Alpha1 antitrypsin deficiency in association with both cirrhosis and chronic obstructive lung disease in two sibs

Glasgow, J. F. T.; Lynch, Matthew; Hercz, Albert; Levison, Henry; Sass-Kortsāk, Andrew

doi:10.1016/0002-9343(73)90222-2

Cited by 84 publications

(27 citation statements)

References 17 publications

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“…Recently. panlobular emphysema alone (26) or with cirrhosis (13) (28) in either parent cven with special stains. Liver cells contained abundant lipofuscin granules.…”

Section: Materials and Methods A-antitrypsin Quantitation A N D Typingmentioning

confidence: 99%

Liver in α1-Antitrypsin Deficiency: Morphologic Observations and in Vitro Synthesis of α1-Antitrypsin

Bhan¹,

Grand²,

Colten³

et al. 1976

Pediatr Res

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Extract disease (3). An increased incidence of lung (16) and liver disease (4,In an effort to characterize the hepatic abnormality in patients with a,-antitrypsin deficiency, three unrelated children with the disorder (Pi types Z Z and S Z ) , two heterozygous parents ( P i type MZ), and three normal subjects ( P i type M M ) were studied. As expected, the livers of the ZZ-and SZ-deficient subjects showed abnormal accumulation of a,-antitrypsin in the cisternae of the rough endoplasmic reticulum as judged by immunofluorescent and electron microscopic studies. Their parents ( M Z phenotype) demonstrated identical although less extensive hepatic abnormalities. Short term cultures of liver tissue in the presence of radiolabeled amino acids showed both synthesis and release of a,-antitrypsin in normal control subjects and in the patients with the Z protein.Radiolabeled intracellular a,-antitrypsin could not be found. These studies demonstrate synthesis of a,-antitrypsin by the livers of normal and genetically deficient subjects vitro, and suggest several possible mechanisms for a,-antitrypsin deficiency.5) may occur in persons with intermediate levels of a,-antitrypsin.Hepatocytes from patients with severe a,-antitrypsin deficiency contain abundant a,-antitrypsin protein (23), and it has been postulated that the low serum level in these subjects is associated with a failure of release of the protein from hepatic ribosomes. Although the liver is thought to be the only site of synthesis of this protein (23), no studies in vitro of a,-antitrypsin synthesis have been reported.The present investigation was undertaken to examine the synthesis of a,-antitrypsin and its release from the liver in patients with Z Z and S Z deficiency, the M Z phenotype, and in normal subjects (Pi type MM). MATERIALS AND METHODS a,-ANTITRYPSIN QUANTITATION A N D TYPINGThe concentration of a,-antitrypsin in serum was determined Speculation both by an automated nephelometric method (22) and by electroimmunoassay (17) using monospecific antiserum to a,-antitrypStudies in vitro of the synthesis and release of a,-antitrypsin, as sin obtained from Atlantic Antibodies (28). Genetic typing was shown in the present investigation, may reveal the molecular basis of performed by immunofixation with this antiserum after agarose this genetic disorder.gel electrophoresis at pH 8.6 (15). as well as crossed immunoelectrophoresis after starch gel electrophoresis at pH 4.95 (12).a,-Antitrypsin is a 50,000-dalton glycoprotein that accounts for about 90% of the total trypsin inhibitory capacity of normal human serum. It is also a major extracellular inhibitor of other proteolytic enrymes such as plasmin, elastase, collagenase, chymotrypsin, thrombin, and leukocyte proteases (18). Individuals homozygous for P i V h u s have 5 15% of the normal a,-antitrypsin level and heterozygotes for P i h n d PiS have about 30% of the normal concentration (10). An allele with no detectablc product (Pi-) has also been described (25) and the heterozygotes for this gene have serum ...

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“…Recently. panlobular emphysema alone (26) or with cirrhosis (13) (28) in either parent cven with special stains. Liver cells contained abundant lipofuscin granules.…”

Section: Materials and Methods A-antitrypsin Quantitation A N D Typingmentioning

confidence: 99%

Liver in α1-Antitrypsin Deficiency: Morphologic Observations and in Vitro Synthesis of α1-Antitrypsin

Bhan¹,

Grand²,

Colten³

et al. 1976

Pediatr Res

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show abstract

“…Cirrhosis during oq-AT deficiency is not different from other forms of cirrhosis observed in children, and the usual complications of cirrhosis are observed [19,23,25,50,51]. Cirrhosis seems to be a late manifestation of the disease.…”

Section: In Childrenmentioning

confidence: 93%

“…Cirrhosis of the liver, as described in 1969 by Sharp et al [50], is the most frequent hepatic disorder associated with oq-AT deficiency [1,19,23,25,47]. Cirrhosis during oq-AT deficiency is not different from other forms of cirrhosis observed in children, and the usual complications of cirrhosis are observed [19,23,25,50,51].…”

Section: In Childrenmentioning

confidence: 99%

“…Cirrhosis seems to be a late manifestation of the disease. Cholestatic jaundice with hepatomegaly often appears during the first year of life [53]; in some patients it has been misdiagnosed as 'neonatal hepatitis" [I, 2,47]; in others, no precise aetioiogical diagnosis has been made [19,23,25]. It is difficult at present to ascertain the frequency of this initial icteric episode.…”

Section: In Childrenmentioning

confidence: 99%

“…Aagenaes et al [I] have estimated from the literature that about 50% of children with cirrhosis and a,-AT deficiency had had an icteric episode; they found that 40% of children with neonatal cholestasis observed in their hospital during a 3-year observation period had oq-AT deficiency [1], Sharp and Freier [53] reported that jaundice of the 'obstruc tive type' was observed within the first year in 9 of their 11 cases. Transient disappearance of the cholestatic syndrome is frequently noted [1,2,19,23,25,51,53]; however, hepatomegaly, moderate pruritus, and biochemical abnormalities (increased serum alkaline phosphate activity, serum cholesterol concentration, total lipid, and triglyceride levels; moderately abnormal BSP retention; mild elevation of serum glutamic-pyruvic transaminase) may persist [1,19,23,25,51,53], The constitution of cirrhosis and the appearance of other clinical signs are noted after a variable time interval: within 2 to 10-12 years [50], During this time, somatic growth may be normal [1]; how ever, a retardation of growth and development may be observed [1,23,25]. Evolution may be severe: one of the three children reported by G lasgow et al [23] died at the age of 11 'A years, after an intraperitoneal haemorrhage probably secondary to portal hypertension.…”

Section: In Childrenmentioning

confidence: 99%

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