Renal Dysfunction

Renal injury is a common complication after liver transplantation. The glomerular filtration rate (GFR) can fall as low as 60% of the preoperative GFR measured in the first 6 weeks posttransplantation. It is well known that kidney injury after surgery and long-term chronic renal failure can decrease patient survival. Measurement of the GFR before transplantation is not accurate owing to abnormalities in the fluid status. Creatinine levels may also be inaccurate because they depend on the patient’s muscle mass. Likewise, renal function at the moment of the transplant is not a predictor of postoperative renal function.

The incidence of acute kidney injury after liver transplantation ranges between 48% and 98%. It is very likely that the wide range is secondary to the fact that these studies used different definitions for acute kidney injury. Cabezuelo and colleagues classified acute renal failure after transplantation into early (0–7 days posttransplantation) and late (8–28 days posttransplantation). The most frequent etiologies for early acute renal failure were ischemic acute tubular necrosis and pre-renal azotemia. Sepsis and the use of calcineurin inhibitors were the most common etiologies for patients who developed late acute renal failure.

With the increase in patient survival posttransplantation, chronic kidney disease has become a more common long-term complication. The incidence of chronic kidney disease has been reported as high as 27% at 5 years after transplantation. The most common causes of chronic kidney disease include diabetic nephropathy and calcineurin inhibitor toxicity, with cyclosporine implicated more often than tacrolimus. Focal segmental glomerulosclerosis, acute tubular necrosis, and persistent hepatorenal syndrome have also been implicated. The renal function of all patients after liver transplantation should be monitored regularly. This can be done by screening them for microalbuminuria and measuring GFR regularly. Attention must be given to management of other comorbidities like hypertension, diabetes mellitus, and the use of nephrotoxic drugs.

Osteoporosis

Osteoporosis after transplantation is related to pretransplant and posttransplant factors. Patients with end-stage liver disease are at a higher risk for abnormal bone mineral metabolism, osteoporosis, and fractures. Hepatic osteodystrophy is commonly seen and is related to irregular bone metabolism in patients with advanced liver disease. The prevalence of osteoporosis at the spine or hip ranges between 11% and 52% in patients awaiting liver transplantation. The main posttransplant complications are avascular necrosis, fracture, and osteoporosis. In the first 6 to 12 months after transplantation, the rates of fractures and bone loss significantly increases. Fracture rates range from 17% to 65% of patients with increased bone loss and most commonly affect the spine and ribs.

Guichelaar and colleagues confirmed that there is a higher risk for bone loss in patients with advanced primary sclerosing cholangitis and primary biliary cirrhosis. They also found a direct correlation between corticosteroid use and decreased bone mass. The main effect of steroids in the bone is suppression of bone formation itself. Bone loss and fractures owing to steroid therapy are more frequent during the first 6 months of treatment. It has also been suggested that there may be a rapid decline of this fracture risk after discontinuing therapy with steroids. The use of calcineurin inhibitors may also contribute to osteoporosis.

Even before transplantation, an assessment of bone health should be obtained. All patients should have a dual-emission x-ray absorptiometry scan as part of the pretransplant evaluation as well as serum tests to measure calcium, phosphate, parathyroid hormone, and serum 25-hydroxyvitamin D levels. Patients should follow a healthy diet with good calcium intake, maintain a normal body weight, and participate in physical exercise. Alendronate started after transplantation along with calcium and vitamin D supplementation has been shown to reduce bone loss in patients with osteopenia and osteoporosis.

Osteoporosis

Osteoporosis after transplantation is related to pretransplant and posttransplant factors. Patients with end-stage liver disease are at a higher risk for abnormal bone mineral metabolism, osteoporosis, and fractures. Hepatic osteodystrophy is commonly seen and is related to irregular bone metabolism in patients with advanced liver disease. The prevalence of osteoporosis at the spine or hip ranges between 11% and 52% in patients awaiting liver transplantation. The main posttransplant complications are avascular necrosis, fracture, and osteoporosis. In the first 6 to 12 months after transplantation, the rates of fractures and bone loss significantly increases. Fracture rates range from 17% to 65% of patients with increased bone loss and most commonly affect the spine and ribs.

Guichelaar and colleagues confirmed that there is a higher risk for bone loss in patients with advanced primary sclerosing cholangitis and primary biliary cirrhosis. They also found a direct correlation between corticosteroid use and decreased bone mass. The main effect of steroids in the bone is suppression of bone formation itself. Bone loss and fractures owing to steroid therapy are more frequent during the first 6 months of treatment. It has also been suggested that there may be a rapid decline of this fracture risk after discontinuing therapy with steroids. The use of calcineurin inhibitors may also contribute to osteoporosis.

Even before transplantation, an assessment of bone health should be obtained. All patients should have a dual-emission x-ray absorptiometry scan as part of the pretransplant evaluation as well as serum tests to measure calcium, phosphate, parathyroid hormone, and serum 25-hydroxyvitamin D levels. Patients should follow a healthy diet with good calcium intake, maintain a normal body weight, and participate in physical exercise. Alendronate started after transplantation along with calcium and vitamin D supplementation has been shown to reduce bone loss in patients with osteopenia and osteoporosis.

Cardiovascular Disease

It has been estimated that approximately 26% of patients undergoing workup for liver transplantation have asymptomatic coronary artery disease (CAD). The Framingham score demonstrates a higher 10-year probability of coronary heart disease in liver transplant recipients (11%) when compared with the general population (7%). Patients with mild to moderate CAD have significantly higher rates of complications after transplantation, with markedly increased morbidity and mortality. Risk factors for cardiovascular disease include male gender, smoking tobacco, arterial hypertension, obesity, family history of CAD, diabetes mellitus, and hyperlipidemia. More often than in the regular population, 2 or more of these risk factors are present in the liver transplant patient. Nonalcoholic fatty liver disease is also a strong predictor of diffuse arterial disease; therefore, these patients should be carefully screened before liver transplantation.

The management of risk factors for cardiovascular disease should be proactive and should involve a multidisciplinary team of physicians. An important piece of this team should be the gastroenterologist, who should be familiar with the most recent guidelines for the approach and management of these risk factors. The risk factors for CAD and the approach to their management are discussed.

The Metabolic Syndrome

Patients with cirrhosis become malnourished as part of the natural course of the disease. If the outcomes after liver transplantation are favorable, these patients will recover their original nutritional state and, in some cases, they may cross the limits of a healthy nutrition state. With the increased survival rates after transplantation, metabolic complications are becoming more common. They often lead to an increased morbidity and mortality in this population.

The metabolic syndrome is a combination of metabolic complications that include arterial hypertension, diabetes mellitus, dyslipidemia (high triglycerides and low levels of high-density lipoprotein cholesterol), and obesity. The prevalence of posttransplant metabolic syndrome has been reported to be found in as many as 58% of posttransplant patients. It is known that many of the immunosuppressive agents used after transplant can predispose to the development of metabolic disorders. These factors, combined with others, increase the risk of developing metabolic complications after liver transplantation. Fortunately, most of these factors are modifiable.

Risk factors for the development of metabolic syndrome after liver transplant include advanced age at transplant, increased body mass index (BMI) after transplantation, presence of diabetes before transplantation, smoking history, the use of steroids or cyclosporine, and indication for liver transplant (hepatitis C, alcohol, or cryptogenic cirrhosis).

Despite some differences in prevalence, studies have confirmed the deleterious effect of metabolic syndrome after liver transplantation. Laryea and colleagues showed a higher risk of vascular events in those patients with metabolic syndrome after liver transplantation. These vascular events included acute coronary syndrome, stroke, myocardial infarction, cardiac death, and transient ischemic attacks. There is a higher risk for the development of cirrhosis after transplantation among those patients with both the metabolic syndrome and hepatitis C. After a liver transplant, all patients should be monitored regularly for the development of obesity, dyslipidemia, diabetes, and hypertension. Patients should be encouraged to participate in programs that include diet modifications and exercise.

Obesity

The World Health Organization uses the BMI to define obesity. A person with a BMI greater than or equal to 30 kg/m ² is considered obese. The incidence of obesity during the first year after transplantation has been reported between 15% and 41%. Obesity is a well-known, major risk factor for cardiovascular problems, diabetes mellitus, the metabolic syndrome, sleep apnea, and many other chronic diseases including nonalcoholic steatohepatitis. Weight gain after transplantation is an important marker of recovery after surgery; however, many patients gain more weight than needed. Generally, patients who are overweight or obese before liver transplantation will maintain the same body habitus after transplantation, and one third of patients with normal weight before the surgery will become overweight or obese posttransplantation.

Factors that influence the development of obesity after liver transplantation include genetic factors, decreased physical activity, altered dietary habits, and side effects of medications, especially immunosuppressive drugs. The role of corticosteroid use is controversial; in some studies, their use of was associated with obesity, whereas other studies did not show a correlation. Cyclosporine seems to be related to weight gain more than tacrolimus, but this could be because patients on cyclosporine had higher caloric intakes than those on tacrolimus.

Obesity is a preventable risk factor. A BMI should be calculated at every visit to the transplant center and this should be plotted in tables to evaluate progress. The management of obese and overweight patients must be proactive and should include dietary education, an exercise program, and counseling. In some cases, pharmacologic agents or bariatric surgery could be considered for appropriate candidates. A study with tetrahydrolipstatin (Orlistat) on 15 patients, showed some benefit at 3 and 6 months, but it seemed to interfere with tacrolimus levels. Minimizing the use of steroids in the immunosuppressive regimen may also help to prevent weight gain. Bariatric surgery may be useful in selected cases, but this has not been formally evaluated.

Diabetes

According to the American Diabetes Association, diabetes is defined as an abnormality of one of the following 4 measurements: Hemoglobin A1C, fasting plasma glucose, random elevated glucose with symptoms, or an abnormal glucose tolerance test. New-onset diabetes mellitus is a well-known complication after solid organ transplantation. Its incidence ranges between 2.5% and 25% of liver transplant recipients. Diabetes mellitus can result in reduced patient and graft survival after transplantation.

Risk factors for the development of diabetes after transplant include African-American and Hispanic ethnicities, obesity, age (>40 years), first-degree relatives with diabetes type 2, high triglycerides, low levels of high-density lipoprotein cholesterol, hypertension, and immunosuppressive therapy with corticosteroids, tacrolimus and, to a lesser degree, cyclosporine. Hepatitis C virus (HCV) infection is also recognized as a risk factor for the development of diabetes.

To improve posttransplant patient and graft survivals, blood glucose levels should be monitored regularly in all patients. If a patient is diagnosed with new-onset diabetes after transplantation, specific testing must occur. Hemoglobin A1C should be checked every 3 months as wells as periodic screening for diabetic complications including tests for microalbuminuria, ophthalmologic examinations and foot care annually. The approach to the treatment of these patients should include life-style modifications and when not sufficient, antidiabetic agents. Further interventions include adjustment of immunosuppressive therapy to achieve a target hemoglobin A1C of less than 7%. The use of the antiglycemic agents should follow the conventional approach recommended by organizations like the American Diabetes Association. However, it is important to remember that most of the oral medications available are metabolized by the liver. Their use should be limited to patients with stable graft function.

Hypertension

Hypertension is commonly defined as a blood pressure higher than 140/90 mmHg. The prevalence after liver transplantation has been reported as high as 77%. Elevation of systemic vascular resistance is felt to be one of the causes of hypertension after liver transplantation. Calcineurin inhibitors can amplify this increase in the systemic vascular resistance by potentiating the release of vasoconstricting agents and reducing the expression of vasodilatory agents. Some studies have reported a lesser prevalence of hypertension in patients treated with tacrolimus when compared with those treated with cyclosporine. Another factor contributing to the elevation of blood pressure is the use of corticosteroids, which cause retention of salt and water while suppressing nitric oxide production.

Currently, hypertension guidelines do not have specific recommendations for the management of hypertension in liver transplant patients. As with other risk factor for cardiovascular disease, the management of hypertension in the liver transplant patient must start with lifestyle modifications, including weight control, dietary restrictions, regular exercise, and smoking cessation. The goal is a blood pressure lower than 140/90 mmHg and lower than 130/80 for those patients with additional cardiovascular risk factors. If these measures are insufficient, pharmacologic therapy should be initiated. Because of their potent vasodilatory effect, calcium channel blockers are commonly used in transplant patients. Nifedipine, amlodipine, or isradipine may interact less with the cytochrome P450 system resulting in reduced effect on the immunosuppressive levels. Another group of medications that has been used is selective β-blockers. These medications are especially useful in those patients with reflex tachycardia owing to calcium channel blockers or in those patients with a high cardiac output state after transplantation. If monotherapy with any of these drugs is not successful, they can be combined with a thiazide diuretic.

Another important consideration is the role of steroids as a possible cause of the hypertension. Stegall and colleagues demonstrated that hypertensive medications could be stopped in some patients after steroid withdrawal. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and spironolactone can be used, but patients should be monitored closely because of the tendency of these agents to cause hyperkalemia.

Dyslipidemia

Most patients with end-stage liver disease have abnormal lipid metabolism. The prevalence of dyslipidemia after liver transplantation ranges from 66% to 85%, with hypertriglyceridemia being the most common. Predictive factors include greater weight gain after transplantation and the immunosuppressive regimen used. There are some reports that the use of tacrolimus may have a lower incidence of dyslipidemia when compared with cyclosporine. Tarantino and colleagues followed 29 kidney transplant patients taking tacrolimus over 6 years after transplantation and described significant changes in plasma lipid concentration only during the first 6 months of therapy. Although steroids may produce dyslipidemia, a steroid-free immunosuppression regimen posttransplantation has not been shown to reduce the rates of dyslipidemia.

Dyslipidemia after transplantation often persists despite dietary modifications. A fasting lipid profile should be performed every year in all liver transplant patients. Life-style modifications should be encouraged when the low-density lipoprotein cholesterol level is above 100 mg/dL, and if there is little improvement, pharmacologic therapy should be initiated. In those patients with a baseline low-density lipoprotein cholesterol level of 130 mg/dL or the presence of diabetes mellitus, pharmacologic therapy is indicated.

Despite multiple concerns, statins remain the drug of choice for transplant patients. Statins have been used in solid organ transplant recipients for several years and are usually well tolerated. Low initial doses with titration as needed and close follow-up should be considered. For a patient with pure hypertriglyceridemia, fish oil can be used with minimal side effects.

Medication Interactions

Tacrolimus, cyclosporine, mycophenolate mofetil, and sirolimus are among the most commonly prescribed immunosuppressive agents in the liver transplant population. Additional medications that are administered to the patient may alter the serum levels of these agents and thus the level of immunosupression. Tables 1 and 2 include many commonly prescribed medications that may alter the serum levels of these common immunosuppressive agents. All patients should be instructed to discuss any new medications with their health care provider.

Alcohol Abuse

Despite being a controversial indication for liver transplantation, end-stage liver disease secondary to alcohol abuse is a common disease condition that leads to transplantation. Because alcoholics may be responsible for their condition, some have suggested that these individuals be given lower priority for organ allocation. Survival after transplantation owing to alcoholic liver disease is similar to that of other causes, but it will be compromised if there is recidivism after surgery. Even though the majority of patients transplanted because of alcoholic liver disease will have a positive outcome, some of them will resume alcohol consumption.

Factors linked with recurrence of alcohol abuse after liver transplantation include pretransplant abstinence duration (<1 year), presence of dependence versus abuse, presence of other psychiatric illnesses (mainly depression and anxiety), coexistent drug abuse, and quality of social support. Refining patient selection based on risk factors for alcohol abuse recurrence might improve survival after transplantation. Vigilant monitoring for recurrent alcoholism should be undertaken after transplantation is complete.

Tobacco Abuse

With the improvement of immunosuppressive regimens, the main causes of long-term morbidity and mortality after liver transplantation are cardiovascular diseases, metabolic disturbances, and malignancies. Smoking is a well-recognized risk factor for cardiovascular diseases and some malignancies. Up to 20% of transplant centers consider smoking as a contraindication for liver transplantation.

Addiction to both alcohol and tobacco combined has been reported in about 90% of alcoholics. DiMartini and colleagues reported that among those patients transplanted for alcoholic liver disease, 50% were smoking at 3 months after the surgery. They also reported that the number of cigarettes per day increased throughout the first 12 months after transplantation.

A study published by Marrero and colleagues reported the association between smoking and the development of hepatocellular carcinoma (HCC) in patients with cirrhosis. They recommended closer evaluation of smoking history of patients undergoing workup for liver transplantation. It is reasonable to predict that transplant recipients who continue smoking after surgery might have increased prevalence of medical problems.

Tobacco addiction is a relapsing disorder that requires an active approach to decrease its prevalence and prevent relapse. Intervention programs to reduce smoking should be aimed at active smokers as well as former smokers, and these programs should continue posttransplantation. Diagnosis of smoking abuse and the need to comply with cessation therapies must be reinforced during all physician–patient encounters.

Pregnancy

Patients often recover their ability to conceive after liver transplantation. Contraception should be initiated before this occurs. Liver transplant recipients and their infants are at an increased risk of obstetric complications. A recent study of 206 liver transplant recipients demonstrated higher rates of fetal mortality, antepartum admissions, and maternal and fetal complications. These patients also suffered from an increased rate of both gestational hypertension and postpartum hemorrhage. The most favorable timing of conception after liver transplantation remains controversial. Current recommendations suggest waiting for at least 2 years after transplantation. The favored means of contraception in this population is the barrier method. Hormonal contraception may also be considered; data regarding the use of intrauterine devices after transplantation are lacking. The United states Food and Drug Administration classifies calcineurin inhibitors as pregnancy category C (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Mycophenolate mofetil is classified as a pregnancy category D drug (there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Given the increased risks associated with the use of mycophenolate mofetil, 2 methods of contraception are recommended in those patients receiving this medication. Any transplant patient who becomes pregnant should be considered as a “high-risk” pregnancy because both the mother and the infant are at risk for complications. Their management should be undertaken by a multidisciplinary team including physicians from the division of maternal fetal medicine.

Recurrent Liver Disease

Certain liver diseases may recur even after a successful transplantation. The recurrence of these disease states influences both graft and patient survival. Metabolic diseases and congenital anatomic anomalies often do not recur after liver transplantation. Unfortunately, infectious hepatitis, autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis, primary sclerosing cholangitis, nonalcoholic fatty liver disease, and alcohol-associated liver disease can all recur. Recurrent disease should be considered whenever evaluating a transplant patient with elevated liver enzymes. Special attention should be paid to those individuals with HCV, because viremia and histologic injury after transplantation are almost universal.

Allograft Rejection

The incidence of rejection after liver transplantation has been significantly decreased by advances in immunosuppression. Allograft rejection is usually classified based on time of presentation after transplantation (early vs late), response to immunosuppression (reversible vs irreversible), and histologic features. The “gold standard” for diagnosis of rejection is the liver biopsy. Recurrence of hepatitis C continues to be a challenge when diagnosing rejection, even when a liver biopsy is performed. Table 3 describes the most common characteristics of the different types of rejection.

Table 3

Common characteristics of rejection

	Early Acute	Late Acute	Chronic
Time of presentation	1–30 days	Within 1st year	Months to years
Incidence	20%–40%	20%–40%	<2%
Histologic features	Portal, bile duct, and venous inflammation. Ballooning and bilirrubinostasis are common. Fibrosis not seen.	Portal, bile duct, and venous inflammation. Histologic features are less classical than early acute rejection. Ballooning and bilirrubinostasis are uncommon. Typically mild fibrosis.	In early stages, inflammatory and degenerative changes in bile ducts. After progression, ductopenia (loss of bile ducts) and obliterative arteriopathy are present. Ballooning and bilirrubinostasis are common. Pattern of fibrosis is variable and progresses with time
Differential diagnosis	Biliary obstruction, reperfusion injury	Autoimmune hepatitis (recurrence and de novo), recurrent viral hepatitis	Recurrent primary biliary sclerosis and primary sclerosing cholangitis
Response to treatment	Reversible	Reversible	Irreversible

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