• α1-antitrypsin

Carl-Bertil Laurell (1919–2001) was head of the Clinical Chemistry Department at Malmö General Hospital, University of Lund, Sweden (1954–84) and continued working in the department until his death in 2001. He had an interest in the initial studies of protein biochemistry, and his early paper on electrophoresis studies of serum proteins led to the discovery of subjects with deficient bands in the α₁-globulin region.¹ This region showed the greatest inhibition of trypsin, and the major protein within the band became known as α₁-antitrypsin. Having identified several subjects with a weak α₁ band seen on paper electrophoresis, Laurell and his research fellow Eriksson investigated the patients further. Three of the original five patients had severe early onset pulmonary emphysema suggesting a cause and effect.¹ For many years research focused on understanding the role of this protein in the pathogenesis of emphysema. Enzymes inhibited by α₁-antitrypsin were shown to be capable of producing many of the pathological features of COPD including emphysema, mucous gland hyperplasia, and mucus secretion. Because most of the α₁-antitrypsin in the lung is derived from the circulation by diffusion, low serum levels were associated with low lung concentrations. This resulted in insufficient amounts of α₁-antitrypsin in the lung to protect the tissues from damage by the enzymes—predominantly neutrophil elastase—normally controlled by this inhibitor (the proteinase antiproteinase theory of emphysema).²

The role of serum deficiency in the emphysematous process led to the introduction of augmentation therapy with purified α₁-antitrypsin in 1988. This was a logical approach leading to an increase in the serum and hence the lung concentrations of α₁-antitrypsin to “protective” levels. These studies resulted in “deficiency” being a pathological problem associated with lung disease and the outcome was that α₁-antitrypsin deficiency became largely the domain of respiratory medicine.

However, in 1969 Sharp and colleagues recognised that subjects with the commonest (Pi ZZ) serum deficiency had a relatively high frequency of liver disorders, including neonatal jaundice and cirrhosis.³ Subjects were shown to have hepatocyte accumulation of α₁-antitrypsin which is thought to be the reason for hepatocyte damage. Thus, unlike the lung disease, the liver disease became recognised as an “overload” problem. Accumulation of α₁-antitrypsin is the result of protein polymerisation, and the understanding of this process led to strategies to facilitate secretion and thereby protect the liver.⁴

With growing interest in the genetic nature of diseases and the clinical disorders associated with α₁-antitrypsin abnormalities, many countries developed national registries. This has resulted in the discovery of other clinical conditions that are more frequent in individuals with Pi ZZ antitrypsin, including vasculitis,⁵ Wegener’s granulomatosis,⁶ glomerulonephritis,⁷ and panniculitis.⁸ Thus, the condition is associated with many clinical disease entities and is more representative of a syndrome. These aspects are outlined in fig 1.

Although Pi ZZ has classically been referred to as a “deficiency”, this does not explain all the facets of the diseases. Some relate to “deficiency” while others clearly reflect an “overload”. Much has been learned since α₁-antitrypsin “deficiency” was recognised by Laurell 40 years ago. This syndrome of α₁-antrypsin disorders, and particularly the disparity between “deficiency” and “overload”, has brought researchers together from many fields—including pulmonary, genetics, hepatology, nephrology, dermatology and rheumatology—to extend the understanding of α₁-antitrypsin. Collaborative efforts are leading to strategies that both reduce the “overload” and overcome the “deficiency” which may resolve the many faceted nature of this genetic defect.

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Figure 1

Hepatic polymerisation of the α₁-antitrypsin (Pi ZZ) protein results in both hepatocyte inclusions and decreased serum concentration. The low serum level is reflected in a low lung level of α₁-antitrypsin which is insufficient to protect the tissue from inflammation generated, for example, by cigarette smoking. Prolonged inflammation, together with as yet unknown environmental or genetic factors, leads to airway and parenchymal damage resulting in lung disease. The inflammatory process of vasculitides and panniculitis may also represent a failure to modulate inflammation as a result of low serum and tissue levels of α₁-antitrypsin, in combination with other cofactors yet to be determined. Within the hepatocytes the α₁-antitrypsin polymers cause inflammation that probably plays a role in the transient neonatal jaundice seen in 11% of individuals with Pi ZZ. In most this resolves, but in others childhood cirrhosis develops or the hepatic inflammation persists. Again, as yet undefined genetic or environmental factors may play a role in this persistent inflammation. With time, adult cirrhosis and hepatocellular carcinoma may occur, although the true incidence has yet to be determined.