Medical problems after liver transplantation

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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
• Phenytoin
• Carbamazepine
• St John’s wort.

Patients commenced on these medications will experience increased drug elimination necessitating dose adjustment. Close monitoring of drug levels should be performed when these medications are prescribed and often the dose of cyclosporine or tacrolimus may have to be doubled. There have been cases when ingestion of St John’s wort has precipitated graft rejection. Similarly, cessation of these medications requires appropriate downward dose adjustments.

Agents known to decrease the elimination of cyclosporine and tacrolimus, and therefore increase blood levels, include:

• Ketoconazole
• Fluconazole
• Itraconazole
• Erythromycin
• Cimetidine
• Diltiazem.

The majority of these agents exert their effect by competing for cytochrome P450 metabolism and substantial dose adjustments are often required to avoid toxicity. Features of acute drug toxicity include a rapid decline in renal function as well as neurotoxicity manifesting as seizures, confusion or a fugue-like state.

Two other immunosuppressive drug interactions are worthy of note. An increased incidence of rhabdomyolysis has been reported in patients receiving concomitant cyclosporine and HMG-CoA reductase inhibitors (‘statins’) and rhabdomyolysis can occur at any time while patients are on these medications. Unfortunately, hyperlipidaemia is a well recognised side effect of cyclosporine and lipid lowering agents are frequently indicated in the post-transplant patient. Statins should be commenced at low dose and routine monitoring of creatinine phosphokinase is recommended. Grapefruit juice can markedly augment levels of immunosuppressive agents by selective post-translational down-regulation of intestinal wall cytochrome P450. There is significant interindividual variation in the susceptibility to this interaction, however patients should be warned about the potential for this interesting drug interaction.

There are two issues of note regarding drug interactions with azathioprine:

• Ganciclovir is usually prescribed in patients who develop CMV infection. A common side effect of both azathioprine and ganciclovir is leucopenia and it is therefore prudent to withhold azathioprine if ganciclovir is prescribed to avoid this potentially serious complication.
• Allopurinol is used to control gout. Allopurinol inhibits xanthine oxidase activity, which is an important step in the metabolism of azathioprine. Therefore, when these drugs are used in combination, the activity of azathioprine is potentiated and its dose must be reduced to approximately 25% of the usual dose.

Long-term medical complications

Many of the long-term medical complications seen in liver transplant patients are a result of side effects of cyclosporine, tacrolimus or other immunosuppressive agents. The major complications can be grouped according to body system.

Endocrine complications

Endocrine complications include diabetes mellitus and osteoporosis. The prevalence of diabetes appears to be higher in the early phase after liver transplantation and may relate to higher doses of corticosteroids and immunosuppression that are used during the early stage. Large studies have suggested that the prevalence of diabetes mellitus is higher in patients using tacrolimus compared with those using cyclosporine. Treatment is based on weight loss, oral hypoglycaemic agents and insulin. Osteoporosis is common in patients with end-stage liver disease who often have a number of different contributing factors. Bone loss is accelerated early in the early post-transplant period due to immobility and the effect of agents, including corticosteroids, used for immunosuppression. Preventive therapy is based on the use of calcium and vitamin D supplementation, as well as bisphosphonates, where indicated.

Renal complications

Renal dysfunction is common after liver transplantation and has multiple aetiologies. Hypertension, diabetes mellitus and drug-induced nephrotoxicity—either alone or in combination—are responsible for the majority of cases of renal dysfunction. The renal effects of tacrolimus and cyclosporine can take several forms including renal vasoconstriction, thrombotic angiopathy and, in the chronic form, tubular atrophy and interstitial fibrosis with preservation of glomerular structure. A complete history and physical examination are important to exclude other potential contributing factors. The dose of cyclosporine or tacrolimus should be minimised, sometimes by using a small dose of another kidney sparing agent (e.g. azathioprine).

Cardiovascular complications

Prior to liver transplantation, most patients undergo an extensive cardiovascular evaluation. The majority of patients with significant coronary artery or valvular disease are identified in the pre-transplant work-up and appropriate therapy is undertaken or a decision is made not to proceed. Therefore, significant cardiovascular events are unusual in the early post-transplant period. However, accelerated atherosclerotic heart disease developing after all forms of solid organ transplantation is an important cause of morbidity and mortality. Metabolic complications such as diabetes mellitus, dyslipidaemia, obesity, arterial hypertension and renal disease form the basis of a very pro-atherogenic environment in the liver transplant patient. Clinicians involved in the care of liver transplant recipients should regularly screen for conditions that predispose to atherosclerosis. Yearly screening of patients with fasting lipid profiles, regular evaluation of fasting blood glucose, constant attention to weight gain and appropriate attention to blood pressure control are essential elements of care. Cigarette smoking is common in liver transplant patients and must be addressed and strongly and actively discouraged. Patients often have more than one risk factor for coronary artery disease and therefore stringent management of individual risk factors is indicated.

RECURRENCE OF THE UNDERLYING DISEASE

Chronic liver disease due to hepatitis C virus infection is the most common indication for liver transplantation worldwide. Unfortunately, the infection recurs in almost every patient following transplantation. An acute lobular hepatitis develops in 75% of patients within 6 months of liver transplantation, and this can be difficult to distinguish from acute rejection on liver biopsy. A small proportion of patients (approximately 5%) will develop a specific, accelerated course of liver injury termed fibrosing cholestatic hepatitis, which is usually fatal. Approximately 30% of patients will develop cirrhosis by 5 years after transplantation. Thus the course of liver disease in patients with recurrent HCV infection following liver transplantation is greatly compressed compared with non-transplant patients. A number of factors associated with aggressive recurrence have been identified (Table 49.1). Studies utilising pegylated interferon and ribavirin have reported sustained virological response of 25%–35% although dose reductions of both pegylated interferon and ribavirin are common (80%) and therapy has to be ceased in approximately 25% of patients.

TABLE 49.1 Risk factors associated with severe histological recurrence of hepatitis C virus

• Pulse methylprednisolone for acute cellular rejection
• Antithymocyte globulin use
• Recipient age
• Donor age
• Cytomegalovirus infection
• Pre-transplant viral load
• Post-transplant viral load

Hepatitis B virus (HBV) infection was once regarded as a contraindication to transplantation because of an aggressive and usually fatal recurrence. Post-transplant prophylaxis with a regimen of hepatitis immunoglobulin and an oral nucleoside agent has greatly reduced the risk of recurrence and survival of patients transplanted with HBV is similar to that of patient groups. The frequency of lamivudine resistance due to YMDD and other mutations in viral DNA polymerase is much lower in transplant patients treated with this regimen compared with non-transplant patients treated with lamivudine monotherapy.

Recurrence of hepatocellular carcinoma is uncommon if patients are transplanted when there is a single tumour less than 5 cm in diameter, or no more than three lesions less than 3 cm (Milan criteria) and no evidence of portal vein invasion. Factors that predict increased likelihood of recurrence include vascular invasion and poorly differentiated tumours. Most units regard cholangiocarcinoma as a contraindication to transplantation as recurrence is almost universal. Extensive clinical research trials are being performed at some centres in an effort to identify patients with ‘favourable’ cholangiocarcinoma.

Autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are all known to recur following transplantation, with several series showing recurrence rates of 10%–45%. Hereditary haemochromatosis does not appear to recur following liver transplantation whereas non-alcoholic steatohepatitis is an increasingly common finding after transplantation due to a combination of side effects of immunosuppression and excessive weight gain.

VASCULAR AND BILIARY COMPLICATIONS

Hepatic artery thrombosis

Hepatic artery thrombosis can produce a spectrum of outcomes ranging from an occult event (more likely when occurring as a late event some months post transplant) through multiple liver abscesses and biliary stricturing to acute hepatic failure. Confirmation of the presence of a hepatic artery thrombosis is usually obtained by duplex ultrasonography. Hepatic artery thrombosis requires urgent surgical review with consideration of revascularisation or re-transplantation. Hepatic artery thrombosis can occur months after transplantation and may be associated with a less catastrophic clinical presentation with biliary strictures or liver abscess formation. The most appropriate therapy in these latter situations varies depending on factors including graft function, patient condition and hepatic perfusion.

Mycotic aneurysm

Mycotic aneurysms usually occur at the hepatic arterial anastomosis and rupture of the aneurysm is usually fatal. Survival is dependent on early diagnosis and rapid surgical intervention.

Portal vein thrombosis

Portal vein thrombosis may occur early or some time after transplantation. Occlusion of the portal vein early after transplantation may be associated with a marked elevation of alanine aminotransferase and diagnosis is confirmed by duplex ultrasonography. Early surgical intervention or re-transplantation may be required. In the later postoperative course, portal vein occlusion may present with gastrointestinal bleeding associated with the development of collateral vessel formation or may be asymptomatic. The most appropriate management of a portal vein thrombosis in this situation is dependent on a number of different issues.

Bile leaks

Bile leaks occur early after transplantation and are often associated with abdominal pain, fever and an elevated white cell count. Bile leaks may be associated with hepatic artery thrombosis and a thorough evaluation of vascular patency is required. The site of the bile leak should be properly identified as this will determine appropriate management (e.g. anastomotic leaks often require surgical revision whereas leaks associated with T-tubes may be managed conservatively or by endoscopic stent placement).

Biliary strictures

Biliary strictures may occur at anastomotic or non-anastomotic sites and occur in the setting of bile duct ischaemia or recurrent primary sclerosing cholangitis. Clinical and laboratory features may include an episode of cholangitis or elevated liver function tests. Management of biliary strictures depends on the severity of symptoms, the location of the strictures and liver function. However, endoscopic or surgical management is often required.

SUMMARY

Liver transplantation is a widely available treatment for patients with liver disease. In the early years of transplantation, 1-year and 5-year survival were regarded as the core determinants of a successful transplant program. However, in recent years clinicians have recognised that medical complications related to immunosuppression are the most important determinant of long-term survival of liver transplant patients. As such, proper management of medical issues such as diabetes mellitus, hypertension and renal dysfunction are the central tenets of care of these patients. This chapter highlights the importance of these issues and provides basic instruction on the medical complications seen in the liver transplant patient (Figure 49.1).

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FIGURE 49.1 Approach to the liver transplant patient with abnormal liver function tests.

FURTHER READING

Fischer SA. Infections complicating solid organ transplantation. Surg Clin North Am. 2006;86:1127-1145.

Killenberg PG, Clavien P-A, editors. Medical care of the liver transplant patient, 3rd edn., Malden MA: Blackwell Science, 2006.

Muñoz SJ, Elgenaidi H. Cardiovascular risk factors after liver transplantation. Liver Transpl. 2005;11(supp 1):S52-S56.

Wilkinson A, Pham P. Kidney dysfunction in the recipients of liver transplants. Liver Transpl. 2005;11(supp 1):S47-S51.

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