Cirrhosis and Heterozygous FZ α1-Antitrypsin Deficiency in an Adult

Brand, B; Bezahler, Gerald H.; Gould, Richard

doi:10.1016/s0016-5085(74)80112-5

Cited by 31 publications

(6 citation statements)

References 14 publications

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“…Our cases have not demonstrated any association between the F variant of A1AT and liver disease, although case reports have been described elsewhere in PiFZ heterozygotes [8,15]. The loop sheet polymers formed by the Z protein are retained within the rough endoplasmic reticulum of hepatocytes forming periodic acid Schiff (PAS) positive hepatic inclusions [22], and this accumulation can lead to liver disease including hepatitis, cirrhosis and hepatocellular carcinoma [23] in PiZZ homozygotes.…”

Section: Discussionmentioning

confidence: 73%

“…However, previous reports have suggested that the F variant has abnormal function, and may therefore predispose to the development of lung or liver disease (typical of the Z variant) when co-inherited with another deficiency gene as in the PiFZ heterozygote. In 1974, Brand et al [15] reported a case of liver cirrhosis in a PiFZ heterozygote, although the subject had no evidence of emphysema. Subsequently in 1981, Cockcroft et al [6] reported 3 PiFZ siblings who all had moderate to severe COPD, two of whom had radiological evidence of emphysema.…”

Section: Discussionmentioning

confidence: 99%

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The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote

Sinden

Koura²,

Stockley

2014

BMC Pulm Med

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BackgroundInheritance of the F variant of alpha-1-antitrypsin is associated with normal circulating protein levels, but it is believed to be dysfunctional in its ability to inhibit neutrophil elastase and therefore has been implicated as a susceptibility factor for the development of emphysema. In this study, its functional characteristics were determined following the identification of a unique patient with the PiFF phenotype, and the implications as a susceptibility factor for emphysema are considered both in homozygotes and heterozygotes.MethodsSecond order association rate constants were measured for M, Z, S and F variants of alpha-1-antitrypsin with neutrophil elastase and proteinase 3. Clinical characteristics of the PiFF homozygote and six PiFZ heterozygote subjects were studied.ResultsThe F variant had a reduced association rate constant with neutrophil elastase (5.60 ± 0.83 × 106 M-1 s-1) compared to the normal M variant (1.45 ± 0.02 × 107 M-1 s-1), indicating an increased time to inhibition that was comparable to that of the Z variant (7.34 ± 0.03 × 106 M-1 s-1). The association rate constant for the F variant and proteinase 3 (1.06 ± 0.22 × 106 M-1 s-1) was reduced compared to that with neutrophil elastase, but was similar to that of other alpha-1-antitrypsin variants. Of the six PiFZ heterozygotes, five had airflow obstruction and radiological evidence of emphysema. The PiFF homozygote had airflow obstruction but no emphysema. None of the patients had clinical evidence of liver disease.ConclusionsThe F variant may increase susceptibility to elastase-induced lung damage but not emphysema, whereas co-inheritance with the Z deficiency allele may predispose to emphysema despite reasonable plasma concentrations of alpha-1-antitrypsin.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote

Sinden

Koura²,

Stockley

2014

BMC Pulm Med

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“…There have been insufficient histologic studies of livers of patients serotyped for AlAT to make an assessment of the incidence of chronic liver disease associated with Pi MZ (23). Most reports of MZ Pi type with cryptogenic cirrhosis have been single case reports (5)(6)(7). Three of five Pi MZ patients in our HCC group were noncirrhotic> and the two Pi MZ patients that were cirrhotics had chronic B viral disease as a predisposing etiology of HCC and as the basis of cirrhosis.…”

Section: Discussionmentioning

confidence: 95%

“…Patients with aberrant Pi phenotype with Z gene, so called "partial AlAT deficiency state," have been reported to have had an increased incidence of cirrhosis (5)(6)(7)(8) and HCC (8,10,19,20). The presence of globules of AlAT by immunochemical staining either in the tumor cells or in the nontumor cells (9,20,21) was considered as an indication of Z gene (12).…”

Section: Discussionmentioning

confidence: 99%

α-1-antitrypsin phenotypes in hepatocellular carcinoma

1981

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alpha-1-Antitrypsin deficiency due to homozygous Pi ZZ state is reported to be associated with cirrhosis and hepatocellular carcinoma (HCC); however, the role of heterozygous Pi Z state is not definitely known. In order to investigate the possible association, we studied the phenotypic distribution of alpha-1-antitrypsin variants (Pi) in 124 cases of HCC. Two thousand ten normal American Red Cross blood donors were studied as controls. Twelve patients with HCC had aberrant phenotypes, an incidence of 9.67% as compared to 8.36% among normal controls. Nine of 12 patients with HCC with aberrant Pi type had cirrhosis; 5 of the 9 had cirrhosis due to hepatitis B virus; 2 of the 9 had alcoholic liver disease with cirrhosis, and 2 had cryptogenic cirrhosis. The three patients with HCC arising in noncirrhotic livers who also had aberrant Pi phenotypes, had a relatively rare variety of HCC called fibrolamellar type. Z gene was found in five patients: all five were MZ. Incidence of MZ phenotype in HCC was similar to that of the normal control population (4.0% in HCC and 2.9% in the controls). However, 3 of 5 MZ were associated with fibrolamellar HCC. Another aberrant phenotype found among the patients with HCC was MF (fast moving) which occurred with an incidence of 2.41% as compared to none in the control group. In conclusion, we found no significant increase in the incidence of Z gene among 124 patients with HCC as compared to the normal population.

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“…Cirrhosis occurring in adult homozygous individuals has been described both with (Berg and Eriksson, 1972;Babb et al, 1973;Cohen et al, 1973) and without (Ishak et al, 1972;Kumar et al, 1974) emphysema. In heterozygous individuals emphysema does occur (Kanner et al, 1973;Stevens et al, 1971) and cirrhosis has also been described in two heterozygotes (Campra et al, 1973;Brand et al, 1974), but the combination of cirrhosis and emphysema in the heterozygous state has not been reported before. In the livers of all homozygously deficient individuals (Berg and Eriksson, 1972) the hepatocytes contain globular SSD positive intracytoplasmic masses of material antigenically similar to (xi-AT.…”

Section: Discussionmentioning

confidence: 95%

Adult alpha1-antitrypsin deficiency.

Sweeney¹

1975

J Clin Pathol

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sYNoPsis Three adults with ag-antitrypsin deficiency are described. In two of the cases the deficiency was genetically determined (cases 1 and 2), and each demonstrated unusual features of the disease. The liver in case 1 (homozygous) showed cholangiolar hyperplasia which has been recorded only once before. Case 2 (heterozygous) had emphysema and cirrhosis, a combination not previously documented in a heterozygote, in addition to malabsorption. Case 3 represents a case of spurious a1-antitrypsin deficiency with cirrhosis included to emphasize the diagnostic importance of phenotyping in such cases.

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Cirrhosis and Heterozygous FZ α1-Antitrypsin Deficiency in an Adult

Cited by 31 publications

References 14 publications

The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote

The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote

α-1-antitrypsin phenotypes in hepatocellular carcinoma

Adult alpha1-antitrypsin deficiency.

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