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.

Certain key concepts (Table 1) are common to all three conditions and need to be emphasized at the outset. First, while the recognition of inherited liver disease is often the process of exclusion of more common causes (eg, viruses, alcohol, autoimmunity, and so on) it is important to emphasize that awareness of the clinical features of these metabolic liver diseases should promote a proactive diagnostic evaluation among physicians in many subspecialties. Second, inherited metabolic liver disease may present in childhood or may be delayed until adult life, and in some instances it may regress after childhood or adolescent years only to reappear later in life. Third, with the advent of molecular diagnostic testing, phenotypic assessment of these conditions is now complemented in several circumstances by genotypic evaluation. Fourth, with the availability of effective treatments, there has been a dramatic impact on the prognosis of metabolic liver diseases in both childhood and adult life, further emphasizing the importance of early diagnosis. Finally, in several conditions (eg, A1AT deficiency and Wilson's disease), liver transplantation corrects the primary biochemical abnormality in the liver and effectively cures the disease.

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.

The synthesis of A1AT occurs within the endoplasmic reticulum of the hepatocyte and undergoes multiple complex foldings and insertions of carbohydrate side chains. Genetic mutations responsible for A1AT deficiency may interfere with synthesis, export from the cell, and the ability to function as a proteinase inhibitor.

The Z variant results from a single point mutation leading to the substitution of glutamic acid for lysine at position 342. The resultant variant polypeptide is relatively unstable and becomes polymerized within the endoplasmic reticulum, resulting in the periodic acid-Schiff (PAS)-positive globules that can be seen on light microscopy. Only the A1AT variants that lead to this type of polymerization are associated with liver cell damage. The rare "null" variant is not characterized by accumulation of A1AT within the hepatocyte and is not associated with liver damage.

Approximately 75 allelic variants have been described in the A1AT gene locus resulting in a very complex genetic classification based upon the phenotypic features of the circulating A1AT protein. The most common variant, PI M, is present in approximately 95% of the Caucasian US population and is regarded as the normal variant associated with normal serum levels of functional A1AT. The deficiency alleles, such as PI Z and PI S, may result in decreased levels of circulating A1AT but with completely normal functioning proteins. The MM phenotype is therefore designated as manifesting 100% concentration of circulating A1AT. The heterozygous combinations MZ yields 50%, SZ 37.5%, and ZZ 15% of this normal MM value. Approximately 95% of all A1AT deficiency states leading to clinical manifestations are made up of PI ZZ homozygotes. Certain alleles, such as the S allele, either in the homozygous state or associated with the M allele, do not appear to be associated with the abnormally polymerized molecules within the endoplasmic reticulum and have not been incriminated in the development of liver disease unless combined with the Z allele.^1,4 The products of these various alleles have distinctive characteristics on isoelectric focusing, which provides a means for the specific identification of the PI types (see Diagnosis, below).

The association of A1AT deficiency and liver disease in children was first described in 1969 by Harvey Sharp, MD, at the University of Minnesota.⁵ Many subsequent clinical studies^4,6,7 have observed that liver disease occurrence in A1AT deficiency is bimodal, affecting children in neonatal life or early infancy and, less commonly, adults in late middle life. In both these groups, the homozygous form of A1AT deficiency is the underlying genetic predeterminant (Table 2).

Children With PI ZZ Deficiency of A1AT
Much of the information on the clinical presentation of A1AT deficiency in this population has come from experience in Scandinavia. Two thirds of newborns deficient in A1AT show abnormal liver enzymes, and approximately 10% develop persistent cholestasis during the first year of life. Many of these infants appear to undergo a spontaneous remission, and only about 3% of the originally diagnosed neonates progress to fibrosis or cirrhosis during childhood and teenage years. Nevertheless, careful surveillance revealed that many of these have persistently abnormal liver enzymes.^4,5

Newborns with the most fully expressed form of the disease show evidence of acute neonatal hepatitis with a predominant conjugated hyperbilirubinemia. This jaundice may persist for as long as 1 year, with associated evidence of defective growth and the consequences of malabsorption of fat-soluble vitamins. Physical signs include hepatomegaly, splenomegaly, and possible signs of coagulopathy.

Adults With PI ZZ Deficiency of A1AT
Most adults with PI ZZ, A1AT deficiency are identified by their pulmonary symptoms and show signs and symptoms of chronic obstructive pulmonary disease. This condition is frequently aggravated by cigarette smoking. The prevalence of associated liver disease has probably been underestimated, but 10% to 40% of these adults may have evidence of cirrhosis.^4,6,7,8 The risk of cirrhosis becomes higher with advancing years, particularly in men. In these circumstances, a man older than 50 years with evidence of cirrhosis, portal hypertension, or hepatocellular carcinoma with no underlying predisposing cause should evoke suspicion of an underlying metabolic defect such as hemochromatosis or A1AT deficiency. The features of the liver disease appear to be rapidly progressive when diagnosed at this stage, with a high likelihood of death within 4 years of identification of the liver disease.⁶

Heterozygous A1AT Deficiency
A number of studies ^9,10 have asserted a role for a single mutant allele in the development of so-called cryptogenic liver disease in adults. Since many of these heterozygous states are associated with intermediate A1AT deficiency, it will be necessary to carry out prospective studies to evaluate the pathophysiologic consequences of the heterozygous state. In the pediatric arena, there is no indication of any significant long-term consequences of heterozygous A1AT. In adults, however, it has been suggested ^9,10 that the presence of a single Z allele may increase susceptibility or act synergistically with other risk factors for liver disease. These associated conditions include chronic viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis. Many of these synergistic conditions may be associated with an inflammatory response, leading to further defects in A1AT polymerization and degradation within the hepatocyte.

A1AT deficiency is an example of an inherited metabolic disorder in which the definition of the phenotype also defines the genotype (Table 3). Determination of the A1AT serum level by quantitative immunoprecipitation is insufficient evidence for the diagnosis of A1AT deficiency. This is because measurement of serum levels may be falsely elevated because of the particularly robust acute-phase response of this protein. Therefore, determination of the quantitative level of A1AT must be combined with phenotypic analysis. This defines the phenotype of the variant PI proteins in the serum and is performed by isoelectric focusing. Patients with the most severe form of deficiency have an allelic variant that migrates to a higher isoelectric point and can be defined as PI ZZ phenotypes, and therefore by inference as PI ZZ genotypes. Interpretation of the electrophoretic patterns on isoelectric focusing will determine the homozygous or heterozygous states, and will define the specific mutant alleles based upon their relative position between anode and cathode. Finally, the molecular genetic tools for defining the defect in the nucleotide coding sequence for each of the defective alleles have been developed for population studies but are not routinely available in diagnostic laboratories.

Liver Biopsy
In patients with manifestations of liver disease, liver biopsy for light microscopy and histochemistry and possible electron microscopy is valuable for staging liver disease and for identification of the PAS-positive/diastase-resistant globules within the hepatocytes. In neonates, the globules may be very indistinct and ill-developed, but they increase with age. In adult patients in particular, they may be associated with portal and periportal inflammation. Confirmation of the nature of the globules may be provided by immunohistochemical techniques, using immunoperoxidase coupled to A1AT antibody. Finally, the location of these globules within the endoplasmic reticulum may be confirmed by electron microscopy.

Although methods to improve the serum level of A1AT have been used to mitigate some of the pulmonary manifestations of A1AT deficiency, they offer no significant help in improving the liver injury.

In advanced and decompensating liver disease, the only available approach is OLT. This is the most common inherited disorder leading to liver transplantation in children. As in Wilson's disease, the outcome of OLT is extremely good, and replacement of the liver provides the recipient with the donor A1AT phenotype.

Ultimately, newer approaches that may have an impact on the secretion of A1AT from the hepatocyte may prove to be helpful, but these are in the experimental stage of development. Finally, although consideration of gene therapy may ultimately provide the most hopeful approach for A1AT deficiency, this will have to be achieved with the removal of the aberrant mutant gene, which will pose a very considerable challenge.

Since A1AT deficiency is associated with very variable phenotypic expression, it is reasonable to counsel patients with regard to all other possible sources of liver injury such as alcohol abuse. A similar approach has been adopted with regard to lung injury by counseling patients regarding the deleterious effects of smoking.

The outcomes of treatment, short of liver transplantation, present conflicts of purpose when they are aimed at preventing both liver and lung disease. This is because the benefits of any approach to increasing the serum levels of A1AT to protect the lungs may not always offer similar protection to the liver. Only liver transplantation offers an effective cure for the condition by both correcting the recipient phenotype and normalizing the circulating levels of A1AT.

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