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Abnormalities of Hepatic Protein Metabolism
Three disorders are discussed in this chapter, including α1-antitrypsin deficiency, tyrosinemia, and urea-cycle enzyme defects.
α1-Antitrypsin Deficiency
The description of α1-antitrypsin deficiency and its association with lung disease was reported in 1963 by Laurell and Eriksson. The association between α1-antitrypsin deficiency and hepatic cirrhosis in children was initially identified in 1969 by Sharp and coworkers. Since these original observations, it is clear now that α1-antitrypsin deficiency is a relatively common genetic disorder, affecting one in 1600 to one in 2000 live births and resulting in liver disease in infants, children, and adults, as well as lung disease primarily in adults.
The Characteristics of the α1-Antitrypsin Protein
α1-Antitrypsin is a 52-kDa glycoprotein that is secreted by the hepatocytes, and, to a minor extent, by other tissues including lung and intestinal epithelial cells, neutrophils, and alveolar macrophages. The half-life of α1-antitrypsin is approximately 4 to 5 days. The function of α1-antitrypsin protein is to inhibit chymotrypsin, pancreatic elastase, skin collagenase, renin, urokinase, Hageman factor/cofactor, and the neutral proteases of neutrophils. α1-Antitrypsin protein belongs to a large gene family of serine protease inhibitors referred to as serpins. ,
α1-Antitrypsin is composed of 394 amino acids arranged into three β-sheets (A, β, and C), nine α-helices (A-I), and immobile inhibitory reactive center loop. The interaction between α1-antitrypsin and proteases occurs by the formation of a 1-1 complex. α1-Antitrypsin protein is present in tears, duodenal fluid, saliva, nasal secretions, cerebral spinal fluid, pulmonary secretions, and breast milk. α1-Antitrypsin acts as an acute phase reactant and increases in the setting of inflammation, neoplastic disease, and pregnancy. However, in patients with α1-antitrypsin deficiency, these stimuli do not induce α1-antitrypsin protein.
Phenotyping of α1-Antitrypsin
The serum level of α1-antitrypsin in the plasma ranges from 100 to 200 mg/dL. This plasma level is determined by both α1-antitrypsin gene alleles, which are codominantly inherited. Several techniques including protein electrophoresis on starch gels and isoelectric focusing have contributed to our understanding of the variation in α1-antitrypsin. , α 1 -Globulins appear in this system as a series of characteristic bands of variable intensity. The α1-antitrypsin variants included in an allelic system are called the Pi (protease inhibitor) system, and are named according to their migration velocity in the starch-gel electrophoresis. Faster moving protein complexes are identified by earlier letters in the alphabet, and the slowest moving protein is labeled Z. Thus, the variants of α1-antitrypsin are labeled as M (medium), S (slow), F (fast), or Z (very slow).
Three major categories of α1-antitrypsin variants have been identified as useful clinical markers :
- 1.
Normal, a category that includes the four more common M variants (M 1 to M 4 )
- 2.
Deficient, characterized by the α1-antitrypsin variants Z and S, and a number of less-frequent variants, such as M Malton , M Procida
- 3.
Null, in which no detectable α1-antitrypsin level is seen
At least 100 different alleles of α1-antitrypsin have been described. The normal allele is PiM type with overall allelic frequency of 0.95. The next two most common alleles in the United States are PiS at 0.03 and PiZ at 0.01. Blacks have lower frequencies of these alleles. The highest prevalence of PiZ variant has been reported in Northern and Western European countries, peaking in Southern Scandinavia, Denmark, the Netherlands, the United Kingdom, and Northern France. Table 72.1 depicts the relationship between Pi phenotypes and serum concentration of α1-antitrypsin.
TABLE 72.1
Relationship Between Pi Phenotypes and Serum Concentrations of α1-Antitrypsin
| Phenotype | Serum Concentration (%) |
|---|---|
| MM | 100 |
| MZ | 60 |
| SS | 60 |
| FZ | 60 |
| M- | 50 |
| PS | 40 |
| SZ | 42.5 |
| ZZ | 15 |
| Z- | 10 |
| — | 0 |
Genetics of α1-Antitrypsin Deficiency
The gene encoding α1-antitrypsin ( SERPINA 1) has been cloned and is located on chromosome 14q31-32.2. The α1-antitrypsin gene is 12.2 kb in length and consists of seven exons, designated I A , I B , I C , I (noncoding), and II, III, IV, and V (coding). Exons II to IV are translated into 52-kDa protein. The same gene is responsible for the α1-antitrypsin production in the liver, lung, and macrophages. The first two exons (I A , I B ) and a short 5′ segment of I C are included in the primary transcript in the macrophages, but not in hepatocytes. The protein has three asparagine-linked branched oligosaccharide moieties. The basis for the genetic defect in the PiZ type of α1-antitrypsin deficiency is the substitution of lysine for glutamic acid at position 342 from the carboxy terminus in the Z-type protein. ,
Several mutations within the SERPINA1 gene have been found to cause deficiency. The prevalence of the three major α1-antitrypsin variants (PiM, PiZ, and PiS) is reported as gene frequencies (the frequency of a variant in homozygotes). The highest prevalence of the PiZ variant has been recorded in European populations with a peak in Southern Scandinavia, Denmark, the Netherlands, the United Kingdom, and Northern France. Most recent surveys indicate that α1-antitrypsin deficiency is also prevalent in populations in the Middle East and North Africa, Central and Southern Africa, and Central and Southeast Asia. However, in Far East Asia, the gene frequency of α1-antitrypsin deficiency is rather rare, especially in Japan and Far Eastern populations.
Clinical Manifestations of α1-Antitrypsin Deficiency
Liver Disease in Children
Neonatal cholestasis is the first manifestation of α1-antitrypsin deficiency and is commonly seen in the first few weeks of life. , The affected infants are generally small for gestational age, and the liver is mildly enlarged. Acholic stools and dark urine may be seen. These patients appear to have elevated conjugated bilirubin and mildly elevated serum amino transferase levels. Alkaline phosphatase and γ-glutamyl transpeptidase levels are also elevated. The jaundice usually disappears during the second to the fourth months of life. Neonates may present with liver cirrhosis or bleeding diathesis secondary to vitamin K deficiency.
The histologic picture of the liver may be helpful in predicting the outcome of the liver disease. A picture similar to that of neonatal hepatitis, portal fibrosis with bile duct proliferation, or intrahepatic duct hypoplasia may be noted in the biopsies. Patients with portal fibrosis and bile duct proliferation appear to have worse outcomes. However, the hallmark of the liver biopsy in these patients is the deposition of the periodic acid–Schiff (PAS) stain diastase resistant α1-antitrypsin depositions in the periportal hepatocytes. ,
The number of infants presenting with neonatal cholestasis was addressed in a large prospective study of 202,000 Swedish newborns in which 120 PiZ patients were identified. , Fourteen of the 120 PiZ infants had prolonged obstructive jaundice, and nine had severe clinical laboratory evidence of liver disease. Five patients had only laboratory evidence of liver disease. Eight other PiZ infants had minimal abnormalities in serum bilirubin and hepatic enzyme activity, and variable hepatosplenomegaly. Approximately 50% of the remaining patients with PiZ had abnormal levels of aminotransferase only. Follow-up studies of these patients at 18 years of age showed that more than 85% had persistently normal serum transaminase levels. Forty-eight patients with the phenotype PiSZ were identified in this study. None of these infants had clinical liver disease, but 10 of 42 patients at 3 months and one of 22 at 6 months of age had abnormal liver function tests.
In the United States, screening of 107,038 newborns showed the PiZ phenotype in 21 infants. Of the 18 infants followed, only 1 had neonatal cholestatic jaundice and 5 had hepatomegaly and biochemical abnormalities, or both. At 3 to 6 years of age, none of the children had evidence of hepatic cirrhosis. Other reports indicate that patients with PiZ who present with neonatal cholestasis are more likely to develop serious liver disease in the future compared to those infants without a history of neonatal cholestatic jaundice. The overall risk of death from liver disease in children with PiZ during childhood is estimated at 2% to 3%. Boys are at higher risk compared to girls. Why some patients with PiZ have worse liver disease than others is not known. However, genetic and/or environmental factors may play a role.
Liver Disease in Adults
Single case reports and retrospective studies have suggested that adult patients with PiZ are likely to develop liver disease and hepatocellular carcinoma (HCC). Therefore, it does appear that α1-antitrypsin deficiency should be considered in the differential diagnosis of any adult patient with abnormal liver function tests, liver cirrhosis, portal hypertension, or HCC. It is estimated that the risk of developing hepatic cirrhosis in adults with α1-antitrypsin deficiency is about 10%.
A retrospective study on 13 autopsied cases of α1-antitrypsin deficiency identified in Sweden indicated a strong relation between α1-antitrypsin deficiency, liver cirrhosis, and primary liver cancer. However, the study suggests that male patients are at higher risk of development of liver cirrhosis and hepatoma in α1-antitrypsin deficiency.
The relationship between liver cirrhosis and partial deficiency or heterozygotic phenotype of α1-antitrypsin has not been addressed on a larger scale in the literature. A number of case reports indicate the association of adult-onset liver cirrhosis with PiSZ. In one study, there was an increased prevalence of phenotype MZ in patients with cryptogenic liver cirrhosis and with non-B chronic hepatitis. , However, in another prospective study, the heterozygote state occurred with approximately equal frequencies in patients with and without hepatobiliary disease.
A subset (approximately 3% to 5%) of patients with cystic fibrosis (CF) develop severe liver disease with portal hypertension. It has been reported that the α1-antitrypsin deficiency ( SERPINA1 ) Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (odds ratio ∼5) of developing severe liver disease with portal hypertension.
In general, there is a suggestion that a partial deficiency of α1-antitrypsin is more likely to predispose these patients to liver injury. What is clear is that patients with liver cirrhosis and α1-antitrypsin deficiency are at risk of developing HCC. Indeed, Berg and Eriksson found six hepatomas in the nine cirrhotic adults who were phenotypically PiZ patients. Four of these tumors were HCC and two were cholangiocarcinoma. ,
Liver disease has also been associated with several other allelic variants of α1-antitrypsin deficiency, such as PiM Malton , Pi FZ , Pi W , PiM Duarte , and PiS iiyama .
Lung Disease
The development of lung disease in the pediatric patient is exceedingly rare, despite several reports that suggest that these patients do have increased respiratory infections. However, it is clear that adults with PiZ who are smokers will most likely develop emphysema. , Autopsy studies indicate that approximately 60% of patients with PiZ develop clinically significant lung injury.
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