A 16-year-old girl with advanced cirrhosis and severe alpha1-antitrypsin deficiency of the homozygous PiZZ phenotype was treated by orthotopic liver transplantation. After replacement of the liver with a homograft from a donor with the normal PiMM phenotype, the alpha1-antitrypsin concentration in the recipient's serum rose to normal; it had the PiMM phenotype. Two and a third years later, chronic rejection necessitated retransplantation. Insertion of a homograft from a heterozygous PiMZ donor was followed by the identification of that phenotype in the recipient's serum. Neither liver graft developed the alpha1-antitrypsin glycoprotein deposits seen with the deficiency state. These observations confirm that this hepatic-based inborn error of metabolism is metabolically cured by liver replacement. © 1977

Ashcavai, M

Peters, RL

Porter, KA

Putnam, CW

Redeker, AG

Starzl, TE

D-Scholarship@Pitt

Reprinted from SUROERY, St. Louis . . V ol. 81 , N o. 3, Pages 258-261, March , 19 77 ( Printed In the U. S. A.) ~ (Co pyrig ht © 197) by The C. V. Mos by Company ) . ~1E Liver replacement for alphal-antitrypsin deficiency Charles W. Putnam, M.D., Denver, Colo., Kendrick A. Porter, M.D., London, England, Robert L. Peters, M.D., Mary Ashcavai, B.S., Allan G. Redeker, M.D., Los Angeles, Calif., and Thomas E. Starzl, M.D., Ph.D., Denver, Colo. A 16-yu/.r-o{d girl {uitll advanced cirrhosis and sewn' alpha ,-mllitrypsin deficiency 0/ the homozygous p?Z phenotY/Je was treated by orthotoj}ic liver transplantation. A/tel' repklCfment 0/ the liver lui tli a homograft from a donor with the normal PiM,>} plu:notype, t.he alpha ,-antitrypsin concentration in the recipient's serum rose to normal; it had the Pi"1.lI phenotype. Two and a third years later, chronic rejection necessitated relrausplalltatioll . Insertion 0/ a homograft from a heteroz.ygous PiMZ donal' was /olloll'ed by the identijicatio n o/ Ihat phenotype in the 1'ecipient's serum. Neither liver graft developed the alpha ,-antitrypsin glycoprotein deposits seen with the deficiency state. These observations wnjinll that this he/Jatic- based inborn enol' 0/ metabolism is metabolically l'lIred by hvn' re j}lacemel1t. From the Department oj SU1'gery, Veterans Administration Hospital and University oj Colorado M edical Center, Denver, Colo., the Department oj Patholo!!:y, St. M ary's Hospital M edical School, L ondon, England, the Departments oj Palhology and Medic ine, University oj Southern California, Los Angeles, Calif. A L PH A ,- ANT I T R YPS I N, an inhibito r o f pro teolytic enzy mes such as tr ypsin , ch)lmotrypsin , a nd co ll age-nase, is th e major alpha,-globulin of human plas ma. H e redi ta ry alpha ,-antitrypsin defici e ncy, homozy-go us ph enot)'pe ZZ , predisposes to conge ni ta l in fa n-til e cirrhosisl 8 a nd, occasionally, adult cirrhos is,22 pul-mona ry emph yse ma o f early onset in a dults," and , ra re ly, both he patic and pulmonary di sease in child-hood" or ad ul t li fe? Two and a h alf yea rs ago, we ca rri ed out li ve r re-place m ent in a 16-yea r-o ld pati ent with seve re cirrhosis ca used by a lpha ,-antitrypsin defi ciency, Pizz ph eno-type. Folloh'iog the o pe ration the a lpha ,-a mitryp-Sill ph eno type and co ncentra ti on reve rted to nor mal. Sup ported by resea rch grams MRIS 811 8-01 and 7227-01 from ,he Ve terans Administration , by Grant Nos. AM-17 260 and AM-07772 from the National Institutes o f Hea lth , by Gran t Nos. RR-OOOSI and RR-0069 from the General Cli ni-cal Resea rch Centers Program of the Division o f Resea rch Reso u rces, Na tio nal Institutes of Health, and by th e J osiah Macy, J r., Founda tion (Dr. Starzl). Presen ted at the Second Ann ual Mee ting of th e Ameri<;a n Society of T ranspla nt Su rgeons, Ch icago, 111. , May 20-22, 1976. Re print req uests: Cha ri es W. Putnam, M. D., Ve te rans Ad-ministration HospiIaJ , 1055 Cle rmo nt St. , Den ve r, Colo . 80220. 25 8 S U R G ERY March,1977 When the gra ft was r~j ec te d and retransplanta ti on was perfo rm ed 2'/3 yea rs la te r, th e recipient again adopted the d onor ph enotype , this time the het-e rozygous Pi 'Vl Z fo rm. MATERIALS AND METHODS Pi phenotyping was done by discontinuous acid s tarch electro pho resis fo llowed by counte relectro-pho resis o f the sta rch block in to agar containing goa t antihuma n a lpha ,-anti try psin a ntise rum, as de-sc ribed by Fagerho l a nd La ure ll .6 T he a lpha ,-a nti-trypsin concentration was measured by an immuno-che mical techn ique .'2 H e patic transplamati on was pe rforme d as reported prev iously.20. 2' Liver specime ns were prepared for light and electron microscop y, as desc ribed e lsewhere 20 In addition, horseradish per oxidase la be led antibody to alphat-antitrypsin and pe ri odi c acid Schiff reagent a fte r di astase digesti on we re used. CASE REPORT A 16-yea r-old Caucasian girl (OT 74) with HBs Ag nega-tive, coa rsely nodular cirrhosis was treated by orthoto pic liver tra nsplantation o n Nov. 16, J 973. She made an uneventful recove r y fro m her mo ribund preopera tive state a nd was in good health for more th an 1 V2 yea rs. Gra ft fun cti on then Vol. 8 1, N o.3, pp. 258-261 Volume 81 Number 3 Liver replacement for alphal-antilTypsin deficiency 259 Fig. 1. Sections of the patient's own cirrh otic li ve r from Case OT 74. A. Treated with periodic acid Schiff reagent after digestion with diastase. Stained cyto plasmic globules of varying size are present. (Original magnification x25 0.) B, Reacted with rabbit antihuman alpha,-antitrypsin serum by the three layer immunoenzyme technique and counterstained with methyl green. The result is positive . (Original magnification x250.) (From Palmer, P. E., Delellis, R. A. , and Wolfe, H. J.: Immunohistochemistry of liver in alpha,-antitrypsin deficiency. A compa rative study, Am. J. Clin. Pathol. 62: 350, 1974.) deteriorated steadily to the point that on Feb. 17 , 1976, '27 months after the first liver replacement, re transplantation be-came necessary. Five weeks later, after a stormy postoperati,'e course, she died of pulmonary insu ffi cie ncy. PATHOLOGIC STUDIES The diagnosis of th e original liver di sease was car-ried as e nd stage chronic aggressive hepatit is ulltil re-vi e,,· of the case more than a year later. The correct diagnosis for the cirrhotic liver "as esta blished by li ght microscopy of sections stained ,,'ith periodic acid Schiff reagent after diastase digestion and by imnltlnoelec-tron microscopy (Fig. I). Th e histo pathologic features in consecutive biopsies ot the first homograft represented a combination of subacute and chronic rejection. Follo"'ing a mild rejec-tion episode, the g raft developed cen trilobular choles-tasis "ith bile "thrombi. " Over the next fell ' months some of the hepatocytes became swollen and their ar-rangement. became disord e rly, The amount o f portal connective tissue increased and septa began 10 sub-divid e the liver lobules. About 2 years afte r the acute rejection episod e, the homograft became cirrhotic (Fig. 2, A) and 3 months later had to be removed. The second homograft II';}S not rejected and when the patient died the only abno nnality of the liver "'as some fatty infiltration (Fig. 2, C). There was no ac-cumulation in eithe r hotl)ograft at any time of tbe dis-tinct ive eosinophilic material which is diastase resistant and detect ed lI'ith the periodic acid Schiff reage nt and by immunoelectron microsco py \\'ith peroxidase labeled antibody to alpha I-antitrypsin (Fig. 2, B and D). SEROLOGIC STUDIES A savecl peroperative seru m sample from the recip-ient contai ned 55 mg. per 100 ml. ot' a lpha,-antitryp -sin; the phenotype \Ias pjZz (Table f), A serum samp le from the first organ donor had a normal a lpharantitrypsi n phenotype (Table I). After liver re-placement, the recipient's alphal-antitrypsin concen-tration rose to normal a nd the phenotype \I'as uni-formly mi~fM for th e next 27 months. By coincidence, the second homogra ft came fro m a donor \I'h o sub-sequ e ntly \I'as shown to have the heterozygo us Pill? phenotype and a correspondingly reduced se rum alpha,-antitrypsin conce ntratio n (Table I), Following the retransp laillation, the recipient'S se rum again showed the donor's alpha,-antitrypsin phenotype Cfa-ble J) . The patient'S family \Ias studied. Both parents pro\'Cd to be Pi,\!7, heterozygotes, as were the rec ipien t's t\I'O siblings. A third sibling subseq uently born in April, 1976, also proved to have the Pi )IZ phenotype. DISCUSSION [n 197 1 and 1972, Sharp and the transpl'lllt team at th e University of Minnesota l6. 17 reported the treat-ment by hepat ic transplantation of t\I'O children " '!Jo had liver d isease and homozygo us alphal-antitrypsin defici ency , Both recipients died about one month after operation, HOII'ever, during their bri ef survi va ls, they developed normal leve ls of alphal-antitrypsin. Th e Pi phenotypes apparently "'ere not studied. By virtue of the long period of observation and the 260 Putnam rl al. Surgery lv/arch, J 977 Fig. 2. Histopathology of liver homografts. ,4, Loss of lobular architecture in fi rst liver homograft. (Reticulin stain. Original magnification x35.) n, S,,'ollen hepatocytes arranged in irregular fashion but lacking specific globules in first her homograft. (Periodic acid Schiff after diastase. Original magnification x2:'i0.) C, Normal lobular architecture of' second Ji"er homograft. (Hematoxylin and eosin. Original magnificatiun x 150.) D, Some fatt), inflilratioll, but no specifir globules in second Jiver hor)1ografi. (Periodic acid Schiff after diastC1se. Original magnification x250.) Table I. Alpbal-antitrypsin phenotype and concentration bef'ore and after liver transplantation A IjJlw ,-a lit itr),/)SIII Phenotype Concentration (l11g.l 100 mI.) (normal j 40 to 470) BclOle /rrllIsjJlolI/ ZZ 55 Fint dOllor MM occurrence of a second phenotypic transform;u;on afLer retransplantation, OLir case provides a more com-plete ciimension, adding another example of the COI-rection of liver-based inborn errors of' metabolism by liver replacement to the previously reported ones of Wilson's disease"' n and Niemann-Pick disease.·1 In our patient the pj'lz phenotype of the recipient disappeared promptly after the first transplantation; substitutecl for it \Ias the donor phenotype pj\LII. The fact that no trace of the pre-existing Pizz glycoprotein remained in the serum demonstrated unequivocally that the liver "as the sole source of the alpha,-antitrypsill. Other examples of alpha globulins haying Af!N trallsplant 1811/u. ivlM 264 I 26 II//}. MM 256 S(,(/}Ild dO/l/}r jvlZ 176 liJicr ,P/ml15jJlollt MZ 270 an exclusively hepatic origin inclucle haptoglobin lo, 11, l~ and group-specific component. lO There \I'as no reaSOll to believe that the hOLllogra Its were jeopardized because of the recipient's inborn enor of metabolism. Insteacl, the histopathologic pat-tern in consecu tive biopsies of the faili ng fi rst gra it \Ias a combination of subacute anci chronic rejection. There were no deposits of alphaJ-antitrypsin glycopro-tein in either homograft. Accllmulation of the Z phe-notype glycoprotein in the liver is thought to occur be-cause of the absence of one of the [our carbohydrate side chains found in the normal molecule 2 Thus glycoprotein deposits might be expected \\ith the Pi 'l ;( Volume 8! Number 3 phenotype and have been reponed in the live rs o f some heterozygo us patients," but without a clear as-sociation with li ver disease." In o ur case the seco nd homograft from a mi~Dz don o r h ad not accumulated any visible glycoprotein during eithe r its res ide nce for 25 years in the donor or for 5 weeks in the recipient. Approx imately 10 percent of th e po pulation have ph enoty pes oth e r th a n Pi ,\I,,, , of II'hic h there are at least 17 KO~ T he hete rozygo us ph e notype Pi MZ is fou nd in abo ut 5 percent of the populat io n, and th e frequency of the ho m ozygo us Pj7.z ph enotype has been es timated a t 0.1 perce nt of births. 2:1 Thus th e Pi zZ phenotype is not a rare form of in born error of metabolism. Since about 20 to 30 perce nt o f children with this phenotyp e will deve lop cirrhosis, Sharplti and o thers" ' 5 have e m-phasized that a ll children with li ve r disease should be evaluated ca re full y for alpha,-antitrypsin deficienC)' . The point hardly could be made bette r than from the events in the life of o ur patient. She d eveloped chron ic li ver disease leadin g to I.iver failur e and t.ransplantation with out the diagnosis being made. It was only aft.e r a retrospective re view of her course, re-examination or the excised native liver, and analysis o f her stored preoperative serum had been non e that a full ex -planation fo r her problems finally e vo lved. The skilled technical assistance of Gera ld Haffen de n is ap-preciated. REFERENCES I. Asarian , J., Archibald, R. W. R., and Lieberma n , J. : Childhood cirrhosis associated with alp ha-I-an tilr)'psi n d efi ciency. A ge netic, bioch em ical, and morphologic sLUdy,j. Pediat ... 86: 844, 1975. 2. C han , S . K. , a nd Rees, D. C.: Molecular basis for the alpha-I-protease inhibitor deF.ci ency, Nature 255: 240, 1975. 3. Dalo7..e, P ., Corman, J, Block, P. , et al.: Enzyme re place-ment in Ni emann-Pick disease by li ver ho motransp lan ta-tion, Transplant. Proc. 7 (Suppl. I): 607, 1975. 4 . DuBois, R. S., Gil es, G ., Rodgerson, D.O., e t al.: Or-th olOpic liver transplantation fo r Wilson's disease, Lancet 1: 505, 197 I. 5. Eriksson , S., Moestrup, 1'., and Hagerstra nd, I.: Liver , lung and malignant disease in heterozygous (PiMZ) al-ph a ,-antitrypsin defi cie ncy, Acta Med . Sca nd. 198: 243, 1975. 6. Fagerhol, M. K., and Laurell , C.-B.: T he polymorp hism of " prealbumins" and alpha, antitrypsin in human sera , C1in. Ch im . Acta 16: 199, J 967. Liver Teplacement for alph.a ,-antitrypsin deficiency 261 7. Ghera rdi, G. J.: Alpha,-antitrypsin deficiency and its ef-fect in the liver , Hum. Patho l. 2: 173, 1971. 8. Glasgow, J. F. 1'., Lynch, M. J., Mercz, A., e t al.: Alpha, antitrypsin de F.ciency in association with both cirrhosis and chronic obstructive lu ng disease in two sibs, Am. J. Med. 54: 181, 197 3. 9. Groth , C. G., DuB ois, R. S., Corman, J., e t al. : Metabo lic effects o f hepatic re placement in Wilso n's disease, Trans-plant. Proc. 5: 829, 1973. 10. Kashiwagi , N. , Gro th, C. G., and Starzl, 1'. E.: Changes in serum haptoglobin and grou p speci fic compone nt after o rtho tropic liver ho mo transpla ntation in humans, Proc. Soc. Exp. Bio I. Med . 128: 248, 1968. 11. Laurell , C. B., and Eriksson , S.: The e l.ec tro phoreti c a l-pha, globulin patte rn of serum alpha,-a ntitrypsin d e-ficiency, Scand . J. C lin. Lab. Inves t. 15: 132, 1963. 12. Mancini, G., Carbonara , A. 0., and Heremans , J. F.: I m-munochemical quantitation of an tigens by single radial immunod iffusio n, Immunoche mistry 2: 235 , 1965. 13. Merrill , D. A., Kirkpatri ck, C. H ., 'Nilso n , W. E. C. , et al. : Change in serum haptoglobin type following human li ve r transp la ntation , Proc. Soc. Exp . Bio I. Med. 116: 748 , 1964 14. Morin, 1'., Feldmann, G. , Benhamou, J. -P., ct al.: He terozygous alpha,-antitrypsin deficiency and ci rrh os is in adults, a fortuitous association, Lancet I: 250, 1975. 15. Porter, C. A., Mowat, A . P., Cook, P. J. L., et al.: Alpha ,-antitrypsin deficiency ancl neonatal hepatitis, Br. Med. J. 3: 435, 1972. 16. Sharp, H. L.: Alph a ,-a ntilryps in deficiency, Hosp. Prac. 6: 83, J 971. 17. Sharp, H . L. , Desnick, R. J., and Krivit, W.: The li ve r in inherited me labolic diseases of childhood , in Popper, H ., and Sch a ffn e r , F., editors: Progress in Liver Disease. Vol. TV. New York, 1972, Grune and Stratton, lne., pp. 463-488. 18. Sha rp, H. L., Brid ges , R. A. , Krivit, W., et al. : Cirrhos is assoc iated with alpha-I-antitrypsin deficiency: A previ-o usly unrecognized disorder , J. Lab. Clin. Med. 73: 934 , 1969. 19. Starzl,T E" Marchioro, 1'. L., Rowlands, D. 1'., J r., et al.: Immunosuppression a fter experim en ta l a nd clinica l homo tra nsplantation o f the li ve r , Ann. Surg. 160: 41 1, 1964. 20. Starzl, 1'. E. , Porter, K. A., Putnam, C. W., et al.: Or-thotopic liver transpla ntation in 93 patients, Surg. Gynecol. Obstet. 142: 487, 1976. 2 1. Starzl,T E., a nd Putnam , C. W.: Experience in Hepatic Transplantation. Philadelphia, 1969, W. B. Saunders Com pa n)' . 22. Trige r, D. R., Millward-Sadler, G. H ., Czayko wski, A. A., et a l. : Alpha-I-anti tryps in deF.cien cy a nd li ve r disease in adults, Q. J. Med . 178: 35 1, 1976. 23. \>Villiams, W. D., and Fajardo, L. f .: Alpha-I-antitrypsin deficiency. A hereditary e nigma, Am.J. Clin . Pathol. 61: 3J I, 1974 . 

Liver replacement for alpha<inf>1</inf>-antitrypsin deficiency

http://d-scholarship.pitt.edu/3764/1/31735062109792.pdf

Liver replacement for alpha<inf>1</inf>-antitrypsin deficiency

Abstract

Similar works

Full text

Available Versions

D-Scholarship@Pitt