Preventive Care in Adult Liver Transplant Recipients

Abbreviations

AAA

abdominal aortic aneurysm

BMI

body mass index

CRC

colorectal cancer

CVD

cardiovascular disease

DEXA

dual energy X‐ray absorptiometry

HCC

hepatocellular carcinoma

HPV

human papillomavirus

hrHPV

high‐risk human papillomavirus

USPSTF

US Preventive Services Task Force

Orthotropic liver transplant is a high‐risk surgery with a roughly 10% mortality rate within the first year. However, among the 90% of patients who survive, the majority of their future morbidity and mortality is not driven by direct complications of transplant, but rather by comorbid conditions. Because of the widespread application and success of liver transplantation over the past five decades, there is improved longevity, albeit accompanied by serious long‐term morbidity.¹ Driven by preexisting conditions and side effects of immunosuppressive agents, liver transplant recipients are at increased risk for chronic diseases, such as cardiovascular disease (CVD), metabolic syndrome, renal disease, bone disease, and malignancy.², ³, ⁴, ⁵

Unfortunately, many liver transplant recipients do not receive adequate preventive care. One reason is that transplant centers typically stop managing patients as closely after the first year, yet many nontransplant providers are either hesitant to interfere with such complex patients or assume they are receiving all of their care at the tertiary center.⁶ Thus, this article is geared toward community primary care providers and gastroenterologists who can help improve care for these patients.

Post–liver transplant general health maintenance is similar in some ways to that of the general population, which is largely dictated by US Preventive Services Task Force (USPSTF) guidelines. The USPSTF publishes a long list of preventative care guidelines: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation‐topics/uspstf‐and‐b‐recommendations. Liver transplant recipients are screened for syphilis, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and tuberculosis during transplant evaluation, so we have excluded these recommendations. For the purpose of this review, we focus on USPSTF Grade A and B recommendations related to CVD, malignancy, and osteoporosis, which account for the majority of the long‐term morbidity and mortality among transplant recipients. We also discuss immunization recommendations. Although the transplant constituency is encompassed in some of the recommendations, the full alignment of preventive services with posttransplant care is lacking (Table 1).

TABLE 1.

Screening Recommendations Relevant to Liver Transplant Recipients

USPSTF Grade A and B Recommendations	General Population	Liver Transplant Population
CVD
AAA	One‐time screening for AAA with ultrasonography in men aged 65‐75 years who have ever smoked	Same
Diabetes screening	Screen for abnormal blood glucose in adults aged 40‐70 years who are overweight or obese	Screen frequently for hyperglycemia; diagnose diabetes mellitus once on stable immunosuppression regimen
Aspirin use to prevent CVD and CRC	Initiate low‐dose aspirin for primary prevention of CVD and CRC in adults aged 50‐59 years who have a 10% or greater 10‐year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low‐dose aspirin daily for at least 10 years	Same
Healthful diet and physical activity for CVD prevention in adults with cardiovascular risk factors: behavioral counseling	Offer or refer adults who are overweight or obese and have additional CVD risk factors to intensive behavioral counseling interventions to promote a healthful diet and physical activity for CVD prevention	Same
Hypertension screening	Screen for high blood pressure in adults aged ≥18 years; obtain measurements outside of the clinical setting for diagnostic confirmation before starting treatment	At every clinic visit; home blood pressure monitoring
Statin use	Statin prescribed when all of the following criteria are met: (1) patients are aged 40‐75 years; (2) they have one or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking); and (3) they have a calculated 10‐year risk for a cardiovascular event of ≥10%. Identification of dyslipidemia and calculation of 10‐year CVD event risk require universal lipids screening in adults aged 40‐75 years	Yearly lipid panel; statins are acceptable to use in liver transplant recipients; avoid fibric acid derivatives, bile acid sequestrates, and nicotinic acids
Tobacco cessation	Ask all adults and pregnant women about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and US Food and Drug Administration–approved pharmacotherapy for cessation to adults who use tobacco	Same
Weight loss to prevent obesity‐related morbidity and mortality	Offer to refer adults with BMI >30 to intensive, multicomponent behavioral interventions	Same
Malignancy
Tamoxifen use to reduce risk: women at increased risk for breast cancer	Offer to prescribe risk‐reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects	Insufficient data. Tamoxifen may cause steatohepatitis
Breast cancer screening	Biennial screening mammography for women aged 50‐74 years	Annual
Cervical cancer screening	Screen for cervical cancer every 3 years with cervical cytology alone in women aged 21‐29 years. For women aged 30‐65 years, the USPSTF recommends screening every 3 years with cervical cytology alone, every 5 years with hrHPV testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting)	Annual
CRC screening	Screen for CRC starting at age 50 years and continuing until age 75 years	Consider more frequently, but insufficient data to support this
Lung cancer screening	Annual screening for lung cancer with low‐dose computed tomography in adults aged 55‐80 years who have a 30 pack‐year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery	Same
Skin cancer prevention	Counsel young adults, adolescents, children, and parents of young children about minimizing exposure to ultraviolet radiation for persons aged 6 months to 24 years with fair skin types to reduce their risk for skin cancer	SPF >30; yearly full‐body skin examination
Bone disease
Osteoporosis	Screen for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years who are at increased risk for osteoporosis and women 65 years and older	All patients should have DEXA before transplant; bone mineral density (BMD) screening yearly for patients with osteopenia and every 2‐3 years for patients with normal BMD
Suggested preventive care not addressed in USPSTF Grade A and B recommendations
		Dental examinations
		Eye examinations
		Vaccinations
		Screening for renal dysfunction
		Infection prophylaxis

Health Maintenance and Immunization

Like the general population, post–liver transplant patients should have an annual history and physical examination, annual dental examinations with twice‐yearly cleanings, and eye examinations. Transplant recipients should receive vaccines (except live‐attenuated). Recommended vaccines for liver transplant recipients include pneumococcal (polyvalent 23 and 13), hepatitis A and B, tetanus‐diphtheria, yearly influenza, and the new subunit herpes zoster vaccination. Inactivated vaccines can be administered starting at 3 months posttransplant, with the exception of influenza, which can be given as early as 1 month.⁷

Cardiovascular

Liver transplant recipients should have blood pressure measurements at every clinic visit, and home blood pressure monitoring should be used to diagnose hypertension.⁸ Target blood pressure should be less than 130/80 mm Hg with a combination of lifestyle and pharmacological agents, although benefits of tighter control have not been studied. Because glucocorticoids, cyclosporine, tacrolimus, and weight gain posttransplant predispose the patient to diabetes, organ transplant recipients should be screened for hyperglycemia, with a formal diagnosis of posttransplant diabetes being made once a patient is stable on an immunosuppressive regimen and in the absence of acute infection.

Liver transplant recipients are at significant risk for hyperlipidemia. Risk assessment can be done using the American Heart Association pooled cohort equation, and lipid assessment should be considered annually depending on the risk level.⁸ For patients receiving mammalian target of rapamycin inhibitor (mTORi), triglycerides should be repeated at least every 6 months per package insert. Statins are indeed safe after liver transplant, although pravastatin and atorvastatin are preferred.⁹ Fibric acid derivatives, bile acid sequestrates, and nicotinic acids frequently interact with immunosuppression medications. A 12‐hour fasting lipid profile should be obtained within 3 to 6 months after initiation of lipid‐lowering therapy, a dose change, or a change in risk factors for dyslipidemia. Because these patients have significant risk factors for cardiac disease, stress testing every 5 years and more frequently in patients with preexisting coronary artery disease is prudent, insurance permitting. Encouraging physical activity, healthy body mass index (BMI), and smoking cessation (if applicable) as a means to reduce metabolic and cardiovascular complications is imperative.

Renal

Renal disease occurs to some extent in almost all liver transplant recipients, especially because the Model for End‐Stage Liver Disease score prioritizes recipients with preexisting kidney injury. During the first year, urinalysis, microalbumin, and creatinine/glomerular filtration rate (GFR) should be measured in the frequency that the clinician believes appropriate. After the first year, creatinine/GFR and yearly microalbumin are recommended.⁸ Patients receiving sirolimus or everolimus should be monitored more frequently for proteinuria, which is a well‐recognized complication of mTORi immunosuppressants.

All calcineurin inhibitors can cause hyperkalemia. Tacrolimus, the primary antirejection agent used in liver transplant, can also cause type 4 renal tubular acidosis, subsequently worsening hyperkalemia. Although the use of angiotensin‐converting enzymes inhibitors may be beneficial from a renal and cardiovascular standpoint, they can be dangerous without the monitoring of potassium levels and renal dysfunction.

Bone Disease

Bone loss is an important source of morbidity in post–liver transplant patients, often exacerbated by the use of glucocorticoids superimposed on a clinical picture of prior immobility, hypogonadism, and chronic liver disease. In the first 5 years after transplant, screening by bone mineral density (BMD) should be done yearly for osteopenic patients and every 2 to 3 years for patients with normal BMD. Patients should perform weight‐bearing exercise and receive calcium and vitamin D supplements, kidney function permitting.⁸

Malignancy

De novo malignancies, especially squamous cell and basal cell carcinomas, are more prevalent after liver transplant than in the general population. Because of this, smoking cessation and sunscreen application (SPF 30 or higher) must be a reinforced topic. Liver transplant recipients need regular cancer screenings, which in some situations are more intensive than the general population, for example, annual full‐body dermatological examination, and in women, annual pap smear and human papillomavirus (HPV) testing (until negative three times and then every 3 years) and annual mammography.¹⁰, ¹¹ Lung and colon cancer screening guidelines are the same as for the general population, although some centers perform them more frequently.

Hepatocellular carcinoma (HCC) surveillance with magnetic resonance imaging or ultrasound/alpha fetoprotein every 6 months should be performed in patients whose grafts have developed advanced fibrosis or cirrhosis as a result of recurrent disease and in selected patients with hepatitis B at earlier stages. In addition, periodic cross‐sectional imaging of the body and chest should be considered in patients who are at high risk for recurrence of HCC posttransplant.

Conclusion

Most of these long‐term complications can be mitigated, in part, by having the patient on the lowest effective doses of immunosuppressive agents. The transplant team should still manage the immunosuppression, as well as rejection episodes, biliary complications, recurrent liver disease, among others. Although long‐term complications of liver transplant are no secret to transplant professionals, it is often the primary care provider who is ordering the preventive screenings.¹² To best care for liver transplant recipients, collaboration between the transplant center and primary care with clear delineation of responsibility is indispensable. Alternatively, another solution could be a transplant medical home model, in which the transplant center has embedded primary care. The USPSTF should also consider expanding recommendations for specific populations when available evidence indicates a lower threshold for recommended screenings.