Endocrine dysfunction (Hormone imbalances)

in Diamond Blackfan Anemia

Dr Amit LahotiDr Phyllis Speiser

Cohen Children’s Medical Center of New YorkNorth Shore LIJ Hospital System

Diamond Blackfan Anemia (DBA) is a rare condition.

Really!!!

5-7 per 1,000,000 live births

1 per 100,000 live births

1 per 500 African-American live births

DBA

Beta thalassemia

Sickle-cell disease

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.

Treatment course of DBA

BMT recipients

Pros and cons of DBA treatments Corticosteroids Chronic Transfusions Bone marrow

transplant

Pros 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

Where do hormones come from and what do they do?

Risk of Hormone disorders

in patients with DBA: Is it real?

*Unpublished data presented at Pediatric Endocrine society meeting at Washington DC, 2013

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

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.

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.

Hormone problems can start in childhood!

You are never “too young” to be tested.

Early diagnosis can avoid later problems.

What are these conditions?How common are these?

Are you at risk?How can you be tested for these?

How are they treated?

Questions?

HypogonadismAbsent or delayed pubertyWhat is it?

HypogonadismWhat 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

Hypogonadism

Males: Testosterone injections or skin gel.Females: Estrogen oral or skin gel.

Blood sampling for pituitary puberty-regulating hormones (LH and FSH) and sex hormones (Testosterone or Estradiol). Bone age x-ray of hand.

• With iron overload: 30-50%• After BMT: Females- ovarian malfunction in ~100%Males- testicular dysfunction in 0-40%

How common?

How to diagnose?

How to treat?

HypothyroidismInsufficient thyroid hormoneWhat is it?

Hypothyroidism

Or, no symptoms at all!!! ( especially in early stages)

Feeling cold out of ordinary

Not growing well

Hypothyroidism

Once a day thyroid hormone (tablets)

By measuring blood levels of:Thyroid stimulating hormone (TSH); andTotal and free Thyroid hormone (T4)

• Patients with iron overload: 2-20 %• Patients on steroids and after BMT: Less common, frequency unknown

How common?

How to diagnose?

How to treat?

Adrenal insufficiency

Stress hormone (cortisol)

Salt retaining hormone (Aldosterone)

Male hormones

What is it? Not enough adrenal hormones

Adrenal insufficiency

Symptoms may be missed or attributed to anemia or missed!

Dark color of non-sun- exposed areas

Low BP and dizziness

Extreme tiredness

Nausea, vomiting, abdominal pain, diarrhea, constipation

Muscle weakness

Adrenal insufficiency

Hydrocortisone: to replace stress hormone. May only be needed during periods of stress.Fludrocortisone: salt-retaining hormone.

Blood measurements of:8 AM cortisol level, Plasma renin activity, aldosterone, Androstenedione and DHEAS levels

Patients on steroids: considered to have adrenal insufficiency

Patients with iron overload: biochemical adrenal insufficiency (often partial): 18-45%

How common?

How to diagnose?

How to treat?

Question #1

• Which of the following is NOT a part of the endocrine system?

a)Thyroidb)Pituitaryc) Appendix d)Adrenals

Question #2

• This gland is sometimes called the master gland, though it is only about the size of a pea

a)Thyroidb)Pituitaryc) Pineald) Hypothalamus

Question #3

• Which of the following is the largest endocrine gland in the body:

a)Thyroidb)Parathyroidc) Pancreasd)Adrenal

Diabetes mellitusWhat is it? Not enough insulin hormone

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

Diabetes mellitus

• Diet changes, • Insulin therapy and/or • Oral medications

• Fasting blood glucose• Fructosamine level (HbA1c may not be reliable if on transfusions)• Oral glucose tolerance test

• With Iron overload: 9-14%• On Chronic glucocorticoids: dose dependent. May be

reversible.• BMT: depends on pre-transplant factors.

How common?

How to diagnose?

How to treat?

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!!!

Growth problems

Multiple causes of poor growth in DBA patients

Short stature

Anemia and ?DBA itself

Absent/ Abnormal puberty

Iron overload

Low Growth hormone Hypothyroidism

Glucocorticoids

Growth problems

• Specific to the cause. • However, final height may still be low for mid-parental height.

• Regular growth monitoring for early detection• Laboratory testing to rule out specific endocrine causes.

• 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?

How to diagnose?

How to treat?

Bone disorders

How?

Bone disorders

Multiple causes of poor bone density in DBA patients

Weak bones

Hypogonadism

Low Vitamin D & parathyroid gland failure

Iron overload

? Low Growth hormone Diabetes mellitus

Glucocorticoids

Bone disorders

• Treat any co-existing hormone problem• Vitamin D supplements: Adequate level?• Other medications: Bisphosphonates• Newer drugs being developed.

• Test for other endocrine problems• Blood levels of Calcium, parathyroid hormone and vitamin D• Bone mineral density scan

• With Iron overload: upto 50%• On Chronic glucocorticoids: Dose and duration

dependent.• After Bone marrow transplant: Not known

How common?

How to diagnose?

How to treat?

Importance of Screening

• Vague symptoms may also be seen with anemia itself. • Often no/minimal symptoms in early stages.

Diabetes screening in non- diabetic otherwise asymptomatic beta thalassemia patients

14% impaired glucose

tolerance

1.5% Diabetes mellitus

84.5%: normal

Importance of Chelation

Normal glucose

tolerance

Impaired glucose

tolerance (IGT)

Insulin dependent diabetes mellitus

Years 12.4%

~10 Years

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.

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.

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

About our research studySPECIFIC AIMS:1. To study the effects of iron overload on various endocrine

glands in DBA patients receiving transfusions.2. To estimate how common are these hormone

abnormalities in the DBA population and correlate it with measures of iron overload.

3. To recommend a possible method to screen the at-risk DBA patients for endocrine dysfunctions at regular intervals.

4. 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.

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

About our research study

Our goal is 75 DBA patients and 25 thalassemia patients total for the study.

THANK YOU IN ADVANCE FOR YOUR PARTICIPATION!!!

• 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.

THANKS FOR LISTENING!!!