Iron overload and atherosclerosis.
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Arteriosclerosis↗
Biomedical subjects
C Niederau
Publications and source records attributed to C Niederau.
Menadione-induced oxidative stress inhibits cholecystokinin-stimulated secretion of pancreatic acini by cell dehydration.
The present study evaluated the effects of free radicals generated by menadione on morphology and function of pancreatic acinar cells focusing on enzyme secretion, stimulus-secretion coupling, and cell hydration. Various experiments evaluated morphology and function of isolated rat pancreatic acinar cells exposed to menadione. Menadione instantaneously generated free radicals (luminol and deoxyribose assays) followed by a time-dependent cell injury (uptake of trypan blue). Early ultrastructural changes included vacuolization and alterations of mitochondria, endoplasmic reticulum, and nucleus. Menadione caused a rapid glutathione oxidation followed by a depletion in reduced glutathione. An increase in lipid peroxides and a depletion of adenosine triphosphate were seen only after 30-60 minutes. Menadione markedly inhibited amylase release stimulated by cholecystokinin (CCK) and carbachol and simultaneously caused cell shrinkage after a few minutes. Similar degrees of cell shrinkage induced by hyperosmolar incubation and by menadione inhibited amylase secretion to a similar extent. CCK binding and its effect on calcium and inositol 1,4,5-trisphosphate (IP3) were not affected by menadione. Menadione (without CCK) induced an instantaneous increase of intracellular calcium followed by a slow constant increase. In single cells, menadione induced calcium oscillations with a frequency lower than that seen after CCK stimulation. Some morphologic and functional alterations owing to menadione-induced oxidative stress may be caused by adenosine triphosphate and glutathione depletion, lipid peroxidation, and changes in cytosolic calcium. The marked inhibition of secretagogue-stimulated enzyme secretion owing to menadione may be mediated to a large part by cell dehydration, whereas classical steps of stimulus-secretion coupling like receptor binding, calcium release, and IP3 generation remained unchanged.
Adenosine Triphosphate↗
[Demonstration of HFE polymorphism in German patients with hereditary hemochromatosis].
BACKGROUND AND OBJECTIVE: Hereditary haemochromatosis (HH) is the most common genetically determined disease of the white population which by iron overload causes multiorgan functional impairment. Recently the gene for HH (HFE gene) has been located on chromosome 6. The development of HH is thought to be caused by two point mutations that lead to an amino acid exchange of tyrosine for cysteine on codon 282 (Cys282Tyr) and of histidine by aspargic acid on codon 63 (His63Asp). PATIENTS AND METHODS: 75 patients with phenotypically confirmed HH were examined genetically. The analysis of the HFE-gene mutation was done on genomic DNA by restriction digestion with the restriction enzymes Rsal and Mbol. RESULTS: Homozygosity for the Cys282Tyr mutation was found in 66 (88%) of the patients, while two were heterozygous. Of seven patients with wild-type sequence of the amino acid position 282, three (43%) had a His63Asp exchange. Overall only four patients had neither of the two mutations. CONCLUSIONS: Because of different geographical distributions, a knowledge of the mutation rate is important for patients with HH. to assess the diagnostic value of the gene test. For the first time gene analysis makes it possible to diagnose HH before clinically significant iron overload occurs. It may further improve prognosis of the disease by early application of therapeutic blood-letting.
Amino Acid Sequence↗
[The effect of chelidonium- and turmeric root extract on upper abdominal pain due to functional disorders of the biliary system. Results from a placebo-controlled double-blind study].
BACKGROUND: Right upper abdominal pain may often be caused by biliary dyskinesia. Choleretica and cholekinetica are widely used for medical treatment of complaints due to biliary dyskinesia despite of a lack of randomized clinical trials which may prove their efficacy and potency. PATIENTS AND METHODS: The present prospective multicenter pilot study analyzes the effects of Cholagogum F Nattermann (dried extracts from Schöllkraut and Curcuma) in comparison with placebo in patients with dumpy or colicky abdominal pain in the right upper quadrant due to biliary dyskinesia. Cholagogum was given in 39 patients and placebo in 37 patients for 3 weeks, respectively. RESULTS: The reduction of dumpy and colicky pain was more rapid during the first treatment week in patients who received Cholagogum F when compared to those who received placebo. The reduction of other complaints (feeling of being filled up, food intolerance, nausea, vomiting, meteorism) (secondary variables) was similar in patients who received Cholagogum F versus placebo during the whole treatment period. The were no side-effects in patients who received Cholagogum. CONCLUSIONS: The study presents the first solid indication that extracts from Schöllkraut/Curcuma (Cholagogum F Nattermann) which have widely been used in daily practice for many decades have beneficial effects on pain due to biliary dyskinesia.
Abdominal Pain↗
Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation.
A 36-year-old woman was admitted for hepatosplenomegaly and anemia. Bone marrow cytology showed "sea-blue histiocytes", vacuolated macrophages and plasma cells. As primary liver disease, malignancy or hematologic disorders were excluded, and plasma chitotriosidase activity was increased 27-fold over control, the presence of a lysosomal storage disease was suspected. Biochemical analysis of skin fibroblasts revealed normal glucocerebrosidase and sphingomyelinase activity, but lipid analysis showed a more than 15-fold accumulation of cholesterol esters within the cells. The activity of lysosomal acid lipase (LAL) in fibroblast homogenates was decreased to 12% of control subjects. Mutational analysis of the patient's blood showed the homozygous G-->A mutation at position -1 of the exon 8 splice donor site (E8SJM-allele) known for adult cholesteryl ester storage disease (CESD); the polymorphic background was that of the complex haplotype -6Thr, 2Gly, 894 G-->A. Based on clinical, laboratory, cytological and and biochemical findings, CESD can clearly be separated from other more frequent inherited lysosomal storage diseases, e.g. atypical forms of Gaucher disease.
Adult↗
Supraphysiologic concentrations of cerulein induce apoptosis in the rat pancreatic acinar cell line AR4-2J.
Little is known as yet about the role of apoptosis in pancreatic damage. This study evaluated the effects of supraphysiologic concentrations of the cholecystokinin (CCK) analog, cerulein, which causes cell damage in vitro and acute pancreatitis in vivo, on cell proliferation and DNA fragmentation in the rat pancreatic acinar cell line AR4-2J. Cerulein inhibited the cell proliferation of AR4-2J time- and dose-dependently to approximately 60% of the control level at 10(-6) M after 72 h. DNA fragmentation, as assessed by both electrophoresis and enzyme-linked immunosorbent assay (ELISA), occurred at cerulein concentrations > or = 10(-8) M. The maximal DNA fragmentation as measured by ELISA was reached after 24 h. Cerulein at concentrations > or = 10(-9) M induced wild-type p53. Glutathione (1 mM) diminished the effects of cerulein on both cell proliferation and DNA fragmentation, whereas spermine (100 microM), which partially attenuated DNA fragmentation, did not have an effect on cell proliferation. The CCK-A-receptor antagonist loxiglumide completely abolished the effect of cerulein on DNA fragmentation. The serine-protease inhibitor FUT-175 (10 microM), the cysteine-protease inhibitor NCO-700 (5 mM), and ethylene glycol tetraacetic acid (EGTA; 500 microM) all had no effects on the changes in cell proliferation and DNA fragmentation induced by cerulein. The data suggest that supraphysiologic concentrations of cerulein rapidly induce apoptosis in AR4-2J cells and only later inhibit cell proliferation. These effects are mediated by CCK-A receptors. Cerulein-induced apoptosis may involve the induction of wild-type p53 or glutathione depletion or both.
Animals↗
Role of cholecystokinin in the development and progression of acute pancreatitis and the potential of therapeutic application of cholecystokinin receptor antagonists.
This presentation reviews the role of cholecystokinin (CCK) as a contributory factor for the development and progression of acute pancreatitis (AP) and the perspective of CCK receptor antagonists for treatment of AP. High, supraphysiological concentrations of CCK induce AP in various species including man. There is also evidence that physiological increases in plasma CCK deteriorates AP in several animal models. The latter findings support the hypothesis that CCK plays a contributory or permissive role for the development of AP. The majorities of experimental studies show that the prophylactic and therapeutic use of CCK antagonists ameliorates AP. The latter effects were clearly shown for models of biliary AP in which plasma CCK is increased due to a feedback mechanism. However, CCK antagonists also had beneficial effects in models in which plasma CCK is not increased. In animal strains which do not have a CCK-A-receptor due to a genetic abnormality AP induced by a certain noxious factor does not develop to the same severity when compared to animals with a normal CCK-A-receptor. Thus, CCK acts as a permissive or contributory factor for the development and progression of AP. There is also evidence that CCK antagonists have a potential therapeutic benefit. Clinical studies will evaluate their therapeutic potential for patients with AP.
Acute Disease↗
Haemochromatosis and the liver.
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Genetic Testing↗
[Diabetes mellitus in hemochromatosis].
The degree of glucose intolerance and diabetes mellitus in hemochromatosis is closely associated with the stage of iron overload and thus also the stage of the accompanying liver disease. Similar to other liver diseases glucose intolerance due to insulin resistance precedes diabetes mellitus also in hemochromatosis. Insulin resistance is probably caused by alterations of insulin or glucose metabolism in the liver and potentially also in extrahepatic peripheral tissue. Diabetes mellitus is found more frequently in iron overload when compared with other forms of chronic liver disease and cirrhosis, respectively. In advanced iron overload, iron accumulation in pancreatic B-cells deteriorates pancreatic insulin secretion and leads to insulin-dependent diabetes mellitus which cannot be reversed by iron removal. In contrast, early alteration of glucose intolerance and insulin resistance may partially be improved by phlebotomies. Thus, in the future we should aim to diagnose hemochromatosis in early stages which are not associated with diabetes mellitus or liver cirrhosis.
Diabetes Mellitus↗
Fecal excretion of alpha 2-macroglobulin: a novel marker for disease activity in patients with inflammatory bowel disease.
BACKGROUND: Quantification of fecal alpha 1-antitrypsin (AAT) excretion is established for estimation of enteric protein loss and assessment of disease activity in inflammatory bowel disease (IBD). In contrast, little is known about prevalence, course, and clinical significance of intestinal leakage of larger-size serum antiproteinases in these disorders. SUBJECTS AND METHODS: Firstly, 23 IBD patients (Crohn's disease, CD, n = 17, and ulcerative colitis, UC, n = 6) were examined at 34 independent episodes (relapse, n = 16, remission, n = 18) for parallel serum and fecal alpha 2-macroglobulin (AMG) and AAT concentrations by standard immunonephelometry, and compared to 40 healthy controls. From these IBD patients, secondly, a random cohort of twelve individuals (9 CD, 3 UC) was prospectively followed for those parameters at about monthly intervals for 7-14 (median 10.5) months. RESULTS: The threshold of detection for fecal AMG concentration was about 0.06 mg per gram dry weight stool (mg/g dws) under the present analytical conditions. While in healthy subjects fecal AMG was demonstrated at very low levels only (< or = 0.07 mg/g dws), it was found in CD and UC patients at elevated concentrations of < 0.06-3.18 (median 0.17) and < 0.06-1.91 (median 0.40) mg/g dws, respectively. Fecal AMG contents were more increased in active IBD compared to quiescent disease (p = 0.03), and they correlated to Crohn's Disease Activity Index in CD patients (p = 0.05), while not to Clinical Activity Index in UC individuals (p = 0.46). Post hoc evaluation of follow-up data suggested two distinct groups of IBD patients either with or without consistently detectable fecal AMG excretion, with the first ones exhibiting a more active clinical course than the latter ones (p < or = 0.02). CONCLUSIONS: AMG is excreted in feces of healthy subjects in traces only, while its stool concentration is largely increased in IBD patients where it reflects clinical disease activity. This novel stool parameter may be of potential value in the diagnostic and prognostic management of these individuals.
Adolescent↗
[Hereditary hemochromatosis--new developments after discovery of the HFE gene].
Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, resulting in an increased iron deposition and multiorgan failure. Recently a candidate gene of HH, termed HFE, has been identified on chromosome 6, coding for a protein homologous to major histocompatibility complex (MHC) class I molecules. Two mutations of the hemochromatosis gene leading to an exchange of cysteine to tyrosine at aminoacid 282 and histidine to asparagine at aminoacid 63, are retained responsible for the development of hereditary hemochromatosis. The Cys282Tyr-mutation disrupts a disulfid bond and thus abrogates binding of the mutant HFE-protein to beta 2-microglobulin and its presentation on the cell surface. The His63Asp-mutation seems to play a role in pH-regulated dissociation of the transferrin receptor/transferrin complex in the lysosome. Mutations of the HFE-protein alter the affinity of the transferrin receptor for its ligand transferrin and may thus cause an intracellular accumulation of iron. Knowledge of the responsible gene allows a molecular diagnosis of HH. The new genetic marker can be used for screening and confirmation of HH reducing the need for confirmatory liver biopsies. Compared to standard screening parameters like ferritin and transferrin saturation genetic testing will allow the diagnosis of HH in an early, asymptomatic state before iron accumulation has occurred. As a normal life expectancy of patients with HH can be achieved if iron reduction is initiated early, genetic testing may thus be of great benefit for patients with HH.
Algorithms↗
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT)
BACKGROUND: Only 15-20% of patients with chronic hepatitis C achieve a sustained virological response with interferon therapy. The aim of this study was to compare the efficacy and safety of interferon alpha2b in combination with oral ribavirin with interferon alone, for treatment of chronic infection with hepatitis C virus (HCV). METHODS: 832 patients aged 18 years or more with chronic HCV who had not been treated with interferon or ribavirin, were enrolled and randomly allocated one of three regimens: 3 mega units (MU) interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 48 weeks; 3 MU interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 24 weeks; or 3 MU interferon alpha2b three times a week and placebo for 48 weeks. All patients were assessed for safety, tolerance, and efficacy at the end of weeks 1, 2, 4, 6, and 8, and every 4 weeks during treatment. After treatment was completed patients were followed up on weeks 4, 8, 12, and 24. The primary endpoint was loss of detectable HCV-RNA (serum HCV-RNA <100 copies/mL) at week 24 after treatment. FINDINGS: Sustained virological response at 24 weeks after treatment, was found in 119 (43%) of the 277 patients treated for 48 weeks with the combination regimen, 97 (35%) of the 277 patients treated for 24 weeks with the combination regimen (p=O.055), and 53 (19%) of the 278 patients treated for 48 weeks with interferon alone (p<0.001 vs both combination regimens, intention-to-treat analysis). Logistic regression identified five independent factors significantly associated with response: genotype 2 or 3, viral load less than 2 million copies/mL, age 40 years or less, minimal fibrosis stage, and female sex. Among patients with fewer than three of these factors the odds ratio of sustained response was 2.6 (95% Cl 1.4-4.8; p=0.002) for the 48 week combination regimen compared with 24 weeks of the combination regimen. Discontinuation of therapy for adverse events was more frequent with combination (19%) and monotherapy (13%) given for 48 weeks than combination therapy given for 24 weeks (8%). INTERPRETATION: An interferon alpha2b plus ribavirin combination is more effective than 48 weeks of interferon alpha2b monotherapy and has an acceptable safety profile. Patients with few favourable factors benefit more from extending the duration of combination therapy to 48 weeks.
Administration, Oral↗
Loss of vision in Gaucher's disease and its reversal by enzyme-replacement therapy.
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Adult↗
[Cardiac troponin T in the diagnosis and follow up of suspected myocarditis].
BACKGROUND AND OBJECTIVE: Results of routine laboratory tests for demonstrating myocardial damage in patients suspected of having myocarditis are often negative. This study was undertaken to ascertain (1) whether measuring Tropinin T (cTnT) in these patients can sensitively determine myocardial cell death, (2) to what extent this correlates with the findings of endomyocardial biopsy, and (3) whether measurement of cTnT can provide noninvasive assessment of the course of myocarditis. PATIENTS AND METHODS: 80 consecutive patients (52 men, 28 women) with clinically suspected myocarditis were investigated. The main clinical symptoms were heart failure (n = 45), angina pectoris (n = 25) or cardiac arrhythmias (n = 10). In most patients the symptoms had developed in temporal relation to a viral infection. Coronary heart disease was excluded in all by coronary angiography. Interventricular septal endomyocardial biopsies were examined histologically and immunohistologically. cTnT was measured with a highly sensitive sandwich-immunoassay. RESULTS: An increased level of cTnT (> 0.1 ng/ml) was demonstrated in 28 of the 80 patients (35%). Myocarditis was diagnosed histologically in only 5 patients, but immunohistologically in 26 of 28 (93%) with a raised cTnT level and in 23 of 52 (44%) with a normal cTnT level. The cTnT level was more frequently elevated in patients with a brief rather than a long history of myocarditis. After 6 months the cTnT level was elevated in only 4 of 28 patients with myocarditis, but the myocardial biopsy showed persisting myocarditis in 14 patients. CONCLUSION: Measurement of cTnT is a very sensitive way of demonstrating myocardial cell damage in patients clinically suspected of having myocarditis. Immunohistological analysis can often provide positive results even if the histological findings are unremarkable. The sensitivity in diagnosing of cTnT is greatest when the patient is tested shortly after the onset of symptoms.
Acute Disease↗
Screening for hemochromatosis and iron deficiency in employees and primary care patients in Western Germany.
BACKGROUND: Many physicians still believe that iron overload (hemochromatosis) is an uncommon disorder. OBJECTIVE: To estimate the frequency of iron overload and iron deficiency in a group of employees and a group of outpatients. DESIGN: Prospective screening study. SETTING: Western Germany. PARTICIPANTS: 3012 asymptomatic employees and 3027 outpatients of nine practitioners. MEASUREMENTS: Serum ferritin levels and transferrin saturation were measured. Participants with repeatedly abnormal results had thorough clinical evaluations to identify the cause of iron deficiency or overload. RESULTS: Gross iron overload (elevated transferrin saturation and ferritin levels) was proven by liver biopsy and phlebotomy treatment in 28 participants (0.4% of female outpatients, 0.7% of male outpatients, 0.2% of female employees, and 0.4% of male employees) and in six siblings of these participants. Of the 34 participants with iron overload, 30 were precirrhotic. Because 60% of an unselected group of employees with elevated transferrin saturation but normal ferritin levels were assumed to have early hemochromatosis, the prevalence of hemochromatosis was estimated to be 1.8% among patients (1.9% in women and 1.6% in men) and 1.0% among employees (1.1% in women and 1.0% in men). Iron deficiency was found in 6.8% of female patients, 2.4% of male patients, 6.0% of female employees, and 0.5% of male employees. CONCLUSIONS: Iron deficiency was more common in women, and iron overload was more common in men. Among male employees, iron overload was almost as common as iron deficiency.
Adult↗
First long-term results of imiglucerase therapy of type 1 Gaucher disease.
BACKGROUND/AIMS: In the early 1990s, enzyme replacement therapy with modified placental glucocerebrosidase (alglucerase, Genzyme Corporation, Cambridge, MA, USA) was shown to arrest or reverse complications and to improve quality of life in patients with type 1 Gaucher's disease. More recently, modified recombinant glucocerebrosidase (imiglucerase, Genzyme Corporation) has been shown to be safe, effective and clinically equivalent to alglucerase by two studies which presented data for 12 months' follow-up. This case report, with 30 months' follow-up, represents the first publication of long-term results of imiglucerase therapy of type 1 Gaucher's disease in Europe. METHODS: Retrospective analysis of safety and efficacy of 30 months' imiglucerase infusions, 40 U/kg body weight every 2 weeks for 17 months, then 60 U/kg every 2 weeks for 13 months, in an elderly male patient with severe type 1 Gaucher's disease. RESULTS: No adverse reactions occurred, and anti-imiglucerase antibody assay was negative at 17 months. Clinically, the patient responded rapidly and markedly. Within several months, bone pain decreased notably, enabling him to abandon crutches. Abdominal pain abated, fatigue decreased and physical fitness and general well-being improved. Nosebleeds and haematomas ceased. Dosage increase massively reduced hepatosplenomegaly and produced much greater improvement in laboratory values, especially platelet count. Bone pain diminished further, so that this formerly disabled patient now walks and climbs stairs without complains. Also of note, aminotransferases, gamma-GT, total protein, and prothrombine time improved, suggesting improvement of liver function. CONCLUSIONS: This case documents long-term safety and efficacy of recombinant enzyme replacement in type 1 Gaucher's disease.
Adult↗
[Form of progression of chronic hepatitis C with viral coinfection and additional liver diseases].
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Flaviviridae↗
Prognosis of chronic hepatitis C: results of a large, prospective cohort study.
The prognosis of chronic hepatitis C virus (HCV) infection is still ill-defined. The present study prospectively evaluated mortality and complications in a large cohort of patients with chronic hepatitis C. The study included 838 anti-HCV and HCV-RNA-positive patients who were followed for 50.2 +/- 26.9 months (mean +/- SD; range, 6-122 months) in a prospective protocol. During follow-up, 62 patients died (31 from liver disease and 31 from other causes), and 12 patients needed liver transplantation. When compared with a matched general population, hepatitis C increased mortality mainly when cirrhosis was present and in patients who were less than 50 years old at study entry. During follow-up, a further 30 patients developed nonlethal complications of cirrhosis. By multivariate regression, survival was decreased by cirrhosis, long disease duration, history of intravenous drug abuse, and excessive alcohol consumption, whereas interferon therapy improved survival. Alanine transaminase (ALT), bilirubin, sex, and genotype had no effect on survival. The risk of hepatocellular carcinoma (HCC) (n = 17) was increased by cirrhosis and to a lesser degree by long disease duration and high bilirubin, whereas interferon therapy, genotype, and other factors had no effect. Chronic hepatitis C is a disease with considerable mortality and morbidity when cirrhosis is present at diagnosis. Patients who acquire the infection early in life have a markedly increased mortality even when cirrhosis is absent at diagnosis. The age at diagnosis therefore should play a major role in therapeutic considerations. The present data also suggest that interferon therapy has a long-term clinical benefit, although it did not reduce the risk of liver cancer.
Adult↗