The Endocrine System

Fifth year

29 July 2020

Outline

• Congenital Hypothyroidism

• Diabetes Mellitus

• Short stature

• Congenital adrenal hyperplasia

Congenital hypothyroidism

Hormones of the thyroid gland

• Tetriiodothyronine T4( Thyroxin)

• Triiodothyronine T3

• Calcitonin

• Function

1. Increase basal metabolic rate

2. Stimulate growth in children

3. Increase O2 consumption

4. Stimulate protein synthesis

5. Affect the carbohydrate, lipid, and vitamin metabolism

• Serum TSH levels are the most accurate test of thyroid function

• Serum TSH levels are elevated in primary hypothyroidism

• TSH is suppressed in hyperthyroidism

• After the neonatal period, normal levels of TSH are <6 mIU/L

• TSH may be subnormal in central (secondary) hypothyroidism

• Or often it is “inappropriately” in the normal range, despite a low serum T4 or free T4 level

At birth

• Acute release of TSH; peak serum concentrations reach 60 mU/L 30 min

• A rapid decline occurs in the ensuing 24 hr and a more gradual decline over the next 5 days to <10 mIU/L

• The acute increase in TSH produces a dramatic increase in levels of T4 and T3 in about 4 hr

• T4 levels gradually decrease during the 1st 2 wk of life to 12 µg/dL.

Congenital hypothyroidism

• Most cases are not hereditary and result from thyroid dysgenesis

• Some cases are familial: inborn errors of thyroid hormone synthesis (dyshormonogenesis) and may be associated with a goiter

• Most infants with congenital hypothyroidism are detected by newborn screening programs in the 1st few wk after birth, before obvious clinical symptoms and signs develop

• 1:4000 newborn worldwide

Etiology

• Thyroid Dysgenesis

Aplasia, Hypoplasia, Ectopic Gland- Causes of dysgenesis (85% unknown, 15% hereditary)

• Inborn errors of T4 synthesis, secretion, utilization

• Transient Hypothyroidism, maternal autoimmune thyroiditis, maternal medication for Graves disease

• Endemic cretinism from iodine deficiency

Etiology classification

Central or Hypopituitary hypothyroidism

• TRH , Mutation, deficiency,

unresponsiveness, multiple

pit deficiency as

craniopharyngioma

Primary hypothyroidism

• Defect in thyroid development

• Defect in hormone synthesis

• Defect in thyroid hormone

transport

• Iodine defeceincy

• Maternal Antibodies:

thyrotropine receptor antibody

• Maternal medications radio

iodine, iodide, amiodarone

Clinical manifestation

• Infant protected for first few weeks of life, maternal hormones

• Large head size ( Brain Myxedema), wide suture and large fontanels

• Macroglossia

• Distended abdomine, U hernia

• Dry & rough skin, cold mottling, hypothermia

• Sensory neural deafness(10%)

Clinical manifestation

• Poor sucking, constipation

• Hypo-activity and prolonged sleeping

• Cardiomegaly and pericardial effusion

• Macrocytic anemia

• Hypertonia and slow reflexed( Knee Jerk)

• Prolonged physiologic Jaundice

Diagnosis

• Primary hypothyroidism, low t3, T4, High

TSH

• XR: delay in skeletal maturation. epyphesial

dysgenesis

• US and radioisotope scan looking for the

presence and function

• Autoantibodies

• Other hormone deficiencies

Most common preventable mental

retardation

If screening is positive confirm and do other needed

investigation

Treatment

• Should be started on L- thyroxin as soon as

possible

• Dose 10-15 Mcg /kg/day

• Daily in the morning

• Monitoring of T4 and TSH level

• Repeat test in 6-8 weeks of any changes

• Early diagnosis and treatment leads to normal

linear and intellectual growth

Diabetes Mellitus

Definition

• Chronic, metabolic disease characterized by

hyperglycemia as a cardinal biochemical feature

• Epidemiology 285 million people have DM

• Male to female; 1:1

• Incidence 7 million per year

• 2 peaks: 5-7 years, Puberty

Characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss

In its most severe forms, ketoacidosis( TI DM) or a non–ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death

Symptoms are not severe, or absent, no hyperglycaemia sufficient to cause pathological and functional changes for a long time before the diagnosis ( T2 DM)

Presentation

Diagnosis

Etiologic Classifications of Diabetes

Mellitus 1. Type 1 diabetes (β-cell destruction ultimately leading to complete

insulin deficiency)

2. Type 2 diabetes (variable combinations of insulin resistance and insulin deficiency)

3. Genetic defects of β-cell function: MODY (maturity-onset diabetes of the young) syndrome

4. Drug : cyclosporine, Tacrolimus, sirolimus , Glucocorticoids

5. Diseases of exocrine pancreas- Cystic fibrosis

6. Infections: Congenital rubella, CMV, HUS

7. Genetic syndromes: Prader-Willi , Down and Turner syndrome

T1DM (IDDM)

1. 10% of new cases

2. low or absent endogenous insulin (90% of the total β-cell mass is destroyed by the time clinical disease )

3. dependence on exogenous insulin

4. Ketoacidosis

5. a median age of 7-15 yr

6. 4 stages: preclinical β-cell autoimmunity, onset of clinical diabetes, transient remission “honeymoon period,” established DM

7. Susceptibility is controlled by MHC II . Auto AB to islet cell cytoplasm (ICA), insulin autoantibody (IAA), antibodies to glutamic acid decarboxylase, and ICA512

T2DM (NIDDM)

1. 80% of new cases

2. Older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity

3. not insulin dependent

4. infrequently develop ketosis

5. The presentation is more insidious

6. Excessive weight gain, fatigue secondary to insulin resistance, incidental glycosuria during

7. Acanthosis nigricans a sign of insulin resistance

Environmental Factors

• Viral infections: Congenital Rubella Syndrome, Enteroviruses, Mumps

• Diet Breastfeeding may lower the risk of T1DM, either directly or by delaying exposure to cow’s milk protein

• The Hygiene Hypothesis: Possible Protective Role of Infections

Treatment

• Insulin therapy

Insulin Peak Duration of action

Lispro/Aspart

20 min 4hr

Regular 15min 7hr

NPH/Lente

12min 12hr

Glargine 5 24

Ultralente

9 18

Long acting Glargine Detemir

Given once/day, peakless, baseline insulin Q12 hr

Rapid Acting Aspart , Liprso, Glulisine

Start immediately and peak in 20 min

Regular Actrapid Used in DKA as infusion

Intermediat acting NPH, Lente Combined with glargine

Insulin Pump

Retinopathy with potential blindness

Nephropathy that may lead to renal failure

Neuropathy with risk of foot ulcers, amputation

Autonomic dysfunction, including sexual dysfunction

People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease

Diabetes Long-term complication

Short Term Complications

• Diabetic keto acidosis

• Nonketotic Hyperosmolar Coma

• 100% preventable

Diabetic ketoacidosis

• Metabolic abnormalities resulting from a severe deficiency of insulin

1. 20-40% of children with new-onset diabetes

2. known DM who omit insulin doses

3. Intercurrent illness

• Diagnosis:

1. Hyperglycemia> 200

2. Ketonemia, ketonuria

3. metabolic acidosis with high anion gap, serum bicarbonate <18

Pathophysiology

Hyperglycemia produces osmotic diuresis

The loss of calories and electrolytes, dehydration - physiologic stress

stress hormones- epinephrine, cortisol, growth hormone, and glucagon

impairing insulin, antagonizing its action , promoting glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis ,decreasing glucose utilization and glucose clearance

accelerated lipolysis

Insulin deficiency and glucagon excess shunts the free fatty acids into ketone body principally β-hydroxybutyrate acetoacetate, and acetone

Accumulation of these keto acids results in metabolic acidosis (diabetic ketoacidosis and compensatory rapid deep breathing in an attempt to excrete excess CO2 (Kussmaul respiration)

progressive dehydration, acidosis, hyperosmolality, decreased cerebral oxygen utilization, impaired consciousness and coma

Principle of management

• Insulin therapy

• Balanced diet

• Regular exercise

• Regular monitoring

Short Stature

Definition

Etiology of short stature

• Normal variant: Familial, constitutional, idiopathic

• Chronic illness : Chronic renal failure, IBD……

• Endocrine causes, Hypothyroidism, growth H disorder

• Syndromic short stature: Turner

• IUGR, SGA

• Skeletal dysplasia

• Nutritional deficiency

Short stature

• Defined: height that is 2 standard deviations (SD) or more below the mean height for individuals of the same sex and chronologic age in a given population or below 3rd percentile

• Growth velocity below 25th percentile over 6-12 month

• Expected height is med parental height

Boys MPH= Father ht +( Mother ht +13)

2

Girls MPH= Father ht+ Mothers ht - 13

2

Children whose projected height differs from their genetic potential by more than 5 cm (2 in) should be further evaluated or referred to an endocrinologist

Bone Age

• Appearance of various

epiphyseal center & fusion

of epiphysis with

metaphysis

• X Ray for hand and wrest

using Gruelich- Pyle atlas

Delayed bone age

• Constitutional short stature

• Hypothyroidism

• Celiac disease

• GH deficiency

Constitutional versus Familial

• Constitutional: Have

relative with

constitutional growth

delay

• Delayed bone age

• Predicted adult height

appropriate to familial

pattern

• Familial ( genetic),

normal bone age normal

growth velocity,

predicted adult height

appropriate to the

familial pattern

Familial short stature

• A Child who is short, looks normal, normal PE

• bone age is not delayed

• Parent(s) is/are short and normal

• Looking at the growth chart of this child, he's

growing on his own centile

• The child is genetically destined to become a

short adult.

• Nothing can be done to this child

Constitutional Short Statur

• The child look different shorter than their peers but normal

• This is more common in boys than in girls.

• Parent(s) is/are not short, but may have been so during their childhood

• parents had delayed puberty

• The child will most probably have late puberty and have his/her peak height velocity later on reaching a final normal height = (catch-up growth)

• His/her final height will usually be in the lower half of the target range

Endocrine causes

• Growth hormone deficiency and resistance

• Thyroxine deficiency

• Cortisol excess (Cushing disease or

exogenous)

Growth Hormone deficiency

• Congenital or acquired: Isolated GH

deficiency Multiple AP deficiencies

• True permanent deficiency

• Functional/temporary deficiency

• partial or complete

• Isolated or part of multiple anterior pituitary

hormone deficiencies (pan-hypopituitarism)

Since the pituitary gland is a midline structure,

any structural midline anomaly/defect should

raise the question of a possible pituitary hormone

deficiency. Examples of midline anomalies are

cleft palate, central incisor and septo-optic

dysplasia.

Hypopituatrism

Neonatal presentation

• Hypoglycaemia (GH and cortisol deficiency)

• Prolonged jaundice (cortisol and T4 deficiency)

• Micropenis ± cryptorchidism (Gn deficiency

• Nystagmus (suggestive of optic nerve hypoplasia)

• High pitch voice

Childhood & adolescent:

• Growth failure (GH deficiency)

• Features of T4 deficiency (fatigue, weight gain, dry skin)

• Features of cortisol deficiency (fatigue, susceptibility to and difficulty shaking off intercurrent illnesses)

• Pubertal failure

• Recognized related diagnosis (like a known lesion, irradiation or an affected family member)

Growth failure

• Not useful to measure GH levels because it is

pulsatile

• Measure IGF-1 and IGF-BP3

• Accurate growth hormone deficiency testing

involves a stimulation test, which measures the

level of GH in the blood after receiving a

medication that triggers the release of GH,

such as insulin, arginine, clonidine or glucago

Diagnosis

• Based on clinical, biochemical parameters Radiologic evaluation of bone age

• Central nervous system MRI or CT scan to evaluate the hypothalamic-pituitary region and to exclude other conditions

• Evaluation and management by a pediatric endocrinologist Laboratory evaluation

• Measurements of GH, IGF-1, and IGF-1–binding protein levels

• Determination of peak GH levels after stimulation test Special testing

• Family history and genetic analyses (e.g., search for PROP1 and POU1F1 mutations)

Indication for GH treatment

• GH deficiency

• Turner syndrome

• Chronic renal failure before transplantation

• Idiopathic short stature

• Small-for-gestational age short stature, Prader-Willi syndrome

• SHOX gene abnormality

• Noonan syndrome

GH therapy side effect

• Edema

• Reactions at the site of injection

• Scoliosis worsening

• Hypothyroidism

• Otitis media

• Benign intracranial hypertension

• GH decreases insulin sensitivity so in children who were SGA must monitor annual fasting insulin and GLC

• Theoretical risk of increased malignancy

Congenital Adrenal

Hyperplasia

• Hypothalamic CRH

stimulates the release of

pituitary ACTH governs

the synthesis and release

of cortisol and adrenal

androgens

Adrenal Dysfunction

Decrease function: Adrenal insufficiency

• Congenital adrenal hyperplasia

• Addison disease

• Infection (TB, sepsis)

• Adrenoleukodystrophy

Increase function:

• Cushing syndrome (High Cortisol

• Hyperaldosteronism (High aldestrone )

• Pheochromocytoma (High catecholamine)

1. Cholesterol side chain cleavage= desmolase

2. 3B Hydoxysteroid dehydrogenase

3. 17 ᾀ hydroxylase and 17,20 –lyase

4. 21 B Hydroxylase

5. 11 B Hydroxylase

6. Aldosterone synthetase (11 &18 hydroxylase & 18 oxidase

21 Hydroxylase deficiency

• More than 90% of CAH cases are caused by 21-hydroxylase

deficiency.

• required for synthesis of aldosterone & cortisol,

respectively

• NEWBORN SCREENING

11 B Hydroxylase Deficiency

3β-Hydroxysteroid dehydrogenase

deficiency

Questions