Pediatric Annals

Liver Transplantation

David H Van Thiel, MD

Abstract

Ever since the NIH consensus conference on liver transplantation which was held in June 1983, liver transplantation has become accepted as standard therapy for a variety of advanced chronic liver diseases both in children and adults.1 Since then, most state medicaid programs, medicare, the armed forces, the Civilian Health and Medical Program of the Uniformed Services (CHAMPUS), the Veterans Administration and most medical insurance programs including Blue Cross/Blue Shield have either paid for the procedure or have acknowledged their willingness to do so. As a result of such widespread willingness to finance the procedure, liver transplantation programs have become increasingly more evident and are presently functioning at many medical centers throughout the country. As might be expected, at a point in time of proliferating programs and evolving indications for the procedure, considerable controversy presently exists as to who might be a candidate for liver transplantation, what specifically the preoperative evaluation should consist of and when the procedure should be offered and performed on a given candidate. The following are my own prejudices developed as a consequence of being involved intimately in a liver transplant program over the last 5 years at the University of Pittsburgh.

INDICATIONS FOR AND PROGNOSIS FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION (OLT)

The indications for orthotopic liver transplantation are conceptualized best as being segregated into three types of hepatic diseases. In order of their acceptance by others in the field they are:

1) chronic advanced end stage liver disease

2) hepatic cancer

3) fulminant hepatic failure

These three rather large generic indications for the performance of the procedure differ remarkably in terms of their short- and long-term prognosis following the procedure, the clinical presentation of the patient at the moment of transplantation, the urgency of its application, the specific diseases or conditions which are included in each, and finally the age of the candidate.

Specifically, in terms of both short- and long-term prognosis, children do better than do adults. Thus, the survival rates reported by most centers doing both pediatric and adult cases consistently demonstrate a 10% to 15% better overall survival rate for children as compared to adults. Most programs can achieve a 75% to 80% 1-year survival rate for children and recently one program has reported a 1-year survival rate of 90% for children. In contrast, the overall 1year survival rate for adults usually is between 50% to 70% depending upon the program and the kind of patients being operated on at a given institution.

Interestingly, a factor such as prior surgery has little if any impact on the overall prognosis for survival in children following liver transplantation but has a substantial effect in adult recipients. Thus, adults with prior hepatobiliary or major abdominal surgery (particularly biliary drainage procedures, portacaval shunting procedures, and total colectomy with an ileostomy) have an overall 10% to 15% poorer immediate prognosis as compared to adults without such prior surgical procedures.

Not unexpectedly, patients with a principally cholestatic chronic liver disease such as primary biliary cirrhosis or sclerosing cholangitis (in adult cases) and biliary atresia (in the pediatric experience) do better than similarly aged patients with hepatocellular diseases such as post-necrotic cirrhosis due to any of the usual causes including prior viral disease, cryptogenic, autoimmune, or neonatal hepatitis. Moreover, patients with advanced hepatocellular failure, with major synthetic deficits such as those with welladvanced alpha- 1-antitrypsin deficiency do less well than those with otherwise similarly severe advanced fibrotic liver disease complicated by portal hypertension such as the candidates with post-necrotic cirrhosis.

THE PREOPERATIVE EVALUATION

A reasonable guide for the preoperative evaluation of potential liver transplant recipients has been reported by lwatsuki et…

Ever since the NIH consensus conference on liver transplantation which was held in June 1983, liver transplantation has become accepted as standard therapy for a variety of advanced chronic liver diseases both in children and adults.1 Since then, most state medicaid programs, medicare, the armed forces, the Civilian Health and Medical Program of the Uniformed Services (CHAMPUS), the Veterans Administration and most medical insurance programs including Blue Cross/Blue Shield have either paid for the procedure or have acknowledged their willingness to do so. As a result of such widespread willingness to finance the procedure, liver transplantation programs have become increasingly more evident and are presently functioning at many medical centers throughout the country. As might be expected, at a point in time of proliferating programs and evolving indications for the procedure, considerable controversy presently exists as to who might be a candidate for liver transplantation, what specifically the preoperative evaluation should consist of and when the procedure should be offered and performed on a given candidate. The following are my own prejudices developed as a consequence of being involved intimately in a liver transplant program over the last 5 years at the University of Pittsburgh.

INDICATIONS FOR AND PROGNOSIS FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION (OLT)

The indications for orthotopic liver transplantation are conceptualized best as being segregated into three types of hepatic diseases. In order of their acceptance by others in the field they are:

1) chronic advanced end stage liver disease

2) hepatic cancer

3) fulminant hepatic failure

These three rather large generic indications for the performance of the procedure differ remarkably in terms of their short- and long-term prognosis following the procedure, the clinical presentation of the patient at the moment of transplantation, the urgency of its application, the specific diseases or conditions which are included in each, and finally the age of the candidate.

Specifically, in terms of both short- and long-term prognosis, children do better than do adults. Thus, the survival rates reported by most centers doing both pediatric and adult cases consistently demonstrate a 10% to 15% better overall survival rate for children as compared to adults. Most programs can achieve a 75% to 80% 1-year survival rate for children and recently one program has reported a 1-year survival rate of 90% for children. In contrast, the overall 1year survival rate for adults usually is between 50% to 70% depending upon the program and the kind of patients being operated on at a given institution.

Interestingly, a factor such as prior surgery has little if any impact on the overall prognosis for survival in children following liver transplantation but has a substantial effect in adult recipients. Thus, adults with prior hepatobiliary or major abdominal surgery (particularly biliary drainage procedures, portacaval shunting procedures, and total colectomy with an ileostomy) have an overall 10% to 15% poorer immediate prognosis as compared to adults without such prior surgical procedures.

Not unexpectedly, patients with a principally cholestatic chronic liver disease such as primary biliary cirrhosis or sclerosing cholangitis (in adult cases) and biliary atresia (in the pediatric experience) do better than similarly aged patients with hepatocellular diseases such as post-necrotic cirrhosis due to any of the usual causes including prior viral disease, cryptogenic, autoimmune, or neonatal hepatitis. Moreover, patients with advanced hepatocellular failure, with major synthetic deficits such as those with welladvanced alpha- 1-antitrypsin deficiency do less well than those with otherwise similarly severe advanced fibrotic liver disease complicated by portal hypertension such as the candidates with post-necrotic cirrhosis.

What then are the criteria for considering a given patient with advanced chronic liver disease as being a candidate for the procedure? The criteria are quite simple. In order for a given patient to be a legitimate candidate for orthotopic hepatic transplantation because of chronic advanced liver disease he or she should have two of the following four criteria2:

1) a total bilirubin level of 15 mg/dl or more,

2) a prothrombin time which is uncorrectable and greater than the control by 5 seconds,

3) a serum albumin of 2.5 g/dl or less,

4) hepatic encephalopathy which prevents the individual from functioning at his normal level, despite full medical therapy with lactulose ± neomycin and a protein-restricted diet.

There are several circumstances that override these major indications for liver transplantation in a given individual patient. First, given a choice between doing a portacaval shunting procedure or a liver transplant in a patient 50 years of age or less, I would opt for a transplant; second, patients with advanced, usually cholestatic liver disease who begin to experience either severe unrelenting bone pain or spontaneous fractures should be offered transplantation before they become permanently disfigured as a result of their bone disease; third, patients with advanced cholestatic liver disease with severe pruritus which is incapacitating to the point of being a cause for suicidal ideation should be offered liver transplantation, regardless of the other factors identified above.

A unique form of "chronic liver disease" in children for which liver transplantation should be considered early, even in the absence of overt structural liver disease and certainly before the development of associated irreversible metabolic or neurologic disease, consists of the numerous liver-based metabolic diseases of children such as the Crigler-Najjar syndrome, protoporphyria, the glycogen storage diseases (types I and IV), the various recognized enzymatic deficiencies of the urea cycle, tyrosinemia, long and short chain fatty acid acyltransferase deficiencies, cerebrotendinous xanthomatosis, various as yet ill-defined enzymatic deficits in bile acid biosynthesis, and homozygous type two hyperlipoproteinemia.3 A similar group of childhood metabolic diseases, but as yet less clearly amenable to liver transplantation because of their involvement of extrahepatic organs, are the various lipid storage diseases and glycolipidoses such as Gaucher's disease. Niemann- Pick disease, Sea blue histiocytosis, Wolman's disease, etc. Certainly liver transplantation improves the immediate plight of some children with such diseases but its role in the long-term management of such diseases is as yet most uncertain. Whether the immediate improvement observed in such cases continues sufficiently long enough to justify the performance of the procedure remains to be determined.

Both the prognosis and indications for liver transplantation in patients with hepatic cancer differ considerably from those identified for patients with chronic advanced liver disease. Specifically, the immediate perioperative prognosis for such patients is usually excellent and approaches, if not surpasses, that reported for previously unoperated patients with cholestatic liver disease, ie, 80% to 90% at 1 year. The long-term prognosis, however, is less hopeful, ie, 50% at 2 years. This occurs despite careful pretransplantation evaluations to identify pre-existent metastases including CT scanning, sonography and occasionally arteriography and/or laparotomy. Fifty percent or more of such patients will have an overt recurrence of their original disease in 1 to 3 years and will ultimately the as a result.4,5 Nonetheless, the remaining few do quite well and justify continued performance of the procedure in cases of hepatoma, particularly fibrolamellar hepatomas, but not in cases of cholangiolar carcinoma. I have never seen a patient with cholangiolar carcinoma who has received a liver transplant and survived for more than 1 year without overt evidence of recurrent disease. As a result of this dismal experience, I do not think the procedure is justified in such cases except under experimental protocols.

The very successful immediate or short-term survival in patients with hepatic cancer reflects the fact that hepatic function is generally well maintained in such cases and that portal hypertension is usually not a concomitant problem. Thus, in contrast to the usual situation with advanced chronic liver disease, surgery is rather easy to perform in the patients with hepatic cancer as compared to those with hepatocellular failure and portal hypertension. Liver transplantation for hepatic cancer should only be applied to those patients in whom primary tumor resection is not possible.

The newest and therefore least clear-cut situation for which liver transplantation has been applied, at least currently, is the circumstance of fulminant hepatic failure. This indication encompasses as diffuse a group of diseases as does the first indication, chronic advanced liver disease. Thus, for example fulminant Wilson's disease, fulminant viral hepatitis (A, B, Non-A, Non-B), fulminant drug induced liver disease (valproic acid, disulfiram, gold, etc.), fulminant toxin exposure (industrial solvents, pesticides, mushroom poisoning, etc. ), and fulminant idiopathic diseases such as Stage 3 or 4 Reye's syndrome and acute fatty liver of pregnancy are in this category. The prognosis for survival in such cases is determined in large measure by the pace of the primary liver disease rather than the surgical procedure per se. Thus, whether an acceptable donor organ can be identified and harvested quickly enough; whether the medical support systems available can maintain such potential recipients until a donor organ is found; and the intrinsic course of the primary liver disease are the major determining factors for the overall survival of such patients. Logistic rather than technical problems are the major determinants of success in such cases. A summary of our experience in Pittsburgh in such cases is shown in Table 1. Obviously, in cases of fulminant hepatic failure due to type A, B, Non-A, Non-B or delta agent hepatitis, the risk of recurrence in the newly transplanted organ is substantial and may be as high as 100%. Fortunately, recurrent disease is not the equivalent of fulminant disease and despite very high rates of recurrent disease, long-term survival is possible and should be expected in such cases assuming a donor organ can be identified and harvested in sufficient time to allow for successful grafting. Although the data are not yet available to support such a conclusion, it is not unreasonable to assume that recurrent fulminant hepatitis in such patients should be quite rare and be equal to that reported to occur in the population at large (0. 1%), as the donor organ is immunologically different from that of the host and more appropriately reflects the susceptibility of the population at large rather than that of the recipient for such an occurrence.

Table

TABLE 1LIVER TRANSPLANTATION EXPERIENCE WITH FULMINANT HEPATIC FAILURE

TABLE 1

LIVER TRANSPLANTATION EXPERIENCE WITH FULMINANT HEPATIC FAILURE

Table

TABLE 2PREOPERATIVE EVALUATION OP POTENTIAL UVER TRANSPLANT RECIPIENTS

TABLE 2

PREOPERATIVE EVALUATION OP POTENTIAL UVER TRANSPLANT RECIPIENTS

THE PREOPERATIVE EVALUATION

A reasonable guide for the preoperative evaluation of potential liver transplant recipients has been reported by lwatsuki et al (Table 2).b With appropriate care being given to the state of hydration, renal status and presence or absence of encephalopathy, a complete evaluation of potential recipients is absolutely necessary. It is further indicated because many patients are referred to transplant centers with no specific diagnosis at all (20% to 30%), or worse, the incorrect diagnosis (20%); a legitimate estimate of the prognosis for such patients is not possible without a specific diagnosis. Thus the patient and his physicians may be forced to choose for or against proceeding with transplantation without sufficient data to make such an important decision. It is our practice to do all of the tests identified by lwatsuki6 with the exception that upper and lower gastrointestinal radiologic procedures are rarely, if ever, indicated. Colonoscopy is indicated in those cases with sclerosing cholangitis and in all cases complicated by lower gasrrointestinal bleeding. Angiography is reserved for cases of biliary atresia, because of the high frequency of vascular malformations in such children and cases in which the patency of the portal or hepatic veins cannot be derermined with less invasive techniques such as sonography or dynamic CT scanning. Cholangiography is performed only if insufficient data are available about the anatomy of the biliary tree or a concern about the presence or absence of cholangiolar carcinoma exists. The standard utilization of upper and lower gastrointestinal endoscopy provides important information concerning the presence or absence of portal venous collaterals and has led to the detection of previously occult gastric adenocarcinoma and colonic carcinoma which prohibited the performance of transplantation in patients with these lesions, who might otherwise have been transplanted.

PREOPERATIVE MANAGEMENT

Prior to the actual performance of surgery, the recipient should be free of all extrahepatic infection and have any intrahepatic or biliary tract infection either eliminated or maximally controlled. The patency of the portal vein must be known to the surgeon. Finally, the patient should be fully trained in the techniques of incentive spirometry and pulmonary hygiene, thereby enhancing the application of such techniques and care in the first 2 to 3 postoperative days.

OPERATIVE TECHNIQUES AND PROBLEMS

The utilization of a nonheparin containing vascular bypass system from the recipient's portal and left femoral veins to the recipient's left auxiliary vein has given the operating surgeon the opportunity to complete the ahepatic phase of the procedure while maintaining the recipient's cardiac output by returning the blood from the subdiaphragmatic portions of the body to the heart.7 This advance has reduced markedly the blood product requirements experienced by most patients during the procedure prior to its application.

A second surgical advance has been the standard utilization of a recipient to donor choledochocholedochostomy as the biliary anastomosis of choice. Whenever the donor's or the recipient's biliary tree is thought to be inadequate or uncertain, a recipient Roux-en-Y-jejunal loop to donor biliary tree is indicated as the biliary anastomatic procedure of choice.4

A third surgical advance has been the development of vascular grafting techniques to either replace or bypass a clotted portal vein or inadequate or anomalous arterial supply to the donor organ. 8,9 The former technique is useful also when a prior portacaval anastomosis has been performed and needs to be taken down during the transplant procedure.

POSTOPERATIVE PROBLEMS

The major postoperative problems that occur following orthotopic liver transplantation can be divided into those that occur immediately (0 to 24 hours), those that occur early (24 to 48 hours postoperatively), those that occur in the subacute period (2 to 12 days postoperatively) and those that occur after 13 days, or the late period. The major problems in the immediate (0 to 24 hour) postoperative period are those of vascular overload due to the "excessive" fluid and blood administration experienced during the surgical procedure itself. The judicial use of diuretics and antibiotics and care being taken as to the choice and rate of fluids and electrolytes to be administered during this critical postoperative period can make the difference between early extubation or increasing pulmonary insufficiency and adequate renal function or the requirement for either hemo- or peritoneal dialysis during subsequent postoperative periods.

During the early postoperative (24 to 48 hour) period, technical failure such as hepatic arterial or portal-vein thrombosis are the most urgent complications and usually signal graft failure. Any abnormality of hepatic function during this period should signal the need for urgent sonographic examination of the vessels for the presence of clot, pulsations and flow. If necessary, isotopie scanning techniques can be used as a confirmatory diagnostic technique to demonstrate the presence or absence of normal to enhanced hepatic blood flow during this period. Hepatic Xenon- 133 wash out studies may prove to be useful as well and currently are under evaluation at our institution. Should evidence of a vascular complication be obtained, subsequent efforts expended for early retransplantation are probably better spent than are putative efforts expended for repair of the vascular abnormality detected. 10 Such procedures usually fail and have a tremendous cost in terms of lost time, effort and life.

The major problems observed during the early postoperative period (36 to 48 hours) or during the early subacute postoperative period (2 to 5 days) are biliary tract dehiscence, leak, obstruction or sepsis and are best discovered by means of a t-tube cholangiogram, culture of bile or transhepatic cholangiography either before or after a DisidaTc-99m scan. Should a biliary tract complication be detected, conversion to a Roux-en-Y bile duct to jejunal limb anastomosis is the operative procedure of choice.4 During the rest of the subacute period, 2 days to 12 days postoperatively, infection and progressive renal dysfunction are the two most common clinical problems and frequently occur together or are a consequence of therapy directed toward the other. Meticulous attention to the fever record, abdominal wall or hepatic tenderness, the suture line or drainage discoloration or change in character, and any change in chest wall expansion should signal the physician to search for a source of infection. Should the usual techniques of sputum/ urine examination, chest x-ray and blood and other fluid cultures fail to identify a source for the fever, sonographic and CT techniques may be helpful. Should the source of the infection still not be localized, laparotomy is indicated.

After 12 days during the late period, rejection is the major clinical problem. Of course, any pre-existing clinical problem can either mask or complicate rejection during this period. The best method for diagnosing rejection and also for eliminating other causes of postoperative problems such as CMV or Herpes hepatitis, biliary obstruction, cholangitis, new or recurrent type B or Non-A Non-B hepatitis is a liver biopsy.11-13 The serum level of gamma glutamyl transpeptidase is also quite useful at this time as levels > 500 IU/1 usually are associated with rejection or biliary tract obstruction, the latter of which can be examined easily with any of a variety of Cholangiographie techniques. If such Cholangiographie studies are negative, a liver biopsy is indicated.

POSTOPERATIVE CARE AND SUBSEQUENT FOLLOWUP

At our institution, following liver transplantation, patients are maintained in the surgical intensive care unit for 2 to 4 days, on average, until they are extubated and they are stabilized in terms of their vital signs and urinary output. At this time, measures of hepatic excretory function (serum bilirubin level) may show little change or only slight improvement, while measures of hepatic injury ie, SGOT (AST), SGPT (ALT) and alkaline phosphatase are quite variable. In contrast, evidence of hepatic function in terms of regulating intermediary metabolism, ie, maintaining normal blood glucose, blood ammonia and plasma amino acid levels and amino acid ratios, and synthetic function such as clotting factors, should be evident in uncomplicated cases.

Patients are transferred to the surgical ward for postoperative care as soon as they are stable and demonstrate consistent improvement in hepatic function. After 3 to 6 days a ttube cholangiogram is obtained to demonstrate an adequate biliary tree, free of strictures and leaks. Postoperatively, the patients usually are kept in the hospital for 6 weeks while drains are removed and their surgical incisions heal. After 6 weeks, they are discharged and are followed as outpatients on a weekly or twice weekly schedule as individually indicated for an additional 6 weeks. During this latter period they are educated as to the problems and concerns of their obligate lifelong immunosuppression therapy. At 12 weeks, patients are allowed to return to their home and to the primary care of their local referring physician. They still maintain monthly ( × 6) and then semiannual ( × 2) and finally annual followup visits thereafter.

IMMUNOSUPPRESSION

Presently, maintenance immunosuppression at the University of Pittsburgh consists of cyclosporine at 7 to 10 mg/kg/ day in two divided doses and IO to 20 mg prednisone per day.14 Rejection crises are managed by administering 1 g boluses of solumedrol or a 5-day burst of steroids eg 200, 160, 120, 80, 40 mg methylprednisone per day, in descending order. Should either no response or only a minor response occur, a course of monoclonal antibodies, developed to mature T lymphocytes (OKT3) usually is administered. New immunosuppressive agents and different courses of action are to be anticipated and will continue to be incorporated into the "state of the art" clinical management of transplant patients as they are developed and tried.

The preceding indications and course of action are not immutable or the only way, yet they represent my current practice which has been developed as a result of experience at the University of Pittsburgh.

REFERENCES

1. NIH Consensus Development Conference Statement: Liver Transplantation, June 20-23, 1983. Hepatology 1984; 4:107S-109S.

2. Van Thiel DH, Schade RR, Stani TE, et al: Liver transplantation in adults. Hematology 1982; 2:637-640.

3. Zitelli BJ, Malatack JJ, Gartner JGJ, et al: Orthotopic liver transplantation in children with hepatic based metabolic disorder. Transplant Proc: 1983; 15:1284-1287.

4. Stani TE, lwatsuki S, Van Thiel DH, et al: Evolution of liver transplantation. Hepatology 1982; 2:614-636.

5. Stani TE, lwatsuki S. Shaw BW Jr, et al: Treatment of fibrolamellar hepatoma with partial hepatectomy or with total hcpatectomv and liver transplantation. Surg Gynecol Obstet, to be published.

6. Iwatsuki S, Shaw BW Jr, Stani TE: Current status of hepatic transplantation. Semm Liver Dis 1983; 172-180.

7. Shaw BW Jr. Martin DJ, Marquez JM, et al: Venous bypass in clinical liver transplantation. Ann Surg 1984; 200:524-534.

8. Shaw BWJr, lwatsuki S, Bron K. et al: Portal vein grafts in hepatic transplantation. Surg Gynecol Obstet, to be published.

9. Shaw BW Jr, lwatsuki S, Stani TE: Alternative methods of hepatic Rraft arteriahzation. Surg Gynecol Obstet 1984; 159:265-272.

10. Shaw BW Jr, Gordon RD, lwatsuki S, et al: Hepatic retransplantation. Transplant Prue 1985. 17:265-271.

11. Demetris AJ. LaskyS, Van Thiel DH, et al: Pathology of hepatic transplantation. Am J Pathol 1985; 118:151-161.

12. Snover DC, Sibley RK, Freese DK, et al: Orthotopic liver transplantation, a pathological study of 63 serial liver biopsies from 17 patients with special reference to the diagnostic features and natural history of rejection. Hepatology 1984; 4:1212-1222.

13. Eggink HF, Hofstee N, Gips CH, et al: Histolopathology of serial graft biopsies from liver transplant recipients. Am J Pathol 1984; 114: 18- 31.

14. Stani TE, Klintmalm GBG, Weil R III et al: Liver transplantation with the use of cyclosporin A and prednisone. N Engl J Med 1981; 305:266-269.

TABLE 1

LIVER TRANSPLANTATION EXPERIENCE WITH FULMINANT HEPATIC FAILURE

TABLE 2

PREOPERATIVE EVALUATION OP POTENTIAL UVER TRANSPLANT RECIPIENTS

10.3928/0090-4481-19850701-05

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