Alpha-1 Antitrypsin Deficiency

Basics

DESCRIPTION

α₁-antitrypsin (AAT) deficiency is an autosomal codominant genetic disorder that causes lung, liver, and skin disease.
Lung disease in AAT deficiency can develop after the 3rd decade of life and progress to emphysema.
Liver disease may present as jaundice in infants or as elevated liver enzymes, portal hypertension, or cirrhosis in older patients.
Skin disease is more rare and presents as necrotizing panniculitis in adults (mean age of onset is 40 years).
AAT deficiency is caused by a deficiency of AAT, which is a serine protease inhibitor (Pi), comprised of a 55-kDa glycoprotein that is primarily synthesized in the liver and released into the circulation.
AAT is the main inhibitor of neutrophil proteases.
Classic PiZZ AAT deficiency is caused by homozygosity for Z mutant allele of AAT.

EPIDEMIOLOGY

Most common genetic cause of liver disease in children and of emphysema in adults

INCIDENCE

Incidence of the PiZZ genotype is highest in Caucasians in North America, Australia, and Europe, particularly in Scandinavia, British Isles, Northern France, and the Tyrol region of Italy.
In the United States, the PiZ allele is found in ~14.5 per 1,000 people, with higher frequency in Caucasians and lower frequency in Asians, blacks, and Hispanics.
The incidence of classic AAT deficiency (PiZZ) is 1 in 1,800 to 2,000 live births.

PREVALENCE

It has been estimated that approximately 70,000 to 100,000 individuals are affected in the United States.
Of these genetically affected individuals, fewer than 10% are estimated to have been diagnosed with AAT deficiency.
Approximately 25 million people in the United States are thought to be carriers of a mutant allele.

RISK-FACTORS

GENETICS

AAT is a serine Pi encoded by the SERPINA1 gene, which is located on the long arm of chromosome 14.
The normal allele is M, with >100 variant alleles identified.
The classic PiZZ genotype is the result of a point mutation at position 342 in the AAT gene, which encodes a substitution of lysine for glutamate.
The S allele (second most common mutation) occurs from a substitution of valine for glutamate at position 246.
Patients with PiZZ alleles have serum AAT levels, which are < 15% of normal.
Heterozygous carriers of the Z allele are found in 1.5–3% of the population. In and of itself, this genetic mutation is not a cause of liver disease, but it may contribute to pathophysiology of other liver diseases.
PiMS, PiMZ, and PiSS are also not directly associated with liver disease, although referral center data reports patients with chronic liver disease having a higher frequency of PiMZ than would be predicted by chance.
The mutant S protein, when coexpressed with Z-protein, can form abnormal polymers leading to liver disease, which is identical to PiZZ patients.
Because ~10% of affected PiZZ or PiSZ individuals have clinically significant liver disease, there may be other genetic or environmental factors that are important modifiers of AAT.

PATHOPHYSIOLOGY

Lung disease in patients with PiZZ results from inadequate levels of AAT to protect the lungs from destructive enzymes, such as elastase, leading to early emphysema.
- This process is further worsened by exposure to cigarette smoke and environmental pollutants.
Liver disease occurs from accumulation of the abnormal Z mutant protein within liver cells.
- The mutant Z gene is transcribed, translated, and then translocated into the endoplasmic reticulum (ER).
- Some molecules undergo proteolytic degradation, others aggregate to form large protein polymers, and few are secreted, leading to intrahepatocyte accumulation and thereby resulting in low AAT serum levels.
- ER-associated degradation of mutant Z-protein is less efficient, leading to a great burden of protein in the liver and increased liver injury.
- Autophagy degradation has also been proposed as an important route for degradation of the AAT mutant Z polymers.
Panniculitis involves inflammation of the fat underneath the skin, causing hardening in lumps and patches, likely due to the unrestrained, destructive action of neutrophil elastase.

ETIOLOGY

Mutations in the SERPINA1 gene result in lung disease through unopposed protease activity and in liver disease by intracellular retention of mutant AAT.

Diagnosis

HISTORY

Highly variable presentation in neonates and young children
Most infants develop cholestatic jaundice, hepatosplenomegaly, poor feeding, and poor weight gain.
Jaundice typically improves around 1 year of age and can then lead to either a continuation of liver disease, progression to cirrhosis, or normal liver function.
Older children can present as asymptomatic chronic hepatitis, poor feeding, failure to thrive, hepatosplenomegaly, or complications of portal hypertension and cirrhosis.
Risk of hepatocellular carcinoma in AAT may be independent of cirrhosis.
Fulminant hepatic failure is rare but has been reported.

PHYSICAL-EXAM

There may be signs of jaundice, hepatosplenomegaly, abdominal distention, and other stigmata of chronic liver disease.

DIFF-DIAGNOSIS

The differential diagnosis varies with age at presentation.
Infants generally present with jaundice; the differential diagnosis in infants should include biliary atresia, anatomic biliary abnormalities, congenital infections, galactosemia, and tyrosinemia (see “Neonatal Cholestasis” and “Jaundice” for complete listing).
In older children, viral (hepatitis viruses, EBV, and CMV), toxic (ethanol, acetaminophen), metabolic (Wilson disease), and obstructive causes should be considered.

TESTS

INITIAL-TESTS

Elevated total and conjugated bilirubin, elevated serum transaminases, hypoalbuminemia, or coagulopathy
Gold standard assessment is protein electrophoresis to determine the Pi phenotype.
Serum levels of AAT can be helpful to guide workup before phenotype results are available.
Quantitative serum AAT levels
- PiMM: 80 to 200 mg/dL
- PiZZ: ≤20 to 45 mg/dL
- Pi null/null phenotype: 0 mg/dL
- As an acute-phase reactant, AAT levels can be falsely negative, as they may rise into the normal range in an ill patient.
Abdominal ultrasound with Doppler can be useful to assess for portal hypertension and/or for pretransplantation evaluation in the setting of end-stage liver disease.

DIAG-PROCED-SURGERY

Diagnosis is determined by identification of the AAT phenotype by serum protein electrophoresis.
Liver biopsy is not required for diagnosis but can help to support it.
Pathologic findings
- Liver biopsy findings can be variable in infants and may include giant cell transformation, lobular hepatitis, steatosis, fibrosis, hepatocellular necrosis, bile duct paucity, or bile duct proliferation.
- Globular eosinophilic inclusions in some hepatocytes can be seen under H&E stain, which represent dilated ER membranes with polymerized mutant protein.
- Staining with periodic acid–Schiff (PAS) followed by digestion with diastase to stain glycoproteins can be performed to highlight these globules.
- These findings are sometimes seen in other liver diseases, are not visible in all hepatocytes, and may even be absent in neonates.

Treatment

There is no specific treatment for the liver disease associated with AAT deficiency.
Management involves supportive care to try to prevent complications of chronic liver disease.
Patients with advanced liver disease should avoid alcohol and other hepatotoxins.
Liver transplantation can be considered for end-stage liver disease. When transplanted, the graft will secrete normal AAT and stop further progression of lung disease.
Due to increased risk of hepatocellular carcinoma, surveillance imaging and/or α-fetoprotein levels should be considered.
Patients should be cautioned to avoid smoking, secondhand smoking, and other inhalation injury.
Although enzyme replacement therapy can be used in adults to prevent progression of lung disease, it has no effect on liver disease.
Vaccination against hepatitis A and B

MEDICATION

Ursodeoxycholic acid, a choleretic agent, can be used to manage cholestasis and pruritus in patients with liver disease.
Augmentation therapy
- Pooled human plasma–derived AAT (alpha-1 antiprotease) is the most efficient way to increase the circulating levels of AAT in the plasma and lung.
- Therapy has been reported to decrease the rate of decline in 1-second forced expiratory volume (FEV₁) and mortality rate during the period of study.

SURGERY

There is no primary therapeutic surgical intervention for AAT deficiency aside from liver transplantation.
Surgery in patients with native livers can be used to treat complications of portal hypertension.
Orthotopic liver transplantation should be considered in patients with end-stage liver disease.
Following transplantation, serum phenotype, and AAT level return to donor levels. Lung damage will not progress but is unlikely to be reversed after liver transplantation.
For lung disease, volume reduction surgery or lung transplantation may be considered.

Ongoing Care

FOLLOWUP-RECOMMENDATIONS

MONITORING

Annual liver and pulmonary function testing
Surveillance for hepatocellular carcinoma in PiZZ patients is suggested, but consensus on frequency and methodology is lacking.

PROGNOSIS

Approximately 10% of PiZZ and PiSZ individuals will have clinically significant liver disease during childhood; ~50% of the remaining individuals will have mildly elevated aminotransferases. Further significant liver disease may develop later in life.

COMPLICATIONS

Patients with liver disease may develop complications of chronic liver disease including portal hypertension, cirrhosis, and/or hepatocellular carcinoma.
Lung disease may progress to early-onset lower lobe emphysema.

Additional Reading

Miranda E, Pérez J, Ekeowa UI, et al. A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency. Hepatology. 2010;52(3):1078–1088. [PMID:20583215]
Perlmutter DH. Alpha-1-antitrypsin deficiency: diagnosis and treatment. Clin Liver Dis. 2004;8(4):839–859. [PMID:15464658]
Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res. 2006;60(2):233–238. [PMID:16864711]
Steiner SJ, Gupta SK, Croffie JM, et al. Serum levels of alpha1-antitrypsin predict phenotypic expression of the alpha1-antitrypsin gene. Dig Dis Sci. 2003;48(9):1793–1796. [PMID:14561003]
Stoller JK, Brantly M. The challenge of detecting alpha-1 antitrypsin deficiency. COPD. 2013;(10 Suppl 1):26–34. [PMID:23527684]
Teckman J. Alpha1-antitrypsin deficiency in childhood. Semin Liver Dis. 2007;27(3):274–281. [PMID:17682974]
Teckman J. Liver disease in alpha-1 antitrypsin deficiency: current understanding and future therapy. COPD. 2013;(10 Suppl 1):35–43. [PMID:23527737]
Teckman J, Jain A. Advances in alpha-1-antitrypsin deficiency liver disease. Curr Gastroenterol Rep. 2014;16(1):367. [PMID:24338605]

Codes

ICD9

273.4 Alpha-1-antitrypsin deficiency

ICD10

E88.01 Alpha-1-antitrypsin deficiency

SNOMED

30188007 alpha-1-Antitrypsin deficiency (disorder)

FAQ

Q: Do all patients with presumed AAT require liver biopsy for diagnosis?
A: No. A liver biopsy is not required for diagnosis but may help be performed to support it.
Q: Are PAS-positive, diastase-resistant globules on liver biopsy diagnostic for AAT deficiency?
A: No. Diagnosis is made by identification of the AAT phenotype by serum protein electrophoresis. Evidence of these globules on liver biopsy can support the diagnosis but may be absent in PiZZ neonates.
Q: Will liver transplantation for AAT deficiency have any effect on the lungs?
A: Yes. When a patient with AAT deficiency gets an orthotopic liver transplant, serum levels of AAT usually return to normal. This halts further progression of lung disease but does not reverse lung damage, which has already occurred.

Authors

Christine K. Lee, MD