Aust. N.Z. J. Med. (1976), 6, pp. 467469 CASE REPORT
Immunological Changes and liver Disease Associated with al -Antitrypsin Deficiency R. A. Joske', R. L. Leedmantand L. R. Matzf From the Department of Medicine, University of Western Australia, and the Departments of Medicine and Pathology, Royal Perth Hospital
Summary: Immunological changes and liver disease associated with alpha-1 -antitrypsin deficiency. R. A. Joske, R. L. Leedman and L. R. Matz, Aust. N.Z. J. Med., 1976, 6, pp. 467-469.
A female aged 60 years with heterozygous alpha- 1 -antitrypsin deficiency developed a progressive and ultimately fatal liver disease with the clinical, biochemical. immunological and histological characteristics of active chronic hepatitis. It is suggested that the hepatic disease of A-AT deficiency be included among the types of liver disease which may initiate a progressive immunopathic response.
Alpha,-antitrypsin (A-AT) includes a group of proteins of hepatic origin which function as inhibitors of proteolytic enzymes such as trypsin. Congenital deficiency of A-AT was described first by Laurel1 and Eriksson', and is inherited as a polymorphic autosomal recessive. Several clinical associations of A-AT deficiency have been described. Severe pulmonary emphysema presenting in young or middle-aged adults is the most frequent's 3 * 4, but atrophic ', jejunitis'. 6, angiitis and glomer~lonephritis~~ thyroiditis9 and liver disease have been reported. The liver disease of A-AT deficiency was reported first in children", where it presents as neonatal hepatitis and cholestatic jaundice of infancy. It may progress to cirrhosis. Liver involvement differs in adults.". l 2 It may be found in heterozygotes or homozygotes, and with or without respiratory d i ~ e a s e . ' ~ *Department of Medicine, University of Western Australia. tDepartment of Medicine, Royal Perth Hospital. Department of Pathology, Royal Perth Hospital. Correspondence, Dr. R. A. Joske, University Department of Medicine, Perth Medical Centre, Shenton Park, WA 6008 Accepted for publication: 17 June, 1976
The histological characteristic in the liver of A-AT deficiency is the presence a f distinctive intracytoplasmic granules in hepatocytes. The granules, which may not be present in all cells, vary in size (0.5 ,u to 20 p) and number, and tend to be clustered in cells in the periportal areas and about hepatic veins. In haematoxylin and eosin preparations they are invisible or weakly eosinophilic, but are periodic acidSchiff (PAS) positive, and diastase resistant. Electron microscopic studies show the granules to be single membrane bound, roughly oval and occasionally irregular, containing a homogeneous, moderately electron dense substance. l4 These granules accumulate in the endoplasmic reticulum, and this contrasts with the conventional, accumulation of substances in the lysomes in other inherited storage disease. Although having immunogenicity with plasma A-AT, the glycoprotein from the hepatic inclusions is severely deficient in carbohydrate components and completely lacks sialic acid, but has an essentially similar polypeptide core.' These granules may occur without liver disease, but in some instances there is an increase in periportal connective tissue leading to a macronodular cirrhosis.16, l 7 There is a high incidence of hepatocellular carcinoma.' Laboratory findings vary. The serum crlglobulin and A-AT are invariably depressed. The y-globulin is increased in some cases, but autoantibodies have not been reported.8. 1 3 3 l 9 There is evidence relating A-AT deficiency and immunological changes. Many of the disorders reported to accompany A-AT deficiency are immunopathic in origin. Falk and his colleaguesz0 have demonstrated multiple immuno-humoral abnormalities in patients with respiratory disease due to A-AT deficiency.
'
468
JOSKE ET AL.
VOL.
6, NO. 5
August 1974
Jan. 1975
TABLE 1 Some laboratory investigations in a patient with liver disease and A-AT deficiency Date Test
Oct. 1972
Normal value
March 1973
Dec. 1973
April 1974
-
Serum bilirubin Serum alkaline phosphatase Serum glutamic oxaloacetic transaminae Serum albumin Serum al-globulin Serum y-globulin Serum creatinine Serum calcium
1 .O mg per 100 ml 20-85 units 6-40 Karmen units 3.5-4.5 g per 100 ml 0.2-0.5 g per 100 ml 0.9- 1 . 6 g per 100 ml 0.5-1.2mgper 100ml 9.5-10.5 mg per 100 ml
The present paper reports a case which provides evidence that immunological factors may operate in some cases of liver disease associated with A-AT deficiency to produce the syndrome of active chronic hepatitis. Case Report
A female patient born in 1911 was admitted to hospital in 1971 because of upper gastrointestinal haemorrhage. A diagnosis was made of hepatic cirrhosis, but no further details were available. She was first admitted to the Royal Perth Hospital in August 1972 following a further massive haematemesis. Despite conservative management the bleeding continued and a porta-caval shunt was performed one week after admission. Her post-operative course was complicated by pulmonary infection. She was discharged two weeks after operation. She was readmitted three weeks later because of portalsystemic encephalopathy. Examination showed jaundice and splenomegaly. Response to protein withdrawal and oral framycetin was rapid. She was seen regularly during the next two years. Her condition slowly deteriorated. She developed severe osteoporosis with multiple compression fractures, requiring three admissions to an orthopaedic unit. Her final admission, early in 1975, was occasioned by hepatic decompensation with encephalopathy and ascites. Her response to treatment was poor and she died two months later. Autopsy was not performed.
2 .7 640 87 -
3.2 320 65 2.8 0 .2 2.7 0.7 8.3
4.2 322 90 2.2 -
0.8 8.8
4.8 580 105 1.8 0.1 2.6 1.0 8 .4
-
2.6 0 .1 2.7 -
9 .7 219 I46 1.9 -
1.1 7 .9
irregular coarse bands of fibrous tissue containing a moderate infiltration with mononuclear lymphocytes and plasma cells and occasional segmented leucocytes. Moderate piecemeal necrosis was present (Fig. 1). The appearances were of a developing macronodular cirrhosis as a result of aggressive hepatitis (Fig. 2). A number of hepatocytes contained PAS-positive, diastase resistant cytoplasmic granules characteristic of A-AT deficiency (Fig. 3). The significance of these was not realised till after the patient’s death. Discussion
There is little doubt that this patient had A-AT deficiency. This is supported by characteristic and diagnostic biochemical findings and liver biopsy appearances. The diagnosis was only achieved post mortem, so that genetic studies were not possible. The serum A-AT was in the heterozygote range. The liver disease meets the diagnostic criteria of active chronic hepatitis.” There was a progressive liver disease of over six months’ duration leading to a macronodular cirrhosis,
Investigations
Some of these are included in Table 1. In addition, the serum IgG was 2560 mg per 100 ml (normal: 800-1600); IgA, 490 mg per 100 ml (90-500); IgM, 505 mg per 100 ml (80-300). Anti-nuclear factors and anti-smooth muscle antibody not present. Anti-mitochondria1 antibody titre (using human tissue) 1 : 125. Anti-parietal cell antibody titre, 1 : 125. HB-antigen and a-foetoprotein, not detected. The serum a,-antitrypsin was estimated after death on stored serum, and was 0 . 9 g per litre. (The normal value is 2.0 to 5.0 g per litre, and this result is in the heterozygote range.) Liver biopsy was performed at operation during her first admission. The hepatic architecture was distorted by
FIGURE 1. Photomicrograph of the liver showing inflammatory activity in fibrous septum with piece-meal necrosis. (H & E ~ 2 1 0 )
OCTOBER,
1976
A-ANTITRYPSIN DEFICIENCY LIVER DISEASE
469
FIGURE 2. Photomicrograph of the liver showing macronodular cirrhosis. (H 8 E ~ 1 0 0 )
FIGURE 3. Photomicrograph of the liver showing PAS positive, diastase resistant cytoplasmic inclusions characteristic of alpha-1 -antitrypsin deficiency. (H & E ~850)
and accompanied by high SGOT levels, hypergammaglobulinaemia and demonstrable autoantibodies in significant titre. Liver biopsy showed appearances of aggressive hepatitis in a late, cirrhotic stage. Since A-AT deficiency may be associated with immunological abnormality (vide supra), it is suggested that immunopathic liver disease of the active chronic hepatitis type may complicate the liver disease of A-AT deficiency. This is known to occur in some cases of Wilson’s disease and haemochromatosis.”* 2 3 In this event, the liver lesion of A-AT should be added to the list of factors that may initiate progressive immunopathic liver disease, and, conversely, should be sought in the investigation of such patients.
D S.. OSKVIG.R. M.. ASCHENBRENER, C. A A. I.. JOHNSON. 6 . GREENWALD. and RANDA.D.C. (1975): I,-antitrypsin deficiency. emphysema. cirrhosis. and intestinal mucosal atrophy. J . Amer. med. Ass. 231, 273. 7. MILLER,F. and KUSCHNER.M. (1969): Alpha,-antitrypsin deficiency, emphysema. nccrotizing angiitis and glomerulonephritis. Amer. J M e d . 46, 615. 8. GLASGOW.J. F . T., LYNCH,M. J.. HERCZ.A,. LEVISON,H. and SASSKORTSAK,A. (1973): Alpha, antitrypsin deficiency in association with both cirrhosis and chronic obstructive lung disease in two sibs, Amrr. J. M e d . 54, 181. 9. NICHOLLS.M. G. and JANUS.E. D.(1973): Hashimoto’s thyroiditis and homozygous alpha,-anlilrypsin deficiency. Am!. N.Z.J. M r d . 3, 516. 10. SHARP,H. L.. BRIDGES.R. A,, KRIVIT. W. and FREIER.E. F. (1969). Cirrhosis associated with alpha-I-antitrypsin deficiency: A previously unrecognized inherited disorder. 1. Lob. clin. M e d . 73, 934. I I . FELDMAN. G.. BIGNON.J. and C H A N I N I AP. N . (19741: The liver in 01)antitrypsin deficiency. Digestion 10. 162. 12. BRUNT.P. W. (1975): Alpha-I-antitrypsin deficiency and liver disease, Modern Trends Gosrroenrerol. 5, 134. J. L., CRAIG.J . R.. PETERS.R. L. and REVNOLDS. T . B. (1973): 13. CAMPRA. Cirrhosis associated with partial deficiency of alpha-I-antitrypsin in an adult, Ann. inrern. M i d . 78, 233. 14. GORDON, W. H.. DIxON. J., MITTMAN.C. and LIEBERMAN. I . (1972): Alpha,-antitrypsin (A,AT) accumulation in livers of emphysematous patients with A , A T deficiency, Hum. Porh. 3, 361 15. JEPPSSON.J:O.. LARSSON.C. and ERIKSSON. S. (1975): Characterization of alpha,-antitrypsin in the inclusion bodies from the liver in alpha,antitrypsin deficiency. New Engl. J. Med. 293, 576. 16. ISHAK. K. G.. JENIS,E. H.. MARSHALL, M . L.. BOLTON.B. H. and BATTISTDNE. G. C. (1972): Cirrhosis of the liver associated with a,-antitrypsin deficiency. Arch. Path. 94, 445. 17. BRAND.8.. BEZAHLER. G. H. and COULD,R. 11974): Cirrhosis and heterozygous F S u,-antitrypsin deficiency in an adult. Gasrrornrerolog,! 66. 264. 18. BERG.N. 0. and ERIKSSON. S. (1972): Liver disease in adults with alpha,antitrypsin deficiency. N m Engl. J. Med. 287. 1264 19. KRONER.T. (1973): u,-Antitrypsin-Mange1 mil Hepatopathie und Eisenuberladung. Schnsiz med. Wschr. 103, 1192. 20. FALK,G . A,. SISKIND. G . W. and SMITH.I. P. Jr. (1971): Chronic obstructive pulmonary disease: A subgroup of patients identified by serum alpha-Iantitrypsin and immunoglobulin concentrations, Anrrr. R P I , . resp. Dis. 103, 18. 21. JosrF.. R. A. (I975): Active chronic hepatitis. Modern Trends Gosrrornrrrol. 5, 418. 22. STERNLEIB. 1. and SCHEINBERG. 1. H. (1972): Chronic hepatitis as a first manifestation of Wilson’s disease. Ann. inrern. M c d . 16. 59. 23. JOSKE.R. A. and TRAUB.M. (1975): Haemochromatosis. active chronic hepatitis. and familial IgA deficiency. Digesrion 12, 32.
References I . LAURELL. C. B. and ERIKSSON. S . (1963): The electrophoretic u,-globulin pattern of serum in z,-antitrypsin deficiency. Srand. J d i n . Lah Inserr 15, 132. S. (1964): Pulmonary emphysema and alpha,-antitrypsin defi2. ERIKSSON. ciency, Acra mrd. srarid 175, 197. 3. HUTCHISON, D.C. S . , COOK.P 1. L.. BARTER, C. E.. HARRIS. H. and HUGHJONES.P. (1971): Pulmonary emphysema and u,-antitrypsin deficiency. Brir med. J . 1, 689. 4. STEVENS, P. M.. HNILICA. V. S.. JOHNSON.P. C. and BELL.R. L. (1971): Pathophysiology of hereditary emphysema. Ann. inrrm. M r d . 74. 672. 5 SWEENEY. E. C. (1975): Adult a,-antitrypsin deficiency. J . clin. Porh. 28. 613.
Immunological Changes and liver Disease Associated with al -Antitrypsin Deficiency R. A. Joske', R. L. Leedmantand L. R. Matzf From the Department of Medicine, University of Western Australia, and the Departments of Medicine and Pathology, Royal Perth Hospital
Summary: Immunological changes and liver disease associated with alpha-1 -antitrypsin deficiency. R. A. Joske, R. L. Leedman and L. R. Matz, Aust. N.Z. J. Med., 1976, 6, pp. 467-469.
A female aged 60 years with heterozygous alpha- 1 -antitrypsin deficiency developed a progressive and ultimately fatal liver disease with the clinical, biochemical. immunological and histological characteristics of active chronic hepatitis. It is suggested that the hepatic disease of A-AT deficiency be included among the types of liver disease which may initiate a progressive immunopathic response.
Alpha,-antitrypsin (A-AT) includes a group of proteins of hepatic origin which function as inhibitors of proteolytic enzymes such as trypsin. Congenital deficiency of A-AT was described first by Laurel1 and Eriksson', and is inherited as a polymorphic autosomal recessive. Several clinical associations of A-AT deficiency have been described. Severe pulmonary emphysema presenting in young or middle-aged adults is the most frequent's 3 * 4, but atrophic ', jejunitis'. 6, angiitis and glomer~lonephritis~~ thyroiditis9 and liver disease have been reported. The liver disease of A-AT deficiency was reported first in children", where it presents as neonatal hepatitis and cholestatic jaundice of infancy. It may progress to cirrhosis. Liver involvement differs in adults.". l 2 It may be found in heterozygotes or homozygotes, and with or without respiratory d i ~ e a s e . ' ~ *Department of Medicine, University of Western Australia. tDepartment of Medicine, Royal Perth Hospital. Department of Pathology, Royal Perth Hospital. Correspondence, Dr. R. A. Joske, University Department of Medicine, Perth Medical Centre, Shenton Park, WA 6008 Accepted for publication: 17 June, 1976
The histological characteristic in the liver of A-AT deficiency is the presence a f distinctive intracytoplasmic granules in hepatocytes. The granules, which may not be present in all cells, vary in size (0.5 ,u to 20 p) and number, and tend to be clustered in cells in the periportal areas and about hepatic veins. In haematoxylin and eosin preparations they are invisible or weakly eosinophilic, but are periodic acidSchiff (PAS) positive, and diastase resistant. Electron microscopic studies show the granules to be single membrane bound, roughly oval and occasionally irregular, containing a homogeneous, moderately electron dense substance. l4 These granules accumulate in the endoplasmic reticulum, and this contrasts with the conventional, accumulation of substances in the lysomes in other inherited storage disease. Although having immunogenicity with plasma A-AT, the glycoprotein from the hepatic inclusions is severely deficient in carbohydrate components and completely lacks sialic acid, but has an essentially similar polypeptide core.' These granules may occur without liver disease, but in some instances there is an increase in periportal connective tissue leading to a macronodular cirrhosis.16, l 7 There is a high incidence of hepatocellular carcinoma.' Laboratory findings vary. The serum crlglobulin and A-AT are invariably depressed. The y-globulin is increased in some cases, but autoantibodies have not been reported.8. 1 3 3 l 9 There is evidence relating A-AT deficiency and immunological changes. Many of the disorders reported to accompany A-AT deficiency are immunopathic in origin. Falk and his colleaguesz0 have demonstrated multiple immuno-humoral abnormalities in patients with respiratory disease due to A-AT deficiency.
'
468
JOSKE ET AL.
VOL.
6, NO. 5
August 1974
Jan. 1975
TABLE 1 Some laboratory investigations in a patient with liver disease and A-AT deficiency Date Test
Oct. 1972
Normal value
March 1973
Dec. 1973
April 1974
-
Serum bilirubin Serum alkaline phosphatase Serum glutamic oxaloacetic transaminae Serum albumin Serum al-globulin Serum y-globulin Serum creatinine Serum calcium
1 .O mg per 100 ml 20-85 units 6-40 Karmen units 3.5-4.5 g per 100 ml 0.2-0.5 g per 100 ml 0.9- 1 . 6 g per 100 ml 0.5-1.2mgper 100ml 9.5-10.5 mg per 100 ml
The present paper reports a case which provides evidence that immunological factors may operate in some cases of liver disease associated with A-AT deficiency to produce the syndrome of active chronic hepatitis. Case Report
A female patient born in 1911 was admitted to hospital in 1971 because of upper gastrointestinal haemorrhage. A diagnosis was made of hepatic cirrhosis, but no further details were available. She was first admitted to the Royal Perth Hospital in August 1972 following a further massive haematemesis. Despite conservative management the bleeding continued and a porta-caval shunt was performed one week after admission. Her post-operative course was complicated by pulmonary infection. She was discharged two weeks after operation. She was readmitted three weeks later because of portalsystemic encephalopathy. Examination showed jaundice and splenomegaly. Response to protein withdrawal and oral framycetin was rapid. She was seen regularly during the next two years. Her condition slowly deteriorated. She developed severe osteoporosis with multiple compression fractures, requiring three admissions to an orthopaedic unit. Her final admission, early in 1975, was occasioned by hepatic decompensation with encephalopathy and ascites. Her response to treatment was poor and she died two months later. Autopsy was not performed.
2 .7 640 87 -
3.2 320 65 2.8 0 .2 2.7 0.7 8.3
4.2 322 90 2.2 -
0.8 8.8
4.8 580 105 1.8 0.1 2.6 1.0 8 .4
-
2.6 0 .1 2.7 -
9 .7 219 I46 1.9 -
1.1 7 .9
irregular coarse bands of fibrous tissue containing a moderate infiltration with mononuclear lymphocytes and plasma cells and occasional segmented leucocytes. Moderate piecemeal necrosis was present (Fig. 1). The appearances were of a developing macronodular cirrhosis as a result of aggressive hepatitis (Fig. 2). A number of hepatocytes contained PAS-positive, diastase resistant cytoplasmic granules characteristic of A-AT deficiency (Fig. 3). The significance of these was not realised till after the patient’s death. Discussion
There is little doubt that this patient had A-AT deficiency. This is supported by characteristic and diagnostic biochemical findings and liver biopsy appearances. The diagnosis was only achieved post mortem, so that genetic studies were not possible. The serum A-AT was in the heterozygote range. The liver disease meets the diagnostic criteria of active chronic hepatitis.” There was a progressive liver disease of over six months’ duration leading to a macronodular cirrhosis,
Investigations
Some of these are included in Table 1. In addition, the serum IgG was 2560 mg per 100 ml (normal: 800-1600); IgA, 490 mg per 100 ml (90-500); IgM, 505 mg per 100 ml (80-300). Anti-nuclear factors and anti-smooth muscle antibody not present. Anti-mitochondria1 antibody titre (using human tissue) 1 : 125. Anti-parietal cell antibody titre, 1 : 125. HB-antigen and a-foetoprotein, not detected. The serum a,-antitrypsin was estimated after death on stored serum, and was 0 . 9 g per litre. (The normal value is 2.0 to 5.0 g per litre, and this result is in the heterozygote range.) Liver biopsy was performed at operation during her first admission. The hepatic architecture was distorted by
FIGURE 1. Photomicrograph of the liver showing inflammatory activity in fibrous septum with piece-meal necrosis. (H & E ~ 2 1 0 )
OCTOBER,
1976
A-ANTITRYPSIN DEFICIENCY LIVER DISEASE
469
FIGURE 2. Photomicrograph of the liver showing macronodular cirrhosis. (H 8 E ~ 1 0 0 )
FIGURE 3. Photomicrograph of the liver showing PAS positive, diastase resistant cytoplasmic inclusions characteristic of alpha-1 -antitrypsin deficiency. (H & E ~850)
and accompanied by high SGOT levels, hypergammaglobulinaemia and demonstrable autoantibodies in significant titre. Liver biopsy showed appearances of aggressive hepatitis in a late, cirrhotic stage. Since A-AT deficiency may be associated with immunological abnormality (vide supra), it is suggested that immunopathic liver disease of the active chronic hepatitis type may complicate the liver disease of A-AT deficiency. This is known to occur in some cases of Wilson’s disease and haemochromatosis.”* 2 3 In this event, the liver lesion of A-AT should be added to the list of factors that may initiate progressive immunopathic liver disease, and, conversely, should be sought in the investigation of such patients.
D S.. OSKVIG.R. M.. ASCHENBRENER, C. A A. I.. JOHNSON. 6 . GREENWALD. and RANDA.D.C. (1975): I,-antitrypsin deficiency. emphysema. cirrhosis. and intestinal mucosal atrophy. J . Amer. med. Ass. 231, 273. 7. MILLER,F. and KUSCHNER.M. (1969): Alpha,-antitrypsin deficiency, emphysema. nccrotizing angiitis and glomerulonephritis. Amer. J M e d . 46, 615. 8. GLASGOW.J. F . T., LYNCH,M. J.. HERCZ.A,. LEVISON,H. and SASSKORTSAK,A. (1973): Alpha, antitrypsin deficiency in association with both cirrhosis and chronic obstructive lung disease in two sibs, Amrr. J. M e d . 54, 181. 9. NICHOLLS.M. G. and JANUS.E. D.(1973): Hashimoto’s thyroiditis and homozygous alpha,-anlilrypsin deficiency. Am!. N.Z.J. M r d . 3, 516. 10. SHARP,H. L.. BRIDGES.R. A,, KRIVIT. W. and FREIER.E. F. (1969). Cirrhosis associated with alpha-I-antitrypsin deficiency: A previously unrecognized inherited disorder. 1. Lob. clin. M e d . 73, 934. I I . FELDMAN. G.. BIGNON.J. and C H A N I N I AP. N . (19741: The liver in 01)antitrypsin deficiency. Digestion 10. 162. 12. BRUNT.P. W. (1975): Alpha-I-antitrypsin deficiency and liver disease, Modern Trends Gosrroenrerol. 5, 134. J. L., CRAIG.J . R.. PETERS.R. L. and REVNOLDS. T . B. (1973): 13. CAMPRA. Cirrhosis associated with partial deficiency of alpha-I-antitrypsin in an adult, Ann. inrern. M i d . 78, 233. 14. GORDON, W. H.. DIxON. J., MITTMAN.C. and LIEBERMAN. I . (1972): Alpha,-antitrypsin (A,AT) accumulation in livers of emphysematous patients with A , A T deficiency, Hum. Porh. 3, 361 15. JEPPSSON.J:O.. LARSSON.C. and ERIKSSON. S. (1975): Characterization of alpha,-antitrypsin in the inclusion bodies from the liver in alpha,antitrypsin deficiency. New Engl. J. Med. 293, 576. 16. ISHAK. K. G.. JENIS,E. H.. MARSHALL, M . L.. BOLTON.B. H. and BATTISTDNE. G. C. (1972): Cirrhosis of the liver associated with a,-antitrypsin deficiency. Arch. Path. 94, 445. 17. BRAND.8.. BEZAHLER. G. H. and COULD,R. 11974): Cirrhosis and heterozygous F S u,-antitrypsin deficiency in an adult. Gasrrornrerolog,! 66. 264. 18. BERG.N. 0. and ERIKSSON. S. (1972): Liver disease in adults with alpha,antitrypsin deficiency. N m Engl. J. Med. 287. 1264 19. KRONER.T. (1973): u,-Antitrypsin-Mange1 mil Hepatopathie und Eisenuberladung. Schnsiz med. Wschr. 103, 1192. 20. FALK,G . A,. SISKIND. G . W. and SMITH.I. P. Jr. (1971): Chronic obstructive pulmonary disease: A subgroup of patients identified by serum alpha-Iantitrypsin and immunoglobulin concentrations, Anrrr. R P I , . resp. Dis. 103, 18. 21. JosrF.. R. A. (I975): Active chronic hepatitis. Modern Trends Gosrrornrrrol. 5, 418. 22. STERNLEIB. 1. and SCHEINBERG. 1. H. (1972): Chronic hepatitis as a first manifestation of Wilson’s disease. Ann. inrern. M c d . 16. 59. 23. JOSKE.R. A. and TRAUB.M. (1975): Haemochromatosis. active chronic hepatitis. and familial IgA deficiency. Digesrion 12, 32.
References I . LAURELL. C. B. and ERIKSSON. S . (1963): The electrophoretic u,-globulin pattern of serum in z,-antitrypsin deficiency. Srand. J d i n . Lah Inserr 15, 132. S. (1964): Pulmonary emphysema and alpha,-antitrypsin defi2. ERIKSSON. ciency, Acra mrd. srarid 175, 197. 3. HUTCHISON, D.C. S . , COOK.P 1. L.. BARTER, C. E.. HARRIS. H. and HUGHJONES.P. (1971): Pulmonary emphysema and u,-antitrypsin deficiency. Brir med. J . 1, 689. 4. STEVENS, P. M.. HNILICA. V. S.. JOHNSON.P. C. and BELL.R. L. (1971): Pathophysiology of hereditary emphysema. Ann. inrrm. M r d . 74. 672. 5 SWEENEY. E. C. (1975): Adult a,-antitrypsin deficiency. J . clin. Porh. 28. 613.
