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Long-term management of liver transplant recipients: A review for the internist

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Malignancy

The risk of several malignancies increases after liver transplantation. Liver transplant recipients have an incidence of cancer 2.1 to 4.3 times greater than age- and sex-matched controls.24,47–49

Skin cancers are the most common and account for almost 40% of malignancies in organ transplant recipients.50 Whereas basal cell carcinoma is more common in the general population, squamous cell carcinoma is equally common in liver transplant recipients.

Multiple clinical studies have linked calcineurin inhibitors and azathioprine to the development of skin cancer. Annual skin examinations in addition to avoiding other risk factors such as smoking and sun exposure are generally recommended. Changing the immunosuppressants to sirolimus in high-risk patients may lower their chance of developing skin cancer.51,52

Patients with ulcerative colitis who undergo liver transplantation because of sclerosing cholangitis are at higher risk of colon cancer and require annual colonoscopy with surveillance biopsies. Patients who undergo transplantation for alcoholic liver disease seem to have a higher risk of pulmonary and oropharyngeal cancers.53,54

It is important that transplant patients adhere to recommended cancer screening guidelines, in view of their increased risk. Studies have shown improved overall survival in liver transplant recipients who underwent intensive cancer surveillance.55

Renal insufficiency

Renal insufficiency is a well-recognized complication of liver transplantation and is associated with an increased long-term death rate.56,57

The incidence of renal insufficiency increases dramatically over time. Ojo et al,57 in a study of almost 37,000 liver transplant recipients, found that the incidence of chronic kidney disease (defined as an estimated glomerular filtration rate < 30 mL/min/1.73 m2) was 13.9% at 3 years, 18% at 5 years, and approximately 26% at 10 years.

Risk factors include the use of calcineurin inhibitors (both cyclosporine and tacrolimus), older age, female sex, lower pretransplant glomerular filtration rate, postoperative acute renal failure, diabetes, hypertension, hepatitis C virus infection, and transplantation before 1998.58,59 Replacing a calcineurin inhibitor with mycophenolate mofetil or sirolimus may be considered with communication with the transplant center, as mycophenolate mofetil or sirolimus are associated with a lower risk of renal injury.60–64

All liver transplant recipients should avoid nonsteroidal anti-inflammatory drugs and nephrotoxic medications

Starting 1 year after liver transplantation, primary care providers should screen for renal dysfunction by obtaining kidney function tests every 6 months, including urinalysis and microalbuminuria assessment. Equations for estimating the glomerular filtration rate used in practice, such as the Modification of Diet in Renal Disease Study equation, rely mainly on serum creatinine, which may lead to overestimating renal function in some circumstances. Therefore, other equations can be used to confirm the estimated glomerular filtration rate measured by creatinine clearance, and to more accurately evaluate kidney function. Calculators are available at www.kidney.org/professionals/kdoqi/gfr_calculator.

All liver transplant recipients should avoid nonsteroidal anti-inflammatory drugs and nephrotoxic medications, and should have their hypertension and diabetes adequately controlled.

Bone diseases

Osteopenia is another major complication of liver transplantation. One-third of liver transplant recipients have a bone mineral density below the fracture threshold.65

Multiple factors contribute to increased bone loss after transplantation, including use of corticosteroids, use of calcineurin inhibitors (cyclosporine, tacrolimus), poor nutrition, vitamin D deficiency, immobility, sarcopenia (reduced muscle mass), hypogonadism, smoking, and alcohol abuse.66 Even at low doses of less than 7.5 mg per day, corticosteroids inhibit osteoblast activity and increase bone resorption.

Studies have reported rapid bone loss at around 6 months after transplantation.67–69 However, long-term follow-up of bone mineral density up to 15 years after transplantation revealed an improvement mainly in the 2nd postoperative year, with no deterioration afterward.65

High-risk patients need to be identified early with appropriate screening and evaluation. Evaluation includes dual-energy x-ray absorptiometry and serum levels of calcium, phosphorous, parathyroid hormone, testosterone (men), estradiol (women), and alpha-25-hydroxyvitamin D. These tests are typically done before transplantation and then every other year afterward.

We recommend a daily dose of calcitriol and a calcium supplement to all our liver transplant patients.70 If osteoporosis (a T-score 2.5 or more standard deviations below the mean) or a fragility fracture occurs, then the patient may benefit from an oral bisphosphonate. Calcitonin has also been shown to improve bone mineral density in patients with osteoporosis after liver transplantation.71

Hyperuricemia and gout

Although hyperuricemia is common in liver transplant recipients (reported in approximately 47%), the development of clinical gout is less common (6%).72 Asymptomatic hyperuricemia requires observation only and is not usually treated in liver transplant recipients.

Acute attacks of gout are typically managed with colchicine 0.6 mg every 2 hours, up to five doses. Prednisone can be considered if symptoms persist despite treatment with colchicine. Allopurinol in an initial dose of 100 mg daily is used as maintenance therapy to reduce production of uric acid.73 However, because of the potential for drug interactions, the combination of azathioprine and allopurinol should be avoided.

Psychiatric complications and quality of life

Depression is common in liver transplant recipients, significantly more so in patients who received a transplant because of hepatitis C.74 The type of immunosuppressant is not associated with the incidence of depression. When indicated, the internist may start the patient on a selective serotonin reuptake inhibitor such as citalopram 20 mg daily, as these medications are usually effective and well tolerated in liver transplant patients.73

Liver transplantation has a major positive effect on quality of life. Most patients with end-stage liver disease have poor quality of life before transplantation, but this seems to improve notably afterward. A meta-analysis showed significant improvement in posttransplant physical health, sexual functioning, daily activities, and social functioning compared with before transplantation.75

Alcohol abuse and smoking

Patients who underwent liver transplantation because of alcoholic liver disease should be advised to abstain from alcohol.19 Patients who underwent the procedure for a different indication are advised to avoid excessive alcohol intake, as it is proven to lower the survival rate.20 Alcohol recidivism and smoking (including marijuana) are major problems, and internists are best positioned to address these issues and treat them.

Vaccinations

All liver transplant recipients should be vaccinated against influenza, pneumococcal infection, and tetanus. Hepatitis A and B vaccines are typically given before transplantation. In general, live vaccines such as measles-mumps-rubella and varicella are not recommended after any solid organ transplant.76

A study in Germany showed that immunization rates were too low in solid-organ transplant recipients, and almost 90% of patients were not adequately informed about immunizations.77 Hence, there may be room for improvement, and primary care providers should take the lead toward better outcomes in this regard.

Recurrence of the primary liver disease after transplantation

Different primary liver diseases recur with different frequencies.

Hepatitis C has the highest rate of recurrence of the liver diseases.78,79 Reinfection with hepatitis C virus after liver transplantation is almost universal and can follow different patterns. One of the most aggressive patterns is fibrosing cholestatic hepatitis, which frequently leads to graft failure and death, and hence necessitates urgent detection and treatment.

Hepatocellular carcinoma also has a high recurrence rate.80 Surveillance with liver ultrasonography or computed tomography is required every 6 months for the first 5 years after liver transplantation.

Other liver diseases. Nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and hepatitis B infection also tend to recur after liver transplantation.46,81 On the other hand, alpha-1 antitrypsin deficiency, Wilson disease, hemochromatosis, and metabolic disorders are “cured” after liver transplantation.

It is important to detect any increase in liver enzymes above baseline. An elevation of 1.5 times the upper limit of normal or more should trigger further investigation.

Allograft dysfunction

A number of complications can develop in the liver allograft and result in abnormal liver function tests and, if not treated, graft failure. The most common causes of late graft dysfunction include recurrence of primary liver disease, biliary complications, and chronic rejection.46

Vascular complications include hepatic artery thrombosis and stenosis and are usually evaluated by liver ultrasonography and Doppler scan of the hepatic artery and venous structures.24

Biliary strictures give a cholestatic picture, with elevated bilirubin and greater elevation of alkaline phosphatase than of alanine aminotransferase and aspartate aminotransferase. Strictures are usually treated by endoscopic dilation and stenting, but they may eventually require surgery.

Late acute cellular rejections occur in 10% to 20% of cases and are a risk factor for chronic rejection. Liver biopsy is needed to make the diagnosis, and pulsed doses of corticosteroids remain the backbone of treatment therapy.

Chronic rejection is not common, occurring in 3% to 4% of liver transplant recipients.46 Treatment is based on increasing immunosuppression and ensuring compliance with prescribed medications. However, chronic rejection may not respond well, and repeat transplantation may be the last resort for some patients.

WHEN TO REFER TO THE HEPATOLOGIST

Some situations require referral to the hepatologist or the transplant center. In general, the following are best managed by a hepatologist: adjustment of immunosuppressive drugs and dosages, allograft dysfunction, vascular and biliary complications, progressing renal dysfunction, and recurrence of primary liver disease. Early communication with a hepatologist and the transplant center is recommended in these cases.

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