbing
  • Bilateral inspiratory crackles
  • Systemic symptoms (arthralgia, fatigue, low-grade fever, myalgia, weight loss)
  • Exertional dyspnea & nonproductive cough are the 2 most common presenting symptoms in patients with idiopathic pulmonary fibrosis
    • Dyspnea is the most prominent symptom
  • Symptoms are nonspecific as it may present in patients with cardiac & pulmonary disease
  • Approximately 5% of the patients are asymptomatic
    • Asymptomatic patients develop their symptoms approximately 1000 days after the diagnosis of idiopathic pulmonary fibrosis on routine chest radiograph & usual interstitial pneumonia on lung biopsy 
  • It would take about 1-2 years (median duration of symptoms) before a diagnosis of idiopathic pulmonary fibrosis is established

Risk Factors

  • Cigarette smoking
  • Environmental exposure to metal dust (brass, lead, steel) & wood dust
  • Occupational exposure (farming, livestock, salon waste, stone cutting/polishing, vegetable dust)
  • Infections (Epstein-Barr virus, Hepatitis C, cytomegalovirus)
  • Gastroesophageal reflux disease via microaspiration
  • Familial pulmonary fibrosis
    • Further studies are needed to prove the association of the genetic polymorphisms for cytokines, enzymes, profibrotic molecules, coagulation pathway genes, surfactant protein-A & -B, immunomodulatory genes, & matrix metalloproteinase & idiopathic pulmonary fibrosis

Epidemiology

  • Prevalence & incidence rates of idiopathic pulmonary fibrosis varies & depends on:
    • Ascertainment
    • Methods of reporting
    • Age
      • Incidence increases as the age advances especially on the 6th & 7th decade of life
      • Rarely seen in patients <50 years old
    • Geographic location of the population
  • Cases are higher in men than in women

Pathophysiology

Histopathology

  • Characteristic histopathologic features of usual interstitial pneumonia include:
    • Presence of abnormal proliferation of mesenchymal cells
    • Varying degrees of fibrosis
    • Overproduction & disorganized disposition of collagen & extracellular matrix
    • Honeycomb cysts
  • The histological hallmark of usual interstitial pneumonia is the presence of a subepithelial fibroblast foci
  • Inflammation, aberrant fibroblast & epithelial cell function, or abnormal epithelial-mesenchymal interactions with little or without an inflammatory component may play a role in the development of fibrosis in idiopathic pulmonary fibrosis
  • The initiation & perpetuation of a fibrotic response, which is considered a trigger for the development of idiopathic pulmonary fibrosis, will depend on:
    • Genetic factors
    • Environmental triggers
    • Imbalance of oxidants & anti-oxidants
    • Imbalance of Th1 & Th2 cell-derived cytokines
  • Marked proliferation of type II epithelial cells & loss of type 1 epithelial cells may be present
  • Serum concentrations of lung surfactant proteins SP-A & SP-D, & Kerbs von Lungren 6 antigen (KL-6) are increased in patients with idiopathic pulmonary fibrosis
    • A change in the concentration of KL-6 may be used as a marker for the activity of the disease
  • Abnormalities of the alveolar epithelium cells (AECs) causing altered reepithelization in idiopathic pulmonary fibrosis  patients include loss of type 1 epithelial cells, proliferation of type 2 epithelial cells, & impaired regenerative capacity of the epithelium
    • On electron microscopy, the space between the alveolar epithelium & capillary endothelium is where the resident mesenchymal cells are located
  • Excess collagen deposition within the extracellular matrix that may be due to decreased collagenolytic activity prevents re-expansion of collapse lung tissue
  • Recurring lung tissue injury & TNF-alpha gene polymorphisms have been linked to excessive collagen synthesis
  • Cytokines & growth factors that stimulates fibroblast proliferation & matrix synthesis include resident epithelial cells, endothelial cells & fibroblasts located within the lungs
  • TNF-α may be increased in patients with idiopathic pulmonary fibrosis but its role in idiopathic pulmonary fibrosis is not clear
  • Overexpressed molecules from a lung tissue or blood sample include:
    • Fibrotic cytokines
    • Matrix metalloprotein (MMP-7 & MMP-1)
    • Surfactant protein A1
    • Cyclin A2 (CCNA2)
    • Alpha-defensins
  • Gamma interferon is deficient in patients with idiopathic pulmonary fibrosis

Genetic Factors

  • Several gene mutations that may possibly play a role in the development of idiopathic pulmonary fibrosis:
    • Mutation surfactant proteins A2 (SP-A2) & C (SFTPC)
    • Risk locus for chromosome 11
    • Telomerase gene mutations (eg TERT, TERC, DKC1, TNF-2)
    • In patients with fibrotic idiopathic interstitial pneumonias, association with TERT, MUC5B & TERC telomerase gene 3q26 were confirmed
      • Other associated genes: Loci FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), & chromosomal regions 7q22 & 15q14-15
      • TOLLIP & SPPL2C are additional genes that were recently identified & both are associated with disease susceptibility
    • In patients with familial interstitial pneumonia (FIP), regulator of telomere elongation helicase 1 (RTEL 1) gene (rare variant), a DNA helicase that regulates the stability & replication of a telomere, were identified
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