A 16½-year-old girl with type I glycogen storage disease was treated by orthotopic liver transplantation under cyclosporin/steroid immunosuppression. All metabolic stigmata of the disease were relieved and 1 year postoperatively she follows a normal diet and lifestyle

Alper

Alper Ca

Folkman

Greene

Kashiwagi

Merrill

Nordlie

Raum

Starzl

English

PubMed

Malatack, JJ

Finegold, DN

Iwatsuki, S

Shaw Jr, BW

Gartner, JC

Zitelli, BJ

Roe, T

Starzl, TE

Name not available

Liver transplantation for type I glycogen storage disease

Jeffrey Malatack, J

Iwatsuki, Shunzaburo

Carlton Gartner, J

Roe, Thomas

Finegold, DavidN

Shaw, ByersW

Zitelli, BasilJ

Starzl, ThomasE

D-Scholarship@Pitt

THEI.ANCET.MAY 14.1983 LIVER TRANSPLANTATION FOR TYPE I GLYCOGEN STORAGE DISEASE J. JEFFREY MALWACK SHVNZABVRO IWATSUKI J. CARLTON GARTNER THOMAS ROE* DAVID N. FINEGOLD BYERS W. SHAW.JR BASILJ. ZITELLI THOMAS E. STARZL Departmenzs of Pediama and Surgery, University Health Center of PillsburgJr, Pillsburglr, Pmnsylwnia 15261, USA; and Department of Pediatrics, University of Southern California * Summary A l6Ih-year-old girl with type I glycogen storage disease was 'treated by orthotopic liver' transplantation under cyclosporinlsteroid immunosuppression. All metabolic stigmata of the disease were relieved and I year postoperatively she follows a normal diet and lifestyle. Introduction STUDIES of haptoglobin, 1-3 group-specific component,3,4 and numerous other products of hepatic synthesis5- 9 have shown that liver homografts permanently retain their original metabolic specificity after transplantation. Consequently, liver transplantation has been regarded for some years4 as a potentially decisive way to treat those inborn errors of metabolism which result partly or completely from defects in hepatic function. This objective has been realised in several different metabolic disorders.8,9 We report here the first use of liver transplantation for the treatment of type I glycogen storage disease, a disorder caused by glucose-6-phosphatase deficiency . Case-report The patient was a girl aged l6lh yr whose sibling had died in infancy of the same disease. Ai age 2112 yr she had had a prolonged hypoglycaemic seizure which resulted in transient blindness, hemiparesis, and a residual seizure disorder requiring therapy with anticonvulsants. She continued to have recurrent hypoglycaemia, acidosis, hyperuricaemia, hyperlipidaemia, abnormal coagulation, and epistaxes, and her growth was retarded. After an end-to-side portacaval shunt at age 8 yr, 10 all these abnormalities were relieved except hypoglycaemia. The frequency of feedings necessary to avoid hypoglycaemic symptoms increased from every 4-5 h to every 2·n. Subsequentlx, overnight nutrient infusions were begun by nasogastric tube. I . During me 2 yr before transplantation, multiple filling defects in her enlarged liver were seen on liver scans, with a dominant lesion in Ihe right lobe. These were thought (and were later proved) to be slowly growing adenomas, hut the possibility ofa malignant change could nO! be ruled out. She had episodes of severe upper abdominal pain and liver swclling. In the year before transplantation, she had jlUndice with a peak serum bilirubin concentration of 8 mgldl (137 P. RIBEIRO AND OTHERS; REFERENCES-continued 11. AsmUSltD J, Kjeldsea K. Intimal ugtrlltructur~ of bum.n umbilical IIktics. CiraJ.,,,,. Ru 1975;:It: 579-89. 32.A""us ... " Artorial <banJ .. i. infaDII a(.molti", IlIOlho". P."l'aa Mid] 1978; N. 200-04. U. MusII,d IF. MIICphy EA. Mot! a(smolti", an blood toogulation .nd pla .. l<t aum.u in man. B, Mid] 1963; i: &46. 34. !.<vi ... P. AnlCllte dJrn a(<ipr...., smoIti", on platel .. fUnctioD. CiT",,,,,_ 1973; 43: 619-23. 35. F ..... ' v. a....brDJH. F'JC R, EIftbod Ul. Platele. survivallncl tho d ... lop ...... t a( coroc>ory .... ery cIUna< in tIx ,.,..'" adult: ./Tects .. cipto .. t .II1oItiDI. "_ family bialory and tD<dic:oJ .ho .. ",. Cimtlat;"" 1981; G. 546-51. 36. Roc. R. TIle .... trialwan lIICIatlxrooclerociJ .• b. R", MId 1979;:Ie: t-IS. . 37. SUlruo D. Thompoon GI.. 0UIey CM. Tray"", 1M. Stei"". RE. Con'lIIti", pa.tftDI 0( C'Of'OftIry Itbtrwclc:rods in aorDlOCholtttrrolaernk smoktrs and pI!ietus wirh r.milioJ bypc.cholaltrOlacmil. B, MId] 1981; 213: IJ53-60. 1073 mrnoUl) and serum alkaline phosphatase exceeding 3000 IU, encephalopathy with blood ammonia levels around 350 jig/dl (206 jimolll), and persistent increases in serum transaminases. She was treated by protein restriction and intermittent intravenous alimentation. Her management was complicated by bacterial pseudomembranous colitis which was relieved by cholestyramine. At the time of transplantation, she was small with normal vital signs. Tanner stage III pubertal changes, and tilt typical "potato face" of type I disease. She had bilateral right visual· field defects. The liver and spleen were palpable IOand6 cm below the right and left costal margins. respectively. There was no ascites. Orthotopic iransplantation (liver replacement) was done with conventional techniques}2 The donor was a 14-year-oid boy of the same blood type. Cold ischaemia' of the graft was 5 h. Detachment of the portacaval shunt, closure of the resulting defect in the iruerior vena cava, and anastomosis of the portal vein to the graft ponal vein were not difficult. Biliary reconstruction was with an end-(o-end duct anastomosis over a T·tube stent. The T-tube was clamped at 4 wk and removed at 7 wk. Postoperatively, a small bile leak and right subphrenic haematoma necessitated a minor drainage procedure. Immunosuppression was with cyclosporin and prednisone.8 After 5 wk she was discharged on daily doses of 12 mg/lc.g cyclosporinand 15 mg prednisone. There bas been no evidence of rejection. After I yr, the daily cyclosporin dose is 9 mglkg and prednisone has been reduced to 5 mglday. Results The histopathological findings in the native liver, which weighed 3400 g, were consistent with type I glycogen storage disease. There were multiple hepatic adenomas. Biochemical studies of samples quick-frozen at -70°C and stored on dry ice were done by Dr Barbara Illingworth Brown, Washington University, St Louis. The findings., including absence of glucose-6-phosphatase activity, were typical of type I glycogen storage disease (table). The glycogen concentration in the liver was 8' 7"lo. Metabolic investigations were done 6 wk postoperatively. The oral glucose tolerance test was normal after transplantation, with no hypoglycaemia at 3 h-in contrast to the grossly aberrant findings at age 8 yr, just before the portacaval shunt (fig. I). At age 8 yr, fasting for a brief period caused hypoglycaemia, whereas after transplantation, euglycaemia was maintained through a full day offasting (fig. 2). Postoperatively, in either the fasting or the postprandial state, intramuscular injection of glucagon caused plasma glucose increments greater than I QOG1o (fig. 3). Standard liver function tests have been normal for I yr. Serum or plasma concentrations of lactates, lipids, and uric acid have been normal. The patient'S lifestyle has been transformed. She eats three meals a day. For the first time in her life, she can participate in the educational and social overnight activities that are pan of normal teenage development. LIVER ENZYME ACTIVITY OF EXClSED UVER' Enzyme Glucosc-6-pllO$phalasc IkbTllDChing enzyme Phosphorylase Fruct_ diphosphatasc L ysomal • -glucosidase Patient (jAmol/minig m.er) 0'08 0·58 18·5 g'l 2·32 Controls (jAmolJminlgliftr) 3·7 -14,4 0,25- 0·75 12·6 -32'4 4'2 -15'5 0'63- 2·85 • Analyses by Dr Barbara Illingworth Brown. The liver specimen contained UDT~ glycogen (normal<5'1'.). Control patienl5 had liver biopsies bcca~ of metabolic disorders, heponomcgaly. or railure to IbriYt:. Tbe control ranges include or least 10 dilT.r.nt samples. 1074 120 2 Time (h) Fig. I-Oral glucose tolerance test al age 8 yr (before portacaval shunt) and 6 wlr. afler transplantation. I mgldl = O· 055 mmol/1. 100 6pm \ \ yA~U 120m 6pm Tillll! of day 120m 6pm Fig. 2-Response of blood glucose concentrations during fasting al age 8 yr (before portacaval shunl), and 6 wit after liver , transplantation. Discussion Type I glycogen storage disease was the first inborn error of metabolism to be classified on the basis of deficiency of a specific enzyme, glucose·6·phosphatase. 13 This enzyme is found in the liver, kidneys, and intestine. 14 Deficiency of glucose·6-phosphatase activity precludes normal breakdown of glycogen to glucose and inhibits gluconeogenesis. The consequent metabolic disturbances include growth retardation, acidosis, lactic acidaemia, hyperlipidaemia, and hyperuricaemia. IS Effective treatment for the disease has been developed only within the past two deca~esI and our patient has participated in each step of this therapeutic evolution. The first step was the demonstration that portal-systemic diversion ameliorated all of the, disease THE LANCET, MAY 14, 1983 200 160 80 o L,-_-,-I _----'-,_-----' 20 40 60 Time (min) Fia. 3-GluCDse response to 1 tug intramuscular glucagon in fastine and fed llate, , wlr. after liver transplantatioll. manifestations except hypoglycaemia. IO,16 Folkman et al17 showed that the same benefits could be achieved acutely by continuous parenteral alimentation. In an extension of this observation, Greene et alII reported such good palliation, including control of hypoglycaemia, with round-the-clock enteral alimentation that this has become the treatment of choice. The.overnight feedings. have usually been by gastric tube. Liver transplantation is a more specific option, but one which has been too dangerous to consider except for life-threatening complications such as those in our patient. However, the criteria for candidacy for this procedure will probably become less restrictive in view of the improved results with liver replacement that are being reported. I Although liver transplantation does not provide glucose-6-phosphatase directly for the kidneys or intestine, there has been no evidence of incompleteness of metabolic correction by the normally functioning transplanted liver. Tlus ",ork ",as supported by research grants from til<: Veterans AdmJOistrauoo; by project grant A.\I. 29961 from the National Institutes of Health; and by grant RR 00084 from the General Clinical Research Centers Program of til<: Di\"lSlon of Research Resources. NalIonallnstituttS of Health. Correspondence shou Id II<: addressed to J. J. .\I.. Addendum About I yr after transplantation, the patient had an episode of melaena. Oesophageal varices were the site of the haemorrhage. Superior mesenteric artery angiography and transhepatic portography revealed extrahepatic portal vein thrombosis. Excellent collatc:ra1 filling of the intrahepatic portal vein and its branchc$ was seen, indicating that the homograft still had good hepatopetal splanchnic flow. Sclerotherapy controlled the bleeding and liver functioos and carbohydrate metabolism continue normal IlEFERENCES I. SIan! TE. Marcbioro n., R_landa DT Jr. Kirkpalriclt 01, WiItoD WEe. Rilkiod D. 'lVoddeU ..... ImmuDOSUppreuioa alier "pt'i .... nt.1 ..... dinial ....... ""'Ia_ 0(1110 livcr.A •• ,s"IJ f~; ... : 411-". 2. M<rriII DA. Kirl<paaicl< 01. Wilson WEe, Riley CM. Chance in .. rum boptoslabin I)'P< followiDC ........ li.e, I,,".planlilioll. Pro< $«'b, Bioi M.t 1964; UI: 748-51. 1. KaIuwoci N. GnxII 00, Stint TE. Cbo", .. ill IUUm blptopobin and _p IptCiI'IC CGlDpooemalicrcwtbotopiclive, bomotransplantltion ill huDUtlI. 1'ro< So< Exp Bioi MIff 1968; 121: 247-50. . RqtTtlluJ corrli"utd al/ool O/1It:c1 J>att \ \ --KDK--D--~-----~-->-----~-I-~K~-K-.. r. .. .. ,..' t-,,' THE I.ANCET, MAY 14, 1983 THROMBOXANE AzlN SKIN-BLEEDING·TIME BLOOD AND IN CLOTTED VENOUS BLOOD BEFORE AND AFTER ADMINISTRATION OF ACETYLSALlCYUC ACID MARGARETA THOR. .. GREN SHAHIDA SHAFI G.V.R.BoRN Department of InUTnllI MediciFlt! and Community Health Scienu, University of Lund, pt::gtde~ and Dtpartment of Pharml1C(}/ogy, Ki1lg's co//egt, Londcm Summary The 'Simplate' technique for measuring skin bleeding time was adapted to quantify thromboxane A, in the emerging blood as the stable degradation product thromboxane B, in twelve Swedish and ten English volunteers. During the bleeding time throm-boxane B, concentrations increased, but as the rate of blood loss feII the rate of production of thromboxane A2 was constant. The English subjects had shorter bleeding times and produced more thromboxane A2 than the Swedish sub-jects. When the Swedish subjects were grouped according to bleeding times those with the shortest had more thromboxane A2 than those with longer bleeding times. Clotting venous blood in vitro produced much more thromboxane Az than bleeding-time blood and there was no correlation with bleed-ing time. Determination of the opacity of cloning blood to form thromboxane Az is therefore irrelevant to in-vivo haemostasis. Acetylsalicylic acid greatly diminished the appearance of thromboxane Az in the bleeding time and prevented the increase ofthromboxane Az concentration with time. Introduction THE extent to which physiological haemostasis depends on prostaglandins and related .endogenous agents is still uncer-tain. Inhibition of prostaglandin biosynthesis by acetylsali-cylic acid is associated with increases in bleeding time.l-3 Some familial bleeding tendencies are associated with deficiencies in the synthesis ofthromboxane A, by platelets.4 Neither of these raise bleeding time by more than about twice. Studies in human beings given thromboxane-Az-synthetase inhibitors indicate that haemostasis depends only to a minor extent on thromboxane A2.5 We have alreadY shown that the impairment of human haemostasis by acetylsalicylic acid or by a diet enriched with fish, both of which diminish prostaglandin formation, occurs by different mechanisms.6,7 To determine the contribution of thromboxane A2 to primary haemostasis of healthy human beings in vivo, we measured thromboxane Az (as its stable 1075 metabolite thromboune B2) in blood coming from standard incisions made for determining skin bleeding time and the thromboxane A2 produced during in-vitro clotting of venous blood from the same individuals, determined before and after they ingested one dose of acetylsalicylic acid. Subjects and Methods The subjects were twelve apparently healthy Swedish male volunteers (mean age 29±1 SEM years) who had taken DO drugs for at least 2 weeks before these investigations. Mter an overnight fast for 12 h the bleeding time was determined on one arm. From a similar incision OIl the other arm blood was collected for thromboxane B2 determinations. Thromboxane B2 was also determined in a blood sample from the antecubital vein of that arm. A fortnight later the determinations were repeated before and 2 h after oral administration of a single dose of acetylsalicylic acid (5 mg/kg body-weight). In ten similar English subjects, bleeding times and thrombolWle B2 levels in bleeding-time blood were determined once in the same way. Bleeding times were determined by the same observer in all the subjects. Bleeding times were determined with the standard 'Simplate I' device (General Diagnostics Inc).8,9 The blood emerging from [he skin incision was removed quantitatively every 305 with a disc of filter paper (Wharman no I) until bleeding stopped. The bleeding· time·blood volumes were measured by eluting tbe spots of blood from the filter paper into DflIbkin's solution as previously described. 7 In each eluate the haemoglobin concentflltion was determined spectrophotometrically and the corresponding blood volume obtained from standard curves. The results were expressed as,..1 of blood emerging in each 30 s period.. Thromboxane Az ronctntflltions in the bleeding-time blood were determined by radioimmunoassay of the stable degradation product thromboxane B2• The blood emerging from skin incisions made by the simplate I device was collected in 1 min periods into capillary tubes containing !mown volumes of a mixture of 100 mmolll ethylenediamine tem-acetic acid and 5· 59 mmolll indomethacin to inhibit in·vitro formation of thromboxane B2. After mixing, the tubes were CCatrifu~ at 15 000 g for 2 min. The clear supernatants were removed, frozI:n, stored at - 20°C, and assayed later for thromboxane B2• The thromboxane B2 standard (U51541 lot 0071-CLM.()59C) and the antibodies against thromboxane B2 (21) were kindly supplied by Dr John Pike of the Upjohn Company, Kalamazoo, USA, and Dr John Vane of the Wdlcome Foundation Ltd, Beckenbam, UK, respectively. The total amounts of thromboxane B2 formed in the bleeding-time blood were calculated for each individual by summing the products of the concentflltions and the volumes of successive blood samples. Thomboxane B, formation was determined also in the serum from blood collected by venepuncture into glass tubes in which it was made to clot by incubation at 37°C for 1 h. The tubes were centrifu~ at 2000 g for 10 min, the supernatant sefll sepafllted, frozen, stored at - 20·C, and assayed for thromboxane B, by the same procedure. The results wue enluated statistically by Student's I test. J. I. MALA TACK AND OTHERS: REFERENCES-t:tmrilllUld 4. Kasbiwali N. Special immunocbemiaJ studi ... I.: Surzl TE, ed. Ea",,_ in Ixpatic t ..... pl.nt .. _. Philadelphia: W 1 Satu>d<11, 1969: 394-407. 5. Alpor CA,JobJllOn AM, linch AG, M ...... FD. Humon CD~I Evidence for tbe liver. tlx primary Ii .. o/'symbcsis. sa.-1969; 10: 286-88. 6. Alper c.. JlJum 0, Awdth 1., mKt~ncK BH, T.ylor PO, Starzl TE. Stlidies oI'hcpotic 'r.tlxli. '" .... of pQsma proI<iDo, iDcNdinc O<OIOfI)ucoid, thnaf.rrin, .lp .... l· .ntitrypsin, C8, .nd Factor I. eli. I .... "", I .. ",."""",,,,,, 1980; I.: 84-89. 7. Raum 0, MarCUI 0, Alper CA, Lewy" T.yl ... PO, St.rz! TE. Syntlxs;' oI'bu"",. plaamino,.. by the tiftr . .sama 19110;211,1036-37. 8. Stanl TE, l ... tIUki S, V ... Thiel OR, GenMr Ie. litem B1, MalatKk JJ, Schade JUt, Shaw BW Jr, Hobla TR, ItaocadIoI JT, Porter ItA Evolution 01' liftr tr ... pla ... ,ion. e~ 19112; 2: 614-36. . 9. Zi .. 1li 8J, M.latadt JJ, Gut .. r Je. $bow IW Jr,lwatluki S, Starzl TE. Onbolopic: li .. r ' .... plantati ... ill children wid> bepotic-llu<d lJICubolic di_. Tlflrupl .. ,P_(inpresaj. 10. St.rzI TE. Putnam CT, Po".r ItA, IbJcrimsoo CG, Connan I, Brown 81, Gatlin R W, Rod&cnon DO, Greenc HL Portal di""';on for the treatmen' 01' ",..... storale diKaK in _. Aw. s.., 197 1; 17.: 5Z5-19. II. G,ee .. H1., SIaaim AE. Neil 0, Burr 1M. Con.inuous """,._1 intr ..... ric feedinl for _ .. _ 01' typo I "yeOC.n l1ora,. di ..... N E.,I J Mid 1976; ZH: 421-25. IZ. Starzl TE (wid> d>c ..atanc< 0( Pu,aam CWj. bapcrit~ in bcpotic transplan ••• ion. Philadelphia: W 1 s.uDdeI1, 1969: 1-551. 13. Cori GT, Cori CF. O"C--6-pIIoop/>a .... in tlx li..:r in ,I)'tOCtft Ilon", di ..... J Bit>la-I9S2;_661-67. 14. Nord/it RC. omc-+plMapbawo, bydrolytic.nd .,ntlxti< Ktivi.ies. I.: Boytr PO, cd. The _ New York: Academic: Pr..., 1971: 50-610. 15. Greene HI., SIoooim AE. Burr 1M. Type 1,Iycocen 110111< diorMc: I ... rKbo~c basis i for adnDca iII...--. Adv PIIhoa" 1979; II: 61-92. 16. Starzl TE, ~ n.. Seat ... loW, lIlinporrb B, W .... U wa, fares TO, Hemnana TJ. no. dI' ... o(porrocavol ,ranlpoai,ion on c:arI>obyclrll< mC1lboli ... , Eapcri_1DII diAia/ absemot ....... s.'I"Y 1965; 11. 617-97. 17. fol):O' .. n), PIIiIippart A, Tu WJ, Crilkt J Jr. PortacaYl11lluM (0< ")'COC.n srora,. disc»<: ... 0( proIonced intr""""" bypo •• li ... n .. ti"" before IUI,ery. S.rlfry 1972; 72: 31»-14. 

LIVER TRANSPLANTATION FOR TYPE I GLYCOGEN STORAGE DISEASE

J Jeffrey Malatack

Shunzaburo Iwatsuki

J Carlton Gartner

Thomas Roe

DavidN Finegold

ByersW Shaw

BasilJ Zitelli

ThomasE Starzl

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LIVER TRANSPLANTATION FOR TYPE I GLYCOGEN STORAGE DISEASE

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