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The pathogenesis of liver disease in alpha1-antitrypsin (AAT) deficiency is thought to relate to the accumulation of abnormal AAT within the endoplasmic reticulum of hepatocytes, and has been discussed in detail in the medical literature.1-5
Neonatal Disease
Liver disease develops in a small subset of children with AAT deficiency. However, AAT deficiency is the most common genetic cause of liver disease in children and the most frequent genetic disease for which children undergo liver transplantation.6
Approximately 70% of PiZZ infants have abnormal liver function tests at birth, with neonatal hepatitis developing in about 10% of affected infants.7 Normal hepatic function is restored in the majority of affected infants; however, cirrhosis develops in approximately 21% of these patients, progressing to portal hypertension and hepatic failure by the second decade of life.8
Adolescents and Adults
Follow-up from a prospective screening study conducted in Sweden showed that ≥85% of PiZZ individuals have no evidence of liver dysfunction at 18 years of age.9 However, AAT deficiency-associated liver disease has been identified in late childhood, early adolescence, and adulthood.
Although there was initial speculation that emphysema and liver disease in AAT-deficient individuals were mutually exclusive, it is now clear that both adults and children with hepatic involvement can also have destructive lung disease.10 It is not known if augmentation therapy with purified AAT to achieve physiologic plasma levels in these patients will alter the course of hepatic disease associated with AAT deficiency. However, this would seem unlikely given the pathogenic mechanism described above.
References:
| 1. |
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Sharp HL, Bridges RA, Krivit W, et al. Cirrhosis associated with alpha1-antitrypsin deficiency: A previously unrecognized inherited disorder. J Lab Clin Med. 1969; 73:934-939. |
| 2. |
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Yunis EJ,Agostini RM Jr, Glew RH. Fine structural observations of the liver in alpha1-antitrypsin deficiency. Am J Pathol. 1976;82:265-286. |
| 3. |
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Feldmann G, Martin JP, Sesboue R, et al. The ultrastructure of hepatocytes in alpha1-antitrypsin deficiency with the genotype PiZ. Gut. 1975;16:796-799. |
| 4. |
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Palmer PE, Gherardi GL, Baldwin JM, et al. Adult liver disease in SZ phenotype alpha1-antritrypsin deficiency. Ann Intern Med. 1978;88:59-60. |
| 5. |
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Perlmutter DH. Liver injury in alpha1-antitrypsin deficiency. Clin Liver Disease. 2000;4:387-408. |
| 6. |
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Perlmutter DH. Liver injury in alpha1-antitrypsin deficiency. Clin Liver Disease. 2000;4:387-408. |
| 7. |
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World Health Organization, Human Genetics Programme, Division of Noncommunicable Diseases. Alpha1-antritypsin deficiency. Report of a WHO meeting, Geneva, 18-20 March 1996. |
| 8. |
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Brantly M, Nukiwa Y, Crystal RG. Molecular basis of alpha1-antitrypsin deficiency. Am J Med. 1988;84(Suppl6A):13-31. |
| 9. |
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Perlmutter DH. Liver injury in alpha1-antitrypsin deficiency. Clin Liver Disease. 2000;4:387-408. |
| 10. |
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Glasgow JFT, Lynch MJ, Hercz A, Levison H, Sass-Kortsak A. Alpha1-antitrypsin deficiency in association with both cirrhosis and chronic obstructive lung disease in two sibs. Am J Med. 1973;54:181-194. |
Important Safety Information
Prolastin®, Alpha1-Proteinase Inhibitor (Human) is indicated for chronic replacement therapy of individuals having congenital deficiency of alpha-1 PI (alpha1-antitrypsin deficiency) with clinically demonstrable panacinar emphysema. Weekly Prolastin® therapy has demonstrated a low occurrence of side effects. In clinical studies with Prolastin®, reactions were observed in 1.16% of infusions, the most common events being fever (0.77%), light-headedness (0.19%), and dizziness (0.19%). As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Individuals with selective IgA deficiencies who have known antibody against IgA (anti-IgA antibody) should not receive Prolastin®, since these patients may experience severe reactions, including anaphylaxis, to IgA which may be present.
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