[Patients with increased liver enzyme levels--when and how are they to be examined?].
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Alanine Transaminase↗
Biomedical subjects
R Hultcrantz
Publications and source records attributed to R Hultcrantz.
Intracellular fate of ferritin in HeLa cells following microinjection.
It is known that following iron overload newly synthesized ferritin molecules accumulate in lysosomes. However, the way in which these molecules enter the lysosomes has not been clarified. In order to assess if these molecules can be taken up by lysosomes from the cell sap, i.e., by way of autophagy, ferritin was introduced into HeLa cells through microinjection with a glass capillary. The fate of the ferritin was studied after varying intervals with the electron microscope. Shortly after microinjection ferritin molecules could be observed in the cell sap. After both 1 and 2 h, they were found in clusters and still mainly in the cell sap. After 4 h, ferritin molecules were present not only in the cell sap and in autophagic vacuoles but also in occasional secondary lysosomes. After 12 h, they were seen mainly in lysosomes, undergoing degradation. In no instance were ferritin molecules translocated into other organelles such as mitochondria, Golgi apparatus, or endoplasmic reticulum. The present study demonstrates that ferritin can be introduced into cells by glass capillary microinjection without cell damage. From its initial location in the cell sap ferritin is taken up into the lysosomal vacuome. Autophagy is considered to be the principal mechanism for the transfer of the ferritin molecules into lysosomes.
Autophagy↗
Spontaneous regression of Budd-Chiari syndrome (hepatic venous occlusion) in a young female.
A case of occlusion of the hepatic veins in an 18-year-old girl is presented. The onset was sudden with massive ascites and markedly impaired general condition. The diagnosis was based on liver biopsy and angiograms of the caval and hepatic veins as well as of the celiac artery. No predisposing factors could be found. The patient was treated conservatively with laparocentesis and diuretics. Clear improvement was seen after two weeks, and after four weeks she had no ascites and could be discharged. All liver function tests were then normalized. After three months, all diuretics could be withdrawn, and in the following 11 years she has remained completely recovered. The case illustrates that also widespread thrombi of the hepatic veins may sometimes rapidly dissolve spontaneously, with apparent total reconstitution of hepatic function. This case is unusual since previously reported cases have had high mortality rates and, in surviving cases, operative procedures or large doses of diuretics have been required to control the ascites.
Adolescent↗
Carbohydrate-deficient transferrin in serum in patients with liver diseases.
Carbohydrate-deficient transferrin (CDT) in serum was analyzed by isocratic microanion exchange chromatography at pH 5.65 followed by a transferrin radioimmunoassay in 102 patients with biopsy-verified liver diseases. CDT values were normal in all of the 87 nonalcohol-abusing patients irrespective of type or degree of liver disease. Thirteen of the 15 alcoholic patients (87%) with current abuse showed elevated CDT values while in abstaining alcoholics with remaining liver disease the values were normal. No correlations were found between CDT level and volume density of liver fibrosis or steatosis or values of a number of clinicochemical liver tests. The only significant correlation demonstrated was between CDT concentration and the level of present daily alcohol consumption in the alcoholic patients. These results indicate that CDT can be used as a marker of present but not previous alcohol abuse, even in patients with various liver diseases.
Adolescent↗
Liver investigation in 149 asymptomatic patients with moderately elevated activities of serum aminotransferases.
The accidental finding of raised levels of serum aminotransferase levels may lead to extensive investigations of the liver in apparently healthy people. To identify diagnostic groups and their need for investigations, we have evaluated the results of all investigative procedures carried out in 149 asymptomatic patients with persistently raised serum levels of aminotransferases. Fatty liver was found in 64%. These patients often had a high body weight. A high alcohol intake and diabetes mellitus were also noted. Chronic active or persistent hepatitis was found in 20% of the patients. Six per cent had cirrhosis, 4% had alpha 1-antitrypsin deficiency, and 3.5% had hemochromatosis. Apart from ferritin, alpha 1-antitrypsin, and markers for hepatitis B, blood tests were of little value for distinguishing among different diagnostic groups. This was the case also for the imaging procedures, and neither liver scintigraphy nor ultrasonography was a reliable source of diagnostic information. The results of our study indicate that diagnosis in this group of patients cannot be made without liver biopsy.
Alanine Transaminase↗
Levels of malondialdehyde production in rat liver following loading and unloading with iron.
Rats were given daily injections of an iron sorbitol citric acid complex in a total dose of 50 mg Fe3+/100 g of body weight and either killed immediately after iron loading, or investigated 2 months later. Among the latter animals, one group was subjected to weekly phlebotomies in order to mobilize iron from the stores, while another group was not further treated. Quantitation of iron and malondialdehyde production was performed on homogenates of liver, kidney and spleen from controls and rats in the different experimental groups, and the distribution of iron in granular form was studied in the livers by means of electron microscopy. The results showed substantially increased amounts of iron in the organs studied after iron-loading and also augmented malondialdehyde production in the liver and kidney (but not in the spleen). A decreased malondialdehyde production was recorded two months after iron-loading in the kidney and spleen of non-bled animals; this decrease was exaggerated in the same organs from bled animals. The production of malondialdehyde as well as the iron content in the livers of both bled and non-bled rats 2 months after iron loading was higher than in the controls. The evidence obtained suggested that the accumulation of iron in the liver was causally related to increased lipid peroxidation. Judging from the morphological appearances this change did not result in cell damage, the only pertinent morphologic alteration being the occurrence of iron particles in the lysosomal vacuome and the cell sap.
Animals↗
Isolation of two lysosomal populations from iron-overloaded rat liver with different iron concentration and proteolytic activity.
Iron overload results in an accumulation of electron-dense iron-containing particles (IPs) such as ferritin and hemosiderin within the lysosomes of rat liver cells. In order to evaluate the effect or iron overload on lysosomal function, efforts were made to isolate lysosomes with different iron contents by means of ultracentrifugation in Percoll and Metrizamide gradients. Lysosomes isolated on the Percoll gradient were characterized ultrastructurally by a uniform matrix consisting mainly of IPs and these lysosomes contained a high iron concentration and showed a very low proteolytic activity. They may, therefore, constitute, or be equated, with a special type of residual bodies. They were also fragile, as judged by their significant release of enzymes during incubation in vitro. Lysosomes isolated in the Metrizamide gradient contained remnants of sequestered organelles and some IPs. These organelles displayed a somewhat impeded proteolytic activity compared with control lysosomes, as well as preserved membrane stability during incubation in vitro. We suggest that these may be precursors of the heavily iron-laden lysosomes recovered in the Percoll gradient. Our findings demonstrate that different populations of lysosomes exist in iron-overloaded rat liver cells, which show specific characteristics with regard to ultrastructural appearance, iron content and proteolytic activity. Differing iron contents is the most likely reason for their diverging densities and membrane integrities, whereas the difference in proteolytic activity could be a result of varying amounts of degradable substrate.
Animals↗
Minimal liver disease in young persons with homozygous and heterozygous alpha-1-antitrypsin deficiency.
Of 120 patients who were investigated for moderately elevated liver function tests as the only sign of liver disease, 6 young persons had alpha-1-antitrypsin (AAT) deficiency. Three had a homozygous (Pi ZZ) and three had a heterozygous (Pi MZ) AAT deficiency as measured with isoelectric focusing. An extensive investigation ruled out all other causes of liver disease. The three homozygous patients showed typical periodic acid-Schiff (PAS)-positive globules in their liver biopsies and slight fibrosis, whereas none of the heterozygous patients showed these features. Electron microscopical investigation also showed typical findings in the homozygous but not in the heterozygous patients. Further development of liver disease in these young and apparently healthy AAT-deficient patients with early signs of liver damage is not known. It is possible that these patients will develop severe liver disease later in life. It was possible to detect only the three homozygous patients by histochemical examination of liver tissue, since the heterozygous patients did not show PAS-positive globules in their liver.
Adult↗
Studies on the rat liver following iron overload: an analysis of iron and lysosomal enzymes in isolated parenchymal and non-parenchymal cells.
Iron overload is known to affect the liver. In order to study the effect of iron on various liver cellular and subcellular compartments and the alterations due to mobilization of iron, an experimental model has been developed previously. In this study iron stores in parenchymal and non-parenchymal cells have been investigated during iron loading and unloading. Following completion of the experimental procedures, liver cells were isolated by means of collagenase perfusion (parenchymal cells) and pronase treatment (nonparenchymal cells). It was found that iron overload did not result in significantly increased levels of three lysosomal enzymes, and that the enzyme activities were not altered as iron was mobilized. Iron stores were localized largely in parenchymal cells, and these stores decreased after cessation of iron loading. The iron content was further lowered if the animals were bled. The non-parenchymal cells of the liver initially stored a relatively small part of the administered iron but this increased in the two months following iron loading. On the other hand if the animals were bled there was a pronounced decrease in iron content of these cells as well as in parenchymal cells. It is concluded that iron overload does not affect lysosomal enzymes and that iron stores in both parenchymal and non-parenchymal cells can be mobilized in response to increased demand.
Acid Phosphatase↗
Studies on the rat liver following iron overload. A morphometrical investigation of parenchymal and Kupffer cells.
The lysosomal vacuome of parenchymal and Kupffer cells of the liver has been shown to be involved in the storage of iron during iron overload. In order to morphologically quantify alterations in the course of this process a morphometrical analysis of liver cells and subcellular organelles (lysosomes, autophagic vacuoles, and mitochondria) has been performed. The results showed that the Kupffer cells increased in volume density (Vv) as the cells became loaded with iron whereas other cell compartments were unaffected. The volume density of Kupffer cell lysosomes was slightly increased when expressed on "per cell" basis. However, since the volume of the Kupffer cells increased simultaneously, the total volume of the lysosomes in these cells was increased more than 100%. Parenchymal cell lysosomal Vv increased approximately 100% following iron loading. This increase in parenchymal cell lysosomes was most pronounced in periportal cells while centrilobular cells were less affected in this respect. Both Kupffer cell Vv and lysosomal Vv in Kupffer and parenchymal cells were decreased when enhanced mobilization of iron was induced by bleeding. The results agree with the notion that the increase in Vv of the lysosomal vacuome during iron overload is due to the accumulation of iron binding storage proteins.
Animals↗
A case of haemobilia following percutaneous liver biopsy treated by selective arterial embolization.
A case is reported of severe hemobilia following a percutaneous liver biopsy. Hepatic ultrasound and computed tomography showed evidence of blood in the bile ducts and gall bladder. A selective arteriography revealed extravasation of blood in the liver. The bleeding ceased following selective embolization of the damaged artery after embolization with spongostan through the catheter used for the arteriogram. Following the embolization no further signs of bleeding were noted and the patient recovered completely.
Adult↗
Studies on the rat liver following iron overload: biochemical studies after iron mobilization.
We have characterized the distribution of iron in different organs of the rat, as well as in subcellular fractions of rat liver during iron loading and during physiologic and induced mobilization of iron. Elimination of iron through the bile was also measured. Iron loading was achieved by giving Jectofer injections, and unloading was obtained by weekly phlebotomizations. To study the fate of iron in the lysosomal compartment we have modified the method for the isolation of iron-loaded lysosomes (residual bodies) using Percoll as gradient medium. Thirty per cent of the stored iron was recovered in the liver, and this compartment gradually decreased during unloading. The spleen stored a minor part initially. This part was, however, increased 2 months after the loading was completed. A high concentration of iron was recovered in isolated liver lysosomes. A substantial portion was also found in the microsomal fraction and the ensuing 100,000 x g supernatant. Ultrastructural investigation showed few ferritin or hemosiderin granules in the microsomal fraction. After unloading, the lysosomes evidently decreased in density both in bled and nonbled animals concomitant with a decrease in iron content. In addition to lysosomes, iron was also mobilized from the microsomal fraction. Biliary iron was increased 100 per cent after iron loading and was further enhanced during unloading, in spite of the lowered concentration of iron in the liver. Enzymatic analysis suggested that in the bled animals iron-loaded lysosomes disappeared more rapidly from Kupffer cells than from the parenchymal cells.
Animals↗
Studies on the rat liver following iron overload.
Sprague-Dawley rats were given Jectofer injections to obtain iron overload in rat liver Kupffer and parenchymal cells. The release of iron was studied on the light and electron microscopical level by bleeding of the iron loaded animals and comparing the results with non bled controls. During the mobilization of iron. Kupffer cells showed a rapid and almost complete disappearance of electron dense iron containing particles (IP) while there was only limited decline of IPs in the parenchymal cells. Iron was demonstrated with X-ray microanalysis at the ultrastructural level, and presence of acid phosphatase was revealed using a histochemical method based on precipitation of lead phosphate at sites of enzyme activity in combination with X-ray microanalysis. It was demonstrated that all IP-containing cytoplasmic bodies also showed presence of acid phosphatase implying that all of them represented lysosomes. The mechanism of release of iron from Kupffer and parenchymal cells was discussed with special emphasis on the role of the lysosomes and the relationship between their contents and other cellular structures.
Acid Phosphatase↗
Studies on the rat liver following iron overload. Electron probe x-ray microanalysis of acid phosphatase and iron.
Previous electron-microscopic studies on the liver have shown that following excessive administration of iron to experimental animals, small particles believed to represent ferritin and/or hemosiderin (electron-dense iron-containing particles [IPs]) accumulate in membrane-bound bodies--many with a lysosome-like structure--in liver parenchymal and Kupffer cells. Further identification of the IP-containing bodies has been facilitated by the application of histochemical techniques for the demonstration of acid phosphatase. The results have shown that reaction product was deposited over organelles similar in appearance to the IP-containing ones, indicating that they were lysosomes. However, the granular nature of the reaction product makes it difficult or impossible to decide whether IPs are present simultaneously with reaction product in the organelle. In order to clarify this qualitative aspect, x-ray microanalysis has been utilized to identify iron and lead (reaction product) in the various structures thought to represent lysosomes. The results indicate that all IP-containing bodies also show the presence of reaction product, and thus can be regarded as lysosomes. However, in the parenchymal cells there may exist a small population of iron-deficient lysosomes (only lead could be shown). The latter may correspond to "primary lysosomes."
Acid Phosphatase↗
Studies on the rat liver following iron overload. 1. Fine structural appearance.
Iron overload of the rat liver following parenteral administration of Jectofer (an iron sorbitol citric acid complex) was studied in the electron microscope. Abundant ferritin-like granules were present in parenchymal and Kupffer cells, partly free in the cell sap and partly concentrated in 3 types of membrane-bound organelles, with characteristic appearances. In the parenchymal cells these organelles consisted of lysosome-like structures, apparent autophagic vacuoles, and vacuoles lacking features linking them to specific cytoplasmic elements. Organelle-bound ferritinlike granules in the Kupffer cells were demonstrated in lysosomelike structures, in phagocytic vacuoles, and in tubular and vacuolar elements referred to as "type 1" and "type 2" bodies. No ferritin-like granules were observed in other cell types than parenchymal and Kupffer cells.
Adipose Tissue↗
Ultrastructural liver pathology in patients with minimal liver disease and alpha 1-antitrypsin deficiency: a comparison between heterozygous and homozygous patients.
A light and electron microscopic investigation of liver tissue from three homozygous (Pi-type ZZ) and three heterozygous (Pi-type MZ) alpha 1-antitrypsin deficiency patients is presented. All had slightly elevated levels of serum amino transferases as the only signs of liver damage. Light microscopical investigation showed minor periportal fibrosis and periodic acid-Schiff-positive globules in the homozygous patients, but no specific findings besides fatty changes were seen in the heterozygous patients. Electron microscopical investigation was performed on periportal and centrilobular areas separately. In the three homozygous patients, dilatation of endoplasmic reticulum was found in many periportal liver parenchymal cells. In these cells, a marked increase in peroxisomes was also noted and in some instances they showed signs of cell necrosis. Evidence of Kupffer cell heterophagy of such cells was also found, thus indicating that they had died. Only in one liver parenchymal cell from one of the three heterozygous patients was evidence of a dilated endoplasmic reticulum found. No increase in peroxisomes was found and no apparent signs of liver cell necrosis were noted. An increased amount of lipofuscin-like material in the lysosomes was encountered in liver cells both from patients with homozygous and heterozygous alpha 1-antitrypsin deficiency. Based on these findings, it is suggested that cell death occurs in cells with a dilatation of the endoplasmic reticulum. If these findings are important for the pathogenesis in liver disease in alpha 1-antitrypsin deficiency, the present study suggests that the risk to develop liver disease is less in heterozygous patients since, with one exception, alterations of the same nature were not found in their hepatocytes.
Adult↗
Morphological findings in the liver of children with cystic fibrosis: a light and electron microscopical study.
Liver tissue from five children with cystic fibrosis, obtained through percutaneous liver biopsies, have been investigated via light and electron microscopy. None of the patients had clinical evidence of liver disorder, and their blood chemistry was mainly normal. Light microscopy showed slight fibrosis in three cases, more advanced fibrosis in one case and focal cirrhotic changes in one case. All patients had fatty infiltration in the hepatocytes and glycogen in the nuclei of these cells. Electron microscopy showed an increase in the number of Ito cells around the portal tracts and also fibrosis in all patients. In the majority of hepatocytes, no evident necrosis was seen. Hypertrophy of the smooth endoplasmic reticulum and the Golgi apparatus were noted. Large lysosomes containing lipofuscin and lipids were also present. No direct evidence of cholestasis could be seen in the hepatocytes. The bile canaliculi were not dilated and did not contain bile plugs. No bile pigment was seen in the cells, and direct evidence of cholestasis was thus not found in the hepatocytes. Other organelles, such as the rough endoplasmic reticulum, peroxisomes and mitochondria, had a normal appearance. Bile ducts, even when seen in fibrotic portal tracts, were not dilated. The ultrastructural findings cannot explain the basis for the liver cell damage. Cholestasis does not seem to be a presumable etiological factor as judged from the findings in the present study.
Alanine Transaminase↗
Susceptibility of cultured rat hepatocytes to oxidative stress by peroxides and iron. The extracellular matrix affects the toxicity of tert-butyl hydroperoxide.
The aim of this study was to set up an in vitro model for studying the importance of an altered extra-cellular matrix composition and its importance for the resistance to oxidative stress, in hepatocytes from normal and iron loaded rats. Primary cultures of hepatocytes from iron loaded and normal rats were plated on a laminin rich extracellular matrix or on collagen type I, and incubated with tert-butyl hydroperoxide (TBH). Malon dialdehyde (MDA) and the activities of lactate dehydrogenase (LDH) in cell culture medium were analyzed. The protein synthesis, the concentrations of glutathione and the expression of manganese-superoxide dismutase and ferritin genes were measured. All hepatocytes contained lower concentrations of glutathione when plated on collagen than on EHS. Ferritin H and Mn-SOD gene expression showed no difference. The rate of lipid peroxidation in iron loaded hepatocytes exposed to TBH was higher on collagen than in those plated on EHS (0.95 +/- 0.28 microM MDA vs. 1.62 +/- 0.22 microM MDA, p < 0.05). Iron loaded cells were in general more susceptible to TBH than were normal hepatocytes (MDA, LDH, protein synthesis and glutathione content). Lipid peroxidation could be prevented by adding desferrioxamine. In conclusion, we show that the combination of iron overload and collagen matrix in rat hepatocytes leads to an increased susceptibility to oxidative stress. These findings may be of interest for the further studies on effects of iron overload and the altered matrix composition in liver fibrosis.
Animals↗