Sten Eriksson

Risk of Cirrhosis and Primary Liver Cancer in Alpha1-Antitrypsin Deficiency

Previous reports have suggested an association between homozygous alpha 1-antitrypsin deficiency, cirrhosis, and primary liver cancer. To assess the risk of these complications we conducted a retrospective study based on 17 autopsied cases of alpha 1-antitrypsin deficiency identified during the period 1963 to 1982 in the city of Malmö, Sweden. During the study period, autopsies were performed in 38,250, or 68.2 percent, of all patients in the city who died. From the homozygote frequency in the population, 21 of these were expected to have alpha 1-antitrypsin deficiency. The disease had been diagnosed in 20, and autopsies had been performed in 17 (1 child and 16 adults). Each autopsied case was matched with four controls selected from the same autopsy register, and the Mantel-Haenszel odds ratio (ORmh) was calculated. The results indicated a strong relation between alpha 1-antitrypsin deficiency and cirrhosis (ORmh = 7.8; 95 percent confidence limits, 2.4 to 24.7) and primary liver cancer (ORmh = 20; 95 percent confidence limits, 3.5 to 114.3). When data were stratified according to sex, these associations were statistically significant only for male patients. We conclude that men with alpha 1-antitrypsin deficiency may be at higher risk for cirrhosis and primary liver cancer. The apparent male predominance suggests the additive effects of exogenous factors.

Biliary Excretion of Bile Acids and Cholesterol in Bile Fistula Rats. Bile Acids and Steroids.

Summary 1. A detailed analysis of excretion of taurocholic taurochenodesoxycholic acid and cholesterol in bile duct cannulated rats has been undertaken. 2. A constant excretion pattern consisting of 2 parts was observed: A) Excretion of preformed bile acids present in the enterohepatic circulation during 12 hours following cannulation; B) An increased formation of bile acids resulting in a 10-20 fold increased synthesis of bile acids (40-70 mg/day), as compared to synthesis of bile acids in the intact animal (3-4 mg/day), is present from the second or third day.

Evidence of increased intestinal synthesis and extracellular deposition of IgM in primary biliary cirrhosis. An immunofluorescence study of liver and small-intestinal biopsy specimens.

Direct immunofluorescence showed intense extracellular granular deposition of IgM and C3 in liver and small-intestinal biopsy specimens from patients with primary biliary cirrhosis. In contrast, IgM deposits were not observed in liver tissue from patients with other liver diseases, whereas small-intestinal IgM deposits were seen also in 2 of 17 patients with various intestinal disorders. The tissue deposition of IgM did not vary with plasma IgM levels, degree of cholestasis, or histological stage of the disease but seemed to reflect an abnormal property of the IgM molecule. The number of IgM-positive mononuclear cells in intestinal mucosa from patients with primary biliary cirrhosis was markedly increased, suggesting increased local synthesis of IgM. Deposition of IgM with complement-activating ability might contribute to the development of tissue damage in primary biliary cirrhosis. In addition, the apparent specificity of these IgM deposits in liver for primary biliary cirrhosis might be of diagnostic value when histological classification is difficult.

Endocrine Cells in the Human Oxyntic Mucosa: A Histochemical Study

The oxyntic mucosa of the human stomach harbors at least five different endocrine cell types (ECL cells, A-like or X cells, somatostatin cells (D), enterochromaffin (EC) cells, and D1 or P cells). Little is known about their functional roles, and of the hormones they produce only somatostatin has been identified. The relative frequency and regional distribution of the different endocrine cell populations were studied in 13 adults with no manifest gastrointestinal disease. From each of them at least three biopsy specimens were taken at seven fixed locations within the oxyntic mucosa. The specimens were examined for the different endocrine cell types by means of immunocytochemistry (staining with antisera against chromogranin A,5-hydroxytryptamine, and somatostatin) and silver staining techniques (demonstration of argyrophil cells by the methods of Grimelius or Sevier-Munger). Chromogranin-positive cells included all endocrine cells identified by the other staining techniques. Grimelius-positive cells included all endocrine cells except the somatostatin cells. Sevier-Munger-positive cells, finally, included the ECL cells and the EC cells. The frequency of ECL cells could be calculated by subtracting the number of EC cells from the number of Sevier-Munger-positive cells. The ECL cells represented 35% of the total endocrine number, somatostatin cells 26%, and EC cells 25%. The remaining 14% consisted of A-like cells, D1 cells, and P cells. Generally, the endocrine cells predominated in the basal portion of the glands, but the various populations of endocrine cells were not uniformly distributed in the various regions of the oxyntic mucosa. However, representative specimens could be obtained from the main body of the stomach, and the results indicate that the examination of a fairly small number of specimens from the main body of the stomach may be sufficient for assessing the frequency of endocrine cells in the oxyntic mucosa of individual patients.

Strong link between the alpha1-antitrypsin PiZ allele and Wegener's granulomatosis

Abstract. Objectives. To ascertain whether a relationship exists between the PiZ alpha1‐antitrypsin (α1AT) variant and antineutrophil cytoplasm antibodies (ANCA)‐positive vasculitis in a large group of Swedish patients, and whether analysis for the presence of the PiZ variant might be useful for diagnostic or prognostic purposes.

Purification and Partial Characterization of PAS-Positive Inclusion Bodies from the Liver in Alpha1-Antitrypsin Deficiency

Abstract To characterize the periodic acid-Schiffpositive inclusion bodies from cirrhotic livers of patients with homozygous alpha1-antitrypsin deficiency we isolated and analyzed such material. The main component of the inclusion bodies was a protein with approximately the same molecular size as serum alpha1-antitrypsin. Immunologic similarity between the isolated protein and serum alpha1-antitrypsin was established by the isolates ability to react with fluorescein-isothiocyanate-conjugated antibodies against serum alpha1-antitrypsin and to raise antibodies gainst it in rabbits, and with the double immunodiffusion technic. On agarose-gel electrophoresis hepatic antitrypsin migrated as an alpha2-globulin before and after neuraminidase treatment. Chemical analysis showed a complete absence of sialic acid. Hepatic antitrypsin had a pronounced tendency to form insoluble macroaggregates. An insufficient sialylation of antitrypsin in the liver appears to be one of the basic defects in alpha1-antitrypsin defic...

Chronic ‘Cryptogenic’ Liver Disease and Malignant Hepatoma in Intermediate AlpharAntitrypsin Deficiency Identified by a Pi Z-Specific Monoclonal Antibody

Using a monoclonal antibody against the Pi Z genetic variant of alpha 1-antitrypsin in an enzyme-linked immunosorbent assay, we have screened plasma samples from 857 consecutive patients with liver disease for the presence of Pi Z alpha 1-antitrypsin. Intermediate alpha 1-antitrypsin deficiency (Pi MZ and SZ) was found in 64 cases, or 7.6%, compared with an expected 4.8% (p less than 0.001). The plasma alpha 1-antitrypsin level was subnormal in only 50% of them. Forty-three of the 64 heterozygotes were men, compared with 494 of 857 (58%) in the total study population (p less than 0.001). At least 14 heterozygotes had cryptogenic liver disease, compared with 3 of 128 sex- and age-matched controls from the same study population (p less than 0.001). Malignant hepatoma occurred in 6 heterozygotes compared with 1 control (p less than 0.01), and in 13 of all 793 non-Pi Z patients (p less than 0.001).

Characterization of α1-Antitrypsin in the Inclusion Bodies from the Liver in α1-Antitrypsin Deficiency

Abstract α1-antitrypsin was isolated from periodic acidSchiffpositive inclusion bodies from the hepatocytes of patients with α1-antitrypsin deficiency and further purified to enable more detailed chemical analysis. Amino acid and cyanogen bromide fragmentation studies showed a close similarity between hepatic and serum (PiMM) antitrypsin in contrast to the carbohydrate analysis, which revealed markedly deficient glycosylation of hepatic antitrypsin. A complete lack of sialic acid and a relative deficiency of all other carbohydrate components could fully explain the difference of approximately 6000 daltons in molecular size between the two proteins. The accumulation of hepatic globules is probably related to the physical properties of the defective antitrypsin, which include marked insolubility and tendency toward aggregation. The results strongly suggest an abnormal amino acid sequence in the peptide chain of the deficient antitrypsin. The interference with glycosylation may be related to steric hindrance...

The Electrophoretic α1-Globulin Pattern of Serum in α1-Antitrypsin Deficiency

Th e main constituents of the a,-fraction obtained on paper electrophoresis in a barbital buff er are α1-lipoproteins, orosomucoid (acid glycoprotein), Schmid’s (1953) and Schultze et al.’s α1-3.5 S glycoprotein (Schultze, Giillner, Heide, Schonenberger & Schwick 1955), which Schultze, Heide & Haupt (1962) recently proved to be identical with a,-antitrypsin (10–12). Th e variation, in heaIth and disease, of the a,-lipoproteins, or at least of lipids in the electrophoretic albuminα1 region, has received fairly wide attention (for references see Lindgren & Nichols 1960) (9). Th e electrophoretic α1-lipoprotein fraction migrates faster and spreads more, widely than most of the other components. Its electrophoretic behavior also varies with the duration of storage of the serum and with variations of the intermediary lipid metabolism. It is the heaviest normal al-component (about 300 mg per 100 ml) calculated as protein, but it is electrophoretically heterogenous and does not give rise to any well demarcated electrophoretic protein peak, which is evident on comparison of the paper and agar gel electrophoretic patterns after staining for lipids and proteins. Th e orosomucoid, which normally occurs in a concentration of about 75 mg per 100 ml (Goodman, Ramsey, Simpson & Brennan 1957) produces no demonstrable peak on paper or in agar gel electrophoresis, because it is partly masked by the slower part of the albumin fraction, and it stains only faintly with bromphenol blue (Sundblad & WallinNilsson 1962) (4, 15). Th e α1x component normally occurs in a concentration of about 30 mg per 100 ml (Schultze, Heide & Haupt 1962), which is not high enough to produce a distinct peak on paper electrophoresis (11, 13). Burtin (1960) has stated that the strongly antigenic 3.5 S a,-glycoprotein (α1Z, α1-antitrypsin) is the dominating normal α1-component. We have accepted this concept for two reasons. Th e precipitation maximum of the line formed by antiα1-antitrypsin corresponds to the α1-protein peak obtained on paper and agar gel electrophoresis with diff erent buff ers. It may be deduced from data given by Jacobson (1955) on the α1antitrypsin activity that if the molecular weight of the α1-antitrypsin is about 60,000, the mean normal concentration will be 0.18 g per 100 ml. Th is amount of protein is in accord with the intensity of the relatively sharply demarcated alpha-1-band obtained on paper electrophoresis. We cannot accept Burtin’s statement, based on the appearance of immunoelectrophoretic patterns, that the main al-component varies little in pathological sera. On the contrary, the α1-antitrypsin varies considerably in disease (Jacobsson 1955), which is in accordance with the observed variations of the electrophoretic α1-band (3). In this article we present some patients with a new type of dysproteinemia characterized by very pronounced α1-antitrypsin defi ciency. Th e sera were revealed as abnormal on routine inspection of the paper electrophoretic strips at the laboratory since the α1 pattern had an atypical confi guration with no distinct α1-band. Th e numerical values of the electrophoretic α1-fractions fell within or just below the lower range of the normal variation. Originally published in Scandinavian Journal of Clinical and Laboratory Investigation 1963, 15 (2): 132–140 reprinted with permission.

Inhibition of Alzheimer beta-peptide fibril formation by serum amyloid P component.

A 39-43-amino acid residue-long fragment (β-peptide) from the amyloid precursor protein is the predominant component of amyloid deposits in the brain of individuals with Alzheimers disease. Serum amyloid P component (SAP) is present in all types of amyloid, including that of Alzheimers disease. We have used an in vitro model to study the effects of purified SAP on the fibril formation of synthetic Alzheimer β-peptide 1-42. SAP was found to inhibit fibril formation and to increase the solubility of the peptide in a dose-dependent manner. At a 5:1 molar ratio of Aβ1-42 peptide to SAP, fibril formation was completely inhibited, and approximately 80% of the peptide remained in solution even after 4 days of incubation. At lower SAP concentrations, e.g. at peptide to SAP ratio of 1000:1, short fibrillar like structures, lacking amyloid characteristics, were formed. These structures frequently contained associated SAP molecules, suggesting that SAP binds to the polymerizing peptide in a reaction which prevented further fibril formation.