Late Complications and Recurrence of Disease After Transplantation

Obesity

In 2010 12 states had more than 30% of their adult residents with a body mass index greater than 30 kg/m ² , and this increases every year. The reported prevalence of obesity after liver transplantation varies from 17% to 41%. Before transplant the effects of chronic illness lead to significant loss of muscle mass and fat; however, after transplant many patients gain considerable weight. It has been shown that immunosuppression contributes to this weight gain: steroids are known to increase weight gain with dose and duration being critical factors in the amount of weight gained. Of note, minimal data suggest that rapamycin may not cause as much weight gain after liver transplantation as calcineurin inhibitors.

Although portion control, well-balanced diets, and most importantly exercise are the cornerstones of any weight management program, often patients are not adherent. Tetrahydrolipstatin (Orlistat) should be avoided because it decreases absorption of cyclosporine and can even lower levels of tacrolimus. Especially in morbidly obese pretransplant patients with low Model for End-Stage Liver Disease (MELD) scores without complications of portal hypertension, bariatric surgery with a lap band or gastric sleeve can be considered to achieve and maintain weight loss before transplant to improve the chances that patients remain candidates for transplant and minimize their operative complications and long-term comorbid conditions. Weight loss surgery can also be performed near and after liver transplantation, although the data are limited in this cohort.

Diabetes

Ten percent to 30% of patients have diabetes before liver transplant, and an additional 15% to 40% of patients develop de novo diabetes after liver transplant, leading to a prevalence that in some studies is as high as 61%. Preexisting risk factors may contribute to diabetes development, such as male sex, family history, obesity, and excess alcohol consumption. Risk factors for de novo diabetes development include obesity, older age, black race or Hispanic ethnicity, corticosteroid use (dose and duration are critical components), and calcineurin inhibition (tacrolimus has a greater impact than cyclosporine). Of note, the IL28B genetic polymorphism TT (as opposed to CT or CC) increases the risk for posttransplant diabetes development in hepatitis C (HCV)-viremic patients. In turn, hepatitis C viremia impairs insulin sensitivity, and sustained virological response improves this. Unfortunately, HCV-infected patients with persistent diabetes experience accelerated fibrosis progression.

At a minimum, yearly fasting glucose testing in low-risk individuals is recommended as surveillance. In patients with mild elevations in glucose levels, exercise independent of weight loss can improve insulin sensitivity and should always be recommended. Next, corticosteroid minimization and possible cessation will improve glycemic control. Possibly for those on tacrolimus, lowering the levels or switching to cyclosporine can improve glucose regulation. However, in patients with overt diabetes, medications are needed. Although insulin is always a safe option, weight gain is common. Metformin can safely be used in patients with good liver and kidney function and has the least potential to exacerbate weight gain. This has led some to prefer this agent. The sulfonylureas glipizide and glimepiride can also be used without altering doses of immunosuppressive medications. In addition, glucagon-like peptide-1 agonists, amylin analogues, and α-glucosidase inhibitors can be used in patients after transplant without immunosuppressive alterations. Other medications can be used, but additional monitoring of the immunosuppressive medications is required and doses may need adjustment. However, despite control, diabetes in univariate analysis was a predictor of death with a hazard ratio of 1.08 per year.

For patients with diabetes, yearly eye examinations and measurement of microalbuminuria should be performed. Also the threshold for treatment of hypertension changes from a blood pressure greater than 140/90 mm Hg to a blood pressure greater than 130/80 mm Hg. This is because patients with diabetes have an increased risk for diabetic-related complications such as nephropathy, retinopathy, neuropathy, and atherosclerosis. Therefore it is even more imperative to manage hyperglycemia, hypertension, and dyslipidemia in the diabetic post–liver transplant population.

Hypertension

Pretransplant decompensated cirrhosis causes low blood pressure from hepatic nitric oxide release leading to vasodilation and underperfusion of the kidneys. However, after transplant this physiological situation is reversed, and patients are initiated on medications that frequently cause hypertension. As a result, hypertension affects up to 77% of recipients. Calcineurin inhibitors (cyclosporine more than tacrolimus) cause peripheral vasoconstriction, decrease production of vasodilators, decrease renal sodium and water excretion, and ultimately impair renal function. Steroids, in isolation or in addition to calcineurin inhibitors, result in salt and water retention and suppress vasodilator production.

Aggressive treatment of hypertension is essential to avoiding chronic renal insufficiency, cardiac complications, and stroke. To accomplish this prevention, patients with diabetes or chronic renal insufficiency should achieve a systolic blood pressure below 130 mm Hg and a diastolic blood pressure below 80 mm Hg, although patients without diabetes or chronic renal insufficiency only need to achieve a systolic blood pressure below 140 mm Hg and a diastolic blood pressure below 90 mm Hg.

First-line treatment remains lifestyle modifications, including salt restriction, increased exercise, and weight loss if appropriate. This should be followed by steroid minimization and possible discontinuation when appropriate, because data have shown this to be of possible benefit. When these simple measures fail, patients on calcineurin inhibitors should have dihydropyridine calcium channel blockers (e.g., nifedipine) initiated because of their vasodilatory effects. Although dihydropyridine calcium channel blockers are considered the first-line agents for the management of post–liver transplant hypertension, some patients do not tolerate them (most commonly secondary to peripheral edema). For patients on other immunosuppressive agents or those who do not tolerate dihydropyridine calcium channel blockers, β-blockers can be used. Carvedilol has been studied and shown efficacious for the treatment of hypertension after liver transplant; however, it does require calcineurin inhibitor adjustment. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers can also be used, but hyperkalemia is more common and needs to be followed. These agents are especially attractive in patients with concomitant diabetes, heart failure, or renal dysfunction.

In patients with an incomplete response to single-agent therapy, additional agents are required to avoid long-term renal complications. Diuretics can be used to combat renal sodium and water retention, and sympathetic blockers, such as clonidine, can also be used when needed. Although calcineurin inhibition remains the mainstay of immunosuppression after liver transplant, calcineurin withdrawal though the use of mammalian target of rapamycin (mTOR) inhibitors and/or mycophenolate mofetil (MMF) decreased blood pressure.

Dyslipidemia

Elevations of serum cholesterol and triglyceride levels are common consequences of immunosuppression. Steroids and cyclosporine are strongly associated with increased cholesterol and triglyceride levels, whereas sirolimus has a more profound effect on triglyceride levels. Tacrolimus may have a minor negative effect, and MMF has no effect on lipid levels. Of note, HCV-viremic patients often have lower cholesterol levels because cholesterol biosynthesis is an integral part of progeny virion production, and if cure is achieved, these levels may subsequently increase.

Yearly lipid panel assessments are needed in all post–liver transplant patients. Because the 10-year cardiovascular event rate exceeds 20%, the goal low-density lipoprotein level for these patients is less than 100 mg/dL and the goal triglyceride level is less than 100 mg/dL. Although lifestyle modifications with diet, exercise, and weight reduction when appropriate are always recommended, they seldom are sufficient to achieve the targets necessary to avoid vascular complications. The first-line therapy for patients with elevated cholesterol is 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition. Pravastatin is the only drug in this class without drug interactions with the immunosuppressive medications and therefore is frequently the drug of choice, but all the others may be used as long as levels of immunosuppressive medications are adjusted appropriately, although this is rarely clinically significant. HMG-CoA reductase inhibition may cause transient elevations in aminotransferase levels, but the medication should be stopped only for true hepatotoxicity defined as aminotransferase levels that are greater than five times the upper limits of normal with an elevated bilirubin level. These medications should always be started in low dose to determine tolerability and increased as needed to achieve goals for low-density lipoprotein levels. In patients unable to tolerate HMG-CoA reductase inhibitors, ezetimibe has been used.

In patients with isolated elevations of triglyceride levels, fish oil can always be used safely. Fibrate medications can also be used, but the risk for complications increases, especially if these medications are combined with HMG-CoA reductase inhibition.

Bile acid–binding resins can interfere with absorption of immunosuppressive medications, and nicotinic acid preparations are generally poorly tolerated and also carry a risk for hepatotoxicity.

Renal Dysfunction (see Chapter 74 )

Renal dysfunction is common after liver transplant and results in end-stage renal disease requiring hemodialysis in 18% of patients at 5 years and 28% at 10 years. The change from Child-Turcotte-Pugh score to MELD organ allocation incorporated creatinine into the selection of patients for liver transplant. Although this change was intended to select only patients with preoperative hepatorenal syndrome, patients with chronic renal insufficiency receive the same priority advantage. Unfortunately, this has lead to a doubling in the need for simultaneous liver and kidney transplantation and may increase the prevalence of chronic kidney disease after liver transplant.

Chronic kidney disease has been shown to decrease patient survival after liver transplant. Therefore it is essential to avoid progressive renal dysfunction whenever possible through tight control of diabetes and hypertension and avoidance of nephrotoxic agents such as nonsteroidal antiinflammatory drugs (NSAIDs) and gentamycin. In patients with mild to moderate renal impairment, it is commonly caused by calcineurin inhibitor toxicity; however, it remains essential to evaluate patients for other common and rare causes of renal dysfunction that may be treatable, especially nephrotoxic medication use and hepatitis C–induced renal complications. When calcineurin inhibitors are the culprit, mTOR- or MMF-based immunosuppressive regimens are used by many centers despite a lack of evidence that conversion to mTOR inhibitors is associated with any measurable improvement in renal function, although long-term follow-up studies are still needed. For MMF, many centers use this drug for its renal-sparing effects, and there are data from randomized, controlled trials demonstrating a significant improvement in renal function for patients started on MMF from the time of transplant. This has resulted in a trend toward the use of combination therapy (MMF/tacrolimus) compared to tacrolimus monotherapy ( Fig. 80-1 ). However, there are relatively limited data on the benefit of conversion to MMF from tacrolimus to improve renal function.

In patients with progressive renal failure, early referral for renal transplantation is prudent because liver transplant recipients’ survival on dialysis is poor. In addition, kidney-after-liver transplant provides the added benefit of improved renal function with little change to the immunosuppressive exposure to the patient.