Endocrine dysfunction (Hormone imbalances) in Diamond Blackfan Anemia

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Endocrine dysfunction (Hormone imbalances) in
Diamond Blackfan Anemia

• Dr Amit Lahoti
• Dr Phyllis Speiser
• Cohen Childrens Medical Center of New York
• North Shore LIJ Hospital System

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

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Treatment course of DBA
BMT recipients
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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
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Where do hormones come from and what do they do?
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Risk of Hormone disorders in patients with DBA
Is it real?
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Unpublished data presented at Pediatric
Endocrine society meeting at Washington DC, 2013
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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

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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.

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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.

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Hormone problems can start in childhood!
You are never too young to be tested. Early
diagnosis can avoid later problems.
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What are these conditions?How common are these?
Are you at risk?How can you be tested for
these?How are they treated?
Questions?
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Hypogonadism
What is it?
Absent or delayed puberty
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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

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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?
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Hypothyroidism
Insufficient thyroid hormone
What is it?
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Hypothyroidism
Feeling cold out of ordinary
Not growing well
Or, no symptoms at all!!! ( especially in early
stages)
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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?
Once a day thyroid hormone (tablets)
How to treat?
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Adrenal insufficiency
Not enough adrenal hormones
What is it?
Stress hormone (cortisol)
Salt retaining hormone (Aldosterone)
Male hormones
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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!
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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?
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Quiz Time!!!
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Question 1

• Which of the following is NOT a part of the
  endocrine system?
• Thyroid
• Pituitary
• Appendix
• Adrenals

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Question 2

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

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Question 3

• Which of the following is the largest endocrine
  gland in the body
• Thyroid
• Parathyroid
• Pancreas
• Adrenal

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

• Both iron overload and glucocorticoids lead to
• ?in insulin secretion and
• ? in insulin sensitivity

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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?
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Growth Problems

• For patients lt18 years age
• How many of you are shown your/ your childs
  growth chart during the visit with the
  pediatrician or hematologist?
• How many of you have asked to see your/ your
  childs growth chart during these visits?
• Growth chart is an important tool to detect poor
  growth or short stature at an early age!!!

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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
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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?
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Bone disorders
How?
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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
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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?
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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
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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.
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Treatable nature of most of these conditions!-
Thats 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.

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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
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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.

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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

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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!!!

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Thanks for listening!!!