Gartner, JC

Iwatsuki, S

Malatack, JJ

Shaw, BW

Starzl, TE

Zitelli, BJ

PubMed

Gartner Jr, JC

Name not available

Orthotopic liver transplantation in children with hepatic-based metabolic disease

D-Scholarship@Pitt

1/ I Orthotopic Liver Transplantation in Children With Hepatic-Based Metabolic Disease B. J. Zitelli. J. J. Malatack. J .. C. Gartner. Jr., B. W. Shaw. S. Iwatsuki. and T. E. Starzl SUCCESSFUL orthotopic liver transplan-tation provides a unique opportunity to study systemic effects of hepatic-based meta-bolic disease and to potentially provide a cure for previously often fatal illnesses. From May 9, 1981 through the next 12 months, 23 patients received orthotopic liver transplants. Children ranged from 7.5 months to 18 years of age. Each patient re-::eived cyclosporin-A (CyA) and steroids. Eight of the 23 patients had identifiable metabolic disease, and 3 of the 8 had associated hepatic neoplasms. Seven of the 8 patients had evidence of correction of the underlying metabolic defect or showed clinical improvement. The eighth patient died prior to documenting correction of the defect. Metabolic indications for transplantation included: alpha-I-antitrypsin (AJA T) defi-ciency (4), glycogen storage disease type I (GSD 1) (with adenomas) (1), herediatry tyrosinemia (with hepatocellular carcinoma) (1), Sea Blue Histiocyte syndrome (with hepatocellular carcinoma) (1), and Wilson's disease (I). Two of the 8 patients died. Each had AJAT deficiency. One died 6 weeks after transplant due to an hepatic' abscess, and the other died 3.5 months after transplant secon-dary to a cerebral hemorrhage. Patients with AJAT deficiency are summa-rized in Table 1. All patients had end-stage liver disease and/or severe portal hyperten-sion. Three of the 4 patients had abnormally low levels of AJAT (2 with Pi ZZ and I with Pi SZ). Each of these 3 patients had periodic acid-Schiff stain positive and diastase-resis-From the University of Pittsburgh Health Center. University of Pittsburgh. Pittsburgh. Pa. Reprint requets should be addressed to Dr. B.J. Zitel-Ii. Univeristy of Pittsburgh Health Center. University of Pittsburgh, Pittsburgh, Pa. 15261. @ 1983 by Grune & Stratton. Inc. 0041-1345/83/1501-0309$01.00/0 1284 tant granules in hepatocytes. A fourth patient, OT 226. had a normal AlA T level and was Pi MZ. Her liver did not demonstrate the char-acteristic intracytoplasmic granules. Post-transplant. 3 of the 4 patients had normal AJAT levels and. where measured. assumed the Pi type of the donor. OT 203 died prior to measuring his AlA T level and Pi type. Nota-bly, the 2 patients who died had no evidence of granule accumulation in transplanted liver. GSD I was diagnosed in OT 218 after presenting with acidosis, hypoglycemia. growth failure. and hepatomegaly. She had a sibling who died of the same disease at 2.5 years of age. At 8 years of age she underwent a portocaval shunt, which helped her growth but did not improve her hypoglycemia. She required frequent daytime feedings and con-tinuous nocturnal nasogastric feedings. She developed progressive hepatomegaly, poor growth, and hepatic tumor nodules. She hem-orrhaged into the tumor nodules, developed encephalopathy, and was transplanted in Feb-ruary of 1982. Postoperatively she developed mild hyper-glycemia that resolved within 48 hr. She maintained clinically normal glucose homeo-stasis on 3 normal meals per day and no nocturnal feedings. Six weeks posttransplant, detailed carbohydrate metabolic studies con-firmed a normal 24-hr fast, normal oral glu-cose tolerance test, and a brisk response to parenterally administered glucagon. She is now leading a virtually normal life at home. Hereditary tyrosinemia, Fanconi's renal tubular disease, and rickets were diagnosed in OT 206 at I year of age. Strict dietary therapy normalized her serum amino acids and cor-rected the renal defect with healing of her rickets. In July 1981 she was discovered to have hepatocellular carcinoma and developed progressive liver failure with markedly ele-vated alpha-fetoprotein (AFP) levels. She was Transplantation Proceedings. Vol. XV. No.1 (MarchI. 1983 ~ i ( ~K I , , ~f I t .... I 3 LIVER TRANSPLANT IN METABOLIC DISORDERS 1285 Table 1. Liver Transplantation For Metabolic Disease Age Follow-up (Yearsl OT Sex Diagnosis Pretranspllll1t Posnranspllll1t Current Staws IMonths) 192 10 a A,AT A,AT 44. Pi SZ A,AT 174 Pi MM Well. bili 0.6 13 201 4a A,AT A,AT "LOW:' Pi ZZ A,AT"NL" Died 6 weeks,liver abscess 203 18 a A,AT A,AT "LOW:' Pi ZZ A,A T NOT DONE" Died 31!z mo .. cerebral hemorrhage 226 4~ A,AT A,AT 157 Pi ZZ A,AT85MM Well, bili 1.3 4 218 16 ~ GSDI Nocturnal Feeds, Liver NL 24 hr fast, OGTT, Well. biliO.5 3 Tumor. poor growth glucagon stimula-tion 206 O~ Tyrosinemia Cirrhosis, dietary ra- NL amino acids, ",FP, Well, bili 1.1 8 striction, liver tu- regular diet, no tu-mor. high ",FP mor 222 79 Sea Blue Cirrhosis, neurodegen- No tumor. neurologic Well. bili 0.8 5 Histiocyte eralive disorder. improvement liver tumor 202 13 a Wilson's Ataxia. Cogwheel ri- Normal inteliect. mild Well. bili 0.7 Cu 99 10 gidity. liver and bilateral foot drop Ilg/ dl ceruloplasmin renal failure. coma. 27 mg/dl Cu 651lg/ dl cerulo-plasmin 4 mg/dl A,AT. alpha - 1 - antitrypsin (deficiency) (mg/dl); Pi. protease inhibitor type; NL. normal; BiIi, total bilirubin (mg/dl); GSD I, glycogen storage disease. type I; aFP. alpha fetoprotein; Cu. serum copper. normal 80-120 Ilg/dl; ceruloplasmin, normal 20-40 mgidl; oral glucose tolerance test. transplanted on 11/13/81. Urine and plasma amino acids remained normal postoperatively without any dietary restriction, and her AFP levels fell to zero by 3 weeks after transplant. In addition. there has been no evidence of recurrent tumor. She has had problems of hypertension and rejection, both of which ha ve been controlled, and is now leading a virtually normal life. OT 222 was diagnosed as having a variation of the Sea-Blue Histiocyte syndrome in November 1981 after evaluation for pro-gressive hepatic disease and a degenerative neurologic disorder. Hepatosplenomegaly was discovered at 2-3 months of age, and evalua-tion for an etiology was unfruitful. Liver enzymes were twice normal. Bone marrow and ophthalmologic exams were normal. Liver biopsy at 5 months of age demonstrated cirrhosis without cholestasis. She had a single myoclonic seizure at that time. She developed normally until 5 years of age when parents noted an unsteady gait, tremor, and a paresis of upward gaze. She had hyperactive deep tendon reflexes. mild hypertonicity, dysdiado-chokinesia, extensor plantar reflexes, mild truncal ataxia with a normal mental age. At 6 years of age she developed cogwheel rigidity. Repeat ophthalmologic exam and ceruloplas-min were normal, and CA T scan of the head demonstrated mild cerebral atrophy. Electro-encephalogram was consistent with a meta-bolic disorder. Leukocyte lysozomal enzymes, hepatic sphingomyelinase, and hepatic sphin-gomyelin were normal. An occult hepatocellu-lar carcinoma was discovered without evi-dence of metastases. In November 1981, a bone marrow demonstrated foamy histiocytes characteristic of Sea-Blue Histiocyte syn-drome. On 2/24/82, OT 222 underwent hepatic transplantation without complications save for moderate postoperative hypertension. She was discharged 3 weeks posttransplant on Cy A and prednisone. Nearly 4 months posttransplant her neuro-logic status has significantly improved. Prior to transplant she could not stand indepen-dently from a chair and could walk short 1286 distances only with the aid of a walker. Peg board exercises were extremely frustrating. Currently, she is walking short distances with-out the walker, only holding somltOne's hand, and is able to get up independently from her seat. She can place pegs in the board with greater facility. Teachers describe her as hav-ing more stamina, being more vocal, and socially interactive. Current liver enzymes and bilirubin are normal. OT 202 was an almost 13-year-old boy in a gifted class in school when he developed suba-cute hepatitis diagnosed as Wilson's disease. Despite d-penicillamine therapy, he developed progressive liver failure. ataxia and cogwheel rigidity, gastrointestinal hemorrhage. ascites. encephalopathy, and hepatorenal syndrome requiring dialysis. On 9/20/81 he underwent orthotopic liver transplantation with rapid improvement in his sensorium and renal fail-ure. His hospital course was marked by grad-ual improvement in his neurologic function, although a mild right hemiparesis was noted. He had persistently high urinary copper excretion (182-434.ug Cu/ g Cr) with normal-ization of ceruloplasmin (27 mg/dl) by 4 weeks posttransplant. Penicillamine challenge did not significantly increase urine copper excretion. Currently, the patient is in his regular advanced class in school and has only a mild bilateral foot drop as his only neurologic residua. Liver function tests are normal on Cy A and prednisone. DISCUSSION Orthotopic liver transplantation for hepat-ic-based inborn errors of metabolism offers a unique opportunity to correct previously often fatal disorders. In our 4 patients with AIAT deficiency, liver transplantation led to assumption of the donor Pi type and/or nor-malization of the serum AIAT level where measured. Two patients were heterozygous (MZ, SZ) and assumed a homozygote MM state posttransplant. These data confirm simi-lar information reported by Hood et al.I on 7 patients who underwent liver transplantation with AIAT deficiency. Long-term follow-up ZITELLI ET AL. of Hood's patients as well as our patients reveal no tendency toward reversion to the original phenotype, diminution of serum levels of AlA T, or development of other complica-tions of A\AT deficiency.2 It is impossible to state, however, if these patients may escape complications during longer follow-up. Never before has anyone with GSD I been able to lead a life with virtually normal glu-cose hemeostasis. Our patient is the first with GSD I treated with liver transplantation. Postoperatively she demonstrated clinically normal carbohydrate metabolism. More for-mal testingJ confirmed the clinical impression, revealing only minor perturbations of slightly prolonged glycemic phase to parenteral gluca-gon, perhaps reflecting the effect of her low-dose steroid therapy. While liver transplanta-tion appears to correct the hepatic-based glucose-6-phosphatase deficiency, it perhaps should be held in reserve for those patients who have failed vigorous medical therapy or have developed irreversible and progressive liver disease. Also, while the hepatic defect is corrected with transplantation, no evidence to date exists as to whether other organs affected by the enzyme deficiency show any benefit from hepatic transplantation. Our patient OT 206 with hereditary tyro-sinemia is the second patient with this disor-der to be transplanted, and the longest survi-vor (8 months). Fisch and Starzl4 reported one other patient who normalized serum tyrosine and urinary metabolites as early as 48 hr posttransplant. Their patient died after 3 months of sepsis and portal vein thrombosis. Our patient has no clinical evidence of any residual metabolic defect. Ongoing studies, however, are continuing to search for such defects remaining in other organs, since the long-term implications of hepatic transplanta-tion in tyrosinemia are not known. Perhaps with the improved survival of liver transplant patients,S it may be warranted to consider transplantation prior to the onset of lethal complications as malignancy or hepatic fail-ure. The Sea-Blue Histiocyte syndrome is char-I ,( ,J ~K t -r T t ( J r 1 { { J. j, rl~ J ~ y I \ K~ I Y I i· LIVER TRANSPLANT IN METABOLIC DISORDERS acterized by the presence of blue, foamy his-tiocytes in the bone marrow. Patients may have progressive neurologic deterioration after a period of normal development charac-terized by ataxia, vertical supranuclear oph-thalmoplegia, dementia, and often seizures along with visceromegaly with an as yet unde-termined intracellularly stored substance.6 Our patient had normal liver sphingomyelin and normal leukocyte sphingomyelinase activ-ity, suggesting this disorder may not be a variant of Niemann-Pick disease. In addition, she did not demonstrate dementia, although it may have been early in her clinical course. Despite a lack of basic understanding of the pathophysiology, it appears that the defect may be hepatic-based, and that liver trans-plantation may have some beneficial effect on halting neurologic deterioration, and perhaps may reverse neurologic impairment. Much work remains to further elucidate this unusual problem. Neurologic impairment was clearly re-versed in the patient with Wilson's disease. Liver transplantation clearly reversed the metabolic defects of copper metabolism as well. Groth et al.7 reported 2 teenage boys who underwent transplantation for Wilson's dis-ease. One had neurologic involvement that slowly improved over the following 17 months. These patients, like ours, demonstrated nor-malization of serum copper and ceruloplas-min. Hepatic copper, not yet measured in our patient. WaS normal in Groth's 2 patients. It appears that liver transplantation may nor-malize the biochemical abnormalities in Wil-son's disease, and perhaps more dramatically, "~ ... 12B7 may reverse the neurologic deterioration suf-fered by these patients. Overall, it appears that orthotopic liver transplantation may be an effective mode of therapy for hepatic-based and often fatal inborn errO'rs of metabolism. While underly-ing metabolic defects may be corrected, long-term effects of transplantation in these disor-ders are not known and require further obser-vation. In addition, with survivors of such disorders potentially living to reproductive adulthood, genetic counselling becomes in-creasingly important for these patients and their families. ADDENDUM Since the submission of this manuscript, patient OT 222 with the Sea-Blue Histiocyte syndrome has had a plateau of neurologic improvement II months posttransplant. Sub-sequent bone marrow examination still dem-onstrates storage histiocytes and there is evi-dence of a small amount of storage material in the Kupffer cells of the transplanted liver. Because Kupffer cells in the transplanted liver are of recipient origin, it is not surprising that metabolic defects possibly originating in re-ticuloendothelial cells are not corrected by hepatic transplantation. Although the meta-bolic defect in the Sea-Blue Histiocyte is unknown, results in our patient suggest that it is not liver-based. Patient GT 202 with Wilson's disease has continued neurologic improvement with reso-luti,em of his foot drop 15 months posttrans-plant. Hepatic copper in the liver homograft is normal. REFERENCEs I. Hood 1M. Koep LJ, Peters RL. et al: N Engl 1 !'vied 302:272. 1980 2. Starzl TE: Personal communication 3. Malatack 11. Finegold ON, Roe TF, et al: (in preparation) 4. Fisch RO. McCabe ERB. Doeden 0, et al: 1 Pediatr 94:592. 1978 5. Starzl TE, Klintmalm GBG, Porter KA, et al: N Engl J MK~d 305:266,1981 6. Nevilk, BGR, Lake BD, Stephens R, et al: Brain 96:97.1973 7. Groth CG. Dubois RS, Corman J, et al: Transplant Proc 5:829. 1972; " ::l r g i-i-o j-,e )-\-r-:s 1-\-T :11 s, Ie III .s, le :d .ic ot :m th en ns 

Orthotopic Liver Transplantation in Children With Hepatic-Based Metabolic Disease.

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Orthotopic Liver Transplantation in Children With Hepatic-Based Metabolic Disease.

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