Alpha and beta cell evaluation in patients with thalassaemia intermedia and iron overload

Insulin and glucagon secretion were studied during an oral glucose tolerance test and arginine infusion in 11 patients with thalassaemia intermedia, who showed laboratory evidence of iron overload. Mean blood glucose concentrations in patients with thalassaemia intermedia were significantly higher than normal and 3 of 11 patients had impaired glucose tolerance. The principal abnormality appears to be a deficiency in insulin and glucagon from the pancreas in response to oral glucose tolerance and arginine stimulation tests. Several factors, such as iron overload, chronic hypoxia, zinc deficiency and increased catecholamine production secondary to anaemia, might play a part in the pathogenesis of these abnormalities. Each of these factors affect individual cases to a varied degree. Our data emphasize the mildness of carbohydrate defect as compared to the degree of insulinopenia and indicate the necessity for prescribing measures which prevent excessive iron deposition and improve iron excretion in thalassaemic patients with iron overload.     

Combined oral and parenteral iron chelation in beta thalassaemia major

Thalassaemics in Malaysia are poorly chelated because desferrioxamine is too expensive and cumbersome for long term compliance. The efficacy and tolerability of the oral chelator deferiprone, and the effects of using a combination therapy in our patients were studied. Ten patients completed the study and the mean serum ferritin reduced from 7066.11 ug/L (2577-12,896 ug/L) to 3242.24 ug/L (955-6120 ug/L). The liver iron concentration did not show a significant drop (19.6 vs 18.2 mg/g dry weight) although 3 patients showed reductions ranging from 30-40%. Concomitant use of desferrioxamine increased the urinary excretion from a mean of 13.66 mg/day to 27.38 mg/day. Main side effects seen were nausea and rashes.     

Iron overload despite partial gastrectomy

Iron overload was found in 3 patients who had undergone partial gastrectomy: a 61-year-old woman developed iron overload because she may have had idiopathic haemochromatosis and had also been given parenteral iron; in a 62-year-old man with thalassaemia minor, iron overload may have developed because of increased oral iron ingestion, low serum folate, increased, albeit ineffective, erythropoiesis and sideroblastic anaemia; a 74-year-old man with thalassaemia minor developed iron overload without exogenous therapy and died from a hepatoma. These cases illustrate that partial gastrectomy fails to protect patients from developing iron overload, particularly if given uncontrolled iron therapy.     

Tinnitus in a patient with beta-thalassaemia intermedia on long-term treatment with desferrioxamine.

A women with beta-thalassemia intermedia, and iron overload following many years'' treatment with oral iron, was treated with subcutaneous desferrioxamine. During the course of this treatment she developed tinnitus, which was considered to be a rare complication of the use of this chelating agent. The mechanism of this effect is not understood.     

Thalassaemia control in developing countries--the Sri Lankan perspective

Beta thalassaemia is a Mendelian recessive disorder. The economic and social cost of the disease is high due to patients' life long need for monthly blood transfusions and treatment with desferrioxamine, an iron chelating agent. Wider availability of cheaper drugs is on the horizon. If there is no concomitant reduction in the number of new thalassaemia major births, there will be a cumulative increase in numbers requiring treatment. The frequency and severity, and the economic and social costs of thalassaemia, support the case for the introduction of a carrier screening and counselling program in Sri Lanka. A three-pronged plan emphasising professional, political and public education in outlined.     

Endocrinopathies in patients with thalassemias

Thalassemia major is a hereditary disorder of hemoglobin synthesis resulting in severe anemia. Treatment consists of multiple blood transfusions, a complication of which is iron overload. Excessive iron is then deposited in almost all tissues but primarily in the liver, heart and the endocrine glands. Lately, desferrioxamine has been used as a chelating agent in an attempt to prevent the complications of tissue damage by iron deposition. Early introduction of the chelating agent to combat iron overload in vulnerable organs leads to improved life expectancy. However, these patients often present with multiple endocrine dysfunction such as growth failure, hypogonadism, abnormalities in glucose metabolism, hypothyroidism, hypoparathyroidism and less frequently hypoadrenalism. We briefly review the current status of endocrine gland abnormalities in patients with thalassemia major.     

Iron-chelating and anti-lipid peroxidation properties of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in long-term iron loading β-thalassemic mice

ObjectiveTo evaluate the iron-chelating properties and free-radical scavenging activities of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) treatment in chronic iron-loaded β-thalassemic (BKO) mice.MethodsThe BKO mice were fed with a ferrocene-rich diet and were orally administered with CM1 [50 mg/(kg.day)] for 6 months. Blood levels of non-transferrin bound iron, labile plasma iron, ferritin (Ft) and malondialdehyde were determined.ResultsThe BKO mice were fed with an iron diet for 8 months which resulted in iron overload. Interestingly, the mice showed a decrease in the non-transferrin bound iron, labile plasma iron and malondialdehyde levels, but not the Ft levels after continuous CM1 treatment.ConclusionsCM1 could be an effective oral iron chelator that can reduce iron overload and lipid peroxidation in chronic iron overload β-thalassemic mice.     

Thalassaemia: a study on the perception of patients and family members

Marked improvement in the management of thalassaemia has not been matched by progress in psychosocial rehabilitation as thalassaemia continues to pose challenges to patients and their family members. Few studies have been carried out in Malaysia to look at such issues. This study is therefore to explore the concerns, beliefs and feelings about thalassaemia. It was conducted in the year 2009 over 7 months on "focus groups", in patients aged 8-22 years and parents attending Paediatric Clinic of Tengku Ampuan Afzan Hospital, Kuantan, Pahang. Results showed that concerns and adverse impact were related to lower grades in education, poor self-image, less chance of employment, marriage, financial burden and social integration. Compliance to subcutaneous iron chelator was poor. There were various concerns related to blood transfusion therapy. It is evident that thalassaemia greatly affects the psychosocial dimensions and a more structured long term psychosocial support is needed to improve quality of life of patients.     

Endocrine complications in transfusion dependent thalassaemia in Penang Hospital

Frequent blood transfusions can lead to iron overload which may result in several endocrine complications especially in the absence of adequate chelation therapy. The objectives of this study are to determine the prevalence of endocrine complications in transfusion dependent thalassaemia patients and the correlation of endocrine complications with the degree of iron chelation. This retrospective study looked at cases of adult patients with transfusion dependent thalassaemia treated in the Haematology Unit, Penang Hospital. Of the 25 transfusion dependent thalassaemia patients, there were 10 male and 15 female patients respectively with almost equal number of Malay and Chinese patients (13 and 12 patients respectively). Short stature was seen in 36.0% of our patients. In our cohort, 12 patients had delayed puberty (male 70.0% and female 33.3%). Prevalence of osteoporosis was 36.0%. Hypogonadism was noted in 40.0% of males and 46.7% of females. 53.4% of the female population had menstrual abnormalities with prevalence of primary and secondary amenorrhoea at 26.7% each. The prevalence of other endocrinopathies was much lower: 8.0% had diabetes mellitus and only one patient had hypocortisolism. Iron chelation appeared insufficient in our study population. The high frequency of endocrine complications noted in our study supports the rationale for regular follow-up of transfusion dependent thalassaemic patients to ensure early detection and timely treatment of associated complications.     

Hearing loss attributed to desferrioxamine in patients with beta-thalassaemia major

Sensorineural hearing loss was detected in nine (33%) of 27 patients with beta-thalassaemia major. All were receiving regular hypertransfusion and nightly subcutaneous infusions of desferrioxamine. A retrospective analysis of these patients was undertaken to determine the risk factors for the development of deafness. No statistically significant differences were found between the affected and unaffected groups with respect to age, ferritin levels or lengths of time that they had received desferrioxamine, but the trends were similar to those reported by other authors. However, the desferrioxamine dosage was similar in both our groups (less than 60 mg/kg a day), and lower in the affected group than other authors have reported. Two patients experienced some resolution of their deafness when their dosage of desferrioxamine was lowered. These results suggest that the ototoxic effect of desferrioxamine is dose-related and can occur at relatively low doses of the drug.     

Cobalt Excretion Test for the Assessment of Body Iron Stores

Iron absorption is under delicate control and the level of absorption is adjusted to comply with the body's need for iron. To measure the intestinal setting for iron absorption, and thereby indirectly assess body iron requirements, cobaltous chloride labelled with ⁵⁷Co or ⁶⁰Co was given by mouth and the percentage of the test dose excreted in the urine in 24 hours was measured in a gamma counter. Seventeen control subjects with normal iron stores excreted 18% (9-23%) of the dose. Increased excretion, 31% (23-42%), was found in 10 patients with iron deficiency anemia and in 15 patients with depleted iron stores in the absence of anemia. In contrast, 12 patients with anemia due to causes other than iron deficiency excreted amounts of radiocobalt within the normal control range. In patients with iron deficiency, replenishment of iron stores by either oral or parenteral iron caused the previously high results to return to normal.

Excretion of the test dose was normal in portal cirrhosis with normal iron stores but it was markedly increased in patients with cirrhosis complicated by either iron deficiency or endogenous iron overload. It was also raised in primary hemochromatosis. Excretion of the dose was reduced in gluten-sensitive enteropathy. Gastrointestinal surgery and inflammatory disease of the lower small intestine had no effect on the results except that some patients with steatorrhea had diminished excretion.

The cobalt excretion test provides the clinician with a tool for the assessment of iron absorption, the detection of a reduction in body iron stores below the level that is normal for the subject in question, the differentiation of iron deficiency anemia from anemia due to other causes, and the investigation of patients with iron-loading disorders.

     

Assessmrent of iron overload in thalassaemic patients by magnetic resonance imaging: a pilot study

The patients of thalassaemia major need repeated blood transfusion which leads to excess iron deposition in various organs like liver, heart, pituitary etc. This iron accumulation causes various complications and ultimately organs' failure. There is no non-invasive, standard and reliable method to know the status of iron overload in various organs of the body. This paper attempts to use magnetic resonance imaging to know the liver iron overload in 8 thalassaemic patients as a pilot study. Eight children suffering with thalassaemia and 3 controls who were the normal siblings of the patient group underwent magnetic resonance imaging of the abdomen using spin-echo T, weighted sequence. Blood serum ferritin levels in the patients' group were also determined on the same day of magnetic resonance imaging examination. It was observed that the ratio of magnetic resonance imaging signal intensity (in spin-echo T1 weighted image) in paraspinous muscle to liver was significantly different in normal control (0.65) compared to that in thalassaemia patients (2.1 to 11.4 depending upon extent of iron deposition). The magnetic resonance signal intensity ratio correlated with the blood serum ferritin level of patients (p = 0.01) which is generally taken as indirect measure of body iron burden. Spin-echo sequence is the simplest imaging sequence and it increases the chance of its routine use. The study concludes that magnetic resonance imaging has good potential to quantify the liver iron deposition non-invasively and may denote the efficacy of iron-chelation therapy which is used to reduce the body iron burden in these patients.     

以尿钙排泄量为效应指标评价枸橼酸氢钾钠颗粒人体生物等效性

目的以24h尿液钙离子累计排泄量为指标,比较国产和进口枸橼酸氢钾钠颗粒剂的生物等效性。方法36名男性健康志愿者按自身交叉设计,随机口服枸橼酸氢钾钠颗粒剂的受试制剂（国产）或参比制剂（进口）5．0g,（洗脱期7d）。分别收集给药前（空白）和给药后0～2、2～4、4～6、6～8、8～10,10-2、12～24h的尿液,记录尿量,采用原子吸收分光光度法测定尿液钙离子浓度,计算给药前、后24h尿液钙累积排泄量。结果受试制剂给药前、后24h尿钙累积排泄量为（128．47±76．45）mg和（163．53±81．28）mg;参比制剂给药前、后24h尿钙累积排泄量为（128．34±59．55）mg和（179．65±103．96）mg。给予受试制剂和参比制剂后24h尿钙排泄量分剐比用药前增加（35．06±61．26）mg和（51．31±73．18）mg,两制剂间没有显著性差异（P〉0．05）。结论国产和进口枸橼酸氢钾钠颗粒剂具有生物等效性,尿液钙离子累计排泄量可用于国产和进口构橼酸氢钾钠颗粒剂生物等效性评价。     

Are thalassemia patients oxidatively challenged?

BackgroundRepeated blood transfusions is the mainstay of treatment for beta thalassemia major patients. Multiple blood transfusions lead to significant iron overload in these patients. Iron overload causes liberation of oxygen free radicals and peroxidative lipid injury. This study has been designed to study whether thalassemics suffer from oxidative injury. It also aims to study the quantum of oxidative injury.MethodsIt is a cross sectional study using cases and controls. Thirty thalassemic patients receiving multiple blood transfusions were included in this study and thirty healthy age and sex matched controls were recruited for the study. Serum ferritin levels, malondialdehyde, nitric oxide levels were estimated.ResultsLevels of all the three parameters were significantly increased (p < 0.05) in the cases compared to controls. Mean levels of all three parameters were correlated with serum ferritin levels and number of blood transfusions in increasing order. All the parameters showed fair degree of correlation (r ≥ 0.25, p ≤ 0.05).ConclusionThalassemic patients receiving multiple blood transfusion suffer from iron overload which results in increased oxidative stress.     

Providing a cure for beta thalassaemia major

The current treatment options for beta thalassaemia major patients include conservative treatment with blood cell transfusions and iron chelation or stem cell transplantation. Regular blood transfusions inevitably lead to multi-organ haemosiderosis and are attended by risks of blood-borne infections. Results from stem cell transplantation are good and suggest that this should be offered as first line therapy when a matched sibling donor is available because the patient is often cured and able to live a normal life. Of 38 Malaysian children who underwent bone marrow or cord blood transplantations using matched sibling donors, 29 (76%) are now cured.     

Urinary iron loss in the nephrotic syndrome--an unusual cause of iron deficiency with a note on urinary copper losses.

Two patients with long-standing nephrotic syndrome are described in whom urinary iron losses may have contributed towards an iron deficiency state. Seven other nephrotic patients were also studied. Increased urinary iron excretion was found in six out of nine patients and increased urinary copper excretion in all eight patients in whom it was measured. Trace metal losses in the urine in nephrotics may be important clinically.     

Resistance to recombinant human erythropoietin due to aluminium overload and its reversal by low dose desferrioxamine therapy.

Seventeen severely anaemic and transfusion-dependent haemodialysis patients with a haemoglobin less than 7 g/dl were treated with recombinant human erythropoietin (r-Hu-EPO). Aluminium toxicity was diagnosed by a positive desferrioxamine (DFO) test and bone biopsy. Seven out of eight patients without aluminium toxicity responded to r-Hu-EPO therapy. Similarly all patients with aluminium toxicity (n = 4) but pre-treated with standard dose of DFO prior to r-Hu-EPO therapy responded but none of the patients with untreated aluminium toxicity (n = 5) responded to r-Hu-EPO therapy. In order to achieve adequate response in these patients, r-Hu-EPO and DFO had to be given in combination. The dose of desferrioxamine used to reverse r-Hu-EPO resistance was less and also used for a short time. We therefore confirm r-Hu-EPO resistance owing to aluminium overload and report its successful and safe reversal with low dose DFO therapy.     

排氚片对小鼠体内氚的促排作用

【目的】评价排氚片对动物体内氚的促进排出作用。【方法】以氚水一次性腹腔注射建立ICR雄性小鼠染毒模型,用低、中、高三个剂量【生药6．5、13．0、26．0g·（kg·d）-1】排氚片连续灌胃10d,以小鼠代谢笼法收集灌胃后不同时间点2h或4h内的排尿量,液闪测量尿液放射性计数,计算各时间点尿中单位时间的氚排出量,同时于灌胃第10d取血并处死小鼠,测定血清及各脏器组织中氚的滞留量。【结果】排氚片各剂量组尿氚排出效果均较阴性对照组为佳,且以中剂量组最佳,低剂量组次之,高剂量组反而最差;排氚片中、低、高剂量组血清氚滞留量分别较阴性对照组减少67．4％、43．9％和32．5％;各脏器组织中氚滞留量较阴性对照组降低程度依次为中剂量组〉低剂量组〉高剂量组。【结论】6．5～26．0g·（kg·d）。排氚片生药对小鼠体内氚具有显著的促进排出作用。促排效果以中剂量13．0g·（kg·d）-1为最佳;低剂量6．5g·（kg·d）-1次之;高剂量26．0g·（kg·d）-1时,促排效果反而下降。     

阿司匹林抗氧化作用机制的探讨

目的 探讨阿司匹林（AS）抗氧化作用的机制。方法 观察不同浓度的AS在抗H2O2损伤内皮细胞过程中诱导铁蛋白（Fn）表达的情况,以及添加外源性FeCI3和细胞内铁螯合剂去铁胺时对AS诱导Fn表达的影响。结果 极低剂量（0．1mmol/L）的AS即可诱导内皮细胞Fn表达超过对照25％（P＜0．05）,使乳酸脱氢酶（LDH）释放率减少50％,保护74．4％的细胞避免H2O2的损伤,同时使氧自由基指标丙二醛明显下降。AS与Fn表达之间表现出剂量与时间依赖关系,且对细胞的保护作用逐渐增强。但使用去铁胺去除细胞内游离铁能明显降低AS诱导Fn表达的作用,而加入FeCI3后诱导Fn表达的作用增强。结论 初步证实AS的抗氧化作用是通过影响细胞内铁代谢变化,增加Fn表达实现的。