RESUMEN
Hemochromatosis has often been associated with progressive iron overload, but the natural history of iron accumulation in untreated C282Y homozygotes has been reported infrequently. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101 168 primary care participants for iron overload using transferrin saturation, unbound iron-binding capacity, Serum ferritin (SF), and HFE C282Y and H63D genotyping. SF was measured at initial screening (IS) and again when selected participants returned for a clinical examination (CE). The change in SF over the observation period (defined as ferritin rate of change) was analyzed according to age, gender, initial SF, initial SF/age, transferrin saturation, and iron removed by phlebotomy in C282Y homozygotes. Seventy-four male and 133 female untreated C282Y homozygotes were observed over a median of 112 days (34-924 days) between IS and CE. In men, SF increased in 54% and decreased in 46%. In women, SF increased in 50% and decreased in 50%. The significant variables affecting the SF rate were initial log SF (P = 0.0027) and transferrin saturation (P < 0.0001). Male C282Y homozygotes with higher SF rates (n = 27, upper 50th percentile) had significantly greater iron removed by phlebotomy (mean 4.93 g, range 1.0-17 g) than those with lower SF rates (n = 26, lower 50th percentile) (mean 2.6 g, 0.42-7.1, P < 0.05). SF was as likely to decrease as increase in untreated C282Y homozygotes over this relatively brief observation period. Incremental increases in SF are not inevitable in untreated C282Y homozygotes.
Asunto(s)
Ferritinas/sangre , Hemocromatosis/sangre , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Proteína de la Hemocromatosis , Homocigoto , Humanos , Hierro/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Iron overload phenotypes in persons with and without hemochromatosis are variable. To investigate this further, probands with hemochromatosis or evidence of elevated iron stores and their family members were recruited for a genome-wide linkage scan to identify potential quantitative trait loci (QTL) that contribute to variation in transferrin saturation (TS), unsaturated iron-binding capacity (UIBC), and serum ferritin (SF). Genotyping utilized 402 microsatellite markers with average spacing of 9 cM. A total of 943 individuals, 64% Caucasian, were evaluated from 174 families. After adjusting for age, gender, and race/ethnicity, there was evidence for linkage of UIBC to chromosome 4q logarithm of the odds (LOD) = 2.08, p = 0.001) and of UIBC (LOD = 9.52), TS (LOD = 4.78), and SF (LOD = 2.75) to the chromosome 6p region containing HFE (each p < 0.0001). After adjustments for HFE genotype and other covariates, there was evidence of linkage of SF to chromosome 16p (LOD = 2.63, p = 0.0007) and of UIBC to chromosome 5q (LOD = 2.12, p = 0.002) and to chromosome 17q (LOD = 2.19, p = 0.002). We conclude that these regions should be considered for fine mapping studies to identify QTL that contribute to variation in SF and UIBC.
Asunto(s)
Pruebas Genéticas/métodos , Genoma Humano , Hemocromatosis/genética , Hierro/metabolismo , Sitios de Carácter Cuantitativo , Adulto , Negro o Afroamericano/genética , Anciano , Pueblo Asiatico/genética , Femenino , Frecuencia de los Genes , Genotipo , Hemocromatosis/etnología , Hemocromatosis/prevención & control , Proteína de la Hemocromatosis , Hispánicos o Latinos/genética , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Indígenas Norteamericanos/genética , Hierro/sangre , Escala de Lod , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Fenotipo , Población Blanca/genéticaRESUMEN
INTRODUCTION: The delay of several days between an erythropoietic stimulus and the subsequent increase in intestinal iron absorption is commonly believed to represent the time required for body signals to programme the immature crypt enterocytes and for these cells to migrate to the villus. Recent data however suggest that signals from the body to alter absorption are mediated by circulating hepcidin and that this peptide exerts its effect on mature villus enterocytes. METHODS: We have examined the delay in the absorptive response following stimulated erythropoiesis using phenylhydrazine induced haemolysis and correlated this with expression of hepcidin in the liver and iron transporters in the duodenum. RESULTS: There was a delay of four days following haemolysis before a significant increase in iron absorption was observed. Hepatic hepcidin expression did not decrease until day 3, reaching almost undetectable levels by days 4 and 5. This coincided with the increase in duodenal expression of divalent metal transporter 1, duodenal cytochrome b, and Ireg1. CONCLUSION: These results suggest that the delayed increase in iron absorption following stimulated erythropoiesis is attributable to a lag in the hepcidin response rather than crypt programming, and are consistent with a direct effect of the hepcidin pathway on mature villus enterocytes.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Eritropoyesis/fisiología , Absorción Intestinal/fisiología , Hierro/metabolismo , Análisis de Varianza , Animales , Regulación de la Expresión Génica/fisiología , Hemólisis/efectos de los fármacos , Hemólisis/fisiología , Hepcidinas , Hígado/metabolismo , Masculino , Fenilhidrazinas/farmacología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Transferrina/metabolismoRESUMEN
In previous analyses of transferrin saturation data in African Americans and Caucasians from the second National Health and Nutrition Examination Survey (NHANES II), subpopulations were found consistent with population genetics for common loci that influence iron metabolism. The goal of this new study was to determine if these transferrin saturation subpopulations have different levels of iron stores. Statistical mixture modeling was applied to transferrin saturation data for African Americans and Caucasians from the third National Health and Nutrition Examination Survey (NHANES III), and then the mean serum ferritin concentrations were determined for the transferrin saturation subpopulations that were identified. After adjustment for diurnal variation, 3 subpopulations of transferrin saturation were identified in each racial group. Satisfying Hardy-Weinberg conditions for major locus effects, in both racial groups the sum of the square roots of the proportion with the lowest mean transferrin saturation and the proportion with the highest mean transferrin saturation was approximately 1. When weighted to reflect the US adult population as a whole, these subpopulations of increasing transferrin saturations had progressively increasing mean age-adjusted serum ferritin concentration values in each ethnic grouping as stratified by sex (trend test, P <.002 for all). These results are consistent with the concept that population transferrin saturation subpopulations reflect different levels of storage iron.
Asunto(s)
Ferritinas/sangre , Encuestas Epidemiológicas , Hierro/sangre , Transferrina/metabolismo , Adulto , Población Negra , Ritmo Circadiano , Femenino , Ferritinas/genética , Frecuencia de los Genes , Antígenos de Superficie de la Hepatitis B/sangre , Anticuerpos contra la Hepatitis C/sangre , Humanos , Pruebas de Función Hepática , Masculino , Selección de Paciente , Factores Sexuales , Transferrina/genética , Estados Unidos , Población BlancaRESUMEN
Automated storage and analysis of the results of serial haematologic studies are now technically feasible with present-day laboratory instruments and devices for data storage and processing. In current practice, physicians mentally compare a laboratory result with previous values and use their clinical judgement to determine the significance of any change. To provide a statistical basis for this process, we describe a new approach for the detection of changes in patient-specific sequential measurements of standard haematologic laboratory tests. These methods include hierarchical multiple regression modelling, with a weighted minimum risk criteria for model selection, to choose models indicating changes in mean values over time. This study is the first to analyse sequential patient-specific distributions of laboratory measurements, utilizing mixture distribution modelling with systematic selection of starting values for the EM algorithm. To evaluate these statistical methods under controlled conditions, we studied 11 healthy human volunteers who were depleted of iron by serial phlebotomy to iron-deficiency anaemia, then treated with oral iron supplements to replete iron stores and correct the anaemia. Application of sequential patient-specific analyses of haemoglobin, haematocrit, and mean cell volume showed that significant departures from past values could be identified, in many cases, even when values were still within the population reference ranges. Additionally, for all subjects sequential alterations in red blood cell volume distributions during development of iron-deficiency anaemia could be characterized and quantified. These methods promise to provide more sensitive techniques for improved diagnostic evaluation of developing anaemia and serial monitoring of response to therapy.
Asunto(s)
Pruebas Hematológicas , Modelos Lineales , Distribuciones Estadísticas , Administración Oral , Algoritmos , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/tratamiento farmacológico , Recuento de Células Sanguíneas , Índices de Eritrocitos , Femenino , Hematócrito , Humanos , Hierro/administración & dosificación , MasculinoRESUMEN
Interest in including screening for hemochromatosis in the routine medical care of adults has grown in recent years. In March 1997, at a meeting on iron overload at the Centers for Disease Control and Prevention, the directors of four hemochromatosis screening programs described the major challenges that they faced and the lessons that they learned in implementing their programs. Seven issues were consistently described as important challenges: 1) changes in case definitions of hemochromatosis, 2) selection of screening threshold values and identification of false-positive cases, 3) variability and lack of standardization in screening test measurements, 4) physician education, 5) informed consent and concerns about medical and genetic discrimination, 6) patient compliance with screening and therapy, and 7) incidental detection of iron deficiency. The two programs that have been completed report a prevalence of iron overload from hemochromatosis of 4.2 to 4.5 per 1000 persons screened; this is consistent with findings in the recent literature. All programs report that screening is feasible and propose that hemochromatosis be defined by repeated elevated serum transferrin saturation values(with or without DNA test results) rather than by the clinical outcome of excessive iron in tissue. The goal of screening programs is to diagnose iron status disorders, particularly hemochromatosis, before they lead to iron overload and chronic disease states. Further research is needed on the ability of genetic and phenotypic tests to predict the clinical expression of hemochromatosis. The experiences outlined in this report highlight practical issues that need to be addressed when iron status screening for hemochromatosis is implemented. It is hoped that this information will facilitate similar efforts in other health care settings.
Asunto(s)
Hemocromatosis/diagnóstico , Tamizaje Masivo , Atención Primaria de Salud , Adulto , Biomarcadores/sangre , Educación Médica Continua , Reacciones Falso Positivas , Hemocromatosis/genética , Humanos , Consentimiento Informado , Cooperación del Paciente , Valor Predictivo de las Pruebas , Transferrina/análisisRESUMEN
The sex-linked anemic (sla) mouse carries an anemia that results from an inherited defect of intestinal iron absorption and provides an ideal model with which to investigate this poorly understood yet clinically important process. We have precisely mapped the sla locus within the central region of the X chromosome in relation to a panel of microsatellite markers. Analysis of over 500 progeny from an intraspecific intercross and a smaller intraspecific backcross segregating sla established the following locus order in the sla region: DXMit45-sla- (DXMit16, DXMit96)-DXMit41-DXMit169-DXMit170- DXMit148-(DXMit18, DXMit171)-DXMit84-DXMit64. The two microsatellites DXMit16 and DXMit96 are located 0.60 +/- 0.35cM from sla and form the telomeric limit of the sla region. The mapping of the sla locus is an important first step to identifying the gene itself.
Asunto(s)
Anemia Ferropénica/genética , Ligamiento Genético , Mucosa Intestinal/metabolismo , Hierro/metabolismo , Cromosoma X , Anemia Ferropénica/metabolismo , Animales , Mapeo Cromosómico , ADN Satélite , Modelos Animales de Enfermedad , Marcadores Genéticos , Ratones , Ratones Endogámicos C57BL , FenotipoRESUMEN
BACKGROUND & AIMS: An elevated transferrin saturation is the earliest phenotypic abnormality in hereditary hemochromatosis. Determination of transferrin saturation remains the most useful noninvasive screening test for affected individuals, but there is debate as to the appropriate screening level. The aims of this study were to estimate the mean transferrin saturation in hemochromatosis heterozygotes and normal individuals and to evaluate potential transferrin saturation screening levels. METHODS: Statistical mixture modeling was applied to data from a survey of asymptomatic Australians to estimate the mean transferrin saturation in hemochromatosis heterozygotes and normal individuals. To evaluate potential transferrin saturation screening levels, modeling results were compared with data from identified hemochromatosis heterozygotes and homozygotes. RESULTS: After removal of hemochromatosis homozygotes, two populations of transferrin saturation were identified in asymptomatic Australians (P < 0.01). In men, 88.2% of the truncated sample had a lower mean transferrin saturation of 24.1%, whereas 11.8% had an increased mean transferrin saturation of 37.3%. Similar results were found in women. A transferrin saturation threshold of 45% identified 98% of homozygotes without misidentifying any normal individuals. CONCLUSIONS: The results confirm that hemochromatosis heterozygotes form a distinct transferrin saturation subpopulation and support the use of transferrin saturation as an inexpensive screening test for hemochromatosis. In practice, a fasting transferrin saturation of > or = 45% identifies virtually all affected homozygous subjects without necessitating further investigation of unaffected normal individuals.
Asunto(s)
Hemocromatosis/diagnóstico , Transferrina/metabolismo , Adulto , Anciano , Femenino , Hemocromatosis/genética , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana EdadRESUMEN
From a global perspective, severe systemic iron overload occurs predominantly in individuals affected by geographically specific genetic mutations that permit the daily absorption from the diet of more iron than is physiologically needed. Two main types of hereditary iron overload are well recognized: (1) HLA-linked hemochromatosis in populations derived from Europe and (2) iron overload complicating thalassaemia major and intermedia syndromes in Southeast Asia, the Middle East, and the Mediterranean. Another very common form of iron overload occurs in Africa and is clearly related to high dietary iron content; recent evidence suggests that a genetic predisposition may also contribute to the pathogenesis. Patients with iron overload may develop multiorgan system toxicity; aggressive therapy with phlebotomy or iron chelation to remove excess iron from the body prevents organ damage and prolongs life.
Asunto(s)
Hierro/metabolismo , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/terapia , Animales , Transporte Biológico , Salud Global , Humanos , Absorción Intestinal , Enfermedades Metabólicas/complicaciones , Prevalencia , Distribución TisularRESUMEN
Brain metastasis from transitional cell carcinoma of the bladder is unusual, occurring most often in the presence of widespread systemic metastases. We report on a patient who presented with an isolated cerebellar metastasis and recurrent carcinoma of the bladder, after treatment with local excision and intravesical thiotepa. Further evaluation failed to demonstrate other distant metastases. Excision of the cerebellar lesion revealed transitional cell carcinoma identical to the original bladder tumor. In a review of the literature, we found reports of two similar patients in whom a solitary cerebellar lesion was the first sign of metastasis from carcinoma of the bladder; neither patient had evidence of other distant metastases, and neither previously had received systemic chemotherapy. These observations indicate that central nervous system metastasis from carcinoma of the bladder, while rare, should be considered in the differential diagnosis of solitary intracerebellar lesions in such patients.
Asunto(s)
Carcinoma de Células Transicionales/secundario , Neoplasias Cerebelosas/secundario , Neoplasias de la Vejiga Urinaria/patología , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/terapia , Femenino , Humanos , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
In hereditary hemochromatosis (HH), increased intestinal iron absorption leads to the development of iron overload. To examine the abnormal regulation of iron absorption in this disorder, we analyzed mucosal iron kinetics in six patients with HH and in five normal subjects by using a compartmental model of intestinal iron absorption and systemic ferrokinetics. Subjects were given simultaneous oral and intravenous tracer doses of iron 59-labeled citrate and iron 55-labeled transferrin, respectively. Plasma and whole-body radioactive iron levels were then monitored serially during the next 2 weeks, and mucosal iron transport rate constants were estimated by non-linear least-squares fit of the model to these data. Iron absorption was inversely related to serum ferritin concentration in both normal subjects and patients with HH but was higher in relation to serum ferritin level among the latter (p less than 0.0002). Analysis of mucosal iron kinetics demonstrated a similar inverse relationship between the rate constant for mucosal iron uptake and serum ferritin among all subjects combined, but the mean uptake rate constant in patients with HH did not differ from that of normal subjects (p = 0.71). The mean rate constant for incorporation of iron into the mucosal storage pool in patients with HH also was comparable to that of normal subjects (p = 0.94). In contrast, the rate constant for transfer of mucosal iron to the plasma was higher in patients with HH than in normal subjects for any given serum ferritin level (p less than 0.0001), and the transfer rate constant accounted for 87% of the variability in iron absorption among all subjects. We conclude that the increased iron absorption in HH is mediated primarily by an increase in the rate constant for transfer of mucosal iron to the plasma.
Asunto(s)
Hemocromatosis/metabolismo , Mucosa Intestinal/metabolismo , Hierro/metabolismo , Ferritinas/sangre , Hemocromatosis/genética , Humanos , Absorción Intestinal , Hierro/sangre , Hierro/farmacocinéticaRESUMEN
The quantity and distribution of body iron normally vary little over time. This homeostasis is maintained primarily through control of intestinal iron absorption, but the mechanism of this regulation is unclear. Modern techniques for computer simulation and numerical analysis now make it possible to study the kinetics of iron absorption in vivo. We used a physiologically based mathematical model of iron metabolism to analyze tracer iron kinetics in normal and iron-deficient beagles. The model provides characteristic information about both intestinal and systemic iron exchange, thus permitting formulation of an hypothesis that may explain the regulation of iron absorption under these conditions. The results indicate that control of iron absorption is a function of independent expression of iron requirements by each tissue, including the intestinal mucosa. This hypothesis is consistent with other in vivo and in vitro observations in iron deficiency and may have implications for understanding the mechanism of the altered iron absorption in other disorders of iron metabolism.
Asunto(s)
Computadores , Absorción Intestinal , Hierro/metabolismo , Modelos Biológicos , Animales , Perros , Homeostasis , Mucosa Intestinal/metabolismo , Deficiencias de Hierro , Cinética , MasculinoRESUMEN
The role of haemodynamic factors in the pathogenesis of cerebral infarction is unclear. Watershed or distal field infarction is most often caused by haemodynamic mechanisms. Watershed cerebral infarcts can now be identified in stroke survivors using CT scanning. The clinical findings are presented of 14 patients with cerebral infarction in whom haemodynamic factors contributed to the stroke. Evidence for this diagnosis includes (i) a history of posture-related or exercise-induced syncopal attacks or neurological deficits before and in some cases after the stroke, (ii) the demonstration of watershed or distal field infarction on CT scan, (iii) commencement of symptoms after increase in antihypertensive medications, and (iv) improvement following reduction of treatment. Regional cerebral hypoperfusion may be a more common cause of cerebral infarction than is generally thought. Particular care should be exercised when potent antihypertensive medication is prescribed for elderly hypertensive patients.
Asunto(s)
Infarto Cerebral/fisiopatología , Circulación Cerebrovascular , Hemodinámica , Hipertensión/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Angiografía Cerebral , Circulación Cerebrovascular/efectos de los fármacos , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Hipotensión Ortostática/fisiopatología , Ataque Isquémico Transitorio/fisiopatología , Masculino , Persona de Mediana Edad , Postura , Tomografía Computarizada por Rayos XRESUMEN
Hypothesizing that any effect of an increased serum iron and transferrin saturation on the risk of bacterial infection would be particularly important in immunosuppressed patients, we reexamined the effect of hyperferremia on bacterial growth in vitro and studied the pattern and prevalence of hyperferremia in patients receiving treatment for acute nonlymphocytic leukemia (ANLL). Growth of inocula of Escherichia coli and Staphylococcus aureus was significantly greater (1.3- to 5.8-fold) in fresh or heat-inactivated sera obtained from 10 healthy volunteers 3 hours after oral ingestion of ferrous sulfate (mean +/- SEM transferrin saturation 95% +/- 3%) than before (transferrin saturation 34% +/- 10%). Similarly, in heat-inactivated serum samples obtained from six patients with various malignancies, growth of E. coli was significantly greater (2.3- to 5.5-fold) with the elevated transferrin saturation (97% +/- 3%) present 1 to 7 days after receiving chemotherapy than with the normal transferrin saturation (33% +/- 9%) present before. In a prospective evaluation of serial serum iron studies in 12 patients receiving treatment for ANLL, five patients had normal serum iron concentrations initially, but in each patient the transferrin saturation was elevated after receiving chemotherapy, usually to greater than 90% for greater than 15 days in conjunction with prolonged, profound granulocytopenia and fever.
Asunto(s)
Infecciones Bacterianas/etiología , Tolerancia Inmunológica , Hierro/sangre , Leucemia/sangre , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Escherichia coli/crecimiento & desarrollo , Femenino , Humanos , Interleucina-1/biosíntesis , Leucemia/tratamiento farmacológico , Leucemia/inmunología , Masculino , Persona de Mediana Edad , Riesgo , Staphylococcus aureus/crecimiento & desarrollo , Transferrina/análisisRESUMEN
Absorption of dietary iron requires uptake of iron by the brush border of the intestinal epithelial cells, intracellular transport, and transfer to the systemic circulation. In iron-deficiency anemia, iron absorption is greatly increased, but the individual steps responsible for this increase have not been identified. We have developed a method to evaluate the rate constants for each of these steps, and we report here our results in beagle dogs a) under normal conditions and b) after phlebotomy to produce iron-deficiency anemia. Simultaneous administration of oral 59Fe3+-citrate and intravenous 55Fe-transferrin was used to investigate the kinetics of mucosal iron transport. Plasma levels of both isotopes and the whole-body excretion pattern of 59Fe were monitored sequentially, and the fractional mucosal transport rates were estimated by nonlinear least-squares fit of a physiologically based mathematical model to these data. Under normal conditions the fractional rate of mucosal iron uptake from the intestinal lumen was rate limiting, being less than 1% of the fractional rate of either iron incorporation into the mucosal storage pool or transfer of iron from the mucosa to the plasma. After induction of iron-deficiency anemia, the fractional mucosal iron uptake rate increased sixfold (P less than 0.005), while the rate of incorporation into the mucosal storage pool decreased ninefold (P less than 0.02); in contrast, the fractional rate of iron transfer to the plasma did not change. These results indicate that the enhanced iron absorption in iron-deficiency anemia is attributable to an increase in mucosal iron available for transfer to the plasma, leading in turn to a net increase in iron absorption, despite a normal fractional transfer rate.
Asunto(s)
Anemia Hipocrómica/metabolismo , Mucosa Intestinal/metabolismo , Hierro/metabolismo , Anemia Hipocrómica/sangre , Animales , Volumen Sanguíneo , Perros , Hematócrito , Hemoglobinas/análisis , Absorción Intestinal , Hierro/sangre , Masculino , Modelos Biológicos , Volumen PlasmáticoRESUMEN
Hereditary hemochromatosis is an autosomal recessive disease in which the gene is linked to the HLA system. Investigation of nine unrelated probands and their family members has revealed distinct groups based on biochemical and clinical manifestations of the disease. Four different types of disease expression were identified: Group I--classic hereditary hemochromatosis with elevated transferrin saturation, serum ferritin levels, and liver iron content; Group II--severe iron overload, accelerated disease manifesting at an early age; Group III--elevated total body iron stores, normal transferrin saturation and serum ferritin levels; Group IV--markedly elevated findings on serum biochemical tests, e.g., transferrin saturation, serum ferritin levels, with minimal elevation in total body iron stores. This evidence for several clearly distinguishable modes of expression in different families suggests that more than one genetic lesion in iron metabolism may be responsible for iron overload in hereditary hemochromatosis. This genetic heterogeneity may be helpful in delineating the fundamental abnormalities in iron metabolism in this group of disorders.