Liver Diseases: A1AT Deficiency
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/gastro/alpha1/alpha1.htm
There are many inherited metabolic diseases that may have a pathologic impact on the liver. In many cases the liver component of these diseases is only an epiphenomenon of a more generalized systemic disorder. Examples of such epiphenomena are glycogen and lipid storage diseases in which hepatomegaly is a manifestation of the underlying metabolic defect although the liver is not necessarily the major target organ. However, there are three genetically determined diseases in which the liver may be the principal target organ, with manifestations of acute, subacute, or chronic disease that may become evident in early or later life. These are hereditary hemochromatosis (HH), a major disorder of iron overload; Wilson's disease, a genetic disorder of copper overload; and alpha1-antitrypsin (A1AT) deficiency, a disorder in which the normal processing of a liver-produced protein is disturbed within the liver cell. In some circumstances the awareness of these conditions is brought about by suspicion based on a specific clinical syndrome. In other circumstances these conditions have to be excluded when faced with nonspecific liver disease abnormalities, such as elevated liver enzymes, hepatomegaly, or previously undiagnosed portal hypertension. In the case of hemochromatosis, the approach to early diagnosis has moved one step further, with an awareness that markers of iron overload may be present in the serum long before liver disease has developed. These chapters will be confined to a discussion of these three conditions.
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A1AT deficiency is a common inherited disorder associated with retention of the liver-produced protein A1AT in the liver and low levels of A1AT in the serum. In the most severe form of A1AT deficiency, the clinical features consist of early-onset emphysema, neonatal hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. However, phenotypic expression throughout life is extremely variable. The gene for A1AT is located on chromosome 14, and mutations at the protease inhibitor (PI) locus lead to a single amino acid substitution (glu for lys 342) that impairs secretion of the mutant gene product, leading to retention of A1AT in the hepatocyte and low levels of A1AT in the serum. Since the phenotype is expressed by autosomal codominant inheritance, each allele is responsible for 50% of the circulating A1AT level. Approximately 75 allelic variants have been described, only certain of which are associated with liver disease. The Z allele is the mutation associated with maximum deficiency in A1AT. The frequency of this allele in the US population of European descent is between 0.01 and 0.02, with the homozygous deficiency state affecting 1 in 2,000 to 1 in 7,000 of the population. Since the major deficiency occurs in the PI ZZ phenotype, it has been calculated that 80,000 to 100,000 people in the United States are homozygous for this phenotype. In Scandinavia, the frequency of the Z allele is considerably higher, resulting in one PI ZZ in 1,600 live births. The PI Z allele is confined predominantly to Caucasians and is found rarely in African-Americans or Asians. There are many other allelic combinations that may have clinical relevance, including the MZ heterozygous state and other combinations such as PI SZ, which are also associated with A1AT deficiency in the serum.
There are many inherited metabolic diseases that may have a pathologic impact on the liver. In many cases the liver component of these diseases is only an epiphenomenon of a more generalized systemic disorder. Examples of such epiphenomena are glycogen and lipid storage diseases in which hepatomegaly is a manifestation of the underlying metabolic defect although the liver is not necessarily the major target organ. However, there are three genetically determined diseases in which the liver may be the principal target organ, with manifestations of acute, subacute, or chronic disease that may become evident in early or later life. These are hereditary hemochromatosis (HH), a major disorder of iron overload; Wilson's disease, a genetic disorder of copper overload; and alpha1-antitrypsin (A1AT) deficiency, a disorder in which the normal processing of a liver-produced protein is disturbed within the liver cell. In some circumstances the awareness of these conditions is brought about by suspicion based on a specific clinical syndrome. In other circumstances these conditions have to be excluded when faced with nonspecific liver disease abnormalities, such as elevated liver enzymes, hepatomegaly, or previously undiagnosed portal hypertension. In the case of hemochromatosis, the approach to early diagnosis has moved one step further, with an awareness that markers of iron overload may be present in the serum long before liver disease has developed. These chapters will be confined to a discussion of these three conditions.
...
A1AT deficiency is a common inherited disorder associated with retention of the liver-produced protein A1AT in the liver and low levels of A1AT in the serum. In the most severe form of A1AT deficiency, the clinical features consist of early-onset emphysema, neonatal hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. However, phenotypic expression throughout life is extremely variable. The gene for A1AT is located on chromosome 14, and mutations at the protease inhibitor (PI) locus lead to a single amino acid substitution (glu for lys 342) that impairs secretion of the mutant gene product, leading to retention of A1AT in the hepatocyte and low levels of A1AT in the serum. Since the phenotype is expressed by autosomal codominant inheritance, each allele is responsible for 50% of the circulating A1AT level. Approximately 75 allelic variants have been described, only certain of which are associated with liver disease. The Z allele is the mutation associated with maximum deficiency in A1AT. The frequency of this allele in the US population of European descent is between 0.01 and 0.02, with the homozygous deficiency state affecting 1 in 2,000 to 1 in 7,000 of the population. Since the major deficiency occurs in the PI ZZ phenotype, it has been calculated that 80,000 to 100,000 people in the United States are homozygous for this phenotype. In Scandinavia, the frequency of the Z allele is considerably higher, resulting in one PI ZZ in 1,600 live births. The PI Z allele is confined predominantly to Caucasians and is found rarely in African-Americans or Asians. There are many other allelic combinations that may have clinical relevance, including the MZ heterozygous state and other combinations such as PI SZ, which are also associated with A1AT deficiency in the serum.