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Life with DBA Adrianna Vlachos, MD The Feinstein Institute for Medical Research Hofstra North Shore-LIJ School of Medicine Cohen Children’s Medical Center of New York Pros and cons of DBA treatments Pros Corticosteroids Chronic Transfusions Bone marrow transplant No risk of iron overload First line treatment for severe anemia under 1y Can lead to resolution of anemia Can improve quality of life Cons Risk of low bone density Frequent hospital visits for transfusions Risk of Graft versus Host Disease (GVHD), and infection Excess weight gain & impaired growth Endocrine complications of iron overload Risk of graft rejection Increased risk of diabetes (at high doses) Side-effects of immunosuppressive drugs & radiation Lessons from thalassemia Usual progression of Iron overload Accumulation of iron ◦ Liver ◦ Endocrine glands ◦ Heart Skin ◦ Often this is stepwise in thalassemia major ◦ NOT so in DBA – Why?? Iron overload Eventual fibrosis and organ failure ◦ Heart: cardiomyopathy, conduction disturbances arrhythmia ◦ Liver: abdominal pain, elevated LFTs, hepatomegaly fibrosis and cirrhosis ◦ Skin: bronzing and gray pigmentation ◦ Endocrine dysfunction Liver with iron overload Normal liver Iron stain of liver – iron staining in hepatocytes and histiocytes Trichrome stain of liver – medium magnification to show liver cirrhosis with fibrosis and nodules in a patient with hepatic iron overload (no iron stain) Dilated cardiomyopathy with iron overload Hypertrophic cardiomyopathy Iron stain of heart Pancreas with massive iron overload Normal pancreas Hypogonadism • 30-50% of patients have delayed or absent puberty due to iron overload After myeloablative BMT: ◦ Females - ovarian malfunction in ~100% ◦ Males - testicular dysfunction in 0-40% Screening for pituitary-hypothalamic axis (LH and FSH) and sex hormones (Testosterone or Estradiol) Hypogonadism Reproduction and Infertility ◦ Genitalia: primary hypogonadism ◦ Pituitary gland: gonadotropin insufficiency leading to secondary hypogonadism Menarche to Menopause ◦ DBAR Women’s study open to review Menarche Pregnancy Menopause Preliminary results ◦ Delayed puberty ◦ Early menopause ◦ ? Infertility issues Hypothyroidism Found in 2-20 % of patients with iron overload After bone marrow transplant: common Screening with ◦ Thyroid stimulating hormone (TSH) ◦ Total and free Thyroid hormone (T4) Adrenal insufficiency Symptoms may be missed because of their vague nature. ◦ Dark color of non-sun-exposed areas ◦ Extreme tiredness ◦ Nausea, vomiting, abdominal pain, diarrhea, constipation Patients on steroids: considered to have adrenal insufficiency 8-45% of patients with iron overload can have biochemical adrenal insufficiency (often partial) Screening with 8 AM cortisol level, plasma renin activity, aldosterone, androstenedione and DHEAS levels Diabetes mellitus Both corticosteroid therapy and iron overload can lead to: ↓ in insulin secretion and ↓ in insulin sensitivity Diabetes mellitus • 9-14% of patients with iron overload ? % of patients on chronic corticosteroids ? after bone marrow transplant Screening with • fasting blood glucose • fructosamine level • HbA1c is not reliable while on transfusions!! • oral glucose tolerance test Growth Growth Anemia and ?DBA (RP gene) Iron overload Short stature Absent/ Abnormal puberty Hypothyroidism Low Growth hormone Glucocorticoids Short stature in DBA is multifactorial. Growth Short stature reported in ~30-50% of DBA patients Effect on growth may be due to iron overload or steroids • Screening with regular growth monitoring for early detection and more specific testing to check for endocrine causes. Bone disorders Hypogonadism Iron overload Osteoporosis Low Vitamin D & parathyroid gland failure Diabetes mellitus ? Low Growth hormone Glucocorticoids Osteoporosis is multifactorial in DBA patients. Bone disorders No data yet on bone disorders for DBA patients ◦ With iron overload: ??? ◦ On chronic corticosteroids: ???? ◦ After bone marrow transplant: ??? • Screening of calcium, parathyroid hormone, vitamin D and for other endocrine problems Perform densitometry or DEXA scan • Importance of Chelation Insulin resistance. Decreased insulin secretion. Impaired glucose tolerance. Insulin resistance. High insulin level. Normal glucose tolerance Insulin dependent diabetes mellitus Intensive chelation in patients with impaired glucose tolerance can improve beta-cell function and improve blood glucose values. Less effective in patients who have developed DM and in improving insulin resistance. Treatment for endocrinopathies Timely diagnosis & treatment can prevent morbidity and possible mortality associated with some endocrine conditions. • If not, will develop long-term adverse effects of an undiagnosed/ untreated endocrine problem. *Unpublished data presented at Pediatric Endocrine society meeting at Washington DC, 2013 Endocrine research in DBA with Drs. Lahoti, Speiser, and Harris SPECIFIC AIMS: 1. To study the effects of iron overload on the endocrine system in DBA patients receiving transfusions. 2. To estimate how common endocrinopathies are in the DBA population and correlate them with measures of iron overload. 3. To compare the presence of endocrine dysfunction in the chronic transfusion-dependent DBA population with those not on chronic transfusions. Eligibility Criteria Inclusion criteria: Age 1-39 years; and Diagnosed with DBA and enrolled in DBAR Exclusion criteria: Pregnant; or Have received a bone marrow transplant DBAR Research Study Goal: ◦ 50 transfusion dependent DBA ◦ 25 steroid dependent and remission DBA Completed and report to follow