Post-Liver Transplant Patient Care of the Immunosuppressed Liver

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					Post-Liver Transplant Patient: Care of the Immunosuppressed Liver Transplant
Patient in the Community

Digestive Disease Week
Clinical Symposium
May 18, 2008

Jacqueline Laurin, M.D.
Georgetown University Medical Center
Institute of Transplantation, Hepatobiliary Diseases and Liver/Pancreas Surgery
Washington, DC
jacqueline.m.laurin@medstar.net

Nearly 5,000 liver transplants are performed in the U.S. each year. Post-liver transplant
patients lead productive lives after they return to their communities. The primary care
physician plays a crucial role in the long-term management of these patients. Following
liver transplantation, patients are maintained on immunosuppressive therapy to prevent
graft rejection as well as prophylactic medication to prevent opportunistic infections.
Many of the post-operative problems after liver transplant are a result of side-effects of
the medications used for immunosuppression. Long-term problems include neurologic
complications such as tremors and headaches, endocrinologic complications such as
diabetes mellitus, hyperlipidemia, obesity, and metabolic bone disease, and other
common side effects such as hypertension and renal dysfunction.1-8

Most liver transplant centers discharge patients 3 to 6 weeks after surgery. The
transplant surgeons usually manage the patients in the early months after liver
transplant with incorporation of the hepatologist and primary care physician later in the
management of the patient. The transplant center continues to monitor the patient
through regular blood draws for biochemical liver function tests, renal profiles, complete
blood counts and immunosuppressive drug levels.

A telephone survey of liver transplant nurse coordinators at forty-five transplant centers
in the US was conducted to inquire about post-transplant care in patients who survived 6
months after liver transplant. For the overall care of these patients, 40% of the
transplant centers expect the primary care physicians to be the primary physician, 35%
have the hepatologist manage the patient, and 14% expect the primary care physician
and the hepatologist to jointly be responsible for the overall care. In 11% of the
programs, the transplant surgeon is responsible for the overall long-term care of the
post-transplant patient. Referring gastroenterologists were not expected to have a major
role in the overall care.

In this survey, transplant centers expect to continue to manage immunosuppressive
medications, allograft rejection, infections, biliary complications and recurrent disease,
such as recurrent viral hepatitis and hepatic autoimmune diseases. Complications such
as renal dysfunction, hypertension and bone disease are commonly referred to
subspecialists within the transplant center. Most transplant centers want referring
primary care physicians to manage preventive medicine (cervical Pap smears,
mammograms, evaluation of serum prostate-specific antigen and serum lipid levels, skin
surveillance), annual examinations, vaccination, and diabetes. As transplant programs
continue to grow, the volume of work to provide long-term care to these patients
becomes overwhelming, and primary care physicians will be asked to play a greater role
in the management of these patients.9

Compared with the US population, diabetes and hypertension are significantly more
common in the post-transplant population. In a report by Sheiner et al, hypertension
was seen in 60% of post-liver transplant patients and 50% required more than one drug
for blood pressure control. Diabetes mellitus was noted in 35% of the patients and 60%
of these patients required insulin for glycemic control. Obesity was noted in 47% of the
patients. Cholesterol was increased above pretransplant values in 70% of the group but
the levels were not different from the control group. And cardiac complications were
similar to those of the general population. Renal insufficiency was very common,
present in 80% of the patients but only 4% needed hemodialysis. Recurrent liver
disease was noted in 28% with hepatitis C being the leading cause. 8,9

Primary Care Management Issues

General preventive measures

General preventive measures concentrate on cancer screening (skin, breast, colorectal,
cervical and prostate), standard practice in the management of all patients, regardless of
whether or not they have had a transplant. Other general preventive measures
addressed in routine medical visits include immunizations, coronary artery disease risk
factors, and nutritional issues. Antibiotic and antiviral prophylaxis is managed by the
transplant program and becomes less of an issue as the patient is further out from liver
transplant. By six months post-liver transplant, the patient is on lower doses of
immunosuppression and most medications for prophylaxis of infection have been
discontinued.

During routine medical visits, the health care professional records body weight, blood
pressure and elicits new complaints. The transplant center, in conjunction with the
primary physician, monitors monthly complete blood counts, renal and liver profiles, and
immunosuppressant drug levels.

The US Preventive Services Task Force has published recommendations in healthcare
maintenance.10 http://www.ahrq.gov/clinic/uspstfix.htm These recommendations include
screening for cholesterol, high-density lipoprotein, and triglycerides for men age 35 to 65
years and women aged 45 to 65 years. Periodic blood pressure measurement is
recommended with hypertension defined as average systolic blood pressure >140 and
diastolic blood pressure >90. However, target blood pressure in patients with diabetes is
recommended to be <135/80. Persons at risk for diabetes (obese or family history)
should have fasting glucose measurement performed as a screening test. Fasting
glucose level >140 mg/dl is a specific test for diabetes. Routine screening for thyroid
disease is not recommended. Testing with thyroid-stimulating hormone (TSH) is
recommended in symptomatic individuals.

Malignancy

Recurrent and de novo malignancies are the second leading cause of death in liver
transplant recipients, after age-related cardiovascular complications. Estimates of
developing de novo malignancies after organ transplant range from 4.1% to 16%
depending on the age of the transplant population, length of follow-up, and the


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immunosuppression, which is used. Factors that increase the risk for de novo
malignancies after liver transplant include known preexisting risks factor for cancer, such
as chronic ulcerative colitis and the risk for colon cancer, greater rate of chronic viral
infection and long-term immunosuppressive therapy. Immunosuppression may induce a
state of iatrogenic depression of immune surveillance, creating a condition permissive
for the development of malignancy. Also, immunosuppressives such as the calcineurin
inhibitors, cyclosporine (Neoral, Gengraf) and tacrolimus (FK506, Prograf), and
azathioprine may increase the risk of malignancy through 1) intrinsic carcinogenic
properties, 2) alterations in the cytokine milieu or 3) an independent effect on cell
adhesive properties.11

The greatest incidence of de novo malignancies is seen in cancers associated with
chronic viral infections, such as Epstein-Barr virus (EBV) associated post-transplant
lymphoproliferative disorder (PTLD), and skin cancers, including squamous cell
carcinoma (SCCA) and Kaposi’s sarcoma. Post-transplant lymphoproliferative disorder
(PTLD) is a spectrum condition of lymphocyte proliferation that occurs in the setting of
immunosuppression after transplant. EBV is associated with the majority of PTLD.
PTLD is more common in children (usually EBV seronegative before transplant) and
persons with chronic hepatitis C. More than 90% are of B-cell origin and are believed to
be caused by the binding of EBV to EBV-specific receptor on B-cells. Reduction or
withdrawal of immunosuppression leads to regression of PTLD in most cases. Patients
who do not respond may be treated with interferon alfa, chemotherapy regimens, anti-B-
cell monoclonal antibodies and monoclonal antibody therapy. Skin cancers are the most
common post-transplant de novo malignancy after PTLD. Skin cancer development is
multifactorial depending on sun exposure, age, race and viral causes (human
papillomavirus in Squamous cell carcinoma and herpesvirus 8 in Kaposi’s sarcoma).

There is a greater incidence of oropharyngeal malignancy and colon cancer but the risk
is not increased for liver transplant recipients when the patients are matched for age,
sex, and length of follow-up. However, in patients with alcohol-related liver disease
(ALD) before transplant, the rates of oropharyngeal and lung cancers are 25.5 and 3.7
times greater in the ALD group compared with the general population matched for age,
sex and follow-up. There are no studies showing the risk of esophageal cancer is
significantly increased in patients with Barrett’s esophagus after liver transplant.
However, reported studies suggest there is an increased risk. Rates of genitourinary
cancers are 2.2 times greater than the general population but do not reach statistical
significance in most studies.

Survival with de novo malignancies is generally poor but depends on tumor type. Sheil
et al reported that 10 year survival in all patients with de novo malignancy was only
27%.12 Five year survival in patients with PTLD in the University of Pittsburgh
experience has improved from 50% to 81.2%.13 Transplant patients may present with
more advanced stages of disease emphasizing the need for screening for malignancy to
detect malignancies at an earlier, and potentially treatable, stage. Risks can be
reduced by cessation of risk factors such as sun exposure, alcohol intake and smoking.

Screening

The US Preventive Services Task Force recommends routine breast screening every 1
to 2 years with mammography in women aged 50 to 69 years. High-risk individuals
should start their screening at age 40 years. Pelvic examination and Pap smears,


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including genitalia, perineal and anal examinations for malignancy, should be performed
annually in all female liver transplant recipients who have been sexually active.
Although the Task Force does not recommend digital rectal examinations and prostate
specific antigen other groups believe this screening is beneficial. Patients at average risk
for colon cancer should be screened with colonoscopy every 10 years starting at age 50.
Patients with inflammatory bowel disease for more than 10 years require annual
colonoscopy with surveillance biopsies for dysplasia. Patients with Barrett’s esophagus
require surveillance upper endoscopy for dysplasia as well. .9,10

Annual examinations

Annual examinations with a history and physical examination are needed, no matter how
the patient is doing. The health care professional records body weight, blood pressure,
elicits new complaints and answers health-related questions. Eye examinations
evaluate for diabetic retinopathy and in patients on long-term corticosteroids, the
presence of cataracts should be excluded. Annual dental care for periodontal disease
treatment prevention is recommended. Cyclosporine may cause gingival hyperplasia.
There is no indication for the use of prophylactic antibiotic therapy for dental work solely
because the patient has had a liver transplant.14 Annual skin examinations for
suspicious lesions is essential. Patients should be reminded to wear clothing protective
from sunlight ads use lotion with a high skin protection factor (>30).

Vaccinations

Influenza A and pneumococcal pneumonia can cause severe disease in
immunocompromised persons. Appropriate diagnosis and prompt treatment of these
infections is indicated. For influenza, recommended prophylactic treatment includes
yearly vaccination with trivalent inactivated influenza vaccine. This vaccine appears to
be safe and effective in both children and adult liver transplant recipients.15 Family
members should receive the influenza vaccine as well as all personnel at transplant
centers and medical offices. Pneumococcal polysaccharide vaccine (PPS) may not be
effective for patients during and after liver transplantation.16,17 Despite these findings,
transplant recipients should receive the pneumococcal vaccine.

Liver or attenuated vaccines, such as measles, mumps, rubella, oral polio, Bacille-
Calmette-Guerin, yellow fever, TY21a typhoid, varicella vaccine and the recently
reintroduced smallpox vaccine, should be avoided in liver transplant recipients. These
vaccines may cause viral or bacterial reactivation, proliferation and subsequent illness.
Varicella infection following varicella vaccination has been reported in a liver transplant
recipient.18 About 5% of adult in the US are susceptible to varicella. The frequency and
severity of the disease are greatest in immunocompromised persons and adults. It is
important to be aware of the immune status of the transplant patient in regards to
varicella so varicella-zoster immunoglobulin can be given if the patient is exposed.


Hepatitis A accounts for 100 to 150 deaths in the US per year. This mortality is seen
mainly in the older populations and persons with chronic liver disease. The hepatitis A
vaccine is well tolerated and induces a satisfactory immune response in patients with
chronic liver disease and ideally, patients with chronic liver disease are given the
vaccination before transplant.19 Two doses of the hepatitis vaccine are given 6-12
months apart. The dosing is the same in transplant recipients. The literature addressing


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hepatitis B infection in persons with chronic liver disease has mainly addressed chronic
hepatitis B infection superimposed with chronic hepatitis C or hepatitis delta (D)
infection. Findings have included more severe chronic hepatitis, a higher rate of
cirrhosis and more frequent fulminant hepatitis with HDV infection. Patients with chronic
liver disease have a lower response to hepatitis B vaccination.20 Patients with alcoholic
liver disease have a good response to hepatitis B vaccine when they have mild disease
(93%-100% seroconversion) but those patients with cirrhosis only average a 50%
seroconversion rate.21,22 Patients with chronic liver disease but without cirrhosis should
receive the standard immunization schedule of an adult dose of hepatitis B vaccine at
0,1 and 6 months. The CDC recommends that immunocompromised individuals such as
hemodialysis patients, patients with cirrhosis, and transplant recipients receive a double-
dose of the adult dose vaccine at the intervals of 0,1 and 6 months.23,24

Gout

Both cyclosporine and tacrolimus (FK506) impair the excretion of uric acid thus
increasing the risk for gout. This problem is compounded in persons with renal
insufficiency. Allopurinol may be used after liver transplant but cannot be used in
combination with azathioprine because of the increased risk of myelosuppression.
Nonsteroidal anti-inflammatory drugs and cox-2 inhibitor medications should not be used
after liver transplant because of the risk of renal toxicity. Recommended first line
treatment of gout is colchicine followed by prednisone for more refractory cases.9

Smoking

Hepatic artery thrombosis and other vascular complications are significant causes of
morbidity after liver transplant. Smoking has been demonstrated to increase the risk for
vascular complications, especially arterial complications, after liver transplant. In a report
of 288 transplant performed in 263 patients from one center, the risk of vascular
complications was higher in persons with a history of cigarette smoking than in those
without (17.8% vs. 8%, P = .02). Cigarette smoking cessation at least 2 years before
liver transplant reduced the risk by 58.6%. The incidence of arterial complications in
smokers was 13.5% versus 11.8% in smokers (P = 0.15). Smoking cessation for 2
years before transplant reduced the risk for arterial complications by 77.6%. The
authors recommended that cigarette smoking cessation should be an essential
requirement for liver transplantation candidates to decrease morbidity arising from
vascular complications after liver transplant. Larger and prospective studies are needed
to firmly conclude that cigarette smoking is a direct causative factor of an increased
incidence of vascular complications.25,26

In addition, smoking is associated with an increased risk for cardiovascular disease, lung
disease and malignancy, diseases that are causes of significant morbidity and mortality
after transplant. Thus, all effort should be made to encourage smoking cessation before
and after transplant. Highest rates of smoking cessation efficacy have been achieved
with the use of nicotine patches, bupropion and counseling.27,28

Hypertension and Renal Dysfunction

Renal dysfunction is common after liver transplantation. Patients without early renal
dysfunction after liver transplant are low risk for long-term problems with renal
insufficiency. Hypertension occurs in more that 50% of liver transplant recipients. The


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transplant center must adjust immunosuppression early on to avoid long-term
complications.29

Renal Dysfunction

Cyclosporine (Neoral, Gengraf) and tacrolimus (FK506, Prograf) are both nephrotoxic.
In one center’s experience, the median creatinine clearance was 54 ml/min before
transplant and decreased to 28 ml/min post-transplant. 4.5% of patients developed end-
stage renal disease with a median time to onset of 48 months. Most patients were on
cyclosporine. In Pittsburgh’s experience of 1000 patients, early nephrotoxicity was
common using tacrolimus. But at a mean follow-up of 93 months, >80% of patients had
a mean creatinine of 2.0 mg/dl or less and 1.7 mg/dl at 5 years. Nineteen patients were
on hemodialysis and 20 had undergone kidney transplant. 30,31

Patients who present for liver transplant have a variety of renal abnormalities including
hepatitis C associated renal disease with glomerulosclerosis, membranous
glomerulonephritis, and proliferative glomerulonephritis. Patients with hepatorenal
syndrome have renal vasoconstriction that can predispose to the vasoconstricting effects
of cyclosporine or tacrolimus.

Immediately postoperatively, the transplant centers will avoid the use of cyclosporine or
tacrolimus in high-risk patients with creatinine >2.0 mg/dl, using renal sparing
immunosuppressive agents such as mycophenolate mofetil or rapamycin (sirolimus).
Transplant centers will often lower the dose of cyclosporine or tacrolimus to a minimum
and add mycophenolate mofetil or rapamycin to prevent rejection.

The primary care physician my point out renal insufficiency to the transplant center while
advising the patient to avoid the use of nephrotoxic drugs such as NSAIDs and cox-2
inhibitors. However, it is the responsibility of the transplant center to adjust the patient’s
immunosuppressive regimen.

Hypertension

Hypertension is another common problem after liver transplant occurring in 55-85%.9,29
Hypertension is a risk factor for ischemic heart disease, peripheral vascular disease,
renal failure and death. Cyclosporine and less commonly, tacrolimus, cause
hypertension by inducing vascular constriction of afferent renal arterioles, impairing
glomerular filtration and sodium excretion. The mechanism has not been elucidated but
may be caused by changes in the calcium efflux from smooth muscle cells or reduced
prostacyclin or nitric oxide production. Prednisone also increases the risk of
hypertension, by producing hypervolemia. Steroid withdrawal may be the most
important first step in the management of post-transplant hypertension. Because of the
morbidity associated with hypertension, our goal is to keep the blood pressure below
140/90, and <130/85 in diabetics.

Several classes of drugs are effective in treating hypertension in the post-liver transplant
patient. Cyclosporine and tacrolimus may predispose to salt and water retention, so
diuretics may be used in persons with edema. Thiazide diuretics must be used with
caution because of the risk of causing hyperuricemia. Loop diuretics may be used but
patients must be monitored for potassium and magnesium loss.



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Cyclosporine and tacrolimus cause vasoconstriction so direct vasodilators such as
calcium channel blockers (amlodipine, isradipine, felodipine, nifedipine) are a good first
choice. Alternatives are indirect vasodilators that decrease sympathetic activity
(clonidine and doxazosin). All of these medications can cause headache and fluid
retention. NIcardipine, diltiazem and verapamil have limited use and can cause
increased cyclosporine and tacrolimus levels. Clonidine and doxazosin both may cause
sedation. Beta-blockers can be used and may also be helpful in prophylactic treatment
of headaches caused by cyclosporine and tacrolimus.

Angiotensin-converting enzymes (ACE) inhibitors are not useful immediately after liver
transplant because renin levels decrease in the correction of cirrhosis. Hyperkalemia
and renal insufficiency can be aggravated. However, ACE inhibitors may be preferable
later, if patients have diabetic nephropathy. Losartin, an angiotensin II receptor
antagonist, may be useful later post-transplant as well since cyclosporine upregulates
angiotensin II receptors.29

Diabetes, Hyperlipidemia and Obesity

As liver transplant recipients survive longer, cardiovascular complications are becoming
a major cause of late morbidity and mortality. In a long-term follow-up of the largest
series of liver transplant patients ever reported, cardiovascular events accounted for
8.3% of deaths overall, third in frequency after infection and de novo malignancy. Thus,
it is reasonable to be aggressive in treating the reversible risk factors including diabetes
mellitus, hyperlipidemia, and obesity, as well as hypertension.

Diabetes

Diabetes is reported in 10% to 15% of cirrhotics while impaired glucose tolerance is 4 to
5 times higher with formal testing. Insulin resistance in cirrhotics is caused by impaired
insulin-stimulated glucose transport and glycogen synthesis in skeletal muscle.
Cirrhotics also may have chronic hyperinsulinemia, which may cause insulin resistance.

Unfortunately, the prevalence of diabetes does not decrease after liver transplant. Post-
transplant diabetes prevalence has been reported to be 4.5% to 13.8%. When formal
glucose tolerance testing is used, the prevalence is 53%. Preexisting insulin requiring
diabetics rarely lose their need for insulin after transplant and many patients have to be
converted from oral agents to insulin. The use of corticosteroids and calcineurin
inhibitors (cyclosporine and tacrolimus) increase the risk of hyperglycemia by decreasing
insulin synthesis and secretion and/or inducing insulin resistance and hyperinsulinemia.
Obesity after transplant also increases the risk of insulin resistance. Several studies
have demonstrated that patients with chronic hepatitis C are at increased risk of
developing diabetes post-transplant. The mechanism is not clear and it is not known if
chronic hepatitis C is an independent risk factor for diabetes in the non-transplant
population.21

The management of diabetes in the post-transplant population is similar to that in
nontransplant patients. Transplant centers attempt steroid withdrawal and minimize
doses of cyclosporine and tacrolimus in the management of diabetes. Other
immunosuppressive agents such as mycophenolate mofetil and sirolimus are not
diabetogenic and may be substituted for cyclosporine and tacrolimus. The primary care
provider should insure that the transplant recipient receives education in diabetic


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management. Recommended dietary and lifestyle medications are similar to those in
the nontransplant population. Fortunately, insulin and the presently available oral
hypoglycemic agents do not affect the levels of immunosuppressive agents.32

Hyperlipidemia

Hyperlipidemia occurs in all solid organ transplant recipients being the greatest in heart
transplant recipients and the least for liver recipients. Atherosclerosis may cause a
transplant vasculopathy and may be associated with the “vanishing bile duct syndrome”
or chronic rejection in liver transplant recipients. The prevalence of hyperlipidemia in
adult liver transplant recipients varies. Hypercholesteremia is present in 16% to 43% of
recipients and hypertriglyceridemia in about 40%.

The cause of hyperlipidemia is multifactorial. Many patients gain a significant amount of
weight while taking corticosteroids. Corticosteroids themselves enhance hepatic
secretion of VLDL. Cyclosporine may induce hypercholesterolemia by several different
mechanisms. Tacrolimus is less likely to induce hyperlipidemia and conversion of
patients from a cyclosporine to a tacrolimus based immunosuppressive regimen may
dramatically improve hyperlipidemia. Only the pretransplant cholesterol is an
independent risk factor for the development of post-transplant hyperlipidemia in
multivariate analysis.

In the treatment of hyperlipidemia, lifestyle modifications are implemented first including
dietary treatment of diabetes and obesity, a low-saturated fat diet, exercise program, and
avoidance of smoking and oral contraceptives, when possible. If these measures are
not effective, pharmacological therapy should be instituted. Bile acid resins should be
avoided because of the risk of interfering with immunosuppressive medication
absorption. Nitric acid derivatives have potential hepatotoxicity and should be used as
second line agents. Fibric acid derivatives may cause a myositis, as in the
nontransplant population. So usually the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-
CoA) reductase inhibitors or “statins” are used as first line agents. In addition, the
statins have been reported to play an immunosuppressive and antiproliferative role that
may be helpful in preventing acute and chronic rejection.32-34

Drug modifications may also be helpful. The transplant center may reduce or withdraw
corticosteroids, avoid use of sirolimus and substitute tacrolimus for cyclosporine.
Thiazides and beta-blockers should be avoided.

Obesity

Many patients develop obesity after transplant. In 2 small series, patients had striking
weight gain the first year after liver transplant and then weight gain leveled off. Two-
thirds of patients were overweight or obese 2 years after transplant, especially if they
were overweight or obese before transplant. Prednisone increases appetite and may
lead to obesity. Tacrolimus use is less likely to lead to weight gain (27%) than
cyclosporine use (46%).32 In an analysis of the NIDDK database for a cohort of 800
adult liver transplant recipients, 21.6% of non-obese transplant recipients became obese
over the 2 years after liver transplantation.35




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Obesity may lead to the development or redevelopment of nonalcoholic steatohepatitis
in the transplanted liver. NASH carries the risk of the development of fibrosis and
cirrhosis.36

The treatment of obesity in transplant patients is similar to that in nontransplant patients,
including diet and exercise. Prednisone withdrawal by the liver transplant center may be
beneficial as well as a tacrolimus rather than cyclosporine based regimen. The use of
pharmacological agents for weight reduction should be employed with caution because
of possible drug interactions. Orlistat, the pancreatic lipase inhibitor, causes fat
malabsorption and subsequent weight loss. But this medication may lead to the
malabsorption of cyclosporine, which is fat-soluble, as well as fat-soluble vitamins.
Pharmacological agents for weight reduction should be avoided until they are shown to
be safe and effective in transplant patients.32

Antibiotic Prophylaxis, Infection, Fever

Transplant centers usually use antibiotic, antiviral or antiviral prophylaxis for the first 6
months to one year after liver transplant. After the immunosuppression doses are
decreased, with corticosteroids often being discontinued, the risk of infection decreases
and these prophylactic medications are stopped.

For invasive procedures that may cause bacteremia, standard systemic preventive
antibiotic regimens are used. There is no indication for prophylactic antibiotic therapy
only because the patient is a liver transplant recipient, i.e. for dental procedures.6

Fever in a liver transplant recipient is a common situation and can be difficult to
evaluate, especially if the patient does not have localizing signs or symptoms. If the
patient does not have an obvious source of infection, minimum evaluation includes
urinalysis and urine culture, chest xray, complete blood cell count with differential, blood
cultures and liver function tests. In the first year of transplant, the risk of
cytomegalovirus (CMV) infection is higher and blood may be sent for CMV antigen or
culture.

Opportunistic infections include CMV, herpes simplex, varicella zoster, candida,
Pneumocystis carinii, aspergillus and Epstein-Barr virus. Community acquired infections
should be excluded by history, physical examination and appropriate diagnostic tests for
localizing signs and symptoms. These infections include: upper respiratory infections,
sinusitis, pharyngitis, otitis, pneumococcal pneumonia, urinary tract infections and
genital infection. Causes of fever unique to liver transplant recipients are: cholangitis
due to biliary complications (leaks, strictures), acute intra-abdominal abscesses, acute
liver allograft rejection and recurrent viral hepatitis. If there is any question as to the
evaluation of fever or treatment of infection, the transplant center must be contacted.6

Neuropsychiatric Complications

Neuropsychiatric problems encountered in the primary care setting are usually referable
to the immunosuppressive therapy. These problems may include subtle changes in
personality or motivation, subjective anxiety, tremors, headaches, seizures, stroke and
profound cognitive impairment. The three most common categories of neuropsychiatric
postransplant complications are 1) concurrent pathological process, such as mass
lesion, 2) effects of vacoconstriction secondary to immunosuppressive medications and


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3) central nervous system pharmacodynamic effects of the immunosuppressive
medications. Acute processes may be evaluated with CT scan. Magnetic resonance
imaging may detect more subtle structural changes, usually in the evaluation of chronic
problems. Symptoms referable to vasoconstrictive agents (cyclosporine and tacrolimus)
may respond to switching the immunosuppressive agent but such changes must be
made by the transplant center. Ischemia may result in delirium/confusion or stroke.
These agents also reduce the seizure threshold. Most of these severe neuropsychiatric
problems occur in the early post-transplant period and are managed by the transplant
center. Common later problems such as headaches and tremors often respond to beta
blocker therapy and can be managed in the primary care setting.37 Persistent headache
or other neurologic problems are usually evaluated with head CT or MRI, and sometimes
lumbar puncture, to exclude central nervous system infection or malignancy.

Contraception and Pregnancy

Libido returns soon after liver transplantation and patients should be counseled on
contraception and avoidance of sexually transmitted diseases. Unintended pregnancy
may occur as soon as 1-2 months after liver transplant. Thus contraception should be
initiated before sexual relations are resumed after transplant. Barrier methods are
preferable in the early post-transplant period. Later, when patients are stable, hormonal
therapy may be started. Most centers urge patients to delay pregnancy for 1-2 years
after liver transplant. By this time, patients are on stable immunosuppression and the
risk for opportunistic infection, CMV being of the most concern, is much lower. Usually,
by this time patients have been weaned off of steroids, reducing the risk for hypertension
and preeclampsia. Patients with significant renal insufficiency are at higher risk for
hypertension and graft loss.

If a transplant recipient becomes pregnant, the pregnancy is considered high risk.
Immunosuppression should be continued with close monitoring of drug levels.
Cyclosporine, tacrolimus, prednisone, azathioprine, mycophenolate mofetil and
ganciclovir have been used without association with congenital defects. Common
complications include hypertension and preeclampsia. The physician will survey for
diabetes mellitus. Rarely, patients will develop infection, e.g. CMV. CMV may cause
congenital abnormalities and liver disease in the baby of a mother infected early in
pregnancy. Very rarely, a patient will develop rejection of the transplanted organ while
pregnant. Liver enzyme abnormalities must be referred to the transplant center for
aggressive evaluation. Liver biopsy may be required. The outcome of most
pregnancies is with a live birth, commonly with intrauterine growth retardation.
Spontaneous abortion and stillbirth are rare. Congenital malformations are very rare and
have not been linked to the drugs given to these patients.38



Metabolic Bone Disease

Metabolic bone disease is a common problem in patients with chronic liver disease and
liver transplants.39 Osteoporosis accounts for the majority of cases while osteomalacia is
less common, found in patients with advanced liver disease or severe malabsorption.
The reported prevalence of osteoporosis in patients with chronic liver disease ranges
from 20-100%. The pathogenesis is not clear but is probably multifactorial. These
patients have an increased risk of bone pain and fractures. Bone disease can be


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exacerbated by liver transplantation and the use of corticosteroids. Risk factors for
hepatic osteodystrophy include hypogonadism in both men and woman. Vitamin D
deficiency has not been implicated but decreased tissue sensitivity to circulating vitamin
D because of altered vitamin D receptor genotypes may play a role. Noninvasive
imaging studies such as bone mineral density measurements and radiography can
assess bone mass and fracture risk. Management of osteoporosis includes tobacco and
alcohol cessation and reduction of caffeine ingestion, loop diuretics (i.e. furosemide) and
corticosteroid dosage. Exercise with weight bearing is recommended. Vitamin D
deficiency is treated with ergocalciferol, 50,000 TIW or 25-hydroxycholecalciferol 20 to
50 g daily. Elemental calcium, 1500 mg per day, is recommended. Antiresorptive
agents such as biphosphanates are effective therapy.40

Long-term Immunosuppression and Drug Interactions

Long-term Immunosuppression

Early graft and patient survival are excellent after liver transplant thanks in large part to
the evolution of immunosuppressive agents. One- and five-year patient and graft
survival rates are approaching 90% to 95%. The long-term focus in these individuals is
to reduce toxicity associated with long-term immunosuppression. Available new drugs
offer the potential to reduce toxicity by combination therapy or replacement of toxic
agents. Immunosuppressive medications include corticosteroids, antimetabolites
(azathioprine and mycophenolate mofetil), calcineurin inhibitors (cyclosporine and
tacrolimus) and new agents such as rapamycin (sirolimus).

It is recommended that only physicians with experience in immunosuppression and
management of organ transplant recipients prescribe these drugs and adjust the doses
based on drug levels (cyclosporine, tacrolimus and sirolimus). However, it is important
for primary care physicians and providers to recognize the potential side effects and
drug interactions with these immunosuppressive medications.

Corticosteroids have multiple side effects including osteoporosis, osteonecrosis,
diabetes, hyperlipidemia, hirsutism, cataracts, hypertension, growth retardation in
children and cushingoid habitus. Long-term use increases the risk for cardiovascular
diseases. Steroid-free protocols are now used in many centers.

Azathioprine causes bone marrow suppression (leukopenia and less commonly,
thrombocytopenia). This side effect is dose related. Azathioprine also has potential
hepatotoxicity, may cause pancreatitis and may cause gastrointestinal side effects
(nausea, vomiting, diarrhea). Mycophenolate mofetil’s main side effects are bone
marrow suppression (leukopenia and anemia) and gastrointestinal symptoms, primarily
nausea, abdominal pain, and diarrhea. Mycophenolate mofetil has been associated with
a slight increase in risk for opportunistic infection and lymphoproliferative disease.
Mycophenolate mofetil is being examined for potential use to allow the reduction or total
discontinuation of calcineurin inhibitors, especially in transplant patients with significant
hypertension or renal insufficiency.

The calcineurin inhibitors bind to and inhibit the phosphatase activity of calcineurin which
prevents dephosphorylation and translocation of the nuclear factor of activated T cells.
They have a wide range of side effects. The 1- and 5-year incidence of complications is
as follows: renal toxicity (16%, 48%), cardiovascular (11%, 35%), diabetes (16%, 26%),


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osteoporosis (9%, 22%), cancer (8%, 18%), and hypertension (34%, 52%). These
medications also carry the risk of neurotoxicity (headache, tremor, insomnia),
hyperkalemia, hirsutism (cyclosporine), gum hyperplasia (cyclosporine), infections,
hyperglycemia (tacrolimus), diarrhea (tacrolimus), hypercholesterolemia and
hypomagnesemia.

Rapamycin (sirolimus) blocks T-cell activation at a later time than the calcineurin
inhibitors. Dose-dependent adverse reactions limit the immunosuppressive potential.
These reactions include hyperlipidemia and thrombocytopenia. Hepatic artery
thrombosis has been seen in liver transplant patients give rapamycin in combination with
cyclosporine or tacrolimus in the early postransplant period. However, low dose
rapamycin plus tacrolimus leads to low levels of rejection. Rapamycin is used in steroid-
free protocols with no increase in rejection. And rapamycin is used to allow
discontinuation of calcineurin inhibitors to improve renal function.

Drug Interactions

Drug interactions are common and a source of significant morbidity. The hepatic
cytochrome P-450 system is responsible for the metabolism of cyclosporine, tacrolimus
and sirolimus. Thus use of antibiotics, hormones, anticoagulants and antifungals can
interfere with the elimination of these agents and lead to serious toxicities, especially
renal toxicity. Some drugs, such as erythromycin, increase immunosuppressive drug
levels while other agents, such as warfarin, can lead to extremely low drug levels. It is
important to carefully review all new medications for these effects and educate the
patients to be aware about potential drug interactions.

Medications that inhibit the P-450 enzyme system and can increase blood levels of
these immunosuppressants include: erythromycin, clarithromycin, clotrimazole,
fluconazole, ketoconazole, grapefruit juice, diltiazem, verapamil, nicardipine,
metoclopramide and ranitidine. Inducers of the cytochrome P-450 system that can
decrease blood levels of these immunosuppressants are: warfarin, carbamazepine,
phenytoin, phenobarbital, rifampin, and rifabutin.6,41

Allopurinol inhibits elimination of azathioprine and cannot be given in combination with
azathioprine. Acylovir increases levels of Mycophenolate mofetil. Magnesium and
aluminum hydroxide antacids and cholestyramine decrease intestinal absorption of
Mycophenolate mofetil.

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