51 results
Reply to Webster and Osborne
- Rachel R. Bailey, Dianna R. Stuckey, Bryan A. Norman, Andrew P. Duggan, Kristina M. Bacon, Diana L. Connor, Ingi Lee, Robert R. Muder, Bruce Y. Lee
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 32 / Issue 10 / October 2011
- Published online by Cambridge University Press:
- 02 January 2015, pp. 1047-1048
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- October 2011
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Economic Value of Dispensing Home-Based Preoperative Chlorhexidine Bathing Cloths to Prevent Surgical Site Infection
- Rachel R. Bailey, Dianna R. Stuckey, Bryan A. Norman, Andrew P. Duggan, Kristina M. Bacon, Diana L. Connor, Ingi Lee, Robert R. Muder, Bruce Y. Lee
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 32 / Issue 5 / May 2011
- Published online by Cambridge University Press:
- 02 January 2015, pp. 465-471
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- May 2011
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Objective.
To estimate the economic value of dispensing preoperative home-based Chlorhexidine bathing cloth kits to orthopedic patients to prevent surgical site infection (SSI).
Methods.A stochastic decision-analytic computer simulation model was developed from the hospital’s perspective depicting the decision of whether to dispense the kits preoperatively to orthopedic patients. We varied patient age, cloth cost, SSI-attributable excess length of stay, cost per bed-day, patient compliance with the regimen, and cloth antimicrobial efficacy to determine which variables were the most significant drivers of the model’s outcomes.
Results.When all other variables remained at baseline and cloth efficacy was at least 50%, patient compliance only had to be half of baseline (baseline mean, 15.3%; range, 8.23%–20.0%) for Chlorhexidine cloths to remain the dominant strategy (ie, less costly and providing better health outcomes). When cloth efficacy fell to 10%, 1.5 times the baseline bathing compliance also afforded dominance of the preoperative bath.
Conclusions.The results of our study favor the routine distribution of bathing kits. Even with low patient compliance and cloth efficacy values, distribution of bathing kits is an economically beneficial strategy for the prevention of SSI.
28 - Hereditary aceruloplasminemia
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Handbook of Iron Overload Disorders
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- 01 June 2011
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- 22 July 2010, pp 284-289
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Summary
Hereditary aceruloplasminemia (OMIM #604290) is a rare autosomal recessive disorder due to mutations of Cp, the gene that encodes the copper-binding protein ceruloplasmin (Cp). The first report of hereditary aceruloplasminemia was published in 1987 in Japan. The patient was a 52-year-old woman who had a movement disorder that resembled Parkinson's disease, blepharospasm, retinal degeneration, and diabetes mellitus. Her serum immunofixation test revealed that her serum Cp concentration was very low. Computed tomography scanning revealed increased amounts of iron in her basal ganglia and liver. Subsequent histologic evaluation confirmed that there was increased iron in her basal ganglia and substantia nigra and in her liver, without increased copper.
The frequency of homozygosity for deleterious Cp mutations in non-consanguineous marriages in Japan was estimated to be 1 per 2,000,000 population. Aceruloplasminemia has been reported in several countries including Japan, China, Ireland, Belgium, France, Italy, and the US. More Japanese patients have been reported than any other nationality. Altogether, about 60 patients with hereditary aceruloplasminemia have been described.
Ceruloplasmin (Cp) biochemistry
Cp is a plasma metalloprotein, an alpha-2 glycoprotein polypeptide of 1046 amino acids. A member of the multi-copper oxidase enzyme family, Cp is the principal copper transport protein in plasma. Cp is synthesized in hepatocytes where it binds copper, and is thereafter secreted into plasma. About 95% of circulating plasma copper is bound to Cp; the remainder is bound to albumin, precuprein, and complexes of copper and amino acids. Each Cp molecule can bind and transport six atoms of copper.
Plate section
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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31 - Neuroferritinopathies
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Handbook of Iron Overload Disorders
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Summary
Neuroferritinopathy (OMIM #606159), also known as adult-onset basal ganglia disease, is a progressive movement disorder caused by mutations in the coding region of the ferritin light chain gene (FTL, chromosome 19q13.3–q13.4). Persons with neuroferritinopathy have abnormal ferritin light chain polypeptide, decreased serum ferritin concentrations, and accumulation of iron in the basal ganglia. Curtis and colleagues first described this syndrome in an English kinship in 2001. They also coined the commonly used term “neuroferritinopathy.” Subsequent identification and study of other subjects have revealed additional observations on the genotypes, phenotypes, and epidemiology associated with neuroferritinopathy.
Other mutations of the FTL coding region segregate with a syndrome that comprises hyperferritinemia, absence of iron overload, and absence of ocular cataracts. Mutations of the iron-responsive element of FTL cause a different clinical syndrome characterized by elevated levels of otherwise normal ferritin, cataracts due to ferritin light-chain deposition in the ocular lens, and absence of neurological abnormalities (Chapter 17).
History
In 2001, Curtis and colleagues described late-onset autosomal dominant dystonia that segregated with FTL 460insA in an English kinship. In 2003, Chinnery, Curtis, and colleagues reported a French family in which some members had a similar clinical disorder and the same FTL mutation. In 2007, Chinnery and colleagues compiled observations in 41 patients with neuroferritinopathy and FTL 460insA. They presented between the ages of 38 and 58 years; some had chorea, others had focal dystonia, and others had an akinetic rigid Parkinsonian syndrome. Brain imaging showed basal ganglia cavitation that was confirmed at necropsy.
Contents
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Handbook of Iron Overload Disorders
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- 22 July 2010, pp v-vi
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12 - Hemochromatosis associated with ferroportin gene (SLC40A1) mutations
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- 22 July 2010, pp 171-180
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Summary
Mutations in the SLC40A1 (FPN1) gene that encodes ferroportin (OMIM *604653) cause an uncommon, heterogeneous group of iron overload disorders characterized by an autosomal dominant pattern of inheritance (OMIM #606069). Ferroportin hemochromatosis has been described worldwide in a variety of race/ethnicity groups. SLC40A1 mutations cause two major iron overload phenotype patterns, each depending on the particular mutation and its effect on the function of the transcribed ferroportin protein. In many ferroportin hemochromatosis kinships, serum iron measures and complications of iron overload typical of other types of hemochromatosis are relatively uncommon. The collective term “ferroportin disease” or “hemochromatosis type 4” is sometimes used to describe the clinical manifestations of ferroportin mutations.
History
In 1990, an autosomal dominant form of hemochromatosis was reported in a Melanesian pedigree from the Solomon Islands. All affected individuals had serum iron measures and a pattern of liver iron staining similar to those of HFE hemochromatosis, although linkage of this disorder to chromosome 6p was excluded. In 1999, Pietrangelo and colleagues reported a large Italian family that included persons with an iron overload condition that occurred in pattern consistent with autosomal dominant inheritance. Based on microsatellite marker analyses, this disorder was also not linked to chromosome 6p. In 2001, Njajou and colleagues identified the SLC40A1 mutation N144H associated with autosomal dominant hemochromatosis in a large multi-generation family from the Netherlands.
23 - Iron overload associated with pyruvate kinase deficiency
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- 22 July 2010, pp 251-253
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Summary
Pyruvate kinase (PK) deficiency (OMIM #266200) is caused by mutations in the PKLR gene that encodes PK (chromosome 1q21). This disorder is the most common erythrocyte enzyme defect that causes hereditary non-spherocytic hemolytic anemia. It is transmitted as an autosomal recessive trait. On the basis of gene frequency, it was estimated that the prevalence of homozygous PK deficiency is 51 cases per million in the US white population. Based on data in a health registry, it was estimated that the prevalence of PK deficiency in northern England is 3.3 per million. PK deficiency has a worldwide distribution, but may be more common among individuals of northern European descent. Herein, the pathophysiology of PK deficiency is discussed. The clinical manifestations of this disorder are reviewed with emphasis on the complication of iron overload.
Etiology and pathogenesis
Mature erythrocytes depend on the glycolytic production of adenosine triphosphate (ATP) to meet metabolic requirements. Deficiencies in several glycolytic enzymes can result in hemolytic anemia. These types of hemolytic anemia are not associated with a distinctive morphologic abnormality of erythrocytes, and thus are known collectively as congenital non-spherocytic hemolytic anemias. Most of these disorders are rare and are transmitted as autosomal recessive disorders.
PK deficiency is the most common erythrocyte glycolytic enzymopathy. The predominant PK isoenzyme present in erythrocytes is the R form, encoded by PKLR. Multiple mutations can lead to PK deficiency, and the type of mutation may determine in part the severity of the clinical phenotype.
2 - Normal iron absorption and metabolism
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Handbook of Iron Overload Disorders
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- 22 July 2010, pp 10-27
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Summary
Iron is essential to life because it is the central oxygen ligand in the heme proteins hemoglobin and myoglobin. Accordingly, there are many interactions between iron homeostasis and oxygen regulation and delivery. Iron is also required for cytochrome P-450 enzyme oxidative metabolism and DNA synthesis. In health, body iron content is controlled by absorption that responds to iron losses and the rate of erythropoiesis. Multiple mechanisms provide functional feedback control of iron homeostasis, tissue oxygen sensing and delivery, and the tempo of red blood cell production. The physiologic capacity to excrete iron is very limited. Thus, body iron content is regulated almost entirely by controlled absorption. This chapter reviews the basic physiologic and molecular characteristics of iron metabolism and homeostasis, and their pertinence to iron overload disorders.
Iron physiology
Normal iron homeostasis is maintained by absorption of iron from the diet that precisely balances iron loss, and by controlled iron distribution in the body. Normal healthy adults have 4000–5000 mg of iron (Table 2.1). Daily iron loss occurs due to perspiration, desquamation from skin, and minor injuries, and from the gastrointestinal tract. The rate of this unavoidable iron loss is proportional to body iron stores. Women lose additional iron due to menstruation, pregnancy and childbirth, and lactation. Overall, daily iron losses in adult men and post-menopausal women are approximately 1.0 mg and in menstruating women approximately 1.5 mg. The median iron loss ascribable to pregnancy is 500 mg.
20 - Divalent metal transporter-1 (SLC11A2) iron overload
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- 22 July 2010, pp 228-232
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Summary
Divalent metal transporter-1 (DMT1) is a member of the “natural-resistance-associated macrophage protein” (Nramp) family. DMT1 is upregulated by dietary iron deficiency, is expressed strongly on the microvillus membranes of duodenal enterocytes at the villus tips, and is a key mediator of iron absorption. DMT1 also mediates iron transfer from endosomes into the cytosol of developing erythroid cells. The SLC11A2 gene that encodes DMT1 is located on chromosome 12q13 (OMIM *604653).
In 1964, Shahidi and colleagues described a brother and sister of French-Canadian descent who had hypochromic, microcytic anemia. These siblings also had elevated serum iron concentrations, massive deposition of iron in hepatocytes, and absence of stainable iron in the bone marrow. These children apparently had no defect in transferrin or heme synthesis. Two of their siblings appeared to have normal iron phenotypes. In 2004 and 2005, Priwitzerova and colleagues described a Czech female in a consanguineous kinship who came to medical attention at age 3 months because she had a syndrome of abnormal iron metabolism characterized by severe hypochromic, microcytic anemia, erythroid hyperplasia, abnormal erythroid maturation, elevated serum iron concentration, normal to slightly increased serum ferritin level, and markedly increased serum transferrin receptor levels. In 2005, Mims and colleagues reported that this woman was homozygous for a mutation in SLC11A2.
Clinical description
Clinical observations in patients with two SLC11A2 mutations are limited. In one case, left ventricular hypertrophy was detected before birth, and birth weight was low. Pallor is presumed to have been present in all reported cases.
10 - Porphyria cutanea tarda
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Handbook of Iron Overload Disorders
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- 01 June 2011
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- 22 July 2010, pp 160-168
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Summary
Porphyrias are disorders caused by heritable or acquired deficiency of an enzyme that is required for the normal synthesis of heme. A ring structure, heme is formed by the insertion of an iron atom into protoporphyrin in the final step of the porphyrin synthesis pathway. The usual presenting symptoms and signs of porphyrias are either skin photosensitivity or neurovisceral symptoms and signs. Three types of porphyria are characterized by a predominance of photosensitivity (porphyria cutanea tarda (PCT), congenital erythropoietic porphyria, and erythropoietic protoporphyria). Two types of porphyria are characterized mainly by neurovisceral symptoms and signs (acute intermittent porphyria and aminolevulinate dehydratase deficiency). The two remaining types of porphyria are characterized by both photosensitivity and neurovisceral symptoms and signs (hereditary coproporphyria and variegate porphyria). The seven main types of porphyria, the associated enzyme deficiency, the mode of inheritance, and the major presenting symptoms and signs are displayed in Table 10.1. The only type of porphyria discussed here is PCT, the most common of all porphyrias.
Porphyria cutanea tarda (PCT)
PCT is estimated to occur in about 1 per 5000 to 25,000 individuals in the general population. PCT is caused by decreased specific activity of the uroporphyrinogen decarboxylase enzyme, the fifth enzyme in the heme synthesis pathway. Three types of PCT can be identified on the basis of decreased activity of the uroporphyrinogen decarboxylase enzyme (URO-D) in liver cells or in erythrocytes.
18 - Iron overload in Native Africans and African-Americans
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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Summary
African iron overload
African iron overload occurs in 14%–18% of Bantu-speaking Natives in at least 15 countries in sub-Saharan Africa. This type of non-transfusion iron overload is due primarily to the ingestion of large quantities of iron contained in traditional beer, although unconfirmed evidence suggests that there is an African iron overload gene (Table 18.1).
History
Iron overload in native sub-Saharan Africans was first described by Strachan in his 1929 thesis on tuberculosis. The disorder was originally attributed to infections, to poisoning due to copper, tin, or zinc, or to malnutrition. In 1953, it was hypothesized that the intake of excessive quantities of iron leached from iron vessels used for food preparation could account for “Bantu siderosis.” In 1992, the etiology of African iron overload as a purely dietary disorder was contested with the demonstration that heritable factors may influence the development of this condition.
Clinical description
Patients with early iron overload identified during family or other group testing have no symptoms or signs attributable to iron overload. Symptoms usually do not occur until iron overload is severe; they may develop by late adolescence. Iron overload is progressive in most patients. Weakness and fatigue, abdominal discomfort or pain, or low back or hip pain are common presenting complaints. Iron overload occurs with greater frequency and severity among men than in women. Physical examination in subjects with severe iron overload may reveal hyperpigmentation, hepatomegaly, kyphosis, or femoral neck fracture.
8 - Classical and atypical HFE hemochromatosis
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- 22 July 2010, pp 127-148
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Summary
Hemochromatosis and HFE mutations
The “classical” type of familial hemochromatosis that is transmitted as an autosomal recessive disorder is usually due to homozygosity for the C282Y mutation of the HFE gene. It is expected that mutations of HFE cause the great majority of the cases of heritable iron overload in humans. There are at least 37 known mutations of the HFE gene (Table 8.1) (Chapter 4). Some individuals who are homozygous for any of the known mutations may develop heavy iron overload. At least six mutations are associated with mild iron accumulation; and at least six mutations were discovered in patients who did not have iron overload. There is insufficient reported information in the literature to determine if six of the mutations are sufficiently deleterious to result in iron overload. Approximately 1500 mutations of the cystic fibrosis gene (CF) are known, and the gene encodes a 1480 amino acid protein. In contrast, HFE is much smaller than CF, and encodes a protein of only 343 amino acids. Thus, it is expected that fewer mutations of HFE than mutations of CF will be eventually discovered.
Molecular genetics
Although the autosomal recessive inheritance pattern of “classical” hemochromatosis had long been recognized, identification of the responsible gene remained elusive for many years (Table 8.1). An important breakthrough in the search for the gene occurred in 1976 when hemochromatosis was found to be linked closely to the human leukocyte antigen (HLA)-A*03 region of the short arm of chromosome 6.
1 - History of iron overload disorders
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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Summary
In 1704 in Berlin, Heinrich Diesbach and Johann Konrad Dippel attempted to manufacture a synthetic red pigment. By accident, Dippel mixed potash, animal oil derived from blood, and iron sulfate. Thereafter, he discovered that he had produced an insoluble, light-fast, dark blue pigment. This color was first used extensively to dye the uniforms of the Prussian army, and became known as “Prussian blue.” Almost 150 years later, physicians and scientists recognized the feasibility of visualizing iron in tissue using a similar staining sequence. After more than 250 years, it became practical to quantify iron in blood and tissue, permitting case finding and screening for hemochromatosis and iron overload. Maneuvers to treat iron overload began in the same era. In the interval 1994–1996, the genetic bases of four different iron disorders (X-linked sideroblastic anemia, aceruloplasminemia, hereditary hyperferritinemia-cataract syndrome, and HFE hemochromatosis) were elucidated. The pace of basic science, clinical, and sociological revelations pertinent to hemochromatosis and iron overload disorders continues to accelerate. This chapter provides an abbreviated chronology of these discoveries.
Iron in tissue
In 1847, Rudolph Virchow reported the occurrence of golden brown granular pigment at sites of hemorrhage and congestion in tissue examined by microscopy. The pigment was soluble in sulfuric acid, yielded a red ash on ignition, and produced a positive Prussian blue reaction. In 1867, Max Perls formulated the first practical acidified ferrocyanide reaction for histologic analysis of iron, and applied the staining reaction to a variety of tissues.
32 - GRACILE syndrome
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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Summary
GRACILE syndrome (OMIM #603358) is a rare lethal disorder of infants. The acronym GRACILE represents growth retardation, aminoaciduria, cholestasis, iron loading, and early death. This autosomal recessive disorder is caused by mutations of the BCS1 gene on chromosome 2q33. The human BCS1 gene encodes a homolog of S. cerevisiae bcs1 protein involved in the assembly of complex III (CIII) of the mitochondrial respiratory chain. GRACILE syndrome was first reported from Finland where its estimated population frequency is 1 per 47,000 to 70,000 infants. GRACILE syndrome has been identified in other geographic regions, but population prevalence estimates are not available for most other countries. Other mutations of BCS1 result in clinical and laboratory phenotypes that differ from those of GRACILE syndrome.
Clinical manifestations
GRACILE syndrome has been identified by antenatal testing, but the disorder is readily apparent in neonates and worsens soon after birth (Table 32.1). Growth retardation is a characteristic finding among affected infants. In a study from Finland, the median weight of 17 infants with GRACILE syndrome was 4 SD lower than the median weight in a group of normal infants. All 17 infants had aminoaciduria and cholestasis. Plasma or serum concentrations of lactic acid were typically normal at birth; pH of umbilical cord blood was 7.3 or higher (reference <7.2). Fulminant lactic acidosis developed within 24 hours in all patients. Median lactate levels rose to 12 mmol/L (reference <1.8 mmol/L), and median blood pH values decreased to 7.00 (reference 7.35.45). None of the infants had hypotonia or seizures.
36 - Management of iron overload
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- 22 July 2010, pp 321-341
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Summary
Iron overload is characterized by excessive iron deposition in and consequent injury and dysfunction of target organs, especially the heart, liver, anterior pituitary, pancreas, and joints (Chapter 5). Because physiologic mechanisms to excrete iron are very limited, patients with iron overload and its complications need safe, effective therapy that is compatible with their co-existing medical conditions. Worldwide, prevention of death due to cardiac siderosis is the most important potential benefit of therapy. The incidence of cardiac complications is greatest in patients with beta-thalassemia major and other heritable anemias treated with multiple transfusions. The liver is the primary target organ of iron overload in hemochromatosis and African iron overload, although maintaining normal hepatic function is important in all patients with iron overload. Preventing injury to endocrine organs is critical in children with iron overload. Successful treatment or prevention of iron overload increases quality of life and survival in many patients.
Therapeutic phlebotomy removes iron as hemoglobin, and is thus suitable for treatment of patients with iron overload without severe anemia in whom erythropoiesis is fundamentally normal (Table 36.1). Many reports substantiate the effectiveness, outcomes, and safety of phlebotomy therapy in HFE hemochromatosis and allied disorders. Chelation therapy employs drugs that preferentially bind excess iron and increase its excretion (Table 36.1). Some dietary maneuvers may decrease the absorption of dietary iron, and may be useful as adjunctive therapy for some patients with iron overload, although such treatments do not diminish body iron burdens.
15 - Hemochromatosis associated with transferrin receptor-2 gene (TFR2) mutations
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- 22 July 2010, pp 193-199
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Summary
TFR2 hemochromatosis (OMIM #604250) is a rare autosomal recessive disorder characterized by elevated serum iron measures, parenchymal iron deposition, and complications of iron overload. In some kinships, severe iron overload occurs in children or young adults. In individual cases, the TFR2 hemochromatosis phenotype may resemble that of HFE hemochromatosis or HJVhemochromatosis (Chapter 8).
History
In 1999, Kawabata and colleagues cloned and sequenced a human gene homologous to the TFR gene that encodes classical transferrin receptor (TFR1). They named the newly discovered gene TFR2 (OMIM *604720), and mapped it to chromosome 7q22. Two transcripts (alpha and beta) are expressed from this gene; the alpha transcript is expressed predominantly in the liver. TFR2-alpha is a second transferrin receptor that mediates cellular iron transport in vitro. In normal subjects, most iron uptake by the liver is transferrin mediated. Expression of TFR1 in hepatocytes, as in other non-reticuloendothelial cell types, is down-regulated in response to increased intracellular iron. Consequently, hepatocyte TFR1 is undetectable in patients with HFE hemochromatosis and hepatic iron loading. Nonetheless, hepatic iron loading in HFE hemochromatosis is progressive. Experiments in mice demonstrate that TFR2 makes only a minor contribution to the uptake of transferrin-bound iron by the liver, but rather TFR2 is thought to modulate the signaling pathway that controls hepcidin expression. In 2000, Camaschella and colleagues described persons with hemochromatosis phenotypes in two unrelated Sicilian families who had mutations in TFR2.
Clinical characteristics
The age of onset and severity of iron overload varies moderately in patients with TFR2 hemochromatosis.
29 - Friedreich ataxia and cardiomyopathy
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
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- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 290-293
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Summary
Friedreich ataxia (OMIM #229300) is characterized by ataxia, cardiomyopathy, and accumulation of iron in mitochondria of the dentate nucleus of the cerebellum and of cardiac myocytes. Systemic iron overload does not occur. This is the most common type of heritable ataxia, and affects approximately 1 person per 30,000.
Clinical manifestations
Initial clinical evidence of Friedreich ataxia usually occurs in adolescents and adults less than 25 years of age. In 115 affected individuals in 90 families, the onset of symptoms occurred at mean age 10.5 years. The symptoms and signs that appear during the first 5 years are ataxia of limbs and trunk, and absence of deep tendon reflexes. As the condtion worsens, additional characteristic findings develop, including dysarthria, hypotonia, scoliosis, a Babinski plantar extensor response, loss of position sense in toes, and loss of vibratory sensation in feet. Peripheral neuropathy adds a sensory component to gait ataxia. Affected individuals experience progressive loss of ability to walk, causing 95% to become chair bound by age 44 years. Pes cavus is common, and is caused by nerve injury and consequent atrophy of intrinsic muscles of the feet.
Hypertrophic cardiomyopathy is present in two-thirds of the patients. This typically affects the interventricular septum or the wall of the left ventricle. In some patients, echocardiography demonstrates cardiac hypertrophy or decreased left ventricular ejection fraction before overt heart failure occurs. Heart failure is the most common cause of death in patients with Friedreich ataxia. Oculomotor abnormalities (nystagmus) develop in some patients.
27 - Acquired sideroblastic anemias
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
-
- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 277-283
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Summary
Acquired sideroblastic anemia is a heterogeneous group of disorders characterized by excessive accumulation of amorphous iron deposits in the mitochondria of erythrocyte precursors. Ring sideroblasts, the sine qua non of sideroblastic anemia, are erythroblasts in Prussian blue-stained marrow aspirates that have numerous iron-positive mitochondria that occur in a perinuclear distribution. In sideroblastic anemia, typical ring sideroblasts have a full or partial ring and usually comprise more than 5% of all erythroblasts (Chapter 25, Fig. 25.1a, b). Other erythroblasts in the same specimens may have markedly increased numbers of iron-positive mitochondria that do not form a perinuclear halo. Acquired sideroblastic anemias encompass two main categories: clonal hematopoietic stem cell disorders classified as myelodysplastic syndromes (MDS); and reversible types of sideroblastic anemia due to drugs, chemicals, or other factors. Heritable types of sideroblastic anemia are described in Chapter 25.
Acquired sideroblastic anemia due to myelodysplastic syndromes
Classification
Refractory anemia with ring sideroblasts (RARS) is characterized by erythroid dysplasia, mitochondrial accumulation of mitochondrial iron-containing ferritin (mitoferrin), defective erythroid maturation, and anemia; some patients also have elevated platelet counts. Other patients with MDS and ring sideroblasts are classified as having refractory cytopenias with multilineage dysplasia and ring sideroblasts (RCMD-RS). MDS in patients with either RARS or RCMD-RS may progress to excess marrow blasts (refractory anemia with excess blasts, RAEB) or acute leukemia.
Pathophysiology
Non-germline mutations in marrow stem cells underlie the pathogenesis of MDS, including MDS subcategories typically associated with ring sideroblasts.
25 - Hereditary sideroblastic anemias
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- By James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, University of Utah School of Medicine, Salt Lake City, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
- James C. Barton, University of Alabama, Birmingham, Corwin Q. Edwards, Pradyumna D. Phatak, University of Rochester Medical Center, New York, Robert S. Britton, St Louis University, Missouri, Bruce R. Bacon, St Louis University, Missouri
-
- Book:
- Handbook of Iron Overload Disorders
- Published online:
- 01 June 2011
- Print publication:
- 22 July 2010, pp 260-273
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- Chapter
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Summary
X-linked sideroblastic anemias (XLSA) are characterized by impaired mitochondrial iron metabolism, “ringed” sideroblasts and increased erythropoiesis. In some cases, these disorders cause parenchymal iron overload similar to that of hemochromatosis. Increased iron absorption is upregulated by relative or absolute suppression of hepcidin expression presumably mediated by ineffective erythropoiesis through growth/differentiation factor 15 (GDF15). Iron overload in some patients is exacerbated by erythrocyte transfusion. Mutations in the ALAS2 gene that encodes erythroid-specific 5-aminolevulinate synthase (ALA synthase) account for most cases (OMIM #300751), although rare mutations in other genes on the X chromosome or elsewhere also cause sideroblastic anemia phenotypes and variable degrees of iron loading. Anemia in two-thirds of patients with ALAS2 mutations can be alleviated with simple, non-transfusion therapy. Early recognition and treatment of iron accumulation prevents irreversible organ damage. Informal experience suggests that XLSA may be more common than is generally recognized.
ALAS2 sideroblastic anemia
History
In 1945, Thomas Cooley described the first cases of XLSA in two brothers from a large family in which the inheritance of the condition was documented through six generations. Additional observations in this family and description of a new kinship were published by Rundles and Falls in 1946. In 1956, Harris and co-workers reported the first case of “pyridoxine-responsive anemia.” Ringed sideroblasts were described by Bjorkman in 1956 (Fig. 25.1). Byrd and Cooper coined the term “hereditary iron-loading anemia” in 1961. The term “sideroblastic anemia” was adopted in 1965. By this time, the association of anemia sometimes responsive to pyridoxine and iron overload were widely recognized.