Acute Graft Versus Host Disease in Liver

Acute graft versus host disease of the liver is a serious complication that can occur after a stem cell or bone marrow transplant, when donor immune cells attack the recipient’s liver tissue, typically within the first 100 days after transplantation.

Table of contents

• What is Acute Graft Versus Host Disease in the Liver?
• When Does It Occur?
• Signs and Symptoms
• Organs Most Commonly Affected
• How is it Diagnosed?
• Severity of Liver GVHD
• Treatment Options
• Outlook and Prognosis

What is Acute Graft Versus Host Disease in the Liver?

Acute graft versus host disease (GVHD) is a condition that occurs when immune cells from transplanted tissue recognize the recipient’s body as foreign and attack its cells. In this context, graft refers to transplanted or donated tissue, while host refers to the recipient’s tissues^[1].

GVHD is a common complication following allogeneic hematopoietic stem cell transplant (a transplant using donor cells from another person)^[1]. During an allogeneic transplant, your healthcare provider transplants hematopoietic stem cells (immature blood cells) from a donor into your body. The donated stem cells eventually become mature blood cells^[2].

In GVHD, the donated stem cells (graft) view the recipient’s cells (host) as an unfamiliar threat. As a result, the donated cells attack the recipient’s cells^[2]. When this immune reaction targets the liver, it can cause damage to liver tissue, particularly affecting small bile ducts and liver cells^[3].

Although GVHD after liver transplantation is rare compared to blood stem cell transplants, with an incidence of only 0.1-2%, it carries a very high mortality rate of 80-100%^[5].

When Does It Occur?

Acute classic GVHD presents within 100 days of transplantation with typical clinical features. However, there is also a form called persistent, recurrent, or late-onset acute GVHD that manifests with clinical features of classic acute GVHD but after 100 days of transplantation^[1].

After orthotopic liver transplantation, patients typically present with GVHD symptoms between two to eight weeks after the transplant^[5].

Signs and Symptoms

Symptoms of acute GVHD affecting the liver most often include^[2]:

• Jaundice (yellow discoloration of the skin and/or eyes)
• Abdominal cramping
• Nausea and vomiting
• Dark urine

After orthotopic liver transplantation, patients can present with skin rashes, diarrhea, and bone marrow aplasia (failure of the bone marrow to produce blood cells)^[5].

Clinical signs and symptoms are frequently confounded by the superimposed effects of pre-transplant chemotherapy and radiation, immunotherapy targeted to the underlying disease, GVHD prevention medications, and infection^[3].

Organs Most Commonly Affected

Acute GVHD typically manifests as injury to the skin, gastrointestinal tract, and liver^[3]. Among patients undergoing stem cell transplants, GVHD affects the gastrointestinal tract with or without liver involvement in a significant number of cases. Liver GVHD alone, without gut or skin GVHD, is quite rare^[14].

• Liver
• Gastrointestinal tract
• Skin

How is it Diagnosed?

Diagnosis of hepatic GVHD is made based on clinical and histologic evidence, supported by chimerism studies showing donor HLA alleles in the recipient bone marrow or blood^[5].

Near certainty of GVHD diagnosis can be achieved by combining a high likelihood of GVHD with negative evidence of infection; consistent findings on physical examination, imaging, and examination of tissue; and typical changes in liver cells and small bile ducts. However, tissue examination alone is not the gold standard for diagnosis because of sampling errors^[14].

In some cases, hepatic GVHD may be difficult to distinguish from other disorders such as infection and drug-induced liver injury (DILI, which is damage to the liver caused by medications)^[3]. Several lab tests and imaging studies can be done to diagnose and monitor problems caused by GVHD. These may include^[6]:

• X-ray or CT scan of the abdomen
• Liver function tests
• Liver biopsy

Careful attention to and correlation with clinical findings, laboratory values, and tissue examination is essential for accurate diagnosis^[3].

Severity of Liver GVHD

Healthcare providers grade acute GVHD as mild, moderate, severe, or very severe. The treatment depends on the grade of GVHD. You might not need any treatment if you have grade 1, or mild, GVHD. But you will need some type of treatment for moderate to severe GVHD, which is grade 2 to grade 4^[10].

The severity of liver disease is classified by the level of total serum bilirubin (a substance in the blood that increases when the liver is damaged). Stage 1 indicates a bilirubin level of 2-3 mg/dL, stage 2 is greater than 3-6 mg/dL, and stage 4 is greater than 15 mg/dL^[14].

Treatment Options

After a transplant, the recipient usually takes medicines, such as prednisone (a steroid), which suppress the immune system. This helps reduce the chances or severity of GVHD. Many of these medicines have side effects, including kidney and liver damage. You’ll have regular tests to watch for these problems^[6].

The most common treatment for GVHD is steroids (medications that reduce inflammation and suppress the immune system). Doctors sometimes use a drug called ciclosporin with the steroids. You take ciclosporin as a capsule or you might have it through a drip into your bloodstream^[10].

For patients with grade II-IV acute GVHD, systemic treatment consists of continuing the original immunosuppressive prevention therapy (cyclosporine or tacrolimus) and adding methylprednisolone. The most common starting dosage is 2 mg/kg per day given in 2 divided doses^[9].

Sometimes steroids and ciclosporin do not control GVHD. This is called steroid-resistant GVHD. In this case, your doctor will use other treatments which may include^[10]:

• A type of light therapy called extracorporeal photopheresis (ECP, an immunomodulatory procedure)
• Monoclonal antibodies such as infliximab or rituximab
• Chemotherapy such as methotrexate
• Medicines to suppress the immune system such as mycophenolate mofetil (MMF)
• Medicines that reduce inflammation such as etanercept
• Cancer growth blockers such as ruxolitinib or imatinib

After orthotopic liver transplantation, several therapeutic approaches have been used for the management of GVHD including increased immunosuppression, decreased immunosuppression, and cellular therapies. However, success rates have been low, and new approaches are needed^[5].

Treatment of acute GVHD has evolved from a one-size-fits-all approach to a more nuanced strategy based on predicted outcomes. Lower and time-limited doses of immune suppression for patients predicted to have low-risk GVHD are safe and effective^[14].

Outlook and Prognosis

The outlook depends on the severity of GVHD. People who receive closely matched tissue and cells usually do better. Some cases of acute or chronic GVHD can be treated successfully. However, GVHD can damage the liver, lungs, digestive tract, or other body organs. There is also a risk for severe infections^[6].

GVHD after orthotopic liver transplantation has an extremely high mortality rate of 80-100%. Death typically occurs due to complications related to severe infection, shock, and multiorgan failure^[7].

Although GVHD is associated with increased overall morbidity and mortality, in more severe GVHD, prolonged exposure to immunosuppressive therapies, failure to achieve tolerance, and inadequate clinical responses are the proximate causes of GVHD-related deaths^[14].

If you have had a bone marrow transplant, contact your transplant provider right away if you develop any symptoms of GVHD or other unusual symptoms^[6].