Anthony S. Tavill, MD
Loutfi S. Aboussouan, MD
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 disease, a genetic disorder of copper overload, and alpha1-antitrypsin (α1-AT) deficiency, a disorder in which the normal processing of a liver-produced protein is disturbed within the liver cell.
In some cases, the awareness of these conditions is brought about by suspicion based on a specific clinical syndrome. In other cases, these conditions have to be excluded when faced with nonspecific liver disease abnormalities, such as elevated liver enzyme levels, 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 focus on discussions of these three conditions.
Certain key concepts (Box 1) are common to all three conditions and need to be emphasized at the outset. First, although the recognition of inherited liver disease is often the process of exclusion of more common causes (e.g., viruses, alcohol, autoimmunity), it is important to emphasize that awareness of the clinical features of these metabolic liver diseases should promote a proactive diagnostic evaluation. Second, inherited metabolic liver disease may manifest in childhood or may be delayed until adult life and, in some cases, may regress after the childhood or adolescent years, only to reappear later in life. Third, with the advent of molecular diagnostic testing, phenotypic assessment of these conditions may be now complemented in certain cases 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 (e.g., α1-AT deficiency, Wilson's disease), liver transplantation corrects the primary biochemical abnormality in the liver and effectively cures the disease.
Box 1: Key Concepts
Alpha1-antitrypsin (α1-AT) deficiency is a common inherited disorder associated with retention of the liver-produced protein α1-AT in the liver and low levels of α1-AT in the serum. In the most severe form of α1-AT 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 α1-AT is located on chromosome 14, and mutations at the protease inhibitor (PI) locus lead to a single amino acid substitution (glutamic acid for lysine 342) that impairs secretion of the mutant gene product, leading to retention of α1-AT in the hepatocyte and low levels of α1-AT in the serum. Because the phenotype is expressed by autosomal codominant inheritance, each allele is responsible for 50% of the circulating α1-AT level. Approximately 100 allelic variants have been described, only some of which are associated with liver disease. The Z allele is the mutation associated with maximum deficiency in α1-AT.
The frequency of this pathogenic PI Z allele in the U.S. population of European descent is between 0.01 and 0.02, with the homozygous deficiency state affecting 1 in 2000 to 7000 of the population. The major deficiency occurs in the PI ZZ phenotypes, with indirect epidemiologic approaches and more direct population-based screening methods estimating that about 60,000 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 1600 live births. The PI Z allele is confined predominantly to whites 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 α1-AT deficiency in the serum.
α1-AT is the predominant serine PI in the blood, accounting for the alpha1 peak on serum protein electrophoresis. α1-AT functions by inhibition of tissue proteinases that include enzymes such as neutrophil elastase, cathepsin G, and various other proteinases. This is a relatively low-molecular-weight protein, composed of 394 amino acids and several carbohydrate side chains. α1-AT is also an acute-phase protein, and its synthesis may increase significantly in response to injury or inflammation.
Despite its name, α1-AT reacts much more readily with neutrophil elastase than with trypsin, in a mutually suicidal interaction that normally maintains an adequate protective screen against the elastolytic burden of neutrophil elastase. α1-AT deficiency shifts this balance in favor of elastolytic breakdown, most commonly manifesting as emphysema.
The synthesis of α1-AT occurs within the endoplasmic reticulum of the hepatocyte and undergoes multiple complex foldings and insertions of carbohydrate side chains. Genetic mutations responsible for α1-AT 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 α1-AT variants that lead to this type of polymerization are associated with a gain of function defect leading to liver cell damage. The rare "null" variant is not characterized by accumulation of α1-AT within the hepatocyte and is not associated with liver damage.
In contrast, polymerization of mutated antitrypsin prevents its secretion from the hepatocyte, so that only about 15% of the PI ZZ antitrypsin is secreted into the plasma. Polymerization and the rare null variant both result in a loss of function defect, which increases the risk of developing emphysema.
Approximately 100 allelic variants have been described in the α1-AT gene locus, resulting in a complex genetic classification based on the phenotypic features of the circulating α1-AT protein. The most common variant, PI M, is present in approximately 95% of the U.S. white population and is regarded as the normal variant associated with normal serum levels of functional α1-AT. Only about 15 alleles (encompassing deficiency, dysfunctional, and null alleles) are associated with liver disease, lung disease, or bleeding diathesis. Deficiency alleles, such as PI Z and PI S, may result in decreased levels of circulating α1-AT but with completely normal functioning proteins. The MM phenotype is therefore designated as manifesting a 100% concentration of circulating α1-AT. The heterozygous combination MZ yields 50%, SZ 37.5%, and ZZ 15% of this normal MM value. Approximately 95% of all α1-AT 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 or lung disease unless combined with the Z allele. 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 later, Diagnosis).
Signs and Symptoms
The association of α1-AT deficiency and liver disease in children was first described in 1969 by Harvey Sharp at the University of Minnesota. Many subsequent clinical studies have observed that liver disease occurrence in α1-AT 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 α1-AT deficiency is the underlying genetic predeterminant (Table 1).
Table 1: Clinical Manifestations of Alpha1-Antitrypsin Deficiency*
|Neonatal or infant hepatitis||Chronic obstructive pulmonary disease|
|Prolonged cholestasis in infancy||Chronic hepatitis|
|Hepatosplenomegaly||Cirrhosis with or without portal hypertension
*Alpha1-antitrypsin deficiency may also be asymptomatic.
© 2002 The Cleveland Clinic Foundation.
Children with PI ZZ Deficiency of Alpha1-Antitrypsin
Much of the information on the clinical presentation of α1-AT deficiency in this population has come from experience in Scandinavia. Two thirds of newborns deficient in α1-AT have abnormal liver enzyme levels, 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 the childhood and teenage years. Nevertheless, careful surveillance has revealed that many of these have persistently abnormal liver enzyme levels.
Newborns with the most fully expressed form of the disease show evidence of acute neonatal hepatitis, with a predominantly conjugated hyperbilirubinemia. This jaundice may persist for as long as 1 year, with associated evidence of defective growth and the consequence of malabsorption of fat-soluble vitamins. Physical signs include hepatomegaly, splenomegaly, and possible signs of coagulopathy.
Adults with PI ZZ Deficiency of Alpha1-Antitrypsin
Most adults with PI ZZ α1-AT deficiency are identified by their pulmonary symptoms and show signs and symptoms of chronic obstructive pulmonary disease, with emphysema developing in about 80% to 100% of individuals with that phenotype. This condition is frequently aggravated by cigarette smoking. The emphysema associated with α1-AT deficiency has distinctive features, including early onset (in the fourth or fifth decade of life), predominant involvement of the lung bases, and panacinar pathology. In contrast, individuals with α1-AT-replete emphysema are older, with predominantly apical and centrilobular emphysema.
The prevalence of associated liver disease has probably been underestimated, but 10% to 40% of these adults may have evidence of cirrhosis. The risk of cirrhosis becomes higher with advancing years, particularly in men. In these cases, 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 α1-AT 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 the identification of liver disease.
Heterozygous Alpha1-Antitrypsin Deficiency
A number of studies have asserted a role for a single mutant allele in the development of so-called cryptogenic liver disease in adults. Because many of these heterozygous states are associated with intermediate α1-AT 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 α1-AT. In adults, however, it has been suggested 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 α1-AT poly-merization and degradation within the hepatocyte.
α1-AT deficiency is an example of an inherited metabolic disorder in which the definition of the phenotype also defines the genotype (Box 2). Determination of the α1-AT serum level by quantitative immunoprecipitation is insufficient evidence for the diagnosis of α1-AT deficiency. This is because serum levels may be falsely elevated as a result of the particularly robust acute-phase response of this protein. Therefore, determination of the quantitative level of α1-AT 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 on 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 currently routinely available in diagnostic laboratories.
Epidemiologic considerations have established a threshold amount of α1-AT necessary to protect the lung from emphysema. This protective threshold level is 80 mg/dL by radial diffusion, and 11 μM when referenced to functional elastase activity (normal values, 150 to 350 mg/dL or 20-53 μM, respectively). In PI ZZ individuals, serum α1-AT levels cluster around a mean value of approximately 6 μM.
The American Thoracic Society and European Respiratory Society have provided guidelines that recommend testing for α1-AT deficiency in the following cases: (1) early-onset emphysema (younger than 45 years); (2) emphysema in the absence of a recognized risk factor; (3) emphysema with prominent basilar hyperlucency; (4) unexplained liver disease; (5) necrotizing panniculitis; (6) antiproteinase 3-positive vasculitis (C-ANCA positive vasculitis); (7) family history of any of the following: emphysema, bronchiectasis, liver disease, or panniculitis; or (7) bronchiectasis without evident cause.
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 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 α1-AT antibody. Finally, the location of these globules within the endoplasmic reticulum may be confirmed by electron microscopy.
Box 2: Diagnostic Tests for Alpha1-Antitrypsin Deficiency
© 2002 The Cleveland Clinic Foundation.
In advanced and decompensating liver disease, the only available approach is orthotopic liver transplantation (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's α1-AT phenotype.
Newer approaches that may have an impact on the secretion of α1-AT from the hepatocyte may prove helpful, but these are in the experimental stage of development. Finally, although consideration of gene therapy may ultimately provide the most hopeful approach for α1-AT deficiency, this will have to be achieved with the removal of the aberrant mutant gene, which will pose a considerable challenge.
Because α1-AT deficiency is associated with 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 for those with lung injury–counseling patients regarding the deleterious effects of smoking.
Augmentation therapy refers to the exogenous infusion of purified pooled human plasma α1-AT. It can be given on a weekly, biweekly, or monthly basis. Although this has become the mainstay of specific therapy in α1-AT deficiency with emphysema, the technique offers no significant help in improving the liver injury. Studies have suggested that augmentation can reduce the number of lung infections, slow the rate of decline of lung function, reduce mortality, and reduce the rate of loss of lung tissue as determined by computed tomography (CT) scanning.
The outcomes of treatment, short of liver transplantation, present conflicts of purpose when they are aimed at preventing both liver and lung diseases. This is because the benefits of any approach that increases the serum levels of α1-AT to protect the lungs may not always offer similar protection to the liver. Only liver transplantation offers an effective cure for the condition by correcting the recipient phenotype and normalizing the circulating levels of α1-AT.
- Alpha1-antitrypsin (α1-AT) deficiency is an inherited liver disorder caused by disordered α1-AT secretion by the hepatocyte, with varying phenotypic features.
- The most severe forms are characterized by neonatal hepatitis, chronic hepatitis, cirrhosis, hepatocellular cancer, and early-onset emphysema.
- Approximately 100 allelic variants of the α1-AT gene have been described. The Z variant is the one associated with the most severe phenotypic features.
- Diagnosis is confirmed by phenotypic analysis of the variant forms of α1-AT in the serum and, when there are manifestations of liver disease, by a liver biopsy, with immunohistochemical and ultrastructural evaluations.
- Treatment is by liver transplantation for decompensated liver disease, and by augmentation therapy for the relief and prevention of symptomatic emphysema.
- Liver transplantation cures the metabolic defect in α1-AT deficiency.
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