Archive for the ‘Health’
AlphaiAT deficiency not only represents a deficiency state characterized by inadequate defense against protease excess in interstitial tissue, but also constitutes an example of a previously unknown storage disease. Accumulation of an abnormally-glycosylated ajAT (which is strongly periodically acid-Schiff positive after diastase digestion) in the liver cell is a hallmark of the PiZ-gene expression. The abnormal ctjAT accumulates in the endoplasmic reticulum (ER) of the hepatocytes. One may consequently speak of an ER-storage disease in contrast to the well-known lysosomal storage diseases. AlphajAT deficiency is the first example and an excellent model of an ER-storage disease. Similar aggregations seem to occur in hereditary hypofibrinogenemia and in the recently described ax-antichymotrypsin deficiency. It is sufficient to emphasize that chest physicians taking care of o^AT deficient patients should consider their significant risk for developing liver disease later in life which may progress to cirrhosis and, not infrequently, primary liver cell cancer. Read the rest of this entry »
They emphasized a possible role of elastase in the development of emphysema. In agreement with earlier findings by Hamburger and Haupt,15 they showed that ajAT was an effective inhibitor of pancreatic elastase. Several independent groups should be given credit for focusing interest on the role of leukocyte elastase in the pathogenesis of emphysema. Janoff and Scherer first demonstrated elastase activity in the human leukocyte granules, Olsson showed its high affinity for otjAT, and Lieberman demonstrated lung digestion by leukoproteases which could be inhibited by o^AT. We and others emphasized the early loss of elastic recoil force in these patients19 and Senior et al used purified human leukocyte elastase to produce experimental emphysema in animals. The key role of neutrophilic elastase in human emphysema has gradually been accepted. Today, synthetic elastase inhibitors begin to appear in phase 1 clinical trials. Read the rest of this entry »
Many years later Sveger, by screening 200,000 Swedish newborn children, found an almost identical homozygote frequency, namely one in 1,660. I wrote6 in 1965 that the gene frequency for a!AT deficiency was of such an order of magnitude that a restricted distribution of the gene seemed improbable. It is now known that the PiZ-gene probably is of Scandinavian origin and is evenly distributed there. The gene frequency in Scandinavia and northern Europe is higher than anywhere else in the world. In southern Europe and in the United States, the gene frequency is approximately half of that in Scandinavia; in Japan it is practically nil. Read the rest of this entry »
I suggested that inheritance in o^AT deficiency was recessive. Seen in retrospect this was not quite correct. It is now known that heterozygotes express the products of both normal and abnormal alleles. Today it is quite clear that alleles in the Pi-system are inherited in a codominant autosomal manner which means that all alleles express themselves irrespective of combination. The complex genetic polymorphism of the Pi-system was elucidated in 1967 by Fagerhol and Laurell.8 However, findings suggesting such polymorphism were made already in 1962. It may be of historic interest to mention one observation on the double arband which we published in 1963. This was the first description of PiFM.
Read the rest of this entry »
Such sections confirmed the presence of a panacinar emphysema (Fig 7). It seemed that, as in other genetic entities, the degree of clinical manifestation in o^AT deficiency was highly variable, ranging from complete absence of symptoms to an early onset of an obstructive lung disease with severe dyspnea. In patients with lung disease the clinical picture was also variable but consistent in the sense that obstructive ventilatory insufficiency and radiologic emphysema were almost invariably present. Read the rest of this entry »
Diagnosis and Clinical Presentation in aXAT Deficiency
In 1965, I had collected a larger series of deficient individuals, including 33 probands and their families. The probands had been traced from a variety of files and hospitals and were in no way a representative or an unbiased population sample. They were presented in my PhD thesis as a supplement to Acta Medica Scandinavica.
Based on the laboratory findings available at that time, the new entity was defined by a) an absence of a visible band in the a j-region in paper or agar gel electrophoresis, b) a slightly reduced immu-noelectrophoretic mobility of atAT from deficient individuals, and c) a mean total trypsin inhibitory capacity (TIC) of less than 0.30 mg trypsin inhibited per ml serum. The trypsin inhibitory capacity in normal serum was found to be 1.07 ± 0.12 (SD). Read the rest of this entry »
The First Family with oixAT Deficiency
Early during the clinical evaluation of a!AT deficiency, I had the good fortune to come across a family with three siblings suffering a severe form of obstructive lung disease. This family was the basis of an article in Acta Medica Scandinavica in 1964. One brother had died of lung disease and we lacked a blood sample. A sister and another brother were still alive. All three siblings had a severe form of emphysema (Fig 5). X-ray results were typical, with flat diaphragms and lack of basal vascular markings. They had a very advanced obstructive ventilatory impairment which was irreversible after attempts at bronchodilatation. At this time, we had started to use agar gel to separate the plasma proteins. Read the rest of this entry »