α1-ANTITRYPSIN DEFICIENCY
Deficiency of α1-antitrypsin (α1-AT) is transmitted in an autosomal recessive fashion and leads to an increased risk of lung and
liver disease. This deficiency is one of the most common genetic diseases in the world and the second most common metabolic
disease affecting the liver, the most common being hereditary hemochromatosis (see Chapter 74).[6,7] The following discussion
focuses on the effects of α1-AT deficiency on the liver.
Pathophysiology
The prototypical member of the serpin family of protease inhibitors, α1-AT binds with and promotes the degradation of serine
proteases in the serum and tissues. The most important of these serine proteases is neutrophil elastase, which is inhibited by
α1-AT through formation of a tight 1 : 1 α1-AT-to-elastase complex. Loss of serum α1-AT activity, as occurs in the most common
form of α1-AT deficiency, leads to uninhibited neutrophil elastase activity and is one of the primary mechanism for the premature
development of pulmonary emphysema in affected patients.[8] Another proposed mechanism derives from the observation that
α1-ATZ polymers are proinflammatory toward neutrophils and are found in lung lavage fluid of patients with the protease
inhibitor (Pi) ZZ phenotype of α1-AT deficiency (see later) and emphysema; moreover, instillation of α1-ATZ polymers in murine
lung leads to an influx of neutrophils to the lung.[8,9]
Allelic α1-AT mutant variants produce Pi gene products that can be distinguished from the normal product by electrophoretic
methods; the normal allelic representation is designated PiM. The PiZ variant produces a mutant α1-ATZ protein. Homozygosity
at the PiZ allele is the most common and classic pathologic form of α1-AT deficiency and is capable of leading to liver and lung
disease. The α1-ATZ molecule represents a single amino acid replacement of glutamine with a lysine residue as a result of a
mutation at position 342 of the α1-AT (SERPINA1) gene. More than 100 naturally occurring variants of α1-AT have been
described. Although most of these variants are either of no clinical significance or are extremely rare, two additional variants,
PiSiiyama and PiMmalton, have been reported to be associated with liver injury and even cirrhosis.[8,10-12]
α1-AT is produced almost exclusively in the rough endoplasmic reticulum (ER) of hepatocytes and is subsequently targeted to
the secretory pathway via the Golgi apparatus. Structural misfolding and polymerization of the mutant α1-ATZ protein causes its
aberrant retention in the ER, failure of progression through the secretory pathway, and diminished intracellular degradation. In
persons with the phenotype PiZZ, serum α1-AT activity levels are reduced to less than 15% of normal; this loss of function
accounts for the development of pulmonary disease. Studies suggest that the rate of intracellular degradation may itself be
genetically determined and may influence the expression of disease; α1-ATZ appears to be degraded more slowly in the ER of
PiZZ patients who are susceptible to liver disease than in PiZZ patients who are not susceptible to liver disease. [13]
The exact mechanism for α1-ATZ-induced liver injury is not known. Studies of transgenic mice that express the human ATZ
gene suggest a gain-of-function mechanism by which retention in the ER and accumulation in hepatocytes of mutant α1-ATZ is
responsible for hepatotoxicity.[14] Multiple intracellular signaling pathways, including caspase activation, ER stress responses,
and the autophagic response, are activated by the retention of malformed proteins in the ER.[15] Autophagy is an intracellular
degradative pathway that targets proteins and organelles for destruction during development as well as at times of stress or
nutrient deprivation. One hypothesis under investigation is that increased stimulation of autophagy by accumulation of α1-ATZ
protein leads to ongoing mitochondrial injury, cellular apoptosis, and a chronic cycle of hepatocellular death and regeneration
that may, over time, lead to liver injury and cirrhosis.[7,16] Other genetic and environmental modifiers of the ER “quality control”
process for handling mutant α1-ATZ protein are undoubtedly involved and account for the wide variation in clinical phenotype
observed in the hepatic presentation of PiZZ patients.[7]
Clinical Features
Although the prevalence of the classic α1-AT deficiency allele, PiZ, is highest in populations derived from northern European
ancestry, many racial subgroups are affected worldwide, and millions of persons have combinations of deficiency alleles (i.e.,
PiSS, PiSZ, or PiZZ).[8,17] In the United States, the overall prevalence of deficiency allele combinations is approximately 1 in 490
(i.e., 1 in 1058 for PiSS, 1 in 1124 for PiSZ, and 1 in 4775 for PiZZ).[18] Mounting evidence suggests that heterozygous α1-AT
deficiency states can contribute to the development of cirrhosis and chronic liver failure in adults through mechanisms similar to
those encountered with the PiZZ phenotype.[10-12,19] In addition, the heterozygous α1-AT deficiency state may contribute to
worsening of chronic liver disease caused by hepatitis C viral infection or nonalcoholic fatty liver disease in adults, as well as
cholestatic liver diseases in children.[7,19-22]
In the most unbiased study to date, reported by Sveger,[23] on the epidemiology of liver disease in patients with α1-AT deficiency,
200,000 Swedish infants were screened for α1-AT deficiency, 184 infants were found to have abnormal allelic forms of α1-AT
(127 PiZZ, 2 PiZnull, 54 PiSZ, and 1 PiSnull), and 6 (5 PiZZ and 1 PiSZ) died in early childhood, although only 2 from
cirrhosis.[23] Although about 10% of newborns with α1-AT deficiency (PiZZ) present with cholestasis and as many as 50%
continue to have elevated serum aminotransferase levels at age three months, most are clinically asymptomatic. [23,24] Liver
disease does not develop in patients with null α1-AT phenotypes, whereas early-onset emphysema develops in all of them.[25]
Therefore, the prognosis for patients with liver disease manifesting in infancy as a result of α1-AT deficiency (PiZZ) is highly
variable. Even those children in whom cirrhosis develops can have a highly variable progression to end-stage liver disease
(ESLD), which infrequently leads to liver transplantation.[26] Moreover, siblings with PiZZ have a variable degree of liver
involvement; in a study reported by Hinds and colleagues, five of seven children with PiZZ requiring liver transplantation had
siblings with PiZZ who had no persistent liver involvement.[27] This finding suggests that environmental or additional genetic
factors must be involved in determining the severity of liver disease in α1-AT deficiency; this area is under active scientific
investigation.[28]
Of 150 patients with α1-AT deficiency from Sveger's original study[23] who subsequently underwent evaluation at age 16 and 18
years, none had clinical signs of liver disease. Elevated serum aminotransferase or gamma glutamyl transpeptidase (GGTP)
levels were found in fewer than 20% of patients with a PiZZ phenotype and in fewer than 15% of those with a PiSZ
phenotype.[24] By the third decade of life, analysis of this same cohort of affected persons showed that 6% of PiZZ and 9% of
PiSZ patients had a marginal increase in serum alanine aminotransferase levels.[29]
Even though liver disease is often (but not always) mild during infancy and childhood, patients with α1-AT deficiency have an
increased risk for development of cirrhosis during adulthood; 42% of all PiZZ patients have histologic evidence of cirrhosis at
autopsy.[30,31] Moreover, homozygous α1-AT deficiency raises the risk for development of hepatocellular carcinoma, especially in
men older than 50 years.[31] The diagnosis of α1-AT deficiency should be considered in any patient presenting with noninfectious
chronic hepatitis, hepatosplenomegaly, cirrhosis, portal hypertension, or hepatocellular carcinoma.
Histopathology
Histopathologic features of α1-AT deficiency change as the affected patient ages. In infancy, liver biopsy specimens may show
bile duct paucity, intracellular cholestasis with or without giant cell transformation, mild inflammatory changes, or steatosis, with
few of the characteristic periodic acid–Schiff (PAS)-positive, diastase-resistant globules. These inclusions, which result from
polymerized α1-ATZ protein, are most prominent in periportal hepatocytes, and may also be seen in Kupffer cells.
Immunohistochemistry with monoclonal antibody to α1-ATZ can also be performed to verify the diagnosis. As the patient ages,
these changes may resolve completely or progress to chronic hepatitis or cirrhosis.
Diagnosis
α1-AT is considered a hepatic acute-phase reactant, and its release may be stimulated by stress, injury, pregnancy, or
neoplasia. Because these factors can influence α1-AT production, even in patients with the PiZZ phenotype, the diagnosis of α1AT deficiency should be based on phenotype analysis and not solely on the serum α1-AT level.[32] A liver biopsy specimen,
although not universally recommended, should confirm the diagnosis. Commercial tests are available to detect the most
common mutant alleles by polymerase chain reaction analysis of genomic DNA. In addition, a re-sequencing molecular array
chip is available for rapid sequencing of the entire SERPINA1 gene to allow identification of rare mutant alleles.[33]
Screening guidelines to diagnose α1-AT deficiency in asymptomatic persons have been proposed in an effort to reduce the risk
of emphysema by counseling patients to avoid smoking.[34] Adults with chronic lung disease and siblings of affected patients
with lung or liver disease should be targeted for screening, and appropriate education and genetic counseling should be offered
to patients with α1-AT deficiency identified by screening.
Treatment
The initial treatment of α1-AT deficiency is with symptomatic care. Breast-feeding until the end of the first year of life has been
suggested to decrease the manifestations of cholestatic disease, as may the use of ursodeoxycholic acid.[35] The importance of
providing fat-soluble vitamins, when indicated, adequate nutrition, and counseling to avoid smoking and second-hand smoke
cannot be overemphasized. The role of neonatal screening for α1-AT deficiency is still not settled, although the effect on
smoking practices in patients diagnosed at an early age appears to be positive. If effective therapy for liver disease caused by
α1-AT deficiency becomes available, neonatal screening may become more useful for preventing the need for liver
transplantation.
Although progression to ESLD is uncommon, α1-AT deficiency is the most common metabolic liver disease for which liver
transplantation is performed. Besides replacing the injured organ, transplantation corrects the metabolic defect, thereby
preventing further progression of systemic disease. Between 1995 and 2004, 161 children and 406 adults underwent liver
transplantation for ESLD associated with α1-AT deficiency in the United States; of these, 4.4% of the children and fewer than
1% of the adults were African Americans. Five-year patient survival rates following liver transplantation for the pediatric and
adult patients with α1-AT deficiency were 83% and 90% respectively.[36] Liver transplantation with grafts from donors with
unrecognized α1-AT deficiency appears to have a comparable outcome to transplants using grafts without unrecognized liver
disease.[37]
Replacement therapy with purified α1-AT is the only treatment option approved by the U.S. Food and Drug Administration (FDA)
for lung disease associated with α1-AT deficiency. Patients who received replacement therapy in several studies, including a
small randomized placebo-controlled trial, have had a slower rate of decline in lung tissue and function compared with control
groups, although clinical efficacy has yet to be conclusively demonstrated.[38] This therapy would not be expected to benefit α1AT deficiency–associated liver disease, which results from malprocessed α1-ATZ, not loss of α1-AT protein function.
Other mechanistically based treatment options aimed at influencing the stability or secretion rates of α1-ATZ within the
hepatocyte ER are being investigated. Chemical chaperones such as phenylbutyric acid (PBA) markedly increase secretion of
α1-ATZ in experimental in vitro and in vivo models of α1-AT deficiency.[39] A small pilot study investigated the potential benefits of
PBA in the treatment of children with α1-AT–deficient liver disease. Unfortunately, no statistically significant increase in serum
α1-AT levels occurred in PBA-treated patients, many of whom experienced unacceptable side effects.[40] Another pharmacologic
approach in the early stages of investigation involves the design of small molecules to inhibit α1-ATZ protein polymerization and
increase clearance of intracellular aggregates.[41]
α1-AT deficiency is one of many diseases for which reconstitution of the normal genotype through gene therapy is being studied.
Long-term expression of human α1-AT in murine liver, at therapeutic levels, has been achieved after hydrodynamics-based
intravenous injection of nonviral deoxyribonucleic acid (DNA) constructs.[42] Also, delivery of a vector carrying a ribozyme
designed to target human α1-ATZ messenger ribonucleic acid (mRNA) in the portal vein of transgenic mice that carry the human
PiZ allele led to a 50% reduction in α1-ATZ mRNA levels. In a separate experiment, administration of a vector carrying the
normal PiM allele, which is resistant to ribozyme cleavage, led to long-term expression of human α1-AT protein in both liver and
serum up to one year following injection.[43] These results are promising first steps toward the goal of achieving successful gene
replacement therapy for α1-AT deficiency.