Thromboplastic activity of red cells

WE freely acknowledge the priority of Prof. Quick in discovering and reporting the platelet-like thromboplastic activity of red-cell hæmolysate. No reference was made to his work, as it was our opinion that it would be well known to all workers in this field

Detection and isolation of a hepatic membrane receptor for ferritin

A ferritin receptor has been detected on isolated rat hepatocytes and has been partially purified from rat liver using affinity chromatography. Isolated hepatocytes exhibit approximately 30,000 ferritin binding sites/cell with a binding association constant (Ka) of 1 x 10(8) mol-1 liter. A binding assay has been developed which utilizes a hepatic ferritin receptor coupled to a microparticulate support to facilitate separation of bound and free ligand. This method yielded a Ka of 3 x 10(8) mol-1 liter for the purified hepatic ferritin receptor. Binding of ferritin to the insolubilized receptor was partially inhibited by human lactoferrin but unaffected by 200-fold molar excess of bovine albumin, rat transferrin, or human asialoorosomucoid

Transient Intravascular Haemolysis Associated with Alcoholic Liver Disease and Hyperlipidaemia

Summary: A 44‐year‐old male alcoholic patient developed severe intravascular haemolysis in association with alcoholic liver disease and hyperlipidaemia. In‐vitro incubation experiments provided evidence for a circulating factor in plasma which rendered his own and normal, compatible erythrocytes abnormally susceptible to mechanical damage. The disorder settled spontaneously but recurred 18 months later after a further alcoholic bout, when the presence of the abnormal plasma factor was again demonstrated. It is suggested that there is a spectrum of red cell membrane damage which may occur in association with acute alcoholic liver disease, and in its most severe form this results in intravascular lysis while less affected cells are sequestered in the spleen

Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index

The value of measurement of hepatic iron concentration and determination of the hepatic iron index in distinguishing homozygotes from heterozygotes for hemochromatosis was examined. The study group included 42 homozygotes with an unequivocal diagnosis of hemochromatosis and six individuals who had initial equivocal results but were established as homozygous after extensive follow‐up. These were compared with 15 heterozygotes with no sign of increasing body iron stores who had undergone liver biopsy because of an initial suspicion of raised iron levels. In these subjects a hepatic iron concentration of greater than 75 μmol/gm dry weight was clearly indicative of homozygous hemochromatosis. Body iron accumulation was age‐related both in homozygotes and in these heterozygotes with mild biochemical abnormalities (r = 0.476; p = 0.001 and r = 0.689; p = 0.01, respectively), with a rate of accretion of approximately 5 μmol/gm dry weight/year in homozygotes and 0.9 μmol/gm dry weight/year in heterozygotes. Thus, lower values in young subjects may be consistent with homozygosity, and higher values in older individuals are consistent with heterozygosity. To overcome this problem, the hepatic iron index (hepatic iron concentration divided by age in years) was analyzed and found to separate the two groups effectively, with no homozygote having an index of less than 1.9 and no heterozygote having an index of greater than 1.5. These results in a series of patients who have been followed for a median of 3 yr (range = 1 to 30 yr) validate the use of the hepatic iron index to discriminate hemochromatosis homozygotes from heterozygotes with raised levels of serum ferritin, transferrin saturation or both. (HEPATOLOGY 1990;12:20–25)

Isolation of a human hepatic ferritin receptor

A human hepatic ferritin receptor has been isolated from human liver and has been purified using affinity chromatography. An affinity constant of 6.0 × 10 moles liter was determined for the ferritin receptor. The molecular weight was estimated to be approximately 53,000 by gel electrophoresis. Binding of ferritin to the receptor coupled to a microparticulate support was specific for human liver ferritin with no binding of rat or porcine ferritin. Binding was unaffected by a 100‐fold excess of human transferrin, human asialoo‐rosomucoid and bovine albumin. After treatment of the receptor protein with trypsin, binding was not detected. The human hepatic ferritin receptor may play an important role in the uptake of iron into the hepatocyte in physiological and pathological conditions

Pathways of intracellular trafficking and release of ferritin by the liver in vivo: The effect of chloroquine and cytochalasin D

We have previously shown that the clearance of exogenous ferritin and the release of endogenous ferritin into both serum and bile are altered by the microtubular inhibitor colchicine. In this study we further examined the role of the lysosome‐endosome pathway in ferritin metabolism. We examined the effect of the lysosomotropic agent chloroquine and the microtubular inhibitor cytochalasin D on the uptake and release of ferritin by normal and iron‐loaded rats under basal conditions and in the presence of an exogenous tissue ferritin load. Either chloroquine (50 mg/kg body wt) or cytochalasin D (0.9 μg/100 gm body wt/min) was administered to normal and iron‐loaded rats at zero time. Rats were also infused with either saline solution or rat liver ferritin containing a trace amount of I‐ferritin. The clearance of I‐ferritin from the circulation was not affected by chloroquine or cytochalasin D either in normal or in iron‐loaded rats; however, both chloroquine and cytochalasin D decreased the serum ferritin concentration in normal rats to 39 ± 9 and 22 ± 7 of the baseline serum ferritin levels, respectively, implying that both drugs inhibited the release of endogenous ferritin in normal rats. In iron‐loaded rats both chloroquine and cytochalasin D decreased the biliary ferritin concentration to 11 ± 1 and 37 ± 4 of the baseline ferritin levels, respectively, and the I protein‐bound counts per minute in the bile to 50 of the control result. This finding is consistent with an inhibitory effect of both drugs on the biliary excretion of endogenous ferritin and the intracellular transport of exogenous ferritin, respectively. In the presence of an exogenous tissue ferritin load, there was no detectable inhibitory effect of either drug on the biliary excretion of either endogenous or exogenous ferritin. These results provide the following evidence: (a) the receptor‐mediated endocytosis of ferritin is not dependent on functioning lysosomes or microfilaments; (b) the release of endogenous ferritin into the serum of normal rats and the bile of iron‐loaded rats is a chloroquine‐sensitive, microfilament‐dependent process; (c) the biliary excretion of trace amounts of exogenous ferritin is dependent on both chloroquine‐sensitive vesicles and microfilaments; and (d) increased levels of exogenous ferritin are excreted directly into the bile by way of a second microfilament‐independent, chloroquine‐insensitive pathway. This study provides support for a physiological mechanism for the release of ferritin from the liver. (Hepatology 1994;19:504–513). Copyrigh

Where does the gene for hemochromatosis lie in relation to HLA‐A?

Hereditary Hemochromatosis (HFE) is one of the most common inherited disorders with an estimated frequency of homozygous patients of 0.002‐0.0045. The disease is characterized by increased intestinal iron absorption and progressive iron overload. Affected subjects show clinical symptoms of parenchymal organ damage after the third‐fourth decade of life and have a 200‐fold increased risk of developing hepatocellular carcinoma. Early diagnosis and treatment prevent complications and may normalize life expectancy of patients. The biochemical and genetic defects leading to progressive iron accumulation are still unknown, but the HFE gene is tightly linked to HLA complex on the short arm of chromosome 6. Utilizing HLA serotypes and the study of several polymorphic markers of 6p21, a linkage analysis of the disease locus was performed in a series of Italian hemochromatosis families. The data obtained by linkage analysis and the study of a family with a double recombinant allowed us to better define the HFE gene location with respect to HLA‐class I A and F loci