ALPHA-1-antitrypsin deficiency associated with chronic obstructive airway disease was recognized in 1963 by Laurell and Ericksson.1 In 1969, Sharp2 described the first cases of alpha-1-antitrypsin-deficiency disease in children with cirrhosis. Since then, this inborn error has been recognized as one of the more common factors in cirrhosis of infancy and childhood,3 including “neonatal hepatitis.”4 Alpha-1-antitrypsin is a glycoprotein that accounts for a major portion of the alpha-1 globulin fraction of the serum.5 It is responsible for approximately 90 per cent of the antitrypsin activity6 of the serum, and it also inhibits several other plasma enzymes, including plasmin,7 elastase,8 collagenase,9 and. © 1980, Massachusetts Medical Society. All rights reserved

Allan G. Redeker

Anonymous

Brand

Eisen

Fagerhol

Gastel

Gerhard P. J. Schröter

Hirschberger

Jacobsson

Janoff

John M. Hood

Kueppers

Kuhlenschmidt

Laurell

Lawrence J. Koep

Odièvre

Putnam

Richard Weil

Robert L. Peters

Rynbrandt

Sharp

Thomas E. Starzl

Tálamo

English

PubMed

Hood, JM

Koep, LJ

Peters, RL

Schroter, GPJ

Weil III, R

Redeker, AG

Starzl, TE

Name not available

Liver transplantation for advanced liver disease with alpha-1-antitrypsin deficiency

Schröter, GPJ

Weil, R

D-Scholarship@Pitt

, LIVER TRANSPLANTATION FOR ADVANCED LIVER DISEASE WITH ALPHA-I-ANTITRYPSIN DEFICIENCY JOHN M. HOOD, M.B., B.CH., F.R.C.S., LAWRENCE J. KOEP, M.D., ROBERT L. PETERS, M.D., GERHARD P. J. SCHROTER, M.D., RICHARD WElL, III, M.D., ALLAN G. REDEKER, M.D., AND THm.fAS E. STARZL, M.D., PH.D. ALPHA-I-antitrypsin deficiency associated with n chronic obstructive airway disease was recog-nized in 1963 by Laurell and Ericksson. I In 1969, . Sharp' described the first cases of alpha-l-antitryp-sin-deficiency disease in children with cirrhosis. Since then, this ·inborn error has been recognized as one of the more common factors in cirrhosis of infancy and childhood,] including "neonatal hepatitis." 4 Alpha-t-antitrypsin is a glycoprotein that accounts for a major portion of the alpha-l globulin fraction of the serum. S It is responsible for approximately 90 per cent of the antitrypsin activity' of the serum, and it also inhibits several other plasma enzymes, including plasmin,' elastase,' collagenase,' and chymotrypsin. 'o Cirrhosis de\;e1ops in about 15 per cent ·of patients with homozygous phenotype PiZZ (Pi = protease in-hibitor), II and there have been a few recent reports of cirrhosis in heterozygous patients. 12•n There has been no effective, specific medical treatment for such patients. This report will examine the place of orthotopic liver transplantation in the treatment of seven white patients who had end-stage Ih'er disease due to alpha-I-antitrypsin deficiency. After transplan-tation, the phenotypes of the recipients became those of the donors, and alpha- 'l--antitrypsin levels were restored to normal. Thus, the metabolic basis of the From the Department of Surgery. University of Colorado Heahh Sciences Cenler. the Veterans Administration Medical eenler, Den'·er, Colo .. and the departments of Pathology and Medicine, Rancho los Amigo, Hospital. Downey. Calif. (address reprint requests to Dr. Slarzl al Box C·305, Univer· sity of Colorado Health Sciences Center. 4200 East Ninth Ave., Denver, CO 80262). Supported by grants from the Veterans Administration. ,rants (AM·17260 and AM·07772) from the National Institutes of Health, and ,rants (RR-OOOSI and RR-000(9) from the General Clinical Research Cen· ten Program of the Dh'ision of Research Resources, Nationallnstitutc5 of Health. Dr. Hood participated while on study leave from thc Dcpartment ()f pur~nyI The Queen's University of Belfast, 8dfast, Nonhcrn Ireland. discas(' was corrected for as long as the patients sur-vh'cd the transplantation procedure. Three of the patients are still alive after t3, 21, and 36 months. TIle others died between 12 days and 28 months after transplantation. METHODS Liver replacements were performed in seven patients who had alpha.l.antitrypsin deficiency disease. One ofthese cases has been reported previously." Phenotypes for alpha.l.antitrypsin (Pi) were determined by means of acid·starch electrophoresis followed by crossed immunocle(:trophoresis. as described e1sewhere. u", The nomenclature recommended by the International Alpha-t-anti-trypsin Pi Committee was used." The normal alpha· I-antitrypsin values were established by means of analysis of serum, from 22t3 Red Cross donors in I..os Angeles. all with the phenotype MM. The range of 140 to 470 mg per 100 ml encompassed approximately two standard deviations from the mean. CASE REPORTS Case 1 This case has been reported in detail previously." A 16-year.old girl with alpha-t-antitrypsin.deficiency lh'er disease had an oMho-topic liver transplant in November. 1973. After transplantation her phenotype became MM, identical to the donor's. The graft func-tioned well for 11,7 years but then deteriorated from chronic rejec-tion during the next nine months.· Retransplantation was carried out in February, 1976. and again tht're was change to the donor phenotype, in this case MZ. She died of infection five weeks after the operation. Case 2 A IS-year-old boy who had had a "neonatal hepatitis" was found to have a deficienc), of alpha-I.-antitrypsin and cirrhosis with progressive Ih'cr failure. Lh'cr transplantation was performed in November. 1976. After the operation pneumatosis c),stoides intes· tinalis and rectal bleeding de\·e1oped, necessitating a subtotal col-ectomy. He was discharged in April, 1977. and remains well with normal liver function three years later. Case 3 A 25-year.old man had been wdl until hi$ 17th year, when he had right-sided abdominal pain. At laparotomy, splenomegaly and cirrhosis (Laennec's) were diagnosed. In 1976, at 25 years of age, he had a second lh'er biopsy; the diagnosis of alpha.l·antitrypsin deficiency was established. Because of progressh'e hepatic failure, liver transplantation was carried out in December, 1976. Portal-vein thrombosis was found, requiring phlebothrom~ctomy before an end-to-end portal-\'ein anastomosis could be attempted. After the operation he had progressh·e liver failure. and a second trans· plaination was performed 10 days later. The recipient pOMal vein was clotted. and the second graft was inserted without a pOMal in-flow. The liver failure was not relieved, and he died two days after retransplantation. • Case 4 A fi\'e-year-old girl had been found to have alpha.l.antitrypsin deficiency shortly aftl'r biMh. Hepatic transplantation was per-formed in February, 1978, because of cirrhosis and liver failure. An unsuspected tumor consisting of primitive hepatoC)·tes without neoplastic stromal elements but with some features of hepatoblas-toma was found. She has done well for 21 months and has normal liver function. Reprinted from the Xl''''' England Journal of Medicilll' . 302:272-275 (January 31). 1980 -------------------~------K---------.. I, I Cllse 5 An CDighl-FD~ar-old boy had been found to ~ayDc ~fpha-f-flnlilrFDp­sin-dcCidenc)' disease: in infancy. e~ had cirrhosIs, porlal h)11er-tension, and recurrent bh:eding from esophilgl'al ,·arices. Ortho· topic Ih'cr transplantation "'as carried out in pcpte~ber! .1971:1. Initially, the Ih'er functioned well, but. he de\'doped per!tomus and required three explorator}' laparotomies. At Ci.rst, only Infected "~­eitic fluid was found. but later a lefl subphremc abscess and multi-ple Ih'cr abscesses developed. He diedin November, 1978, of sepsis. Case 6 An II-)'ear-old boy had been found to ha\'e "neonellll hepaJitis" and was subsequently shown to have alpha-l-antitrypsin-deficienc), disease. Because of progressive cirrhosis and ascites, he had an orthotopic Ih'er transplant in October, 1978. He remains well with normal liver function \3 months after transplantation. Case 7 A 9~I -year-old girl had been jaundiced shortly after birth and had progressive Iiyer disease. She was thought to have cf)'Ptogenic cirrhosis but was later shown to be heterozygous for alpha-I-anti-trypsin deficiency. Transplantation was performed in January, 1979. She did well for seven weeks after the operation and then died suddenly from a pulmonary embolus. RESULTS The cases are summarized in Table 1. None of the patients had clinical or laboratory evidence of ob-structive lung disease. Liver failure was the reason for transplantation. After transplantation, good initial graft function was obtained in all but Case 3. The final liver function obtained in each recipientis shown in Table 1. Several serum alpha-I-antitrypsin deter-minations were available for each patient; represen. tath'c individual values at specific times a~ shown in Tanle t. After transplantation, the Pi types of the recipicnts matched those of thc donors (Table 1). DISCUSSION I t is thought that the Pi alleles are inherited as co-dominant alleles, with each allele responsible for the production of its own type of alpha-l-antitrypsin. Chromosome 2 probably carries the Pi aJlck. l ? PiM is the most common allele, with a frequency that varies geographically. In the United States its frequency seems to be 0_938 to 0.950. 11 In people of European ancestry the Z allele has an incidence ol 0.010 to 0.016." Although alpha-I-antitrypsin deficiency is typically associated with either obstructive lung disease or childhood cirrhosis, it has been reported in associa-tion with such diverse conditions as chronic pancrea-titis,19 glomerulonephritis,20 rheumatoid arthritis,21 subcutaneous and systemic panniculitis,u a <:onnec· tive-tissue disorder similar to the Ehlers-DanJos syn-drome,2J and a multisystemic fibrosis. 2• The liver disease associated with alpha-I-antitryp-sin deficiency usually presents as cholestatic jaundice within the first three or four months of Jire,25 and ac-counts for approximately40 per 'cent of aU jaundice in the first. two months of life.2i The condition then usually abates until late childhood or early adoles-cence, when cirrhosis and liver failure appear. The severity of the later disease does not appear related to the degree of jaundice in the early months. %7ln a small Table 1. Characteristics of Seven Patients Who Underwent liver Transplantation for Treatment of Liver Disease with Alpha-1-Antitrypsin Deficiency. CASE )\;0. PHfSOHPfOF PHfSOT\'PE ALPHA-I· B,L/lll.,st hOTHRO., .. " Outc:o.cE RfCIPlf"'T OF DoNOR IEFOJ.£ T.",s-AhllTa, ... PSIN LEVEL- TIMEt PLA:\"TATIOS I£FOkE A"U IEfOllE AFTER IIHORE A"fl qfKAkp~ nllss- TRANS- rR."ss· qKA~"p· TUNS-PL.\!'Io'TA· miy~""· PLASTA- 'L4"TA- miAK~KA· PlA!'I."A-nON TIOS TIOS TIOS TlOX TIOS ''<If'Cdooml "'BI'" looml su ZZ MM (1st) .5.5 264 (.540)§ 27.0 0.6 21 12 Retransplantalion after 27 mo. MZ (2d) Died 5 wk later. 2 ZZ MM 120 420 (ISO) 30.0 O.S 21 II Alive'" weill,... .fter transplantation. 3 ZZ MM .55 140 (8) 41.0 25.0 19 20 Retransplantalion after 10 days. Died 2 days tater .. 4 ZZ MM 20 240 (70) 6.0 0.7 18 II Alive'" well 21 mo after transplaDtation. S ZZ MM .55 390 (18) 10.0 11.0 14 23 Died of sepsis 54 days after transplantation. 6 ZZ MM 30 360 (10'" 4 . .5 0.3 12 11 Alive'" wdI13 mo 36S) afler transplantation. 7 MZ MM 40 190 (33) 60.0 1.0 30 10.S Died rrom pulmonary emboli 53 days after transplantation. ·Ttl. Dorm.1 ran,. is 1.0 to 470 ma per 100 mI. 'The norm.l value is I., ma per 100 m1. Values after transplantation "ere lhe last analyses in the patienls who died; Ihe \'Ilue, on: ~urrKnt for ""Iionl$ still alioc. *In controls. lh. lime ,·ari .. from 10.S to 12 seconds. tFilurcs in ""rrntheses denote nwnher oC days .Cler lim transplantalion that analysis ..... performed. , t . number of patients resolution of the disease occurs.a Patients who do not develop the cholestatic pattern of disease are usually identified either when they present with hepatosplenomegaly or when a sibling is found to have the disease; without liver transplantation, they usually die in childhood or early adulthood from gas-trointestinal bleeding or progressive liver failure. .Fagerhol and LaurelpQ were the first to determine the phenotypes of patients on the basis of antigen-antibody crossed electrophoresis. With this test many polymorphic variants have been identified. The im-portant variant from the clinical standpoint is the homozygote PiZZ, in whom the level of alpha-I-anti-trypsin is 1 to 15 per cent of normal. With the PiNull phenotype that was discovered by Talamo et alK~ there is virtually no measurable alpha-l-antitrypsin, and there is an association with liver disease. The serum level of alpha-l-antitrypsin is less reduced with the mi~fw phenotype, and the clinical implications are less ominous. The pathophysiology of alpha-I-antitrypsin disease is not understood, but much evidence points to the role of the liver in influencing serum levels of the alpha protein. The characteristic histologic feature of the liver of patients with the Z alJele is a rounded cyto-plasmic inclusion body, which is diastase resistant· and positive for the periodic acid-Schiff stain. The in-clusion body is found near the rough endoplasmic re-ticulum and can be shown to be alpha-l-antitrypsin by means of immunochemical methods.) \Vhat causes retention of this material in the liver is not known, but the explanation is almost certainly related to an ab-n.ormal glycoprotein portion of the alpha-I-antitryp-S10 molecule. Jt Early reports suggested that this ab-normality in the glycoprotein '\1as simply a deficiency of sialic acid,'2 but more recently it has been recog-nized that there is also an absence of galactose, an ap-preciable decrease in N-acetylglycosamine, and an almost twofold increase in mannose residues." It has been suggested that such biochemical abnor-malities interfere with the transport of alpha-I-anti-trypsin into the bloodstream from the interior of the hepatocyte where it is synthesized. Some of this ab-normal alpha-I-antitrypsin could diffuse passively into the bloodstream, accounting for the fact that even in the deficient state alpha-I-antitrypsin is not totally absent from serum. If the disease is primarily a failure in the transport of an abnormal protein, the nature of the enzymes responsible for the defective synthesis is unknown. Furthermore, the variability of clinical manifestations is perplexing. All persons with the Z allele accumu-late alpha-t-antitrypsin in their hepatocytes, but ap-parently not all develop liver disease even with the PiZZ state, and hepatic complications are less com-mon in persons with the single-Z-allele states PiMZH and PiSZ. ,. Our heterozygous patient (Case 7) had very low le\'els of alpha-I-antitrypsin before trans-plantation (Table 1); her clinical course and liver his-topathology were entirely consistent with the disease. Although the precise pathophysiology of the dis-ease has not been elucidated, the crucial role of the liver is well demonstrated by the data presented here. h has been shown previously in single-case reports both by us" and by Sharp)! that the phenotype of the recipient becomes that of the donor; this more exten-sive series confirms that such a change occurs. Fur-thermore, data from prolonged follow-up are avail-able on three patients who are still alive, and after periods of up to three years there has been no evidence of reversion to the original phenotype or of a--eiminu~ tion in the serum levels of alpha- t -a ntitrypsin. It seems, therefore, that although the manifestations of the disease are many and variable, the fundamental defect lies within the liver and can be corrected by means of liver transplantation. It remains to be shown that patients who have successful liver transplants are immune to the development of other complications of the disease, such as lung disease, but to date no other complications have been seen. REFERENCES 1. LaureH CoB. Ericksson S. The electrophoretic a I-globulin paltern of serum in patients with G.·antitrypsin deficiency. Scand J Clin Lab Invest. 1963; 15:132-40. 2. Sharp HL. Bridges RA. Krivit W. et a!. Cirrhosis associated with Ilphl-I-antitrypsin deficiency: I previously unrecognized inherited disorder. J Lab Clin Mee!. 1969; 73:934-9. . l. Aascnaes 0. Faserhol M. Elgjo K. Munthe E. Hovig T. Pathology and pathosenesis of liver disease in alpha·l·antitrypsin deficient in-dividuals. PoslBrad Mcd J. 1974; 5O:36507S. 4. Talamo RC. Feingold M. Infantile cirrhosis with hereditary alpha-,-antitrypsin deficiency: clinical improvement in t .. ·o siblings. Am J Dis Child. 1973; 115:84507. 5. Lieberman J. Gaidulis L. Garoutte B. Mittman C. Identification and characteristic. of the common alpha·,-antitrypsin phenotypcs. Chest. 1972; 62:557-64. 6. Jacobsson K. Studies on the trypsin and plasmin inhibitors in human serum. Scand J Clin Lab Invcst (SuppIJ. 1955; 14:55·102. 7. Cra .. :ford GPM. Ogston D. The innuence of a-I-antitrypsin on plasma. urokmase and Hageman factor cofactor. Biochim Biophys Acta. 1974; 3504: 107-13. 8. Janoff A. Inhibition of human granulocyte elastase by serum a,-anti-trypsin. Am Rev Respir Dis. 1972; 105:121-2. 9. Eisen AZ,Bloch KJ. Sakai T. Inhibition of human skin collagenase by buman serum. J Lab Clin Med. 1970; 75:258·63. 10. Ohlsson K. Neutral JeuCOC)1e proteases and elastase inhibited by plasma alpha,-antitrypsin. Scand J Clin Lab In\·cst. 1971; 28:251-3. II. Sharp HL. The current status of G·1-antitrypsin. a protease inhibitor. in gastrointestinal diseasc. Gastroenterology. 1976; 70:611·21. 12. Brand B. Buahler GH. Gould R. Cirrhosis and hcterozYlous FZ ai-antitrypsin deficiency in an adult: case report and review of the literatufC. Gastroenterology. 1974; 66:264-8. 13. Morin T. Manin J.p. Feldman G. Rueff B. Benhamou J-P. Ropanz C. Heterozygous alpha-I-antitrypsin deficiency and cirrhosis in adults, • fortuitous association. Lancet. 1975; 1:2s()'1. 14. Putnam CWo Porter KA. Peters RL. Ashcavai M. Redeker AG. StlIrzl TE. Liver replacement for alpba-.-antitrypsin deficiency. Sursery. 1977; 81:258·61. IS. Rynbrandt DJ. Ihrig J. Kleinerman J. Serum trypsin inhibitory capacity and Pi phenotypes. J. Methods and control values. Am J Clio Pathol. 1975; 630:251-60. 16. Anonymous. International Alpha-I-Antitrypsin Pi System Workshop. Lancet. 1975;1:118. 17. Fagerhol MK. The genetics of alpha-I-antitrypsin and its implications. Postgrad Med J. 1976; 52:Suppl 2:73-9. 18. Kueppers F. Black LF. G,·Antitrypsin and iii deficienc). Am Rev Respir Dis. 1974; 110:176-94. 19. Novis BH. YounS GO. Bank S. Marks IN. Chronic pancreatitis and alpha-I.antitrypsin. Lancet. 1975; 2:748-9. 20. Roy LP. Webster HL. G,-Antitrypsin and mcmbranoprolifcrative glo-merulonephritis. Pediatrics. 1977; 60:784. 21. Cox DW. Huber O. Rheumatoid arthritis and alpha.l-antitryrsin. Lancet. 1976; 1:1216-7. , 22. Rubinstein HM, J.ffer AM, Kudrna JC, et ,I. Alph.·,·antitrypsin deficiency .·itb levere p.nniculitis: report of two cues. Ann Intern Mcd. 1977; 86:742·4. 23. Sch.ndcy)·1 W, Hennebert A. LeBlanc 0, et al. Alpha.l·antitrypsin deficiency of Ihe PiOO type and connective tissue defect. In: Manin JP. cd. L'Alpha.l·antitrypsine ct Ie Systtme Pi. Paris: INSERM, 1975: 97· 107. 24. Pilimer fE. Wolfe HJ, KOSlas C·I. Multisystem fibrosis in alpha·l· antitrypsin deficiency. L.ncel. 1978; 1:221·2. 2S. Odihre M, Martin J.p, Hadchouel M. AI.gille D. Alph.,·antitrypsin deficiency and !i"er disease in children: phenotypes, manifestations. and proanosi,. Pediatrics. 1976; S7:226-3 I. 26. Gastel B. Alpha·l·antitrypsin deficiency. Johns Hopkins Med J. 1971; 142:67·71. 27. Moroz SP, CUll E, Cox OW, SU$-K"rtsak A. Liver disease associated with alpha·l.antitrypsin deficiency in childhood. J Pediatr. 1976; 88:19· 2S. 28. Hirschberger M, Stickler OB. Neonatal hepatitis and alpha·l·antitryp· sin deficiency: the proanosis in five patients. Mayo Clin Proc. 1977; S2:241·S. 29. hatrhol M K, 'Laurell C·B, The pol)'morphism of "prcalbumins" and o"antitf)!"in in human sera. Clin Chim Acta. 1967; 16: 199·203. 30. Tal3mo RC. Lafl,lcy CE, Reed CE, Makino S. a,·Antitrypsin . deficiency: a variant ""th no detectable a I·antitry~inK Science. 1973; 181:70·1. 3t. Bell OF. Carrell RW. Basis of the defe" in alpha·I·lntitr)psin deficiency. Nature. 1973; 243:41()"1. 32. Kllhlcnschmidt MS. Yllnis EJ, I.mmarino RM, Turco SJ, Pelen SP, Olew RH. Demonstration of sialyltransrerasc deficienc), in the serum of • patient "'ith a·l·antitrypsin deficienc), and hepatic arrhosis. Lab Invest. 1974; 31:413·9. 33. Hera A, Katona E, Clill E, el al. Alpha·l·antitrypsin: the presence of excess mannose in the Z \'ari.nt isolated rrom liver. Science. 1978; 201: 1229·32. 34. Ch.n CH, Steer CJ, VCflllI., Jones EA. Alpha-I·antitrypsin deficiency with cirrhosis associated with the protease inhibitor phenotype SZ. Am J Med. 1978; 6S:918-86. 3S. Sharp HL. Alpha·l.antitrypsin deficiency. Hasp Prac:t 1971; 6(S):83 •. 96. "'Copyright, 1980, by the Massaahusells Medical po~iety Printed in the U.S.A. \ 

Liver Transplantation for Advanced Liver Disease with Alpha-1antitrypsin Deficiency

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New England Journal of Medicine

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Liver Transplantation for Advanced Liver Disease with Alpha-1antitrypsin Deficiency

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