Endocrine dysfunction (Hormone imbalances) in Diamond Blackfan Anemia

1. Endocrine dysfunction (Hormone imbalances) in Diamond Blackfan Anemia Dr Amit Lahoti Dr Phyllis Speiser Cohen Children’s Medical Center of New York North Shore LIJ Hospital System

2. Diamond Blackfan Anemia (DBA) is a rare condition. Really!!!

3. 5-7 per 1,000,000 live births DBA Beta thalassemia 1 per 100,000 live births 1 per 500 African-American live births Sickle-cell disease

4. Role of a registry For rare conditions, clear guidelines on how to manage the disease or its complications often not available. A registry provides a unique opportunity to do systematic research. Until more research data are available, doctors use best practices learned from other somewhat similar conditions.

5. Treatment course of DBA BMT recipients

6. Pros and cons of DBA treatments

7. Where do hormones come from and what do they do?

8. Risk of Hormone disorders in patients with DBA: Is it real?

9. *Unpublished data presented at Pediatric Endocrine society meeting at Washington DC, 2013

10. You or some one sitting next to you may have a similar story…. • At 6 months: Diagnosed with DBA • Monthly transfusions started. • Subsequently developed Iron overload • Chelation therapy with Desferal started • At 14.5 years, 7/2004: went to ER for frequent urination, excessive thirst and 15 lb weight loss. Blood glucose markedly elevated. Diagnosed with Diabetes mellitus, • Insulin therapy started • Two months later, 9/2004: Thyroid function tests show Thyroid gland failure. • Thyroid hormone started

11. In the next year… • At 15 years, 12/2004: Teen non-compliant with insulin regimen & diet. Poor blood glucose control, stunted growth, despite normal GH levels. Diagnosed Growth hormone resistance. • Growth hormone therapy started • At 15.75 years, 10/2005: Delayed puberty with evidence of Pituitary failure. • Testosterone therapy started. • At 16.5 years, 5/2006: Multiple seizures related to low blood glucose despite not being compliant with insulin regime. Diagnosed with Adrenal insufficiency • Hydrocortisone therapy started.

12. And as time went by… • Two months later, 7/2006: Complaints of frequent urination at night. Diagnosed Diabetes insipidus. • DDAVP treatment started. • At 17.5 years, 8/2007: Evidence of Diabetic kidney damage. • Enalapril treatment started. • At 18 years, 2/2008: Growth hormone therapy stopped. Adult height: 5 feet.

13. Hormone problems can start in childhood! You are never “too young” to be tested. Early diagnosis can avoid later problems.

14. What are these conditions?How common are these? Are you at risk?How can you be tested for these?How are they treated? Questions?

15. Hypogonadism What is it? Absent or delayed puberty

16. Hypogonadism What is Delayed Puberty? • In girls, no breast development by 13 years, or no periods by 15 years or by 2 years after breast development. • In boys, no testicular enlargement by 14 years

17. Hypogonadism • With iron overload: 30-50% • After BMT: Females- ovarian malfunction in ~100% Males- testicular dysfunction in 0-40% How common? Blood sampling for pituitary puberty-regulating hormones (LH and FSH) and sex hormones (Testosterone or Estradiol). Bone age x-ray of hand. How to diagnose? Males: Testosterone injections or skin gel. Females: Estrogen oral or skin gel. How to treat?

18. Hypothyroidism Insufficient thyroid hormone What is it?

19. Hypothyroidism Feeling cold out of ordinary Not growing well Or, no symptoms at all!!! ( especially in early stages)

20. Hypothyroidism • Patients with iron overload: 2-20 % • Patients on steroids and after BMT: Less common, frequency unknown How common? By measuring blood levels of: Thyroid stimulating hormone (TSH); and Total and free Thyroid hormone (T4) How to diagnose? How to treat? Once a day thyroid hormone (tablets)

21. Adrenal insufficiency Not enough adrenal hormones What is it? Stress hormone (cortisol) Salt retaining hormone (Aldosterone) Male hormones

22. Adrenal insufficiency Dark color of non-sun- exposed areas Low BP and dizziness Extreme tiredness Nausea, vomiting, abdominal pain, diarrhea, constipation Muscle weakness Symptoms may be missed or attributed to anemia or missed!

23. Adrenal insufficiency Patients on steroids: considered to have adrenal insufficiency Patients with iron overload: biochemical adrenal insufficiency (often partial): 18-45% How common? Blood measurements of: 8 AM cortisol level, Plasma renin activity, aldosterone, Androstenedione and DHEAS levels How to diagnose? Hydrocortisone: to replace stress hormone. May only be needed during periods of stress. Fludrocortisone: salt-retaining hormone. How to treat?

24. Quiz Time!!!

25. Question #1 • Which of the following is NOT a part of the endocrine system? • Thyroid • Pituitary • Appendix • Adrenals

26. Question #2 • This gland is sometimes called the master gland, though it is only about the size of a pea • Thyroid • Pituitary • Pineal • Hypothalamus

27. Question #3 • Which of the following is the largest endocrine gland in the body: • Thyroid • Parathyroid • Pancreas • Adrenal

28. Diabetes mellitus What is it? Not enough insulin hormone

31. Diabetes mellitus • Both iron overload and glucocorticoids lead to: ↓in insulin secretion; and ↓ in insulin sensitivity

32. Diabetes mellitus • With Iron overload: 9-14% • On Chronic glucocorticoids: dose dependent. May be reversible. • BMT: depends on pre-transplant factors. How common? • Fasting blood glucose • Fructosamine level (HbA1c may not be • reliable if on transfusions) • Oral glucose tolerance test How to diagnose? • Diet changes, • Insulin therapy and/or • Oral medications How to treat?

33. Growth Problems For patients <18 years age: • How many of you are shown your/ your child’s growth chart during the visit with the pediatrician or hematologist? • How many of you have asked to see your/ your child’s growth chart during these visits? Growth chart is an important tool to detect poor growth or short stature at an early age!!!

35. Growth problems Anemia and ?DBA itself Absent/ Abnormal puberty Iron overload Short stature Hypothyroidism Low Growth hormone Glucocorticoids Multiple causes of poor growth in DBA patients

36. Growth problems • DBA itself: Reported short stature ~30% • Effect on growth due to iron overload or steroids alone is hard to quantify in DBA due to this. • BMT: may improve growth. How common? • Regular growth monitoring for early • detection • Laboratory testing to rule out specific • endocrine causes. How to diagnose? • Specific to the cause. • However, final height may still be low for • mid-parental height. How to treat?

37. Bone disorders How?

38. Bone disorders Hypogonadism Low Vitamin D & parathyroid gland failure Iron overload Weak bones Diabetes mellitus ? Low Growth hormone Glucocorticoids Multiple causes of poor bone density in DBA patients

39. Bone disorders • With Iron overload: upto 50% • On Chronic glucocorticoids: Dose and duration dependent. • After Bone marrow transplant: Not known How common? • Test for other endocrine problems • Blood levels of Calcium, parathyroid • hormone and vitamin D • Bone mineral density scan How to diagnose? • Treat any co-existing hormone problem • Vitamin D supplements: Adequate level? • Other medications: Bisphosphonates • Newer drugs being developed. How to treat?

40. Importance of Screening • Vague symptoms may also be seen with anemia itself. • Often no/minimal symptoms in early stages. 14% impaired glucose tolerance 1.5% Diabetes mellitus 84.5%: normal Diabetes screening in non- diabetic otherwise asymptomatic beta thalassemia patients

42. Importance of Chelation Impaired glucose tolerance (IGT) Years 12.4% Normal glucose tolerance ~10 Years Insulin dependent diabetes mellitus Intensive chelation in patients with IGT can improve beta-cell function, improve blood glucose values. Less effective in patients who have developed DM and in improving insulin resistance.

43. Treatable nature of most of these conditions!- That’s what I love about endocrinology!!! • Timely diagnosis & treatment can prevent morbidity and possible mortality associated with some endocrine conditions. • Versus possible long-term adverse effects of an untreated endocrine problem.

44. What do we need to do? • The only published reports about hormone problems in DBA patients are in form of case reports or case series with few patients. • Collect more information about endocrine problems in DBA patients like you. Vs

45. About our research study SPECIFIC AIMS: • To study the effects of iron overload on various endocrine glands in DBA patients receiving transfusions. • To estimate how common are these hormone abnormalities in the DBA population and correlate it with measures of iron overload. • To recommend a possible method to screen the at-risk DBA patients for endocrine dysfunctions at regular intervals. • To compare the presence of endocrine dysfunction in chronic transfusion dependent DBA population with DBA patients not on chronic transfusions and beta thalassemia major patients on chronic blood transfusions.

46. About our research study Eligibility Criteria: Inclusion criteria: • Age 1-39 years; and • Diagnosed with DBA and enrolled in DBA Registry (DBAR), or • Diagnosed with beta thalassemia major and followed at NSLIJ pediatric hematology division. Exclusion criteria: • Pregnant; or • Having received a bone marrow transplant

47. About our research study • Participation involves a standard endocrine evaluation. • This includes blood tests that can be ordered and drawn at • your primary institution. The participation consent asks for • permission for us to receive the endocrine evaluation results. Our goal is 75 DBA patients and 25 thalassemia patients total for the study. THANK YOU IN ADVANCE FOR YOUR PARTICIPATION!!!

48. Thanks for listening!!!