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Liver Disease in Alpha-1 Antitrypsin Deficiency
Abbreviations
AAT
alpha-1 antitrypsin
ER
endoplasmic reticulum
PAS
periodic acid–Schiff
Pi
protease inhibitor
Alpha-1 antitrypsin (AAT) is the most abundant protease inhibitor and the second most abundant protein in plasma. It is produced predominantly by the liver and in smaller quantities by macrophages as well as by other cells in the lung, small intestine, and kidney. AAT is an acute phase reactant, and although it is named for its antitrypsin activity, its most significant physiologic role is inhibition of neutrophil elastase in the lung; deficiency results in unopposed breakdown of pulmonary connective tissue and development of emphysema. The enzyme is encoded by the Pi (protease inhibitor) gene located on chromosome 14; expression of the two inherited alleles is codominant (ie, proteins encoded by both alleles are produced). The most common allele is PiM , with 95% of the population worldwide being homozygous ( PiMM ). This genotype results in normal serum physiologic levels of 120 to 200 mg/dL. Approximately 100 mutations have been identified in the Pi gene, but the two alleles commonly associated with deficiency states in populations of North European descent are PiZ and PiS , which produce 10% to 20% and 50% to 60% of normal levels, respectively. PiS is the most common deficiency allele in people of Iberian descent. Other rare deficiency alleles are PiMmalton, PiMduarte , and the null alleles, which are associated with up to 15% of normal protein levels. PiMmalton is the most common disease mutation in Sardinia whereas PiSiiyama , although rare, is the most common disease mutation in Japan. The lowest enzyme levels are found in individuals who are homozygous for PiZZ and those with the rare null variants; patients with PiZZ represent the classic form of AAT deficiency disease. In these individuals, emphysema is a “loss of function” disease resulting from low levels of the protease inhibitor, which are inadequate to effectively counteract the destructive action of neutrophil elastase in the lung. The liver disease, on the other hand, is caused by intracellular accumulation of abnormal protein, which cannot be secreted by hepatocytes; this effect is sometimes called “gain of toxic function.” The severity of liver disease varies widely among individuals, suggesting either incomplete penetrance of the genotype, the presence of other modifier genes, the influence of environmental factors, or a combination of these variables.
Terminology
The designations Pi for the AAT gene and Pi for its protein product (serpin peptidase inhibitor 1) are now superseded by SERPINA1 and SERPINA1, respectively. To facilitate uniformity in the study of newly discovered variants, detailed guidelines for their characterization and nomenclature were published more than three decades ago by members of a Pi Nomenclature Workshop held in 1978. The workshop recommended that the Pi allele be designated by consecutive capital letters corresponding to the position occupied by the protein on a gel following isoelectric focusing. When there are no unused letters, figures (eg, M1, M2) or place of origin names (eg, Mpalermo) are used in addition to the letter of the closest allele; figures are preferred for polymorphic alleles and place of origin names for rare alleles. This nomenclature has been widely adopted, and pending wider usage of the new terminology will be deferred to in this text.
Incidence and Demographics
The incidence of AAT deficiency is 1 per 1500 to 3500 in mixed North American and European populations. However, AAT deficiency alleles are not restricted to Caucasians, having been described in African, Asian, and Middle Eastern populations. A comprehensive analysis of control cohorts from several studies from around the world demonstrated that deficiency alleles are found in all ethnic groups and in all geographic regions, albeit at variable frequencies. These data, derived from 373 cohorts in 58 countries, indicate that in a total population of 4.4 billion people in the countries surveyed, there are at least 116 million carriers ( PiMS and PiMZ ) of the deficiency alleles and 3.4 million deficiency allele combinations ( PiSS, PiSZ, PiZZ ). Nevertheless, AAT deficiency is still largely a Caucasian disease, with its highest incidence in people of European descent.
The two alleles, PiZ and PiS , are thought to have originated many generations apart, the former in Scandinavia and the latter in the Iberian peninsula. Although the presence of these alleles in the Middle East, Mediterranean region, and North Africa may be attributed to movement of the Vikings and European armies, their presence in Asia and in the indigenous tribes of Nigeria and South Africa suggests mechanisms other than migration. Worldwide, the “S” allele is more common than the “Z” allele, and in the United States, it is more common in Hispanics than in non-Hispanic Caucasians. The estimated gene frequency of the PiS allele ranges from 1 to 9 per 1000 people and that of the PiZ allele from 1 to 24 per 1000 people in different parts of the world. Among the heterozygous genotypes, PiMS constitutes 70%, PiMZ 28%, and PiSZ 1% of the total heterozygous population.
Clinical Manifestations and Natural History of Liver Disease
PiZZ
The classic phenotype of AAT deficiency disease is exhibited by individuals who are homozygous for the “Z” allele ( PiZZ ). However, the clinical manifestations and their severity vary widely among individuals ( Table 9.1 ). It is also evident from large population screening studies that only a minority of individuals with PiZZ develop chronic liver disease. Although liver disease may present at any time during an individual’s lifetime, there appears to be a bimodal peak for presentation, the first in infancy and early childhood and the second in the fifth decade of life.
Table 9.1
Clinical Presentation of Alpha-1 Antitrypsin Liver Disease
| Phenotype/Age Group | Clinical Presentation |
|---|---|
| PiZZ | |
| Neonates |
|
| Children |
|
| Adults |
|
| PiMZ | |
| Neonates and children |
|
| Adults |
|
| PiSZ | |
| Neonates and children |
|
| Adults |
|
| PiSS | |
| Neonates and children |
|
| Adults |
|
AAT deficiency is the most common genetic cause of metabolic liver diseases in infants. Approximately 70% of newborns with PiZZ have abnormal liver tests, but only about 15% present with clinical signs and symptoms of neonatal cholestatic syndrome. These patients have varying degrees of cholestasis, poor feeding, poor weight gain, hepatomegaly, splenomegaly, and coagulopathy. Clinical manifestations resembling biliary obstruction, such as dark urine and acholic stools, are usually present. Laboratory examination usually reveals elevated total and conjugated bilirubin, elevated serum transaminases, and varying degrees of hypoalbuminemia or coagulopathy. Liver tests gradually improve, normalizing in most children by 1 year of age; by 18 years of age, only about 10% of children have marginally elevated liver tests. A minority of children (2% to 3%) who present in infancy with neonatal cholestasis progress to liver failure or chronic liver disease with fibrosis. Various prognostic factors predicting death or the need for liver transplantation have been described in different studies but have not been universally confirmed; these include male sex, low birth weight, persistent or recurrent jaundice, liver test abnormalities, presence of marked ductular reaction, bile duct paucity, and presence of fibrosis.
The vast majority of the data on the natural history of PiZZ comes from a large Swedish series of 200,000 children screened for AAT phenotypes at birth; approximately half of clinically-well infants with PiZZ had abnormal liver enzymes in the neonatal period and 17% (22/127) had signs of neonatal cholestasis. Four children died in early childhood, either as a result of cirrhosis or with significant fibrosis. The remaining children were followed up at 8, 12, 16, and 18 years of age. At 18 years of age, no patient had clinical signs of liver disease, and most patients had normalized their liver tests, with only 8% having mild elevations of gamma-glutamyl transpeptidase and 15% of alanine aminotransferase. No biopsies were performed in these asymptomatic individuals, but procollagen levels used as a marker of fibrogenesis were not elevated. Follow up at 26 and 30 years of age showed transaminases within the normal range in the majority of individuals, although the levels were higher than in healthy control subjects.
Of the children with liver disease, approximately 15% present for the first time with signs of chronic liver disease without having gone through a phase of neonatal cholestatic syndrome. These children present anywhere from younger than 1 year of age to their teens and may show elevated liver tests, hepatomegaly, splenomegaly, or complications of cirrhosis. In one series, a low albumin level at presentation was an adverse prognostic factor, predicting the need for liver transplantation.
Although the large population study from Sweden has documented the presentation and natural history of PiZZ that first appears in childhood, a similar comprehensive study does not exist for disease that first presents in adulthood, partly because liver disease in adulthood evolves insidiously and patients present abruptly with cirrhosis or its complications. However, a significant number of patients do present in adulthood; a survey by the Alpha-1 Foundation Registry revealed that 74 of 104 respondents had presented with liver disease after 18 years of age. The risk of cirrhosis is greater in men than in women, and the incidence of clinically significant disease and cirrhosis increases with age; this corresponds histologically to more inflammation and fibrosis in older patients than in younger ones. Although the risk of cirrhosis before 20 years of age is small (∼3%), it approaches 30% to 50% in elderly men, and approximately 37% of adult patients with PiZZ have cirrhosis at time of death. Paradoxically, these patients usually represent nonsmokers who have not succumbed to chronic pulmonary disease.
Several, but not all, studies report a higher than usual risk of development of primary liver cancer, including hepatocellular carcinoma, cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma (biphenotypic primary liver carcinoma; see Chapter 39 ). The risk of malignancy is greater than can be attributed to cirrhosis alone, and a significant number of malignancies occur in patients without cirrhosis. There appears to be a male preponderance in the development of hepatocellular carcinoma. The risk of carcinoma is increased in individuals with either PiZZ or PiMZ.
PiMZ
Early studies failed to find an association of the heterozygous PiMZ phenotype with chronic liver disease. However, two observations have emerged in several later series. The first is the presence of this phenotype in a substantial number of cases of “cryptogenic cirrhosis,” and the second is an increased incidence of the PiMZ phenotype in patients with other chronic liver diseases (see Table 9.1 ).
Numerous studies have documented the presence of PiMZ in both children and adults who have cryptogenic cirrhosis, suggesting that the heterozygous state can lead to chronic end-stage liver disease. Although some of these studies predate the discovery of the hepatitis C virus and the recognition of steatohepatitis as a cause of cryptogenic cirrhosis, others have excluded hepatitis C infection as an etiologic agent. The most convincing documentation of the potential of PiMZ to form intracytoplasmic deposits and cause chronic liver disease by itself and in the absence of other concurrent liver diseases, comes from a large histologic series of surgical cases and autopsies. In this well-designed study, the authors performed immunohistochemistry to identify cases with AAT deposition in 1847 consecutive surgical specimens comprising biopsies and resections, as well as 1030 consecutive autopsy cases of adult Caucasian patients. Zygosity was established by single-strand conformational polymorphism and DNA sequencing on paraffin-embedded tissue. The incidence of PiMZ was significantly higher (3.4%) in the surgical resection group than in both the autopsy group (1.8%) and the general population under study (2.8%), suggesting that the carrier state contributed to elevated liver tests or clinical signs of liver disease prompting biopsy or surgical resection. Furthermore, 26 patients did not have concurrent liver disease; the histologic features in this group ranged from normal liver tissue to chronic liver disease including cirrhosis. In a different study of 599 patients who underwent liver transplantation, PiMZ was found in 27% of cases of “cryptogenic cirrhosis.” Both these studies excluded hepatitis C and steatohepatitis as possible etiologic agents, and in both studies, intracytoplasmic globules were seen in some cases.
In addition to the potential of PiMZ to cause chronic liver injury and intracytoplasmic deposition of abnormal protein, heterozygosity also seems to accentuate liver injury of other concomitant chronic liver diseases. Various series have found, albeit not uniformly, an increased incidence of the PiMZ phenotype with hepatitis C viral infection, alcoholic cirrhosis, and nonalcoholic liver disease. The association with chronic viral hepatitis has raised speculation that patients with the PiZ allele are more prone to hepatitis C infection. In an analysis of 599 transplant recipients, the incidence of the PiMZ phenotype was found to be 8.2%, which was significantly higher than the 3% expected in the general population; almost two-thirds of cases were associated with other chronic liver diseases. There are suggestions that the PiMZ phenotype is associated with faster progression and worse outcomes of coexisting liver diseases, including pediatric diseases such as cystic fibrosis and biliary atresia. However, an accelerated course of coexisting hepatitis C infection has not been confirmed by all studies.
Conversely, the natural history of PiMZ liver disease is also affected by the presence of concurrent liver disease. In a cohort of 28 patients with PiMZ who also had another chronic liver disease, there were more intracytoplasmic deposits, greater inflammatory activity, and a higher stage of fibrosis when compared with a cohort of 26 patients with PiMZ who did not have a second coexisting liver disease.
A minority of infants with PiMZ show liver test abnormalities in the first 6 months of life, which gradually normalize (see Table 9.1 ). Of 467 infants with PiMZ detected by a newborn screening program in northern Italy, 101 were followed up at 2, 5, and 12 months of age; 19 children showed hepatic dysfunction at 2 months, 8 at 5 months, and 1 at 12 months. Of these, none of the 57 children followed up at 5 and 10 years of age showed hepatosplenomegaly, abnormal liver enzymes, or abnormal growth.
The “S” Allele
The PiS allele, more common in the population than the PiZ allele, may exist in a homozygous form ( PiSS ), a heterozygous form ( PiMS ), or a double heterozygous form ( PiSZ ). The PiS allele is a deficiency allele; the lowest serum levels are found with PiSZ , followed by PiSS and PiMS , in that order. However, these genotypes rarely cause significant liver disease, although transient elevations of liver tests may be noted in the neonatal period (see Table 9.1 ).
Twenty percent of 54 newborns with PiSZ in the Swedish screening program had abnormal liver tests in the first year of life. These normalized with age; of the individuals followed up at 16, 18, 26, and 30 years of age, none had signs of liver disease and only a minority had marginally abnormal liver tests. Five percent of a separate cohort of 14 infants with PiSZ of 19,432 newborns screened in northern Italy demonstrated a moderate rise in transaminases, but clinical or laboratory signs of cholestasis were not seen during the first year of life. At 5 and 10 years of age, no patient showed hepatosplenomegaly, abnormal growth pattern, jaundice, or abnormal liver tests. The same screening program identified 135 infants with PiMS , approximately 15% of whom had abnormal liver tests at 2 months of age, which normalized within 1 year. Rarely, children may present with conjugated hyperbilirubinemia and features of neonatal hepatitis on biopsy. In a study of 162 children with AAT deficiency referred to a tertiary liver service over a period of 14 years, PiSS and PiSZ were present in 4% and 6% of patients, respectively. Of these, 13 children had other underlying disease that brought them to clinical attention, and four (three with PiSZ and one with PiSS) presented at 2 months of age with conjugated hyperbilirubinemia and neonatal hepatitis. These four were free of jaundice and liver tests were normal on median follow-up of 10.5 months.
Heterozygosity for the “S” allele ( PiMS ), unlike that for the “Z” allele, does not show an increased association with other chronic liver diseases. The phenotype was not overrepresented in a cohort of 599 patients who underwent liver transplantation, and furthermore, the cases were distributed evenly among all liver diseases. However, early studies had reported an association of PiMS with chronic active hepatitis, and it is not certain that hepatitis C infection was ruled out in these patients.
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