Interstitial Lung Disease E-Book

Harold R Collard, Luca Richeldi

• Publisher: Elsevier
• Year: 2017
• ISBN:
  9780323480253
• Topic: Medicine
• Subtopic: Pulmonary & Thoracic Medicine

Clinically focused and designed to provide a to-the-point overview, Interstitial Lung Disease, by Drs. Talmadge King, Harold Collard, and Luca Richeldi, bring you up to date with increased understanding, new treatment protocols, and recent advances in the field. Written by contributing specialists who are global experts in their respective areas, this one-stop reference provides pulmonologists, intensivists, internal medicine physicians, and researchers with a dependable source of information on current treatment options and patient care.
• Evidence for current treatment options for interstitial pneumonia, idiopathic pulmonary fibrosis, and smoking-related interstitial lung diseases.
• Approach to diagnosis of interstitial lung diseases, such as sarcoidosis, hypersensitivity pneumonitis, and Churg-Strauss syndrome.
• Genetic markers for inherited interstitial lung diseases such as dyskeratosis congenita, tuberous sclerosis/LAM, and hyper-IgE syndrome.

Chapter 1

Genetic Interstitial Lung Disease

Christine Kim Garcia

Abstract

Technological advances have led to an explosion of genetic discoveries, shedding new light on the underlying pathogenesis of interstitial lung disease (ILD). Identification of the genetic etiology provides a molecular explanation for the ILD and other patient phenotypes. The goal of this chapter is to summarize (1) genetic syndromes involving multiple organs, in which ILD is one of many different phenotypes and (2) genetic disorders in which ILD is the dominant phenotype. Discoveries of the genetic underpinnings of ILD have identified common pathways of lung fibrosis, including altered surfactant metabolism, increased endoplasmic reticulum stress signaling, and telomere shortening.

Keywords

Common variants; ER stress; Genetics; Interstitial lung disease; Mutations; Pulmonary fibrosis; Rare variants; Surfactant; Telomerase; Telomeres

Key Points

• The interstitial lung diseases (ILDs), or diffuse parenchymal lung diseases, are a heterogeneous collection of more than 100 different pulmonary disorders that affect the tissue and spaces surrounding the alveoli.

• Many of the genes involve pathways that lead to altered surfactant metabolism, increased ER stress signaling, and telomere shortening.

• Genetics provides a molecular framework for explaining phenotypes and, sometimes, provides information that directly affects patient care.

The interstitial lung diseases (ILDs) include a wide variety of relatively uncommon disorders. Technologic advances in sequencing and genotyping have led to an explosion of genetic discoveries, shedding new light on the underlying pathogenesis of ILD. New monogenic syndromes have been described, often with clinically diverse and extreme phenotypes, based on the discovery of single gene mutations. In addition, many apparently disparate clinical presentations have been linked together through the discovery of mutations in the same gene or mutations in multiple genes sharing a common pathway. These genetic discoveries have only further increased the number of discrete ILDs. The genetic etiology provides a molecular framework for the disease and provides patients and their treating physicians with an explanation of phenotypes that are often seen across multiple organs. As more cohorts of patients are described with these rare syndromes, more information will be gleaned about the natural history of disease and best practices for surveillance and treatment. The goal of this chapter is to summarize (1) genetic syndromes involving multiple organs, in which ILD is one of many different phenotypes, and (2) genetic disorders in which ILD is the dominant phenotype.

As a rule, manifestations of ILD even within a single gene syndrome are generally characterized by a spectrum of clinical presentations, a wide range in age of onset, and incomplete penetrance. Thus, a high level of suspicion is needed for many of these disorders. Detecting a pattern of inheritance in large, extended kindreds across multiple generations separated by time and space strongly supports a genetic mechanism of disease. A detailed family history also provides important information about personal and family member phenotypes, providing important clues that may suggest a certain genetic diagnosis. For example, a personal or family history of bone marrow failure, early graying, or liver disease in a patient with adult-onset pulmonary fibrosis suggests a short telomere syndrome. Younger and more severely affected individuals in later generations may reflect genetic anticipation, which can also be seen in short telomere syndromes. Some diseases show a predisposition for affecting a certain gender, for example, affected males and asymptomatic carrier females suggest an X-linked disorder.

All ILDs arise from the infiltration of inflammatory and fibrotic mediators into the lung parenchyma. Very few cells normally reside within the interstitium, which is the delicate space between the alveolar epithelial cells and the capillary vascular endothelial cells. The filling of the interstitial space with inflammatory cells, activated fibroblasts, and extracellular matrix causes irreversible architectural distortion and impairs gas exchange. Most ILDs share similar clinical signs and symptoms, including respiratory distress and cough. Pulmonary restriction and a decreased diffusion capacity are frequently found, as well as radiographic evidence of parenchymal abnormalities. However, the radiographic and histopathologic features of ILDs vary widely. Historically, the type of infiltrating cells, the pattern of infiltration (nodular, reticular, alveolar), the nature of extracellular protein deposits (collagen, elastin, periodic acid–Schiff [PAS]-positive), the location of abnormalities (peripheral, alveolar, peribronchiolar), the pattern of the fibrotic response (fibroblastic foci, temporal/spatial homogeneity, or heterogeneity), and the form of lung destruction (cysts, bronchiectasis, honeycombing) have been used to describe different clinical forms of ILD. Now that genetic underpinnings of some monogenic ILDs are being established, classification by genetic etiology may ultimately supplant historical classification schemes. This will occur most readily for those disorders in which the genetic classification predicts specific treatments (e.g., sirolimus for tuberous sclerosis complex [TSC]–lymphangioleiomyomatosis [LAM]). A genetic classification of ILD is also advisable for those diseases in which the genetic information provides information relevant to patient care. For example, regular screening may lead to earlier interventions to remove premalignant renal cancers in patients with Birt-Hogg-Dubé syndrome (BHDS). Similarly, knowledge of a monogenic short telomere syndrome provides prognostic information regarding the rate of ILD progression and the nature of specific post–lung transplant complications.

In this chapter, I focus primarily on disorders caused by rare mutations and include selected common variants that significantly increase susceptibility to ILD. The nomenclature of diseases follows the genetic classification system adopted by the Online Mendelian Inheritance in Man (http://www.omim.org). Other pulmonary genetic diseases are not covered. I refer to other excellent resources for reviews of alpha-1-antitrypsin deficiency, cystic fibrosis and CFTR-related disorders, primary ciliary dyskinesia, pulmonary capillary or venoocclusive disease, pulmonary malformation syndromes, and disorders that primarily affect the thoracic ...