Disorders of Gas Diffusion Through the Alveolo-capillary Membrane

Disorders of gas diffusion through the alveolo-capillary membrane represent a group of pathological conditions in which the transfer of respiratory gases between alveolar air and pulmonary capillary blood is impaired. These disorders primarily affect oxygen transport, while carbon dioxide elimination is usually preserved until late stages due to the higher diffusibility of CO₂.

Diffusion impairment is a characteristic mechanism of hypoxemic (type I) respiratory insufficiency, typically associated with an increased alveolar–arterial oxygen gradient (A–aDO₂).

Epidemiology

Idiopathic Pulmonary Fibrosis Diagram

Diffusion disorders occur most frequently in patients with interstitial lung diseases, pulmonary fibrosis, and acute inflammatory conditions affecting the alveoli. They are common in both acute settings (e.g. ARDS) and chronic diseases (e.g. idiopathic pulmonary fibrosis). The incidence increases with age and is higher in individuals exposed to environmental toxins, smoking, or chronic inflammatory lung injury.

Definition

Disorders of gas diffusion are defined as conditions in which the rate and extent of gas transfer across the alveolo-capillary membrane are reduced, despite adequate ventilation and pulmonary perfusion.

Key characteristics include:

• impaired oxygen transfer,
• relatively preserved carbon dioxide elimination (early stages),
• increased A–aDO₂,
• hypoxemia that worsens during physical exertion.

From a pathophysiological standpoint, diffusion disorders represent a failure of the alveolo-capillary membrane, rather than a primary disorder of ventilation or perfusion.

Etiology

The causes of diffusion impairment can be grouped according to the underlying structural abnormality:

Alveolar-Capillary Membrane

1. Thickening of the Alveolo-capillary Membrane

• interstitial pulmonary fibrosis,
• interstitial pneumonitis,
• pulmonary edema,
• chronic inflammatory lung diseases.

2. Reduction of Diffusion Surface Area

• emphysema (loss of alveolar walls),
• lung resection,
• advanced interstitial lung disease.

3. Altered Pulmonary Capillary Blood Volume

• pulmonary hypertension,
• microvascular obliteration,
• vasculitic lung diseases.

Pathophysiology

Gas diffusion across the alveolo-capillary membrane is governed by Fick’s law, which states that diffusion is proportional to the surface area and pressure gradient, and inversely proportional to membrane thickness.

Mechanisms of Impaired Diffusion

Diffusion disorders arise due to:

• thickening of the diffusion barrier (fibrosis, edema),
• reduction of effective diffusion surface area,
• shortened capillary transit time during exercise,
• altered pulmonary perfusion.

Oxygen vs Carbon Dioxide Transfer

Oxygen diffusion is affected earlier and more severely than carbon dioxide diffusion because:

• O₂ has lower solubility than CO₂,
• O₂ transfer is more dependent on membrane integrity.

As a result:

• hypoxemia develops early,
• hypercapnia occurs only in advanced disease.

Clinical Presentation

The clinical manifestations depend on disease severity and progression.

Early manifestations:

• exertional dyspnea,
• reduced exercise tolerance,
• mild hypoxemia during physical activity.

Advanced manifestations:

• dyspnea at rest,
• cyanosis,
• tachypnea,
• signs of pulmonary hypertension and cor pulmonale.

Patients may develop progressive respiratory insufficiency, particularly in chronic fibrosing lung diseases.

Diagnostics

Diagnostic evaluation focuses on demonstrating impaired diffusion and excluding other mechanisms of respiratory failure.

Key investigations include:

• arterial blood gas analysis
  • decreased PaO₂,
  • normal or low PaCO₂ (early),
  • increased A–aDO₂.
• pulmonary function tests
  • reduced diffusing capacity for carbon monoxide (DLCO),
  • restrictive ventilatory pattern
• imaging studies
  • chest X-ray,
  • high-resolution CT showing interstitial changes.
• exercise testing
  • worsening hypoxemia during exertion.

Treatment

Management is directed primarily at the underlying disease causing diffusion impairment.

General therapeutic principles include:

• oxygen therapy (particularly effective in diffusion disorders),
• treatment of inflammatory or fibrotic lung disease,
• prevention of further lung injury (smoking cessation, avoidance of toxins),
• management of pulmonary hypertension when present.

In advanced cases, long-term oxygen therapy or lung transplantation may be considered.

References

• Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. Elsevier.
• Hammer GD, McPhee SJ (eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine. McGraw-Hill Education, 2014.
• Maruna P. Examination Tests from Pathological Physiology. Karolinum, 2015.