Iron increases ethanol toxicity in rat liver

Clinical evidence indicates that patients with iron overload are more susceptible to liver cell damage from alcohol than persons with normal iron stores. Iron may act as a co-factor to catalyze the lipid peroxidation induced by hepatotoxic compounds such as alcohol. To elucidate the role of iron in ethanol-induced hepatocellular damage, we developed a new experimental model in the rat. Following dietary carbonyl iron feeding for 8 weeks, animals were pair-fed a liquid ethanol diet for 4 weeks. In iron-fed animals the liver iron content was 6.4 vs. 0.5 micrograms Fe/mg protein in the controls. Blood alcohol concentrations were similar in all ethanol-fed animals. Serum alanine aminotransferase (ALT) levels were elevated to 269 +/- 49 U/l in the iron+alcohol group compared to 52 +/- 6 U/l in the other groups. There was a strong correlation between ALT levels and hepatic iron content in the ethanol-fed animals. Morphologically, the alcohol-fed rats displayed hepatic steatosis, whereas occasional inflammation and iron in Kupffer cells was seen in the iron+alcohol animals. Ultrastructurally, necrotic hepatocytes and cells phagocytosed by Kupffer cells were only encountered in the iron+alcohol group. Compared to controls, the liver content of hydroxyproline was significantly increased in the iron+alcohol group. No morphological evidence of fibrosis was noted. The present study demonstrates biochemical and morphological evidence of increased hepatocellular damage following the combination of iron and ethanol.     

Prenatal cocaine, alcohol, and undernutrition differentially alter mineral and protein content in fetal rats

Alcohol exposure and undernutrition during pregnancy have been associated with altered fetal body composition. Recent observations suggest that cocaine exposure during pregnancy may impair delivery of nutrients to the fetus and could thereby alter body growth and composition. Such effects are important because they can adversely influence physical and neural development. Consequently, we investigated the dose-dependent effects of cocaine on fetal body composition in an animal (rat) model and compared such effects with those caused by prenatal alcohol exposure and undernutrition. Pregnant Sprague-Dawley rats received either 20, 30, 40, or 50 mg/kg cocaine HCl (SC) twice daily from gestation days 7 through 19. Pair-fed (undernutrition) and untreated control groups and a group receiving 3.0 g/kg alcohol (PO) twice daily served as comparison groups (n = 11 to 14/group). Females were sacrificed on gestation day 20. One male and one female fetus was removed from each dam. The fetuses were minced, dehydrated, defatted, and analyzed for content of protein and the minerals Zn, Ca, Fe, Mg, K, and Na. In terms of concentration per unit of fat-free dry solids, male fetuses in the cocaine groups showed significant decreases in protein compared to untreated controls (15+/-3 to 20+/-2 mg/g vs. 24+/-4 mg/g, p = 0.01). There was a significant treatment effect for Ca (p < 0.05), reflecting a trend for decreased Ca concentrations in the fetuses of the cocaine and undernutrition groups. Male fetuses in the alcohol group had significantly elevated Mg levels compared to male fetuses in the other groups (3.0+/-0.8 vs. 1.0+/-0.2 to 2.3+/-0.7 mg/g, p < 0.05). There were some sex differences, with female fetuses having significantly lower concentrations of Mg, Fe, K, and higher protein concentrations than male fetuses. Although the effects were few and modest, these results suggest that prenatal cocaine, alcohol, and undernutrition can differentially alter fetal body weight and composition and, therefore, adversely influence fetal development.     

Women, alcohol, and red cells

Alcohol abuse is known to increase erythrocyte mean cell volume mainly as a consequence of direct toxic effect on the developing red cell. The influence of alcohol on other red cell parameters is unclear. The objective of this cross-sectional survey was to examine the consequences of different alcohol amounts on red cell parameters among women. We compared red cell parameters between female alcoholics, heavy drinkers, and controls. Controls (n = 138) and heavy drinkers (n = 65) consisted of consecutive 40- and 45-year-old women participating in the health screening, and alcoholics (n = 73) of consecutive women coming to a detoxification clinic. Alcoholics had significantly smaller erythrocyte counts (p < 0.01), and higher erythrocyte mean cell volume values (p < 0.001), reticulocyte counts (p < 0.01), and red cell distribution width values (p < 0.001) than controls. No difference between these groups was found, however, in hemoglobin distribution width value. The only red cell difference between controls and heavy drinkers was erythrocyte mean cell volume, which was significantly higher among heavy drinkers (p < 0.001). In alcoholics, red cell distribution width values were even more often increased (in 44%) than erythrocyte mean cell volume values (in 34%). This increase in red cell distribution width was not solely explained by iron deficiency or liver disease. Chronic alcohol abuse not only affects erythrocyte mean cell volume values, but also leads to anisocytosis seen in blood count as an increased red cell distribution width value.     

Nonepileptic seizures and childhood sexual and physical abuse

Nonepileptic seizures (NES) must be distinguished from epilepsy to avoid the adverse effects of unnecessary antiepileptic drugs and to initiate appropriate psychiatric treatment. A higher frequency of prior sexual abuse has been suspected in NES, although no prospective controlled study has compared patients with NES and epilepsy. A series of patients with conversion disorder presenting as epilepsy and 140 patients with complex partial epilepsy (CPE) without evidence of conversion were selected from a series of consecutive admissions to a comprehensive epilepsy center. The groups did not differ with respect to age, years of education, race, or marital status, but the percentage of women was greater in the conversion NES group (73.2%) than in the CPE control group (50.7%; p < 0.002). The frequency of a history of sexual or physical abuse was greater in the NES group (32.4%) than in the CPE controls (8.6%; p < 0.000). Severity of sexual but not physical abuse was significantly greater in the NES group relative to controls (p < 0.05). There was a trend for a closer relationship of the perpetrator of sexual abuse to the victim among the NES patients compared with CPE controls (p < 0.1). These results support the impression that childhood abuse is more common among patients with conversion NES than with epilepsy, and suggests that in some cases childhood abuse may be a contributory pathogenetic factor.     

Optical activity of a nucleotide-sensitive tryptophan in myosin subfragment 1 during ATP hydrolysis

Male rats of the Wistar strain were divided 4 groups, and give a liquid diet of control feed, bezafibrate (150 mg/kg), ethanol, and ethanol plus bezafibrate for 5 week. The effect of bezafibrate supplementation on rats fed ethanol was examined in terms of the fatty acid composition of the phospholipids in the erythrocyte membrane. In the phospholipids profiles of erythrocyte membranes, PI was significantly decreased. The decrease in PI caused by bezafibrate appeared to substantially affect the membrane and consequently lead to changes in the membrane anchor. In the fatty acid composition of the PC, C20: 4 was significantly decreased in the group receiving alcohol (p < 0.05) but increased in the groups receiving bezafibrate (p < 0.05). In the fatty acid composition of the PE, C16: 0 was significantly increased in the three groups when compared with the control, and C20: 4 was decreased in the alcohol group (p < 0.05). In the fatty acid of SM and PI, C20: 4 was decreased and C18: 0 increased in the alcohol group. In the PS, C14: 0 was increased in the alcohol group, and decreased in the alcohol plus bezafibrate group (p < 0.01). The levels of arachidonic acid in the total fatty acids that constituted the membrane phospholipids were decreased in the rats given ethanol (p < 0.05). However, arachidonic acid in the group of bezafibrate supplementation on rats fed ethanol were elevated in comparison with the alcohol group (p < 0.05). With decreasing arachidonic acid as a marker of alcohol tissue injury following chronic alcohol intake, the effects of bezafibrate supplementation appear to contribute to membrane fluidity by altering the biochemical flexibility of the membrane.     

Cerebrospinal fluid levels of transition metals in patients with Parkinson's disease

We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 37 patients with Parkinson's disease (PD) and 37 matched controls. The CSF levels of zinc were significantly decreased in PD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between PD-patient and control groups. There was no influence of antiparkinsonian therapy on CSF levels of none of these transition metals. These values were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group, with the exception of CSF copper levels with the duration of the disease (r = 0.38, p < 0.05). These results suggest that low CSF zinc concentrations might be related with the risk for PD, although they could be related with oxidative stress processes.     

Heavy metal removal by microalgae

The liver is one of the principal sites of iron overload in diseases such as hemochromatosis and beta thalassemia. Hence, much effort has been invested in examining the mechanisms of Fe uptake by hepatocytes. In the present study we have examined the effect of small molecular weight (M(r)) Fe complexes on Fe uptake from iron 59-labeled transferrin (Tf) and 59Fe-labeled citrate by primary cultures of hepatocytes. This was important to assess because Fe-citrate and saturated diferric Tf coexist in the serum of patients with untreated Fe overload. Preincubation of hepatocytes with the low-M(r) Fe complex ferric ammonium citrate (FAC; 25 microg/mL; (Fe) = 4.4 microg/mL) followed by incubation with 59Fe-Tf or 59Fe-citrate ((Fe) = 0.25 to 25 micromol/L) resulted in the marked stimulation of 59Fe uptake. For example, at a physiologically relevant Tf-Fe concentration of 25 micromol/L, there was an 8-fold increase in 59Fe uptake by cells incubated with FAC compared to control cells. In contrast, at Tf-Fe concentrations of 0.25 to 2.5 micromol/L, 59Fe uptake in FAC-treated cells was only 1-fold to 3-fold greater than that in the corresponding controls. These data suggest that the FAC-activated Fe uptake process predominates at physiologically relevant Tf concentrations above the saturation of the Tf receptor (TfR). This is the first study to demonstrate that preincubation of hepatocytes with Iow-M(r)Fe complexes can markedly increase Fe uptake from diferric Tf. In conclusion, these results may help to explain the loading of hepatocytes with Fe that occurs in Fe-overload disease despite marked down-regulation of the TfR.     

Digital replantation in children: a long-term follow-up study

Symptoms of conduct disorder (CD), antisocial personality disorder (ASP), alcohol abuse, drug abuse, and somatization were tabulated for the families of 35 delinquent, substance-abusing (multiple-problem) adolescent male probands and 35 age-matched control males. Alcohol abuse, CD/ASP, and somatization were assessed with either the Diagnostic Interview Schedule (DIS) (for participants aged 18 and up) or the Diagnostic Interview for Children and Adolescents (DICA) (for participants aged 12 to 17). Drug abuse for all participants was assessed with the Substance Abuse Module (SAM) of the Comprehensive Interview for Diagnostic Evaluation (CIDE). As expected, proband groups had significantly more (p < .0001) CD/ASP, alcohol abuse, and drug abuse symptoms than control groups. A significant (p < .01) positive correlation among CD/ASP, alcohol abuse, and drug abuse was found for each group. Somatization was not differentially associated with proband status. It was concluded that identifying male multiple-problem youths also identifies families with a high incidence of similar problems.     

Iron-related indexes in chronic alcoholics. Effect of alcohol withdrawal

BACKGROUND: Increased serum transferrin saturation and ferritin levels have been reported in chronic alcoholics. AIM: To evaluate modifications in serum iron-related indexes in chronic alcohol abusers with and without cirrhosis, at enrolment and after complete alcohol withdrawal. PATIENTS: Fifty-one consecutive chronic alcohol abusers, 33 without and 18 with cirrhosis. METHODS: Liver function tests were performed and transferrin saturation percent and serum ferritin levels measured at time 0 and after 7 and 14 days of complete alcohol withdrawal. RESULTS: Duration of alcohol abuse was significantly longer in patients with cirrhosis than in those without (24 +/- 13 SD vs 18 +/- 13 SD years, p < 0.01). A concomitant increase in transferrin saturation percent and serum ferritin was found in 60% of the cirrhotics and 45% of the non cirrhotic group. During the observation period, transferrin saturation percent and serum ferritin fell significantly in both groups (from 59 +/- 33 SD to 36 +/- 22% SD, p < 0.05, and from 900 +/- 933 SD to 469 +/- 457 SD ng/ml, p < 0.01, in cirrhotics, and from 46 +/- 30 SD to 27 +/- 12% SD, p < 0.01, and from 702 +/- 602 SD to 340 +/- 29 SD ng/ml, p < 0.01, in non cirrhotics). CONCLUSIONS: Iron-related indexes increase with chronic alcohol abuse and return to normal rapidly after complete alcohol withdrawal. In chronic alcoholics the timing of determinations of iron-related indexes is crucial, and screening for possible concomitant genetic haemochromatosis must be postponed.     

Effects of chronic alcohol use and age on human lymphocyte protein kinase C activity

The effects of alcohol exposure on human peripheral circulating lymphocyte protein kinase C (PKC) activity were characterized in lymphocytes harvested from two sample groups. The first group (control) consisted of 30 nonalcoholic male subjects and the second group consisted of nine male subjects with chronic alcoholism. Alcoholic subjects were admitted for detoxification to a substance abuse unit located in a nonprofit community hospital. In this group of subjects, blood was sampled on admission for detoxification (pre-A), and after 5 days (post-A). Subjects received chlordiazepoxide for treatment of alcohol withdrawal symptoms. PKC activities measured in the control, pre-A, and post-A groups expressed as pmol/microgram/min +/- SEM were 5.09 +/- 0.50, 1.81 +/- 0.43, and 3.95 +/- 0.44. Control PKC was significantly higher than pre-A PKC (p < or = 0.05) and post-A PKC was significantly higher than pre-A PKC (p < or = 0.05). Total lymphocyte PKC activity was also found to be inversely related to age, expressed by the relationship log(PKC) = 0.870-0.005(Age), with R = 0.433.     

Blood-to-brain glucose transport and cerebral glucose metabolism are not reduced in poorly controlled type 1 diabetes

Clinical and epidemiological studies suggest that thiazide diuretics can prevent bone loss and decrease the incidence of hip fractures. However, the mechanism of the effect of diuretics on bone is not clearly established. Indapamide (IDP), a sulfonamide diuretic related to thiazides, is used to treat hypertension. Sixty spontaneously hypertensive rats (SHRs) were divided into four groups and treated with or without IDP (1.5 mg/kg/day) during 8 weeks in the presence or absence of a high sodium load (8% NaCl supplementation in the diet). Sodium and calcium excretions were increased in the rats receiving the high sodium load (SHR + 8% NaCl) comparatively with control rats (SHR). IDP decreased and increased, respectively, calcium and sodium excretions. Serum parathyroid hormone (PTH) was unchanged in any group. Bone density was measured at the femur, tibia, and vertebrae, and bone morphometry was performed at the metaphysis of the femur to evaluate bone architecture. Rats fed a high sodium diet had an average 5.5% decreased bone density at every site except the femoral diaphysis. The trabecular bone volume was also decreased (SHR + 8% NaCl vs. SHR, 11.99+/-0.78 vs. 17.51+/-1.5%, p < 0.05). An increase in trabecular separation suggested that these changes were due to increased bone resorption. In the SHR + 8% NaCl + IDP group, IDP increased bone density and trabecular bone volume (SHR + 8% NaCl + IDP vs. SHR + 8% NaCl, 16.52+/-1.04 vs. 11.99+/-0.78%, p < 0.05). Trabecular separation and pyridinoline/creatinine excretion (SHR + 8% NaCl + IDP vs. SHR + 8% NaCl, 136.39+/-9.62 vs. 195.18+/-22.34 nmol/mmol, p < 0.05) were also decreased by IDP. These results show that in rats receiving a high sodium diet, IDP can reverse sodium-induced bone loss and increased bone resorption independently of changes in serum PTH.     

Office and ambulatory blood pressure in patients with craniomandibular disorders

To assess the physiologic response to daily life stress in patients with craniomandibular disorders (CMD), office and ambulatory blood pressure and heart rate were studied in 25 female patients and 25 controls. Significant differences (p < 0.05) were found between the groups for heart rate before the clinical examination and that in the patient group when compared before and after the clinical examination. Higher values were found for mean daytime systolic and diastolic blood pressure in the control group compared with the patient group (p < 0.05). The mean number of systolic blood pressure > or = 140 mmHg during 24 h and daytime was significantly higher (p < 0.05) in the control group than in the patient group. In this study the CMD patients with muscular diagnosis were not more stressed than healthy subjects in the daily activities as evaluated by ambulatory blood pressure measurements.     

Oxidative damage to sarcoplasmic reticulum Ca2+-ATPase AT submicromolar iron concentrations: evidence for metal-catalyzed oxidation

The sarcoplasmic reticulum (SR) calcium ATPase carries out active Ca2+ pumping at the expense of ATP hydrolysis. We have previously described the inhibition of SR ATPase by oxidative stress induced by the Fenton reaction (Fe2+ + H2O2 --> HO. + HO- + Fe3+). Inhibition was not related to peroxidation of the SR membrane nor to oxidation of ATPase thiols, and involved fragmentation of the ATPase polypeptide chain. The present study aims at further characterizing the mechanism of inhibition of the Ca2+-ATPase by oxygen reactive species at Fe2+ concentrations possibly found in pathological conditions of iron overload. ATP hydrolysis by SR vesicles was inhibited in a dose-dependent manner by micromolar concentrations of Fe2+, H2O2, and ascorbate. Measuring the rate constants of inactivation (k inact) at different Fe2+ concentrations in the presence of saturating concentrations of H2O2 and ascorbate (100 microM each) revealed a saturation profile with half-maximal inactivation rate at ca. 2 microM Fe2+. Inhibition was not affected by addition of 200 microM Ca2+ to the medium, indicating that it was not related to iron binding to the high affinity Ca2+ binding sites in the ATPase. Furthermore, inhibition was not prevented by the water-soluble hydroxyl radical scavengers mannitol or dimethylsulfoxide, nor by butylated hydroxytoluene (a lipid peroxidation blocker) or dithiothreitol (DTT). However, when Cu2+ was used instead of Fe2+ in the Fenton reaction, ATPase inhibition could be prevented by DTT. We propose that functional impairment of the Ca2+-pump may be related to oxidative protein fragmentation mediated by site-specific Fe2+ binding at submicromolar or low micromolar concentrations, which may occur in pathological conditions of iron overload.     

Difference in acetylcholine-induced nitric oxide release of arterial and venous grafts in patients after coronary bypass operations

OBJECT: In this study the authors tested the hypothesis that hemorrhagic hypotension and high intracranial pressure induce an increase in cerebrovascular resistance that is caused by sympathetic compensatory mechanisms and can be modified by alpha-adrenergic blockade. METHODS: Continuous measurements of cerebral blood flow were obtained using laser Doppler microprobes placed in the cerebral cortex in anesthetized pigs during induced hemorrhagic hypotension and high cerebrospinal fluid pressure. Eight pigs received 2 mg/kg phentolamine in 10 ml saline, and 13 pigs served as control animals. During high intracranial pressure occurring after blood loss, cerebral perfusion pressure (CPP) (p < 0.01) and cerebral blood flow (p < 0.01) decreased in both groups. Cerebrovascular resistance increased (p < 0.05) in the control group and decreased (p < 0.005) in the phentolamine-treated group. The cerebrovascular resistance was significantly lower in the phentolamine-treated group (p < 0.05) than in the control group. Cerebrovascular resistance increased at lower CPPs in the control group (linear correlation, r = 0.39, p < 0.01) and decreased with decreasing CPP in the phentolamine-treated group (linear correlation, r = 0.76, p < 0.001). CONCLUSIONS: This study shows that the deleterious effects on cerebral hemodynamics induced by blood loss in combination with high intracranial pressure are inhibited by alpha-adrenergic blockade. This suggests that these responses are caused by alpha-adrenergically mediated cerebral vasoconstriction.     

Effect of iron overload and iron deficiency on atherosclerosis in the hypercholesterolemic rabbit

It has been suggested that iron plays an important role in the pathogenesis of atherosclerosis, primarily by acting as a catalyst for the atherogenic modification of LDL. Although some epidemiological data suggest that high stored iron levels are an independent risk factor for coronary artery disease and that iron has been detected in both early and advanced atherosclerotic lesions, the evidence is often contradictory and inconclusive. We used the New Zealand White rabbit to investigate the effects of iron overload (FeO) and iron deficiency (FeD) on atherosclerosis. Groups of 7 rabbits were either iron loaded by injections of iron dextran (FeO group), iron depleted by phlebotomy (FeD group), or given injections of saline (control group) for a total of 9 weeks. All rabbits were fed a chow diet containing 1% (wt/wt) cholesterol for the last 6 weeks of the study. Iron and antioxidant status and cholesterol levels were assayed in plasma before cholesterol feeding (week 3) and at the time that the rabbits were killed (week 9). In addition, the susceptibility of LDL to oxidation was measured and pathological examination of the aortic arch and thoracic aorta performed at the end of the study. FeD significantly decreased the levels of blood hemoglobin, serum iron, and transferrin saturation compared with controls. Conversely, FeO significantly increased transferrin Fe saturation. FeO but not FeD decreased plasma cholesterol levels compared with control animals both before (P < .05) and after (P = .055) cholesterol feeding. Neither FeO nor FeD had a significant effect on the levels of antioxidants and lipid peroxidation products in plasma and aortic tissue or on the susceptibility of LDL to ex-vivo oxidation. FeO significantly decreased aortic arch lesion formation by 56% compared with controls (P < .05), whereas FeD had no significant effect. These results indicate that in this animal model, FeO decreases rather than increases atherosclerosis, likely because iron dextran exerts a hypocholesterolemic effect. Our data do not support the hypotheses that elevation of Fe stores increases or that a reduction of Fe stores by phlebotomy decreases the risk of coronary artery disease.     

Incremental iron overload during reperfusion progressively augments oxidative injury

OBJECTIVE: To determine if a relationship exists between the extent of iron-catalyzed injury and the degree of tissue iron overload during reperfusion. METHODS: To selectively increase tissue iron only during early reperfusion, isolated, buffer perfused rabbit hearts were exposed to 20 microM Fe(2+)-100 microM ADP during the last 3 minutes of ischemia and the initial 4 minutes of reperfusion. Control groups were exposed to ADP and iron-ADP regimens that did not increase intracellular iron. All the hearts received 30 minutes of normothermic global ischemia and 30 minutes of reperfusion. Heart function was monitored continuously throughout each experiment. Tissue iron and biochemical markers were analyzed at the end of experiments. RESULTS: Hemodynamic recovery was decreased and tissue lipid peroxide levels were increased in the 20 microM Fe(2+)-100 microM ADP group compared to controls. The recoveries of developed pressure and positive/negative dP/dT at 30 minutes of reperfusion were negatively correlated with tissue iron levels, while cytosol and membrane lipid peroxide levels correlated positively with the iron levels during reperfusion. CONCLUSION: The extent of oxidative injury during reperfusion was directly related to the tissue iron burden present during reperfusion. Increased lipid peroxidation was the principal chemical marker of iron-catalyzed injury.     

HCV and diabetes mellitus: evidence for a negative association

OBJECTIVE: Uncontrolled, retrospective clinical studies have recently claimed that HCV infection could trigger the onset of diabetes mellitus (DM). We sought to verify the association between DM and liver diseases of different etiology, stage, and severity in a prospective study including gender- and age-matched controls. METHODS: Two hundred forty-seven patients with liver cirrhosis (184 men, 116 with an associated hepatocellular carcinoma, 34% in Child-Pugh's class A) were evaluated (group 1). One hundred fifty-seven (63.5) of them were HCV positive, 38 (15.5%) HBV positive, 49 (19.8%) alcohol abusers, and three (1.2%) cryptogenic. Two control groups were also included. The first control group consisted of 138 patients with chronic hepatitis due to HCV infection (73.9%), HBV infection (15.9%), or alcohol abuse (10.2%) (group 2). The second control group included 494 patients with an acute osteoarticular trauma, age- and gender-matched with patients in group 1 (group 3). RESULTS: Diabetes mellitus was present in 32.3%, 3.6%, and 9.7% of patients in groups 1, 2, and 3, respectively. When compared with controls (group 3), DM was significantly less frequent in group 2 (p < 0.004) and significantly more frequent in group 1 (p < 0.0001). The prevalence of DM was not different among patients with HCV, HBV infection, or alcohol abuse. In group 3, the prevalence of DM appeared to increase steadily with age. On the contrary, in patients with liver cirrhosis (group 1) DM was detected in about 20-30% of cases in all decades of age. In group 2, diabetics were found only in the 7th and 8th decades of life. At multivariate analysis cirrhosis and age were the only two factors independently associated with DM; odds ratios were 12.5 (95% confidence interval [C.I.], 6.74-20.4) for cirrhosis, and 1.47 for age (95% C.I. 0.39-2.55). CONCLUSIONS: Our findings disprove HCV infection as a trigger factor for DM, which should not be listed among the various extrahepatic manifestations of this viral infection.     

Correlation between soluble transferrin receptor and serum ferritin levels following bone marrow transplantation for thalassemia

This study analyzes the serum transferrin receptor (sTfR) levels in a series of 230 ex-thalassemics with a follow-up of 1 to 9 years after bone marrow transplantation (BMT) for homozygous beta thalassemia. Ex-thalassemics are individuals, cured of homozygous beta thalassemia by BMT, who maintain different degrees of iron overload acquired during the pretransplant period. Both in experimental and clinical conditions, sTfR concentrations have been shown to be a quantitative measure of body iron status. This study was carried out to assess whether the level of sTfR may be of help in determining the extent of iron overload in ex-thalassemics. Patients who received the marrow from their HLA-identical sibling donor heterozygous for beta thalassemia, namely heterozygous ex-thalassemics, displayed significantly higher levels of sTfR than patients transplanted from their normal sibling donors (normal ex-thalassemics). This finding suggests that increased erythropoiesis, albeit in part ineffective in heterozygous ex-thalassemics, is responsible for the sTfR increment. Both heterozygous and normal ex-thalassemics had significant lower sTfR levels than their heterozygous (p < 0.003) or normal (p < 0.0001) donors, respectively. These differences may be ascribed to the presence of iron overload in ex-thalassemics in comparison to their normal or heterozygous donors who did not present excess of iron in the body. A significant inverse correlation between sTfR and serum ferritin levels (r = -0.54, p < 0.0001) was found when normal ex-thalassemics were considered. In heterozygous ex-thalassemics, the lack of correlation between these two parameters may be explained by the enhanced erythropoietic activity of individuals with thalassemic trait. These results suggest that the level of sTfR may be a useful indicator of iron overload in normal ex-thalassemics.     

A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anaemia in haemodialysis patients with iron overload

BACKGROUND: Functional iron deficiency may develop and cause erythropoietin resistance in haemodialysis patients with iron overload. Controversy remains as to whether intravenous iron medication can improve this hyporesponsiveness due to decreased iron availability, or whether iron therapy will aggravate haemosiderosis. Intravenous administration of ascorbic acid has been shown to effectively circumvent resistant anaemia associated with iron overload in a small preliminary study. To elucidate further the possible mechanisms of this resistance, a parallel, comparative study was conducted to compare the effects of intravenous iron and ascorbate therapies in iron-overloaded haemodialysis patients. METHODS: Fifty haemodialysis patients with serum ferritin of > 500 microg/l were randomly divided into two protocols. They were further stratified into controls (Control I, n = 11) and intravenous iron group (IVFE, n = 15) in protocol I; and into controls (Control II, n = 12) and intravenous ascorbic acid group (IVAA, n = 12) in protocol II. Controls had a haematocrit of > 30% and did not receive any adjuvant therapy. IVFE and IVAA patients were hyporesponsive to erythropoietin and functionally iron deficient. Ferric saccharate (100 mg dose) was administered intravenously postdialysis on five consecutive dialysis sessions in the first 2 weeks; and ascorbic acid (300 mg dose) thrice a week for 8 weeks. Red cell and iron metabolism indices were examined before and following therapy. RESULTS: Mean values of haematocrit and transferrin saturation were significantly lower, and erythropoietin dose was higher in IVFE and IVAA patients compared to controls. Intravenous iron therapy neither improved erythropoiesis nor reduced erythropoietin dose during 12 weeks. Iron metabolism indices significantly increased at 2 and 6 weeks, but decreased at 12 weeks returning to the baselines. In contrast, mean haematocrit significantly increased from 25.8+/-0.5 to 30.6+/-0.6% with a concomitant reduction of 20% in erythropoietin dose after 8 weeks of ascorbate therapy. Serum ferritin modestly fell but with no statistical significance. The enhanced erythropoiesis paralleled a rise in transferrin saturation from 27+/-3 to 48+/-6% and serum iron from 70+/-11 to 107+/-19 microg/dl (P<0.05). CONCLUSIONS: Short term intravenous iron therapy cannot resolve the issue of functional iron deficiency in haemodialysis patients with iron overload. Intravenous administration of ascorbic acid not only facilitates iron release from storage sites, but also increases iron utilization in the erythron. Our study draws attention to a potential adjuvant therapy, intravenous ascorbic acid, to treat erythropoietin-hyporesponsive anaemia in iron-overloaded patients.     

Detection of human herpesvirus 8 DNA in Kaposi''s sarcoma lesions and peripheral blood of human immunodeficiency virus-positive patients and correlation with serologic measurements

PURPOSE: We reviewed our experience with a clinical pathway instituted in December 1993 for all nonurgent abdominal aortic aneurysm (AAA) surgery. METHODS: We analyzed a reference group of 49 consecutive pre-pathway AAA patients (group I) and the 44 patients enrolled in the first year of the pathway (group II). On the basis of the interim review of data collected during the first year, pathway modifications were made, and 34 patients enrolled after these modifications (group III) were also analyzed. RESULTS: Comparison of groups I and II showed that institution of the pathway resulted in a marginally significant reduction in mean charges of 14.7% (p = 0.09), and a slight fall in mean length of stay (LOS) (13.8 vs 13.1 days, NS) and mortality rate (4.1% vs 2.3%, NS). For group II, a significant correlate (p < 0.05) of increased charges was fluid overload as diagnosed by chest radiograph. This recognition led to active efforts to reduce perioperative fluid administration. Comparison of groups II and III revealed that the practice modifications led to marked reduction in the incidence of fluid overload (73% vs 24%; p < 0.01), mean charges (30.4% reduction; p < 0.05), mean LOS (13.1 vs 10.2 days; p < 0.05), and median LOS (11 vs 8 days). Multiple regression analysis of all pathway patients showed that preoperative renal insufficiency is a significant predictor of both increased LOS (p < 0.01) and charges (p < 0.01), but that age, sex, and coronary disease were not predictive. Of the postoperative parameters analyzed, important correlates of increased charges were acute renal failure (p < 0.01) and fluid overload (p < 0.01). CONCLUSIONS: Institution of a clinical pathway for AAA repair resulted in significant charge reduction and a slight reduction in stay. Practice modifications based on interim data analysis yielded further significant reductions in charges and LOS, with overall per-patient charge savings (group I vs III) of 40.6% (p < 0.05) and overall LOS reduction of 3.5 days (p < 0.05). The reduction in actual charges was seen despite an overall increase in the hospital rate structure. Comparing groups I, II, and III, we found no indication of increasing mortality rate. Ongoing analysis has identified correlates of increased charges, potentially permitting identification of high-cost subgroups and more focused cost-control efforts. Rather than restricting management, clinical pathways with periodic data analysis may improve quality of care.