What is fibrosis?

What is Fibrosis?

Fibrosis is the abnormal accumulation of collagen and extracellular matrix components in response to injury, characterized by the replacement of normal tissue with fibrous connective tissue, which can lead to organ dysfunction and failure if left untreated. 1

Definition and Pathophysiology

Fibrosis is a pathological process that occurs as part of the body's wound healing and tissue repair mechanisms. While initially adaptive, persistent activation of fibrotic processes becomes detrimental to organ function. The key components of fibrosis include:

• Formation of excessive fibrous connective tissue in response to injury 2
• Accumulation of extracellular matrix components, particularly collagen, at the site of injury 2
• Progressive stiffening of affected tissue, leading to architectural distortion and functional impairment 1

Types of Fibrosis

Fibrosis can be classified based on the pattern and distribution within affected tissues:

1. Bronchiolocentric fibrosis:

   • Characterized by thickening of peribronchiolar alveolar septa by collagen deposition 3
   • Often accompanied by peribronchiolar metaplasia (extension of bronchiolar epithelium onto thickened septa) 3
   • Most commonly results from centrilobular injury due to inhalation of fumes/dust, aspiration, or systemic diseases with airway inflammation 3

2. Nonspecific interstitial pneumonia-fibrosis:

   • Shows diffuse alveolar septal thickening by collagen deposition 3
   • Maintains underlying pulmonary alveolar architecture creating a "dusty cobweb" appearance 3
   • Results from diffuse alveolar inflammation followed by fibrosis 3

3. Usual interstitial pneumonia:

   • Fibrosis accentuated at the periphery of the pulmonary lobule, in subpleural regions 3
   • Often shows microscopic honeycombing with irregular airspaces lined by bronchial epithelium 3
   • Contains fibroblast foci at the interface between fibrotic and less-involved regions 3

Stages and Progression

Fibrosis typically advances through progressive stages:

• In liver disease, fibrosis is staged from F0 (no fibrosis) to F4 (cirrhosis) 1
• Advanced fibrosis (F3-F4) correlates with increased risk of complications including cancer, portal hypertension, and clinical decompensation 1
• Progression rates vary depending on the underlying cause and organ affected 1

Mechanisms of Fibrosis

Three primary physiological mechanisms drive fibrosis development:

1. Inhalation injury or airway inflammation:

   • Leads to bronchiolocentric fibrosis
   • Examples: respiratory bronchiolitis from smoking, hypersensitivity pneumonia, asbestosis 3

2. Alveolar inflammation:

   • Results in nonspecific interstitial pneumonia-fibrosis
   • Characteristic of autoimmune connective tissue disease, drug reactions, and some cases of hypersensitivity pneumonia 3

3. Abnormal senescence:

   • Associated with usual interstitial pneumonia
   • Linked to shortened telomeres and mutations in the telomerase pathway 3
   • Affects oldest cells located in distal peripheral acinar tissues 3

Histological Characteristics

Histologically, fibrosis can be further classified as:

• Active fibrosis: Abnormal accumulation of collagen associated with an increased number of stromal cells (fibroblasts or myofibroblasts) 3
• Inactive fibrosis: Abnormal accumulation of collagen without an associated increase in stromal cells 3
• Desmoplasia: Cellular fibroinflammatory response accompanying invasive carcinoma, including hyperplasia of fibroblasts and deposition of fibrous connective tissue 3

Clinical Significance and Complications

Fibrosis has significant clinical implications:

• Worldwide, fibrotic diseases cause over 800,000 deaths per year, accounting for ~45% of total deaths 2
• Fibrosis can lead to organ malfunction and death when it progresses in an uncontrolled manner 2
• In liver disease, fibrosis can progress to cirrhosis, portal hypertension, and end-stage liver disease 1
• In pulmonary fibrosis, progressive loss of lung function can lead to respiratory failure 3

Diagnosis

Diagnosis of fibrosis depends on the affected organ but may include:

• Imaging: CT scans showing fine reticulation, intralobular lines, and architectural distortion 3
• Serum biomarkers: FIB-4, NAFLD fibrosis score, ELF test for liver fibrosis 1
• Elastography: Transient elastography (FibroScan), MR elastography 1
• Biopsy: Gold standard for diagnosing and staging fibrosis, though subject to sampling variability 1

Management Approaches

Management of fibrosis focuses on:

1. Identifying and treating the underlying cause
2. Risk stratification based on fibrosis severity
3. Surveillance for complications
4. Serial monitoring of fibrosis progression using non-invasive tests 1

For specific conditions like idiopathic pulmonary fibrosis, antifibrotic medications such as pirfenidone may be used to slow disease progression 4.

Conclusion

Fibrosis represents a common pathological endpoint of numerous disease states. Understanding its mechanisms is crucial for developing targeted therapies to prevent progression and potentially reverse established fibrosis.