The anaemia of chronic disease.
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Anemia↗
Biomedical subjects
E J Fitzsimons
Publications and source records attributed to E J Fitzsimons.
Inappropriate antidiuretic hormone secretion, abdominal pain and disseminated varicella-zoster virus infection: an unusual and fatal triad in a patient 13 months post Rituximab and autologous stem cell transplantation.
We report a case of varicella-zoster virus (VZV) infection associated with severe abdominal pain, inappropriate antidiuretic hormone (ADH) secretion (SIADH) and death, 13 months post-autologous peripheral blood stem cell transplantation (PBSCT). This unusual clinical triad has been reported twice in the setting of allogeneic bone marrow transplantation, however it has not been reported after autologous transplantation and never so long after transplantation. We speculate as to why this occurred, as early recognition might have altered the clinical outcome.
Abdominal Pain↗
Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.
X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband's maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH) HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance of HFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.
5-Aminolevulinate Synthetase↗
Spontaneous regression of an anaplastic large cell lymphoma in the oral cavity: first reported case and review of the literature.
Lymphomas account for 2-5% of all oral malignancies and are the third most common in this site. This case report appears to be the first in the world literature describing spontaneous regression in the oral cavity of a subset of non-Hodgkins lymphomas known as Ki-1 anaplastic large cell lymphomas (ALCL). Ki-1 ALCL account for 2-7% of all non-Hodgkins lymphomas and the clinical presentation is variable; they may arise de novo or in the setting of a separate primary lymphoma and commonly present in the extra-nodal location. Disease severity is also variable with waxing and waning lesions at one extreme which may spontaneously regress to bone marrow involvement in around 12% of cases. This case is especially interesting since the patient is a farmer, given the recent evidence that there may be a link between non-Hodgkins lymphoma and this occupation.
Aged↗
Malignant and corticosteroid-dependent idiopathic anaphylaxis: successful responses to ketotifen.
BACKGROUND: Malignant idiopathic anaphylaxis refers to the most severe form of idiopathic anaphylaxis where defined episodes of idiopathic anaphylaxis are not controlled when the prednisone is reduced below at least 60 mg every other day or 20 mg daily. Corticosteroid-dependent idiopathic anaphylaxis refers to patients with idiopathic anaphylaxis who require continuous daily or alternate day prednisone at threshold doses for control of idiopathic anaphylaxis. Ketotifen has been reported to help induce remission in some patients with idiopathic anaphylaxis and has steroid sparing effects in other patients with idiopathic anaphylaxis. METHODS: We present five patients, two with malignant idiopathic anaphylaxis and three with corticosteroid-dependent idiopathic anaphylaxis, who responded to the administration of ketotifen. RESULTS: All five patients, while receiving ketotifen, had a reduction or resolution of their episodes of idiopathic anaphylaxis and prednisone was tapered and discontinued. CONCLUSION: Ketotifen is shown to be successful in inducing remission in two patients with malignant idiopathic anaphylaxis and in three additional patients with corticosteroid-dependent idiopathic anaphylaxis. An additional patient with malignant idiopathic anaphylaxis had prednisone stopped after elective hip surgery.
Adrenal Cortex Hormones↗
Recurrence of allergic bronchopulmonary aspergillosis in the posttransplant lungs of a cystic fibrosis patient.
Cystic fibrosis (CF) is an autosomal recessive disease of exocrine origin. Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic disorder caused by colonization of the airways with Aspergillus fumigatus. A fumigatus has been cultured from posttransplant lungs in CF patients. Colonization of posttransplant lung with Aspergillus is a recognized phenomenon. In this case report, however, we present a patient who developed ABPA both before and after lung transplant. This patient meets the criteria for ABPA based on serologic results. ABPA may be a complication in post-CF lung transplant patients and serologic analysis should be considered when eosinophilia and pulmonary infiltrates or decline in lung function occurs.
Adult↗
Acquired sideroblastic anaemia induced by a copper-chelating agent.
Acquired sideroblastic anaemia may be related to drugs and other chemicals that inhibit the activity of mitochondrial enzymes involved in haem synthesis. We report a case of secondary acquired sideroblastic anaemia following administration of triethylene tetramine dihydrochloride (trientine), a second-line copper-chelating agent used in the treatment of Wilson's disease. The anaemia improved after dose reduction of trientine. The mechanism of induction of sideroblastic anaemia in this case is unclear, but trientine does not appear to alter the function of two key mitochondrial haem enzymes, and may instead act directly on mitochondrial iron metabolism.
Adolescent↗
The molecular basis of the sideroblastic anemias.
The sideroblastic anemias display remarkable clinical and hematologic heterogeneity but share in common mitochondrial iron loading as evidence of unhinging between intracellular iron metabolism and heme biosynthesis. Molecular defects responsible for this unhinging have now been identified and appear to display matching heterogeneity. Mutations in the erythroid-specific ALA synthase 2 (ALAS2) gene cause microcytic anemia, whereas mitochondrial DNA deletions are responsible for Pearsons syndrome with a macrocytic anemia. The molecular basis for other causes including X-linked non-ALAS2-associated autosomal inheritance and for the more frequent acquired forms of this disorder awaits discovery. Speculation about their causes includes disturbed intracellular iron homeostasis involving iron-responsive factors involved in the translational control of ALAS2 and in certain nuclear and mitochondrial genes important for erythroid mitochondrial metabolism.
5-Aminolevulinate Synthetase↗
Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.
X-linked sideroblastic anemia (XLSA) is caused by mutations of the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) resulting in deficient heme synthesis. The characteristic hypochromic, microcytic anemia typically becomes manifest in the first three decades of life. Hematologic response to pyridoxine is variable and rarely complete. We report two unrelated cases of highly pyridoxine-responsive XLSA in geriatric patients previously diagnosed with refractory anemia and ringed sideroblasts. A previously unaffected 77-yr-old male and an 81-yr-old female were each found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded dramatically to pyridoxine with normalization of hemoglobin values. Sequence analysis identified an A to C transversion in exon 7 (K299Q) of the ALAS2 gene in the male proband and his daughter. In the female proband a G to A transition was identified in exon 5 (A172T). This mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. Each patient's recombinant mutant ALAS2 enzyme had marked thermolability. Addition of pyridoxal 5'-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of XLSA can be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and ALAS2 mutations. These findings emphasize the need to consider all elderly patients with microcytic sideroblastic anemia as candidates for XLSA, especially if pyridoxine responsiveness is demonstrated.
5-Aminolevulinate Synthetase↗
Regulation of haem biosynthesis in normoblastic erythropoiesis: role of 5-aminolaevulinic acid synthase and ferrochelatase.
The development of haem biosynthetic enzyme activity during normoblastic human erythropoiesis was examined in seven patients. The first and last enzymes of the haem biosynthetic pathway, ALA synthase and ferrochelatase, were assayed by radiochemical/high performance liquid chromatographic (HPLC) methods. An assay for ferrochelatase activity in human bone marrow was developed. Enzyme substrates were protoporphyrin IX and 59Fe2+ ions. 59Fe-labelled haem was isolated by organic solvent extraction/sorbent extraction followed by reversed-phase HPLC. Optimal activity occurred at pH 7.3 in the presence of ascorbic acid, in darkness and under anaerobic conditions. Haem production was proportional to cell number and was linear with time to 30 min. The assay was sensitive to the picomolar range of haem production. ALA synthase and ferrochelatase activity was assayed in four highly purified age-matched erythroid cell populations. ALA synthase activity was maximal in the most immature erythroid cells and diminished as the cells matured with an overall five fold loss of activity from proerythroblast to late erythroblast development. Ferrochelatase activity was, however, more stable with less than a two fold change in activity observed during the same period of erythroid differentiation. Maximal activity occurred in erythroid fractions enriched with intermediate erythroblasts. These results support sequential rather than simultaneous appearance of these enzymes during normoblastic erythropoiesis. Quantitative analysis of relative enzyme activity however indicates that at all times during erythroid differentiation ferrochelatase activity is present in excess to that theoretically required relative to ALA synthase activity since ALA and haem are not produced in stoichiometric amounts. The lability of ALA synthase versus the stability and gross relative excess of ferrochelatase activity indicates a far greater role for ALA synthase in the regulation of erythroid haem biosynthesis than for ferrochelatase.
5-Aminolevulinate Synthetase↗
Filgrastim fails to improve haemopoietic reconstitution following myeloablative chemotherapy and peripheral blood stem cell rescue.
The morbidity of high-dose chemotherapy has been considerably reduced by the use of autologous peripheral blood progenitor cell reinfusion. Most studies have used myeloid colony-stimulating factors after stem cell reinfusion, making it difficult to determine the relative contribution of each of these variables to the early recovery of blood cells. The financial implications of colony-stimulating factor use are an area of concern as dose intensification in chemosensitive malignancies is increasingly employed. We have studied 19 consecutive patients receiving high-dose chemotherapy with and without filgrastim (Amgen, granulocyte colony-stimulating factor, G-CSF) after stem cell infusion to examine its effect on the kinetics of blood cell recovery, the complications of myelosuppression and the associated costs. Analysis of the two treatment groups reveals that administration of filgrastim 10 micrograms kg-1 day-1 following stem cell reinfusion does not further accelerate haemopoietic recovery, fails to reduce the incidence of neutropenic fever or antibiotic usage and significantly increases the cost of the procedure. The results of this study do not support the routine use of filgrastim after high-dose chemotherapy and peripheral blood stem cell reinfusion.
Adolescent↗
Pyridoxine-refractory congenital sideroblastic anaemia with evidence for autosomal inheritance: exclusion of linkage to ALAS2 at Xp11.21 by polymorphism analysis.
A son and daughter of unaffected parents had transfusion dependent, pyridoxine-refractory sideroblastic anaemia from birth. Their haemoglobin levels were 4.3 and 6.4 g/dl, respectively. delta-Aminolaevulinate synthase activity in erythroblasts from fractionated marrow of the sister was 135 pmol delta-aminolaevulinate formed/10(6) erythroblasts/hour (normal range = 110-650 pmol). While mutations of the erythroid-specific delta-aminolaevulinate synthase gene (ALAS2) at Xp11.21 have been reported in patients with X linked sideroblastic anaemia, sequence analysis of the ALAS2 gene in the son did not identify any mutations in the coding region, the intron/exon boundaries, or the 1 kb 5' promoter region. A useful polymorphism was found in the 3' region of the ALAS2 gene, a G to A transition, 220 nt 3' of the AATAAA polyadenylation signal. Mismatch PCR at this site and subsequent discrimination by XmnI restriction analysis of 148 alleles identified the gene frequency of this polymorphism to be 25%. Analysis of the inheritance of this intragenic polymorphism showed that the affected sibs received different maternal alleles at the ALAS2 locus, excluding mutations in this gene as the cause of their sideroblastic anaemia. Furthermore, the absence of a dimorphic erythrocyte population in the mother, coupled with the demonstration of random X inactivation in her peripheral leucocytes, showed that the mother was not the carrier of any X linked sideroblastic anaemia mutation. These results strongly suggest that the sideroblastic anaemia in this family is an autosomal recessive trait.
5-Aminolevulinate Synthetase↗
Death of a classified worker probably caused by overexposure to gamma radiation.
This paper describes the case of an industrial radiographer who was seriously overexposed to gamma radiation. The exact circumstances of this exposure were not established but it was concluded that he was repeatedly irradiated probably to a total average whole body dose of at least 10 Gy over several years. Also, a much larger dose to a hand required its partial amputation. He developed myelodysplasia, which progressed to acute myeloid leukaemia from which he died. Karyotypic examination of the leukaemic blasts showed changes very similar to those associated with secondary leukaemia that may develop after radio or chemotherapy. The paper describes his medical case history, the investigation of his workplace, and the attempts to estimate his radiation dose by chromosomal analysis of blood lymphocytes and electron spin resonance of dental enamel and bone.
Acute Disease↗
Vitamin D analogues, marrow fibrosis and psoriasis.
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Adult↗
A study of the pathogenesis of Helicobacter pylori negative chronic duodenal ulceration.
In the past five years 12 patients have been identified presenting with chronic duodenal ulcer (DU) disease and with no evidence of current or recent Helicobacter pylori (H pylori) infection. Four of them were taking regular non-steroidal anti inflammatory agents, one was subsequently found to have Crohn's disease of the duodenum, and one to have the Zollinger-Ellison syndrome. The remaining six patients with idiopathic DU disease were remarkable for their absence of the A1 blood antigen gene. Detailed studies of gastric function were performed in these six patients and compared with H pylori positive patients with DU and with healthy volunteers. The median integrated gastrin response in the patients with idiopathic DU (2810 (range 750-8750) ng/l min) was similar to that of the H pylori positive patients with DU (3355 (550-8725)) and higher than that of the H pylori negative healthy volunteers (560 (225-1125)). The median peak acid output in the patients with idiopathic DU (37 mmol/h, range 17-52) was similar to that of the H pylori positive patients with DU (40 (15-57)) and higher than that of the non-ulcer controls (22 (16-29)). The median percentage of a liquid meal retained in the stomach at 60 minutes was less in the patients with idiopathic DU (23 (15-33)) than in H pylori negative healthy volunteers (34 (30-53) p < 0.01). The median percentage of a solid meal retained at 60 minutes was less in the patients with idiopathic DU (54 (9-83)) than in either H pylori negative healthy volunteers (87 (49-95) p<0.01) or H pylori positive patients with DU (79 (51-100) p<0.01). In conclusion, three abnormalities of gastric function are prevalent in patients with H pylori negative idiopathic DU disease - hypergastrinaemia, increased acid secretion, and the one feature distinguishing them from H pylori positive patients with DU - rapid gastric emptying of both liquids and solids. Each of these abnormalities will increase the exposure of the duodenal mucosa to acid and thus explain its ulceration. The absence of the blood group A1 antigen gene is consistent with a genetic basis for the disturbed gastric function linked to the ABO blood group antigen genes.
ABO Blood-Group System↗
Immunocytochemical demonstration of T4 content and TSH-binding by cells of the thyroid of the developing chick embryo.
The numerical densities (Nv) of immunostained thyroxine (T4)-positive cells and thyrotropin-stimulating hormone (TSH)-positive cells were determined in chick embryos on Day 5.5 through Day 11.5 and Days 5.5, 7.5, 9.5, 10.5, 11.5, 12.5, 13.5, 14.5, 15.5, 16.5, and 17.5, respectively. The data demonstrate that selected cells of the "prefollicular" thyroid contain T4 and bind TSH at least as early as Day 5.5. The Nv of immunocytochemically demonstrable T4-positive cells increases gradually from Day 5.5 to Day 10.5, exhibiting a statistically significant increase (P less than 0.05) between Day 10.5 and Day 11.5. Similarly, the Nv of TSH-binding cells (Nv TSH) rises slowly from Day 5.5 until Day 11.5, followed by a statistically significant (P less than 0.05) increase between Day 11.5 and Day 12.5. The peak Nv TSH value on Day 12.5 is followed by a decline (P less than 0.05) on Day 13.5, and from Day 14.5 through Day 17.5, Nv TSH values remain relatively constant. Changes in the Nv of T4-positive and TSH-binding cells over developmental time are discussed with regard to pituitary regulation of the chick embryo thyroid and the possible contribution of the yolk to circulating T4 levels.
Animals↗
Discrepant INR values strike again.
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Animals↗
Hybridomas to specific streptococcal antigen induce tissue pathology in vivo; autoimmune mechanisms for post-streptococcal sequelae.
A gross examination of organs from approximately 100 mice which were producing ascites fluids toward a series of streptococcal reactive monoclonal hybridomas showed, in some animals, what appeared to be autoimmune-like findings. A pattern of major lung pathology was associated with specific clones. These specific hybridomas led to the development of an experimental autoimmune animal model mimicking a Goodpasture's syndrome. Tissue injury was induced in mice, on a dose dependent basis, by the injection of monoclonal antibody generated against streptococcal cell membrane (SCM) antigens. A more severe onset of the pathology, also on a dose dependent bases, was induced by placement of the anti-SCM mAb secreting hybridoma cells into the peritoneal cavity of the host. Severity of observed lesions was dependent upon the number of cells injected (10(5), 5 x 10(5), 10(6) or 10(7], as well as the animals' sex. Severe and total hemorrhagic lungs were seen in animals challenged with 1 x 10(6) hybridomas cells when sacrificed on the tenth day. In all cases the lesions were greater in the female litter mate than the male. Gross and histologic observations were confirmed by lung/body weight ratios. Pulmonary hemorrhage ranged from slight, when mAb was injected at a low dose of 24 micrograms/g, to severe when 96 micrograms/g was injected. Reported findings were based on the review of approximately 300 mice. Immunochemical evaluations and ELISAs confirmed the ability of these anti-SCM mAb to react with glomerular basement membrane (GBM) antigens as well as lung basement membrane (LBM). Mitogenic experiments indicated that the parent immunogen (SCM) used to generate immunocytes was non-stimulatory to lymphocytes.
Animals↗