Eur J Pediatr (1992) 151 [Suppl 1] : $32-$38

European Journal of

Pediatrics

9 Springer-Verlagi992

Orthotopic liver transplantation in liver'based metabolic disorders Alex P. Mowat Department of Child Health, Variety Club Children'sHospital, Kings CollegeHospital, Denmark Hill, London SE5 9RS, United Kingdom

Abstract. The efficacy of orthotopic liver transplantation (OLT) in the management of more common liver-based metabolic disorders associated with severe liver damage, alpha-l-antitrypsin deficiency (PIZZ), Wilson disease and tyrosinaemia has been demonstrated and indications defined. An early mortality in excess of 15% and finite resources limit its use. Phenotypic heterogeneity make the precise indication in other disorders less certain. In disorders in which endstage liver disease is less frequent such as cystic fibrosis, haemochromatosis and galacosaemia it has been a very effective therapy. It has been used with encouraging results in disorders in which the liver is structurally normal such as Crigler-Najjar type I, primary hyperoxaluria type I and primary hypercholesterolaemia. In these it should be performed before there is permanent damage to brain, kidneys or heart. OLT in the short term prevents hyperammonaemic coma in urea cycle defects and may prevent extrahepatic disease in glycogen storage disease type IV. Its limitation in reversing all metabolic effects in these and other disorders is discussed. It is ineffective in protoporphyria or Niemann Pick disease type II (Sea Blue Histiocyte syndrome) in which the transplanted liver acquires the lesions of the initial disorder and extrahepatic features progress. Early referral provides optimum circumstances to assess the benefits of OLT as compared with those of other forms of management and to achieve transplantation at the ideal time. The place of OLT in management will require constant review as metabolic disorders are better defined, new forms of therapy evolve and as techniques of liver transplantation and modes of immunosuppression improve. Key words: Orthotopic liver transplantation - Metabolic disorders - New treatment modes

Introduction Orthotopic liver transplantation (OLT) is a therapeutic option which is being used increasingly [5, 8, 9, 40, 51] in the treatment of monogenetic liver-based metabolic disorders as the outcome following transplantation improves [6, 31, 49, 50, 56, 64]. In the Cambridge/King's College GSD = Glycoganstorage disease; OLT = orthotopic liver transplantation; PI = prognosticindicator

Abbreviations:

Hospital liver transplantation programme, for example, analysis of the first 100 children transplanted between December 1983 and March 1990 gave an overall survival rate of 65% with the 1-year survival rate in the last 2 years being 86% [50]. Five-year survival rates ranging from 64%-78% have been reported [6, 56, 64]. The outcome is better in those transplanted for metabolic disorders [5] and if performed before there is growth retardation [39]. Infants under 12 months of age provide a major challenge but even in these, 1-year survival of 65% has been achieved [54]. Successful transplantation has been accomplished in the 1st month of life [37]. In North America segmental grafts from living relatives have given survival rates of 90% in infants in whom portoenterostomy for biliary atresia had been unsuccessful [63]. Deaths are rare between 2 and 5 years after OLT. Over 90% of survivors have a good quality of life with normal development and the majority have catch-up growth. The longest surviving recipient was reported to be well more than 20 years after transplantation [56]. Constraints limiting the use of liver transplantation There are certain limitations which curb the use of this powerful therapy. Even in the best circumstances between 10% and 15% die within 3 months of grafting. Removing the diseased liver completely and replacing it by all or part of a liver from a donor of identical blood group remains a demanding surgical procedure. The bile duct, hepatic artery, portal vein and hepatic veins or inferior vena cava require careful anastomosis to the appropriate host vessels. Immunosuppression is most commonly achieved with cyclosporin A, azathioprine and corticosteroids. Large doses of the latter are required initially, with in some services additional antilymphocytic globulins. A period of intensive patient care follows in which potentially lethal complications are common. In the early weeks there is a very slender margin of safety between giving too much immunosuppressive therapy with an enhanced risk of infection and other toxic effects and giving too little with risk of graft dysfunction from rejection. Distinguishing acute rejection, which is treated with increased doses of corticosteroids and/or antilymphocytic antibodies, from systemic infection (viral, bacterial, fungal and/or protozoal) and from major complications requiring surgical management such as bile duct

$33 obstruction, hepatic artery thrombosis and/or portal vein thrombosis is a major challenge. Graft-versus-host disease may add to the difficulties [2]. Preventing chronic rejection which is heralded by an insidious deterioration of liver function is another major difficutly. Up to 40% of recipients require regrafting for_ primary nonfunction, vascular thrombosis or chronic rejection. The patient is at risk from longer term surgical complications affecting the anastomosed channels and medical complications, particularly related to the life-long requirement for immunosuppression. Opportunistic infections and community acquired infections are always a danger. A worrying complication is Epstein Barr virusrelated lymphoproliferative disease which is frequently fatal unless immunosuppressive drugs are stopped. In one paediatric series an incidence of over 2.8% per year was reported [33]. This has been reported as a compliation with the most recently introduced immunosuppressive agent FK 506. Lack of donor livers matched for size, blood group and cytomegalovirus status remains a major difficulty with the increasing application of liver transplantation. Surgical advances including reduction hepatectomy, split liver grafting and the use of live donors have helped [6, 63,64]. Another important limiting factor is scarcity of intensive care facilities and trained nursing staff. Major costs include operating room time, donor retrieval, laboratory tests, blood (which should be cytomegalovirus negative if recipient and donor are negative), blood products, drugs and drug monitoring. The emotional strain on the family is immense. They are likely to face a number of life threatening complications, particularly in the immediate post operative weeks. Periods of elation and exhilaration may be followed by periods of despair and sadness as new complications develop.

Indications for transplantation OLT has been employed most commonly in liver-based metabolic disorders causing one of three categories of advanced liver disease: acute liver failure, complications of cirrhosis or potential hepatoma formation. It is the only effective therapy in patients with structurally normal livers but with a severe metabolic perturbation which can cause permanent damage to brain, kidneys or heart. Rarely it has been used in disorders such as the milder forms of urea cycle defects which can usually be controlled by diet or other means but which in particular individuals such management leaves a considerable risk of neurological damage or cause an intolerable quality of life. In all three circumstances an estimate must be made of the risks associated with OLT as compared with those of other forms of management.

Transplantation clarifying the liver's role in metabolism The liver's role in metabolic processes has been illustrated by the outcome of OLT. With relatively short periods of

follow up it appears to be curative in disorders associated with liver damage, in those causing damage to other vital organs and in haematological disorders such as protein C deficiency and in haemophilia a and b. Conversely one transplant recipient has developed Factor XI deficiency [15], another Gilbert syndrome [20]. In tyrosinaemia type 1 [27, 44], urea cycle disorders [47, 60] and cholesteryl ester storage disease [16] OLT does not reverse all metabolic abnormalities. In some but not all cases it appears to arrest the progression of glycogen storage disease type IV over 3-4 years at least [52]. OLT does not control the extrahepatic features of protoporphyria [21] or Niemann Pick Disease type II (Sea Blue Histiocyte syndrome) [17]. In both lesions specific for the primary disorder develop in the transplanted liver, presumably within the host endothelial or Kupffer cell which become established in all transplanted livers. For such disorders transplantation of fetal liver and thymic cells deserves consideration [59].

Transplantation in disorders causing life threatening liver damage

Alpha-l-antitrypsin deficiency (genotype PiZZ) Alpha-l-antitrypsin is encoded by a single structural gene, the Protease inhibior (PI) locus 10.2 kb in length, on chromosome [email protected] [3, 24]. The inheritance of alpha-l-antitrypsin is codominant, with each allele functioning separately. More than 75 genetic variants of the glycoprotein have been identified. The clinically important variant, PIZ arises from a point mutation at codon 342 which results in the replacement of glutamic acid by lysine. With a homozygote frequency of 1 : 1660 to 1:7000 newborns of European descent alpha-l-antitrypsin deftciency (genotype PiZZ) is one of the more common single gene defects associated with significant disease, and by far the most common causing severe liver disease. Up to 20% develop liver damage. What causes liver damage or determines its severity is unknown. 10%-15% develop symptomatic liver disease in childhood [24]. In 90% this takes the form of a hepatitis with conjugated hyperbilirubinaemia. In 10% it is complicated by a serious bleeding diathesis due to vitamin K malabsorption. One to 2% present in later childhood or adult life with cirrhosis with no history of prior jaundice in infancy. There appears to be a statistically significant increased risk of cirrhosis and primary hepatoma in males over the age of 50. Although children with liver disease have increased lung volumes [22] early progression to emphysema is unusual. In adults the co-existence of emphysema and cirrhosis is rarely recognised. Approximately 5% of affected infants remain jaundiced and progress to decompensated cirrhosis with death in the 1st year of life. In approximately 25% of the remainder the hepatitis resolves completely. Approximately 25% die from complications of cirrhosis at ages ranging from 6 months to 17 years. Hepatic decompensation developed with ascites, hyponatraemia, recurrence of jaundice, haematemesis or severe fail-

$34 ure to thrive after a period of well being. Haematuria and/or albuminuria due to glomerular lesions may occur [30, 58]. Death from liver disease occurred within 2 months-4 years of the onset of such developments [24]. Another 25% survive through the first decade although they have histologically confirmed cirrhosis. A further 25% without liver biopsy evidence of cirrhosis have persistently abnormal liver function tests with or without clinical features of portal hypertension. The management is that of chronic cholestasis and of cirrhosis. Although advances in molecular genetics and in recombinant DNA technology suggest novel means of treatment may soon be feasible [3, 24], there is no specific treatment for endstage liver damage associated with alpha-l-antitrypsin deficiency short of liver transplantation. Liver transplantation in this disorder increases the serum alpha-l-antitrypsin concentration to the normal range and changes the phenotype to that of the donor [8]. The features of endstage cirrhosis are reversed. The results are similar to those in other forms of cirrhosis except that hypertension may be more frequent [42]. The longest follow up is only 16 years making it too early to determine whether OLT will prevent emphysema [56]: Liver transplantation should be planned as soon as cirrhosis decompensates or if it is complicated by recurrent variceal bleeding not readily prevented by injection therapy. Preferably it should occur before renal complications develop.

Wilson's disease Wilson's disease, an autosomal recessive disorder occurring world wide with an estimated frequency of 1 : 50,000 is due to a defective gene on chromosome 13q14 near the esterase D locus [67]. An abnormality in the transport, storage and excretion of copper by the liver results in copper accumulation and tissue damage. The exact pathogenesis of the defective copper metabolism is unclear [11, 25, 57]. Effective treatment of Wilson's disease has been available in the form of penicillamine since 1956. Since then other chelating agents and/or oral zinc sulphate have been used successfully if toxic side-effects of penicillamine cause it to be withdrawn. Zinc has been used as the sole mode of therapy in patients presenting with neurological features [23] and in one child with moderate liver damage [36]. Can there still be a role for liver transplantation? Unfortunately all too frequently there is because of delay in considering the disorder or performing the investigations which are essential to establish the diagnosis. Liver damage then may be so severe that death occurs within 1 week from acute liver failure or within 2 months from decompensated cirrhosis. Early symptoms are frequently nonspecific. Symptomatic liver involvement in Wilson's disease may mimic any form of acute or chronic liver disease. The initial presentation may be Coomb's negative haemolysis, an apparent nephrotic syndrome, renal tubular abnormalities including rickets, neurological or personality changes or non-specific features such as abdominal pain, fever or

arthralgia. The pathognomonic Kayser-Fleischer rings are seen, by slit-lamp examination of the cornea, in only 50% of patients presenting before 16 years of age. The most specific diagnostic tests are a low serum caeruloplasmin and high urinary copper excretion but considerable care is required in their interpretation since both false-positive and false-negative results occur. A 24h urinary copper excretion of > 25 gmol collected while taking 0.5g of penicillamine at 0 and 12h is the most accurate single diagnostic test [10]. A particular difficulty is in distinguishing fulminant presentation of Wilson's disease from other causes of acute liver failure [1]. Patients presenting with fulminant hepatic failure die as do those with decompensated cirrhosis. If encephalopathy occurs, haemofiltration or plasmapheresis [48] or heterotopic liver transplantation [55] may keep the patient alive until OLT is possible. For the patient with decompensated cirrhosis we developed a prognostic index based on the degree of abnormality of the prothrombin time, serum aspartate aminotransferase and bilirubin concentration at the time of instituting therapy [41]. It has proved a useful prognostic indicator (PI) in some [31] but not all other reports [18]. In a further 20 symptomatic children in our unit it remained useful but less exact. We therefore recommend that urgent transplantation is essential if the PI is > 9, while penicillamine is likely to be effective if the PI is < 6. If the PI is from 6 to 9 the patient should be listed for OLT and treated with penicillamine and zinc. If the PI falls progressively OLT may be unnecessary unless other complications of cirrhosis develop. The patient requires careful supervision to control complications of cirrhosis until jaundice clears and the serum albumin becomes normal. Liver transplantation must also be considered for those who relapse because therapy has been stopped against medical advice. Hepatic decompensation occurs within 6-18 months and rarely (if ever) is controlled by re-instituting penicillamine. Will such patients take immunosuppressants indefinitely? Following transplantation serum caeruloplasmin levels return to normal over the course of 1-2 months. Radiolabelled copper studies show normal copper uptake by the liver graft with prompt biliary excretion. KayserFleischer rings may persist for up to 2.5 years. Neurological abnormalities may improve rapidly but some improvement may occur over the course of the next 4 years even in those with very advanced disease [46].

Tyrosinaemia type I (fumaryl acetoacetate hydrolase deficiency, EC 3.7.1.2) Hereditary tyrosinaemia is a heterogeneous disorder due to an inherited defect of fumaryl acetoacetate hydrolase. The gene has been mapped to chromosome 15q23-25. The disorder is characterized by progressive hepatocellular damage with a high propensity to hepatoma formation by 5 years of age, renal tubular dysfunction, and hypophosphataemic rickets. The diagnosis should be excluded in any child with chronic liver disease or rickets [13, 27]. The acute form presents in the first weeks or

$35 months of life with failure to thrive, vomiting, diarrhoea, a cabbage-like odour, hepatomegaly, oedema, ascites, splenomegaly and a bleeding diathesis with melaena and epistaxis. Jaundice develops in about one-third of patients. Death from liver failure is usual by 8 months of age with only 10% surviving beyond 12 months. The chronic form may continue from the acute or present between 6 months and 18 years of age with features of cirrhosis, hypophosphataemic rickets and/or renal tubular or glomerular dysfunction. Episodes of acute abdominal pain, polyneuropathy and hypertension with intermittent porphyria-like biochemical abnormalities occur in up to one-third. Death from hepatic failure with or without tumour formation or renal failure usually occurs in the first decade but survival into adult life does occur. Dietary restriction of phenylalanine, tyrosine and methionine, mitigating the effects of renal tubular damage and prompt treatment of intercurrent infections improve wellbeing and promote growth for a time but it has yet to be shown that they delay the inevitable progression to liver or renal failure or the development of hepatocellular carcinoma. Liver transplantation must be considered in infants with the acute form as soon as growth arrest occurs or there is a severe coagulopathy not reversed by parenteral vitamin K but if possible it should be delayed until the second 6 months of life. For the chronic form, liver transplantation should be considered by the second birthday because of the high risk of malignancy spreading to tissues outside the liver. If the ultrasound and/or CT scans of the liver are normal transplantation can be delayed. It is frequently impossible to differentiate between malignant transformation as opposed to regeneration nodules in the liver of a child with tyrosinaemia by ultrasound, CT scanning or angiography [13, 27, 32, 44]. Hepatocellular carcinoma may be present with the alpha-fetoprotein concentration normal; conversely high serum concentrations are present with no malignancy in the resected liver: A sharp rise in concentration has been considered an indicator of malignancy but this is not invariably true. OLT may be necessary in patients with recurrent episodes of acute liver failure or for repeated neurological crises. Liver transplantation allows the patient to take a normal diet, prevents further neurological crises but does not correct the excessive urinary excretion of succinylacetone which is presumed to be renal in origin. It is not clear whether such patients are more prone to progressive renal failure than other OLT recipients receiving cyclosporin A. Combined liver and renal transplantation is advised if there is severe glomerular failure with a. glomerular filtration rate of < 40 ml/min per 1.73 m 2 [44].

Cystic fibrosis Of patients with cystic fibrosis between 10% and 20% develop features of cirrhosis by adult life. The major problems are alimentary bleeding from oesophageal varices and massive splenomegaly with features of hypersplenism. Liver transplantation has been reported with 50% surviving with a very good quality of life, without

evident deterioration of pulmonary function [35, 64]. In at least one instance combined liver-heart-lung transplant has been performed. The role of OLT in this condition is at present less well defined than in other forms of cirrhosis with less multi-system involvement. Pulmonary infections have proved less troublesome than anticipated. Disseminated aspergiUosis and other fungal infections are contraindications.

CholesteTyl ester storage disease Liver transplantation undertaken for uncontrollable bleeding from oesophageal varices in a 14-year-old with cholesteryl ester storage disease failed to prevent elevation of serum triglycerides [16]. Prolonged follow up will be required to assess its effect on pulmonary, vascular or renal disease.

ByIer disease This is a form of progressive familial intrahepatic cholestasis of unknown pathogenesis which causes death from chirrhosis or heart failure. The low serum apolipoprotein A-1 concentration is corrected by OLT performed for cirrhosis [5].

Haemochrornatosis Haemochromatosis of the idiopathic adult HLA-related form is controlled by venesection but this may not decrease the risk of hepatocellular carcinoma for which OLT may be indicated. It is rarely required for endstage liver disease. In neonatal haemochromatosis excess iron is deposited in the same tissues as in the adult form [65]. It is often rapidly fatal. It may represent a number of disorders [19, 65] with different pathogenesis with possibly differing response to OLT.

Glycogen storage diseases Glycogen storage diseases (GSD) are disorders in which the concentration and/or molecular structure of glycogen is abnormal in any tissue of the body [4, 9, 53]. Increased intrahepatic fibrosis and rarely cirrhotic changes occur particularly in type III GSD but can occur in types I and VI, with adenomata developing particularly after puberty in types I and III [53]. These appear to be slow growing but can be associated with massive bleeding and alpha-fetoprotein positive malignant change. Focal glomerulonephritis associated with proteinuria, haematguria, renal calculi and renal failure may be detected from 8 years of age in type I GSD. In types lb and c recurrent neutropenia makes the patient very susceptible to bacterial infection. In type III cardiac failure and sudden death may occur. Liver transplantation corrects the metabolic and growth effect of the disorder [26]. It should be considered in infants with very severe GSD type 1 disease which cannot be controlled by diet and in adults with malignant disease confined to the liver [54]. Its role in those with adenomata, which may be stable for up to 5 years, has not been defined.

$36 Type IV disease is characterised by cirrhosis with or without evidence of cardiac or brain involvement. Death from cirrhosis or heart failure is usual by 5 years but survival to 8 years of age may occur. In five patients transplanted at 20-46 months of age there was no accumulation of amylopectin-like polysaccharide in the transplanted livers, decreased amylopectin in myocardial biopsies and no progression of cardiac disease up to 6 years later [52].

Transferase deficiency galactosaemia: galactose-l-phosphate uridyl transferase deficiency Galactosaemic neonates with severe coagulopathy and/ or hyperbilirubinaemia require exchange transfusion. Infants with severe metabolic derangement may die within a few days on a galactose-fiee diet. The majority do improve and have no subsequent hepatic problems. A few patients with very advanced cirrhosis may decompensate in childhood or early adult life. They become candidates for liver transplantation [5, 43]. Hepatocellular carcinoma may develop. What effect liver transplantation would have on learning difficulties which occur despite of appropriate dietary care or on hypergonadotrophic hypogonadism with infertility reported in females is unknown [50].

Transplantation in disorders causing irreversible damage to other vital organs

Primary hyperoxaluria type I Primary hyperoxaluria type I is an autosomal recessive disorder with deficient peroxisomal alanine: glyoxylate aminotransferase (EC 2.1.44) activity leading to renal and cardiovascular damage. There is both genetic and phenotypic heterogeneity [12, 29, 38]. Medical treatment takes the form of a large fluid intake, and a low intake of calcium, oxalate and vitamin C and D intake, with pyridoxine and phosphate or magnesium oxide supplements. Initially renal transplantation was attempted for this disorder but calcium oxalate caused early graft failure. This led to the introduction of liver and kidney grafting which has proved successful. Another approach is to perform a liver transplantation then to proceed to renal transplantation when the oxalate pool is diminished so as to avoid renal allograft failure. Unfortunately severe bone disease may develop in the interval [29, 34]. It is important that transplantation be performed before severe cardiovascular disease arises due to systemic oxalosis [61, 62]. It essential to maintain a very high urinary output for the first few days post-transplant when the renal oxalate load is still very high [8, 9].

Crigler-Najjar type I Crigler-Najjar type I is characterised by a complete failure of bilirubin glucuronide formation in the liver. There is a genetically heterogeneous deficiency of hepatic microsomal UDP-glucuronyltransferases (UDPGTases) with

a complete lack of bilirubin UDPGTases [66]. Enzymatic activity cannot be induced by phenobarbitone. Such patients develop kernicterus unless this is prevented by exchange transfusion in the neonatal period and by phototherapy given for up to 12 h each night [45]. As the child gets older phototherapy becomes less effective and OLT becomes necessary to prevent brain damage which can occur at any age during exacerbations of hyperbilirubinaemia associated with intercurrent infections. OLT should be considered before phototherapy ceases to be practical, effective or the jaundice socially unacceptable, possibly about 4 years of age [51].

Primary hypercholesterolaemia Primary hypercholesterolaemia caused by homozygous deficiency of low-density lipoprotein receptors treated by diet, drugs, LDL-plasmapheresis or ileal by-pass may still progress to intractable myocardial ischaemia. In such patients liver transplantation produces an 80% decrease in lipids but usually the patient also requires cardiac transplantation or coronary artery bypass [5, 8].

CoaguIopathies Haemophilia A, haemophilia B [56] and protein C deficiency [7] have all been treated successfully by liver transplantation. In haemophilia OLT has been undertaken for endstage liver disease induced by viral contaminated blood products. The transplanted liver usually becomes infected and may suffer liver damage of any grade of severity.

Urea cycle disorders Urea cycle disorders show considerable genetic and phenotypic variability with a continuous spectrum of clinical expression [14]. Those with neonatal onset frequently die or develop mental retardation before liver transplantation is considered or becomes a reasonable prospect with current techniques. Cases of later onset have a better prognosis with strict dietary and drug control. To my knowledge it is only in such cases that OLT has been performed when it is clear that dietary management is ineffective but there is no significant brain damage [28, 47, 60]. OLT prevents hyperammonaemic crises but arginine and citrulline supplements are required.

Discussion Liver transplantation to date has given a good quality of life to patients with range of metabolic disorders. It has provided new insight into the basic metabolic defects in many disorders and has helped to define the hepatic contribution to their pathopyhsiology. There are at present major problems which prevent its more widespread use particularly in early infancy when liver-based metabolic disease is often lethal or causes severe brain damage. Its place in management will require constant review as metabolic disorders are more clearly understood and their

$37 h e t e r o g e n e i t y b e c o m e s b e t t e r d e f i n e d a n d n e w f o r m s of t h e r a p y e v o l v e a n d as t e c h n i q u e s of liver t r a n s p l a n t a t i o n and modes of immunosuppression improve.

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Orthotopic liver transplantation in liver-based metabolic disorders.

The efficacy of orthotopic liver transplantation (OLT) in the management of more common liver-based metabolic disorders associated with severe liver d...
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