Ninth Cooley's Anemia Symposium

Agenda

*Presentation times are subject to change

Day 4: Saturday, October 24

Nutritional Deficiencies in Patients with Thalassmia

Ellen B. Fung, PhD RD, Elliott Vichinsky, MD, Children’s Hospital & Research Center at Oakland, Oakland, CA

Optimal nutritional status is imperative for achieving the genetic potential for growth and pubertal development in children as well as for robust immune function and bone health in adults. Patients with thalassemia are known to have abnormal growth, altered pubertal development and immune function as well as deficits in bone mineral acquisition. The etiology of these co-morbidites is typically ascribed to the toxic effects of transfusion related iron-overload. Though the relationship of nutritional status to abnormal growth, pubertal development, immune status and bone health has been shown in other chronic diseases, few studies have specifically focused on aspects of nutritional status and its relationship to health in patients with thalassemia.
Over the last decade, our group and others have observed deficiencies of up to 75% of patients studied in vitamins C, D, and selenium and up to 40% of patients appear deficient in copper, zinc, folate and other B vitamins. Typically, depleted circulating levels of nutrients have been observed despite seemingly adequate dietary intake. This disconnect between intake and circulating levels suggest that patients with thalassemia may have increased needs for certain nutrients due to either poor nutrient absorption, elevated losses or increased nutrient turnover.

Dairy intake and weight bearing physical activity are reduced in subjects with thalassemia and are related to poor bone health. Alternatively, higher fat mass has been shown to be protective in both transfused and non-transfused patients. These preliminary findings will be shared, in addition to results from an ongoing placebo controlled trial of zinc supplementation on bone health. Alternative therapies which utilize nutrient and antioxidant supplementation in addition to increased physical activity may improve nutritional status and overall health in this population, as well as decrease long term co-morbidities such as reduced bone mass.

Nutrition and Antioxidant Therapies in Thalassemia

Ashutosh Lal, M.D^1,2, Novie Ko, BS¹, Elliott Vichinsky, MD², Bruce Ames, PhD¹, Jung H Suh, MPH PhD^{1. 1}Children’s Hospital Oakland Research Institute, ²Hematology/Oncology, Children’s Hospital & Research Center at Research Center Oakland, Oakland, CA

The contribution of micronutrient deficiencies to the disease burden experienced by individuals with thalassemia may be considerable. Micronutrient depletion in thalassemia is appropriately considered in the context of iron overload and chelation therapy, and antioxidant defenses have received the most attention. The prevalence of certain deficiencies, particularly vitamin C, vitamin E, vitamin D, zinc and copper, is common, and can promote or worsen pathophysiologic mechanisms such as oxidative stress, immune dysfunction and bone mineral deficits. Chronic increase in free radical production can interfere with metabolism through oxidative modification of proteins and lipids. A metabolomics approach utilizing high-throughput liquid chromatography linked tandem mass spectrometric analysis of metabolites can demonstrate metabolic changes in response to sub-optimal nutrition. Using this approach, differences in the sulfur amino acid metabolism between thalassemia major and control subjects were detected in the plasma and also within the transfused donor red blood cells. The glutathione pool is expanded with accumulation of precursor compounds, but a significantly higher proportion of glutathione and cysteine exist in the oxidized state. Characterization of the compensatory mechanisms would help towards targeted interventions to restore the plasma and red cell redox balance. We propose gauging the utility of antioxidant therapy based on its remediating effects on altered metabolism, instead of specific markers of oxidative damage. Nutritional interventions should occur in the background of stable and effective chelation and transfusion therapies. The eventual goal is to evaluate whether target organ damage in thalassemia can be diminished through maintenance of optimal micronutrient status and the control of systemic oxidative stress.

Ferritin Regulation For Antioxidant Protection, And Iron Nutrition

Elizabeth C. Theil, CHORI (Children's Hospitals and Research Center Oakland), Oakland, USA; University of California, Berkeley, CA

Iron/oxygen reactions, the source of much oxidant damage, are also the substrates for cellular ferritin catalysis used to make the ferritin iron and oxygen mineral, ferrihydrite. Cellular ferritin functions as an oxidant protector by consuming iron and oxygen. Recent data show that ferritin genes are regulated by the same inducers that regulate oxidant protection enzymes such as quinone reductase and thioredoxin reductase.

In normal health, the cellular ferritin mineral i is a biological iron concentrate, inside the protective ferritin protein cage, that is used to synthesize iron–proteins such as hemoglobin and metabolic enzymes. During iron overload cellular ferritin also traps excess iron. Most of the iron in iron overload is in cellular ferritin and degraded ferritin (hemosiderin). Cellualr ferritin synthesis is increased in iron overload by removing a regulator that inhibits ferritin mRNA function. Usually the effect is so small that the iron content of ferritin increases causing protein damage and ferritin conversion to toxic hemosiderin.

Three novel ways to manipulate ferritin that can minimize effects of excess iron are:
1. Increase rates of removal of iron from ferritin by unfolding ferritin protein pores.
2. Increase rates of synthesis by targeting ferritin mRNA.
3. Decrease nutritional iron uptake with ferritin-rich (whole legume) foods, since the absorption mechanism is different than for iron salts or heme.
The stage of development of each of the three approaches will be described and new directions defined. Part Support: NIH, Cooley’s anemia and CHORI Foundations

Session IX: Clinical Syndromes in Thalassemia and Disease Severity

Alpha Thalassemia Syndromes

Elliott Vichinsky, MD, Children’s Hospital & Research Center Oakland, CA

Alpha thalassemia is the most common genetic disorder of hemoglobin synthesis, affecting up to 5% of the world’s population. It represents a group of conditions resulting from reduced or absent synthesis of one to all four of the alpha globin genes. Deletional or non-deletional mutations occur on chromosome 16. The severity of the syndrome ranges from completely asymptomatic to fatal in utero. Hemoglobin H disease, a mutation of three alpha globin genes, is more severe than previously recognized. Anemia, hypersplenism, hemosiderosis, growth failure, and osteoporosis are commonly noted as the patient ages. It can occur in all ethnic groups. In California, one in 9000 births has Hemoglobin H disease. Alpha thalassemia major, a usually fatal in utero disease, is now recognized to have a complex molecular and phenotypic expression with increasing births being reported. Surviving newborns without intrauterine transfusion often have congenital anomalies and neurocognitive injury. Serious maternal complications often accompany pregnancy. Doppler ultrasonography with intrauterine transfusion ameliorates these complications.  The high incidence of this disorder in many populations mandates population screening and prenatal diagnosis of at-risk couples. Universal newborn screening has been adopted in several regions, with necessary DNA confirmatory testing.

Phenotype/Genotype Correlation in Thalassemia Intermedia

C.Borgna-Pignatti, MD, Pediatric Department, University of Ferrara, Ferrara, Italy

Thalassemia intermedia is an heterogeneous clinical syndrome, spanning from an almost asymptomatic condition in which the slight anemia is diagnosed during a routine check-up, to a severe disease, often transfusion-independent only at the price of intense medullary expansion and extramedullary erythropoiesis. The pathophysiology of beta-thalassemia depends on the degree of alpha/non alpha globin chain imbalance. Any factor able to decrease the imbalance in homozygous beta thalassemia will improve the clinical picture. These factors include milder thalassemia alleles, increased production of fetal hemoglobin, concurrent alpha thalassemia. On the other hand, there are individuals with heterozygous beta thalassemia in whom the imbalance, and therefore the clinical picture, is made more severe by the co-inheritance of one or more supernumerary alpha globins. Genetic modifiers can also have a role in the development of complications in patients with thalassemia intermedia. The metabolism of bilirubin is influenced by the common A(TA)(n)TAA promoter mutation at the UGT1A1 locus, that has been demonstrated to be a risk factor for gallstones formation. The inheritance of the C282Y or the H63D polymorphism in the HFE gene can increase the iron absorption and make the hemosiderosis, often present in these patients, more severe. Several mutations at the basis of increased thrombophilia in the non thalassemic population could increase the already present thrombotic predisposition. Other as yet nonconclusive studies have investigated the correlation between osteoporosis and genes involved in bone metabolism, or between cardiac disease and the polymorphisms of apolipoprotein ε-4allele or glutathione S-transferase. There is no doubt, however, that the genetic heterogeneity at the basis of the phenotypic variability thalassemia intermedia will continue to be elucidated

Session X: The Adult Thalassemia Patient

Reproductive Issues in Females with Thalassemia

Sylvia T. Singer, MD¹, Annie Higa¹, Nancy Sweeters PNP^1, Olivia Vega BSc¹, Tiffany Chin BAIB¹, Deborah Trevithick PNP², Marcel Cedars MD²

¹Hematology/Oncology and Clinical Research Center at Children’s Hospital and Research Center Oakland CA; ²Division for Reproductive Endocrinology, UCSF,  Oakland, CA

Achievement of reproductive capacity and creating a family has become a great mission for many thalassemia major (TM) patients. Despite recent progress in assessment of reproductive function–there is limited implementation for females with thalassemia. Though infertility is thought to results primarily from iron toxicity to the pituitary-gonadal axis function, the extent of direct toxicity to the ovaries and amount of the ovarian function preserved in TM females is unknown. Since the natural mechanism of follicle aging is thought to result from oxidative stress, it is likely that in thalassemia females iron-induced oxidative damage can result in earlier follicular aging. Currently, there is no good data on the relation of reproductive potential-both pituitary function and ovarian reserve-to iron overload during puberty and adult life. We studied the predictors of reproductive impairment in 23 adult females with TM (median age 29 years, range 17-42). 20/23 had primary or secondary amenorrhea. FSH, LH and estradiol were low or undetectable in 16/23 women. Ovarian reserve testing (ORT) was determined by ultrasound for an antral follicular count (AFC), obtained in 16 women, and showed a poor AFC for age (4-7 follicles) in 10/16 (66%) women, intermediate AFC (8-12) in 3 and a normal AFC in 3 women. Anti-mullerian-hormone (AMH) levels were low (mean=2.9 ng/ml) and declined with age, correlating with AFC (R2=0.006). These findings demonstrate a low ovarian reserve in a majority of adult females with TM. Elevated LIC and NTBI were more prevalent in women with a low ovarian reserve and hypogonadotropic hypogonadism. Further study on the extent of iron load and toxicity and how it relates to ovarian reserve through puberty and adulthood, are needed.

Thrombosis, Stroke and their Prevention

M. Domenica Cappellini, MD¹, Giovanna Graziadei MD¹ , Khaled M. Musallam, MD^2, Ali T. Taher, MD², ¹Universitá di Milano, Policlinico Foundation IRCCS, Milan, Italy, 2American University of Beirut Medical Center, Beirut, Lebanon

The presence of a high incidence of thromboembolic events (TEE) has led to the identification of a hypercoagulable state in the thalassemia syndromes.¹ However, there are relatively few epidemiological data on the overall frequency of these complications. The largest clinical study to date, by Taher et al.², on 8860 thalassemia patients demonstrated that TEE occurred 4.38 times more frequently in thalassemia intermedia (TI) than thalassemia major (TM) patients, with more venous events occurring in TI and more arterial events (including stroke) occurring in TM. The study described age beyond 20 years, splenectomy, transfusion naïvety, family history and previous thrombotic events as the main risk factors for developing TEE. Moreover, in a study done to assess the rate of brain damage in patients with benign hemoglobinopathies, 37.5% of patients with TI showed asymptomatic brain damage on magnetic resonance imaging (MRI).³ More recently, unpublished data by Taher et al.⁴ on splenectomized TI patients observed a 60% rate of silent brain abnormality by MRI rising to 86.7% when combining MRI to position emission tomography (PET). The main risk factors for the development of silent strokes were increasing age and transfusion naïvety. Autopsy findings in thalassemia patients have confirmed hypercoagulability as a pathologic state. Autopsy series in patients with TM and TI describe the presence of DVT, pulmonary embolism and recurrent arterial occlusion, with thrombi in small and large pulmonary vessels.¹ Current understanding of the underlying pathophysiology describes a procoagulant activity of damaged circulating red blood cells (RBCs), co-inheritance of coagulation defects, depletion of antithrombotic factors, endothelial inflammation and conditions that increase thrombotic burden. These factors have been observed at a higher rate in splenectomized patients.⁵ Several studies have identified a role for transfusion therapy to control the rate of TEE since it decreased numbers of pathological RBC exhibiting indices of membrane damage.¹ The available data on the use of anticoagulants, antiplatelet, or other agents in thalassemia are either lacking or involve small, poorly controlled and/or relatively low-quality studies. However, TI patients who experience TEE and receive aspirin afterwards had a lower recurrence.² Treatment with the fetal hemoglobin-inducing agents, hydroxycarbmide and decitabine, results in decreases in plasma markers of thrombin generation. Hydroxycarbamide may decrease coagulation activation by reducing phospholipid expression on the surface of both RBC and platelets and decreasing RBC adhesion to thrombospondin. In addition to being a nitric oxide donor, hydroxycarbamide may also decrease hemostatic activation by its effect in decreasing the white blood cell count and particularly monocytes that express transcription factor. Another approach would be to correct the reactive oxygen species-induced RBC membrane damage using antioxidants, although this approach has not yet been verified in clinical trials.1 It may also be possible to design a thalassemia-tailored thrombosis risk-assessment model (RAM) to estimate thrombotic risk as a function of intrinsic and extrinsic factors. Moreover, tests for predisposing factors could also be performed, particularly in high-risk patients. If clinically verified, this type of model could serve as a guideline for possible preventative treatment to decrease the incidence of TEE, which can cause significant morbidity and mortality.¹

Osteoporosis in Beta-Thalassemia: Pathophysiology and Management

Evangelos Terpos, MD, PhD¹ & Ersi Voskaridou, MD, PhD^2
1Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece & ²Thalassemia Center, Laikon General Hospital, Athens, Greece

Osteoporosis represents a prominent cause of morbidity in patients of both genders with beta-thalassemia major (TM) or thalassemia intermedia. The pathogenesis of bone loss in thalassemia is multifactorial. The delay in sexual maturation, the presence of diabetes and hypothyroidism, the parathyroid gland dysfunction, the accelerated hemopoiesis with progressive marrow expansion, the direct iron toxicity on osteoblasts, the iron chelators, the deficiency of growth hormone or insulin growth factors have been identified as major causes of osteoporosis in thalassemia.

Osteoporosis is a progressive disease; thus prevention and early diagnosis are very important. Adequate hormonal replacement, effective iron chelation, improvement of hemoglobin levels, calcium and vitamin D administration, physical activity, and no smoking consist the main to-date measures for the management of the disease. However, despite the normalization of hemoglobin levels, adequate hormone replacement and effective iron chelation, patients continue to show an unbalanced bone turnover resulting in seriously diminished bone mineral density (BMD). During the last decade, novel pathogenetic data suggest that the reduced osteoblastic activity, which is believed to be the basic mechanism of bone loss in TM, is accompanied by a comparable or even greater increase in bone resorption. Increased levels of receptor activator of nuclear factor-kappaB ligand (RANKL) and bone resorption markers (N- and C-terminal cross-linking telopeptide of collagen type-I) support the presence of increased osteoclast activity in thalassemia patients. Therefore, the role of bisphosphonates, that are potent inhibitors of osteoclast activation, arises as major in the management of osteoporosis in these patients. Oral alendronate and intravenous pamidronate and zoledronic acid have shown efficacy in increasing BMD in thalassemia patients. However, many aspects have to be clarified before the broad use of bisphosphonates in TM-induced osteoporosis: which one? how long? and at what dose?

Other novel agents that stimulate bone formation such as teriparatide, a recombinant peptide fragment of parathyroid hormone and strontium ranelate, a second anabolic agent that prevents osteoporotic fractures in postmenopausal women are being studied but their effects in TM-induced osteoporosis have not been reported to-date. Antibodies against RANKL, such as denosumab, with proven efficacy in postmenopausal osteoporosis and antibodies against dickkopf-1, which has been found to be increased in TM patients with osteoporosis, or against sclerostin (SOST) may be future agents for the effective management of this difficult complication of thalassemia.

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