Does the Heterozygous State of Alpha‐1 Antitrypsin Deficiency Have a Role in Chronic Liver Diseases? Interim Results of a Large Case‐Control Study

Regev, Arie; Guaqueta, Constanza; Molina, Enrique; Conrad, Andrew; Mishra, Vishnu S.; Brantly, Mark; Torres, Maria; Medina, Maria de; Tzakis, Andreas G.; Schiff, Eugene R.

doi:10.1097/01.mpg.0000226387.56612.1e

Cited by 72 publications

(61 citation statements)

References 20 publications

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“…Consistently, the minimal liver abnormalities found in both the proband and his mother are probably unrelated to the presence of the defective P brescia α 1 AT allele. These results agree with the presence of only occasional hepatic α 1 AT deposits and the still debated causal association between heterozygous α 1 AT deficiency (PI*M/Z) and chronic liver disease (Fischer, et al, 2000;Regev, et al, 2006). We can suppose that protein polymerization of P brescia α 1 AT could be not sufficient in the heterozygous state to become detectable as liver inclusions.…”

Section: Discussionsupporting

confidence: 80%

Molecular characterization of the new defective P_bresciaalpha1-antitrypsin allele

et al. 2009

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Alpha1-antitrypsin (α 1 AT) deficiency is a hereditary disorder associated with reduced α 1 AT serum level, predisposing adults to pulmonary emphysema. Among the known mutations of the α 1 AT gene (SERPINA1) causing α 1 AT deficiency, a few alleles, particularly the Z allele, may also predispose adults to liver disease. We have characterized a new defective α 1 AT allele (c.745G>C) coding for a mutant α 1 AT (Gly225Arg), named P brescia . The P brescia α 1 AT allele was first identified in combination with the rare defective M würzburg allele in an 11-year-old boy showing significantly reduced serum α 1 AT level. Subsequently, the P brescia allele was found in the heterozygous state with the normal M or the defective Z allele in nine and three adults respectively. In cellular models of the disease, we show that the P brescia mutant is retained in the endoplasmic reticulum as ordered polymers and is secreted more slowly than the normal M α 1 AT. This behaviour recapitulates the abnormal cellular handling and fate of the Z α 1 AT and suggests that the mutation present in the P brescia α 1 AT causes a conformational change of the protein which, by favouring polymer formation, is etiologic to both severe α 1 AT deficiency in the plasma and toxic protein-overload in the liver.

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Section: Discussionsupporting

confidence: 80%

Molecular characterization of the new defective P_bresciaalpha1-antitrypsin allele

et al. 2009

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“…Although these PI mutations were associated with hyperferritinemia and sinusoidal iron accumulation, they were not associated with more severe liver damage in NAFLD ( 270 ). Regev et al showed that, in patients with liver disease, there was a disproportionately higher prevalence of PI *Z among NAFLD patients with decompensated liver disease (5.0%) compared with NAFLD patients with less severe liver disease (1.9%) ( 271 ).…”

Section: Resultsmentioning

confidence: 99%

Genetic determinants of hepatic steatosis in man

Hooper

Adams

Burnett

2011

Journal of Lipid Research

118

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in childhood in some individuals, with a prevalence of 10% found in an autopsy study of 2-19 year olds from the United States ( 5 ). The prevalence of NAFLD increases with advancing age, with a peak between 40 and 69 years of age ( 2, 6 ).A cut-off of 5.5% hepatic steatosis has been accepted as the threshold to diagnose fatty liver, based on the 95th centile of hepatic fat content in low-risk subjects [normal body mass index (BMI), normal glucose tolerance, lack of excessive alcohol ingestion, and normal liver function tests] ( 1, 7 ). Subjects with NAFLD may have a range of histopathological changes (

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“…Although homozygous individuals are more likely to develop liver disease, even a single ␣1-ATZ mutation may predispose patients to hepatic injury 3,4,7,32 and act as a modifier gene in the progression of liver disease in patients suffering from cystic fibrosis, 8 non-alcoholic fatty liver disease, and hepatitis C. 5 However, most patients homozygous for the Z mutation never develop clinically relevant liver disease. The development of liver injury in this model therefore must require an environmental or genetic factor in addition to the Z mutation.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Homozygosity for the ␣1-ATZ mutation (also referred to as PiZZ) is generally required for the development of liver disease, although several studies report an increased risk to heterozygous individuals. [3][4][5][6][7] A single ␣1-ATZ mutation may also predispose patients with cystic fibrosis to significant liver disease. 8 Therefore, the ␣1-ATZ mutation not only may cause liver injury but it may act as a modifier gene that exacerbates other forms of liver disease.…”

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confidence: 99%

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

et al. 2007

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Alpha-1 antitrypsin (␣1-AT) deficiency is the most common genetic cause of liver disease in children. The homozygous ␣1-ATZ mutation (PiZZ) results in significant liver disease in 10% of all affected patients. The ␣1-ATZ mutation also may lead to worse liver injury in the setting of other liver diseases such as cystic fibrosis, nonalcoholic fatty liver disease, and hepatitis C. Although cholestatic injury is common to many forms of liver disease, its effect on the PiZZ phenotype is unknown. To elucidate the interplay of cholestasis and the PiZZ phenotype, we performed bile duct ligation (BDL) on C57BL/6 mice possessing a transgenic ␣1-ATZ mutation and littermate controls. PiZ transgenic mice undergoing BDL developed more liver fibrosis by quantification of Sirius red staining (P ‫؍‬ 0.0003) and hydroxyproline (P ‫؍‬ 0.007) than wildtype mice after BDL. More activated hepatic stellate cells (HSCs) and apoptotic cells also were observed in the PiZ BDL model. Quantitative real time polymerase chain reaction (PCR) of the endoplasmic reticulum (ER) stress markers CHOP and GRP78 were 4-fold and 2-fold more up-regulated, respectively, in PiZ BDL mice when compared with wild-type BDL mice (P ‫؍‬ 0.02, P ‫؍‬ 0.02). Increased apoptosis was also noted in PiZ BDL mice by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and cleaved caspase-3 histological staining. Conclusion: PiZ transgenic mice are more susceptible to liver fibrosis induced by cholestasis from BDL. Cholestasis therefore may lead to increased fibrosis in ␣1-AT deficiency, and the ␣1-ATZ mutation may act as a modifier gene in patients with concurrent cholestatic liver diseases such as cystic fibrosis.

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Does the Heterozygous State of Alpha‐1 Antitrypsin Deficiency Have a Role in Chronic Liver Diseases? Interim Results of a Large Case‐Control Study

Cited by 72 publications

References 20 publications

Molecular characterization of the new defective P_bresciaalpha1-antitrypsin allele

Molecular characterization of the new defective P_bresciaalpha1-antitrypsin allele

Genetic determinants of hepatic steatosis in man

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

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Does the Heterozygous State of Alpha‐1 Antitrypsin Deficiency Have a Role in Chronic Liver Diseases? Interim Results of a Large Case‐Control Study

Cited by 72 publications

References 20 publications

Molecular characterization of the new defective Pbresciaalpha1-antitrypsin allele

Molecular characterization of the new defective Pbresciaalpha1-antitrypsin allele

Genetic determinants of hepatic steatosis in man

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

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Molecular characterization of the new defective P_bresciaalpha1-antitrypsin allele

Molecular characterization of the new defective P_bresciaalpha1-antitrypsin allele