- Email: [email protected]
Primary care management of the liver transplant patient
Primary Care Management Transplant Patient ROWEN K. ZETTERMAN, M.D.,
F.A.c.P.,
F.A.c.G.,
Omaha,Nebraska
The patient referred for liver transplantation typically has complications from a progressive, irreversible liver injury. Less traditional complications of end-stage liver disease, such as bone disease and some hepatobiliary malignancies, may also prompt referral. However, there are contraindications to liver transplantation, such as metastatic malignancy and persistent substance abuse. Each patient should be referred as early as possible. The evaluation process includes a complete physical examination and social and psychologic evaluations. If transplantation is agreed upon, the patient is listed by clinical status and enters a waiting period for a donor liver. Following transplantation, the patient is maintained on a regimen of immunosuppressive drugs to prevent allograft rejection. Each patient is also maintained on prophylactic medications, to decrease the risk of opportunistic infection. Many of the postoperative problems in liver transplantation are a result of immunosuppression, either as side effects of the medications used to prevent and control rejection or from the intensity of the resulting immunosuppression. These problems include headaches, systemic hypertension, acute and chronic allograft rejection, renal dysfunction, opportunistic infection with cytomegalovirus or Pneumocystis carinii, disease recurrence, and neoplasia. Routine, long-term care includes systematic clinical follow-up and repetitive blood tests. Communication among the transplant center, the patient, and the referring physician are essential to a successful outcome over the long term.
from the Department of Internal Medicine, Section of Digestive Diseases and Nutrition, Universitv of Nebraska Medical Center, Omaha, Nebraska. Requests for rebrints should be addressed to: Rowen K. Zetterman, M.D., Department of Internal Medicine, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, Nebraska 681982000.
M-LOS
of the Liver
T
he success of liver transplantation has changed the clinical role of the gastroenterologist in the management of patients with end-stage liver disease. As these patients are often referred to specialized liver transplantation centers where both preoperative care of complications and early postoperative management following liver transplantation are provided, the primary-care gastroenterologist may be principally involved in the selection of patients for transplantation, the timing of referral to the transplant center, and the long-term postoperative management when the patient returns home. This article is intended for the practicing gastroenterologist. The criteria for selection, the evaluation process, and the long-term postoperative problems of the transplant patient will be discussed. The events at the liver transplant center will not be presented in any detail.
CANDIDATEREFERRALAND EVALUATION Indications for Liver Transplantation The typical patient referred for liver transplantation will have complications of a progressive, irreversible liver injury. This includes both patients with cirrhosis as well as those with fulminant injury when recovery is unlikely [1,2]. The types of liver disease and the complications leading to consideration of transplantation are presented in Tables I and II, respectively. Age is not a mandatory criterion for candidacy, as patients >60 years do as well with the transplant procedure as younger recipients [3]. However, patients ~70 years are less likely to receive new livers. Obviously, physiologic age is more important than chronologic age where operations are being considered. If variceal hemorrhage due to portal hypertension from cirrhosis develops, treatment considerations should include liver transplantation. This is especially true of those patients who have developed other complications of their liver disease, including coagulopathy, ascites, hypoalbuminemia or encephalopathy. For Child-Pugh class A patients with variceal bleeding, other therapies, such as endoscopic therapy or distal splenorenal shunt procedures, can also be considered. The patient with spontaneous bacterial peritonitis or intractable as-
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cites should also be referred for consideration of liver transplantation, as they also have an increased early mortality. We often follow the patient with persistent coagulopathy in the absence of other major complications for too long a period of time. When the prothrombin time remains > 16 see despite administration of subcutaneous vitamin K, there is usually little hepatic reserve, and these patients should be evaluated before they develop more serious complications. Less traditional complications of end-stage liver disease may also prompt referral. Bone disease can develop with any type of liver disease but is most prevalent in those with primary biliary cirrhosis. This hepatic osteodystrophy can result in severe back pain. As there is no other satisfactory treatment for osteodystrophy, liver transplantation may be the only recourse for improvement. Fatigue can be an incapacitating symptom in patients with cirrhosis and is typically most prevalent in those with primary biliary cirrhosis. When lifestyle must be altered to accommodate fatigue, the time has come to consider transplantation. Some hepatobiliary malignancies deserve consideration. In those with hepatocellular carcinoma, we will consider candidates who have three or fewer tumors that are <5 cm in maximum diameter and in whom we can treat with preoperative chemoembolization. The risk of recurrence is sufficiently rapid to limit consideration of patients with larger tumor burdens [4]. Fibrolamellar carcinomas, however, should be referred for evaluation, as they are slow growing, typically occur in the absence of underlying cirrhosis, and often metastasize late [5]. This means that transplantation has a chance at cure. Small coincidental hepatocellular carcinomas are often found during the evaluation of patients referred because of other complications of liver disease; these patients can generally be considered for transplantation without preoperative intervention. Cholangiocarcinomas also have a high rate of recurrence following liver transplantation [51. We will only consider those patients with ductular carcinomas sufficiently small that they can receive both preoperative intraductal irradiation introduced through a percutaneous stent and chemotherapy. Without such treatments, recurrence rates, even of small Klatskin tumors, preclude transplantation.
TABLEI Some Indications for Consideration of Liver Transplantation A. Diseasesassociatedwithfulminatihepaticfailure 1. Viralhepatitis,A, B,BtD; andunknownviruses 2. Drugor toxininducedliver injury 3. Wilson’sdisease 4. Acutefatty liverof pregnancy B. Endstageliverdisease 1. Hepatocellulardisease Autoimmunechronichepatitis Chronicviralhepatibs Chronicdruginducedhepatitis Alcoholiccirrhosis Alpha-l-antkrypsindeficiency Wrlson’sdisease 2. Cholestaticdisorders Primarybiliarycirrhosis Sclerosingcholangiis Secondarybiliarycirrhosis Arteriohepaticdysplasia Cysbcfibrosis 3. Vasculardisorders BuddChiarisyndrome Venoocclusivedisease 4. Miscellaneous Polycysticliverdisease Congenitalhepaticfibrosis 5. Metabolicdisorders Hemcchrcmatosis Tyrosinemia Giycogenstoragedisease Familialhypercholesterolemia C. Malignancy 1. Primaryhepaticmalignancy Somehepatocellularcarcinomas Fibrolamellarhepatocellularcarcinomas Somecholangiocarcirwmas Somehemangiwdotheliomas Someangiosarcomas 2. Selectedmetastahcdisorders Gastrinomas Carcinoidtumors
TABLEII Indications for Liver Transplantation in Those Wti Progressive, Irreversible Lwer Injury Varicealhemorrhage Uncontrolledasciies Spontanewsbacterialperitonitis Portosystemicencephalopathy Hepatorenalsyndrome Persistentcoagulopathy Hepabcosteodyshophy Severefatigue Malnutrttion Uncontrolledbiliarysepsis Somehepatobiliirymalignancies
Contraindications to Liver Transplantation
There are both absolute and relative contraindications to liver transplantation (Table III). While metastatic malignancy should be a contraindication, those patients with gastrinomas and carcinoid tumors should still be considered. Many will have metastases limited to the liver and have long remis-
sions or cures following transplantation, if the primary lesion has also been removed. Substance abuse can be a difficult problem to evaluate. Most centers refuse those with active al-
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tients who are also HBV-DNA tive.
TABLEIII Contraindications To Liver Transplantation
Absolutehtraindicalionr Activesubstanceabuse AIDS Mostmetastaticmalignancies Uncontrolledsepsis Severecardiacdisease Uncontrolledpulmonarydisease ChronichepatiisBvirus disease?
coholism. This means that the patient with hepatic failure related to alcoholic hepatitis will not be considered. These patients typically present with recent active alcoholism and such severe clinical illness that evaluation of social support or the patient’s understanding of their disease is not feasible. Because of concerns about operative outcome and recidivism, a carefully controlled clinical trial of liver transplantation is needed before this issue can be resolved. To be an acceptable candidate, alcoholic patients need to recognize that alcohol is the cause of their liver injury, have a good social support network, and/or have an active program of abstention and counseling, such as with Alcoholics Anonymous. The relative contraindications are more difficult to evaluate and impose. Whereas acquired immunodeficiency syndrome (AIDS) is an absolute contraindication, the presence of antibody to human immunodeficiency virus (HIV) is not. At present, these patients can be considered [l], although a very careful evaluation to exclude signs of immunosuppression and AIDS is required. Hepatitis B virus (HBV) disease is also a difficult clinical question. There is a high rate of graft reinfection, with such severe liver dysfunction that long-term outcome is poor [6]. At present, the patient who is hepatitis B surface antigen (HBsAg) positive should not be considered if they are also HBV-DNA and hepatitis B e antigen (HBeAg) positive. While there have been some studies to suggest that perioperative infusions of hyperimmune antibody to HBsAg can reduce the risk of graft reinfection [71, the small numbers of patients and the heterogeneous nature of the underlying HBsAg disease (including coexistent hepatitis D virus) in these studies does not permit a conclusion to be made. However, it may be acceptable to consider those HBsAg-positive paJanuary 17, 1994
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nega-
Evaluation
Relalive Conlfaindkaths HIVposiitlvii Hypoxemialhepatopulmonarysyndrome) Socialor familyproblemsthat precludetransplantation Primaryhepatobillarycarcmomas? Alcoholichepatitis?
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When should a patient be referred for consideration of liver transplantation? The basic answer from most transplant centers will be “early.” While there is a fine line between too early and too late, there is evidence to support earlier evaluation and transplantation. Those patients sufficiently well to be awaiting their new liver as an outpatient will have l-year survival that is significantly better than those who are so ill as to be hospitalized or placed in the intensive care unit [8]. The evaluation process can usually be completed as an outpatient and costs approximately $3,000 (depending on the extent of workup required) [9]. If coronary angiography is needed, additional costs will be incurred. Each patient undergoes a careful history and physical examination to confirm the disease etiology, the severity of illness, its complications, and the indications for liver transplantation. If additional diseases are identified, further workup can be scheduled. Each patient will get a minimum cardiopulmonary evaluation, including a chest x-ray, pulmonary function tests, and an electrocardiogram. If hypoxemia is present, assessment of the degree of right-to-left shunting is completed. Echocardiography and coronary angiography may be necessary in those with advanced age, symptoms, or significant risk factors for coronary artery disease. Equally important to the physical evaluation is the social and psychologic evaluation. Identification of significant and perhaps limiting psychosocial problems before transplantation can lead to early intervention and better preparation. After completion of the evaluation process, the patient is discussed at a meeting of the transplant team. Everyone who has seen or evaluated the patient has an opportunity to present their findings. If all agree that transplantation should be undertaken, the patient is listed by their clinical status (according to the United Network of Organ Sharing [UNOS] criteria) at home (status l), at home but requiring continued medical intervention because of liver disease (status Z), in the hospital (status 3), or in the ICU (status 4). During the waiting process, the transplant center should be informed of any clinical changes involving the patient. Hospitalization at any hospital can be utilized to change to a higher status. At present, patients with blood type 0 who are at home can wait 12-15 months for a donor organ to become available. Because of this length of time, the transplant center may wish to see the patient during the waiting process to watch
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for development of problems that may affect the patient’s status or transplantability.
TABLEIV Out@ent Taper of lmmunosuppression in Adult Recipients
POSTTRANSPLANT CARE
Steroid Dose
It is necessary to set the stage for the discussion of the long-term follow-up of the posttransplant patient with a brief overview of the immediate postoperative care. Following transplantation, the patient is maintained on a regimen of immunosuppressive drugs to prevent allograft rejection [lo]. This is usually a combination of prednisone and cyclosporin, with or without azathioprine. Some centers also utilize antilymphocyte globulin (ALG) as induction therapy the first few days following transplantation. Many of the early complications following liver transplantation (e.g., opportunistic infections) are a direct result of immunosuppression. The patient is typically hospitalized for 2-4 weeks following transplantation and then remains as an outpatient at the transplant center for an additional 2-4 weeks. Those who leave the hospital early will usually require a longer initial outpatient program to adjust medications and permit recovery before returning home. A complete blood count, liver panel, renal panel, and cyclosporin (CsA) level is initially drawn daily and then in decreasing frequency as the patient improves. By discharge to home, lab frequency is usually twice weekly. Patients are also maintained on prophylactic medications to decrease the risk of opportunistic infection, such as cytomegalovirus (CMV) and pneumocystis pneumonia 1111. Acyclovir is utilized daily for 3 months to prevent CMV infection [12], with adjustments in the dosage for coexisting renal insufficiency. During hospitalization, we utilize pentamidine to decrease the risk of pneumocystis pneumonia 1131. Once the patient is an outpatient, trimethoprim-sulfamethoxazole is given 2 days each week for a full year to prevent pneumocystis. If the patient is allergic to sulfamethoxazole, monthly aerosolized pentamidine can be continued. Prednisone and CsA are continuously maintained to prevent rejection of the hepatic allograft. The dosage of each is reduced with time as the likelihood of allograft rejection diminishes (Table IV) [14]. Additional medications for hypertension and edema are prescribed as needed.
Late Complications of Liver Transplantation
Many of the postoperative problems in liver transplantation are a result of immunosuppression, either as side effects of the medications used to prevent and control rejection or from the intensity of the resulting immunosuppression. CsA can cause January 17,
1st month Month3 Month6 Month12 After1year
Cyclorporin Level *
900-llOOng/mt
15-20 mg/day lo-15mg/day
800-lOOOng/mt 600-800@ml 400-700ng/mt 300-600ng/mt
7.5-10 mg/day 5-7.5 mg/day 5 mgfday
Adapted from 1141. *Whole blood radloimmunoassay utihztng a polyclonal antibody.
TABLEV Management of Chronic Hypertension Step1: Dietarysodiumresbiction. Step2: Loopdiuretics[e.g.,furosemldei Step3: Beta-blockade(e.g.,propranololl Step4: Vasodilators(e.g.,prazosin)or Calciumantagonists(e.g.,niiedipine) Step5: Angiotensio-converting enzymeinhibitors (e.g., captoprili Step6: Other agents(e.g.,minoxidil) *Adapted from [141.
hirsutism, gingival hyperplasia, rhinorrhea, hypercholesterolemia, hypertension, renal dysfunction, and headaches [El. HEADACHES: Headaches typically occur within 2 months following transplantation [14] and may be associated with nausea, scotomata, and photophobia. As other causes of central nervous system dysfunction can also occur, each patient deserves an initial workup including computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid studies following lumbar puncture. The headaches may respond to p blockers, calcium antagonists or nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs should be used with caution, as they may potentiate renal dysfunction in the transplant patient. SYSTEMIC HYPERTENSION: Hypertension is a frequent problem following liver transplantation, and approximately 60% of transplanted patients require medication for control [ 161. The mechanism is multifactorial and aggravated by preexisting [17] and postoperative renal dysfunction [ 181 and cyclosporin [19]. The management of hypertension is outlined in Table V [ 141. Dietary sodium restriction remains the mainstay of control. If there is continuing evidence of peripheral edema, administration of a loop diuretic may be helpful. However, renal dysfunction may limit its use. Sequential addition of medications, including p blockers, vasodilators, and/or calcium antagonists will control blood pres1994
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sure elevation in most patients. As the dose of cyclosporin is reduced, the degree of systemic hypertension and the need for medications will also decrease. ACUTE ALLOGRAFT REJECTION: Rejection typically occurs in the first few months following liver transplantation [20,21]. Rejection is less probable with the passage of time [22] and may follow a reduction in the level of immunosuppression. While progressive elevation of liver tests (both aminotransferase and gamma-glutamyl transpeptidase levels) can be a clue to the presence of allograft rejection, only liver biopsy can provide a definitive diagnosis [23,24]. Because late elevation of liver tests might also indicate biliary problems, an ultrasound examination should be completed prior to liver biopsy to look for bile duct dilation. It may even provide clues to the presence of rejection [25]. Patients with acute allograft rejection are treated with: (a) intravenous (IV) corticosteroid boluses; (b) a recycle of high-dose IV steroids over 6 days; or (c) an intravenous antilymphocyte globulin, such as OKT3 [ 14,26281. Response is monitored by a reduction in liver tests or confirmation of control of rejection by liver biopsy. Whereas steroid recycles can often be accomplished at the primary care center, administration of OKT3 with its attendant side effects and greater risk of opportunistic infection usually dictates that it be administered at the transplant center. RENAL DYSFUNCTION: Although it is not a contraindication to operation [29], preexisting renal failure can have an adverse effect on outcome of patients following liver transplantation [30,31]. Hemodialysis is utilized until acute renal failure recovers following transplantation [32]. CsA frequently results in renal dysfunction [33], as it reduces intrarenal vascular perfusion and glomerular filtration [34]. However, renal function tends to remain stable over long periods of time [35]. Thus, serum creatinine and urea nitrogen levels should be monitored closely, though need for intervention is usually limited. As CsA dosage is reduced, some improvement in creatinine and urea nitrogen levels may follow. Patients receiving CsA are sensitive to dehydration, and increases in creatinine may respond to extra oral fluid intake. CsA can also induce hyperkalemia; intermittent administration of kayexalate may be necessary. OPPORTUNISTIC INFECTION: IllfeCtiOUS COmpliCations of liver transplantation are most frequent in the first 2-3 months following liver transplantation [11,36]. Bacterial infections are the most common infection in the early postoperative interval [37] and can be a cause of early postoperative mortality [38]. Risk factors for bacterial infections include lA-14s
operation duration, high preoperative bilirubin levels, prior biliary tract surgery, retransplantation, roux-en-Y choledochojejunostomy, the need for postoperative dialysis, and a prolonged ICU stay [11,36,39,40]. Viral, fungal, and protozoa1 infections also develop, though only pneumocystis infection is more likely to occur after the first 2 months [ll]. Administration of oral antibiotic combinations in the perioperative period may reduce bacterial and fungal infections [41]. Cytomegalovirus (CMV) disease will occur in approximately 35% of liver transplant recipients [42] and is more likely if a CMV seronegative recipient receives an organ from a CMV-positive donor. It is also more frequent following retransplantation or with administration of antilymphocyte antibody preparations for control of acute cellular rejection [42,43]. CMV seronegative patients should receive CMV-negative blood products before and during liver transplantation and, if possible, a CMV-negative donor organ should also be utilized. CMV disease typically begins within 60 days of transplantation, but it can be a late cause of allograft dysfunction. In our series, onset as late as 290 days was observed [421. Symptoms of CMV disease can include fever, leukopenia, pneumonia, diarrhea, or hematochezia from CMV colitis, nausea, and vomiting due to gastroparesis from CMV gastroduodenitis, or increased liver tests as a consequence of CMV hepatitis. CMV infection of the liver is the most frequent and can be identified by histologic examination (clusters of polymorphonuclear leukocytes about hepatocytes with characteristic nuclear inclusions) and/or viral culture [42,441. Acyclovir is utilized for the first 3 months following transplantation in an effort to reduce CMV infection. In addition, if a patient receives either a CMV seropositive donor organ or OKT3 for control of rejection, we administer prophylactic ganciclovir. If CMV disease should develop, ganciclovir is generally effective in control [45,46]. Fungal infections result in disseminated infection, peritonitis, pneumonitis, fungemia, or colonization [47-491 and are more likely with retransplantation, multiple transfusions, roux-en-Y anastomoses, preoperative steroid use, vascular complications, and use of antibiotics, or when transplantation is urgent [47]. Selective bowel decontamination [41] and low-dose intravenous amphotericin B [503 may reduce the risk of fungal disease. Pneumocystis ccwinii infections are characteristically late in onset. While most occur within 6 months of transplantation 1111, we have seen it develop later. Thus, we continue trimethoprimsulfamethoxazole or aerosolized pentamidine prophylaxis for a total of 12 months. If a patient devel-
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SYMPOSIUM ON HEPATICDISEASE/ ZEllERMAN
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ops progressive dyspnea or interstitial infiltrates, bronchoalveolar lavage for pneumocystis identification should be immediately completed. BILE DUCT DISEASE: Early biliary dysfunction may be a consequence of hepatic artery occlusion, which results in breakdown of the biliary anastomosis or biliary necrosis [51,52], technical factors [53], or strictures [54]. If hepatic artery occlusion is suspected, Doppler ultrasonography is useful to identify its presence [55]; urgent hepatic artery reconstruction and thrombectomy is required [56]. Other biliary leaks can often be managed by placement of a nasobiliary tube [5’73 or intraductal stent [58]. Patients with biliary necrosis from hepatic artery occlusion may require repetitive percutaneous dilation of strictures or long-term placement of intrabiliary stents [59,60]. Bile duct strictures develop in up to 20% of recipients at either the site of the duct-to-duct or rouxen-Y anastomosis [59]. Management can include dilation or stenting of the stricture or conversion of the choledochostomy to a roux-en-Y anastomosis [59]. If a transplant patient develops increases in gamma-glutamyl transpeptidase, alkaline phosphatase, or bilirubin levels, biliary obstruction must be considered and evaluated by ultrasonography and/ or cholangiography. In patients with duct-to-duct anastomoses, a T-tube is left in place for 6 months. Despite this length of time, the T-tube tract may still be poorly formed, and bile leaks can occur following its removal. Patients with T-tube leaks should be hospitalized, to receive broad-spectrum antibiotics and pain control. Although many will spontaneously close the bile duct leak, some will require placement of nasobiliary drainage or stents [5’7,58], and an occasional patient will need operative intervention to control the leak. CHRONIC ALLOGRAFT REJECTION: Chronic allograft rejection will develop in approximately 5% of recipients [21] and is a cause of late graft failure 1611. It may follow early episodes of acute cellular rejection that are unresponsive to therapy. Chronic rejection is characterized by persistent abnormalities of liver tests and increasing cholestasis, with or without a significant decline of synthetic function [62]. A liver biopsy will identify mononuclear portal inflammation, arteriopathy, centrilobular cholestasis, and a reduction in interlobular bile duct numbers 1621. Retransplantation may be required, although some patients with chronic ductopenic rejection spontaneously resolve [63,64]. DISEASE
RECURRENCE:
LOIlg-tH-III
follow-Up
Of
the liver transplant patient should include a watchful eye for recurrence of the primary indication for liver transplantation. Hepatitis B virus disease [6],
hepatocellular carcinoma 161, hepatic C virus infection [65], autoimmune chronic hepatitis [66], primary biliary cirrhosis [671, and cholangiocarcinoma [6] have all been suggested to recur. Hepatocellular carcinoma has even been identified in a recipient who developed recurrent HBV infection of the allograft [68]. NEoPLAsiA: Several types of tumors are more common in the immunosuppressed patient [14]. Squamous cell carcinomas of the cervix, vulva, perineum, skin, and lip are more frequent than in the general population. Sun exposure adds to the risk of skin carcinomas. Lymphoproliferative disorders (non-Hodgkin’s lymphomas) are usually of B-cell origin and a consequence of Epstein-Barr virus (EBV) infection 169-711. They are increased 30-fold in frequency following immunosuppression and are typically extranodal in location. They usually involve the liver and gastrointestinal tract, though other sites of disease may also be noted. Treatment is the discontinuance of immunosuppression and acyclovir. Long-term Care OFFICE FOLLOW-UP: When the patient is discharged from the transplant center, the primarycare physician (gastroenterologist or internist) should begin routine, systematic clinical follow-up. This may be more frequent during the first year, and eventually only one or two visits each year is all that is needed. However, any new complaints from the patient should be heeded. If there are any doubts as to their significance, the transplant center can be called to discuss the problem. A routine history and physical should be completed each year. This should include a cervical Pap smear (women), rectal examination, and stool guaiac testing. Because of the use of long-term corticosteroids and the risk of cataracts, an annual eye examination should be provided. Routine dental evaluations should be scheduled because of periodontal disease with immunosuppression. Other screening tests should include annual mammograms for women and flexible sigmoidoscopies every 3 years for both men and women. LABORATORY TESTS: Each patient requires repetitive blood tests, including a complete blood count, liver profile (aminotransferases, gamma-glutamyl transpeptidase, alkaline phosphatase, and bilirubins), electrolytes, cyclosporin (or FK506) level, blood urea nitrogen, and creatinine. These values are sent to the transplant center and reviewed. If there are concerns, the transplant center will notify the patient of the need to have repeat lab tests. If rejection or biliary injury seems possible, the patient will either be brought to the transplant center
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for further evaluation or the workup will be arranged through the primary-care gastroenterologist. In the early months following liver transplantation, the workup will usually be completed at the center. ETHANOL USE: The use of alcoholic beverages is discouraged following transplantation. For the patient with prior alcoholism, recidivism is a continuing concern, and ethanol use is forbidden. Intervention with referral to an alcohol counseling center may be required, if alcohol use resumes. For nonalcoholic patients, ethanol might cause fluctuation of aminotransferases and interfere with the evaluation of allograft function. SEXUAL ISSUES: It is important to discuss sexual issues early following transplantation. Initial contraception is recommended for all. While normal pregnancy may be possible for female recipients, pregnancy carries risks and should be delayed until there has a been a return to normal life and activity. In men, spermatogenesis may improve following their transplantation, and an unwanted pregnancy may develop in the partner. There is little information regarding pregnancy in liver transplant patients. However, reports from studies of kidney transplant patients indicate that normal pregnancy is possible, although there is an increased risk of premature labor, pre-eclampsia, and neonatal hyperbilirubinemia [14]. Of 246 pregnancies in kidney recipients, 82% resulted in live births, though 58% were premature and 38% of the newborns had low birth weights. Of the remainder, 11% ended in miscarriage and 2% were stillborn. Therapeutic abortion was carried out in 5% of the patients who became pregnant. These data indicate that pregnancy following kidney transplantation is of higher risk than normal. It seems likely that liver allograft recipients would have similar outcomes. If the transplant recipient becomes pregnant, prenatal care should be provided by an obstetrician skilled in high-risk obstetrics. RECIPIENT TRAVEL: Travel by the liver transplant recipient is acceptable. However, the itinerary should be made available to the transplant center as soon as possible so that arrangements for continued lab tests can be made. In addition, transplant centers near the destination can be identified and addresses provided to the patient for emergency care, if needed. COMMUNICATION: Communication among the transplant center, the patient, and the referring physician are essential to the long-term success of the liver allograft and transplant patient. The transplant center should be called if the referral physician has any doubts about the continuing care of the recipient. The center should always be called lA-16s
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if there are persisting complications or new illnesses, such as poorly controlled hypertension, dyspnea, interstitial pneumonitis, chronic cough, worsening azotemia or liver tests, or continuing headaches.
SUMMARY It could be said that the patient who undergoes liver transplantation for end-stage liver disease simply exchanges one serious disorder for another that requires equally demanding care. However, most liver transplant patients do well once they are able to return to their homes. They simply need careful, thoughtful, and continuing follow-up by their primary-care physician and the liver transplant center. Communication among the patient, the primary-care physician, and the transplant center is essential to this successful outcome.
REFERENCES 1. Starzl TE, Demetris AJ, Van Thiel D. Liver transplantation (part 1). N Engl J Med 1989; 321: 1014-22. 2. Hockerstedt K. Liver transplantation today. Stand J Gastroenterol 1990; 25: l10. 3. Pirsch JD, Kalayoglu M, D’Alessandro AM, et al. Orthotopic liver transplantation in patients 60 years of age and older. Transplantation 1991; 51: 431-3. 4. Yokoyama I, Carr B, Saitsu H, lwatsuki S, Starzl TE. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer 1991; 68: 2095-100. 5. Starzl TE, Demetris AJ, Van Thiel D. Liver transplantation (part 2). N Engl J Med 1989; 321: 1092-g. 6. Hart J, Busuttil RW, Lewin KJ. Disease recurrence following liver transplantation. Am J Surg Pathol 1990; 14: 79-91. 7. Didier S, Bismuth A, Mathieu D, et al. Passive immunoprophylaxis after liver transplantation in HBsAg positive patients. Lancet 1991; 337: 813-5. 8. Mora NP, Klintmalm GB, Solomon H, Goldstein RM, Gonwa TA, Husberg BS. Survival after liver transplantation in 300 consecutive patients: the influence of age, clinical status, and pretransplant disease. Transplant Proc 1992; 24: 156-7. 9. Donovan JP, Zetterman RK, Burnett DA, Sorrel1 MF. Preoperative evaluation, prep aration, and timing of orthotopic liver transplantation in the adult. Sem Liv Dis 1989; 9: 168-75. 10. Klompmaker IJ, Haagsma EB, Gouw ASH, Verwer R, Slooff MJH. Azathroprine and prednisolone immunosuppression versus maintenance triple therapy including cyclosporine for orthotopic liver transplantation. Transplantation 1989; 48: 814-8. 11. Kusne S, Dummer JS, Singh N, et al. Infections after liver transplantation. Medicine 1988; 67: 132-43. 12. Stratta RJ, Shaefer MS, Cushing KA, et al. Successful prophylaxis of cytomegalovirus disease after primary CMV exposure in liver transplant recipients. Transplantation 1991; 51: 90-7. 13. Leoung GS, Feigal DW, Montgomery AB, et al. Aerosolized pentamidine for pro phylaxis against Pneumocystis carinii pneumonia. N Engl J Med 1990; 323: 769-82. 14. Shaw SW, Stratta RJ, Donovan JP, Langnas AN, Wood RP, Markin RJ. Postoperative care after liver transplantation. Sem Liv Dis 1989; 9: 202-30. 15. Neuberger J, Williams R. Long-term use of cyclosporin in liver grafting. In: Calne R, ed. Liver Transplantation, 2nd ed. London: Grune and Stratton, 1987; 319-27. 16. Busuttil RW, Colonna JO, Hiatt JR, et al. The first 100 liver transplants at UCLA. Ann Surg 1987; 206: 387-402. 17. NobleJamieson G, Barnes ND, Thiru S, Mowat AP. Severe hypertension after liver transplantation in antitrypsin deficiency. Arch Dis Childhood 1990; 65: 121721. 18. Ringe 8, Bechstein WO, Bunzendahl H, Wonigeit K, Frei U, Pichlmayr R. Chronic renal dysfunction and hypertension after hepatic transplantation in adults treated with cyclosporine A. Transplant Proc 1988; 20: 639-41. 19. Mark AL. Cyclosporine, sympathetic activity, and hypertension. N Engl J Med 1990; 323: 748-50.
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20. Adams D. Mechanisms of liver allograft rejection in man. Clin Sci 1990; 78: 343-50. 21. Klinfmalm GBG, Nery JR, Husberg BS, Gonwa TA, Tillery GW. Rejection in liver transplantation. Hepatology 1989; 10: 978-85. 22. Nakhleh RE, Schwarzenberg SJ, Bloomer J, Payne W, Snover DC. The pathology of liver allografts surviving longer than one year. Hepatology 1990; 11: 465-70. 23. Colina F, Mollejo M, Moreno E, et al. Effectiveness of histopathological diagnoses in dysfunction of hepatic transplantation. Arch Pathol Lab Med 1991; 115: 9981005. 24. Demetns Al, Qian S, Sun H, Fung JJ. Liver allograft rejection: an overview of morphologic findings. Am J Surg Pathol 1990; 14: 49-63. 25. Marder DM, DeMarino GB, Sumkin JH, Sheahan DG. Liver transplant rejection: value of the resistive index in doppler US of hepatic arteries. Radiology 1989; 173: 127-9. 26. Klintmalm GB. Rejection therapies. Dig Dis Sci 1991; 36: 1431-3. 27. Esquivel CO, Fung JJ, Markus B, et al. OKT3 in the reversal of acute hepatic allograft rejection. Transplant Proc 1987; 29: 2443-6. 28. Colonna JO, Goldstein LI, Brems JJ, et al. A prospective study on the use of monoclonal anti-T3cell antibody fOKT3) to treat steroid-resistant liver transplant re jection. Arch Surg 1987; 122: 1120-3. 29. Gonwa TA, Klintmalm GB, Hugsberg BS, Olson L, Nery J, Roden J. Liver transplantation in patients with preexisting acuteand chronic renal failure. Transplant Proc 1988; 20: 561-3. 30. Brems JJ, Hiatt JR, Colonna JO, etal. Variables influencing the outcome following orthotopic liver transplantation. Arch Surg 1987; 122: 1109-11. 31. McCauley J, Van Thiel DH, Starzl TE, Puschett JB. Acute and chronic renal failure in liver transplantation. Nephron 1990; 55: 121-8. 32. Wilson MV, Knight TF, Shaw BW, Wood RP. The use of nonheparinized hemodialysis after orthotopic liver transplantation-the University of Nebraska Medical Center experience. Transplant Proc 1988; 20: 634-6. 33. Klintmalm GBG, lwatsuki S, Starzl TE. Nephrotoxicity of cyclosporin A in liver and kidney transplant patients. Lancet 1981; i: 470-l. 34. Laskow DA, Curtis JJ, Luke RG, et al. Cyclosporineinduced changes in glomerular filtration rate and urea excretion. Am J Med 1990; 88: 497-502. 35. Bantle JP, Paller MS, Boudreau RJ, Olivari MT, Ferris TF. Long-term effects of cyclosporine on renal function in organ transplant recipients. J Lab Clin Med 1990; 115: 233-40. 36. Colonna JO, Winston DJ, Brill JE, et al. Infectious complications in liver transplantation Arch Surg 1988; 123: 360-4. 37. Corti A, Sabbadini D, Pannacciulli E, et al. Early severe infections after orthotopic liver transplantation. Transplant Proc 1991; 23: 1964. 38. Markin RS, Stratta RJ, Woods GL. Infection after liver transplantation. Am J Surg Pathol 1990; 14: 64-78. 39. George DL, Arnow PM, Fox AS, et al. Bacterial infection as a complication of liver transplantation: epidemiology and risk factors. Rev Infect Dis 1991; 13: 387-96. 49. Martin M, Kusne S, Alessiani M, Simmons R, Starzl TE. Infections after liver transplantation: risk factors and prevention. Transplant Proc 1991; 23: 1929-30. 41. Rossaint R, Raakow R, Lewandowski K, et al. Strategy for prevention of infection after orthotopic liver transplantation. Transplant Proc 1991; 23: 1965-6. 42. Stratta RJ, Shaefer MS, Markin RS, et al. Clinical patterns of cytomegalovirus disease after liver transplantation. Arch Surg 1989; 124: 1443-50. 43. Rakela J, Wiesner RH, Taswell HF, et al. Incidence of cytomegalovirus infection and its relationship to donor-recipient serologic status in liver transplantation. Transplant Proc 1987; 19: 2399-402. 44. Snover DC, Hutton S, Balfour HH, Bloomer JR. Cytomegalovirus infection of the kver In transplant recipients. J Clin Gastroenterol 1987; 9: 659-65. 45. Salmela K, Hockerstedt K, Lautenschlager I, et al. Ganciclovir in the treatment of severe cytomegalovirus disease in liver transplant patients. Transplant Proc 1990; 22: 238-40. 46. Shaefer MS, Stratta RJ, Markin RS, et al. Ganciclovir therapy for cytomegalovirus disease in liver transplant recipients. Transplant Proc 1991; 23: 1515-6. 47. Castaldo P, Stratta RJ, Wood RP, et al. Clinical spectrum of fungal infections after orthotopic liver transplantation. Arch Surg 1991; 126: 149-56. 48. Tollemar J, Ericzon BG, Holmberg K. Andersson J. The incidence and diagnosis
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of invasive fungal infections in liver transplant recipients. Transplant Proc 1990; 22: 242-4. 49. Kusne S, Dummer JS, Singh N, et al. Transplant Proc 1988; 20: 650-l. 59. Mora NP, Klintmalm G, Solomon H, Goldstein RM, Gonwa TA, Husberg BS. Selective amphotericin B prophylaxis in the reduction of fungal infections after liver transplant. Transplant Proc 1992; 24: 154-5. 51. D’Alessandro AM, Kalayoglu M, Pirsch JD, et al. Biliary tract complications after orthotopic liver transplantation. Transplant Proc 1991; 23: 1956. 52. Zajko AB, Campbell WL, Logsdon GA, et al. Biliary complications in liver allo grafts after hepatic artery occlusion: a 6.5 year study. Transplant Proc 1988; 20: 607-9. 53. Lerut J, Gordon RD, lwatsuki S, et al. Biliary tract complications in human orthotopic liver transplantation. Transplantation 1987; 43: 47-51. 54. Evans RA, Raby ND, O’Grady JG, et al. Biliary complications following orthotopic liver transplantation. Clin Radiology 1990; 41: 190-4. 55. Langnas AN, Marujo W, Stratta RJ, Wood RP, Shaw BW. Vascular complications after orthotopic liver transplantation. Am J Surg 1991; 161: 76-83. 56. Langnas AN, Marujo W, Stratta RJ, Wood RP, Li S, Shaw BW. Hepatic allograft rescue following arterial thrombosis. Transplantation 1991; 51: 86-90. 57. O&off JW, Roberts JP, Gordon RL, Ring EJ, Ascher NL. The management of T tube leaks in orthotopic liver transplant recipients with endoscopically placed nasobiC iary catheters. Transplantation 1990; 49: 922-4. 58. Ward EM, Wiesner RH, Hughes RW, Krom RAF. Persistent bile leak after liver transplantation: biloma drainage and endoscopic retrograde cholan giopancreatographic sphincterotomy. Radiology 1991; 179: 719-20. 59. Stratta RJ, Wood RP, Langnas AN, et al. Diagnosis and treatment of biliary tract complications after orthotopic liver transplantation. Surgery 1989; 106: 675-84. 60. Ward EM, Kiely MJ, Maus TP, Wiesner RH, Krom RAF. Hilar biliary strictures after liver transplantation: cholangiography and percutaneous treatment. Radiology 1990; 177: 259-63. 61. Quiroga J, Colina I, Demetris AJ, Starzl TE, Van Thiel DH. Cause and timing of first allograft failure in orthotopic liver transplantation: a study of 177 consecutive patients. Hepatology 1991; 14: 1054-62. 62. Freese DK, Snover DC, Sharp HL, Gross CR, Savick SK, Payne WD. Chronic rejection after liver transplantation: a study of clinical, histopathological and immune logical features. Hepatology 1991; 13: 882-91. 63. Hubscher SG, Buckels JAC, Elias E, McMaster P, Neuberger J. Vanishing bileduct syndrome following liver transplantation-is it reversible?Transplantation 1991; 51: 1004-10. 64. Noack KB, Wiesner RH, Batts K, van Hoek B, Ludwig J. Severe ductopenic rejection with features of vanishing bile duct syndrome: clinical, biochemical, and histologic evidence for spontaneous resolution. Transplant Proc 1991; 23: 144851. 65. Poterucha JJ, Rakela J, Lumeng L, Lee C-H, Taswell HF, Wiesner RH. Diagnosis of chronic hepatitis C after liver transplantation by the detection of viral sequences with polymerase chain reaction. Hepatology 1992; 15: 42-5. 66. Wright HL, BouAbboud CF, Hassanein T, et al. Disease recurrence and rejection following liver transplantation for autoimmune chronic active hver disease. Transplantation 1992; 53: 136-9. 67. Dietze 0, Vogel W, Margreiter R. Primary biliary cirrhosis LPBC) after liver transplantation. Transplant Proc 1990; 22: 1501-2. 68. Luketic VA, Shiffman ML, McCall JB, Posner MP, Mills AS, Carithers RL. Primary hepatocellular carcinoma after orthotopic liver transplantion for chronic hepatitis B infection. Ann Intern Med 1991; 114: 212-13. 69. Langnas AN, Castaldo P, Markin RS, Stratta RJ, Wood RP, Shaw BW. The spectrum of Epstein-Barr virus infectron with hepatitis following liver transplantation. Transplant Proc 1991; 23: 1513-4. 70. Randhawa PS, Markin RS, Starzl TE, Demetris AJ. Epstein-Barr virus-associated syndromes in immunosuppressed liver transplant recipients. Am J Surg Patholl990; 14: 538-47. 71. Nalesnik MA. Involvement of the gastrointestinal tract by Epstein-Bar virusassociated posttransplant lymphoproliferative disorders. Am J Surg Pathol 1990; 14: 92-100.
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F.A.c.P.,
F.A.c.G.,
Omaha,Nebraska
The patient referred for liver transplantation typically has complications from a progressive, irreversible liver injury. Less traditional complications of end-stage liver disease, such as bone disease and some hepatobiliary malignancies, may also prompt referral. However, there are contraindications to liver transplantation, such as metastatic malignancy and persistent substance abuse. Each patient should be referred as early as possible. The evaluation process includes a complete physical examination and social and psychologic evaluations. If transplantation is agreed upon, the patient is listed by clinical status and enters a waiting period for a donor liver. Following transplantation, the patient is maintained on a regimen of immunosuppressive drugs to prevent allograft rejection. Each patient is also maintained on prophylactic medications, to decrease the risk of opportunistic infection. Many of the postoperative problems in liver transplantation are a result of immunosuppression, either as side effects of the medications used to prevent and control rejection or from the intensity of the resulting immunosuppression. These problems include headaches, systemic hypertension, acute and chronic allograft rejection, renal dysfunction, opportunistic infection with cytomegalovirus or Pneumocystis carinii, disease recurrence, and neoplasia. Routine, long-term care includes systematic clinical follow-up and repetitive blood tests. Communication among the transplant center, the patient, and the referring physician are essential to a successful outcome over the long term.
from the Department of Internal Medicine, Section of Digestive Diseases and Nutrition, Universitv of Nebraska Medical Center, Omaha, Nebraska. Requests for rebrints should be addressed to: Rowen K. Zetterman, M.D., Department of Internal Medicine, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, Nebraska 681982000.
M-LOS
of the Liver
T
he success of liver transplantation has changed the clinical role of the gastroenterologist in the management of patients with end-stage liver disease. As these patients are often referred to specialized liver transplantation centers where both preoperative care of complications and early postoperative management following liver transplantation are provided, the primary-care gastroenterologist may be principally involved in the selection of patients for transplantation, the timing of referral to the transplant center, and the long-term postoperative management when the patient returns home. This article is intended for the practicing gastroenterologist. The criteria for selection, the evaluation process, and the long-term postoperative problems of the transplant patient will be discussed. The events at the liver transplant center will not be presented in any detail.
CANDIDATEREFERRALAND EVALUATION Indications for Liver Transplantation The typical patient referred for liver transplantation will have complications of a progressive, irreversible liver injury. This includes both patients with cirrhosis as well as those with fulminant injury when recovery is unlikely [1,2]. The types of liver disease and the complications leading to consideration of transplantation are presented in Tables I and II, respectively. Age is not a mandatory criterion for candidacy, as patients >60 years do as well with the transplant procedure as younger recipients [3]. However, patients ~70 years are less likely to receive new livers. Obviously, physiologic age is more important than chronologic age where operations are being considered. If variceal hemorrhage due to portal hypertension from cirrhosis develops, treatment considerations should include liver transplantation. This is especially true of those patients who have developed other complications of their liver disease, including coagulopathy, ascites, hypoalbuminemia or encephalopathy. For Child-Pugh class A patients with variceal bleeding, other therapies, such as endoscopic therapy or distal splenorenal shunt procedures, can also be considered. The patient with spontaneous bacterial peritonitis or intractable as-
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cites should also be referred for consideration of liver transplantation, as they also have an increased early mortality. We often follow the patient with persistent coagulopathy in the absence of other major complications for too long a period of time. When the prothrombin time remains > 16 see despite administration of subcutaneous vitamin K, there is usually little hepatic reserve, and these patients should be evaluated before they develop more serious complications. Less traditional complications of end-stage liver disease may also prompt referral. Bone disease can develop with any type of liver disease but is most prevalent in those with primary biliary cirrhosis. This hepatic osteodystrophy can result in severe back pain. As there is no other satisfactory treatment for osteodystrophy, liver transplantation may be the only recourse for improvement. Fatigue can be an incapacitating symptom in patients with cirrhosis and is typically most prevalent in those with primary biliary cirrhosis. When lifestyle must be altered to accommodate fatigue, the time has come to consider transplantation. Some hepatobiliary malignancies deserve consideration. In those with hepatocellular carcinoma, we will consider candidates who have three or fewer tumors that are <5 cm in maximum diameter and in whom we can treat with preoperative chemoembolization. The risk of recurrence is sufficiently rapid to limit consideration of patients with larger tumor burdens [4]. Fibrolamellar carcinomas, however, should be referred for evaluation, as they are slow growing, typically occur in the absence of underlying cirrhosis, and often metastasize late [5]. This means that transplantation has a chance at cure. Small coincidental hepatocellular carcinomas are often found during the evaluation of patients referred because of other complications of liver disease; these patients can generally be considered for transplantation without preoperative intervention. Cholangiocarcinomas also have a high rate of recurrence following liver transplantation [51. We will only consider those patients with ductular carcinomas sufficiently small that they can receive both preoperative intraductal irradiation introduced through a percutaneous stent and chemotherapy. Without such treatments, recurrence rates, even of small Klatskin tumors, preclude transplantation.
TABLEI Some Indications for Consideration of Liver Transplantation A. Diseasesassociatedwithfulminatihepaticfailure 1. Viralhepatitis,A, B,BtD; andunknownviruses 2. Drugor toxininducedliver injury 3. Wilson’sdisease 4. Acutefatty liverof pregnancy B. Endstageliverdisease 1. Hepatocellulardisease Autoimmunechronichepatitis Chronicviralhepatibs Chronicdruginducedhepatitis Alcoholiccirrhosis Alpha-l-antkrypsindeficiency Wrlson’sdisease 2. Cholestaticdisorders Primarybiliarycirrhosis Sclerosingcholangiis Secondarybiliarycirrhosis Arteriohepaticdysplasia Cysbcfibrosis 3. Vasculardisorders BuddChiarisyndrome Venoocclusivedisease 4. Miscellaneous Polycysticliverdisease Congenitalhepaticfibrosis 5. Metabolicdisorders Hemcchrcmatosis Tyrosinemia Giycogenstoragedisease Familialhypercholesterolemia C. Malignancy 1. Primaryhepaticmalignancy Somehepatocellularcarcinomas Fibrolamellarhepatocellularcarcinomas Somecholangiocarcirwmas Somehemangiwdotheliomas Someangiosarcomas 2. Selectedmetastahcdisorders Gastrinomas Carcinoidtumors
TABLEII Indications for Liver Transplantation in Those Wti Progressive, Irreversible Lwer Injury Varicealhemorrhage Uncontrolledasciies Spontanewsbacterialperitonitis Portosystemicencephalopathy Hepatorenalsyndrome Persistentcoagulopathy Hepabcosteodyshophy Severefatigue Malnutrttion Uncontrolledbiliarysepsis Somehepatobiliirymalignancies
Contraindications to Liver Transplantation
There are both absolute and relative contraindications to liver transplantation (Table III). While metastatic malignancy should be a contraindication, those patients with gastrinomas and carcinoid tumors should still be considered. Many will have metastases limited to the liver and have long remis-
sions or cures following transplantation, if the primary lesion has also been removed. Substance abuse can be a difficult problem to evaluate. Most centers refuse those with active al-
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tients who are also HBV-DNA tive.
TABLEIII Contraindications To Liver Transplantation
Absolutehtraindicalionr Activesubstanceabuse AIDS Mostmetastaticmalignancies Uncontrolledsepsis Severecardiacdisease Uncontrolledpulmonarydisease ChronichepatiisBvirus disease?
coholism. This means that the patient with hepatic failure related to alcoholic hepatitis will not be considered. These patients typically present with recent active alcoholism and such severe clinical illness that evaluation of social support or the patient’s understanding of their disease is not feasible. Because of concerns about operative outcome and recidivism, a carefully controlled clinical trial of liver transplantation is needed before this issue can be resolved. To be an acceptable candidate, alcoholic patients need to recognize that alcohol is the cause of their liver injury, have a good social support network, and/or have an active program of abstention and counseling, such as with Alcoholics Anonymous. The relative contraindications are more difficult to evaluate and impose. Whereas acquired immunodeficiency syndrome (AIDS) is an absolute contraindication, the presence of antibody to human immunodeficiency virus (HIV) is not. At present, these patients can be considered [l], although a very careful evaluation to exclude signs of immunosuppression and AIDS is required. Hepatitis B virus (HBV) disease is also a difficult clinical question. There is a high rate of graft reinfection, with such severe liver dysfunction that long-term outcome is poor [6]. At present, the patient who is hepatitis B surface antigen (HBsAg) positive should not be considered if they are also HBV-DNA and hepatitis B e antigen (HBeAg) positive. While there have been some studies to suggest that perioperative infusions of hyperimmune antibody to HBsAg can reduce the risk of graft reinfection [71, the small numbers of patients and the heterogeneous nature of the underlying HBsAg disease (including coexistent hepatitis D virus) in these studies does not permit a conclusion to be made. However, it may be acceptable to consider those HBsAg-positive paJanuary 17, 1994
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nega-
Evaluation
Relalive Conlfaindkaths HIVposiitlvii Hypoxemialhepatopulmonarysyndrome) Socialor familyproblemsthat precludetransplantation Primaryhepatobillarycarcmomas? Alcoholichepatitis?
lA-12s
and HBeAg
When should a patient be referred for consideration of liver transplantation? The basic answer from most transplant centers will be “early.” While there is a fine line between too early and too late, there is evidence to support earlier evaluation and transplantation. Those patients sufficiently well to be awaiting their new liver as an outpatient will have l-year survival that is significantly better than those who are so ill as to be hospitalized or placed in the intensive care unit [8]. The evaluation process can usually be completed as an outpatient and costs approximately $3,000 (depending on the extent of workup required) [9]. If coronary angiography is needed, additional costs will be incurred. Each patient undergoes a careful history and physical examination to confirm the disease etiology, the severity of illness, its complications, and the indications for liver transplantation. If additional diseases are identified, further workup can be scheduled. Each patient will get a minimum cardiopulmonary evaluation, including a chest x-ray, pulmonary function tests, and an electrocardiogram. If hypoxemia is present, assessment of the degree of right-to-left shunting is completed. Echocardiography and coronary angiography may be necessary in those with advanced age, symptoms, or significant risk factors for coronary artery disease. Equally important to the physical evaluation is the social and psychologic evaluation. Identification of significant and perhaps limiting psychosocial problems before transplantation can lead to early intervention and better preparation. After completion of the evaluation process, the patient is discussed at a meeting of the transplant team. Everyone who has seen or evaluated the patient has an opportunity to present their findings. If all agree that transplantation should be undertaken, the patient is listed by their clinical status (according to the United Network of Organ Sharing [UNOS] criteria) at home (status l), at home but requiring continued medical intervention because of liver disease (status Z), in the hospital (status 3), or in the ICU (status 4). During the waiting process, the transplant center should be informed of any clinical changes involving the patient. Hospitalization at any hospital can be utilized to change to a higher status. At present, patients with blood type 0 who are at home can wait 12-15 months for a donor organ to become available. Because of this length of time, the transplant center may wish to see the patient during the waiting process to watch
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for development of problems that may affect the patient’s status or transplantability.
TABLEIV Out@ent Taper of lmmunosuppression in Adult Recipients
POSTTRANSPLANT CARE
Steroid Dose
It is necessary to set the stage for the discussion of the long-term follow-up of the posttransplant patient with a brief overview of the immediate postoperative care. Following transplantation, the patient is maintained on a regimen of immunosuppressive drugs to prevent allograft rejection [lo]. This is usually a combination of prednisone and cyclosporin, with or without azathioprine. Some centers also utilize antilymphocyte globulin (ALG) as induction therapy the first few days following transplantation. Many of the early complications following liver transplantation (e.g., opportunistic infections) are a direct result of immunosuppression. The patient is typically hospitalized for 2-4 weeks following transplantation and then remains as an outpatient at the transplant center for an additional 2-4 weeks. Those who leave the hospital early will usually require a longer initial outpatient program to adjust medications and permit recovery before returning home. A complete blood count, liver panel, renal panel, and cyclosporin (CsA) level is initially drawn daily and then in decreasing frequency as the patient improves. By discharge to home, lab frequency is usually twice weekly. Patients are also maintained on prophylactic medications to decrease the risk of opportunistic infection, such as cytomegalovirus (CMV) and pneumocystis pneumonia 1111. Acyclovir is utilized daily for 3 months to prevent CMV infection [12], with adjustments in the dosage for coexisting renal insufficiency. During hospitalization, we utilize pentamidine to decrease the risk of pneumocystis pneumonia 1131. Once the patient is an outpatient, trimethoprim-sulfamethoxazole is given 2 days each week for a full year to prevent pneumocystis. If the patient is allergic to sulfamethoxazole, monthly aerosolized pentamidine can be continued. Prednisone and CsA are continuously maintained to prevent rejection of the hepatic allograft. The dosage of each is reduced with time as the likelihood of allograft rejection diminishes (Table IV) [14]. Additional medications for hypertension and edema are prescribed as needed.
Late Complications of Liver Transplantation
Many of the postoperative problems in liver transplantation are a result of immunosuppression, either as side effects of the medications used to prevent and control rejection or from the intensity of the resulting immunosuppression. CsA can cause January 17,
1st month Month3 Month6 Month12 After1year
Cyclorporin Level *
900-llOOng/mt
15-20 mg/day lo-15mg/day
800-lOOOng/mt 600-800@ml 400-700ng/mt 300-600ng/mt
7.5-10 mg/day 5-7.5 mg/day 5 mgfday
Adapted from 1141. *Whole blood radloimmunoassay utihztng a polyclonal antibody.
TABLEV Management of Chronic Hypertension Step1: Dietarysodiumresbiction. Step2: Loopdiuretics[e.g.,furosemldei Step3: Beta-blockade(e.g.,propranololl Step4: Vasodilators(e.g.,prazosin)or Calciumantagonists(e.g.,niiedipine) Step5: Angiotensio-converting enzymeinhibitors (e.g., captoprili Step6: Other agents(e.g.,minoxidil) *Adapted from [141.
hirsutism, gingival hyperplasia, rhinorrhea, hypercholesterolemia, hypertension, renal dysfunction, and headaches [El. HEADACHES: Headaches typically occur within 2 months following transplantation [14] and may be associated with nausea, scotomata, and photophobia. As other causes of central nervous system dysfunction can also occur, each patient deserves an initial workup including computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid studies following lumbar puncture. The headaches may respond to p blockers, calcium antagonists or nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs should be used with caution, as they may potentiate renal dysfunction in the transplant patient. SYSTEMIC HYPERTENSION: Hypertension is a frequent problem following liver transplantation, and approximately 60% of transplanted patients require medication for control [ 161. The mechanism is multifactorial and aggravated by preexisting [17] and postoperative renal dysfunction [ 181 and cyclosporin [19]. The management of hypertension is outlined in Table V [ 141. Dietary sodium restriction remains the mainstay of control. If there is continuing evidence of peripheral edema, administration of a loop diuretic may be helpful. However, renal dysfunction may limit its use. Sequential addition of medications, including p blockers, vasodilators, and/or calcium antagonists will control blood pres1994
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sure elevation in most patients. As the dose of cyclosporin is reduced, the degree of systemic hypertension and the need for medications will also decrease. ACUTE ALLOGRAFT REJECTION: Rejection typically occurs in the first few months following liver transplantation [20,21]. Rejection is less probable with the passage of time [22] and may follow a reduction in the level of immunosuppression. While progressive elevation of liver tests (both aminotransferase and gamma-glutamyl transpeptidase levels) can be a clue to the presence of allograft rejection, only liver biopsy can provide a definitive diagnosis [23,24]. Because late elevation of liver tests might also indicate biliary problems, an ultrasound examination should be completed prior to liver biopsy to look for bile duct dilation. It may even provide clues to the presence of rejection [25]. Patients with acute allograft rejection are treated with: (a) intravenous (IV) corticosteroid boluses; (b) a recycle of high-dose IV steroids over 6 days; or (c) an intravenous antilymphocyte globulin, such as OKT3 [ 14,26281. Response is monitored by a reduction in liver tests or confirmation of control of rejection by liver biopsy. Whereas steroid recycles can often be accomplished at the primary care center, administration of OKT3 with its attendant side effects and greater risk of opportunistic infection usually dictates that it be administered at the transplant center. RENAL DYSFUNCTION: Although it is not a contraindication to operation [29], preexisting renal failure can have an adverse effect on outcome of patients following liver transplantation [30,31]. Hemodialysis is utilized until acute renal failure recovers following transplantation [32]. CsA frequently results in renal dysfunction [33], as it reduces intrarenal vascular perfusion and glomerular filtration [34]. However, renal function tends to remain stable over long periods of time [35]. Thus, serum creatinine and urea nitrogen levels should be monitored closely, though need for intervention is usually limited. As CsA dosage is reduced, some improvement in creatinine and urea nitrogen levels may follow. Patients receiving CsA are sensitive to dehydration, and increases in creatinine may respond to extra oral fluid intake. CsA can also induce hyperkalemia; intermittent administration of kayexalate may be necessary. OPPORTUNISTIC INFECTION: IllfeCtiOUS COmpliCations of liver transplantation are most frequent in the first 2-3 months following liver transplantation [11,36]. Bacterial infections are the most common infection in the early postoperative interval [37] and can be a cause of early postoperative mortality [38]. Risk factors for bacterial infections include lA-14s
operation duration, high preoperative bilirubin levels, prior biliary tract surgery, retransplantation, roux-en-Y choledochojejunostomy, the need for postoperative dialysis, and a prolonged ICU stay [11,36,39,40]. Viral, fungal, and protozoa1 infections also develop, though only pneumocystis infection is more likely to occur after the first 2 months [ll]. Administration of oral antibiotic combinations in the perioperative period may reduce bacterial and fungal infections [41]. Cytomegalovirus (CMV) disease will occur in approximately 35% of liver transplant recipients [42] and is more likely if a CMV seronegative recipient receives an organ from a CMV-positive donor. It is also more frequent following retransplantation or with administration of antilymphocyte antibody preparations for control of acute cellular rejection [42,43]. CMV seronegative patients should receive CMV-negative blood products before and during liver transplantation and, if possible, a CMV-negative donor organ should also be utilized. CMV disease typically begins within 60 days of transplantation, but it can be a late cause of allograft dysfunction. In our series, onset as late as 290 days was observed [421. Symptoms of CMV disease can include fever, leukopenia, pneumonia, diarrhea, or hematochezia from CMV colitis, nausea, and vomiting due to gastroparesis from CMV gastroduodenitis, or increased liver tests as a consequence of CMV hepatitis. CMV infection of the liver is the most frequent and can be identified by histologic examination (clusters of polymorphonuclear leukocytes about hepatocytes with characteristic nuclear inclusions) and/or viral culture [42,441. Acyclovir is utilized for the first 3 months following transplantation in an effort to reduce CMV infection. In addition, if a patient receives either a CMV seropositive donor organ or OKT3 for control of rejection, we administer prophylactic ganciclovir. If CMV disease should develop, ganciclovir is generally effective in control [45,46]. Fungal infections result in disseminated infection, peritonitis, pneumonitis, fungemia, or colonization [47-491 and are more likely with retransplantation, multiple transfusions, roux-en-Y anastomoses, preoperative steroid use, vascular complications, and use of antibiotics, or when transplantation is urgent [47]. Selective bowel decontamination [41] and low-dose intravenous amphotericin B [503 may reduce the risk of fungal disease. Pneumocystis ccwinii infections are characteristically late in onset. While most occur within 6 months of transplantation 1111, we have seen it develop later. Thus, we continue trimethoprimsulfamethoxazole or aerosolized pentamidine prophylaxis for a total of 12 months. If a patient devel-
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ops progressive dyspnea or interstitial infiltrates, bronchoalveolar lavage for pneumocystis identification should be immediately completed. BILE DUCT DISEASE: Early biliary dysfunction may be a consequence of hepatic artery occlusion, which results in breakdown of the biliary anastomosis or biliary necrosis [51,52], technical factors [53], or strictures [54]. If hepatic artery occlusion is suspected, Doppler ultrasonography is useful to identify its presence [55]; urgent hepatic artery reconstruction and thrombectomy is required [56]. Other biliary leaks can often be managed by placement of a nasobiliary tube [5’73 or intraductal stent [58]. Patients with biliary necrosis from hepatic artery occlusion may require repetitive percutaneous dilation of strictures or long-term placement of intrabiliary stents [59,60]. Bile duct strictures develop in up to 20% of recipients at either the site of the duct-to-duct or rouxen-Y anastomosis [59]. Management can include dilation or stenting of the stricture or conversion of the choledochostomy to a roux-en-Y anastomosis [59]. If a transplant patient develops increases in gamma-glutamyl transpeptidase, alkaline phosphatase, or bilirubin levels, biliary obstruction must be considered and evaluated by ultrasonography and/ or cholangiography. In patients with duct-to-duct anastomoses, a T-tube is left in place for 6 months. Despite this length of time, the T-tube tract may still be poorly formed, and bile leaks can occur following its removal. Patients with T-tube leaks should be hospitalized, to receive broad-spectrum antibiotics and pain control. Although many will spontaneously close the bile duct leak, some will require placement of nasobiliary drainage or stents [5’7,58], and an occasional patient will need operative intervention to control the leak. CHRONIC ALLOGRAFT REJECTION: Chronic allograft rejection will develop in approximately 5% of recipients [21] and is a cause of late graft failure 1611. It may follow early episodes of acute cellular rejection that are unresponsive to therapy. Chronic rejection is characterized by persistent abnormalities of liver tests and increasing cholestasis, with or without a significant decline of synthetic function [62]. A liver biopsy will identify mononuclear portal inflammation, arteriopathy, centrilobular cholestasis, and a reduction in interlobular bile duct numbers 1621. Retransplantation may be required, although some patients with chronic ductopenic rejection spontaneously resolve [63,64]. DISEASE
RECURRENCE:
LOIlg-tH-III
follow-Up
Of
the liver transplant patient should include a watchful eye for recurrence of the primary indication for liver transplantation. Hepatitis B virus disease [6],
hepatocellular carcinoma 161, hepatic C virus infection [65], autoimmune chronic hepatitis [66], primary biliary cirrhosis [671, and cholangiocarcinoma [6] have all been suggested to recur. Hepatocellular carcinoma has even been identified in a recipient who developed recurrent HBV infection of the allograft [68]. NEoPLAsiA: Several types of tumors are more common in the immunosuppressed patient [14]. Squamous cell carcinomas of the cervix, vulva, perineum, skin, and lip are more frequent than in the general population. Sun exposure adds to the risk of skin carcinomas. Lymphoproliferative disorders (non-Hodgkin’s lymphomas) are usually of B-cell origin and a consequence of Epstein-Barr virus (EBV) infection 169-711. They are increased 30-fold in frequency following immunosuppression and are typically extranodal in location. They usually involve the liver and gastrointestinal tract, though other sites of disease may also be noted. Treatment is the discontinuance of immunosuppression and acyclovir. Long-term Care OFFICE FOLLOW-UP: When the patient is discharged from the transplant center, the primarycare physician (gastroenterologist or internist) should begin routine, systematic clinical follow-up. This may be more frequent during the first year, and eventually only one or two visits each year is all that is needed. However, any new complaints from the patient should be heeded. If there are any doubts as to their significance, the transplant center can be called to discuss the problem. A routine history and physical should be completed each year. This should include a cervical Pap smear (women), rectal examination, and stool guaiac testing. Because of the use of long-term corticosteroids and the risk of cataracts, an annual eye examination should be provided. Routine dental evaluations should be scheduled because of periodontal disease with immunosuppression. Other screening tests should include annual mammograms for women and flexible sigmoidoscopies every 3 years for both men and women. LABORATORY TESTS: Each patient requires repetitive blood tests, including a complete blood count, liver profile (aminotransferases, gamma-glutamyl transpeptidase, alkaline phosphatase, and bilirubins), electrolytes, cyclosporin (or FK506) level, blood urea nitrogen, and creatinine. These values are sent to the transplant center and reviewed. If there are concerns, the transplant center will notify the patient of the need to have repeat lab tests. If rejection or biliary injury seems possible, the patient will either be brought to the transplant center
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for further evaluation or the workup will be arranged through the primary-care gastroenterologist. In the early months following liver transplantation, the workup will usually be completed at the center. ETHANOL USE: The use of alcoholic beverages is discouraged following transplantation. For the patient with prior alcoholism, recidivism is a continuing concern, and ethanol use is forbidden. Intervention with referral to an alcohol counseling center may be required, if alcohol use resumes. For nonalcoholic patients, ethanol might cause fluctuation of aminotransferases and interfere with the evaluation of allograft function. SEXUAL ISSUES: It is important to discuss sexual issues early following transplantation. Initial contraception is recommended for all. While normal pregnancy may be possible for female recipients, pregnancy carries risks and should be delayed until there has a been a return to normal life and activity. In men, spermatogenesis may improve following their transplantation, and an unwanted pregnancy may develop in the partner. There is little information regarding pregnancy in liver transplant patients. However, reports from studies of kidney transplant patients indicate that normal pregnancy is possible, although there is an increased risk of premature labor, pre-eclampsia, and neonatal hyperbilirubinemia [14]. Of 246 pregnancies in kidney recipients, 82% resulted in live births, though 58% were premature and 38% of the newborns had low birth weights. Of the remainder, 11% ended in miscarriage and 2% were stillborn. Therapeutic abortion was carried out in 5% of the patients who became pregnant. These data indicate that pregnancy following kidney transplantation is of higher risk than normal. It seems likely that liver allograft recipients would have similar outcomes. If the transplant recipient becomes pregnant, prenatal care should be provided by an obstetrician skilled in high-risk obstetrics. RECIPIENT TRAVEL: Travel by the liver transplant recipient is acceptable. However, the itinerary should be made available to the transplant center as soon as possible so that arrangements for continued lab tests can be made. In addition, transplant centers near the destination can be identified and addresses provided to the patient for emergency care, if needed. COMMUNICATION: Communication among the transplant center, the patient, and the referring physician are essential to the long-term success of the liver allograft and transplant patient. The transplant center should be called if the referral physician has any doubts about the continuing care of the recipient. The center should always be called lA-16s
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if there are persisting complications or new illnesses, such as poorly controlled hypertension, dyspnea, interstitial pneumonitis, chronic cough, worsening azotemia or liver tests, or continuing headaches.
SUMMARY It could be said that the patient who undergoes liver transplantation for end-stage liver disease simply exchanges one serious disorder for another that requires equally demanding care. However, most liver transplant patients do well once they are able to return to their homes. They simply need careful, thoughtful, and continuing follow-up by their primary-care physician and the liver transplant center. Communication among the patient, the primary-care physician, and the transplant center is essential to this successful outcome.
REFERENCES 1. Starzl TE, Demetris AJ, Van Thiel D. Liver transplantation (part 1). N Engl J Med 1989; 321: 1014-22. 2. Hockerstedt K. Liver transplantation today. Stand J Gastroenterol 1990; 25: l10. 3. Pirsch JD, Kalayoglu M, D’Alessandro AM, et al. Orthotopic liver transplantation in patients 60 years of age and older. Transplantation 1991; 51: 431-3. 4. Yokoyama I, Carr B, Saitsu H, lwatsuki S, Starzl TE. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer 1991; 68: 2095-100. 5. Starzl TE, Demetris AJ, Van Thiel D. Liver transplantation (part 2). N Engl J Med 1989; 321: 1092-g. 6. Hart J, Busuttil RW, Lewin KJ. Disease recurrence following liver transplantation. Am J Surg Pathol 1990; 14: 79-91. 7. Didier S, Bismuth A, Mathieu D, et al. Passive immunoprophylaxis after liver transplantation in HBsAg positive patients. Lancet 1991; 337: 813-5. 8. Mora NP, Klintmalm GB, Solomon H, Goldstein RM, Gonwa TA, Husberg BS. Survival after liver transplantation in 300 consecutive patients: the influence of age, clinical status, and pretransplant disease. Transplant Proc 1992; 24: 156-7. 9. Donovan JP, Zetterman RK, Burnett DA, Sorrel1 MF. Preoperative evaluation, prep aration, and timing of orthotopic liver transplantation in the adult. Sem Liv Dis 1989; 9: 168-75. 10. Klompmaker IJ, Haagsma EB, Gouw ASH, Verwer R, Slooff MJH. Azathroprine and prednisolone immunosuppression versus maintenance triple therapy including cyclosporine for orthotopic liver transplantation. Transplantation 1989; 48: 814-8. 11. Kusne S, Dummer JS, Singh N, et al. Infections after liver transplantation. Medicine 1988; 67: 132-43. 12. Stratta RJ, Shaefer MS, Cushing KA, et al. Successful prophylaxis of cytomegalovirus disease after primary CMV exposure in liver transplant recipients. Transplantation 1991; 51: 90-7. 13. Leoung GS, Feigal DW, Montgomery AB, et al. Aerosolized pentamidine for pro phylaxis against Pneumocystis carinii pneumonia. N Engl J Med 1990; 323: 769-82. 14. Shaw SW, Stratta RJ, Donovan JP, Langnas AN, Wood RP, Markin RJ. Postoperative care after liver transplantation. Sem Liv Dis 1989; 9: 202-30. 15. Neuberger J, Williams R. Long-term use of cyclosporin in liver grafting. In: Calne R, ed. Liver Transplantation, 2nd ed. London: Grune and Stratton, 1987; 319-27. 16. Busuttil RW, Colonna JO, Hiatt JR, et al. The first 100 liver transplants at UCLA. Ann Surg 1987; 206: 387-402. 17. NobleJamieson G, Barnes ND, Thiru S, Mowat AP. Severe hypertension after liver transplantation in antitrypsin deficiency. Arch Dis Childhood 1990; 65: 121721. 18. Ringe 8, Bechstein WO, Bunzendahl H, Wonigeit K, Frei U, Pichlmayr R. Chronic renal dysfunction and hypertension after hepatic transplantation in adults treated with cyclosporine A. Transplant Proc 1988; 20: 639-41. 19. Mark AL. Cyclosporine, sympathetic activity, and hypertension. N Engl J Med 1990; 323: 748-50.
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20. Adams D. Mechanisms of liver allograft rejection in man. Clin Sci 1990; 78: 343-50. 21. Klinfmalm GBG, Nery JR, Husberg BS, Gonwa TA, Tillery GW. Rejection in liver transplantation. Hepatology 1989; 10: 978-85. 22. Nakhleh RE, Schwarzenberg SJ, Bloomer J, Payne W, Snover DC. The pathology of liver allografts surviving longer than one year. Hepatology 1990; 11: 465-70. 23. Colina F, Mollejo M, Moreno E, et al. Effectiveness of histopathological diagnoses in dysfunction of hepatic transplantation. Arch Pathol Lab Med 1991; 115: 9981005. 24. Demetns Al, Qian S, Sun H, Fung JJ. Liver allograft rejection: an overview of morphologic findings. Am J Surg Pathol 1990; 14: 49-63. 25. Marder DM, DeMarino GB, Sumkin JH, Sheahan DG. Liver transplant rejection: value of the resistive index in doppler US of hepatic arteries. Radiology 1989; 173: 127-9. 26. Klintmalm GB. Rejection therapies. Dig Dis Sci 1991; 36: 1431-3. 27. Esquivel CO, Fung JJ, Markus B, et al. OKT3 in the reversal of acute hepatic allograft rejection. Transplant Proc 1987; 29: 2443-6. 28. Colonna JO, Goldstein LI, Brems JJ, et al. A prospective study on the use of monoclonal anti-T3cell antibody fOKT3) to treat steroid-resistant liver transplant re jection. Arch Surg 1987; 122: 1120-3. 29. Gonwa TA, Klintmalm GB, Hugsberg BS, Olson L, Nery J, Roden J. Liver transplantation in patients with preexisting acuteand chronic renal failure. Transplant Proc 1988; 20: 561-3. 30. Brems JJ, Hiatt JR, Colonna JO, etal. Variables influencing the outcome following orthotopic liver transplantation. Arch Surg 1987; 122: 1109-11. 31. McCauley J, Van Thiel DH, Starzl TE, Puschett JB. Acute and chronic renal failure in liver transplantation. Nephron 1990; 55: 121-8. 32. Wilson MV, Knight TF, Shaw BW, Wood RP. The use of nonheparinized hemodialysis after orthotopic liver transplantation-the University of Nebraska Medical Center experience. Transplant Proc 1988; 20: 634-6. 33. Klintmalm GBG, lwatsuki S, Starzl TE. Nephrotoxicity of cyclosporin A in liver and kidney transplant patients. Lancet 1981; i: 470-l. 34. Laskow DA, Curtis JJ, Luke RG, et al. Cyclosporineinduced changes in glomerular filtration rate and urea excretion. Am J Med 1990; 88: 497-502. 35. Bantle JP, Paller MS, Boudreau RJ, Olivari MT, Ferris TF. Long-term effects of cyclosporine on renal function in organ transplant recipients. J Lab Clin Med 1990; 115: 233-40. 36. Colonna JO, Winston DJ, Brill JE, et al. Infectious complications in liver transplantation Arch Surg 1988; 123: 360-4. 37. Corti A, Sabbadini D, Pannacciulli E, et al. Early severe infections after orthotopic liver transplantation. Transplant Proc 1991; 23: 1964. 38. Markin RS, Stratta RJ, Woods GL. Infection after liver transplantation. Am J Surg Pathol 1990; 14: 64-78. 39. George DL, Arnow PM, Fox AS, et al. Bacterial infection as a complication of liver transplantation: epidemiology and risk factors. Rev Infect Dis 1991; 13: 387-96. 49. Martin M, Kusne S, Alessiani M, Simmons R, Starzl TE. Infections after liver transplantation: risk factors and prevention. Transplant Proc 1991; 23: 1929-30. 41. Rossaint R, Raakow R, Lewandowski K, et al. Strategy for prevention of infection after orthotopic liver transplantation. Transplant Proc 1991; 23: 1965-6. 42. Stratta RJ, Shaefer MS, Markin RS, et al. Clinical patterns of cytomegalovirus disease after liver transplantation. Arch Surg 1989; 124: 1443-50. 43. Rakela J, Wiesner RH, Taswell HF, et al. Incidence of cytomegalovirus infection and its relationship to donor-recipient serologic status in liver transplantation. Transplant Proc 1987; 19: 2399-402. 44. Snover DC, Hutton S, Balfour HH, Bloomer JR. Cytomegalovirus infection of the kver In transplant recipients. J Clin Gastroenterol 1987; 9: 659-65. 45. Salmela K, Hockerstedt K, Lautenschlager I, et al. Ganciclovir in the treatment of severe cytomegalovirus disease in liver transplant patients. Transplant Proc 1990; 22: 238-40. 46. Shaefer MS, Stratta RJ, Markin RS, et al. Ganciclovir therapy for cytomegalovirus disease in liver transplant recipients. Transplant Proc 1991; 23: 1515-6. 47. Castaldo P, Stratta RJ, Wood RP, et al. Clinical spectrum of fungal infections after orthotopic liver transplantation. Arch Surg 1991; 126: 149-56. 48. Tollemar J, Ericzon BG, Holmberg K. Andersson J. The incidence and diagnosis
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of invasive fungal infections in liver transplant recipients. Transplant Proc 1990; 22: 242-4. 49. Kusne S, Dummer JS, Singh N, et al. Transplant Proc 1988; 20: 650-l. 59. Mora NP, Klintmalm G, Solomon H, Goldstein RM, Gonwa TA, Husberg BS. Selective amphotericin B prophylaxis in the reduction of fungal infections after liver transplant. Transplant Proc 1992; 24: 154-5. 51. D’Alessandro AM, Kalayoglu M, Pirsch JD, et al. Biliary tract complications after orthotopic liver transplantation. Transplant Proc 1991; 23: 1956. 52. Zajko AB, Campbell WL, Logsdon GA, et al. Biliary complications in liver allo grafts after hepatic artery occlusion: a 6.5 year study. Transplant Proc 1988; 20: 607-9. 53. Lerut J, Gordon RD, lwatsuki S, et al. Biliary tract complications in human orthotopic liver transplantation. Transplantation 1987; 43: 47-51. 54. Evans RA, Raby ND, O’Grady JG, et al. Biliary complications following orthotopic liver transplantation. Clin Radiology 1990; 41: 190-4. 55. Langnas AN, Marujo W, Stratta RJ, Wood RP, Shaw BW. Vascular complications after orthotopic liver transplantation. Am J Surg 1991; 161: 76-83. 56. Langnas AN, Marujo W, Stratta RJ, Wood RP, Li S, Shaw BW. Hepatic allograft rescue following arterial thrombosis. Transplantation 1991; 51: 86-90. 57. O&off JW, Roberts JP, Gordon RL, Ring EJ, Ascher NL. The management of T tube leaks in orthotopic liver transplant recipients with endoscopically placed nasobiC iary catheters. Transplantation 1990; 49: 922-4. 58. Ward EM, Wiesner RH, Hughes RW, Krom RAF. Persistent bile leak after liver transplantation: biloma drainage and endoscopic retrograde cholan giopancreatographic sphincterotomy. Radiology 1991; 179: 719-20. 59. Stratta RJ, Wood RP, Langnas AN, et al. Diagnosis and treatment of biliary tract complications after orthotopic liver transplantation. Surgery 1989; 106: 675-84. 60. Ward EM, Kiely MJ, Maus TP, Wiesner RH, Krom RAF. Hilar biliary strictures after liver transplantation: cholangiography and percutaneous treatment. Radiology 1990; 177: 259-63. 61. Quiroga J, Colina I, Demetris AJ, Starzl TE, Van Thiel DH. Cause and timing of first allograft failure in orthotopic liver transplantation: a study of 177 consecutive patients. Hepatology 1991; 14: 1054-62. 62. Freese DK, Snover DC, Sharp HL, Gross CR, Savick SK, Payne WD. Chronic rejection after liver transplantation: a study of clinical, histopathological and immune logical features. Hepatology 1991; 13: 882-91. 63. Hubscher SG, Buckels JAC, Elias E, McMaster P, Neuberger J. Vanishing bileduct syndrome following liver transplantation-is it reversible?Transplantation 1991; 51: 1004-10. 64. Noack KB, Wiesner RH, Batts K, van Hoek B, Ludwig J. Severe ductopenic rejection with features of vanishing bile duct syndrome: clinical, biochemical, and histologic evidence for spontaneous resolution. Transplant Proc 1991; 23: 144851. 65. Poterucha JJ, Rakela J, Lumeng L, Lee C-H, Taswell HF, Wiesner RH. Diagnosis of chronic hepatitis C after liver transplantation by the detection of viral sequences with polymerase chain reaction. Hepatology 1992; 15: 42-5. 66. Wright HL, BouAbboud CF, Hassanein T, et al. Disease recurrence and rejection following liver transplantation for autoimmune chronic active hver disease. Transplantation 1992; 53: 136-9. 67. Dietze 0, Vogel W, Margreiter R. Primary biliary cirrhosis LPBC) after liver transplantation. Transplant Proc 1990; 22: 1501-2. 68. Luketic VA, Shiffman ML, McCall JB, Posner MP, Mills AS, Carithers RL. Primary hepatocellular carcinoma after orthotopic liver transplantion for chronic hepatitis B infection. Ann Intern Med 1991; 114: 212-13. 69. Langnas AN, Castaldo P, Markin RS, Stratta RJ, Wood RP, Shaw BW. The spectrum of Epstein-Barr virus infectron with hepatitis following liver transplantation. Transplant Proc 1991; 23: 1513-4. 70. Randhawa PS, Markin RS, Starzl TE, Demetris AJ. Epstein-Barr virus-associated syndromes in immunosuppressed liver transplant recipients. Am J Surg Patholl990; 14: 538-47. 71. Nalesnik MA. Involvement of the gastrointestinal tract by Epstein-Bar virusassociated posttransplant lymphoproliferative disorders. Am J Surg Pathol 1990; 14: 92-100.
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