Posttransplantation Care: Role of the Primary CarePhysician Versus Transplant Center

Timothy M. McCashland

Key Points1. Forty percent of transplant centers expect the primarycare physician to be the primary physician; 40% have botha primary care physician and a hepatologist manage thepatient.2. Transplant centers expect primary care physicians toprovide general preventive medicine, physical examina-tions, vaccinations, and, rarely, management of hyperten-sion, renal dysfunction, and diabetes.3. A high percentage of primary care physicians feel com-fortable caring and managing the overall health care of along-term liver transplant patient.4. Primary care physicians feel at most ease managingpreventive care, annual physical examinations, hyperten-sion, diabetes mellitus, hyperlipidemia, bone disease, andvaccinations.5. Primary care physicians should be aware of the com-mon medical conditions of the liver transplant patientof hypertension, diabetes, obesity, hyperlipidemia, andrecurrent disease.6. Common medical conditions for both the transplantcenters and primary care physicians are hypertension, dys-lipidemia, diabetes mellitus, malignancy, bone disease,pregnancy, vaccination, infectious prophylaxis, andheadaches. (Liver Transpl 2001;7:S2-S12.)

The continued success of liver transplantation has cre-ated a special role for primary care physicians in the

overall care of patients post–liver transplantation. Interest-ingly, no information exists regarding how and when toincorporate the primary care physician into the manage-ment of these distinct patients. Furthermore, no studieshave evaluated the outcome of liver transplant recipientsmanaged by primary care physicians versus continuedmanagement by the transplant center. Last, as liver trans-plantation reaches its third decade, the volume of workrequired to manage all patient needs becomes an over-whelming task for the transplant center. Therefore, theinternist or family practitioner will constitute a larger rolein the long-term care of liver transplant recipients. In this

review, aspects of care for liver transplant recipients com-mon and unique to primary care and transplant physiciansare explored. Several comprehensive reviews of medicalcomplications and management of liver transplant recipi-ents have been published previously.1-7

Transplant Program Expectations

The evolution of care in most transplant centers is forthe transplant surgeon to manage the immediate post-operative care, with gradual incorporation of hepatolo-gists and primary care physicians.1,2 Transplant hepa-tologists can provide insight into medical problemsfrom an educational background of internal medicineand gastroenterology. However, centers differ on whento transfer care to the primary physician. Most patientsare discharged from the transplant center 3 to 6 weeksafter surgery. However, the transplant center continuesto monitor the patient after transplantation through theevaluation of biochemical liver function tests andimmunosuppressive drug levels.

No information exists on when most centers transfercare from the transplant center or whether transplantcenters still want the responsibility of the majority ofcare for the patient. Thus, I performed a telephonesurvey of liver transplant nurse coordinators at 45 trans-plant centers in the United States to inquire about whois responsible for specific care aspects of liver transplantrecipients in their centers after 6 months of survival.

Results

What is the role of the transplant coordinator? In eachprogram evaluated, the liver transplant coordinatorserves as primary liaison with primary care physiciansand reviews routine follow-up laboratory results ofpatients. Programs performing less than 40 trans-plantations per year had an average of three livertransplant coordinators, and programs performingmore than 40 transplantations had an average of fourcoordinators. The majority of programs have tele-phone systems with audex and voice mail programs,which result in delay and obstruction of immediatecommunication with primary care physicians. Oneof the 45 programs billed for telephone outpatientmanagement. The program billed for immunosup-pression management with documentation of the

From the Department of Internal Medicine, The University ofNebraska Medical Center, Omaha, NE.

Address reprint requests to Timothy M. McCashland, MD, Univer-sity of Nebraska Medical Center, Department of Internal Medicine, 600S 42nd St, Omaha, NE 68198-3280. Telephone: 402-559-4871; FAX:402-559-3434; E-mail: tmccash@surgery.unmc.edu

Copyright © 2001 by the American Association for the Study ofLiver Diseases

1527-6465/01/0711-1003$35.00/0doi:10.1053/jlts.2001.28513

S2 Liver Transplantation, Vol 7, No 11, Suppl 1 (November), 2001: pp S2-S12

time required for interpretation and changes inimmunosuppression medications. Thus, a majorityof required follow-up management is not reim-bursed, and a large portion of the coordinator’s timeis spent on the telephone, rather than in directpatient care. This is expensive for transplant centers,but a necessary vital role in optimal patient care.

Do transplant centers expect primary care physicians toassume the overall care of liver transplant recipients? Fortypercent of programs responded yes, an additional40% have the transplant hepatologist assume overallcare, and 13% had both the hepatologist or surgeonand primary care physician work together. Referringgastroenterologists were not expected to providemuch assistance or have a major role in the overallcare (Table 1). There was no difference in optionsbetween large or small programs. Thus, primary carephysicians, especially at locations removed fromtransplant centers, commonly are expected to takeover most of the management of the patient. Only55% of programs send a packet of overall guidelinesand/or protocols to primary care physicians; thus,

transplant centers are not doing a very good job ofproviding guidelines to these physicians.

Transplant programs expect to continue to manageimmunosuppression, acute allograft rejection, recur-rent disease, and biliary complications (Table 1). Man-agement of immunosuppression medications wasdivided equally between hepatologists and transplantsurgeons; however, a slightly greater percentage of sur-geons managed acute rejection.

Rarely do transplant centers want primary care phy-sicians to manage hypertension, renal dysfunction, ordiabetes mellitus. Commonly, these complications arereferred to cardiologists, nephrologists, and endocrinol-ogist at the transplant center.

What specific roles of management do transplant centersexpect of primary care physicians? Every center wanted pri-mary care physicians to provide general preventivemedicine (cervical Papanicolaou’s smears, mammo-grams, evaluation of serum prostate-specific antigenand serum lipid levels, skin surveillance) that is notunique to transplant recipients. Sixty-five percent ofcenters wanted annual physical examinations and up-to-date vaccinations under the auspices of primary care.Treatment and evaluation of bone disease and preg-nancy were less common (40% and 28%).

Primary Care Expectations

What Do Primary Care Physicians BelieveAbout Their Role in the Long-TermManagement of Liver Transplant Recipients?

I randomly sent a four-question mailed survey to pri-mary care (family medicine/internal medicine) physi-cians listed as primary care physicians for liver trans-plant recipients from the University of NebraskaMedical Center (Omaha, NE).

Results

Twenty-five of 30 physicians responded to the mailedsurvey. A surprisingly high percentage of physicians (73%)were comfortable managing the overall health care ofpatients. A majority (55%) believed that the best methodof care was to call the transplant center for only liver trans-plant–related problems. Less commonly, 36% wanted tomanage only diseases familiar to their practice, and rarely(9%), primary care physicians wanted to either manage allthe care or have the transplant center manage all healthcare of patients (Table 2). One might assume there wouldbe some trepidation by primary care physicians to assumecare of these complex patients; however, the opposite wasreported. This is only a single-center experience and maynot be generally applicable.

Table 1. Transplant Center Expectationsof Primary Care Providers

Who becomes the primary physician responsible for theoverall care of patient after 6 months post–livertransplantation? (Overall percentage)

Family practice/internist 40%Referring

gastroenterologist0%

Transplant hepatologist 35%Transplant surgeon 11%Primary care and

hepatologist14%

Packet of guidelines/protocols sent to primary carephysicians?

Yes 45%No 55%

What categories do transplant centers want referringprimary care physicians to manage?

(Overall percentage)Preventive medicine 100%Annual examinations 65%Vaccination 65%Diabetes 60%Bone disease 40%Hypertension 37%Pregnancy 28%Sexual issues 15%

0% for management of immunosuppression medications,renal dysfunction, allograft rejection, infections, andrecurrent disease.

S3Role of Primary Care in Liver Transplantation

Primary care physicians feel at ease managing gen-eral preventive care, annual physical examinations,hypertension, diabetes mellitus, hyperlidemia, bonedisease, and vaccinations. Ambiguous options werenoted for management of anti-infection prophylaxis,recurrent disease, renal dysfunction, gout, and biliarydisorders. Primary care physicians were most uncom-fortable caring for transplant-related entities of allo-graft rejection, immunosuppression, and pregnancy(Table 2).

Does This Clarify the Role and ManagementScheme Incorporating PrimaryCare Physicians?

I believe this small study points out common groundfor both primary care and transplant physicians. Moreindependence to primary care physicians may help allparties involved.

Required Knowledge

To properly care for liver transplant recipients who havesurvived longer than 1 year, one first must have knowledgeof common posttransplantation medical complications.Sheiner et al8 provided this very important information,allowing both primary care physicians and transplant cen-ters to be aware of complications and intervene early. I

believe this is required reading by physicians caring forliver transplant recipients. These investigators reported onmedical complications in patients surviving longer than 5years after transplantation. Compared with the US popu-lation, hypertension and diabetes were significantly moreprevalent. Hypertension was present in 60% of patients,and half these patients required more than one drug forcontrol. Diabetes mellitus was noted in 35%, which is sixtimes the expected rate, and 60% of patients requiredinsulin for treatment. Obesity was common, with 47% ofpatients rated moderately or severely obese at follow-up.An increase in cholesterol levels from pretransplantationvalues was seen in 70% of patients; however, levels were nodifferent from those of control groups. Interestingly, com-pared with the US population, cardiac complications weresimilar to those of the general population. Renal insuffi-ciency was common (80%), but only 4% of patientsrequired hemodialysis. Recurrent liver disease was seen in28%, with hepatitis C as the leading cause. These andother topics are discussed in further detail.

Primary Care Management Issues

General Preventive Medicine

The practice of healthcare screening for common dis-eases in all patients has become routine in the primary

Table 2. Primary Care Expectations of Liver Transplant Management

Do you feel comfortable caring for or managing the overall health care of post–liver transplantation patients?Yes 73%No 27%

What method are you most comfortable with regarding management of patients?Call transplant center for advice for only liver transplant–related problems 55%Management of familiar diseases for your practice 36%Have transplant center manage all health care of patient 10%Manage all health care issues 9%

What categories are you comfortable managing regarding post–liver transplantation patients?Hypertension medications 100%General preventive care 91%Annual physical examination 91%Diabetes mellitus 82%Hyperglycemia 82%Vaccines 82%Bone disease 73%Anti-infection prophylaxis 55%Gout 55%Recurrent disease 45%Renal disease 45%Immunosuppression 27%Biliary disease 27%Allograft rejection 18%

S4 Timothy M. McCashland

care setting. Liver transplant recipients are no differentand will benefit from this comprehensive evaluation.Healthcare maintenance now includes regular and cal-culated testing for dyslipidemia, hypertension, neoplas-tic disease (breast, colorectal, cervical, and prostate),diabetes mellitus, and thyroid disease.

The US Preventive Services Task Force9 publishedextensive recommendations in healthcare maintenance.These recommendations are applicable to transplantrecipients. Both transplant programs and primary phy-sicians are comfortable providing these services, and Ibriefly provide these recommendations.

Screening for cholesterol, high-density lipoprotein,and triglycerides is recommended for all men aged 35 to65 years and women aged 45 to 65 years. Periodicscreening for hypertension is recommended for allpatients aged older than 21 years. Current blood pres-sure criteria for the diagnosis of hypertension are anaverage diastolic pressure of 90 mm Hg or greaterand/or an average systolic pressure of 140 mm Hg orgreater.10

Routine breast cancer screening every 1 to 2 years bymeans of mammography and clinical breast examina-tion is recommended for women aged 50 to 69 years.For high-risk individuals, recommendations are to startscreening at the age of 40 years.11 Patients at averagerisk for colon cancer should undergo colonoscopy every10 years. Annual fecal occult blood testing should startat 50 years of age.12 Routine screening for cervical can-cer with Papanicolaou’s testing is recommended every 3years for all women who are or have been sexuallyactive.13 Interestingly, routine screening for prostatecancer with digital rectal examination and prostate-specific antigen is not recommended by the task force.9

However, others believe this is cost-effective and bene-ficial.14

Individuals at high risk for diabetes (obese or familyhistory) should have fasting plasma glucose levels deter-mined as the screening test. A single fasting glucose levelgreater than 140 mg/dL is specific for diabetes(�99%).15 Routine screening for thyroid disease withthyroid function tests is not recommended.9 Testingthyroid-stimulating hormone levels is the standard fordetecting hyperthyroidism and hypothyroidism insymptomatic individuals.16

Annual Examinations

An annual history and physical examination arerequested by all transplant centers regardless of howwell the patient is doing. Seeing the patient allows oneto better evaluate the patient’s obesity, mental health,and ability to return to work and allows the patient an

opportunity to ask health-related questions. Eye exam-inations to evaluate cataract formation and diabeticchanges caused by long-term corticosteroid use shouldbe incorporated. Annual dental evaluations for peri-odontal disease should not be overlooked. Skin cancersare the most common malignancy post–liver transplan-tation, and patients should be examined thoroughlyand reminded of skin protection using lotion with ahigh (�30) skin protection factor.17 Some programsrecommend annual examination by a dermatologist.

Obesity

Significant weight gain is frequently reported in trans-plant recipients.18-21 Appetite stimulation from pred-nisone, freedom from pretransplantation diet restric-tions, decreased anorexia, and an increased sense ofwell-being may lead to an increase in weight. Palmer etal reported that 16 of 28 patients became overweightwithin 16 months post–liver transplantation.18 Primarycare physicians can have a crucial part in the early detec-tion of the ascent to moderate or severe obesity. TheNational Heart, Lung, and Blood Institute andNational Institute of Diabetes and Digestive and Kid-ney Diseases clinical guidelines for the treatment ofobesity recommend an initial target of 10% of baselineweight, which should proceed at a rate of 1 to 2 lb/wk.22

These recommendations are applicable to transplantrecipients, as well. Patients outside these limits shouldseek treatment from a nutritionist and assessment ofexercise capabilities.21 Reduction or withdrawal of cor-ticosteroid therapy may aid in this cause.

Gout

Hyperuricemia is a common morbidity associated withliver transplantation.23 Both cyclosporine and tacroli-mus can impair the excretion of uric acid. In the pres-ence of renal insufficiency, gout may develop. Inabstract form, Gibbs et al23 reported a 46% prevalenceof hyperuricemia in patients post–liver transplantation.Six percent developed gout, and all responded to allo-purinol therapy. In my center, acute gout is treated withcolchicine, 0.6 mg, every 2 hours for a maximum of fivedoses. Potential serious side effects are myoneuropathy,aplastic anemia, and leukopenia. The second-line treat-ment is prednisone, starting at an initial dose of 40 mgtapered over 7 days. Nonsteroidal anti-inflammatorydrugs and cox-2 inhibitor medications, which can pre-cipitate acute renal failure, are avoided. Periodic mon-itoring of uric acid levels and treatment with allopuri-nol, 100 mg/d, and periodic monitoring of uric acidlevels will prevent recurrent attacks. The combination

S5Role of Primary Care in Liver Transplantation

of azathioprine and allopurinol may lead to myelosup-pression.

Compliance

Compliance problems may severely affect the long-term outcome of transplantation. Dew and Kormos24

examined rates of persistent noncompliance in varioustreatments in heart transplant recipients and reportedthese results: monitoring blood pressure, 34%; immu-nosuppressive medication, 20%; smoking, 19%; diet,18%; having blood work completed, 15%; clinic atten-dance, 9%; and heavy drinking, 6%. Predictors of post-transplantation noncompliance are still inaccurate.25

However, young adolescents, polysubstance abusers,and patients with psychiatric diagnoses (major depres-sion, personality disorders, and high anxiety) have thegreatest risk for noncompliance. Recidivism of alcoholuse in patients who underwent transplantation forLaennec’s cirrhosis has been reported in up to 30% ofpatients with pathological drinking.26 A primary carephysician may be perceived as a nonthreatening indi-vidual who can recognize early warning signs of alcoholuse. Favorable factors to prevent the resumption ofalcohol use include substitute activities, improved self-esteem, and rehabilitation of relationships.26

Complications Common for Both PrimaryCare Physicians and Transplant Centers

Cardiovascular Complications: Hypertensionand Dyslipidemia

This topic was recently reviewed in a supplement toTransplantation in December 2000.27 The mortalityrate of cardiovascular disease in renal transplantation iswell established; however, it remains understudied inthe liver transplantation population.28 Most immuno-suppression medications potentiate risk factors forhypertension, hyperlipidemia, and posttransplantationdiabetes. Sirolimus has pronounced effects on hyperlip-idemia.29

The incidence of hypertension in liver transplantrecipients has ranged from 55% to 85%.30,31 The pro-posed mechanism of calcineurin inhibitors involvesvasoconstriction of afferent renal arterioles and subse-quent impairment of glomerular filtration and sodiumexcretion.32 Corticosteroids also contribute to hyper-tension by producing hypervolemia.33 Because of themorbidity of cardiovascular disease, aggressive inter-vention is needed to maintain blood pressure at lessthan 140/90 mm Hg.

Hypertension treatment with the initiation ofdiuretic therapy (furosemide) is the first step in man-

agement. If hypertension persists, vasodilator treatmentwith calcium channel blockers is preferred because of itscounteractive effects on vasoconstriction and possiblereduced nephrotoxicity.34 Amlodipine is our favoredagent secondary to its lack of interactions with cal-cineurin inhibitors. Diltiazem and verapamil areavoided because they alter cyclosporine and tacrolimuslevels. Angiotensin-converting enzyme inhibitors arethird-line agents and may be especially useful inpatients with diabetes and congestive heart failure.Monitoring of potassium levels and renal dysfunction isrequired after starting therapy. �-Blockers and �-block-ers are used infrequently.

Hyperlipidemia is an established risk factor for thedevelopment of cardiovascular disease in transplantrecipients.35 Mixed hyperlipidemia (types 2a, 2b, and4) of high cholesterol and triglyceride levels is the pat-tern noted after transplantation.36 Clinicians shouldattempt to attain total cholesterol levels less than 200mg/dL, low-density lipoprotein levels less than 130mg/dL, and normal triglyceride levels. Dietary modifi-cation restricting saturated fat and cholesterol hasproven difficult in transplant recipients, but should stillbe attempted.37 The most commonly used drugs are3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors or statins.38 Fibric acid derivatives,bile acid sequestrates, and nicotinic acids frequentlyinteract with immunosuppression medications. Mychoice is to start with atorvastatin, which reduces serumtriglyceride and cholesterol levels. Pravastatin has beenused successfully in heart transplantation and may alsoreduce natural killer-cell cytotoxicity.39 Rarely, myo-cytitis has been reported with HMG-CoA reductaseinhibitors administered with calcineurin inhibitors. Mycenter monitors fasting lipid profiles at 3 and 6 months,then annually. Data are not available for the most cost-effective monitoring regimen.

Diabetes Mellitus

Posttransplantation diabetes develops in 7% to 33% ofpatients, with 90% of patients initially requiring insulintherapy.40 It is not known how many patients requirelong-term insulin use or how frequently diabetic com-plications develop. Diabetogenic medications in thispopulation include corticosteroids, cyclosporine, andtacrolimus, whereas azathioprine, mycophenolicmofetil, and sirolimus may be devoid of diabetogeniceffects.29,41 Other independent risk factors includeadvanced age, race (Hispanic and black), family history,and early postoperative glucose intolerance. Posttrans-plantation diabetes lessens graft and patient survival inrenal transplant recipients, but has unknown effects in

S6 Timothy M. McCashland

liver transplantation.40 Management of posttransplan-tation diabetes is similar to that in nontransplantationpatients.40 Tight control to reduce cardiovascular risksremains the optimal goal. Oral hypoglycemic agents arenot routinely administered. Reduction and withdrawalof corticosteroid therapy will improve the control ofhyperglycemia and may allow the removal of insulintherapy.

Malignancy

Are liver transplant recipients at greater risk for the develop-ment of de novo malignancies? Several studies have differ-ing options.42-44 Early accounts reported lymphoma(57%) and skin cancer (15%) to be the most commontumors.45 The Pittsburgh group reported a greater inci-dence of oropharyngeal cancers (relative risk, 7.6), espe-cially in patients who underwent transplantation foralcoholic liver disease.46 The most recent article, fromHaagsma et al,42 reported an overall relative risk of 4.3compared with the general population. Specific relativerisks were as follows: 70, nonmelanoma skin cancer;2.7, nonskin solid cancer; 30, renal cell cancer; and12.5, colon cancer. Major strengths of the study aredescribed in an accompanying editorial by Duvoux44;longer follow-up provides a much different profile ofmalignancy. The most common de novo malignanciesseen at the University of Nebraska Medical Center(Omaha, NE) were lymphoma (20%), oropharyngeal(15%), pancreas (15%), and colon cancer (15%; D.Sudan, personal communication, May 2001). Patientswith long-standing ulcerative colitis who underwenttransplantation for sclerosing cholangitis are at greaterrisk for colon cancer and require annual colonoscopywith surveillance biopsies.47,48 However, several studiesdid not report a greater incidence of colon cancer.49

Awareness of and surveillance for these commontumors by proper examination and screening tech-niques may be performed by primary care physicians ortransplant physicians.

Bone Disease

Osteoporosis is defined as an absolute decrease in theamount of bone. Predisposing factors for osteoporosisin transplant recipients include calcium and vitamin Ddeficiency, low muscle mass, immobility, corticosteroiduse, hormone imbalance, poor nutritional status, alco-hol abuse, smoking, menopause, and immunosuppres-sive medications.50 The most rapid bone loss occurs inthe first 3 to 6 months after transplantation, with earlybone loss of 2 to 15 times the normal rate.51 Interest-ingly, bone recovery continues for up to 2 to 7 years

after transplantation.52-54 Crosbie et al55 reported thataccelerated bone loss in the transplant setting is causedby more bone resorption exceeding bone formation.Furthermore, calculation of an uncoupling index(osteocalcin-deoxypyridinoline) correlated well withbone mineral density and may serve as a noninvasivemeans to identify high-risk individuals.55

An in-depth review of osteoporosis treatment in livertransplant recipients was recently published.50 Briefly,Davies et al56 reported that vitamin D3, 400 to 4,000IU, improves bone mineral density. Neuhaus et al,57 ina large study, reported that best results were achievedwith daily doses of 0.5 �g of calcitriol, 1 g of calcium,and 25 mg of sodium fluoride. Valero et al58 andRiemens et al59 reported encouraging results withetidronate, �1-hydroxyvitamin D3, and calcium. Therole of estrogens remains understudied.

Pregnancy

Recovery of normal menstrual function occurs fre-quently in women after liver transplantation.60 Manyexperts in obstetrical care have advised waiting a fullyear before pregnancy in these patients, and some advisewaiting up to 2 years.61,62 Review of a single-centerexperience showed favorable maternal and neonataloutcomes in liver transplant recipients.63 Recently,Amenti et al64 reported results from the NationalTransplantation Pregnancy Registry for 136 pregnan-cies from 41 transplant centers. Live births were notedin 78%, spontaneous abortion occurred in 17%, andstillbirths occurred in 4%. Cesarean sections were per-formed in more than 50% of cases.

Maternal complications included cytomegalovirusinfection, elevated serum creatinine levels, and acuterejection in a minority of patients. One patient hadworsening chronic rejection requiring retransplanta-tion, and two patients had severe progressive hepatitisC, resulting in death. Fetal outcomes of low birthweights (32% to 43%) and prematurity (33% to 43%)were the most common fetus-related complications.

Common transplantation medications carry preg-nancy categories of B to X and need to be reviewed withextensive counsel from a multidisciplinary team of phy-sicians, which should include an obstetrician skilled inhigh-risk obstetrics (Table 3).

Vaccines

Immunosuppressed liver transplant recipients are atrisk for pulmonary and extrapulmonary complicationsof influenza. In addition, secondary bacterial pneumo-nia after influenza is common in immunocompromised

S7Role of Primary Care in Liver Transplantation

patients. Only three studies were published on the effi-cacy of influenza vaccination in adult liver transplantrecipients, ranging from 50% to 95% seroconver-sion.65-67 Side effects associated with the vaccine wereminimal and less than those in controls. The threeinvestigators recommended a second dose to increaseresponse rates. Soesman et al67 showed an improvementin response from 68% to 80% after a second vaccina-tion. An updated review of influenza before and afterliver transplantation was published recently by Duchiniet al.68 They recommended mandatory influenza vacci-nation for all personnel at transplant centers, as well ashousehold contacts.

All centers recommend hepatitis A and B and pneu-mococcal vaccinations before transplantation. Arslan etal69 studied nonvaccinated patients with pretransplan-tation detectable immunoglobulin G (IgG) antibody tohepatitis A virus (anti-HAV) levels and noted that 29%became negative for IgG anti-HAV at 2 years post–livertransplantation. Of interest, Gunther et al70 reportedthat patients had seroconversion rates of 97% to HAVvaccination at a mean of 48 months posttransplanta-tion. However, of concern, at 2 years postvaccination,only 59% had protective antibody titers. Furthermore,79% of patients administered tacrolimus had protectiveanti-HAV titers, but only 39% of cyclosporine-treatedpatients had protective levels. Both studies raise thequestion of the need for booster HAV vaccination orwhether immunologic memory at exposure is sufficient.

Prevention of hepatitis B after liver transplantationhas evolved over the last 10 years. Initial results withonly hepatitis B immunoglobulin (HBIG) treatment

after transplantation are recurrence rates of 58% to83%.71 HBIG therapy providing a protective level ofantibody to hepatitis B surface antigen (anti-HBs) of500 IU/L is expensive ($18,000 to $36,000/y). Com-bination HBIG and lamivudine therapy has preventedrecurrence in nearly 100% of patients.72 A multicentertrial assessing lamivudine monotherapy before and aftertransplantation reported that lamivudine was partiallyeffective in preventing recurrent hepatitis B. Thus,using a combination of HBIG and lamivudine still isthe optimal therapy.73 A pilot trial of double-doserecombinant hepatitis B virus vaccine to liver transplantrecipients aiming at discontinuation of HBIG therapywas reported by Sanchez-Fueyo et al.74 Anti-HBs titersgreater than 10 IU/L developed in 14 of 17 patients.However, as noted in an editorial by Ishitani,75 thesewere atypical patients long after transplantation withlow titers (�10 IU/L); therefore, further studies areneeded before recommending this policy. An extensivereview of hepatitis B and liver transplantation was pub-lished recently by Shouval and Samuel.76

Streptococcus pneumoniae is the most common causeof bacterial community-acquired pneumonia. Pneu-mococcal vaccination before transplantation is recom-mended. McCashland et al77 reported that patientswith end-stage liver disease responded to the vaccine;however, IgA and IgM levels declined rapidly within 6months of vaccination. In addition, IgG and IgA levelswere at or less than baseline values 3 months after trans-plantation. Again, the question of need for boosters orimproved timing needs to be resolved.

Anti-Infection

Prophylaxis against Pnemocystis carinii is performed byall transplant programs with the administration of tri-methoprim-sulfamethoxazole or monthly pentamidineinhalation for 6 months to 1 year. Prevention of viralinfections using antiviral and antifungal agents mayoccasionally be performed during times of greaterimmunosuppression. Prophylactic antibiotic use forinvasive procedures is recommended; however, the useof macrolide antibiotics will increase immunosuppres-sant levels.

Primary care physicians must be aware that infec-tions are the most common cause of morbidity andmortality in liver transplant recipients.78 Even suchcommon infections as pharyngitis, urinary tract infec-tions, otitis, and pneumonia can rapidly progress tosepsis and multiorgan failure. Patients who present withfevers should undergo a meticulous examination, withevaluation of urine, blood, and sputum cultures. Chestradiographs, complete blood counts, and liver function

Table 3. Pregnancy Categories for TransplantationMedications

Category B (no evidence of risk in humans)PrednisoneUrsodeoxycholic acid

Category C (risks cannot be ruled out)CyclosporineTacrolimusMycophenolate mofetilSirolimusGanciclovirInterferonLamivudineFoscarnet

Category D (evidence of risk)Azathioprine

Category X (contraindicated)Ribavirin

S8 Timothy M. McCashland

studies are the initial tests. Signs of sepsis (hemody-namic instability, sustained temperature � 38.5°C, orfocal signs) should prompt primary care physicians toconsider transfer of the patient to the transplant center.

Headaches

Headaches are frequent in the immediate postoperativeperiod, but rarely persist months to years later.79 Highcyclosporine or tacrolimus levels and hypertension areusually implicated. However, often no cause is found.Persistent headaches should be evaluated by computedtomography or magnetic resonance imaging of thebrain and lumbar puncture. Rare causes in immuno-suppressed patients include Cryptococcus species, Nocar-dia species, Listeria species, and herpes virus. Trials of�-blockers, calcium channel blockers, and, rarely, non-steroidal anti-inflammatory medications are helpful.

Causes of Late Deaths

Several studies have addressed causes of death in livertransplant recipients who survived beyond 1 year.80-82

A review of 656 patients at the University of Nebraskawho survived more than 1 year after liver transplanta-tion showed that 130 patients (20%) had died (D.Sudan, personal communication, May 2001). Causesof death included recurrent disease (20%), de novomalignancy (16%), graft failure (15%), cardiac disease(14%), renal failure (7%), cerebrovascular disease(7%), sepsis (7%), noncompliance (5%), other (5%),and trauma (3%). Patients who underwent transplan-tation after 55 years of age were 2.9 times more likely todie of de novo malignancy and 4.5 times more likely todie of cardiovascular disease. Compared with the gen-eral population, death from sepsis was 100 times morelikely after liver transplantation. Renal failure was 75times more common than observed in the general pop-ulation. Asfar et al83 noted that immunosuppression-related deaths from chronic rejection, opportunisticinfection, and lymphoma accounted for 40% of latedeaths. Other causes included recurrent hepatobiliarymalignancy (20%), cardiovascular disease (23%), andhepatitis B (8%). Thus, diligent surveillance for recur-rent hepatitis, infections, malignancy, and cardiac riskfactors and the prevention of worsening renal failure arevital.

Transplant Center Management

Results from the survey of transplant centers and opin-ions of primary care physicians indicate that these cat-egories are best managed by the transplantation center:

immunosuppression, allograft rejection, recurrent dis-ease, biliary complications, and renal dysfunction.Entire courses at this meeting (International LiverTransplantation Society postgraduate course) previ-ously were devoted to these topics; therefore, they arenot reviewed here. However, I believe it is paramount toreview the interactions of immunosuppressant medica-tions with commonly used drugs (Table 4). In addition,primary care physicians should be aware that recurrenthepatitis C, autoimmune hepatitis, primary biliary cir-rhosis, and primary sclerosing cholangitis may occurand can account for changes in liver function test resultsand clinical status. Rapid or slowly progressive renaldysfunction is a common event in liver transplant recip-ients and mandates early communication with thetransplant center.

Communication

Because increasing numbers of patients are survivinglonger than 5 years posttransplantation, the volume ofpatients at the transplant center may overwhelm itscapabilities to manage every need of these patients.Thus, I believe that a computerized medical record,such as Ottr (Organ Transplant Tracking record [HKSMedical Information Systems, Omaha, NE]) (Fig. 1)

Table 4. Common Drug Interactions in TransplantationMedications

Drugs that increase levels of cyclosporine, tacrolimus, andsirolimus

Diltiazem, nicardipine, verapamilKetoconazole, clotrimazole, fluconazole, itraconazoleRifampin, clarithromycin, erythromycinMetrocloprimideDanazol

Drugs that decrease levels of cyclosporine, tacrolimus, andsirolimus

RifampinPhenobarbitalPhenytoinCarbamazepine

AzathioprineAllopurinol increases levelsAngiotensin-converting enzyme inhibitors may induce

anemia, leukopeniaMay decrease anticoagulation effect of warfarin

Mycophenolate mofetilMay increase acyclovir levelsAntacids and cholestyramine decrease absorption

Drugs that increase levels of sirolimusSimultaneous Neoral

S9Role of Primary Care in Liver Transplantation

improves management and instantaneous communica-tion among nurses, transplant physicians, and referringphysicians. It allows the sequence of events and thoughtprocesses of the management team to be followed tem-porally. Searching through charts to find the exactanswer is inefficient and leads to medical errors. Physi-cians need accurate, fast, and reliable information tooptimize patient care with assistance from the trans-plant center. Audex and phone messages are not theanswer. In addition, transplant centers are doing a poorjob of providing a packet of guidelines and protocols forprimary care physicians. A picture may be worth a thou-sand words; however, it may take a thousand words topaint the correct picture if you are unfamiliar with thedaily care of liver transplant recipients.

References1. Weisner RH, Martin P, Stribling R. Post-transplant care/medi-

cal complications. In: Norman D, Suki W (eds). Primer ontransplantation. 1st ed. Thorofare, NJ: 1998:343-362.

2. O’Grady JG, Williams R. Postoperative care: Long-term. In:Maddrey WC, Sorrell MF (eds). Transplantation of the liver.2nd ed. East Norwolk, CT: Appleton & Lange, 1998:207-224.

3. Ghobrial RM, Rosen HR, Martin P. Long-term issues in livertransplantation. In: Norman D, Turka L (eds). Primer on trans-plantation. 2nd ed. Mt Laurel, NJ: 2001;581-590.

4. Shaw BW, Stratta RJ, Donovan JP, Langnas AN, Wood RP,Markin RJ. Postoperative care after liver transplantation. SeminLiver Dis 1989;9:202-230.

5. Zetterman RK, McCashland TM. Long-term follow-up of theorthotopic liver transplantation patient. Semin Liver Dis 1995;15:173-180.

6. Munoz SJ. Long-term management of the liver transplant recip-ient. Med Clin North Am 1996;80:1103-1120.

7. Reich D, Rothstein K, Manzarbeitia C, Munoz S. Commonmedical diseases after liver transplantation. Semin GastrointestDis 1998;9:110-125.

8. Sheiner PA, Magliocca JF, Bodian CA, Kim-Schluger L, AltacaG, Guarrera JA, et al. Long-term medical complications inpatients surviving �5 years after liver transplant. Transplanta-tion 2000;69:781-789.

9. US Preventive Services Task Force. Guide to clinical preventiveservices (ed 2). Baltimore: Williams & Wilkins, 1996.

10. Joint National Committee on Detection, Evaluation and Treat-

Figure 1. Patient fact screen (Organ Transplant Tracking Record [HKS Medical Information Systems, Omaha, NE]).(Copyright HKS Medical Information Systems. Used with permission.)

S10 Timothy M. McCashland

Image Unavailable.Please See Print Journal.

ment of High Blood Pressure. The Fifth Report of the JointNational Committee on Detection, Evaluation, and Treatmentof High Blood Pressure. Bethesda, MD: National Institutes ofHealth, pub no. 93-1088, 1993.

11. American Cancer Society. Guidelines for the cancer-relatedcheckup: An update. Atlanta, GA: American Cancer Society,1993.

12. Fleischer DE, Goldberg SB, Browning TH, Cooper JN, Fried-man E, Goldner FH, et al. Detection and surveillance of colo-rectal cancer. JAMA 1989;261:580-585.

13. American College of Obstetricians and Gynecologists. Recom-mendations on frequency of Pap test screening. Committeeopinion no. 152. Washington, DC: American College of Obste-tricians and Gynecologists, 1995.

14. Woolf SH. Screening for prostate cancer with prostate-specificantigen: An examination of the evidence. N Engl J Med 1995;333:1401-1405.

15. National Diabetes Data Group. Classification and diagnosis ofdiabetes mellitus and other categories of glucose tolerance. Dia-betes 1979;28:1039-1057.

16. Eggertsen R, Petersen K, Johansson PM, Eggertsen R, PetersenK, Nystrom E. Screening for thyroid disease in a primary careunit with a thyroid-stimulating hormone assay with a low detec-tion limit. BMJ 1988;297:1586-1592.

17. Penn I. Post-transplantation de novo tumors in liver allograftrecipients. Liver Transpl Surg 1996;2:52-59.

18. Palmer M, Schaffner F, Thung SN. Excessive weight gain afterliver transplantation. Transplantation 1991;51:797-800.

19. Munoz S, Deem R, Moritz MJ, Martin P, Jarrell BE, MaddreyWC. Hyperlipidemia and obesity after orthotopic liver trans-plantation. Transplant Proc 1991;23:1480-1483.

20. Hasse J. From malnutrition to obesity: Changes in nutritionalstatus associated with liver transplantation. Nutrition 1999;15:507-508.

21. Weseman RA, McCashland TM. Nutritional care of the chronicpost-transplant patient. Top Clin Nutr 1998;13:27-34.

22. Anonymous. Executive summary of the clinical guidelines on theidentification, evaluation, and treatment of overweight and obe-sity in adults. Arch Intern Med 1998;158:1855-1867.

23. Gibbs P, Gimson AE, et al. Hyperuricaemia after liver transplan-tation [abstract]. Hepatology 2000;32:314A.

24. Dew M, Kormos R. Early post-transplant medical complianceand mental health predict physical morbidity and mortality oneto three years after heart transplantation. J Heart Lung Trans-plant 1999;18:549-562.

25. Bunzel B, Laederach-Hofmann K. Solid organ transplantation:Are there predictors for posttransplant noncompliance? A litera-ture overview. Transplantation 2000;70:711-716.

26. Osorio R, Ascher N, Avery M, Bacchetti P, Roberts JP, Lake JR.Predicting recidivism after orthotopic liver transplantation foralcoholic liver disease. Hepatology 1994;20:105-110.

27. Monaco AP. Redefining expectations in transplantation: Man-agement of cardiovascular risk. Transplantation 2000;70(suppl):S40-S45.

28. Guckelberger O, Bechstein WO, Neuhaus R, Luesebrink R,Lemmens HP, Dratschmer B, et al. Cardiovascular risk factors inlong-term follow-up after orthotopic liver transplantation. ClinTransplant 1997;11:60-65.

29. Groth CG, Backman L, Morales JM, Calne R, Kreis H, Lang P,et al. Sirolimus (rapamycin)-based therapy in human renal trans-plantation: Similar efficacy and different toxicity compared withcyclosporine. Transplantation 1999;67:1036-1042.

30. Textor SC. De-novo hypertension after liver transplantation.Hypertension 1993;22:257-267.

31. Textor SC, Canzanello VJ, Taler SJ, Schwartz L, Augustine J.Hypertension after liver transplantation. Liver Transpl Surg1995;1:20-28.

32. Midtvedt K, Neumayer HH. Management strategies for post-transplant hypertension. Transplantation 2000;70(suppl):S64-S69.

33. Zeier M, Mandelbaum A, Ritz E. Hypertension in the trans-planted patient. Nephron 1998;80:257-268.

34. Duvoux C, Cherqui D, Di Martino V, Metreau JM, Salvat A,Lauzet JY, et al. Nicardipine as antihypertensive therapy in livertransplant recipients: Results of long-term use. Hepatology1997;25:430-433.

35. Jindal RM, Sidner RA, Hughes D, Pescovitz MD, Leapman SB,Milgram ML, et al. Metabolic problems in recipients of livertransplants. Clin Transplant 1996;10:213-217.

36. Munoz S, Deems R. Hyperlipidemia and obesity after liver trans-plantation. Transplant Proc 1991;23:1480-1483.

37. Rao VK. Posttransplant medical complications. Surg Clin NorthAm 1998;78:113-132.

38. Wierzbicki AS. The role of lipid lowering in transplantation. IntJ Clin Pract 1999;53:54-59.

39. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L,Wang XM, et al. Effects of pravastatin on outcomes after cardiactransplantation. N Engl J Med 1995;333:621-627.

40. Jindal RM, Hjelmesaeth J. Impact and management of post-transplant diabetes mellitus. Transplantation 2000;70(suppl):S58-S63.

41. Jindal RM, Sidner RA, Milgrom ML. Post-transplant diabetesmellitus: The role of immunosuppression. Drug Saf 1997;16:242-257.

42. Haagsma EB, Hagens VE, Schaapveld M, van den Berg AP, deVries EGE, Klompmaker IJ, et al. Increased cancer risk after livertransplantation: A population-based study. J Hepatol 2001;34:84-91.

43. Kelly DM, Emre S, Guy SR, Miller CM, Schwartz ME, SheinerPA. Liver transplant recipients are not at increased risk for non-lymphoid solid organ tumors. Cancer 1998;83:1237-1243.

44. Duvoux C. De novo tumours after liver transplantation inadults. What is the actual risk? J Hepatol 2001;34:161-164.

45. Penn I. Posttransplantation de novo tumors in liver allograftrecipients. Liver Transpl Surg 1996;2:52-59.

46. Jain AB, Yee LD, Nalesnik MA, Youk A, Marsh G, Reyes J, et al.Comparative incidence of de novo nonlymphoid malignanciesafter liver transplantation under tacrolimus using surveillanceepidemiologic end result data. Transplantation 1998;66:1193-1200.

47. Narumi S, Roberts JP, Emond JC, Lake J, Ascher NL. Livertransplantation for sclerosing cholangitis. Hepatology 1995;22:451-457.

48. Knechtle SJ, D’Alessandro AM, Harms BA, Pirsch JD, Belzer FO,Kalayoglu M. Relationships between sclerosing cholangitis, inflam-matory bowel disease, and cancer in patients undergoing liver trans-plantation. Surgery 1995;118:615-620.

49. Loftus EV, Aguilar HI, Sandborn WJ, Tremaine WJ, Krom RA,Zinsmeister AR, et al. Risk of colorectal neoplasia in patientswith primary sclerosing cholangitis and ulcerative colitis follow-ing orthotopic liver transplantation. Hepatology 1998;27:685-690.

50. Tien MH, Bajjoka IE. Treatment options for osteoporosis in

S11Role of Primary Care in Liver Transplantation

chronic liver disease patients requiring liver transplantation. AnnPharmacother 1999;33:233-235.

51. Hay JE. Bone disease after liver transplantation. Liver TransplSurg 1995;1:55-63.

52. Hamburg SM, Piers DA, van den Berg AP, Slooff MJH,Haagsma EB. Bone mineral density in the long term after livertransplantation. Osteoporos Int 2000;11:600-606.

53. Giannini S, Nobile M, Ciuffreda M, Iemmolo RM, Dalle Car-bonare L, Minicuci N, et al. Long-term persistence of low bonedensity in orthotopic liver transplantation. Osteoporos Int 2000;11:417-424.

54. Feller RB, McDonald JA, Sherbon KJ, McCaughan GW. Evi-dence of continuing bone recovery at a mean of 7 years after livertransplantation. Liver Transpl Surg 1999;5:407-413.

55. Crosbie OM, Freaney R, McKenna MJ, Curry MP, Hegarty JE.Predicting bone loss following orthotopic liver transplantation.Gut 1999;44:430-434.

56. Davies M, Mawer EB, Klass HJ, Lumb GA, Berry JL, WarnesTW. Vitamin D deficiency, osteomalacia, and primary biliarycirrhosis—Response to orally administered vitamin D3. Dig DisSci 1983;28:145-153.

57. Neuhaus R, Lohmann R, Rayes N, Hierholzer J, Neuhaus P.Calcitriol in prevention and therapy of osteoporosis after livertransplantation. Transplant Proc 1999;31:472-473.

58. Valero MA, Loinaz C, Larrodera L, Leon M, Moreno E,Hawkins F. Calcitonin and biphosphonates treatment in boneloss after liver transplantation. Calcif Tissue Int 1995;57:15-19.

59. Riemens SC, Oostdijk A, van Doormaal JJ, Thijn CJ, Drent G,Piers DA, et al. Bone loss after liver transplantation is not pre-vented by cyclical etidronate, calcium and alpha calcidol. TheLiver Transplant Group Groningen. Osteoporos Int 1996;6:213-218.

60. Cundy TF, O’Grady JG, Williams R. Recovery of menstruationand pregnancy after liver transplantation. Gut 1990;31:337-338.

61. Ville Y, Fernandez H, Samuel D, Bismuth H, Frydman R. Preg-nancy in liver transplant recipients: Course and outcome in 19cases. Am J Obstet Gynecol 1993;168:896-902.

62. Molmenti EP, Jain AB, et al. Liver transplantation and preg-nancy. Clin Liver Dis 1999;3:163-174.

63. Miller JC, Mastrobattista JM, Katz AR. Obstetrical and neonataloutcome in pregnancies after liver transplantation. Am J Perina-tol 2000;1:299-302.

64. Armenti VT, Herrine SK, Radomski JS, Mortiz MJ. Pregnancyafter liver transplantation. Liver Transpl 2000;6:671-685.

65. Blumberg EA, Albano C, Pruett T, Isaacs R, Fitzpatrick J, BerginJ, et al. The immunogenicity of influenza virus vaccine in solidorgan transplant recipients. Clin Infect Dis 1996;22:295-302.

66. Burbach G, Bienzle U, Stark K, Rayes N, Neuhaus R, Serke S, etal. Influenza vaccination in liver transplant recipients. Trans-plantation 1999;67:753-755.

67. Soesman NMR, Rimmelzwaan GF, Nieuwkoop NJ, BeyerWEP, Tilanus HW, Kemmeren MH, et al. Efficacy of influenzavaccination in adult liver transplant recipients. J Med Virol2000;61:85-93.

68. Duchini A, Hendry RM, Redfield DC, Pockros PJ. Influenzainfection in patients before and after liver transplantation. LiverTranspl 2000;6:531-542.

69. Arslan M, Wiesner RH, Poterucha JJ, Gross JB, Zein NN. HepatitisA antibodies in liver transplant recipients: Evidence for loss ofimmunity posttransplantation. Liver Transpl 2000;6:191-195.

70. Gunther M, Stark K, Neuhaus R, Reinke P, Schroder K, BienzleU. Rapid decline of antibodies after hepatitis A immunization inliver and renal transplant recipients. Transplantation 2001;71:477-490.

71. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Ben-hamou JP, Bismuth H. Liver transplantation in Europeanpatients with the hepatitis B surface antigen. N Engl J Med1993;329:1842-1847.

72. Markowitz J, Martin P, Conrad AJ, Markmann JF, Seu P, YersizH, et al. Prophylaxis against hepatitis B recurrence following livertransplantation using combination lamivudine and hepatitis Bimmunoglobulin. Hepatology 1998;28:585-589.

73. Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al.A multicenter United States-Canadian trial to assess lamivudinemonotherapy before and after liver transplantation for chronichepatitis B. Hepatology 2001;33:424-432.

74. Sanchez-Fueyo A, Rimola A, Grande L, Costa J, Mas A, NavasaM, et al. Hepatitis B immunoglobulin discontinuation followedby hepatitis B virus vaccination: A new strategy in the prophy-laxis of hepatitis B virus recurrence after liver transplantation.Hepatology 2000;31:496-501.

75. Ishitani M. HBV vaccination and liver transplantation for hep-atitis B: Winning by recruiting from within? Liver Transpl 2000;6:659-661.

76. Shouval D, Samuel D. Hepatitis B immune globulin to preventhepatitis B virus graft reinfection following liver transplantation:A concise review. Hepatology 2000;32:1189-1195.

77. McCashland TM, Preheim LC, Gentry-Nielsen MJ. Pneumo-coccal vaccine response in cirrhosis and liver transplantation.J Infect Dis 2000;181:757-760.

78. Winston D, Emmanouilides C, Busuttil RW. Infections in livertransplant recipients. Clin Infect Dis 1995;21:1077-1089.

79. Stein DP, Lederman RJ, Vogt DP, Carey WD, Broughan TA.Neurological complications following liver transplantation. AnnNeurol 1992;31:644-649.

80. Iwatsuki S, Starzl TE, Gordon RD, Esquivel CO, Todo S, TzakisAG, et al. Late mortality and morbidity after liver transplanta-tion. Transplant Proc 1987;19:2373-2377.

81. Backman L, Gibbs J, Levy M, MacMillan R, Holman M, Hus-berg B, et al. Causes of late graft loss after liver transplantation.Transplantation 1993;55:1078-1082.

82. Ramos HC, Reyes J. Weaning of immunosuppression in long-term liver transplant recipients. Transplantation 1995;59:212-217.

83. Asfar S, Metrakos P, Fryer J, Verran D, Ghent C, Grant D, et al.An analysis of late deaths after liver transplantation. Transplan-tation 1996;61:1377-1381.

S12 Timothy M. McCashland