Liver Transplantation (LT) outcomes have improved dramatically over the decades. The 1-year and 5-year survival after LT is around 85% and 70% respectively. With increasing numbers of long-term survivors, Primary Care Physicians (PCPs) are seeing larger numbers of solid organ recipients in their practice.

In addition to routine healthcare needs unrelated to the transplant, PCPs are faced with complex management of chronic illness that have unique implications due to chronic immunosuppression. This article helps to illustrate the common issues which may be encountered by PCPs and the co-management of patients after LT.

I. IMMUNOSUPPRESSANTS AFTER LIVER TRANSPLANT

Early after LT, patients are usually on a combination of two to three immunosuppressive medications, including a calcineurin inhibitor (CNI), an antimetabolite, and/or corticosteroids. Later, most centres taper doses of immunosuppressive drugs and eliminate all but the CNIs. There is considerable variation between centres as to the particular medications used and the specific timing of their tapering and discontinuation. Laboratory tests on all recipients are reviewed on a regular basis (most often monthly, but more or less frequently based on patient health, organ function and centre-specific protocols).

There are several side effects common to both CNIs including hyperkalemia, hypertension, neurotoxicity (headaches, tremors, neuropathy and seizures) and nephrotoxicity. It is also associated with diabetes. Occasionally, patients are prescribed ciclosporin which is more commonly associated with dyslipidemia and gingival hyperplasia.

Corticosteroids are generally given in large doses during the first week after LT and tapered rapidly to low levels or completely eliminated within weeks or months following LT. Given the substantial long-term side effects of corticosteroids, it is important to try to eliminate or minimise corticosteroids use in transplant recipients as soon as possible.

Drug interactions of immunosuppressants

Tacrolimus, cyclosporin and sirolimus have dose-related toxicity and relatively narrow therapeutic windows. The two pathways that are important for CNIs metabolism are cytochrome P-450 3A4 and P-glycoprotein. Certain drugs can induce or inhibit the cytochrome P-450 3A4 pathway resulting in rapid or slow metabolism of CNIs. Tables 1 and 2 provide a list of common substances that can increase or decrease levels of immunosuppressants.

II. CHRONIC CONDITIONS DUE TO CHRONIC IMMUNOSUPPRESSION

Chronic Renal Impairment (CRF)

Common aetiologies of renal dysfunction after liver transplantation are CNI toxicity, hypertensive vascular changes, diabetic nephropathy, membranoproliferative glomerulonephritis (MPGN) and IgA nephropathy. Signs and symptoms of patients with CRF include anaemia, renal osteodystrophy and electrolyte abnormalities.

Patients who develop CRF after liver transplantation have increased morbidity and mortality, therefore early identification and referral to a renal specialist is essential.

Diabetes

The prevalence of overt diabetes in LT patients may be as high as 33%. Incidence of de novo post-transplant diabetes is greatest during the first year after LT.

Management of post-transplant diabetes is similar to patients without liver disease with the same treatment goals to prevent renal failure, neuropathy, retinopathy, cardiovascular and cerebrovascular disease. Many patients require insulin therapy in the early stages. Oral hypoglycaemics can be used for a lesser degree of hyperglycaemia with little concern of interaction with immunosuppressive medications or damage to the transplanted liver. Early withdrawal or dose reduction of corticosteroids may improve glycaemic control.

Hypertension

Hypertension is a common complication in the post-transplant patient. The goal of antihypertensive therapy should be a blood pressure below 130/80.

Treatment of hypertension may include thiazide or loop diuretics especially in those patients with peripheral oedema, but must be used with caution, since they can increase the risk of hyperuricemia.

The Calcium Channel Blockers (CCBs), particularly the dihydropyridine class, are a particularly attractive choice because their vasodilatory effects may overcome the vasoconstriction induced by the CNIs. Diltiazem, verapamil and nicardipine should be avoided as they can increase serum levels of the CNIs.

Beta-blockers are less effective generally than CCBs, but can be used and do not affect CNI levels. The exception is carvedilol, which can cause elevated levels of CNIs and usually requires reduction in CNIs dosages to maintain therapeutic serum levels.

ACE inhibitors and angiotensin II receptor blockers are not used initially for hypertension, because of the increased risk of renal insufficiency and hyperkalaemia in early post-transplant recipients. However, once the acute problems early after LT have resolved, these agents may have a role to prevent diabetic nephropathy and the effect of ciclosporin upregulating angiotensin II receptors.

Dyslipidemia

Between 16% and 43% of liver transplant recipients have increased plasma cholesterol. Most patients with non-cholestatic liver disease have low serum cholesterol levels due to impaired hepatic synthesis and esterification.

Risk factors for post-transplant hypercholesterolemia include female gender, cholestatic liver disease, pre-transplant cholesterol elevation, diabetes, obesity and use of beta-blockers, diuretics or immunosuppressive agents.

Ciclosporin, steroids and sirolimus have a significant effect on serum lipid levels. Tacrolimus has a minor effect, whereas mycophenolate and azathioprine have no significant effect on serum lipids.

Initial treatment for dyslipidaemia is lifestyle changes.

All agents correcting lipoprotein metabolism have been used successfully in liver transplant patients, but have potential side effects.

Nicotinic acid can cause significant flushing, hyperglycaemia, hyperuricemia, gastrointestinal distress or rarely, hepatotoxicity.

Bile acid sequestrants (cholestyramine, colestipol and colesevelam) can decrease plasma mychophenolate levels by 35%. In addition, bile acid sequestrants can decrease absorption of CNIs. Thus, bile acid sequestrants should not be used in patients taking mychophenolate and should be given greater than 2 hours before or after CNI dosing.

Fibric acids (gemfibrozil, fenofibrate and clofibrate) can cause biliary sludge, dyspepsia or myopathy. Ezetimibe can be used, but with monitoring of CNI levels.

If a statin is used, hydrophilic statins (pravastatin or fluvestatin) are preferred since they are not metabolised by the same cytochrome 450 3A4 metabolic pathway that metabolises CNIs and sirolimus. The lipophilic statins (atorvastatin, lovastatin and simvastatin) are metabolised by the cytochrome P-450 3A4 metabolic pathway and must be used with caution, since they are associated with higher rates of myotoxicity at dosages greater than 20 mg/day.

The combination of a lipophilic statin and a fibric acid may significantly increase the risk of myotoxicity. Management of dyslipidaemia requires close patient follow-up to observe for possible side effects from the medications.

Obesity

It is common for patients post-transplant to have an improved sense of well-being, contributing to overeating. Liver recipients, who were overweight pre-operatively, tend to gain more weight. Patients transplanted for non-alcoholic steatohepatitis can develop recurrent steatosis in their liver if they gain weight after LT.

Treatment for obesity involves sensible diet, abstinence from alcohol, aerobic exercise programmes and considering altering immunosuppressive medications (lowering or discontinuing corticosteroids or switching from cicloporin to tacrolimus).

Gout

Hyperuricemia is common in post-transplant recipients. Frequently, this condition occurs as a result of decreased uric acid excretion related to CNIs.

Preventing attacks usually consists of allopurinol and avoiding contributing medications, including thiazide diuretics, low-dose aspirin and nicotinic acid. Allopurinol can be used in patients on immunosuppressive agents, except with azathioprine (not commonly used in liver transplant recipients in Singapore), since the combination may increase the risk of azathioprine toxicity, including mylosuppression.

Acute gout attacks are treated with colchicine and corticosteroids as second line treatment. NSAIDs should be avoided in patients taking CNIs, since the combination can induce nephrotoxicity.

Metabolic Bone Disease

Many patients with chronic liver disease have decreased bone density before liver transplantation due to chronic liver disease. Bone loss occurs at an accelerated rate after LT and nadirs 6 months after the surgery. At 1 year after LT, bone densities are usually equivalent to the bone density at the time of transplant. The prevalence of skeletal fractures within 2 years after liver transplant is about 13%. Increased bone resorption is the prime contributor to the decline in bone density.

In patients transplanted due to cholestatic-related cirrhosis, additional factors contributing to osteoporosis include vitamin D malabsorption and unconjugated bilirubin impairing the proliferation of osteoblasts.

Non-pharmacologic therapies include alcohol and smoking cessation, increased physical activity and a balanced diet with 1500 mg of calcium and 800 IU of vitamin D daily. Treatment for osteoporosis in liver transplant recipients is not different from other patients and drugs used for treatment are not usually toxic to the liver.

Another important metabolic bone disease is osteonecrosis of the femoral head, which presents as hip pain due to corticosteroid use. This is diagnosed by Magnetic Resonance Imaging (MRI) and may require hip replacement.

SUMMARY

With advances in surgical techniques, post-operative care and immunosuppressant regimes, transplant patient survival has increased enormously. The increase in patient survival has uncovered increased rates of cardiovascular disease, bone disease and renal disease in this patient group.

Indeed, this appears likely to happen as in the coming years with more patients receiving transplants and the overall survival of transplant patients improving, both primary and secondary care physicians should work hand-in-hand to provide comprehensive patient care. Communication between primary and secondary care in transplant medicine will help make this transition smooth and beneficial for patients as well as healthcare professionals.

Dr Reina Lim Tee Gan graduated with MBChB from the University of Glasgow, United Kingdom in 2003. She obtained her post-graduate degree in internal medicine, MRCP(UK) in 2006. She was awarded an advanced fellowship training in transplant hepatology at the University Hospitals Birmingham, UK in 2010 and subsequently obtained specialist accreditation in the field of Hepatology and Gastroenterology in 2012. She completed a PhD in “The metabolic effects of hypoxia and chronic hepatitis C” at the University Hospitals Birmingham, UK in 2016.

She is currently a Consultant at the Department of Gastroenterology and Hepatology, Singapore General Hospital and has an area of interest and expertise in liver transplant, metabolic liver disease and alcoholic liver disease.

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