Chronic granulocytic leukemia in a patient with a renal allograft.

A man received a cadaver renal allograft for end-stage renal failure. After 35 months of immunosuppressive therapy with azathioprine and prednisone, he developed septicemia and a high leukocyte count. In spite of successful treatment of the infection, the leukocyte count continued to rise and a diagnosis of Philadelphia chromosome positive chronic granulocytic leukemia was made. An increased incidence of malignant disease, especially lymphoreticular malignancy, is well described in immunosuppressed patients with allografts. However, the association of chronic granulocytic leukemia and immunosuppressive therapy previously has not been reported. An additional etiological factor in this patient may have been the extensive diagnostic radiological investigations undertaken in childhood. The recent addition of allopurinol to the immunosuppressive therapy has normalized the platelet and leukocyte counts, probably by potentiating mercaptopurine.

Osteoporosis in African hemosiderosis: role of alcohol and iron.

This paper aims to examine the relative contributions made by alcohol and iron overload and hypovitaminosis C to the osteoporosis associated with African hemosiderosis. To characterize this bone disorder, we examined double-tetracycline-labeled iliac crest bone biopsies and serum biochemistry in 53 black male drinkers, 38 with (Fe+) and 15 without (Fe-) iron overload, and in controls. We reasoned that abnormalities found in both patient groups were likely to be caused by alcohol abuse and those found only in the Fe+ group to be caused by iron overload and hypovitaminosis C (iron/C-). The patient groups differed only with respect to greater erosion depth (p < 0.05) and abnormal markers of iron overload in the Fe+ group. Ascorbic acid levels were lower in the Fe+ group than in controls (p < 0.001). Bone volume and trabecular thickness were significantly lower in both patient groups compared with controls and therefore likely caused by alcohol. There were no positive correlations between formation and erosion variables in either patient group, which suggests uncoupling of formation from erosion, possibly as a result of alcohol abuse. Prolonged mineralization lag time associated with thin osteoid seams was found in 32% of patients, affecting both groups. This rules out osteomalacia and suggests osteoblast dysfunction, probably caused by alcohol. The number of iron granules in the marrow correlated with erosion depth (r = 0.373, p < 0.01), trabecular number (r = -0.295, p < 0.05), and trabecular separation (r = 0.347, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects.

The human leukocyte antigen (HLA)-linked iron-loading gene (HFE) associated with the autosomal recessive disorder known as hereditary hemochromatosis occurs in about 10% of subjects of European descent, most of whom are unaffected heterozygotes. In contrast, the 3 to 5 per 1,000 who are homozygotes are at risk of developing severe and potentially lethal iron overload, with damage to a number of organs, including the liver, pancreas, heart, joints, and the endocrine glands. Although the removal of the excess iron by repeated venesections is simple, effective, and safe therapy, much of the organ damage, once it has occurred, is irreversible. Because symptoms are often nonspecific, it is important for physicians in the relevant specialties to develop a high index of suspicion and to apply widely the appropriate screening tests, including transferrin saturation and serum ferritin concentration. Equally important is the detection of affected family members, who are usually siblings, before they have developed significant iron overload. In addition, screening of populations in which the prevalence of hereditary hemochromatosis is high has become an attractive and cost-effective option, especially now that the molecular structure of the HFE gene has been defined. Using this approach it is now possible to detect individuals homozygous or heterozygous for the gene using a simple polymerase chain reaction-based test. The application of this exciting new tool promises to provide fresh insights into the range of phenotypic expression in hereditary hemochromatosis. A challenge for the future will be to define the genetic or environmental factors responsible for iron overload in up to 20% of patients with clinical hemochromatosis who do not have the HFE gene.

Fortification of curry powder with NaFe(111)EDTA in an iron-deficient population: initial survey of iron status.

A survey of iron status was conducted in 984 volunteers (404 males and 580 females) from an Fe-deficient population before an Fe-fortification trial. Hemoglobin, percentage saturation of transferrin, and serum ferritin were used to assess Fe status and to calculate body Fe stores. Almost 30% of males and 60% of females had evidence of Fe deficiency. The distribution of body Fe stores for both males and females was shifted to the left compared with a population in the United States. In females 24% had Fe-deficiency anemia, 13% Fe-deficient erythropoiesis, and 16% depleted stores. Multiple regression analysis failed to show any relationship in women between age, parity, and duration of menses and measurements of Fe status. In males Fe deficiency was more frequent for those less than 18 y and alcohol abusers had increased serum ferritin and calculated body Fe compared with nondrinkers.

Fortification of curry powder with NaFe(111)EDTA in an iron-deficient population: report of a controlled iron-fortification trial.

A targeted, double-blind controlled iron fortification trial using Fe(111)-EDTA in masala (curry powder) was directed towards an Fe-deficient Indian population for 2 y. The Fe status of the fortified group improved more than that of control subjects. Improvement reached significance over control subjects for females in hemoglobin (p = 0.0005), ferritin (p = 0.0002), and body Fe stores (p = 0.001) and for males in ferritin (p = 0.04). The prevalence of Fe-deficiency anemia (IDA) decreased from 22 to 5% in fortified females. Premenopausal women, multipara women, and women with prolonged menstruation or initial IDA benefitted most from fortification. The mean increase in body Fe stores in females with initial IDA was 9.0 +/- 1.3 mmol, representing an increased absorption of 12 mumol/d. Fortified subjects with normal Fe status did not accumulate excessive body Fe and there was no alteration in serum Zn concentrations. Targeted fortification is a safe and effective means of combatting Fe deficiency.

EDTA and the absorption of iron from food.

Iron EDTA is an effective fortificant in meals of low iron bioavailability. Na2EDTA, added to food to prevent oxidation, enhances iron bioavailability by chelating added iron. This study examines the optimal ratio of EDTA to iron causing enhanced iron absorption. Iron absorption from a rice-based meal of low iron bioavailability containing increasing molar ratios of EDTA to iron, was compared in 127 women volunteers by using standard double isotope techniques. Iron deficiency was present in 38% of the women. Mean standardized absorptions, at EDTA-iron ratios of 0.25, 0.5, and 1, were 11.3%, 13.5%, and 8.8%, respectively, compared with 3.8% when no Na2EDTA was present. In meals of high iron bioavailability, Na2EDTA (EDTA:Fe, 1.0) produced little enhancement (potato-based meal) nor inhibited iron absorption (apple-based meal). Na2EDTA added to meals with molar ratios of EDTA to iron between 1.0 and 0.25 significantly increases iron absorption provided the meal is of low iron bioavailability.

Inhibitory effect of nuts on iron absorption.

The effects on iron absorption of nuts, an important source of dietary protein in many developing countries, were measured in 137 Indian women. When the absorption from bread and nut meals (walnuts, almonds, peanuts, and hazelnuts) was compared with that from bread meals, the overall geometric mean absorption from the nut meals (1.8%) was significantly less than from the bread meals alone (6.6%, t = 9.8, p less than 0.0005). In contrast, coconut did not reduce absorption significantly. All the nuts tested contained significant amounts of two known inhibitors of Fe absorption (phytates and polyphenols) but the amounts in coconut were significantly less than in the other nuts. Fifty milligrams ascorbic acid overcame the inhibitory effects of two nuts that were tested (Brazil nuts and peanuts). This is different from that found previously for soy protein, another potent inhibitor of Fe absorption.

Curry powder as a vehicle for iron fortification: effects on iron absorption.

Curry powder was investigated as a vehicle for targeted iron (Fe) fortification, and especially for NaFeEDTA, by assessing its acceptability to consumers and its effects on Fe absorption. A random survey in an Indian community in the Republic of South Africa, indicated that fortified premixed curry powder was acceptable in terms of color, palatability, and stability. The effect of curry powder on Fe absorption from a potato meal was assessed in 64 Indian housewives. Curry powder caused a significant though modest rise in Fe absorption in two of the studies (t = 2.716, p less than 0.05 and t = 3.126, p less than 0.025) but, in the third, the effect was noted only in the more Fe-depleted subjects. There was no enhancement of Fe absorption from a dhal soup of low-Fe bioavailability (t = 0.224, p greater than 0.1). The results of both the human and animal studies suggested that curry powder's overall mild enhancing effect on Fe absorption was due to its capacity to stimulate gastric acid secretion.

Changing patterns of dietary iron overload in black South Africans.

Over the last 17 years there has been a significant reduction in the prevalence and severity of dietary iron overload in urban blacks of Johannesburg. This is attributed to a decrease in the consumption of traditionally brewed beer of high iron content over this period. A 40% reduction was found in hepatic iron concentrations measured in necropsy specimens from 248 male patients who died in 1976 as compared with 220 who died in 1959 and 1960. While hepatic iron concentrations rose with age in both groups there was no evidence of iron accumulation during the period between the two studies. Hepatic iron concentrations measured in 345 female subjects were many fold less than those of males and the 1976 group did not differ significantly from the 1959 to 1960 group. A paradoxical increase in the prevalence of portal fibrosis and cirrhosis was seen and may be due to the effects of increased ingestion of spirits and fortified wine in recent years. Iron overload was significantly greater in males with carcinoma of the esophagus and in those with idiopathic heart failure when compared to subjects who died of other causes. This suggests excessive exposure of these subjects to traditionally brewed beverages and the adulterants present in them.

The relative effect of ascorbic acid on iron absorption from soy-based and milk-based infant formulas.

The effect of varying concentrations of ascorbic acid on the absorption of iron from a soy-based infant milk formula containing 6 mg iron/100 g was examined in 64 adult Indian females using the extrinsic radioactive tag method. The corrected geometric mean absorption from the basic soy formula was only 1.8%. Addition of ascorbic acid in a concentration of 40 mg/100 g, did not significantly increase absorption (3.3%; t = 1.8, p greater than 0.07) but raising the concentration to 80 mg/100 g did so (6.9%; t = 2.4, p less than 0.02). No further significant increase was noted when the concentration of ascorbic acid was increased to 160 mg/100 g (7.7%; t = 0.4, p greater than 0.7). The inhibitory effect of soy on iron absorption was further demonstrated by a direct comparison between the soy-based formula and a similar product based on cows' milk. The comparison was made at two concentrations of ascorbic acid. At 40 mg/100 g the geometric mean iron absorption from the soy formula was 2.4% compared with 5.3% from the milk formula (t = 2.8, p less than 0.02), while the corresponding values at 80 mg ascorbic acid/100 g were 7.2 and 19.5%, respectively (t = 3.4, p less than 0.02). The present results confirm the marked inhibitory effect of soy protein on iron absorption and calculations from the absorption figures suggest that such formulas should contain at least 12 mg/100 g iron together with ascorbic acid in a molar ratio of approximately 4:1 if they are to be adequate in terms of iron nutrition.

Malaria pigment and extracellular iron. Possible target for iron chelating agents.

Extracellular iron is necessary for many biochemical reactions involved in Plasmodium falciparum growth and multiplication. The incorporation of radioactive iron taken up by the parasite was found, electrophoretically and via gamma counting, to be mainly associated with the haemozoin only in the presence of the active metabolism of the parasite. The potent antimalarial activity of desferrioxamine, a ferric iron chelating agent, has shown that iron deprivation is inhibitory to the parasite. We propose that the mechanism of action of desferrioxamine in addition to the chelation of iron from the parasitic compartment, chelates iron from the haemozoin crystal resulting in free radical generation and parasite death. The ability of desferrioxamine and not the ferrous iron chelating agent, 2,2'-bipyridyl, to chelate the non-haem iron from the haemozoin structure indicates that the oxidative state of iron associated with the haemozoin structure is ferric in nature.

Estimation of PR and ER by immunocytochemistry in breast cancer. Comparison with radioligand binding methods.

Immunocytochemical assays for progesterone receptor (PR) using monoclonal antirabbit PR antibodies (PR-ICA) and for estrogen receptor (ER) (ER-ICA) were compared with radioligand binding (dextran-coated charcoal [DCC]) methods for receptor determination in patients with breast cancer. Immunocytochemical staining for PR was exclusively nuclear in localization. In this regard, PR staining is similar to previous findings for ER; PR-ICA showed a sensitivity of 89% and specificity of 100%. ER-ICA was also 89% sensitive and similarly specific. There was good correlation between the degree and intensity of staining and quantitative binding of radioligand. Receptor-positive tumors, however, show considerable variation of immunocytochemical staining, suggesting heterogeneity of cellular PR content. The availability of an immunocytochemical assay for PR increases the discriminatory potential for these methods of receptor determination.

Vincristine, Adriamycin and Dexamethasone (VAD) as Primary Therapy in Advanced Multiple Myeloma: A Single Centre Experience.

Vincristine, adriamycin and dexamethasone (VAD) combination chemotherapy was used as first line therapy in eleven patients with severe myeloma. Eight patients (73%) responded to VAD, six of them achieved complete remission (55%) with paraprotein concentrations falling to zero after a median of three treatment cycles. Median duration of response was 18.5 months with three patients remaining in CR for > 40 months. Median survival for all patients is greater than 62 months. Both infection (two deaths, both non-responders) and a significant decline in cardiac ejection fraction were encountered although only two patients required treatment for cardiac failure. The VAD regimen appears to be an effective first line treatment for severe myeloma producing prolonged survival and rapid response. Further trials with VAD induction followed by maintenance therapy appear to be justified.

The promotive effect of soy sauce on iron absorption in human subjects.

The effects on iron absorption of a traditionally fermented Japanese soy sauce added to soy and rice meals were assessed. The addition of soy sauce to a soy flour meal could not overcome the strong inhibition of iron absorption (geometric mean absorption 7.2 per cent with soy sauce vs. 8.7 per cent without, P = 0.5). However, soy sauce added to a rice meal instead of soy flour significantly improved the geometric mean iron absorption (13.9 per cent with soy sauce vs. 5.2 per cent with soy flour, P = 0.002) and had a promotory effect on absorption from a rice meal alone (11.4 per cent with soy sauce vs. 3.5 per cent without, P = 0.0002). Although soy sauce contains appreciable amounts of organic acids, the addition of 340 mg lactic acid to rice did not enhance iron absorption (3.1 per cent with lactic acid vs. 2.2 per cent without, P = 0.11). The promotory effect of soy sauce on iron absorption appears to be due not only to its lack of soy protein content but may also be due to the presence of fermentation products other than organic acids.

A traditional beverage prevents iron deficiency in African women of child bearing age.

OBJECTIVE: To determine if a traditional item in the diet might be useful in preventing iron deficiency in African women of child-bearing age. DESIGN: In a prospective study, the iron status of women who did and did not drink traditional beer high in iron and folic acid, was compared. Iron status was determined by a combination of haemoglobin, serum ferritin and transferrin saturation. SETTING: The study was conducted amongst rural villagers in the Murehwa and Zaka districts of Zimbabwe and in Mpumalanga Province, South Africa. SUBJECTS: 112 women aged between 12 and 50 y from a population of 425 rural people participating in on-going family genetic studies. RESULTS: Women who consumed traditional beer had significantly higher serum ferritin concentrations and transferrin saturations compared to non-drinkers (P = 0.0001 and 0.03 respectively). Iron deficiency anaemia was not present in drinkers but the prevalence in non-drinkers was 13%. Forty seven percent of the non-drinkers and only 14% of the drinkers had evidence of iron deficiency (P = 0.002). Six (21%) of the drinkers and none of the non-drinkers had evidence of iron overload (transferrin saturation > 55% and serum ferritin > 400 ug/l). CONCLUSION: We conclude that the consumption of traditional beer, rich in iron, protects women against iron deficiency. While the use of an alcoholic beverage is not ideal, our findings suggest that indigenous cultural practices might be successfully employed or adapted for promoting iron nutrition.

A systematic evaluation of bathophenanthroline, ferrozine and ferene in an ICSH-based method for the measurement of serum iron.

The chromogenic substrates ferrozine and ferene were compared to bathophenanthroline disulphonic acid for the measurement of iron concentrations in aqueous and serum samples in an assay based on that of the Iron Panel of the International Committee for Standardisation in Haematology. Ferrozine and ferene were more sensitive than bathophenanthroline. Copper at physiological concentrations in plasma caused only minimal positive interference with all three chromogenic substrates when thioglycollic acid was used as the reducing agent, but when ascorbic acid was used significant positive interference occurred with ferrozine and ferene. Interference due to contaminating haem was comparable with all agents. Bilirubin and carotene produced no interference. Profound reductions in colour development were noted with EDTA plasma.

HLA-linked hemochromatosis and other forms of iron overload.

Inherited forms of iron overload are common. HLA-linked hemochromatosis and possibly African iron overload are associated with a significant risk of developing hepatocellular carcinoma. Early diagnosis and treatment, before substantial iron overloading occurs, reduces morbidity and mortality. HLA-linked hemochromatosis is easily diagnosed, and routine screening in European-derived populations may be appropriate.

Fractured neck of femur in black patients: a prospective study.

We explored the role of iron overload, deficiency of vitamin C and alcohol abuse in the aetiology of cervical and intertrochanteric fractures of the neck of the femur as a result of minor trauma. We studied prospectively 72 patients (45 men, 27 women). Levels of serum iron markers, vitamin C and alcohol markers were measured. Consumption of alcohol was estimated using questionnaires. The findings were compared with those of an age- and gender-matched control group. The mean age of the men was 59.5 years and of the women 66.9 years, with a male predominance. In the men, iron overload, as shown by high levels of serum ferritin (p < 0.001) and deficiency of vitamin C (p < 0.03), as well as abuse of both Western and the traditional type of alcohol, appear to be important aetiological factors. In women, alcohol abuse was also common, but iron markers and levels of vitamin C did not differ significantly from the control group.

Tuberculosis and iron overload in Africa: a review.

Both pulmonary tuberculosis and dietary iron overload are common conditions in sub-Saharan Africa. The incidence of tuberculosis has increased markedly over the last decade, primarily as a result of the rapid spread of infection with the human immunodeficiency virus (HIV). Dietary iron overload affects up to 10% of adults in rural populations and is characterized by heavy iron deposition both in parenchymal cells and in macrophages. Mycobacterium tuberculosis grows within macrophages and, at the same time, the antimicrobial function of macrophages is important in the body's defence against tuberculosis. In vitro, the loading of macrophages with iron reduces the response of these cells to activation by interferon-gamma and diminishes their toxicity against micro-organisms. In the clinical setting, dietary iron overload appears to increase the risk for death from tuberculosis even in the absence of the acquired immunodeficiency syndrome. The combination of dietary iron overload and infection with the HIV, with impaired function of both macrophages and T-cells, may make patients especially vulnerable to tuberculosis. It is possible that the prevention and treatment of dietary iron overload could contribute to the control of tuberculosis in African populations.

Iron deficiency and the developing world.

The dietary intake of iron in underdeveloped countries is based mainly on non-hem iron which is absorbed to a lesser degree that hem iron and is subjected to many interferences from inhibitors generally present in the diets, such as phenols, phytates, fibers, etc. Food fortification with iron is considered to be the best and cheapest long-term approach for correcting the deficiency. The iron source selected for this purpose has to be soluble, and of high bioavailability, even in a diet rich in inhibitors. Ferrochel may prove to be this type of compound.