Introduction

Enzyme replacement therapy (ERT) is an important treatment option for many human diseases. While it can be a highly effective therapy, individuals undergoing ERT may experience a range of side effects. 

Some commonly reported side effects of ERT include:

• Gastrointestinal side effects
• Hypersensitivity reactions
• Injection site reactions
• Systemic side effects
• Long-term effects

In this guide, we will not only introduce the side effects commonly reported with ERTs but also explore how to identify and manage them. This will be important for individuals considering or currently undergoing ERT, to ensure the most effective and safe treatment experience.

Enzyme Replacement Therapy (ERT)

Enzymes are proteins that play a vital role in various essential functions in the human body. Some individuals may lack the required level of a specific enzyme to perform a particular function. In these cases, enzyme replacement therapy (ERT) is a treatment which administers the required enzyme to an individual, to increase their enzyme levels to a healthy threshold. ERT is, therefore, an effective therapy to compensate for low enzyme levels in patients. 

While ERT can be effective in treating diseases associated with low enzyme levels in patients, it is important to be aware of potential side effects. In this article, we will discuss the common side effects so that you are not only better informed about undergoing ERT but also equipped with the knowledge to manage these side effects effectively.

Diseases treated with ERT

ERT has been prescribed for various diseases. The first example of ERT was used to replace the alpha-1 antitrypsin (AAT) enzyme. This enzyme, which is produced in the liver, plays a role in protecting the human lungs. Individuals with low levels of AAT are therefore at an increased risk of suffering lung damage. When these patients were supplemented with additional AAT through ERT, it reduced lung damage and was found to have limited side effects.¹

Since the success of restoring AAT enzyme levels in patients, ERT has been applied to many other diseases. For example, Gaucher, Pompe, and Fabry diseases are all caused by low levels of particular enzymes within the body and have been successfully treated through ERT. As of 2016, there are 12 ERTs available in the US market.² 

What causes side effects in ERT?

Although ERT has been a promising therapy for multiple diseases, it is not without its side effects. As with all treatments, some individuals may react more poorly to ERT and exhibit side effects. Most reactions are mild and can be treated through other common medications such as antihistamines.² 

Therefore, being aware of potential side effects and how they can be treated is of utmost importance when considering or starting ERT. Below are side effects reported in some ERT patients and their respective management strategies. Importantly, there may be other side effects that are specific to different types of ERT. While we are focusing on common side effects across most ERTs, your doctor can offer more tailored advice on potential side effects for your unique circumstances and treatment options.

Types of side effects in ERT

Gastrointestinal side effects

Gastrointestinal side effects are commonly associated with ERT, particularly in ERT patients with pancreatic diseases. These can manifest as nausea, vomiting, abdominal pain, diarrhoea, constipation, and bloating. ERT may cause these side effects as the sudden introduction of enzymes into the human gut can cause irritation and sensitivity in some individuals. 

While these side effects are generally not concerning, individuals experiencing persistent gastrointestinal discomfort after ERT should alert their doctors. In some cases, the amount and dosage of ERT can be adjusted to minimise these side effects. Additionally, it is important for individuals to ensure they are eating and drinking well even when experiencing gastrointestinal side effects. This helps maintain adequate hydration and nutrition. 

Hypersensitivity reactions

As ERT introduces a new enzyme into the patient’s body, the immune system may sometimes mistake it for a foreign substance, which triggers an immune reaction. Similar to how our body’s immune system fights off the annual flu virus, it can also react similarly to the enzymes in ERT. This can result in unwanted allergic responses as a side effect of starting ERT. When the immune system reacts to harmless substances in this way, it is known as hypersensitivity.

Some hypersensitivity reactions occur immediately after the administration of ERT. These immediate hypersensitivity reactions normally present as a rash, itching, or swelling on the face or throat. Contrastingly, delayed hypersensitivity reactions can occur several days or weeks after receiving ERT. The symptoms are similar to immediate hypersensitivity reactions but also include fever and joint pain. 

Hypersensitivity reactions are the most common side effect of many ERTs, although they tend to be mild and resolve independently. These reactions have been reported in ERT clinical trials for diseases such as lysosomal acid lipase deficiency.³ 

In mild cases of hypersensitivity, taking antihistamines can effectively manage these side effects. However, if symptoms persist or become more severe, immediate medical assistance should be sought. This could indicate anaphylaxis, which is a life-threatening allergic reaction requiring immediate medical attention. 

Hypersensitivity can also indicate that ERT is not as effective within an individual. This is because the immune response against the introduced enzyme can reduce its concentration within the body thereby decreasing its effectiveness. Therefore, patients experiencing hypersensitivity are strongly encouraged to notify their healthcare professionals. Healthcare providers may increase monitoring to measure the immune response in these patients through antibody testing. The dosage of ERT is also often adjusted in patients with hypersensitivity. Other treatment options may be explored if hypersensitivity persists after adjustment of ERT dosage. 

Injection site/infusion reactions

As ERT is normally administered through injection, some side effects may arise at the site of injection. These are common and some patients have reported pain, swelling or itchiness in the area of ERT injection. However, these side effects are generally short-lived and do not usually require additional management.⁴ 

Systemic side effects

Unlike hypersensitivity reactions, some side effects do not occur in a specific area of the body. These side effects, such as fever, fatigue, and headaches are commonly reported in patients after ERT.⁵ Pain-relieving medications, including paracetamol or ibuprofen, can be taken to manage these symptoms. These side effects are not normally concerning due to their mild and short-lasting nature.⁵ However, if systemic side effects persist or worsen over time, patients are advised to notify their healthcare professional. 

Long-term effects 

While long-term side effects and complications are rare in ERT, patients need to be aware of potential symptoms to ensure rapid identification and management. These tend to be specific to the type of ERT being received, and it is best to consult with your doctor for more information. 

FAQs

Should I undergo ERT if I am worried about the potential side effects?

As with all therapies, it is critical to evaluate the benefits and side effects of ERT. Opting for ERT is dependent on your unique health status and personal preferences. This guide aims to describe the importance of managing potential side effects and is not intended to cause unnecessary worry. It is best to seek advice and express concerns to your doctor to make a fully informed decision about undergoing ERT. 

When should I notify my doctor of my side effects?

If you are experiencing severe or persistent side effects, please seek medical attention from your doctor. It is best to remain in communication regarding any concerns or unexpected symptoms following ERT. 

I think I am experiencing a side effect of ERT, but it was not included in this article. What can I do?

While this article describes the most common side effects associated with ERT, this is by no means an exhaustive list. ERT for different conditions will have specific side effects which may not have been included. If you suspect that you are experiencing a side effect of ERT, it is best to seek medical advice from your doctor. 

Is ERT available for my type of disease?

Your doctor should describe the available treatment options for your specific health condition. It is important to note that ERT is only approved for select diseases caused by enzyme deficiencies. Not all enzyme deficiency diseases have ERT as a treatment option. 

Summary

In conclusion, ERT is an important treatment option for a variety of diseases which are caused by the deficiency of a particular enzyme in the human body. By administering the enzyme lacking in these individuals, ERT can restore healthy levels within the body and alleviate symptoms of the disease. 

However, as with all treatments, patients considering or undergoing ERT should be aware of its potential side effects. Not every patient experiences identical side effects and it is dependent on the individual’s tolerability to their ERT treatment regimen. The commonly reported side effects across different ERTs include gastrointestinal symptoms, hypersensitivity reactions, injection site reactions, and systemic symptoms. Other long-term side effects tend to be specific to the type of disease and ERT. 

While these side effects are generally mild and do not require additional medical attention, rare cases are severe and should be reported to a healthcare professional immediately. It remains crucial, however, to understand these symptoms to make informed decisions regarding ERT treatment and management. This guide aims to discuss some of these side effects and alert patients when to best seek medical advice from their doctor.