American Journal of Gastroenterology
C 2008 by Am. Coll. of Gastroenterology
Published by Blackwell Publishing
ISSN 0002-9270
doi: 10.1111/j.1572-0241.2008.01955.x
CME
Liver Disease in Alpha 1-Antitrypsin Deficiency: A Review
Kyrsten D. Fairbanks, M.D. and Anthony S. Tavill, M.D., F.A.C.P., F.R.C.P., F.A.C.G.
Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio
Alpha 1-antitrypsin deficiency is an inherited metabolic disorder that predisposes the affected individual to chronic
pulmonary disease, in addition to chronic liver disease, cirrhosis, and hepatocellular carcinoma. Just over one-third
of genetically susceptible adult patients with the most severe phenotype, PiZZ, develop clinically significant liver
injury. The clinical presentation of liver disease is variable, and the genetic and environmental factors that
predispose some individuals to liver disease while sparing others are unknown. The mechanisms of liver and lung
disease are distinct and unique. This article reviews the liver disease associated with alpha 1-antitrypsin deficiency,
emphasizing the genetic defect, molecular pathogenesis, natural history, and promising therapies.
(Am J Gastroenterol 2008;103:2136–2141)
INTRODUCTION
Alpha 1-antitrypsin deficiency is an inherited metabolic disorder in which mutations in the coding sequence of the serine
protease inhibitor, alpha 1-antitrypsin, prevent its export from
the hepatocyte. As a result, there is a deficiency in the concentration of circulating alpha 1-antitrypsin, predisposing to
early-onset panlobular emphysema, even in nonsmokers (1).
In addition, the abnormal accumulation of the glycoprotein in
hepatocytes results in programmed cell death, hepatic inflammation, fibrosis, and cirrhosis. Histopathologic examination
of liver specimens from patients with alpha 1-antitrypsin deficiency demonstrates the classic intracellular globules that
stain positive with periodic acid-Schiff (PAS) after treatment
with diastase (Fig. 1). These globules represent polymerized
mutant protein retained in the rough endoplasmic reticulum.
The aim of this article is to review the liver disease associated with alpha 1-antitrypsin deficiency, with emphasis on
the genetic defect, molecular pathogenesis, natural history,
and promising therapies. For a recent review of lung disease
associated with alpha 1-antitrypsin deficiency, refer to Stoller
and Aboussouan (2).
GENETICS AND EPIDEMIOLOGY
The gene for alpha 1-antitrypsin is located on the long arm
of chromosome 14, and has been mapped to 14q31–32 (3).
Alpha 1-antitrypsin deficiency is inherited as an autosomal
recessive disorder with codominant expression, as each allele
contributes 50% of the total circulating enzyme inhibitor. To
date, more than 100 alleles have been identified (4), only
some of which are associated with liver disease. Phenotypes
are classified based on migration of the protein product in
gel electrophoresis, and these define the allelic genotypes.
Disease states are associated with mutations in the normal
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gene product, designated PiM, giving rise to the most common deficiency variants PiS (expressing 50–60% of alpha
1-antitrypsin, as defined by immunoassay or nephelometry)
and PiZ (expressing 10–20% of alpha 1-antitrypsin).
Among whites, the most common allele, M, accounts for
95% of alleles, while S and Z account for 2–3% and 1% of alleles, respectively. The most prevalent carrier phenotypes are
PiMS and PiMZ, and deficiency phenotypes are PiSS, PiSZ,
and PiZZ. Rare deficiency alleles, accounting for <5% of Pi
variants in patients with alpha 1-antitrypsin deficiency, include Mmalton, Mduarte, and null, among others. In general,
these alleles contribute 0–15% of normal concentration of alpha 1-antitrypsin. Both Mmalton and Mduarte are associated
with liver inclusions and clinically apparent liver disease (5).
The null phenotype occurs as a result of various mutations,
such as stop codons in coding exons of the alpha 1-antitrypsin
gene, or complete deletion of alpha 1-antitrypsin coding exons, and leads to the absence of any alpha 1-antitrypsin production (6). The latter is therefore not associated with liver
cell inclusions or liver disease, but can lead to pulmonary
manifestations.
Severe alpha 1-antitrypsin deficiency (PiZZ) is found in
approximately 1:3500 live births, and has been described in
all races (7–9). It is, however, most commonly a disease of
whites, as the most prevalent deficiency alleles, Z and S,
are overwhelmingly derived from Northern European ancestry (Z and S alleles), and some Southern European ancestry (S allele). Although it has been described in all races,
the frequency of PiZ varies greatly, being extremely rare in
Asian and Mexican Americans, uncommon in Black Americans (2.6 per 1,000), and more common in Hispanic (9.1 per
1,000) and White Americans (14.0 per 1,000) (10).
DIAGNOSIS
The diagnosis of alpha 1-antitrypsin deficiency is confirmed
solely on laboratory assays. There are several laboratory
methods available for testing alpha 1-antitrypsin deficiency,
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Liver Disease in Alpha 1-Antitrypsin Deficiency
2137
alone cannot distinguish a homozygous deficiency state from
a heterozygous allele paired with a null allele. Diagnosis at a
molecular level, by genotyping, provides definitive diagnosis
of specific known phenotypic variations. It also may identify
suspected new mutations. Commercial kits are available to
detect the most common S and Z alleles. The task force of
the American Thoracic Society and the European Respiratory
Society determined that phenotyping by isoelectric focusing
is the accepted “gold standard” for the diagnosis of alpha
1-antitrypsin deficiency (12).
MOLECULAR PATHOGENESIS
Figure 1. Liver biopsy photomicrographs from a 31-yr-old male
with PiZZ alpha 1-antitrypsin deficiency showing periodic acidSchiff-positive diastase resistant globules (A) confirmed by immunoperoxidase staining, magnification ×128 (B) in hepatocyte cytoplasm, consistent with retained alpha 1-antitrypsin-Z molecules,
magnification ×128.
including quantification of the enzyme inhibitor, phenotyping, and genotyping. Serum alpha 1-antitrypsin concentration
is usually measured by nephelometry, which is replacing the
older immunoassays. Alpha 1-antitrypsin is an acute phase
protein; that is, its synthesis and release from the hepatocyte is
augmented by systemic inflammation. Levels may be thereby
transiently elevated and falsely reassuring in some heterozygous individuals. However, levels of alpha 1-antitrypsin in
the PiZZ homozygous individual would rarely, if ever, reach
a value that would obscure a deficiency state. Low serum
concentrations of alpha 1-antitrypsin have some correlation
with the risk of pulmonary emphysema, whereby the risk rises
below a threshold level of 11 micromolar (570–800 µg/mL,
57–80 mg/dL) (11). Although concentration assays are readily commercially available, protease inhibitor levels alone
should not be used to exclude alpha 1-antitrypsin deficiency,
as they lack both sensitivity and specificity.
Phenotype is defined by isoelectric focusing migration patterns, whereby each alpha 1-antitrypsin isoform migrates to
an electroneutral position in polyacrylamide gel. While phenotyping can identify both common and rare alleles, the assay
is time-consuming and not readily commercially available. In
addition, results may be challenging to interpret. Phenotyping
Alpha 1-antitrypsin is a glycoprotein produced predominantly in the hepatocyte, and to a lesser extent by other tissues,
including macrophages, renal tubular, and small intestinal epithelial cells (13). It functions as a serine protease inhibitor,
and is the predominant inhibitor of neutrophil elastase. Alpha
1-antitrypsin, as is true for other proteins in the serpin family of protease inhibitors, undergoes marked conformational
change when it encounters its protease. Inhibition of elastase is a multistep process beginning with its docking in the
reactive center of alpha 1-antitrypsin. Elastase then cleaves
the reactive center of alpha 1-antitrypsin. This allows marked
tertiary structural change in alpha 1-antitrypsin, which irreversibly inhibits elastase by destroying its structural integrity
and thereby promotes its degradation.
A single amino acid substitution of lysine for glutamate
at position 342 in the coding sequence produces the most
common alpha 1-antitrypsin mutant molecule, PiZ (14). Mutation in the coding sequence promotes spontaneous polymerization in the hepatocyte through insertion of the reactive
center of one protein into the β-sheet of another, known as
“loop-sheet” insertion (15). Polymers of alpha 1-antitrypsin
protein in the endoplasmic reticulum of the hepatocyte are
unable to complete the remainder of the secretory pathway
necessary for secretion from the cell. The S allele, either in
the homozygous state or when coinherited with the M allele,
is not associated with liver disease, as the kinetics of protein
production, degradation, and cellular export promote intracellular protein retention but a lesser degree of glycoprotein
polymerization. However, if the S and Z alleles are coinherited, the protein product will form polymers that are retained
intracellularly, and result in the clinical predisposition to liver
disease. The rate of polymerization of the S protein is much
slower than that of the Z protein, which favors less hepatocyte retention and milder serum deficiency when the mutant
alleles are combined (16–18).
Protein accumulation in the hepatocyte reflects the relative contributions of synthesis, intracellular degradation, and
cellular export. There are at least two pathways responsible
for degradation of mutant alpha 1-antitrypsin in the endoplasmic reticulum. One pathway involves binding of alpha
1-antitrypsin to the transmembrane endoplasmic reticulum
chaperone calnexin, and subsequent binding of ubiquitin to
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Fairbanks and Tavill
the complex, followed by degradation (19). The other pathway involves ubiquitin-independent proteosomal and nonproteosomal mechanisms, such as autophagy (20).
Approximately 37% of adult PiZZ patients have cirrhosis
at the time of death (21, 22). This suggests that other environmental and/or genetic traits predispose some patients to liver
injury while sparing others. A delay in intracellular degradation of the mutant protein, rather than its accumulation in the
endoplasmic reticulum, appears to be one physiologic trait
that separates the unaffected from the susceptible host. It has
been hypothesized that this lag in degradation may be as a result of abnormalities in calnexin, a protein that interacts with
the mutant alpha 1-antitrypsin protein in the endoplasmic
reticulum, and may be necessary for initiating or maintaining the pathway of endoplasmic reticulum degradation (23).
The mechanisms of lung and liver injury are distinct and
unique. Lung injury occurs as a result of deficiency in the
concentration of circulating alpha 1-antitrypsin, allowing uninhibited proteolytic damage to the connective tissue of the
lung. While lung injury may be thought of as a result of
“loss of function,” liver disease occurs because of “gain of
function.” While this may be a misnomer in so far that amplification of intracellular serine protease binding has not
been implicated, the retained alpha 1-antitrypsin glycoprotein in the endoplasmic reticulum contributes directly to liver
injury.
CLINICAL PRESENTATION
Alpha 1-antitrypsin deficiency is the most common genetic
cause of liver disease in neonates and children (10). Adults
with alpha 1-antitrypsin deficiency may present with asymptomatic abnormal liver enzymes indistinguishable from other
common causes of abnormal enzymes, clinical manifestations of advanced cirrhosis, or hepatocellular carcinoma.
The clinical presentation of liver disease in PiZZ alpha
1-antitrypsin-deficient persons is variable. There is a distinct bimodal distribution consisting of neonatal hepatitis and
cholestatic jaundice in infants, and chronic liver disease in
adults with mean age of diagnosis in the fifth decade. Only
10% of alpha 1-antitrypsin-deficient neonates develop neonatal hepatitis, the majority of whom clinically recover. Only
2–3% of PiZZ children progress to advanced fibrosis or cirrhosis requiring transplantation during childhood (24). By
early adulthood, most patients have normal liver enzymes
and minimal or no symptoms of liver disease (10, 25). Autopsy studies, however, have demonstrated that just over onethird of adult PiZZ patients (predominantly males) may develop cirrhosis (21, 22). Interestingly, these were significantly
older than the noncirrhotics, leading the authors to speculate
that the latter may have succumbed at an earlier age because
of more advanced lung disease. Survival following diagnosis of cirrhosis was very limited with 30% having primary
liver cancer at autopsy (22). The genetic and environmental
factors that predispose some patients to liver disease while
Figure 2. Percentage of PiZ individuals with abnormal liver enzymes over time; figure derived from data in reference 25.
sparing others are unknown. One retrospective cohort study
reported that both male gender and elevated mean body mass
index were associated with more advanced liver disease (26).
Whether gender predilection reflects differences in hormonal
milieu or prevalence of confounding hepatotoxins such as alcohol, is unclear. A population-based cohort study from Sweden reported a strong correlation between alpha 1-antitrypsin
deficiency and both cirrhosis and primary liver cancer, significant only for men (21). Studies using the PiZ mouse model of
alpha 1-antitryspin deficiency have demonstrated increased
hepatocellular proliferation restricted to male mice or to female mice administered exogenous testosterone (18).
The only prospective study of the natural history of the
liver disease of alpha 1-antitrypsin deficiency comes from a
Swedish registry of 200,000 infants born between 1972 and
1974 who were screened for alpha 1-antitrypsin deficiency.
One hundred twenty-two infants were deficient (120 PiZZ
and 2 PiZnull). During the first 6 months of life, cholestasis
occurred in 14/122 (11%) of PiZ infants, and 8/122 (6%)
had clinical manifestations of liver disease, such as hepatosplenomegaly, late umbilical stump bleeding, or failure
to gain weight (8). Approximately 50% of clinically well PiZ
infants had abnormal liver enzymes in the neonatal period.
In early childhood, two died of cirrhosis, and two died of
unrelated causes with liver fibrosis noted at autopsy. Children were followed for clinical or biochemical signs of liver
disease, and were last reported at the age of 18 yr (25). No
surviving patient manifested any clinical sign of liver disease,
and fewer than 10% had abnormal liver enzymes, supporting an excellent prognosis of alpha 1-antitrypsin PiZ during
childhood and adolescence (Fig. 2).
Cirrhosis resulting from alpha 1-antitrypsin deficiency is
an established risk factor for hepatocellular carcinoma. Studies using the PiZ mouse model have demonstrated that the
fraction of proliferating hepatocytes is limited almost entirely
to cells devoid of PAS-positive globules (27), suggesting a
proliferative advantage to cells without significant retained
alpha 1-antitrypsin. This has led to the hypothesis that older
cells, which have accumulated mutant alpha 1-antitrypsin
glycoprotein, stimulate younger cells with a proliferative advantage to divide (28). Hepatocellular adenomas and carcinomas arise as a result of accumulated genetic mutations
in stimulated and dividing cells residing in a background
Liver Disease in Alpha 1-Antitrypsin Deficiency
of chronic inflammation. This paradigm is consistent with
the clinical observation that hepatocellular carcinomas in patients with alpha 1-antitryspin deficiency arise specifically in
regions of the liver lacking cytoplasmic globules.
The association between heterozygosity of alpha 1antitrypsin deficiency alleles and risk of developing chronic
liver disease is controversial. A single-center study of all adult
patients undergoing orthotopic liver transplantation found an
increased prevalence of the PiMZ phenotype among all etiologic subgroups of chronic liver disease except cholestatic
diseases. Patients with cryptogenic cirrhosis had an almost
10-fold increase in PiMZ phenotype, while patients with viral, alcoholic, or autoimmune disease had between two- and
fourfold higher prevalence than estimates for the general population (29). Other investigators have found a significant increased prevalence of heterozygous alpha 1-antitrypsin in patients with cirrhosis (30, 31). However, this association is not
universally accepted (32). While the PiMZ phenotype may
confer some increased risk for the development of chronic
liver disease, neither the PiMS nor PiSS phenotypes have
any direct correlation with liver disease (18, 29).
Primary liver cancer in liver disease typically develops
in patients with well-established cirrhosis. However, this
paradigm does not always hold true for patients with underlying alpha 1-antitrypsin deficiency states. Cholangiocarcinoma and combined hepatocholangiocarcinoma have an
increased incidence in patients with alpha 1-antitrypsin deficiency type PiZ. Moreover, these cancers are often found
in patients who have no fibrosis or varying stages of fibrosis,
which fall short of cirrhosis, and in patients with heterozygous mutations without alternative concurrent liver diseases
(33, 34).
The development of pulmonary function impairment in
PiZ patients is extremely variable, although cigarette smoking has been clearly shown to adversely affect lung function.
Many PiZ patients have no clinically significant pulmonary
disease even into late middle age (35). In addition to pulmonary and liver disease, alpha 1-antitrypsin deficiency has
been associated with systemic vasculitis (36), interstitial fibrosis in patients with rheumatoid arthritis (37), relapsing
panniculitis (38), multiple sclerosis (39), peripheral neuropathy (40), and intracranial aneurysms (41).
TREATMENT
There is currently no approved treatment for the liver disease
associated with alpha 1-antitrypsin deficiency short of liver
transplantation. Patients with emphysema resulting from alpha 1-antitrypsin deficiency may be treated with intravenous
purified pooled human plasma alpha 1-antitrypsin, otherwise
known as augmentation therapy (42). Augmentation therapy
has been shown to have biochemical efficacy (i.e., raising
serum levels of alpha 1-antitrypsin above a protective threshold), although evidence for clinical efficacy (i.e., decreasing rate of decline of FEV1 [forced expiratory volume in 1
2139
second]) is less robust (2). Reduced serum concentration of
alpha 1-antitrypsin does not contribute to liver injury, and
augmentation therapy is not considered a potential treatment
option for liver disease. Promising experimental work using
adenovirus-associated, recombinant gene therapy has demonstrated successful gene transfer to peripheral skeletal muscle
with sustained therapeutic secretion of alpha 1-antitrypsin
into serum (43). Gene augmentation strategies such as this
would be expected to ameliorate lung disease while having
little, if any, impact on liver disease.
Treatment strategies for liver disease may be divided into
therapies that prevent protein polymerization, decrease liver
injury, enhance secretion of the mutant protein, or increase
its intracellular, hepatic degradation. The molecular requirements for a peptide that could selectively block polymerization of mutant alpha 1-antitrypsin proteins have been
defined (44), but this has not yet translated into clinical practice. Cyclosporin A has been shown to reduce hepatic mitochondrial injury, even in the presence of accumulated mutant alpha 1-antitrypsin protein (45). The chemical chaperone phenylbutyric acid enhances secretion of functionally
active alpha 1-antitrypsin in cell culture and mouse models
without affecting synthesis or degradation (46). However, a
single study in humans showed no increase in serum levels of alpha 1-antitrypsin with 14 days of phenylbutyric acid
treatment, and significant side effects (47). While the glucosidase inhibitor castanospermine and the mannosidase inhibitors kifunensine and deoxymannojirimycin all mediate
increased secretion of functionally active alpha 1-antitrypsin
in cell culture, the latter two are less promising, as they are
associated with markedly decreased degradation of alpha 1antitrypsin (48). Theoretically, at least, these mannosidase
inhibitors may ameliorate lung injury while permitting liver
damage to continue unchecked. Recent gene therapy studies
using small-interfering RNAs have demonstrated the ability
to downregulate endogenous Z-alpha 1-antitrypsin through
delivery of anti-alpha 1-antitrypsin ribozymes, resulting in
decreased secretion of mutant alpha 1-antitrypsin and decrease in intracellular accumulation. To date, these studies
have been limited to cell culture and transgenic mice models
(49).
For patients who develop decompensated cirrhosis or
early-stage hepatocellular carcinoma, liver transplantation
both replaces the diseased liver and corrects the underlying
metabolic disorder. In pediatric transplant centers, liver transplantation for metabolic liver disease is second only to biliary
atresia as the most common indication for transplant. Alpha
1-antitrypsin deficiency is the primary metabolic liver disease
leading to a transplant in the pediatric age group (50). Overall
outcomes after liver transplantation are excellent in children,
with 3-yr survival rates approaching 85% (51). Prognostic
variables associated with poor outcome without a liver transplant in childhood include jaundice persisting for more than
6 wk, higher aminotransferases at presentation, and severe
bile duct proliferation and stage of fibrosis on liver histology (52). While children with alpha 1-antitrypsin deficiency
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Fairbanks and Tavill
often present with jaundice as a predominant feature, adults
typically come to medical attention because of complications
of portal hypertension or early onset obstructive lung disease. Alpha 1-antitrypsin deficiency is a rare indication for
liver transplantation among adults. Transplant recipients acquire the donor phenotype and have normalization of alpha
1-antitrypsin levels (53). Despite this, it is not known if liver
transplantation can delay the onset or progression of lung
disease. Both graft and patient survival for adults transplanted
for metabolic liver disease is similar to that of other indications for liver transplant (54).
CONCLUSION
Alpha 1-antitrypsin deficiency is a chronic underrecognized
metabolic disease that causes significant liver and lung injury. Since the initial description more than 40 yr ago of the
absence of the alpha-1 band on serum protein electrophoresis
(55), and subsequent recognition of the association between
the alpha 1-antitrypsin deficiency state and liver disease (56),
remarkable progress has been made in understanding its clinical course and molecular basis for disease.
ACKNOWLEDGMENT
We gratefully acknowledge Dr. Mary Petrelli for the original
photomicrographs of the liver biopsy.
Reprint requests and correspondence: Kyrsten D. Fairbanks,
M.D., Department of Gastroenterology and Hepatology, Cleveland
Clinic Foundation, Cleveland, OH 44195.
Received November 1, 2007; accepted March 11, 2008.
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CONFLICT OF INTEREST
Guarantor of the article: Kyrsten Fairbanks, M.D.
Specific author contributions: Kyrsten Fairbanks wrote and
edited the article. Anthony Tavill provided guidance in the
writing and editing of the article.
Financial support: None.
Potential competing interests: None.