Hepatic Graft versus Host Disease - Symptoms, Diagnosis, and Treatment

Introduction:

Hematopoietic stem cell transplantation involves the infusion of hematopoietic (immature cells that can develop into all types of cells) stem cells intravenously to establish blood cell production in individuals whose bone marrow and immune systems are damaged or defective. These hematopoietic cells are found in the bone marrow and peripheral blood stem. This technique is used frequently to treat numerous malignant and nonmalignant diseases.

What Is Hepatic Graft versus Host Disease?

Hepatic graft vs. host disease is the most common complication. It is a severe and potentially life-threatening condition. This condition is difficult to differentiate from other complications of post-hematopoietic cell transplant. Death typically occurs due to associated complications involving severe infection, shock, and multiorgan failure.

What Are the Types of Hepatic Graft versus Host Diseases?

There are mainly two types of hepatic graft vs. host disease:

• Acute Hepatic Graft versus Host Disease: Severe factors are involved in leading to acute graft vs. host disease. The difference that occurs by donor cells fails to recognize cells as foreign cells and leads to the immune response against organs and tissues. Individuals who have received peripheral blood stem from an HLA mismatched donor (human leukocyte antigen) have an increased risk of developing acute GvHD. Other factors include a female donor who was pregnant in the past and the advanced age of the recipient of the donor.
• Chronic Hepatic Graft versus Host Disease: Chronic GvHD appears any time after an allogeneic transplant several years after the transplant. This might involve the skin, mouth, lungs, liver, gastrointestinal tract, genitourinary tract, and neuromuscular system. Chronic conditions occur in individuals who receive stem cells from mismatched HLA (human leukocyte antigen) or HLA-matched unrelated donors, older transplant recipients, and individuals who already have experienced acute graft vs. host disease.

What Causes Hepatic Graft versus Host Disease?

Graft vs. host disease occurs when the donor’s T-cells (the graft) and the host foreign cells attack and damage them. This condition can be mild, moderate, or severe. In rare cases, this can turn life-threatening. Individuals of advanced age are more prone to this reaction and rejection.

What Are the Signs and Symptoms of Hepatic Graft versus Host Disease?

Because of the increased risk of developing infections in this condition, it is very important to look for any physical changes and fever of more than 100.4º Fahrenheit. For a higher bone marrow transplant, the following symptoms occur in acute GvHD:

• Jaundice, yellowish discoloration of mucous membrane, skin, eyes, and abnormal test results.

• Rashes on the skin, reddened areas of skin.

• Nausea and vomiting.

• Diarrhea.

• Abdominal cramping.

In chronic GvHD conditions, the symptoms include:

• Discolored areas, skin thickening or tightening, raised skin, and rashes.

• Dry eyes or vision changes.

• Abdominal swelling.

• Yellow discoloration of the mucous membrane, skin, and eyes, including abnormal blood test results (jaundice).

• White patches, dry mouth, sensitivity, or pain to spicy foods.

• The difficulty in swallowing food, pain in swallowing, or weight loss.

• Fatigue.

• Muscle weakness and pain.

• Shortness of breath.

• Decreased motion in joints or stiffness of joints.

• Vaginal dryness and pain during intercourse.

How Is the Diagnosis Made for Hepatic Graft versus Host Disease?

The diagnosis can be made basically by a physical examination, by observing certain signs and symptoms. Evaluation of the tissues from the site of biopsies and laboratory values can help in the diagnosis of the condition. In chronic GvHD, symptoms may be less in number.

This condition is clinically presented in three different ways.

• When there is marked elevation in alkaline phosphatase and total bilirubin and milder elevation in aspartate transaminase (AST) and alanine transaminase (ALT).

• Peak elevations of aspartate transaminase and alanine transaminase with or without jaundice and along with slowly progressive cholestasis are present.

Due to the increased risk of complications like bleeding, a liver biopsy is indicated for evaluation of post-hematopoietic cell transplantation.

What Is the Treatment Given in Hepatic Graft versus Host Disease?

Hepatic graft vs. host disease is treated on the basis of its forms.

Acute Conditions Are Treated as Follows:

• Primary prophylaxis includes a criterion of Cyclosporine for six months and short-course Methotrexate (MTX) in T-cell replete allogeneic hematopoietic cell transplantation.

• Tacrolimus, most times, is substituted for Cyclosporine to control unrelated donor transplantation.

• Antithymocyte globulin is given before HCT (hematopoietic cell transplantation) to reduce risk.

• Other agents include Mycophenolate, Mofetil, Pentostatin, Alemtuzumab, Cyclophosphamide, Vorinostat, and Abatacept.

• ECP- extracorporeal photopheresis is an immunomodulatory procedure in which lymphocytes are collected and mixed. It is a part of a conditioning regimen together with Pentostatin.

• Novel therapies include the addition of ex vivo cultured mesenchymal cells.

Secondary Therapies Include:

• Ruxolitinib administration is an inhibitor of Janus-associated kinases (JAKs).

• ATG (anti-thrombocyte globulin) or multiple pulses of Methylprednisolone.

• Sirolimus.

• Infliximab.

• Psoralen and ultraviolet A irradiation (PUVA) are beneficial for cutaneous lesions of GvHD.

In Chronic Conditions:

• Administration of high dose of Cyclophosphamide for three to four days after hematopoietic cell transplantation.

• Alemtuzumab regimen before HCT (hematopoietic cell transplant) is recommended.

Secondary Therapies For Chronic Conditions Include:

• MMF(magnetomotive force) is the most used agent used in treating steroid-refractory chronic GvHD. It is also added along with Prednisolone, Cyclosporine, and Tacrolimus for treatment.

• Steroid-refractory chronic GvHD treated with Azathioprine or Thalidomide.

• Ibrutinib is recommended.

• PUVA (Psoralen and ultraviolet A irradiation) therapy plays a key role in refractory cutaneous chronic GvHD.

• Extracorporeal photopheresis, a modification of PUVA treatment, has shown beneficial effects.

What Is the Differential Diagnosis of Hepatic Graft versus Host Disease?

The differential diagnosis of hepatic GvHD is due to liver dysfunction that includes:

• Infection by viral hepatitis (inflammation of the liver caused due to viral infections).

• Immunotherapy-related hepatotoxicity (drugs used in immunotherapy that are capable of severe liver damage).

• Drug-induced liver injury (liver damage due to exposure to certain drugs).

• Sinusoidal obstructive syndrome (damage to small vessels in the liver due to obstruction).

• Sepsis-associated cholestasis (life-threatening condition due to reduced bile flow).

• Malignancies (presence of tumor growth or cancer).

• Post-transplant proliferative disorder.

Conclusion:

Hepatic GvHD is the most common complication that occurs following allogeneic hematopoietic stem cell transplantation and presents as an injury to gastrointestinal mucosa, skin, and liver. This condition can be, most of the time, difficult to distinguish from other complications of hematopoietic cell transplantation. So, careful attention to the correlation between laboratory and clinical findings is important for the diagnosis of hepatic GvHD, along with conditions like increased aminotransferase values. Medical interventions at the right time can help to reduce the risk of this condition.