Alpha 1-antitrypsin deficiency: the spectrum of pathology and pathophysiology.
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Adult↗
Biomedical subjects
E Cutz
Publications and source records attributed to E Cutz.
Improved ventilation of prematurely delivered primates following tracheal deposition of surfactant.
Twelve rhesus monkeys were delivered prematurely at 129, 130, or 131 days. The first breath was inhibited while tracheotomy was performed and a catheter introduced into the umbilical artery. Into the tracheal tubes of six of the newborn monkeys was instilled 0.20 to 0.27 ml. of a natural surfactant (SA) suspension, obtained from lung wash of adult rabbits. Nothing was given to six control monkeys. Breathing was then supported with a ventilator. Although its settings were adjusted in attempts to maintain normal blood gases, the control monkeys developed severe hypercapnia and acidosis, and two died after 4 1/2 and 5 1/2 hours. The remaining four control monkeys and the six treated monkeys were killed after six hours. Pulmonary pressure-volume characteristics were conspicuously better following SA treatment. It was concluded that instillation of SA in the upper airways of premature primates prior to their first breath holds promise as an effective way of preventing respiratory distress.
Animals↗
Release of vasoactive intestinal polypeptide in mast cells by histamine liberators.
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Animals↗
alpha1-Antitrypsin: the presence of excess mannose in the Z variant isolated from liver.
The Z variant of alpha1-antitrypsin was isolated by a new technique from the liver of a patient homozygous for the Z allele of the protease inhibitor locus. The material was homogenous and antigenically competent but had no protease inhibiting capacity. An interesting correlation was found between the subcellular localization and the carbohydrate composition of the Z variant from liver. Carbohydate analysis of this glycoprotein showed an absence of galactose and sialic acid, an appreciable decrease in N-acetylglucosamine, and an almost twofold increase in mannose residues. These data indicate a considerable slowdown in the processing of the oligosaccharides of liver Z variant. In spite of the absence of sialyl residues, the liver Z varant was microheterogeneous by analytical isoelectric focusing. The isoproteins of liver Z variant coincided with those of asialo M variant in the focusing field.
Amino Acid Sequence↗
Hepatic function following portoenterostomy for extrahepatic biliary atresia.
Liver structure and function in 10 patients with extrahepatic biliary atresia were studied after portoenteric anastomosis (Kasai operation). Bile flow adequate to reduce the serum bilirubin concentration was established in five patients (improved group), three of whom became anicteric. The serum bilirubin concentration did not decrease in the remaining five patients (unimproved group). Hepatic effluent collected postoperatively from both groups contained small amounts of cholesterol and bilirubin; bile salts, however, were present in the hepatic effluent of only the improved patients. Liver biopsy specimens obtained postoperatively from the five improved patients showed partial (in two) or complete (in three) relief of cholestasis; hepatic fibrosis, however, was unchanged (in one) or worse (in four). The serum concentrations of bile salts were markedly elevated, despite normal excretion of sodium sulfobromophthalein and rose bengal, in two anicteric patients studied 14 and 24 months postoperatively. It is concluded that neither structure nor function of the liver is normalized by portoenterostomy even in clinically well, anicteric patients.
Bile Ducts↗
Macrophages and epithelial cells in human amniotic fluid: transmission and scanning electron microscopic study.
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Amniotic Fluid↗
Identification of neuro-epithelial bodies in rabbit fetal lungs by scanning electron microscopy: a correlative light, transmission and scanning electron microscopic study.
In the present study, neuro-epithelial bodies (NEB) were identified by scanning electron microscopy (SEM) within the bronchial epithelium of near-term rabbit fetuses. The surface features and topography of NEB were correlated by light and transmission electron microscopy. In SEM, the surfaces of NEB were easily visualized in smaller peripheral airways because of paucity of ciliated cells in these regions. The NEB formed crater-like pits, which were lined with microvilli and had smooth-surfaced nonciliated cells around the rim. Stereo-pair photographs revealed that the latter cells protruded above adjacent bronchiolar mucosa. The SEM also revealed that NEB were preferentially located near or at bronchiolar bifurcations. This is the first report of the three-dimensional structure of pulmonary NEB. Their direct contact with the airway lumen, as well as their strategic location in bronchiolar mucosa, support the suggestion that they are intrapulmonary receptors and help to regulate air-flow in peripheral airways.
Animals↗
Ultrastructure of airways in children with asthma.
This study describes the histopathology and ultrastructure of bronchial mucosa in lung biopsies from two children with bronchial asthma in remission, and compares them with lung samples from two children who died in status asthmaticus. Light microscopy of all samples showed changes typical of bronchial asthma, e.g. mucus plugging, goblet cell hyperplasia, 'thickening of bronchial basement membrane', peribronchial smooth muscle hypertrophy and eosinophilic infiltration. Electron microscopy revealed that the mucus plugs consisted of moderately electron-dense floccular material containing degenerate epithelial cells, macrophages and cell fragments. The luminal surfaces of ciliated cells showed cytoplasmic blebs and abnormal cilia. Mast cells in various stages of degranulation were scattered between bronchial epithelial cells. The subepithelial hyaline layer, commonly referred to as "thickened basement membrane", consisted of collagen fibrils in plexiform arrangement. The basement membrane proper appeared intact. These electron microscopic changes, particularly the presence of mast cells and subepithelial collagen deposits, were also found in autopsy samples. This combined light and electron microscopic study shows that marked, possibly irreversible changes may be present in the lungs of patients with severe bronchial asthma, even when they are asymptomatic. These pulmonary changes could be the direct consequence of mast cell activation and the release of various mediators. No evidence of immune complex deposition was found.
Asthma↗
Reye's syndrome: preservation of mitochondrial enzymes in brain and muscle compared with liver.
The activities of five mitochondrial enzymes tested in liver from patients with Reye's syndrome were measured. Citrate synthase, glutamic dehydrogenase, succinic dehydrogenase, pyruvate carboxylase, and pyruvate dehydrogenase were all outside of the range shown by control samples and well below them in activity. The activity of two extramitochondrial enzymes, glucose-6-phosphatase, which is a microsomal enzyme, and fructose-1,6-diphosphatase, which is a soluble enzyme, were in the normal range in samples from Reye's syndrome patients. In both muscle and brain the activities of the mitochondrial enzyme, citrate synthase, glutamic dehydrogenase, and succinic dehydrogenase were all within the control range. Pyruvate dehydrogenase was found to be normal in muscle from these patients.
Brain↗
Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villus atrophy.
We have studied 5 infants with persistent severe diarrhea from birth and marked abnormalities of absorption associated with failure to thrive leading to death in 4 infants. Three had siblings who died and a sibling of a 4th is ill at present, all with a similar illness; 2 were the products of consanguinous marriages. Exhaustive investigation failed to identify a recognized disease entity in any patient. Steatorrhea, sugar malabsorption, dehydration, and acidosis were severe in all patients, whatever the diet fed. Total parenteral nutrition was used, but excessive stool water and electrolyte losses persisted even when nothing was fed by mouth. There was no evidence of a hematological or consistent immunological defect in any infant and no abnormalities of intestinal hormones were noted. In the duodenal mucosa of all infants we saw similar abnormalities characterized by villus atrophy, crypt hypoplasia without an increase in mitoses or inflammatory cell infiltrate in the lamina propria and in villus enterocytes absence of a brush border, increase in lysosome-like inclusions, and autophagocytosis. In 3 infants studied by marker perfusion of the proximal jejunum we found abnormal glucose absorption and a blunted response of Na+ absorption to actively transported nonelectrolytes; in 2 there was net secretion of Na+ and H2O in the basal state. Our patients evidently suffered from a congenital enteropathy which caused profound defects in their capacity to assimilate nutrients. The similar structural lesion seen in the small intestinal epithelium of all of our cases undoubtedly contributed to their compromised intestinal function, but the pathogenesis of this disorder, if indeed it is a single disease, remains obscure.
Acidosis↗
Hyaline membrane disease. Effect of surfactant prophylaxis on lung morphology in premature primates.
Neonatal lung morphology was evaluated in 12 rhesus monkeys delivered by caesarean section 1 month before term and cared for as human premature neonates. In 6 monkeys, 0.20 to 0.27 ml of natural rabbit surfactant (SA) was instilled intratracheally before the first breath; the other 6 served as controls. Histology and morphometry of the controls' lungs revealed changes typical of hyaline membrane disease (HMD) in human premature infants, whereas the SA-treated lungs showed improved alveolar expansion and only minor lesions typical of HMD. Transmission and scanning electron microscopy of the controls' lungs showed extensive necrosis and desquamation of bronchiolar epithelium, with formation of hyaline membranes; Type I alveolar epithelial cells showed lesions similar to those in bronchioles, but immature Type II cells appeared relatively well preserved. In the lungs of SA-treated animals, the epithelial lining of most airways and alveoli was intact. This first demonstration of the beneficial effect of exogenous SA on lung adaptation in premature primates indicates that prophylaxis with SA might prevent HMD in premature human infants.
Animals↗
Deficient activity of hepatic pyruvate dehydrogenase and pyruvate carboxylase in Reye's syndrome.
The activity of certain hepatic enzymes involved in carbohydrate metabolism was measured in postmortem samples from six cases of Reye's syndrome. The activities of the two exclusively extramitochondrial enzymes, glucose-6-phosphatase and fructose-1,6-diphosphatase, were all within the normal range. Activities of pyruvate carboxylase and pyruvate dehydrogenase, both of which are exclusively mitochondrial enzymes, were below levels, shown by control tissue in every case, the average being 21.7% of the lowest control value for pyruvate carboxylase and 11.6% of that for pyruvate dehydrogenase. Impaired pyruvate metabolism appears to be another feature in Reye's syndrome.
Adolescent↗
Occult pulmonary abnormalities in asymptomatic asthmatic children.
The pulmonary status of 178 asymptomatic asthmatic children with normal time-volume spirograms was further evaluated using flow-volume loops, body plethysmographic studies, and blood gas tensions in arterialized capillary blood. Residual volume (RV) was abnormal in 26%, total lung capacity (TLC) in 33%, RV/TLC% in 41%, and arterial oxygen pressure in 23% of them. All values for expiratory flow measured relative to observed vital capacity (VC), (ie, the forced expiratory volume in one second [FEV1], the mean forced expiratory flow during the middle half of the forced vital capacity [FEF25-75%; FVC], FEV1/VC, and the instantaneous forced expiratory flow after 75% and after 50% of the FVC has been exhaled) were normal, and VC was subnormal in only five instances, but flow rates measured relative to TLC were abnormal in 26% of the patients. Some abnormality of pulmonary function was present in all but 13% of these asymptomatic children. Reliance upon conventional evaluation of pulmonary function by forced expiratory spirograms and freedom from wheezing may frequently give the clinician a false impression of the true conditon of the lungs of the asthmatic child.
Adolescent↗
Acrodermatitis enteropathica, zinc, and the Paneth cell. A case report with family studies.
An infant with acrodermatitis enteropathica was studied before and after starting zinc therapy. Clinical recovery was rapid, and the plasma zinc, serum and mucosal alkaline phosphatase activities returned to normal. Light microscopy of small intestinal biopsies showed normal mucosa. Electron microscopy of the Paneth cells initially revealed abnormal inclusion bodies which disappeared during therapy, suggesting that the abnormality is secondary to zinc deficiency, and not a primary defect. These abnormal inclusions may represent altered secretory granules and a proliferation of lysosomes. We were unable to define the heterozygous state biochemically or histologically.
Acrodermatitis↗
Dissociation of epithelial cells from rabbit trachea and small intestine with demonstration of APUD endocrine cells.
In this study the entire epithelial lining of tracheas and a 15-cm segments of small intestine were dissociated into individual cell components after 45-minute incubation with 1% pronase. Light and electron microscopy of isolated cells confirmed good morphologic preservation of various epithelial cell types dissociated from the trachea and small intestinal mucosa. Of particular interest was the recovery and preservation of APUD endocrine cells, which are known to be widely dispersed amongst various non-endocrine epithelial cells in both the trachea and small intestine. The APUD cells were demonstrated in dissociated cell preparations by a formaldehyde-induced fluorescence method, Grimelius' silver nitrate stain, and electron microscopy. The isolated APUD cells retained their characteristic features, e.g., amine-handling properties, argyrophilia and cytoplasmic dense-core vesicles. The cell dissociation method described in this report provides high yields of viable epithelial cells in single cell suspensions which are suitable for further cell separation into homogeneous populations of single kinds of cells, including the APUD endocrine cells. Availability of methods for isolation of tracheal and intestinal APUD cells will facilitate further studies, in vitro, on secretory, metabolic and functional aspects of these cells.
Amines↗
Liver disease associated with alpha1-antitrypsin deficiency in childhood.
Liver disease in children with alpha1-antitrypsin deficiency and protease inhibitor type ZZ does not necessarily carry a bad prognosis. Fourteen of our 18 patients presented with the neonatal hepatitis syndrome and four had hepatomegaly without jaundice. Although four patients have died of cirrhosis and its complications, and three have severe liver disease, most of the 11 others, of whom four are over 13 years of age, have relatively little clinical, biochemical, or histologic evidence of liver disease. Persistent elevation of SGOT during the third year of life and renal or pulmonary problems were associated with a poor prognosis. Liver biopsy early in the course of the disease was not helpful prognostically but was useful in assessment of the severity of liver disease and demonstration of alpha1AT storage, alpha1AT deficiency was found in 29% of our patients who presented with the neonatal hepatitis syndrome. One of seven apparently healthy Pi type ZZ sibs of our patients had significant liver disease which had not been suspected previously.
Adolescent↗
Electron microscopy of ancient Egyptian skin.
Sections of skin were examined by electron microscopy from the sole of the foot of a 14-year-old Egyptian, who died 3200 years ago and was preserved naturally by desiccation. Remarkable ultrastructural preservation of the epidermal cells and their components was found.
Autopsy↗
Membranoproliferative glomerulonephritis in childhood cirrhosis associated with alpha1-antitrypsin deficiency.
Three alpha1-antitrypsin (alpha1AT) deficient, protease inhibitor type ZZ children who died from cirrhosis and its complications had membranoproliferative glomerulonephritis at postmortem examination. During life, all three had clinical and laboratory evidence of renal disease which became apparent when hepatic decompensation developed. Immunofluorescence studies and electron microscopy performed in one patient revealed subendothelial deposits of alpha1AT, complement, and immune globulins along the glomerular basement membrane. The pathogenesis of these renal lesions is speculative. Glomerular lesions were not observed in kidney sections of 16 children who died from cirrhosis but who were not alpha1AT-deficient. The present study suggests that renal involvement may be yet another manifestation of disease associated with alpha1AT deficiency.
Child↗