Alpha -1 Antitrypsin Deficiency

Ira Shah
Consultant Pediatrician, B.J.Wadia Hospital for Children, Mumbai, India
First Created: 03/05/2001 

Introduction

What is alpha - l-antitrypsin?

Alpha -1- antitrypsin is a glycoprotein produced by the liver. Its primary function is to protect the lungs from neutrophil elastase, which is an enzyme that digests the phagocyte cells and bacteria to promote healing. However, it requires alpha-l - antitrypsin to prevent it from damaging the lung tissue. Alpha-l- antitrypsin is an acute- phase reactant. Its level increases to 3 or 4 times the normal amount at times of infection, pregnancy, or any conditions that cause an increase in neutrophil elastase.

What happens where there is a deficiency of alpha-l- antitrypsin?

In alpha -l deficient persons there is an insufficient amount of alpha-1 antitrypsin circulating in the blood, hence the destructive effect of neutrophil elastase goes unchecked and lung tissue is destroyed causing emphysema, asthma, chronic bronchitis, and repeated chest infections. In some patients, alpha -1- antitrypsin may be produced normally, however, the liver may not secrete the protein into the blood. Such patients may also have cirrhosis of the liver. This is seen in 12-15% of the patients especially children. Very rarely they may suffer from a condition called panniculitis due to the destructive action of unrestrained neutrophils.

How does alpha-1 antitrypsin deficiency occur?

It is a genetic disorder and is inherited as an autosomal recessive condition. The normal phenotype is Pimm. When both parents contain the abnormal gene (Piz) and pass it on to their offspring, it results in a phenotype of PiZZ, which leads to emphysema. Although there are various alleles of the gene and several phenotypes, the phenotypes associated with emphysema are Pisz, PiZZ, and PiNull. The Null gene is one that produces no detectable level of alpha -1 antitrypsin. Patients with Null-Null phenotype are at increased risk for developing emphysema, yet do not suffer liver damage greatly.

How does alpha-1 antitrypsin deficiency occur?

There are two primary theories proposed:
External attack Theory: As there is a lack of alpha-1-antitrypsin in the blood, the liver is subject to attacks by neutrophil elastase, other destructive enzymes, or bacteria.

Internal attack Theory - Alpha-1 antitrypsin is produced normally, however is not secreted in circulation. The alpha-1 antitrypsin that accumulates in the liver cell membrane may cause the destruction of the liver. This theory is the most widely accepted theory. Around 10% of alpha-1 antitrypsin deficient infants develop cirrhosis in childhood. Of the remainder, about 10% develop cirrhosis later. Cirrhosis is commonest in the PiZZ phenotype and is almost not seen in the Pi Null phenotype.

Presentation

In infancy, it presents as cholestasis. In some patients, the cholestasis is so severe that biliary atresia is suspected. In others, features suggestive of DIC and septicemia may be seen. The cholestatic phase is usually of a few months duration; later the clinical picture is dominated by progressive cirrhosis. In a large number of PiZZ infants, there may be moderate hepatomegaly, with a temporary increase in liver enzymes and slightly conjugated hyperbilirubinemia. On biopsy of the liver, PAS+ globules are a constant feature. A correlation between the subsequent clinical course and histologic features of the liver tissue during the initial cholestatic stage can be established:-

  • When fibrosis is slight: all clinical manifestations disappear

  • When fibrosis is extensive - cirrhosis with portal hypertension develops early. With cirrhosis, the liver function decreases, the lobes become fibrosed and there is fat accumulation. This leads to decreased vitamin absorption, decreased bilirubin and hormonal metabolism, and decreased synthesis of albumin and other proteins.

In adults, the main clinical feature is emphysema. Alpha-1 emphysema is also called genetic emphysema and usually causes symptoms in patients when they are in their 30's or 40's. The initial symptom is breathlessness and later leads to chest deformity. Emphysema caused by alpha-1 antitrypsin deficiency is a progressive disease. The lower regions of the lungs are affected first, whereas, in smokers, the damage first occurs in the upper portion of the lungs. In due course, the lungs become hyperinflated due to air trapping causing destruction of the lung tissue, and flattening of the diaphragm occurs due to hyperinflation. Many patients may suffer from chronic bronchitis causing a chronic cough. Asthma is also fairly common. It is characterized by wheezing, cough & shortness of breath. Panniculitis is an inflammation of subcutaneous fat causing the formation of lumps and lesions. It may occur in both children as well as adults.

Diagnosis

Most patients with alpha-1 antitrypsin deficiency have shortness of breath, chronic cough, and abnormal liver function tests. Based on the above findings, if there is suspicion of alpha-1-antitrypsin deficiency, then its presence can be detected by serum protein electrophoresis. Since alpha-1 antitrypsin is the predominant glycoprotein responsible for the 1 globulin band on routine protein electrophoresis, that band is absent in its deficiency. Serum protein electrophoresis is also recommended in relatives of a patient with diagnosed alpha-1 antitrypsin deficiency or if there is a family history of early emphysema especially in non-smokers. The protease inhibitor (Pi) phenotyping system classifies the variants by letters in the alphabet. The slowest moving glycoprotein is labeled Piz, while faster-moving protein complexes can be identified by earlier letters in the alphabet. Patients with alpha-l-antitrypsin levels of 11 um/L (80 mg%) or less are at increased risk of emphysema. Individuals diagnosed as alpha-1 antitrypsin deficient should undergo pulmonary function tests, blood gas analysis, chest X-Ray, electrocardiogram, and graded exercise test. In the case of cirrhosis, a liver biopsy is indicated.

Treatment

At present, the only treatment for these patients is replacement therapy with Human alpha-1 antitrypsin, which is derived from pooled human blood plasma. Replacement therapy is given as IV infusion and is recommended every weekly. It is given in the dose of 60 mg/kg. It is indicated in persons with PiZZ, Piz(Null), or Pi(Null)(Null) and those who have early evidence of panacinar emphysema. Patients should be vaccinated with Hepatitis B and Hepatitis A vaccine preferably before starting therapy. In patients with emphysema, anti-inflammatory steroids and bronchodilators are the treatment of choice. Oxygen therapy may be required in patients' with:

  • Resting PaO2 <55 m Hg or O2 saturation <85%

  • Cor pulmonale.

  • Resting PaO2 >55 mHg or O2 saturation >85% who desaturate to PO2 <55 mHg or O2 saturation <85% with exercise.

Surgery in the form of lung volume reduction by removing damaged portions of the lung is recommended in patients unresponsive to medical treatment. However, there is high mortality with this surgery. There are also chances of air leaks and infection developing after the surgery. If this surgery works, it may help for a year.

Lung transplant: Patients with end-stage lung disease (with at least 18 months expected survival) may be candidates for a lung transplant either unilateral or bilateral. Generally, a single lung transplant is done in patients under 60-65 years of age and double lung transplant is done in patients under 50-55 years of age. The one-year survival rate for a single lung transplant is greater than 90% and the one-year survival rate for a double lung transplant is 85%. The most common cause of death for transplant patients is infection. For patients with liver disease, Phenobarbital or cholestyramine may be beneficial for cholestasis. Diuretics may be required for treating ascites. For patients with severe liver disease, a liver transplant is the only option. Panniculitis may be treated with dapsone and these patients may require long term alpha-l-antitrypsin replacement.

Alpha -1 Antitrypsin Deficiency - Prognosis

Most patients with alpha-1 antitrypsin deficiency live a long and healthy life with little or no sign of lung damage. The chance of avoiding liver damage is also fairly high. However, for those affected, the prognosis depends on several factors namely, the pulmonary function tests, the medical treatment given, and liver involvement.


Alpha -1 Antitrypsin Deficiency Alpha -1 Antitrypsin Deficiency Alpha -1 Antitrypsin Deficiency 03/05/2001
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