Liver Transplant Rejection

When a new liver is transplanted, the body’s immune system may see it as a foreign threat and try to attack it, a process known as rejection. While modern medicine has significantly reduced rejection rates, understanding this complication remains vital for anyone receiving or caring for someone with a transplanted liver.

Table of contents

• What Is Liver Transplant Rejection?
• Types of Liver Transplant Rejection
• How Common Is Rejection?
• Risk Factors for Liver Transplant Rejection
• Signs and Symptoms of Rejection
• How Rejection Is Diagnosed
• Preventing Rejection
• Treatment of Rejection

What Is Liver Transplant Rejection?

Liver transplant rejection is a process in which the recipient’s immune system (the body’s defense system against infections and foreign substances) attacks the transplanted liver^[1]. The main job of your immune system is to protect you from proteins, germs, and other entities that are dangerous to your health. When a new liver is placed in a person’s body, the body sees the transplanted organ as a threat and tries to attack it^[2].

Your immune system has specialized cells called T-cells that constantly circulate in the blood, identifying foreign tissue such as a newly transplanted organ. Human cells carry unique identification molecules called Human Lymphocyte Antigens (HLA), which tell the T-cells that the cells in your body are your own. When you receive an organ transplant, the T-cells notice that the transplanted organ does not have the same HLA antigens as the rest of your body, and they try to destroy the transplanted organ^[5].

The immune system makes antibodies to try to kill the new organ, not realizing that the transplanted liver is beneficial^[2]. If left untreated, transplant rejection can lead to the failure of the new liver^[4].

Types of Liver Transplant Rejection

There are two main types of rejection that can occur after liver transplantation^[4].

Acute rejection typically occurs within the first few weeks to months after the liver transplant. It often presents with sudden and severe signs and symptoms, like yellowing of the skin and eyes, pain, fever, and elevated liver enzymes^[4]. Acute rejection generally occurs in the first 3 to 6 months after transplant^[15]. The liver transplanted organ behaves differently to other solid organ transplants, as acute rejection generally does not impair long-term survival of the transplanted liver in most cases^[3].

Chronic rejection develops gradually, often months or years after transplantation. The symptoms are usually more subtle and include fatigue and gradual changes in liver function tests^[4]. Chronic rejection causes damage to blood vessels and bile ducts inside the liver and may lead to graft failure after liver transplantation. While acute rejection usually responds well to treatment, chronic rejection represents a difficult situation, and a significant proportion of patients do not respond to increased doses of medications that suppress the immune system^[3]. Chronic rejection often leads to retransplantation or death^[3].

How Common Is Rejection?

The incidence of both acute and chronic rejection has declined significantly in recent years due to improved medications that suppress the immune system^[3]. Acute rejection occurs in 15 to 25 percent of liver transplant recipients on Tacrolimus-based immunosuppression regimens and generally improves with steroids in the majority of cases^[3]. All recipients experience some amount of acute rejection^[6].

Risk Factors for Liver Transplant Rejection

Liver rejection after transplantation can happen for several reasons. The most common risk factors include^[4]:

• Not taking immunosuppressive medications as prescribed
• Infections
• Donor-recipient mismatch
• History of previous rejection
• Medication side effects
• Presence of other medical conditions
• Age
• Genetic factors

It is important to work closely with the transplant team to minimize these risks. Steps you can take include undergoing a thorough evaluation process before transplantation and taking all of your medication exactly as prescribed after transplantation^[4].

Signs and Symptoms of Rejection

Research shows that the rejection process begins well before symptoms develop, with what is called “silent” rejection, or subclinical acute rejection^[4]. In subclinical acute rejection, you will likely feel normal.

Abnormal liver blood test results may be the first sign of organ rejection. Rejection does not always cause symptoms you may notice^[15]. When liver rejection symptoms occur, they can vary from patient to patient. The following are the most common symptoms^[2][4][15]:

• Fever greater than 100°F (37.8°C)
• Yellowing of the skin and the whites of the eyes (jaundice)
• Dark colored urine
• Light colored or pale stools
• Pain or discomfort in the abdominal area, particularly in the right upper section
• Swelling of the abdomen or legs
• Unexplained and persistent fatigue or weakness
• Itching
• Persistent nausea and vomiting
• A sudden loss of appetite or weight loss
• Irritability
• Headache
• Confusion or other changes in mental status

You should contact your doctor immediately if you have any of these symptoms^[4][15].

How Rejection Is Diagnosed

The current standard of care to diagnose liver rejection is a liver biopsy, where a sample of the transplanted liver is removed and tested for signs of rejection^[4]. Your doctor will often perform a liver biopsy to see if your body is rejecting the new liver^[15].

Other tests that aid in the diagnosis of liver rejection include^[4]:

• Liver function tests
• Imaging studies
• Immunologic tests
• Clinical evaluation

Novel molecular diagnostic tests assess gene expression patterns in blood to help in the diagnosis of rejection, especially in cases of subclinical or “silent” rejection. These tests can help confirm that a patient’s immunosuppressive medication is correctly balanced and help avoid unnecessary biopsies^[4].

Preventing Rejection

To help keep your body from rejecting the new liver, you will need to take medicines called immunosuppressants. These medicines prevent and treat organ rejection by reducing your immune system’s response to your new liver^[15]. Medications must be given for the rest of the individual’s life to fight rejection^[2].

The anti-rejection medications most commonly used include^[2]:

• Cyclosporine
• Tacrolimus
• Prednisone

You may have to take two or more immunosuppressants. The doses of these medications may change frequently, depending upon your response^[2]. Blood tests to measure the amount of medication in the body are done periodically to make sure you do not get too much or too little of the medications. White blood cells are also an important indicator of how much medication you may need^[2].

Rejection can occur any time the immunosuppressive medicines fail to control your immune system’s response to your new liver^[15]. Failure to comply with the immunosuppression medical regimen is the number one cause of organ failure^[18].

Side Effects of Immunosuppressants

Because anti-rejection medications affect the immune system, individuals who receive a transplant will be at higher risk for infections. A balance must be maintained between preventing rejection and making you very susceptible to infection^[2]. This risk of infection is especially great in the first few months because higher doses of anti-rejection medications are given during this time. You will most likely need to take medications to prevent other infections from occurring. Some of the infections you will be especially susceptible to include oral yeast infection (thrush), herpes, and respiratory viruses^[2].

Other possible side effects of immunosuppressants include^[15]:

• Brittle bones
• Diabetes
• High blood pressure
• High levels of cholesterol and triglycerides in the blood
• Kidney damage
• Weight gain

Long-term use of these medicines can increase your chance of developing cancers of the skin and other areas of your body^[15].

Treatment of Rejection

Acute rejection generally improves with steroid boluses, and steroid-resistant rejection is uncommon^[3]. Chronic rejection may improve with escalation of immunosuppression or may result in irreversible loss of graft function leading to retransplantation or death^[3].

If your transplanted liver fails as a result of rejection, your transplant team will decide whether another transplant is possible^[15].