Long-term management of liver transplant recipients: A review for the internist
ABSTRACTOutcomes and long-term survival rates after liver transplantation have significantly improved over the last 5 decades, but the improved longevity is accompanied by long-term complications such as metabolic syndrome, obesity, cardiovascular disease, cancer, and bone disease. After the first year, the primary care physician assumes a greater role and provides most of the patient’s care. This review provides a source for primary care physicians in managing the long-term medical complications seen in these patients.
KEY POINTS
- Tacrolimus and cyclosporine are the most commonly used immunosuppressive agents in liver transplant recipients. Adverse effects include hypertension, hypercholesterolemia, diabetes (more common with tacrolimus), renal insufficiency, and osteoporosis.
- Hypertension affects 40% to 85% of liver transplant patients. Dihydropyridine calcium channel blockers (eg, amlodipine, nifedipine) are the first-line agents.
- Cardiovascular disease is the third most common cause of death after liver transplantation. Modifying risk factors is essential.
- Skin cancers account for 40% of all cancers after liver transplantation. Intensive screening is required and has been proven to lower the risk of death.
Corticosteroids
Corticosteroids have been the cornerstone of immunosuppression and remain the first line of treatment for acute allograft rejection. High intravenous doses of corticosteroids are usually started in the peritransplant period and are then switched to oral doses, which are tapered and continued with a fixed dose such as 20 mg of prednisone daily for 3 to 6 months after transplantation. However, some transplant centers keep patients on prednisone 5 mg/day indefinitely.
Adverse effects of corticosteroids include diabetes, salt and fluid retention, hypertension, hyperlipidemia, cosmetic changes (acne, cervical fat pad or “buffalo hump”), delayed wound healing, susceptibility to infection, cataracts, osteopenia, and potential adrenal suppression.12 There is concern that the use of these drugs may increase hepatitis C virus replication in patients who received a liver transplant for hepatitis C cirrhosis. Randomized trials have yielded conflicting results.13–15
Drug interactions
Certain drugs can affect the metabolism of calcineurin inhibitors and mTOR inhibitors by inducing CYP3A4, which results in decreasing the levels of the immunosuppressive drugs, or by inhibiting CYP3A4, which has the opposite effect.
Medications that can decrease the levels of calcineurin inhibitors and mTOR inhibitors:
- Anticonvulsants (carbamazepine, phenobarbital, phenytoin)
- Antibiotics (rifampin, isoniazid)
- St John’s wort.
Medications that can increase the levels of calcineurin inhibitors and mTOR inhibitors:
- Antifungals (fluconazole, ketoconazole, itraconazole, voriconazole, aspofungin)
- Antibiotics (azithromycin, erythromycin, clarithromycin)
- Nondihydropyridine calcium channel blockers (diltiazem, verapamil).16
Selected antibiotics are generally well tolerated, such as penicillins, cephalosporins, quinolones, sulfonamides, and topical antifungal agents.
LONG-TERM COMPLICATIONS
Figure 1 summarizes the common long-term complications of liver transplantation.
Hypertension
The prevalence of hypertension after liver transplantation is 40% to 85%, which is markedly higher than in patients with chronic liver disease before liver transplantation.17,18
One of the factors contributing to this increase is the use of immunosuppressive medications. Of these drugs, cyclosporine seems to be the one that most often causes an increase in both the incidence and the severity of hypertension, as it produces widespread vasoconstriction.19 Corticosteroids cause hypertension through their mineralocorticoid effects.
The diagnostic cutoffs for hypertension (ie, 140/90 mm Hg) and the treatment goals in posttransplant patients are similar to those in the general population. However, at our institution we target a blood pressure of less than 130/80 mm Hg in transplant patients because they have a high prevalence of other cardiovascular risk factors such as diabetes, obesity, and renal insufficiency.20
Dihydropyridine calcium channel blockers such as amlodipine and nifedipine are considered the best first-line agents because they dilate renal afferent arterioles, an effect that may counteract the vasoconstriction mediated by calcineurin inhibitors. Nondihydropyridine calcium channel blockers such as diltiazem and verapamil tend to have more marked negative inotropic effects and are not recommended in liver transplant recipients because they increase the levels of calcineurin inhibitors.21
Diuretics (eg, furosemide) might be the second-line agents, especially in patients with peripheral edema.16 One should be vigilant for hyperuricemia if thiazide agents are used.
Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are typically avoided in the early posttransplant period, but they can be started later and have additional benefits in patients with diabetes and congestive heart failure. Starting ACE inhibitors is acceptable in these patients unless there is a contraindication such as allergy to ACE inhibitors, hypotension, history of bilateral renal artery stenosis, significant hyperkalemia, or acute kidney injury. Monitor the serum potassium level closely for hyperkalemia in patients concurrently using calcineurin inhibitors.
Alpha-blockers and beta-blockers can be used as add-on therapy in patients with uncontrolled hypertension with the exception of carvedilol, because it increases the levels of calcineurin inhibitors.22
Blood pressure monitoring by the primary care physician is recommended every 6 months after the early posttransplant period, or more frequently when changes in treatment are being considered.
If hypertension continues to be inadequately controlled despite treatment, changing the immunosuppressive drugs or decreasing the doses can be considered, but the transplant hepatologist must be involved in this decision.23,24
Diabetes mellitus
The prevalence of diabetes mellitus is higher in liver transplant recipients than in the general population, reaching 30% to 40%.17,25 In addition to preexisting diabetes, 15% of liver transplant recipients develop new-onset diabetes.26,27
Risk factors for developing diabetes after liver transplantation include African American or Hispanic ethnicity, obesity, family history, pretransplant diabetes, hepatitis C virus infection, use of corticosteroids, and use of calcineurin inhibitors (tacrolimus more than cyclosporine) and sirolimus.26
In addition to increasing the risk of cardiovascular disease and other diseases, diabetes decreases both patient and graft survival after liver transplantation.28
The management of diabetes and the treatment target after transplantation should follow the American Diabetes Association guidelines for the treatment of type 2 diabetes mellitus.29 Lifestyle modifications, diet, and exercise are as important for transplant patients as for the nontransplant population. Insulin therapy is usually needed in the early posttransplant period to control blood glucose levels well, especially with the high doses of corticosteroids used during the first few weeks. No trials to date have compared oral agents in posttransplant patients. Therefore, the choice of oral hypoglycemic agents should be individualized on the basis of the patient’s characteristics and comorbidities.
We recommend that primary care providers screen all liver transplant recipients for diabetes regardless of their pretransplant status. This can be done by obtaining regular fasting blood glucose levels or a hemoglobin A1c level every 6 months. Additionally, liver transplant recipients diagnosed with diabetes require annual eye examinations to look for cataracts and diabetes-related changes.30
Dyslipidemia
On November 12, 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) released new clinical practice guidelines for treating blood cholesterol levels.31,32 According to these new guidelines, there are four groups of patients for whom treatment with statins is clearly indicated:
- Patients with cardiovascular disease
- Patients with low-density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL
- Patients 40 to 75 years old with type 2 diabetes
- Patients 40 to 75 years old with an estimated 10-year risk of cardiovascular disease of 7.5% or greater.
Liver transplant recipients should be evaluated on an individual basis to see if they fit in any of the four groups and if statin treatment therefore needs to be initiated.
A few things need to be kept in mind. First, the incidence of dyslipidemia after liver transplantation is estimated to be 45% to 69%. Risk factors include obesity, diabetes mellitus, cholestatic liver disease, and immunosuppressant medications.33 Sirolimus has a significant and well-documented association with dyslipidemia. Cyclosporine and corticosteroids are also strongly associated with dyslipidemia. Tacrolimus has a minor effect, and mycophenolate mofetil and azathioprine have no significant effects on serum lipid levels.16
Second, of the seven currently marketed statins, pravastatin and fluvastatin are preferred in liver transplant recipients because they are not metabolized by the same cytochrome CYP3A4 pathway that metabolizes calcineurin inhibitors and sirolimus.34 The doses of 40 to 80 mg daily of pravastatin or 40 mg twice daily of fluvastatin lower low-density lipoprotein cholesterol (LDL-C) levels by approximately 30% to 35%. However, these two agents are considered “moderate-intensity” statins according to the new ACC/AHA guidelines. The only two “high-intensity” statins are atorvastatin (40–80 mg) and rosuvastatin (20–40 mg), but they are both metabolized by CYP3A4. Therefore it is prudent to avoid them with the concurrent use of a calcineurin inhibitor or tacrolimus.
Gemfibrozil does not lower LDL-C and should not be used concomitantly with statins due to unacceptable risk of rhabdomyolysis and myopathy. Fenofibrates are usually avoided due to potential nephrotoxicity in patients receiving cyclosporine. Bile acid sequestrants (cholestyramine, colestipol, colesevelam) can decrease plasma mycophenolate mofetil levels by 35%.16,35 Thus, these agents should be avoided if mycophenolate mofetil is used.
It is reasonable to screen all liver transplant recipients with a fasting lipid profile at 3, 6, and 12 months after transplantation and annually thereafter. Creatine kinase should be measured if the patient complains of severe muscle pain or weakness but not on a routine basis.
Obesity
Approximately one-third of patients who are of normal weight at the time of transplantation will become obese afterward.18,25 Corticosteroid use is an important risk factor for posttransplant obesity, and tapering these drugs helps reduce weight.36 Patients treated with cyclosporine are more likely to gain weight than those who receive tacrolimus.37
Of importance: nonalcoholic fatty liver disease, currently the most common cause of chronic liver disease in adults, is rapidly increasing as an indication for liver transplantation. In fact, the proportion of liver transplantation procedures for nonalcoholic steatohepatitis-related cirrhosis increased from 1.2% in 2001 to 9.7% in 2009, and nonalcoholic steatohepatitis is expected to become the leading indication for liver transplantation in the next 20 years. And because nonalcoholic fatty liver disease is directly linked to obesity, the prevalence of obesity as a complication of liver transplantation will most likely increase in the near future.
Overweight liver transplant recipients may have great difficulty losing weight. Treatment starts with patient education on caloric restriction and exercise. If traditional measures fail to result in adequate weight loss, additional options include switching from cyclosporine to tacrolimus.23
Bariatric surgery may become an option for posttransplant patients. In a recent case series from the University of Minnesota, Al-Nowaylati et al38 reported their experience with seven patients who underwent orthotopic liver transplantation and then open Roux-en-Y gastric bypass. After bariatric surgery, the patients’ mean body mass index declined significantly, and glycemic control and high-density lipoprotein cholesterol (HDL-C) levels improved. However, one patient died of multiple organ failure, to which the bariatric surgery might have contributed.38
Heimbach et al39 conducted a study in patients referred for liver transplantation for whom a rigorous noninvasive weight-loss program before transplantation had failed. The researchers performed combined liver transplantation and sleeve gastrectomy in seven carefully selected patients who had failed to achieve weight loss to a body mass index less than 35 kg/m2 before transplantation. All seven patients lost weight, decreasing their mean body mass index from 49 kg/m2 before the procedure to 29 kg/m2 at last follow-up, and none of them developed posttransplant diabetes or steatosis.
At this time, there is not enough evidence to recommend concurrent orthotopic liver transplantation plus bariatric surgery, or combined orthotopic liver transplantation and sleeve gastrectomy. More study is needed to further evaluate these advanced approaches.
Posttransplant metabolic syndrome
Metabolic syndrome is common after liver transplantation and is strongly associated with increased morbidity in this patient population.40,41 The general definition of metabolic syndrome includes a combination of at least three of the following: hypertension, insulin resistance, hypertriglyceridemia, low HDL-C, and obesity.
The prevalence of metabolic syndrome is higher in patients after liver transplantation than in nontransplant patients. In a review of 252 liver transplant recipients, 52% were diagnosed with posttransplant metabolic syndrome, but only 5% had had it pretransplant.42
Careful screening for posttransplant metabolic syndrome and early recognition of risk factors are important. Nevertheless, the treatment of this condition depends on treating its components according to recommended guidelines.41
Cardiovascular disease
The incidence of cardiovascular morbidity and death is increased after liver transplantation.24 In addition, after liver transplantation, cardiovascular disease is a major cause of death unrelated to liver disease. It accounts for 12% to 16% of deaths and is the third most common cause of late mortality after liver transplantation.43 Of note, a recent study by our group demonstrated that patients undergoing liver transplantation for nonalcoholic steatohepatitis had a significantly higher risk of a cardiovascular event during the 3 years after transplantation than patients undergoing liver transplantation for cholestatic liver disease.44
Risk factors for cardiovascular disease after liver transplantation include older age at transplantation, male sex, posttransplant diabetes, posttransplant hypertension, and the use of mycophenolate mofetil.44 Modifying the risk factors is essential in decreasing the risk of cardiovascular events.
It is reasonable to perform dobutamine stress testing every 3 to 5 years in patients with multiple risk factors for cardiovascular disease, or more frequently in those with preexisting coronary artery disease.45,46
