The full costs of treating patients with inherited disorders of haemoglobin is extremely variable among countries depending on different health care systems, varying methods of obtaining blood, different practices in screening for blood pathogens and different costs of drugs and equipment. It is evident that all countries would benefit from the sharing of experience and expertise in order to harmonize and optimize the quality of treatment as much as possible. The need for management guidelines for Transfusion Dependent Thalassaemias (TDT) is clear. Throughout the past four years, six major TDT management guidelines became available for use by thalassaemia care givers (TIF, US, Canadian, UK, Italian and Australian Guidelines). A comparison among those guidelines has been recently published (Musallam KM et al. Acta Haematologica 2013). In light of a swiftly evolving evidence, the need for revisiting and updating TDT management recommendations remains crucial. More importantly, ensuring access to such guidelines and careful application and implementation should only help arriving at early diagnosis of morbidity to allow prompt and effective management. It would also allow early prediction of risk and would enable preventive measures to be set in place saving unnecessary health care costs.This updated third edition of the TIF guidelines will offer valuable information to all allied healthcare professionals involved in the treatment of patients with TDT. It includes updated information on new approaches for more effective, safe and less laborious treatment, and an overview of the progress achieved to date towards a total cure using methods such as gene therapy and stem cell transplantation.

Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT)

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on the essential composition of infant and follow-on formula. This opinion reviews the opinion provided by the Scientific Committee on Food in 2003 on the essential requirements of infant and follow-on formulae in light of more recent evidence and by considering the Panel’s opinion of October 2013 on nutrient requirements and dietary intakes of infants and young children in the European Union. The minimum content of a nutrient in formula proposed in this opinion is derived from the intake levels the Panel had considered adequate for the majority of infants in the first six months of life in its previous opinion and an average amount of formula consumed during this period. From a nutritional point of view, the minimum contents of nutrients in infant and follow-on formula proposed by the Panel cover the nutritional needs of virtually all healthy infants born at term and there is no need to exceed these amounts in formulae, as nutrients which are not used or stored have to be excreted and this may put a burden on the infant’s metabolism. Therefore, the Panel emphasises that maximum amounts should be interpreted not as target values but rather as upper limits of a range which should not be exceeded. © European Food Safety Authority, 2014

https://orbit.dtu.dk/files/102968574/infant_formula.pdf

Scientific opinion on the essential composition of infant and follow-on formulae.

The combination of transfusion and chelation therapy has dramatically extended the life expectancy of thalassemic patients. The main objective of this study is to determine the prevalence of prominent thalassemia complications. Two hundred twenty patients entered the study. Physicians collected demographic and anthropometric data and the history of therapies as well as menstrual histories. Patients have been examined to determine their pubertal status. Serum levels of 25(OH) D, calcium, phosphate, iPTH were measured. Thyroid function was assessed by T3, T4 and TSH. Zinc and copper in serum were determined by flame atomic absorption spectrophotometry. Bone mineral density (BMD) measurements at lumbar and femoral regions have been done using dual x-ray absorptiometry. The dietary calcium, zinc and copper intakes were estimated by food-frequency questionnaires. Short stature was seen in 39.3% of our patients. Hypogonadism was seen in 22.9% of boys and 12.2% of girls. Hypoparathyroidism and primary hypothyroidism was present in 7.6% and 7.7% of the patients. About 13 % of patients had more than one endocrine complication with mean serum ferritin of 1678 ± 955 micrograms/lit. Prevalence of lumbar osteoporosis and osteopenia were 50.7% and 39.4%. Femoral osteoporosis and osteopenia were present in 10.8% and 36.9% of the patients. Lumbar BMD abnormalities were associated with duration of chelation therapy. Low serum zinc and copper was observed in 79.6% and 68% of the study population respectively. Serum zinc showed significant association with lumbar but not femoral BMD. In 37.2% of patients serum levels of 25(OH) D below 23 nmol/l were detected. High prevalence of complications among our thalassemics signifies the importance of more detailed studies along with therapeutic interventions.

/pdf/metabolic-and-endocrinologic-complications-in-beta-4hwcif01d6.pdf

Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a Scientific Opinion on the nutrient requirements and dietary intakes of infants and young children in the European Union. This Opinion describes the dietary requirements of infants and young children, compares dietary intakes and requirements in infants and young children in Europe and, based on these findings, concludes on the potential role of young-child formulae in the diets of infants and young children, including whether they have any nutritional benefits when compared with other foods that may be included in the normal diet of infants and young children. The Panel concluded on the levels of nutrient and energy intakes that are considered adequate for the majority of infants and young children, and evaluated the risk of inadequate nutrient intakes in infants and young children in living Europe. Dietary intakes of alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), iron, vitamin D and iodine (in some European countries) are low in infants and young children living in Europe, and particular attention should be paid to ensuring an appropriate supply of ALA, DHA, iron, vitamin D and iodine in infants and young children with inadequate or at risk of inadequate status of these nutrients. No unique role of young-child formulae with respect to the provision of critical nutrients in the diet of infants and young children living in Europe can be identified, so that they cannot be considered as a necessity to satisfy the nutritional requirements of young children when compared with other foods that may be included in the normal diet of young children (such as breast milk, infant formulae, follow-on formulae and cow‘s milk). © European Food Safety Authority, 2013

Scientific Opinion on nutrient requirements and dietary intakes of infants and young children in the European Union

In this review a broad overview of historical and current methods for the assessment of iron bioavailability was given. These methods can be divided into iron solubility studies, iron absorption studies, endpoint measures, and arithmetic models. The pros and cons of all methods were discussed. First, studies on in vitro and in vivo iron solubility have been described. The disadvantages of iron solubility include the impossibility of measuring absorption or incorporation of iron. Furthermore, only the solubility of nonheme iron, and not heme iron, can be studied. Second, we focused on iron absorption studies (either with the use of native iron, radioiron or stable iron isotopes), in which balance techniques, whole-body counting or postabsorption plasma iron measurements can be applied. In vitro determination of iron absorption using intestinal loops or cell lines, was also discussed in this part. As far as absorption studies using animals, duodenal loops, gut sacs or Caco-2 cells were concerned, the difficulty of extrapolating the results to the human situation seemed to be the major drawback. Chemical balance in man has been a good, but laborious and expensive, way to study iron absorption. Whole-body counting has the disadvantage of causing radiation exposure and it is based on a single meal. The measurement of plasma iron response did not seem to be of great value in determining nutritional iron bioavailability. The next part dealt with endpoint measures. According to the definition of iron bioavailability, these methods gave the best figure for it. In animals, the hemoglobin-repletion bioassay was most often used, whereas most studies in humans monitored the fate of radioisotopes or stable isotopes of iron in blood. Repletion bioassays using rats or other animals were of limited use because the accuracy of extrapolation to man is unknown. The use of the rat as a model for iron bioavailability seemed to be empirically based, and there were many reasons to consider the rat as an obsolete model in this respect. The double-isotope technique was probably the best predictor of iron bioavailability in humans. Disadvantages of this method are the single meal basis and the exposure to radiation (as far as radioisotopes were used). Finally, some arithmetic models were described. These models were based on data from iron bioavailability studies and could predict the bioavailability of iron from a meal.

The concept of iron bioavailability and its assessment.

Iron status and intake of older infants fed formula vs cow milk with cereal.

Abnormal growth is a common feature of thalassaemia major in children. In an attempt to determine whether it has a nutritional cause, 12 children aged 1 to 3 years with thalassaemia major were studied under metabolic ward conditions. Nutritional status was assessed by anthropometry and biochemistry before and after an intensive nutrition regimen. Five children had wasting or stunting on admission. As a result of the nutrition intervention, mean weight for height improved significantly. The mean height increase of 0.4 cm after one month was not significant. Plasma zinc, depressed in half the children on admission, improved, as did alpha tocopherol, while copper decreased. Plasma insulin-like growth factor-I also increased commensurate with improved growth. Fat absorption was normal in all children. Undernutrition is an important cause of associated growth disturbances in children with thalassaemia major. Malnutrition was primarily caused by inadequate nutrient intake, as indicated by the capacity to gain weight appropriately when provided with nutrition support, and by the absence of intestinal malabsorption. While long term studies are required to determine if nutritional support will prevent stunting, these results underscore its central role in preventing nutritional deficiencies and in promoting normal growth in thalassaemic children.

https://adc.bmj.com/content/archdischild/74/3/224.full.pdf

Nutritional factors and thalassaemia major.

Concerns that consumption of whole cow milk (WCM) by older infants may result in excessive gastrointestinal blood loss and subsequent iron deficiency led us to perform a prospective, randomized study in 104 infants. Infants were assigned to receive WCM beginning at 6 months or one of three formulas beginning at 4-6 months of age and followed until 12 months of age. Gastrointestinal blood loss was similar for all groups, as determined by both qualitative (Hemoccult II) and quantitative testing (HemoQuant). There was no association between concentration of fecal hemoglobin and volume of WCM consumed or iron status by 12 months of age. Of eight infants (seven WCM, one formula) who became iron-depleted, none had excessive fecal hemoglobin excretion. When pooled and analyzed regardless of feeding group, fecal hemoglobin increased with age and was greater at 11 and 12 months than at younger ages. We conclude that although infants fed WCM are at increased risk of developing iron depletion, the iron insufficiency is not due to gastrointestinal blood loss. We further conclude, based on our sample of normal infants age 4-12 months, that fecal hemoglobin concentrations of 0.5-0.8 mg/g stool correspond to the upper limits of normal, values much lower than in adults.

Gastrointestinal blood loss in older infants: impact of cow milk versus formula.

Twelve thalassaemic children under 3 years of age received intensive nutritional support for one month and were discharged on a prescribed diet of locally available foods. Anthropometry, bioelectrical impedance analysis and dietary intake were longitudinally assessed. Mean energy intake was 20% greater than the recommended daily allowance during nutritional supplementation as compared with below the recommended daily allowance before and after the period of nutritional support. Weight, but not height, significantly increased during the support period and was due to increases in both fat free mass and fat mass. Body weight, fat free mass and fat mass declined in line with the reduced intake upon return home; however, height velocity accelerated and exceeded normal through the fourth month before resuming a below normal rate. It can be concluded that (1) nutritional stunting as the result of reduced nutrient intake is an important cause of growth failure in young children with thalassaemia and is responsive to nutritional support, (2) the deficit in height velocity was due to retarded truncal height growth, and (3) the bioelectrical impedance analysis method is suitable for body composition analysis of thalassaemic children.

https://adc.bmj.com/content/archdischild/76/6/509.full.pdf

Nutritional support and growth in thalassaemia major.

Objective. To determine the effects of feeding regimens of varying fat composition on dietary intake and serum lipid and lipoprotein concentrations in older infants. Design, setting, and participants. One hundred four healthy infants aged 4 to 6 months were enrolled from private pediatric practices or public health clinics and were randomly assigned to one of four feeding groups until 12 months of age. Interventions. Infants received whole cow milk or a standard infant formula (48% to 49% of energy as fat from butterfat or a soy-coconut oil blend, respectively) or one of two nearly identical investigational lower fat follow-up formulas (36% kcal from a fat blend of palm olein, corn, and safflower oils) as their primary food source in addition to table foods. Main outcome measures. Nutrient intakes during the study period were characterized qualitatively and quantitatively. Serum lipids, lipoprotein concentrations, and anthropometrics were determined at baseline and at 12 months of age (study completion). Results. Total energy intake was equivalent among feeding groups. Infants fed cow milk had higher mean daily intakes of total fat, saturated fat, monounsaturated fat, and cholesterol. Linoleic acid intake by infants fed cow milk, including that from table foods, was insufficient to meet current recommendations. Mean serum total cholesterol was significantly higher in the infants fed cow milk at age 12 months, whereas mean low density lipoprotein and apolipoprotein B were lower in the infants fed the follow-up formulas. Infants consuming the infant formula or whole cow milk demonstrated greater increases in mean serum total cholesterol, low density lipoprotein, and apolipoprotein B by 12 months of age compared with infants ingesting follow-up formula. Ponderal, linear, and head circumference growth was equivalent among feeding groups. Conclusions. (1) Older infants fed lower fat formula have adequate total energy intake and normal growth. (2) The fat composition of the diets fed to the infants influenced serum lipid and lipoprotein profiles. (3) The fat composition of cow milk is inferior compared with commercial formulas. (4) The optimal fat blend for older infants including the consequences of the standard practice of adding high percentage of coconut oil to infant formulas should be defined further.

Marianne DeWier

Papers

Iron status and intake of older infants fed formula vs cow milk with cereal.

Nutritional factors and thalassaemia major.

Gastrointestinal blood loss in older infants: impact of cow milk versus formula.

Nutritional support and growth in thalassaemia major.

Effect of Dietary Fat on Cardiovascular Risk Factors in Infancy