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Alpha-1 Antitrypsin Deficiency

Introduction

Alpha-1-antitrypsin deficiency is an autosomal recessive condition that results in respiratory and hepatic damage. It is caused by an inherited mutation in the protein alpha-1-antitrypsin (AAT) and multiple different mutations have been identified which lead to the clinical syndrome. 

 

There are three predominant allelic genotypes for AAT: PiM (normal), PiS (causing 50% deficiency) and PiZ (causing 90% deficiency). The combination of alleles that a person expresses determines their serum concentration of AAT. PiSZ and PiZZ can result in clinical disease with more severe manifestation for PiZZ individuals.

 

Alpha-1-antitrypsin deficiency is more common in Caucasians with a prevalence of 1:2000. There is low clinical penetrance of liver disease, only 20% of all homozygotes manifest clinical effects. Children present with neonatal cholestatic jaundice and adults present with chronic hepatitis or cirrhosis. The penetrance of respiratory disease is much higher with 75% of all homozygotes developing COPD, even if they have not smoked.

Pathophysiology

AAT is a serine protease inhibitor that acts as an acute phase protein and is involved in the control of inflammatory cascades. It interacts with a protease produced by neutrophils known as neutrophil elastase. When AAT and elastase bind the protease is inactivated and then the liver clears the whole complex. This process is most important in the lungs because in the absence of alpha-1-antitrypsin there is excess proteolytic activity. This results in inflammation which causes breakdown of alveolar tissue and leads to emphysema (see Fig. 1).

 

Smoking contributes to the development of COPD by inactivating AAT and increasing production of neutrophil elastase. AAT-related emphysema is panacinar, such that alveoli throughout the acinus are equally affected, whereas a centrilobular pattern is seen in patients with normal AAT levels. It also predominantly affects the basal zones, in contrast to most emphysema that affects the upper portions of the lung. In some cases, bronchiectasis may develop rather than emphysema.

 

The pathological basis of liver disease in AAT-deficiency is quite different to that of the lung disease. Though the condition is termed a ‘deficiency’, PiZZ individuals still produce AAT in their hepatocytes. However, it does not reach the serum. There is normal transcription of PiZ and PiS AAT however it undergoes polymerisation in the endoplasmic reticulum, which prevents its release into the blood. The accumulation of AAT inside hepatocytes results in mitochondrial damage and activation of pro-apoptotic pathways that causes hepatocyte death.

 

In some patients, chronic damage and repair leads to fibrosis and cirrhosis. It is likely that co-factors (e.g. alcohol, non-alcoholic fatty liver disease) play a role in development of cirrhosis.

Lung pathology in AAT-deficiency

Illustration of the pathophysiology of emphysema in AAT-deficiency

Presentation and clinical features

Presentation of liver disease is either as a neonate or as an adult (see Table 1). 10% of homozygous neonates develop jaundice and cholestasis, which is followed by hepatomegaly and portal hypertension. However not all develop advanced fibrosis such that only 2-3% go on to require transplantation. It is common for the cholestasis to subside in adolescence, with most patients having normalised liver enzymes by adulthood.

 

10% of PiZZ patients will present in adulthood, usually at around 50 years of age. They may be asymptomatic with abnormal liver function tests: moderately raised ALT/AST, mildly raised bilirubin and moderately raised ALP. 10-15% develop cirrhosis and therefore present with features of chronic liver disease: bleeding oesophageal varices, ascities, confusion (from encephalopathy), infection or bleeding. Signs of chronic liver disease may be found on examination: clubbing, palmar erythema, leukonychia, spider naevi, gynaecomastia, Dupuytren’s contracture and pedal oedema. If cirrhosis is present, then there is a significant risk of hepatocellular carcinoma (HCC) which presents with pain, abdominal swelling or decompensation in a previously stable patient.

 

Heterozygotes do not develop the same clinical disease as homozygotes however they are at increased risk of chronic liver disease. PiMZ individuals are more likely to develop cryptogenic cirrhosis and it may play a role in accelerating chronic hepatitis of other causes; for example, alcoholic liver disease.

 

Respiratory disease presents similarly to emphysema caused by smoking alone although they present younger, at 40-50 years of age, and there may not be any history of smoking. There is progressive shortness of breath on exertion, increased frequency of lower respiratory tract infections and ultimately respiratory failure. On examination there may be; barrel chest, reduced crico-sternal distance, loss of the cardiac dullness, reduced breath sounds and signs of respiratory failure. Investigation would demonstrate an obstructive defect without reversibility, which is consistent with COPD.

 

In addition, AAT-deficiency has the following associations:

–     Pancreatitis

–     Wegener’s granulomatosis

–     Relapsing panniculitis

Summary of clinical features

A table showing the presenting features as a neonate and in adulthood

Investigations and diagnosis

Diagnosis is made using only laboratory assays:

  • Serum AAT concentration is the first investigation if clinical features suggest AAT-deficiency. If concentration is <75% of the lower limit of normal then this is highly suggestive of PiZZ genotype. AAT is an acute-phase protein, so it should be considered whether the patient has any concurrent inflammatory processes.
  • If serum AAT concentration is found to be low then phenotyping using isoelectric focusing allows distinguishing of alleles. However it is not available at all centres and it also cannot differentiate homozygotes and heterozygotes.
  • Genotyping by immunofixation can give a final diagnosis; however, if still inconclusive then gene sequencing may be considered.

 

Other investigations:

  • LFTs and enzyme assays may show raised transaminases and cholestatic enzymes.
  • Protein electrophoresis may show reduced alpha-1-globulin level.
  • Liver biopsy may be performed to grade fibrosis. The classical finding in AAT-deficiency is “periodic-acid Shiff positive globules” in periportal hepatoctyes.
  • Antenatal diagnosis using chorionic villus sampling is possible but is not routine.

 

Investigation of respiratory disease is similar to COPD that is related to smoking only, however the young age of onset prompts tests for AAT-levels (as described above).

  • Chest X-ray and CT chest may demonstrate hyperinflation and bullae formation.
  • Pulmonary function testing will show an obstructive defect that does not reverse with bronchodilators or steroids. Also there is an increased total lung volume and residual volume.
  • Lung biopsy is usually not required given that a clinical diagnosis of emphysema is made in conjunction with phenotyping for AAT-deficiency. If it were to be performed then it would show panacinar emphysema that is more severe at the bases.

Liver histology of AAT-deficiency

Liver biopsy from a patient with alpha-1-antitrypsin deficiency

This image shows part of liver biopsy taken from a patient with alpha-1-antitrypsin deficiency. It has been stained with period-acid Schiff, which strongly stains intrahepatic globules pink [long black arrow]. The hepatocytes containing the globules are concentrated adjacent to a band of fibrous tissue [long black and white arrow]. A mild inflammatory infiltrate and myofibroblastic cells are seen associated with the fibrous tissue [short black and white arrow]. It is likely that this patient has early fibrosis wild mild active hepatitis. If this continues the patient is at risk of developing overt cirrhosis.

Management

There is no targeted therapy for AAT-deficiency liver disease. Liver transplant is the treatment for advanced disease; AAT-deficiency is the 2nd most frequent indication for paediatric liver transplant, with 80% 5-year survival. Transplantation corrects the underlying defect because serum production of AAT will be returned to normal. However it hasn’t been conclusively demonstrated whether transplantation reduces the rate of pulmonary disease. Ursodeoxycholic acid may help with cholestasis in the neonate.

 

Avoidance of alcohol and obesity are important to reduce the risk of progressive disease. AAT-deficiency is not a common indication for transplant in adults however it can treat cirrhosis and be used as a primary treatment for early HCC.

 

For respiratory disease, avoidance of smoking is vital, which may require referral to the NHS Stop Smoking service. Medical treatment for COPD is important to help alleviate symptoms. All patients with emphysema will be treated with salbutamol and ipratropium inhalers. As the disease becomes more severe they may require salmeterol, oral aminophylline and long-term oxygen therapy. This part of the patient’s care will be managed by the general practitioner and nurse specialists. Pulmonary rehabilitation programmes are shown to improve outcome in patients with COPD. Surgery may be used for some patients; those with poor exercise capacity and large isolated bullae may have symptomatic improvement by lung volume reduction.

 

A treatment specific to AAT-deficiency is augmentation therapy. This uses intravenous administration of pooled alpha-1-antrypsin from human donors or by inhalation and has been shown to give prognostic benefit. Lung transplant is an option for patients with end-stage disease and 5-year survival is 50%.

Prognosis

Emphysema is the most common cause of death, with only 5% of patients dying as a result of their liver disease. Obesity and male gender predispose to more advanced hepatic damage.

References

Image "Liver histology of AAT-deficiency" from: Uthman E. Liver: alpha-1-antitrypsin deficiency. (November 2009) Flickr Image Hosting. Available at: http://www.flickr.com/photos/euthman/4165770653/in/photostream/

Fairbanks K.D., Tavill A.S. Liver disease in alpha 1-antritrypsin deficiency: A review. Am J Gastroenterol (2008) 103:2136-2141

Kelly E., Greene C.M., et al. Alpha-1 antitrypsin deficiency. Respiratory Medicine (2010) 104:763-772

Blas, R. Alpha-1-anitrypsin deficiency. Best Practice & Research Clinical Gatroenterology (2010) 24:629-633

Kumar P., Clark M. Clinical Medicine 7th Edition (2009). Elsevier Saunders

Longmore M., Wilkinson I., et al. Oxford handbook of clinical medicine 8th Edition (2010). Oxford University Press

Bloom S., Webster G. Oxford handbook of gastroenterology and hepatology (2006). Oxford University Press

 

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