Chronic graft-versus-host-disease (GVHD) is a serious complication that can happen after an allogeneic stem cell transplant. The procedure replaces damaged or diseased blood cells with healthy stem cells from a donor and is used to treat leukemia, lymphoma, and other blood disorders. Chronic GVHD can affect many organs but most often involves the liver.

Liver problems happen in up to 80 percent of people who receive a hematopoietic stem cell transplant, due to chronic GVHD or other causes. When GVHD affects the liver, it may be called hepatic GVHD or chronic GVHD of the liver.

In this article, we’ll review how chronic GVHD can affect the liver so you can recognize the signs and symptoms and know what to expect.

1. Chronic GVHD Usually Affects the Liver

Chronic GVHD can develop at any time after an allogeneic stem cell transplant, but it occurs only when symptoms last a long time. Acute GVHD usually appears within the first 100 days after a transplant, but it can also show up later. When it does, it only causes sudden, short-term symptoms.

Both acute and chronic GVHD can affect the liver. However, liver problems appear to be more common in people with chronic GVHD. A 2021 study found that 31 percent of people with liver problems after a stem cell transplant still had chronic GVHD one year later. On the other hand, around 15 percent of study participants were diagnosed with acute GVHD.

2. Liver Damage in Chronic GVHD Is Caused by Inflammation

GVHD can develop after a stem cell transplant when the donated cells (the graft) see the recipient’s body (the host) as foreign and attack it. Changes in the host’s immune system can lead to chronic inflammation. Over time, inflammation damages affected organs, like the liver. As the body tries to repair the damage, it replaces healthy tissue with scar tissue in a process called fibrosis.

The scar tissue doesn’t work as well as healthy liver tissue. In the liver, scar tissue can make the bile ducts become narrower. When the bile ducts become narrow, bile — a digestive fluid — can't flow out of the liver properly. This narrowing causes bile to build up in the liver, leading to further damage.

Researchers have found that some conditions may increase the likelihood of developing hepatic GVHD. Males and people with a history of hepatitis C infection may be more likely to have severe GVHD that affects the liver.

3. People With Chronic GVHD of the Liver Can Develop Jaundice

Jaundice causes the skin and whites of the eyes to turn yellow, though this color change may be harder to detect on darker skin tones. It happens when there’s too much bilirubin, a yellow substance released when red blood cells break down. A healthy liver removes bilirubin, but liver damage from chronic GVHD can make this harder. When bilirubin builds up in the blood, it can collect in the skin and eyes, causing jaundice.

Other symptoms of liver damage from chronic GVHD include:

• Dark-colored urine
• Light-colored poop
• Abdominal (stomach) swelling
• Nausea
• Vomiting
• Loss of appetite
• Itching

If you notice any of the above symptoms, it’s important to talk to your healthcare team right away.

4. Blood Tests Can Help Detect Liver Problems

In the early stages, you may not have any noticeable symptoms when chronic GVHD affects the liver. Your healthcare team will monitor your liver function with a group of tests often referred to as liver function tests (LFTs). These tests help monitor the levels of certain substances made by the liver, including:

• Alkaline phosphatase (ALP)
• Alanine transaminase (ALT)
• Aspartate aminotransferase (AST)
• Gamma-glutamyl transferase (GGT)
• Bilirubin
• Lactate dehydrogenase (LDH)

Elevated LFT results can be a sign of liver damage. Bilirubin, ALP, and ALT are most commonly used to help diagnose chronic GVHD of the liver. Other blood tests to check for liver problems may include total cholesterol and a complete blood count.

5. A Liver Biopsy May Be Needed To Diagnose Liver Problems From Chronic GVHD

It’s often difficult to tell if liver disease is caused by chronic GVHD or something else. For example, several other conditions may lead to high LFT results, including:

• Viral infections such as hepatitis
• Side effects of certain medications — Cyclosporine (Gengraf, Neoral, Sandimmune), tacrolimus (Prograf, Astagraf, Envarsus), methotrexate (Trexall, Jylamvo, Otrexup, Rasuvo, RediTrex), and some antibiotics and antifungals used to prevent infection
• Metabolic dysfunction-associated steatohepatitis (MASH) — Liver inflammation caused by fat buildup in the liver
• Gallbladder problems — An infection, inflammation, or blockage

To help your healthcare team understand the cause of your liver problems, a liver biopsy may be necessary. During a liver biopsy, a healthcare provider will use a needle to remove a sample of liver tissue. The tissue sample is then looked at under a microscope to find the cause of liver damage.

Imaging tests, including ultrasound and computed tomography (CT) scans, can also help diagnose chronic GVHD of the liver. Sometimes, these imaging tests are done at the same time as a liver biopsy.

6. Corticosteroids Are Usually the First Treatment for Chronic GVHD

Corticosteroids, also called steroids, are medicines that slow down the immune system and reduce inflammation. They are used to treat various conditions, including allergies, asthma, and autoimmune diseases. Health experts recommend steroids as the first treatment in people with chronic GVHD. Prednisone (Rayos) is an example of a common steroid used for chronic GVHD. Many people take steroids long term to keep chronic GVHD from getting worse.

However, after two years of steroid treatment, more than half of people develop steroid-refractory GVHD. In steroid-refractory GVHD, the disease stops responding to steroid medications. If this happens, other systemic (whole-body) medications can help prevent chronic GVHD from getting worse. Other immunosuppressant therapies or medications that target specific proteins in immune cells are treatment options for steroid-refractory GVHD. However, none of these treatments are specific for chronic GVHD of the liver.

7. Extracorporeal Photopheresis May Improve Chronic GVHD of the Liver

Extracorporeal photopheresis (ECP) is a treatment that uses ultraviolet (UV) light to change how the immune system works. During ECP, lymphocytes (immune cells) are removed from the blood, treated with UV light and a drug called 8-methoxypsoralen (8-MOP), then returned to the body. Doctors may use ECP if steroids don’t work.

Clinical trials, which are research studies that test new treatments, show that ECP can help with chronic GVHD in the liver. A 2014 study found that about 68 percent of people with steroid-refractory chronic GVHD in the liver improved with ECP therapy.

8. Ursodiol Is a Liver-Specific Medication That May Improve Chronic GVHD of the Liver

Ursodiol (Reltone, Urso 250, Urso Forte) is the only liver-specific medication for chronic GVHD of the liver. Ursodiol may help if chronic GVHD affects the bile ducts in the liver. It works by increasing the amount of bile the body makes. It helps to replace the toxic, hydrophobic bile acids in the liver with hydrophilic bile acids, which are less harmful and easier to absorb and excrete. Clinical trials have found that ursodiol can help lower elevated LFTs. It can also improve some symptoms of liver problems, like itching.

Your healthcare team may suggest adding ursodiol to your treatment plan if you have chronic GVHD of the liver. It’s usually taken two to three times per day and may be continued long-term until your symptoms improve.

Ask Your Doctor

Chronic GVHD can affect the liver, but finding it early and getting treatment can help control symptoms and prevent more damage. Regular checkups and liver tests are important for catching any changes, even if you feel fine. If steroids aren’t effective, other treatments like ECP or ursodiol may help. Talk to your doctor about your symptoms and treatment options to find the best plan for managing chronic GVHD of the liver.

Talk With Others Who Understand

On myGVHDteam, the site for people with graft-versus-host disease and their loved ones, people come together to ask questions, give advice, and share their stories with others who understand life with the condition.

Do you or a loved one have liver problems caused by GVHD? Are you receiving the follow-up care and support you need for managing the condition? Share your experience in the comments below.