OVERVIEW: What every practitioner needs to know

Are you sure your patient has alpha-1-antitrypsin deficiency? What are the typical findings for this disease?

Alpha-1-antitrypsin (a1AT) deficiency is an autosomal, co-dominant genetic disease most commonly caused by homozygosity for the Z mutant of the a1AT gene. These patients are called ZZ, or PIZZ in WHO nomenclature. ZZ a1AT deficiency can cause chronic liver disease, chronic metabolic hepatitis, cirrhosis and liver cancer in children and adults, as well as emphysema in adults.

In newborns, a1AT deficiency commonly presents as neonatal cholestasis as part of the “neonatal hepatitis syndrome.” In some cases it is also associated with low birth weight, poor feeding and failure to thrive. A1AT deficiency should be considered in the differential diagnosis of any patient with unexplained liver abnormalities.

ZZ homozygotes occur in about 1 in 2,000 births in North American and European populations. ZZ a1AT deficiency is one of the most common genetic diseases in caucasians, but it is widely under recognized and under diagnosed.

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Highly variable presentation and variable clinical outcomes

The presentation of a1AT deficiency can be highly variable. Less than 20% of patients present in infancy with cholestatic hepatitis. Other patients present later in childhood or adulthood with elevated serum transaminase levels or when hepatomegaly or splenomegaly are detected on routine physical exams. In rare cases patients can present with previously asymptomatic cirrhosis or in fulminant hepatic failure.

Life-threatening disease occurs in about 5% of ZZ patients before the age of 18 years, although as many as 50% of ZZ children may have some type of hepatic abnormality such as unexplained liver test elevations or hepatomegaly. The development of liver disease is uncommon in young adults, but the risk increases with increasing age. Studies suggest that as many as 50% of older ZZ adults will develop cirrhosis, although some patients appear to live normal life spans with little or no liver or lung abnormalities.

The emphysematous lung disease related to a1AT deficiency takes decades to develop and is generally not seen in children. However, ZZ children may be at increased risk for childhood asthma. Smoking, even exposure to passive smoke in childhood, is known to be the most important factor in the development of lung disease, therefore patients and families of all ages should be urgently cautioned against cigarette smoke and environmental lung exposures.

Who should be tested

Testing for a1AT deficiency should be considered in patients at any age with unexplained liver abnormalities. This includes patients with unexplained jaundice, unexplained elevations of AST or ALT, elevations of direct bilirubin, hepatomegaly, cirrhosis or liver cancer. It may also be considered as a second line test in children with unexplained feeding problems or failure to thrive.

Testing should be strongly considered in any non-smoking adult with emphysema, or in smokers with early onset disease or in cases of emphysema with a family history of lung or liver disease. First degree relatives of known patients are commonly offered genetic counseling and the opportunity for testing.

What other disease/condition shares some of these symptoms?

In infants, a1AT deficiency is indistinguishable on clinical grounds from other cholestatic diseases in the neonatal hepatitis syndrome. These include biliary atresia, cystic fibrosis, viral hepatitis, congenital infections, and rare metabolic disorders such as tyrosinemia and galactosemia. Testing for a1AT deficiency is NOT part of the routine newborn screening panel in the United States.

In older children and adults, a1AT deficiency can be confused with acute infectious hepatitis or drug induced liver injury. In adults, the biochemical and histologic features of a1AT deficiency are similar to those of alcoholic liver disease, which can lead to delayed and mistaken diagnosis when specific testing for a1AT deficiency is not performed.

Since a1AT deficiency is a relatively common condition, and can easily and quickly be diagnosed by serum analysis, specific testing for a1AT deficiency is commonly recommended in any presentation of a patient with unexplained liver test abnormalities.

Non-invasive tests, such as for a1AT deficiency, are commonly performed before more invasive procedures such as liver biopsy or surgery. This is commonly the case in the evaluation of cholestatic infants in which a1AT deficiency, as well as biliary atresia and other conditions are also in the differential diagnosis. It is common practice to perform serum testing for a1AT deficiency before invasive testing, such as the cholangiogram by open laparotomy typically required to diagnose biliary atresia.

What caused this disease to develop at this time?

In a1AT deficiency the liver synthesizes the abnormal, mutant Z protein which accumulates in hepatocytes rather than being appropriately secreted. Chronic intrahepatic accumulation of the mutant Z protein causes liver damage. Lung disease in adults results from the deficient circulating levels of a1AT anti-protease activity in serum.

Alpha-1-antitrypsin deficiency has a highly variable clinical course which suggests an important role for genetic and environmental disease modifiers, although specific risk factors are still being identified.

Smoking is thought to be the critical environmental risk for lung disease, and therefore avoiding smoke, second hand smoke, and occupational lung exposures is critical even for children

Animal studies suggest that non-steroidal anti-inflammatory drugs may be especially toxic to the ZZ liver, although this has not been examined in humans. Acetaminophen in conventional doses appears to be safe.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The gold standard for the diagnosis of a1AT deficiency is the identification of the type of a1AT protein (protein “phenotype” or “PI type”) in a patient’s serum as determined by isoelectric focusing. This analysis will distinguish the wild type protein, “M”, from the many possible mutant proteins. The “Z” mutant is by far the most common disease associated mutation. When the serum protein phenotype(s) is known, it is then inferred what DNA mutations the patient carries. This analysis is technically demanding and should only be performed in an experienced reference lab.

Analysis of genomic DNA from leukocytes or buccal swab is considered equal to the gold standard. This is done by PCR but this test only identifies the Z and S mutants.

Some clinicians use spot testing of the total a1AT protein level in serum as a screening test before requesting the more expensive and time consuming gold standard tests. However, levels should be interpreted with caution, as they can vary tremendously with time and during periods of systemic inflammation. Any a1AT serum level result outside the normal range to any degree should be followed with a gold standard test. MZ heterozygous patients, who are generally healthy, typically have a1AT serum levels in the normal range.

Liver biopsy is not required to confirm the diagnosis of a1AT deficiency, although is may be useful in some cases after the diagnosis is established to gauge the degree of liver injury or to assess the impact of comorbid conditions.

Liver biopsy in a1AT deficiency typically reveals the eosinophilic hepatocellular inclusions of a1AT mutant Z protein visible in many peri-portal hepatocytes. However, these inclusions may be absent in very young infants, or otherwise appear similar to lesions in other haptic diseases, and therefore requires examination by a pathologist experienced in metabolic liver disease.

Other histologic features of a1AT deficiency liver disease include mild to moderate lymphocytic lobular inflammation, variable steatosis, fibrosis, cirrhosis, dysplasia or hepatocellular carcinoma. In infants with a1AT deficiency, either bile duct paucity or bile duct proliferation can be seen on liver biopsy, sometimes in a pattern indistinguishable from biliary atresia. It is not recommended to attempt to distinquish a1AT deficiency from biliary atresia based on the liver biopsy alone.

The eosinophilic hepatocellular inclusions typical of a1AT deficiency can be difficult to identify with conventional H&E stain. Often Periodic Acid-Schiff (PAS) stain with diastase digestion is used to highlight accumulations of the mutant Z glycoprotein pink on a neutral blue background (See Figure 1 and Figure 2).

Figure 1.

Photomicrograph of ZZ adult human liver stained with PAS with digestion with arrow showing inclusion (“globule”) of a1AT mutant Z protein

Figure 2.

Photomicrograph of ZZ infant human liver stained with PAS with digestion with arrow showing inclusion (“globule”) of a1AT mutant Z protein

Would imaging studies be helpful? If so, which ones?

Abdominal imaging, especially liver ultrasound, is commonly employed to rule out other conditions which might be confused with a1AT deficiency, or to investigate for comorbid conditions or complications such as evidence of portal hypertension or gallstones.

If you are able to confirm that the patient has alpha-1-antitrypsin deficiency, what treatment should be initiated?

There is no specific treatment for a1AT deficiency liver disease. All patients with a1AT deficiency should have regular evaluation with a physician knowledgeable in metabolic liver disease.

Treatment for the liver disease associated with a1AT deficiency focuses on limiting the complications of chronic liver disease and minimizing the morbidity if complications do occur. Patients can be monitored for fat soluble vitamin deficiency, which can be seen in cholestatic liver conditions, and given supplemental vitamins as needed. General support of nutritional status, growth and development is important in all pediatric liver diseases.

If portal hypertension is suspected, or if coagulopathy is present, then avoidance of non-steroidal anti-inflammatory drugs (NSAIDS) is recommended in all liver diseases. In a1AT deficiency, animal studies suggest that NSAIDS may be especially toxic to the ZZ liver, although this has not been investigated in humans. Acetminophen in intermittent, conventional doses appears to be safe. GI bleeding related to portal hypertension can be managed by the same endoscopic and pharmacologic methods as for other causes of liver disease.

Ursodeoxycholic acid is used by some clinicians in patients with cholestatic liver disease, but there has been no systematic examination of the role of this agent in a1AT deficiency.

Liver transplantation, with excellent success rates, is an option for patients with end stage liver disease.

Avoiding smoke, second hand smoke, and environmental lung exposures is critical for all patients with a1AT deficiency, including children. Adults with a1AT deficiency associated emphysema can be treated with intravenous protein replacement which is thought to slow the progression of existing lung disease, but which is not initiated in childhood.

Patients with confirmed cirrhosis are at increased risk of hepatocellular carcinoma and should be followed using the published screening guidelines. For a typical patient with cirrhosis this would mean a liver ultrasound every 6 months.

What are the possible outcomes of alpha-1-antitrypsin deficiency?

The possible outcomes of Alpha-1-Antitrypsin Deficiency are reviewed above and include chronic liver disease, chronic metabolic hepatitis, cirrhosis and liver cancer in children and adults, as well as emphysema in adults.

What causes this disease and how frequent is it?

A1AT deficiency occurs in approximately 1 in 2,000 births in North America and Europe, and is most common in caucasian populations of Northwest European origin.

The most common disease associated mutation, the “Z” mutant, is most prevalent in Scandanvian populations, especially Denmark.

The “S” mutant of a1AT is most prevalent in Spanish populations.

The classic form of a1AT deficiency is the ZZ homozygous state, which appears to have the greatest risk for both liver and lung disease.

SZ compound heterozygotes have increased risk of liver and lung disease, but it is unclear if the magnitude of the risk is as high as for ZZ patients.

Individuals heterozygous for one normal, wild type M gene and one mutant Z gene, called MZ heterozygotes are generally thought to be asymptomatic carriers. Some evidence suggests a possible small increase in the risk of asthma, some other forms of lung disease, or for increased susceptibility to other forms of liver injury. MZ heterozygosity may be a negative genetic modifier increasing the risk of liver injury in co-morbid conditions such as hepatitis C infection.

In most cases, other a1AT variants are not associated with disease. Individuals carrying null mutations of the a1AT gene are usually not at risk for liver disease, but may be at risk of lung disease in adulthood depending on the a1AT serum level.

A few, rare a1AT mutant genes do exist, such as M-duarte, which if present in association with the Z mutant can cause liver disease. These situations are usually recognized by a profoundly low serum a1AT level which is inconsistent with an MZ phenotype result.

How do these pathogens/genes/exposures cause the disease?

The a1AT gene encodes a protein which is synthesized in large quantities in the liver, but which is also produced in leukocytes and enterocytes. It is secreted into the serum where is it second only to albumin in levels of a single protein. The normal physiologic function of a1AT is to inhibit neutrophil proteases in order to protect host tissues from non-specific damage during periods of inflammation. This function appears to be especially important in the lung.

In a1AT deficiency, the mutant Z gene encodes a mutant protein which is appropriately transcribed and translated in the hepatocyte, but which folds into its final conformation very inefficiently in the endoplasmic reticulum during biogenesis. Quality control mechanisms in the hepatocyte retain the mutant, mis-folded protein molecules, preventing secretion. Most of the mutant Z protein molecules are degraded by intracellar proteolysis pathways, but some attain a specific aggregated (polymerized) conformation forming the hepatocellular inclusions typical of this disease. This accumulation in the liver and the lack of secretion results in a low, “deficient” level of a1AT in serum.

Liver disease is caused by accumulation of the abnormal, mutant Z protein within the hepatocyte. This is a gain-of-function process in which accumulation of the mutant Z protein polymers triggers apoptosis in some hepatocytes. Other hepatocytes and possibly a liver progenitor cell population then proliferate to preserve the hepatic mass. This chronic process of cell death and proliferation can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma.

The lung disease associated with a1AT deficiency is caused by a deficient serum level of circulating a1AT available to inhibit neutrophil proteases which might be released during bacterial killing and phagocytosis. In normal individuals, high levels of a1AT are present in seruma and extracellular fluid to inactivate these neutrophil proteases and thereby protect host tissues from injury.

Other clinical manifestations that might help with diagnosis and management

Some patients with a1AT deficiency may develop panniculitis in adulthood. This is a process of inflammatory ulceration of subcutaneous fat, which can be painful and disfiguring. Although the trigger is not known, IV a1AT protein replacement is sometimes used as a treatment.

What complications might you expect from the disease or treatment of the disease?

In infants, a1AT deficiency can lead to cholestatic jaundice, metabolic hepatitis, poor growth, poor feeding, fat soluble vitamin deficiency, coagulopathy, GI bleeding, cirrhosis and liver failure.

In older children and adults the typical complications of chronic liver disease can be seen, including cirrhosis, portal hypertension, hepatopulmonary syndrome, hepatorenal syndrome, GI bleeding, liver failure and liver cancer.

Asthma may develop in children with a1AT deficiency, but emphysematous lung disease is not seen until adulthood.

It is common for infants to present with cholestatic jaundice due to a1AT deficiency and then to have spontaneous resolution of the cholestasis and hepatitis over the first 2 years of life. Prospective studies from Sweden show that 80% of ZZ infants with neonatal cholestasis are healthy and well, with no signs of liver or lung injury at age 18 years.

In the small number of patients who do go on to develop cirrhosis in childhood, many remain well compensated and stable for many years with normal growth and development. Close monitoring of patients with stable cirrhosis is crucial, but liver transplantation is usually not indicated until complications such as GI bleeding or liver synthetic dysfunction develop.

Are additional laboratory studies available; even some that are not widely available?

Pulmonary function testing is typically initiated as a yearly evaluation in asymptomatic patients at age 18 years, unless they have respiratory symptoms in childhood such as asthma. Children with respiratory symptoms are commonly evaluated by a pediatric pulmonary specialist.

How can alpha-1-antitrypsin deficiency be prevented?

Genetic counseling and family testing should be offered to all relatives of known patients.

Prenatal diagnosis by amniocentesis and chorionic villus sampling is available.

At present, there is no known prevention of a1AT deficiency liver disease, and it is impossible to predict which patients may have severe liver disease and which will be asymptomatic and unaffected. The development of lung and liver disease have different mechanisms, typically occur at different ages, and do not appear to be linked. Patients should limit alcohol consumption depending on the severity of their liver disease as suggested by the American Association for the Study of Liver Diseases guidelines.

Avoiding smoking, second hand smoke and environmental lung exposures are the most important preventative steps which can be taken to reduce morbidity and mortality from a1AT deficiency in both adults and children.

Studies in animals suggest that NSAIDS may be toxic in the a1AT deficient liver, although this has not been examined in humans. Acetaminophen in typical doses appears to be safe.

What is the evidence?

Lindblad, D, Blomenkamp, K, Teckman, J. “Alpha-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model”. Hepatology. vol. 46. 2007. pp. 1228-35. (A presentation of the data showing how a1AT mutant Z protein accumulation in the liver leads to liver disease.)

Teckman, JH. “Alpha1-antitrypsin deficiency in childhood”. Semin Liver Dis. vol. 27. 2007. pp. 274-81. (A detailed review of the clinical aspects of a1AT associated liver disease in humans.)

McGee, D, Strange, C, Mcclure, R. “The Alpha-1 Association Genetic Counseling Program: an innovative approach to service”. J Genet Couns. vol. 20. 2001. pp. 330-6. (A review of available patient support services, including genetic counseling approaches to a1AT deficiency.)

Ongoing controversies regarding etiology, diagnosis, treatment

Research on the cellular mechanisms of disease is ongoing and a variety of clinical trials of potential therapeutic agents are underway. A number of drugs have been shown to have potential benefit in animal studies. However, at present there is no justification for treating human patients with carbamazepine, 4-phenylbutyrate, ursodeoxycholic acid, rapamycin, or cyclosporin outside of a controlled trial.

Protein replacement therapy for adults with a1AT deficiency associated emphysema is available, although efficacy is controversial.