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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 donar 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 metabolism is metabolically cured by liver replacement.
Alpha1-antitrypsin, an inhibitor of proteolytic enzymes such as trypsin, chymotrypsin, and collagenase, is the major alpha1-globulin of human plasma. Hereditary alpha1-antitrypsin deficiency, homozygous phenotype ZZ, predisposes to congenital infantile cirrhosis18 and, occasionally, adult cirrhosis,22 pulmonary emphysema of early onset in adults,11 and, rarely, both hepatic and pulmonary disease in childhood8 or adult life.7
Two and a half years ago, we carried out liver replacement in a 16-year-old patient with severe cirrhosis caused by alpha1-antitrypsin deficiency, PiZZ phenotype. Following the operation the alpha1-antitrypsin phenotype and concentration reverted to normal. When the graft was rejected and retransplantation was performed 2⅓ years later, the recipient again adopted the donor phenotype, this time the heterozygous PiMZ form.
Pi phenotyping was done by discontinuous acid starch electrophoresis followed by counterelectrophoresis of the starch block in to agar containing goat antihuman alpha1-antitrypsin antiserum, as described by Fagerhol and Laurell.6 The alpha1-antitrypsin concentration was measured by an immunochemical technique.12
Hepatic transplantation was performed as reported previously.20, 21 Liver specimens were prepared for light and electronmicroscopy, as described elsewhere.20 In addition, horseradish peroxidase labeled antibody to alpha1-antitrypsin and periodic acid Schiff reagent after diastase digestion were used.
A 16-year-old Caucasian girl (OT 74) with HBs Ag negative, coarsely nodular cirrhosis was treated by orthotopic liver transplantation on Nov. 16, 1973. She made an uneventful recovery from her moribund preoperative state and was in good health for more than 1½years. Graft function then deteriorated steadily to the point that on Feb. 17, 1976, 27 months after the first liver replacement, retransplantation became necessary. Five weeks later, after a stormy postoperative course, she died of pulmonary insufficiency.
The diagnosis of the original liver disease was carried as end stage chronic aggressive hepatitis until review of the case more than a year later. The correct diagnosis for the cirrhotic liver was established by light microscopy of sections stained with periodic acid Schiff reagent after diastase digestion and by immunoelectron microscopy (Fig. 1).
The histopathologic features in consecutive biopsies of the first homograft represented a combination of subacute and chronic rejection. Following a mild rejection episode, the graft developed centrilobular cholestasis with bile “thrombi.” Over the next few months some of the hepatocytes became swollen and their arrangement became disorderly. The amount of portal connective tissue increased and septa began to subdivide the liver lobules. About 2 years after the acute rejection episode, the homograft became cirrhotic (Fig. 2, A) and 3 months later had to be removed.
The second homograft was not rejected and when the patient died the only abnormality of the liver was some fatty infiltration (Fig. 2, C). There was no accumulation in either homograft at any time of the distinctive eosinophilic material which is diastase resistant and detected with the periodic acid Schiff reagent and by immunoelectron microscopy with peroxidase labeled antibody to alpha1-antitrypsin (Fig. 2, B and D).
A saved peroperative serum sample from the recipient contained 55 mg, per 100 ml, of alpha1-antitrypsin; the phenotype was PiZZ (Table I). A serum sample from the first organ donor had a normal alpha1-antitrypsin phenotype (Table I). After liver replacement, the recipient’s alpha1-antitrypsin concentration rose to normal and the phenotype was uniformly PiMM for the next 27 months. By coincidence, the second homograft came from a donor who subsequently was shown to have the heterozygous PiMZ phenotype and a correspondingly reduced serum alpha1-antitrypsin concentration (Table I). Following the retransplantation, the recipient’s serum again showed the donor’s alpha1-antitrypsin phenotype (Table I).
The patient’s family was studied. Both parents proved to be PiMZ heterozygotes, as were the recipient’s two siblings. A third sibling subsequently born in April, 1976, also proved to have the PiMZ phenotype.
In 1971 and 1972, Sharp and the transplant team at the University of Minnesota 16, 17 reported the treatment by hepatic transplantation of two children who had liver disease and homozygous alpha1-antitrypsin deficiency. Both recipients died about one month after operation. However, during their brief survivals, they developed normal levels of alpha1-antitrypsin. The Pi phenotypes apparently were not studied.
By virtue of the long period of observation and the occurrence of a second phenotypic transformation after retransplantation, our case provides a more complete dimension, adding another example of the correction of liver-based inborn errors of metabolism by liver replacement to the previously reported ones of Wilson’s disease4, 9 and Niemann-Pick disease.3
In our patient the PiZZ phenotype of the recipient disappeared promptly after the first transplantation; substituted for it was the donor phenotype PiMM. The fact that no trace of the pre-existing Pizz glycoprotein remained in the serum demonstrated unequivocally that the liver was the sole source of the alpha1-antitrypsin. Other examples of alpha globulins having an exclusively hepatic origin include haptoglobin10, 13, 19 and group-specific component.10
There was no reason to believe that the homografts were jeopardized because of the recipient’s inborn error of metabolism. Instead, the histopathologic pattern in consecutive biopsies of the failing first graft was a combination of subacute and chronic rejection. There were no deposits of alpha1-antitrypsin glycoprotein in either homograft. Accumulation of the Z phenotype glycoprotein in the liver is thought to occur because of the absence of one of the four carbohydrate side chains found in the normal molecule.2 Thus glycoprotein deposits might be expected with the PiMZ phenotype and have been reported in the livers of some heterozygous patients,5 but without a clear association with liver disease.14 In our case the second homograft from a PiMZ donor had not accumulated any visible glycoprotein during either its residence for 25 years in the donor or for 5 weeks in the recipient.
Approximately 10 percent of the population have phenotypes other than PiMM, of which there are at least 17.23 The heterozygous phenotype PiMZ is found in about 5 percent of the population, and the frequency of the homozygous PiZZ phenotype has been estimated at 0.1 percent of births.23 Thus the PiZZ phenotype is not a rare form of inborn error of metabolism. Since about 20 to 30 percent of children with this phenotype will develop cirrhosis, Sharp16 and others1, 15 have emphasized that all children with liver disease should be evaluated carefully for alpha1-antitrypsin deficiency. The point hardly could be made better than from the events in the life of our patient. She developed chronic liver disease leading to liver failure and transplantation with out the diagnosis being made. It was only after a retrospective review of her course, re-examination or the excised native liver, and analysis of her stored preoperative serum had been done that a full explanation for her problems finally evolved.
The skilled technical assistance of Gerald Haffenden is appreciated.
Supported by research grams MRIS 8118-01 and 7227-01 from the Veterans Administration, by Grant Nos. AM-17260 and AM-07772 from the National Institutes of Health, by Grant Nos. RR-00051 and RR-0069 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health, and by the Josiah Macy, Jr., Foundation (Dr. Starzl).
Presented at the Second Annual Meeting of the American Society of Transplant Surgeons, Chicago, Ill., May 20-22, 1976.