Introduction

Gaucher disease is a rare genetic condition that affects 1 in 50,000 to 1 in 100,000 people.¹ It was first discovered in 1882 by Phillippe Charles-Ernest Gaucher, who described the appearance of abnormal cells in the spleen of a woman who had a large spleen (splenomegaly). Findings following this discovery led to this disorder being named Gaucher disease.²

Since then, advances in our understanding of the disorder have led to a greater understanding of what causes this disease and its heterogeneous (variable) nature. This has led to the identification of three different classifications of the disease. 

This article will explore Gaucher disease in more detail, looking at its causes, symptoms, how it can affect a person, and how, in rare cases, it can lead to respiratory complications. It will also discuss what treatment options are available. 

Understanding Gaucher disease

Cause of the disease

Gaucher disease is a type of lysosomal storage disorder (LSD). LSDs are a group of rare disorders characterised by dysfunctional lysosome activity.³ Lysosomes are the recycling centres of the cell – they play a key role in clearing waste from the cell by breaking down abnormal or dysfunctional cellular components. The broken-down material in the cell can then be used for other purposes.

In LSDs, the enzyme lysozyme's ability to break down unwanted material is hindered, leading to functional disruption in the cell. This inability of lysozymes to perform their function is most commonly due to genetics. Genetics is the study of DNA, the instruction manuals in our cells that guide all the biological processes in our bodies and make us who we are.

When genes, short regions of our DNA, are altered, this can affect how the gene is read and what biological product is produced. This can lead to the production of irregular biological products that do not perform their intended function in the body.

In Gaucher disease, the lysozymes function without an enzyme known as glucocerebrosidase (GBA1). GBA1 plays an essential role in the breakdown of lipids (fatty substances) known as glucocerebroside associated with the cell membrane. The absence of GBA1 results in the accumulation of lipids in organs such as the spleen and liver, with the potential to spread systemically.^3,4

The different types of Gaucher Disease

Type I

Type I is the most common type of Gaucher disease. It can be characterized by irregularities in the blood, such as low platelet count and impaired clotting. This can lead to fatigue and susceptibility to bleeding. Additionally, type I can also lead to bone disease and spleen and liver enlargement.⁵ 

Type II

Type II is a neuronopathic Gaucher disease, meaning it can affect neurological development. This type of disease occurs in infancy (age 3-6 months)  and is much rarer than type I, however more severe, often being fatal. Symptoms include early onset brain damage, poor development, seizures, and enlarged spleen and liver.⁵

Type III

Type III, like type II, is also known as a neuronopathic disorder. It has a later and more gradual onset compared to type II, leading into adulthood. Symptoms can include seizures, skeletal irregularities, cognitive difficulties, respiratory problems, and also, like the other types, enlarged spleen and liver.⁵

Symptoms

Symptoms associated with Gaucher disease are as follows:

• Enlarged spleen
• Enlarged liver
• Anaemia
• Fatigue
• Abdominal discomfort
• Skeletal abnormalities 

Lung problems in Gaucher disease

In Gaucher disease, complications in the lungs can arise due to infiltration by Gaucher cells (cells with build-up of lipids). This can lead to the following:

High blood pressure

A build-up of glucocerebroside in the lungs and blood vessels can lead to stiffening and narrowing of the nearby vasculature. This narrowing of the blood vessels means that the gas exchange (oxygen and carbon dioxide) between the alveoli (air-filled sacs in the lungs) and blood vessels is restricted. Symptoms such as shortness of breath and fatigue can manifest.^6,7 

Interstitial lung disease

Glucocerebroside accumulation can lead to inflammation of the lung interstitium (space between alveoli and the surrounding blood vessels. Inflammation can cause scarring, restricting oxygen movement from the lungs into the circulation. Symptoms of this include coughing and difficulty breathing.^6,7

Respiratory infection

Gaucher cells in the lungs can impair normal lung functioning whilst also suppressing immune response. This can potentially lead to infection.^6,7

Splenomegaly

The enlarged spleen in Gaucher disease can press against the diaphragm and lungs, which can cause difficulties with breathing.⁶

Managing lung problems in Gaucher disease

Regular breathing tests

To assess lung function, doctors can carry out a breathing test. A common type of breathing test is spirometry. In spirometry, the patient breathes into a machine called a spirometer after inhaling a medicine known as a bronchodilator, which widens the lungs' airways. The spirometer measures two variables - the amount of air breathed out in one second and the total amount of air breathed out. The results can be compared to a reference to establish whether the breathing is deemed normal based on age. 

Imaging tests (x-rays and CT scans)

Imaging tests produce detailed pictures of a specific area of interest in the body. In this case, it would be a visual of the lungs. The two standard imaging tests that can be used to assess the lungs are X-rays and CT scans.

X-rays are a type of light that can pass through the body. This light is invisible to the human eye, and when it passes through the body, it interacts with different regions of the body. Dense parts of the body, such as bone, make it harder for the light to pass through, thus producing a clear white image. On the other hand, less dense regions, such as tissue, where light can pass through more easily, produce darker areas on the x-ray image.

In CT scans, X-rays are used however they are transmitted in a circular orbit around the body. This produces detailed images of the organ of interest from different angles, giving different perspectives. 

Treatments available

Enzyme replacement therapy (ERT) 

Enzyme replacement therapy (ERT) is a common form of treatment for Gaucher disease. It involves replacing the absent enzymes with artificial enzymes. The dose of ERT is typically administered intravenously and given at regular intervals.⁸

Substrate reduction therapy (SRT)

Substrate reduction therapy is another common form of treatment used in Gaucher disease, which is typically used if a patient does not respond well to ERT. This type of therapy involves limiting the production of the fatty substance glucocerebroside, which builds up in cells.^9,10

Medicines for high blood pressure in the lungs 

Vasodilators are a common treatment option for those with pulmonary hypertension (high blood pressure in the lungs). These drugs work by widening the blood vessels supplying the lungs, which in turn reduces blood pressure. They can be taken orally, inhaled, or injected intravenously (injected into the veins). Examples of vasodilators include epoprostenol, treprostinil, lloprost and selexipag. 

Treatment for lung tissue problems 

The current treatment available for pulmonary fibrosis (lung tissue scarring) is palliative, which aims to relieve symptoms. These include the following:

• Medicines such as pirfenidone and nintedanib help to prevent the worsening of tissue scarring
• Breathing through an oxygenated mask
• Pulmonary rehabilitation - exercising techniques which can promote improved breathing
• Self-care measures - avoid smoking, eat healthily, and exercise regularly (based on advice from a medical professional)

Summary

• Gaucher disease is a type of lysosomal storage disorder (LSD). It is caused by a mutation in the GBA1 gene that encodes for the glucocerebrosidase enzyme found in lysosomes
• There are three types of Gaucher disease - type I, type II, and type III. Type I is the most common. Type I is non-neuronopathic, whereas type II and type III are affecting the nervous system
• Respiratory complications are one of several systemic complications arising from Gaucher disease. Pulmonary hypertension, interstitial lung disease, and respiratory infection are all potential manifestations, although rare
• Treatments for Gaucher disease and respiratory complications can include enzyme replacement therapy, substrate reduction therapy, drugs such as vasodilators, pirfenidone, and also nintedanib. Additionally, non-pharmaceutical measures such as pulmonary rehabilitation and self-care measures such as healthy eating and physical exercise can also help