Stanford University Liver Transplant Program

Tacrolimus (FK506, Prograf)
Cyclosporine (Sandimmune)
Prednisone
Azathioprine (Imuran)
Mycophenolate mofetil (CellCept)

Routine Long-Term Monitoring and Patient Care

Daily activities and quality of life
Diet and exercise
Birth control and pregnancy
Immunizations
Elective surgery

Management of the Consequences of Immunosuppression

Fever and viral syndromes
Hypertension
Obesity, diabetes mellitus and hyperlipidemia

Management of Late Post-Transplant Infections

Community-acquired infections
Opportunistic infections
Chronic hepatitis B
Chronic hepatitis C

Management of Late Post-Transplant Biliary Complications

Recurrence of Original Liver Disease Post-Transplant

Alcoholism
Chronic hepatitis B
Chronic hepatitis C
Hepatobiliary malignancies
Autoimmune liver diseases (PBC, PSC, AIH)

Patients are typically discharged from the hospital 1-2 weeks after liver transplantation and are followed twice weekly initially and then weekly at the transplant center for 4-8 weeks. Patients are then discharged to the management of their personal physician in long-term consultation with the transplant center. Management of complications that may occur after transplantation requires prompt evaluation of what may seem to be trivial complaints. The results of all laboratory data are typically be sent by fax and maintained on a master flow sheet at the transplant center, and local physicians should also maintain their own flow sheet. Referral physicians should expect to regularly communicate with transplant center physicians and/or nurse coordinators, who both play an important role in communicating management plans to physicians and transplant patients.

As patients are followed at home, gradually fewer office visits for symptom survey, assessment of drug compliance, examination, and laboratory testing (CBC, chemistry panel, and trough cyclosporine or tacrolimus levels) are required. Recommended typical visits and laboratory tests are as follows (variations may be necessary according to the specific status of individual patients):

The work-up of elevation of liver chemistries (enzymes ± serum bilirubin) depends on the interval of time after liver transplantation and the rapidity of their rise. A standard approach is outlined in Table 1.

Even though the transplant center will routinely monitor laboratory tests and levels of immunosuppressive drugs, the primary physician will be instrumental in modifying immunosuppressive therapy and following the results of these changes. Referring physicians should communicate with liver transplant nurse coordinators and/or physicians should any questions arise. General guidelines for monitoring and adjusting immunosuppressive drug therapy are outlined in Table 2 (tacrolimus and cyclosporine) and Table 3 (prednisone), and potential drug interactions with tacrolimus and cyclosporine are listed in Tables 4 and 5.

It is generally recommended that adjustments be made in only one immunosuppressive drug (change in dose or start/stop) at any given time. Liver chemistries should be checked 1 week after all changes in immunosuppressive drugs or doses. Further adjustments can then be made, if necessary. There may be variation in absorption rates; toxicity may occur in a patient receiving minimal doses, while for another patient high doses may be needed to achieve adequate therapeutic levels.

Upward dosage adjustment of tacrolimus or cyclosporine may be necessary if target levels are not achieved. On the other hand, downward dosage adjustment is usually required if symptoms of toxicity (high blood pressure, tremors, paresthesias, headaches) are present or if high drug levels (>15 ng/mL) are present on serial determinations (toxic levels are usually associated with elevation of serum potassium, BUN and serum creatinine). Dosage should be decreased by 20-30% and laboratory tests repeated in 3-7 days. Physicians should contact the transplant center if repeat laboratory tests are not improved or if the patient's symptoms do not abate after appropriate changes.

Mycophenolate mofetil (MMF; CellCept) or azathioprine (Imuran) are used when reduction of cyclosporine or prednisone dosage might be beneficial to decrease side effects, such as nephrotoxicity. Either drug is also frequently initiated for recurrent acute allograft rejection. Azathioprine should not be started in patients with WBC counts <4.5 or platelet counts <100,000. If the WBC count falls <3.0 or platelet count <100,000, the dosage should be decreased by 25-50% and laboratory test rechecked in 1 week. The combined use of MMF or azathioprine and tacrolimus has not been thoroughly studied; this combination may lead to overimmunosuppression, and patients receiving this regimen must be followed closely.

Prednisone can ultimately be discontinued in some patients (up to 90% treated with tacrolimus). However, withdrawal of prednisone from patients receiving cyclosporine-based regimens has not been studied in detail and may more often result in rejection. In general, patients receiving tacrolimus and not experiencing previous episodes of acute rejection are candidates for tapering and discontinuation of prednisone. Patients undergoing liver transplantation for chronic hepatitis B or chronic hepatitis C generally undergo a more rapid prednisone taper and may even have prednisone discontinued when they are receiving a cyclosporine-based immunosuppressive regimen. The decision of whether or not to taper a patient off prednisone should be made in consultation with the transplant center. Tapering regimens for prednisone for several different groups of transplant recipients are outlined in Table 3.

Patients are maintained on several different drugs for prophylaxis of frequently encountered infections after liver transplantation.

Nystatin swish and swallow 5 cc qid and nystatin vaginal suppositories q hs for 4-6 weeks post-transplant are recommended for fungal prophylaxis.

Acyclovir is administered in a dose of 200 mg po bid for 3 months post-transplant for prophylaxis of cytomegalovirus if donor and recipient IgG antibody is negative; if either are positive, acyclovir is given in a dose of 800 mg po qid. An alternative drug that may be used is valcanciclovir (Valcyte) 450mg, 1-2 daily. If postoperative herpes simplex/zoster infections develop, the appropriate dose of acyclovir is 5 mg/kg qid for 14 days. The transplant center should be notified if a herpes infection is diagnosed postoperatively so that possible adjustments in immunosuppression can be made.

For the prophylaxis of Pneumocystis carinii pneumonia on a life-long basis, patients are given single-strength trimethoprim-sulfamethoxazole (Septra or Bactrim) 3 times weekly. If this drug is not tolerated, Dapsone 200 mg weekly or aerosolized pentamidine monthly are alternative therapies. In some circumstances, particularly 6-12 months port-transplant when the level of immunusuppression in low, prophylaxis can be discontinued.

Patients undergoing cholangiography or liver biopsy post-transplant should take 1 dose of ciprofloxacin (Cipro) 500 mg po 1 hour prior to the procedures. Prior to routine dental procedures, antibiotic prophylaxis with amoxacillin or alternative drugs according to the American Heart Association guidelines is recommended (Table 6).

Most patients are able to return to work 4-6 months after transplantation. Reduced endurance appears to be related to poor cardiovascular fitness and lack of concentration. Active physical fitness programs and psychotherapeutic support facilitates return to normal or near-normal daily activities. In some cases, depression may occur, in part due to medication side effects, and antidepressants may be useful in this setting.

Most patients can eat a regular diet post-transplant. Late post-transplant, the focus is to avoid excessive weight gain with obesity, problems more often associated with the use of cyclosporine than tacrolimus. Some patients experience edema and occasionally ascites, which may require salt restrictions and a brief period of diuretic therapy.

Chronic liver disease is associated with sexual dysfunction, and liver transplantation usually results in correction of these abnormalities with return of normal sexual functioning 6-9 months post-transplant. Transplant recipients should be advised regarding birth control. Patients are generally recommended to avoid pregnancy, at least during the first year. The safety and risks of oral contraceptives following transplantation is unknown, but concern regarding hepatotoxicity from thrombotic complications, interactions with other medications and exacerbation of hypertension are reasons that these medications are generally avoided. Intrauterine devices are not recommended because of an increased risk of infection. Barrier methods or elective sterilization for the spouse or recipient, if there is no desire to have children, is usually recommended.

The published experience regarding pregnancy after liver transplantation is scant. In recent small reports of pregnancy in liver transplant recipients, graft function appeared to be maintained throughout pregnancy and delivery. The major maternal complications noted were hypertension and anemia, and there was a higher rate of miscarriage compared to the normal population. Finally, despite continued immunosuppression in these patients, the infants born to these mothers generally did well.

When appropriate, according to age, patients should receive routine immunizations prior to liver transplantation. Post-transplant, immunosuppressed patients should not be given attenuated live virus vaccines for fear of causing disease in the recipient. Even though hepatitis B virus (HBV) vaccination has been associated with a poor protective antibody response in patients with advanced liver disease, it may be given prior to transplantation. Studies are underway evaluating the efficacy of double-dose HBV vaccine regimens in chronic liver disease patients. The risk of hepatitis A is low in the United States and HAV vaccine has poor efficacy in advanced liver disease, but it can be administered safely pretransplant or post-transplant.

Flu vaccine should be given annually to patients post-transplant. Pneumovax should be given only to patients who are asplenic.

Transplant recipients undergoing anesthesia and elective surgery should be considered for these operations at the transplant center so that the physicians can manage immunosuppressive drugs postoperatively, especially during the transition between intravenous and oral dosing of immunosuppressive agents. In general, it is recommended to delay elective surgery until >6 months after transplantation, when lower and more stable doses of immunosuppressive drugs are achieved.

Liver transplant recipients experience common viral illnesses with the same frequency as the general population and do not experience more prolonged or severe course. The primary differential diagnosis of importance is bacterial infection that may progress rapidly from a self-limited infection to potentially lethal sepsis. A patient who experiences a body temperature above 38.5°C for more than 24 hours should be examined by a physician and evaluated by blood count, liver chemistry, chest x-ray and urinalysis, with other tests as appropriate according to the nature of the symptoms. Suspected bacterial infections should be treated aggressively with broad-spectrum antibiotics, which can be subsequently modified as culture results become available. Referral physicians should have a low threshold for contacting a physician at the transplant center for advice (Table 7). When antibiotics are utilized, the potential of drug interactions, e.g. erythromycin and cyclosporine, should always be kept in mind (Tables 4 and 5). In patients who are within 3 months of their transplant operation, cytomegalovirus infection should also be considered in the differential diagnosis.

Calcium channel blockers are the first line drugs of choice in patients with hypertension post-transplant. The usual drug regimen is nifedipine (Adalat 10-30 mg tid or Procardia XL 30-90 mg daily). Diuretics (especially HCTZ) may be needed to control resulting peripheral edema in some patients. Furosemide should be avoided long-term because of its potential nephrotoxicity in association with cyclosporine. Diltiazem and verapamil can also potentiate the nephrotoxicity of cyclosporine by increasing therapeutic blood levels and thus are not recommended for hypertension in liver transplant patients.

Beta blockers, followed by ACE inhibitors, are the next best alternatives for blood pressure control. Caution should be used in prescribing ACE inhibitors in patients with elevations of serum creatinine or potassium.

Weight control, oral hypoglycemic agents, and insulin as needed for management of blood sugar post-transplant is recommended. Lipid-lowering drugs may be necessary to control hyperlipidemia post-transplant, but rhamdomyolysis with or without renal impairment has been associated with the use of HMG-CoA reductase inhibitors (e.g., lovastatin or Mevacor). Adjustment of cyclosporine dose and/or prednisone dose may also improve above problems. Active exercise programs are recommended for weight control.

Bacterial pneumonias, urinary tract infections and viral syndromes are often a cause of post-transplant fever and should be considered in all patients with post-transplant fever. These infections are most common in patients with standard immunosuppressive therapy. Erythromycin preparations should be avoided because of their interactions with immunosuppressive drugs.

Pneumocystis carinii pneumonia, tuberculosis and fungal infections can occur and should be considered in patients with fever, particularly those patients who received large doses of immunosuppressive agents for troublesome rejection.

Chronic hepatitis B is diagnosed by recurrence of HBsAg and positive HBcAg and HBsAg staining of the nucleus and cytoplasm of hepatocytes on liver biopsy. This disease may be associated with substantial morbidity and mortality. Biochemically, hepatocellular injury is evident. Recurrence of HBV and management of this problem should be brought to the attention of the transplant center. Oral lamivudine, as well as reduction of immunosuppression (and discontinuation of prednisone), may be effective in improving post-transplant HBV recurrence and survival rates. Adefovir dipivoxil, is effective treatment of patients who develop YMDD breakthrough while receiving lamivudine therapy.

Recurrent HCV infection post-transplant is associated with less than a relative low incidence of graft loss and is generally associated with minimal to moderate postoperative morbidity. There is no proven treatment for recurrent HCV infection post-transplant. Combination antiviral therapy with peginterferon and ribavirin are experimental in this setting but may have benefit; approximately 15-20% will achieve a sustained virological response with disappearance of HCV RNA. Reduction in immunosuppressive drugs does seem to improve hepatitis on liver biopsy and lower serum HCV RNA levels in these patients. There is little correlation between the level of HCV RNA and the degree of hepatocellular injury seen on biopsy post-transplant. Liver biopsy is necessary to determine the extent of injury and exclude acute rejection, a distinction that may be difficult since pathologic features of HCV infection and rejection may overlap.

Anastomotic strictures may be diagnosed by Doppler ultrasound or angiography. These are often progressive over time and difficult to dilate radiologically, often requiring revision of the biliary anastomosis (in approximately 50% of patients). Dilations are usually multiple and done via the transhepatic route. These should be attempted at the transplant center or by an experienced interventional radiologist trained in post-liver transplant biliary radiology.

Intrahepatic biliary strictures are often secondary to ischemia of the hepatic artery (intraoperative or postoperatively), prolonged preservation time, ABO mismatch or chronic rejection. These strictures are progressive over time. Strictures at the hepatic bifurcation may be amenable to dilatation or stenting. Intrahepatic biliary strictures are not amenable to surgical intervention, are progressive and often require retransplantation. In this group of patients, liver enzymes (especially alkaline phosphatase and GGT) and total bilirubin progressively increase and the liver biopsy reveals ductopenia and chronic cholestasis. A small percentage of patients on cyclosporine who develop chronic rejection may benefit from switching to tacrolimus.

The recidivism rate following liver transplantation in patients with alcohol-related end-stage liver disease averages 15%. High-risk patients who have had short periods of sobriety are more likely to return to drinking. It is likely that there is great motivation to remain abstinent during the early period post-transplant. This motivation may fade with longer post-transplant follow-up. Further studies are needed to document long-term recidivism rates as patients are followed up beyond 1 to 2 years after liver transplantation. It appears that the selection of patients with alcoholic liver disease for transplantation should be based on not only a long period of sobriety (greater than 6 months) but also on the presence of psychosocial parameters that predict sobriety. A multidisciplinary approach with assessment of medical, surgical and psychiatric suitability is important. Factors such as admission of the disease of alcoholism by the patient and family members, signing an alcohol contract, participation in alcohol rehabilitation, and absence of psychiatric disease also predict long-term sobriety. Long-term monitoring for recidivism and referral for alcohol rehabilitation when needed are both appropriate. All transplant recipients are counseled to refrain from drinking any alcohol post-transplant, regardless of the preoperative cause of the end-stage liver disease.

Retrospective studies have shown that the strongest predictor of recurrence of HBV infection post-transplant is the presence of pretransplant active HBV replication (detectable serum HBV DNA and HBeAg). Patients with these markers appear to experience reinfection at a higher rate than those with low levels of HBV replication pretransplant, although prophylaxis with hepatitis B immune globulin (HBIG) may override this predictive factor. Hepatitis delta virus (HDV) has been shown to inhibit HBV replication and enhances clearance of HBV post-transplant. In those patients who are persistently HBsAg-negative post-transplant, overall survival is similar to that of patients transplanted for other diseases. Immunoprophylaxis with HBIG long-term in the post-transplant period (10,000 U IV qd x 7 days followed by 10,000 U IV q month thereafter to maintain the anti-HBs level >100-200 mIU/mL) has resulted in a decreased HBV recurrence rate (from 80-100% to 10-20%) and an increased survival. Many centers are exploring the long-term use of lamivudine in combination with HBIG, and the use of the intramuscular rather than intravenous route of administration of lower doses of HBIG.

When HBV reinfection occurs post-transplant in spite of adequate HBIG therapy, patients may or may not be offered retransplantation. Low-dose immunosuppression, particularly prednisone, may reduce the pace of recurrent HBV infection in the allograft. Lamivudine and adefovir have proven benefit in controlling the progression of post-transplant HBV infection.

Chronic hepatitis C is also recurrent in the allograft in >95% of patients who are HCV-positive pretransplant. HCV infection is not typically associated with accelerated or progressive liver disease in the allograft, in contrast to recurrence of HBV infection. However, recent data has implicated HCV as a common cause of post-transplant morbidity and, less often, graft loss, and long-term survival may be reduced. However, the degree of morbidity and survival rate after liver transplantation for chronic hepatitis C are acceptable, and complications of HCV-related cirrhosis are standard indications for transplantation.

It is often difficult to distinguish recurrent HCV infection in the allograft histologically from that of acute cellular rejection. Thus, the diagnosis of recurrent hepatitis C post-transplant may be challenging and may require 2 or 3 biopsies to establish a firm diagnosis. Once recurrent HCV infection has been documented, it is reasonable to reduce immunosuppression in an attempt to decrease viral replication and subsequent hepatitis in the allograft. To date, however, there has been no good correlation between post-transplant serum HCV RNA levels and the degree of histologic viral hepatitis in the allograft.

Recent studies are demonstrating effectiveness of combination antiviral therapy with interferon or peginterferon and ribavirin, with sustained loss of HCV RNA in 15-20% of patients, but when to initiate therapy remains uncertain. Patients require serial liver biopsies, and should be treated when fibrosis is progressive, particularly beyond stage 2.

Patients undergoing liver transplantation with cholangiocarcinoma have disease recurrence in more than 90% of cases. For this reason, these patients are typically excluded from transplantation. Unfortunately, some patients with primary sclerosing cholangitis have tight, benign strictures which cannot be reliably diagnosed in these patients pretransplant. Brush cytology obtained via ERCP may be helpful in making a diagnosis if positive. The presence of proximal biliary ductal dilation in these patients pretransplant documented on a CT scan or ultrasound is highly suspicious for a malignancy. High CA 19-9 levels (>100) have been shown to have a high degree of accuracy in predicting a cholangiocarcinoma in patients with primary sclerosing cholangitis.

Transplantation for primary hepatocellular carcinoma (HCC) is controversial, with historical long-term survival rates of 20-30% at 3 years. However, use of the Milan criteria (single lesions < 5 cm in diameter; or ≤ 3 lesions < 3 cm in diameter) selects patients with reasonably good post-transplant tumor-free survival rates. If patients with HCC are selected for liver transplantation, their disease must be confined to the liver, as documented by CT scans of the abdomen and chest and bone scan. Patients with poor hepatic function and hepatocellular carcinoma are poor candidates for liver resection and may then be offered hepatic transplantation. Adjuvant chemotherapies, particularly when tumors are small and few in number, show promise in improving results of liver transplantation for hepatocellular carcinoma. Post-transplant, these patients must be monitored periodically with alpha-fetoprotein levels and imaging tests as appropriate. Recurrent hepatocellular carcinoma in the allograft, as well as in the lung or brain, is not uncommon.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) may show classic lesions in allograft liver biopsies suggesting recurrent disease. However, whether or not these entities actually recur continues to stimulate debate. There are histologic similarities between PBC and chronic ductopenic rejection that make it difficult to distinguish these 2 diagnoses from each other. Moreover, the AMA persists after liver transplantation, albeit in lower titers. A recent report of a fibroobliterative lesion equivalent to that of PSC together with radiographic documentation of a lesion that resembles PSC recurring in patients with a pretransplant diagnosis of PSC raises the possibility that this disease also recurs post-transplant, although some of these patients had biliary tract infection and could have had secondary sclerosing cholangitis. Cholangiographic findings mimicking PSC have also been reported in patients with chronic recurrent cholangitis, ischemia of the hepatic artery, HIV cholangiography and chronic ductopenic rejection.

There is now good documentation that autoimmune hepatitis (AIH) commonly recurs post-transplant and may be severe enough to require retransplant. Prior to considering a possible recurrence of this disease post-transplant, other etiologies for abnormal aminotransferases need to be ruled out, including drug-induced and viral causes, as well as acute cellular rejection. Patients with AIH should be maintained on somewhat higher levels of immunosuppression long-term and probably not have prednisone discontinued.

Table 1. Approach to elevation of liver tests.

*Liver biopsies should be sent to the transplant center to be reviewed by the transplant team and compared with previous liver biopsies; serial biopsies may be necessary to establish certain diagnoses post-transplant.

Table 2. General guidelines for drug dosage and blood level monitoring for tacrolimus and cyclosporine.

Weeks post-transplant	Daily dosage	Target blood level
Tacrolimus (FK506, Prograf)	(mg/kg/day in 2 divided doses)	(ng/mL)
0-2	0.30	10-15¹
2-8	0.15	7-10
8-26	0.10	5-10²
26-52	0.05	5-10²
>52	0.05³	~5
Cyclosporine (Sandimmune)	(mg/kg/day in 2 divided doses)	(ng/mL)
0-2	20	300-400⁴
2-4	15	300-400
4-12	8-12	300-400
12-26	6-10	300-400
26-52	4-6	200-300
>52	2-4	100-200⁵

¹Target therapeutic blood level by IMX.
²During post-transplant weeks 8-26, target blood levels should be closer to 10 ng/mL; from weeks 26-52, target levels should be closer to 5 ng/mL.
³After week 52, dosage should be tapered to achieve target drug levels of approximately 5 ng/mL as long as liver tests remain stable.
⁴Target blood level by whole blood assay.
⁵Target blood levels for cyclosporine should not fall below 100 long-term.

Table 3. General guidelines for long-term prednisone dosage and regimens for tapering recipients off prednisone.

¹Patients may experience rejection following discontinuation of prednisone; therefore, liver chemistries must be obtained twice weekly for one month to monitor for rejection.

²In patients with chronic hepatitis C, acute rejection may mimic recurrence of hepatitis; thus, careful monitoring of liver chemistries following withdrawal of prednisone is important.

³Most patients on cyclosporine will require small doses of prednisone indefinitely. Exceptions might include patients with recurrent chronic hepatitis B or C, for whom specific recommendations will be made by transplant center physicians.

Table 4. Potential drug interaction with tacrolimus (Prograf)¹.

Potential inhibitors of tacrolimus metabolism resulting in increased tacrolimus levels:

Potential inducers of tacrolimus metabolism resulting in decreased tacrolimus levels:

¹These interactions are theoretical and have not been documented in controlled studies.

Table 5. Documented drug interactions with cyclosporine (Sandimmune).

Inhibitors of cyclosporine metabolism resulting in increased cyclosporine levels:

Table 6. Dental antibiotic prophylaxis protocol.

Since you have had a liver transplant and are immunosuppressed, you require antibiotics before undergoing any type of dental work, including cleaning. Dental procedures commonly cause bacteremia, which is the spread of bacteria into the circulating blood stream. These bacteria may lodge on heart valves, causing bacterial endocarditis, or may result in other infections. Antibiotic prophylaxis is given 1 hour before the procedure to assure that an adequate amount of the antibiotic is in the blood stream. The recently revised recommendations no longer require a second, follow-up dose. The antibiotic dose for children is shown in parentesis in the Table.*

The current American Heart Association recommendations for the prevention of bacterial endocarditis (Dajani et al. JAMA 1997;277:1794-1801) are as follows:

DRUG	STANDARD REGIMEN*
Amoxicillin	2.0 g (children: 50 mg/kg) orally 1 hour before procedure
Alternative regimens for amoxicillin/penicillin allergic patients
Clindamycin	600 mg (children: 20 mg/kg) orally 1hour before procedure
Cephalexin¹ or cefadroxil¹	2.0 grams (children: 50 mg/kg) orally 1hour before procedure
Azithromycin²or clarithromycin²	500 mg (children: 15 mg/kg) orally 1 hour before procedure

*Total pediatric dose should not exceed total adult dose.

¹ Cephalexin should not be used in patients with immediate-type hypersensitivity reactions (urticaria, angioedema, oranaphylaxis) to penicillins in the past.

²One dose of azithromycin or clarithromycin will not significantly alter cyclosporine or tacrolimus blood levels.

Prior to your dental visit, please call the transplant service and we will call the appropriate prescription to your pharmacy; you may also show this paper to your dentist who can prescribe the proper antibiotic for you.

Table 7. When to contact the transplant center.

Unexplained, sustained fever >38.5°C (101.5°F) with or without associated leukocytosis.

Uncontrollable hypertension or persistently elevated blood pressures associated with severe symptoms.

Vomiting for >24 hours, diarrhea >24 hours, gastrointestinal bleeding or acute abdominal pain.

Persistent leukopenia (<3,000 mm³) or unexplained leukocytosis with or without associated symptoms; acute or chronic unexplained lymph node enlargement or tonsillar enlargement.

Before any elective, major surgery or as soon as possible (before or after) any emergency surgery.