Chapter 49 MEDICAL PROBLEMS AFTER LIVER TRANSPLANTATION

KEY POINTS

• Common medical problems after liver transplantation include acute rejection, infections, side effects of immunosuppressive medications, vascular and biliary complications and recurrence of primary disease.

• Acute rejection is characterised by specific histological features and usually responds to methylprednisolone.

• Clinicians should be aware that immunosuppressive treatment can attenuate responses to infections and conventional signs of sepsis may be absent.

• Drugs that alter cytochrome P450 activity may influence blood levels of immunosuppression.

• Long-term medical complications of immunosuppression include hypertension, diabetes mellitus, renal dysfunction and atherosclerosis.

• Recurrent hepatitis C virus infection is an important cause of morbidity and mortality after liver transplantation.

INTRODUCTION

Liver transplantation is a well established therapy for end-stage liver disease. Medical problems that occur in patients following liver transplantation include the following:

• Graft rejection

• Infections

• Side effects and drug interactions with immunosuppression

• Recurrence of the underlying disease

• Vascular and biliary complications.

REJECTION OF THE LIVER GRAFT

Hyperacute rejection

Hyperacute rejection occurs minutes after transplant and results in loss of the graft. Fortunately, this dramatic clinical picture is rare in liver transplantation.

Acute cellular rejection

Acute cellular rejection is the most common type of rejection following liver transplantation. Acute rejection may occur at any time after liver transplantation, but most frequently in the first month and may be provoked by adjustments in immunosuppression. Patients with acute rejection usually have no specific symptoms. Increases in serum alkaline phosphatase and gamma-glutamyltransferase with or without an increased serum bilirubin concentration is the usual pattern of biochemical disturbance. It is important to exclude biliary, vascular and infectious causes of abnormal liver function tests. Ultrasound examination and appropriate laboratory testing for infectious agents are usually performed to help exclude these other causes. However, the diagnosis of acute rejection is best established by liver biopsy, which shows endothelitis and biliary duct inflammation. Most cases of acute rejection respond to a pulse of methylprednisolone (1 g intravenously daily for 3 days).

Chronic rejection

Chronic rejection, despite the inference that it is a late event, can occur within 6 weeks of liver transplantation. It is characterised by an elevated serum bilirubin, alkaline phosphatase and gamma-glutamyltransferase. It is more insidious in progression than acute rejection and is characterised by histological features of paucity of bile ducts associated with arteriole obstruction by foamy macrophages. Chronic rejection does not respond to pulse methylprednisolone. Some patients who are on cyclosporine will benefit from conversion to tacrolimus, and patients already using tacrolimus may benefit from an increased dosage to achieve higher serum levels.

INFECTIONS IN THE LIVER TRANSPLANT RECIPIENT

Infections in the liver transplant recipient are common causes of morbidity and mortality. Physicians attending to liver transplant patients should be extremely vigilant as delays in diagnosis and therapeutic interventions can have very serious outcomes. Clinicians should also remember that immunosuppressive therapy can attenuate the usual systemic responses to infection, and conventional signs of underlying sepsis, such as fever and elevated white cell count, may be absent. Innocent symptoms such as mild fever, cough or vague abdominal pain may indicate serious underlying pathology and the threshold for investigation of such abnormalities should be very low.

It is useful to consider the type of infections in relationship to the time since liver transplantation. Bacterial infections are extremely common in the first month after liver transplantation and common sites of infection include the abdomen (peritonitis, cholangitis, hepatic abscess, wound infection), chest (pneumonia, empyema), urinary tract (a consequence of prolonged catheterisation) and intravenous access sites. A definitive focus of bacterial sepsis may not be found or may be unusually located (e.g. teeth or prostate gland). The viral infections that occur early after liver transplantation include herpes simplex virus (HSV) reactivation, which may be manifest by oral or genital lesions, and HHV-6, which may cause pancytopenia and interstitial pneumonia. Cytomegalovirus (CMV) is extremely common after liver transplant but tends to occur after the first month. The clinical manifestations may be protean and include cytopenia, hepatitis, upper and lower gastrointestinal tract ulceration, pulmonary involvement and an infectious mononucleosis syndrome. Diagnosis may be confirmed by the characteristic histological appearance of inclusion bodies in addition to the detection of a circulating structural protein (pp65) and direct identification of virus by polymerase chain reaction (PCR). However, it is recognised that diagnosis may be very difficult on occasions. Ganciclovir is the antiviral of choice and dose adjustments are required for patients with renal failure (see below for antimetabolite interactions). Similarly, reactivation of varicella tends to occur slightly later after liver transplant and can manifest as shingles, disseminated cutaneous disease or visceral involvement. Epstein-Barr virus infection tends to present as a post-transplant lymphoproliferative disorder that may respond to a reduction in the intensity of immunosuppression. The prevalence of opportunistic infections also relates to the intensity of the immunosuppressive regime. While the frequency of opportunistic infection is proportional to the intensity of the immunosuppression regime, patients are always at risk. Vigilance is required for infections with fungi (Aspergillus, Cryptococcus, Candida), protozoans (Pneumocystis carinii, Toxoplasma gondii) and bacteria (Nocardia, Legionella).

If the attending physician is suspicious of an underlying infection, a complete history and physical examination are required (including oral, dental and rectal examination). Laboratory tests including full blood count, blood cultures, urine examination (and culture) and chest X-ray should be performed. More specialised investigation will depend somewhat on the underlying symptoms. Abdominal ultrasound, computed tomography (CT) scan and cholangiogram may be performed to investigate the possibility of intra-abdominal sepsis, hepatic artery thrombosis or cholangitis. Fluid collections should be aspirated for laboratory evaluation and brain CT scan and lumbar puncture should be considered if there are any neurological symptoms or signs. Appropriate serology for various viral and opportunistic infections should be performed.

IMMUNOSUPPRESSION THERAPY

Advances in immunosuppression therapy have underpinned the dramatic developments in liver transplantation over recent decades. The most commonly used immunosuppressive agents used in transplantation are calcineurin antagonists (cyclosporine, tacrolimus), antimetabolites (azathioprine, mycophenolate) and corticosteroids (prednisone). Immunosuppressive regimens vary between different units but most patients who have had a liver transplant are maintained on a calcineurin antagonist with or without other added agents (e.g. azathioprine or prednisone).

Drug interactions

The terminal metabolism of cyclosporine and tacrolimus occurs via the cytochrome P450 system. Therefore, agents that alter cytochrome P450 activity—whether it be increased or decreased—have the potential to influence their blood levels resulting in drug toxicity or under-immunosuppression. Important inducers of cytochrome P450 metabolism include the following medications:

• Rifampicin

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