Gaucher Disease And The Liver: Impact Of The Disease On Liver Function

Overview 

Gaucher disease (GD) is a rare inherited genetic condition caused by the lack of a substance called glucocerebrosidase. Glucocerebrosidase is an enzyme - a type of protein that facilitates crucial chemical reactions, helping our organs to function properly. Glucocerebrosidase breaks down the fatty substances known as glycolipids, namely glucocerebrosides. In GD patients, the lack of glucocerebrosidase causes an accumulation of glucocerebrosides within the cells, in various body tissues. This build-up is toxic and disrupts the normal function of the affected cells and organs, and this can lead to a range of symptoms in patients.¹ 

One of the commonly affected organs in GD patients is the liver, an essential organ in our body. It is in charge of breaking down nutrients, that are further absorbed in our blood and are necessary for our organs to function properly. The liver also aids in detoxifying most of the chemicals found in our blood, by removing any waste products and harmful substances. Other liver functions include supporting our immune system and creating essential nutrients.² 

With GD leading to a build-up of glycolipids in the liver, not only does this result in the enlargement of the organ, but it also prevents the liver from performing its important functions mentioned above, affecting the patient’s overall health. This article aims to raise awareness of the impact GD has on the liver, its symptoms and diagnosis. It also covers the available treatment options to prevent and stop the detrimental impact on the liver and the overall health of the patient.    

Types of gaucher disease and its symptoms

GD symptoms can vary greatly between patients. Some individuals don’t develop any symptoms (are asymptomatic), and others experience serious complications. The disorder is classically categorised into 3 types, based on the absence or presence of neurological symptoms.³ 

These types are:

• Gaucher disease Type 1 - The most common type in Western countries. It is a non-neuropathic condition(the brain and spinal cord are not affected). Common symptoms include the enlargement of the liver and the spleen, causing abdominal pain, fatigue, nausea and jaundice (yellowing of the eyes and skin). Other typical symptoms include easy bruising due to thrombocytopenia, and bone problems (such as bone pain, bone thinning and fractures)
• Gaucher disease Type 2 - Also known as acute neuronopathic GD. This type occurs in infants (symptoms start within the first 3-6 months of life). Glycoolipids accumulate in the brain, leading to significant neurological complications, including seizures, poor development of motor skills, difficulties in swallowing and involuntary muscle spasms. Alongside such symptoms, the liver and the spleen are typically enlarged. Infants with this form of GD do not usually live long enough to develop bone complications, as death usually occurs between 1 and 3 years old
• Gaucher disease Type 3 -  The most common form of the disorder worldwide. Also known as chronic neuronopathic GD, this type develops by the time a patient is 10 years old. Its symptoms are similar to those of Type 2 patients, however they manifest more gradually. Patients with this type of GD can usually survive into adulthood.  

What causes gaucher disease?

The primary cause of all types of GD is the deficiency of the enzyme glucocerebrosidase. This occurs due to changes (also known as mutations) in the GBA gene, which carries the code responsible for making the enzyme. With changes in this code, glucocerebrosidase cannot be made properly. Therefore, the enzyme can’t break down the glycolipid glucocerebroside. This results in the build-up of glucocerebroside in cells, particularly immune cells -  known as ‘Gaucher cells’. They accumulate in organs all over the body, including the liver, affecting normal organ function by occupying a significant amount of space.¹ 

All 3 types of GD are autosomal recessive genetic disorders: a patient will have inherited a mutated version of the GBA gene from each parent, resulting in two ‘faulty’ copies of the gene, and no healthy copy. If someone only has one copy of the mutated GBA gene (and a healthy copy), they are a ‘carrier’ of the disease but do not experience it themselves.¹ There are over 400 mutations which can cause GD.

Impact of gaucher disease on the liver

In a large portion of GD patients, the liver is affected. However, the extent of liver involvement varies significantly between patients - some have minimal involvement which is not noticed clinically, whereas others have significant symptoms.⁴ This section of the article will discuss all the possible liver complications associated with GD. 

Hepatomegaly

When Gaucher cells accumulate in the liver, it results in organ swelling - the medical term for this is hepatomegaly. Hepatomegaly is one of the most common manifestations of GD - almost all patients experience some enlargement of their liver. Besides abdominal pain, fatigue, nausea and jaundice, hepatomegaly can lead to further consequences in GD patients, affecting their liver function.⁴ 

As Gaucher cells build up in the liver and take up important space, the resident liver cells named hepatocytes are damaged and lose size, strength and vitality. This is known as cell atrophy.⁴ Hepatocytes are vital in helping the liver carry out its essential functions, and their atrophy will affect the liver’s role in detoxifying the blood, helping the immune system and metabolising nutrients effectively.⁵ 

Liver fibrosis, cirrhosis and further complications

With hepatocytes getting damaged due to Gaucher cell accumulation, the liver in GD patients attempts to repair these cells and replaces them with scar tissue. Fibrosis is when an abnormally large amount of scar tissue is formed. Although fibrosis itself does not cause symptoms, if the scar tissue becomes thicker and extends into more areas of the liver, this severe scarring causes symptoms (similar to those experienced with hepatomegaly). This is called cirrhosis. The significant amount of scar tissue in the liver takes up space within the tissue, altering its internal structure, restricting blood flow from getting to the liver and impairing the organ’s functions. Cirrhosis is irreversible, and if not treated early, can be life-threatening.⁶ Cirrhosis could lead to further complications in GD patients (although relatively rare).⁴ These further complications include:  

• Portal hypertension - This is caused by an increased pressure on the blood vessel called the hepatic portal vein, which carries blood from the gastrointestinal tract to the liver. Portal hypertension can be a subsequent result of cirrhosis, as the scar tissue compresses the blood vessel. This reduces the blood flow in the liver, damaging the organ due to its cells’ short supply of oxygen and nutrients. Portal hypertension affects the liver but also restricts the blood flow to other organs (as blood is blocked at one point in the body, stopping its natural flow to all organs). This can cause damage to other organs, as well as internal bleeding⁷
• Hepatocellular carcinoma (HCC) - HCC is the most common type of primary liver cancer. Cirrhosis is one of the main risk factors for this type of cancer. However, in some GD patients, HCC can develop even without the presence of cirrhosis. If the glycolipids accumulate inside the immune cells, the immune system becomes dysregulated and cannot properly protect the body from harmful substances such as cancer cells⁸ 

Diagnosis of gaucher disease

GD is suspected when a patient experiences the symptoms described above caused by the enlargement of the liver and spleen (abdominal pain, fatigue, nausea and jaundice), anaemia, easy bruising, bone problems and/or neurological symptoms. 

The most common diagnostic tool used for GD is the beta-glucosidase leukocyte (BGL) blood test. This tool analyses the levels of the enzyme glucocerebrosidase in the patients’ blood. If levels are low, then this is an indication that the patient has GD. 

Genetic testing can then be done to confirm the diagnosis. Blood or saliva samples are taken from patients, and their DNA is analysed to check for the presence of any mutations in the GBA gene. If a patient has 2 GBA gene mutations this confirms GD diagnosis.   

Liver enzyme alterations 

To specifically assess liver involvement in GD, liver enzyme levels in the blood can also be measured - particularly aspartate transaminase (AST) and alanine transaminase (ALT). These liver enzymes are typically found within hepatocytes. However, if such cells are damaged due to Gaucher cell accumulation, AST and ALT can leak out from the cells and into the blood. Measuring high levels of AST and ALT in the blood is a good indicator that the liver has been affected in GD patients.⁹ 

Treatment and management of gaucher disease 

Although there is no cure for GD, there are effective treatments available to improve a patient’s symptoms and prevent complications from becoming more severe. Unfortunately, there is no treatment available for Type 2 patients, due to the significant irreversible brain damage in a short period. 

The currently approved therapies for GD Type 1 and 3 include:

• Enzyme replacement therapy (ERT) - Given as an intravenous infusion every 2 weeks, ERT aims to replace the missing glucocerebrosidase enzyme with a man-made modified version
• Substrate reduction therapy (SRT) - Given daily as an oral tablet drug, SRT partially blocks the production of the fatty substance glucocerebroside, preventing its further accumulation in immune cells. This particular therapy is only given to specific patient populations - it is not given to children and teenagers, pregnant and breastfeeding patients, and elderly people

GD-specific ERT and SRT ameliorate the symptoms and reduce the size of a patient’s liver back to its normal, healthy size. However, if a patient has severe liver disease, then SRT is not administered as it is not successful in reducing GD progression and liver involvement in these patients.¹⁰ 

It is also advised for GD patients with liver involvement to have routine ultrasound check-ups where their liver is monitored, to screen for any potential liver complications. These check-ups mean that, if a patient’s liver condition worsens, further treatment can be given to treat the complication early and stop it from becoming too severe.¹⁰   

In some patients where the liver is too damaged, ERT and SRT are not effective. When this is the case, liver transplantation is the best treatment.¹¹ 

Summary

GD is an inherited genetic disorder caused by the lack of the enzyme glucocerebrosidase. Without this enzyme, the fatty substances glucocerebrosides cannot be broken down, and instead accumulate in immune cells all over the body. One of the organs commonly affected by such build-ups is the liver, and its functions and structure become compromised. In almost all GD patients, the liver becomes enlarged. In rarer cases, GD can lead to liver fibrosis and cirrhosis, portal hypertension, and an increase in the risk of developing liver cancer. Symptoms associated with liver involvement in GD include abdominal pain, nausea, vomiting and the yellowing of the eyes and skin. Effective treatments to improve a patient’s symptoms include enzyme replacement therapy and substrate reduction therapy. Both therapies help reduce the size of the affected liver. In more severe cases of liver disease in GD, liver transplants are carried out.