Pharmacotherapeutic approach to Thyroid and Parathyroid Disorders

Anantha Harijith, MDAssistant Professor of Pediatrics

University of Illinois, Chicago

Case report Two month old male infant -

recently migrated from Kabul. Parents worked as interpreters in the US embassy.

Birth weight 3.1kg, Current weight 5.1kg-growing well

Parents –happy, only complaint-baby passing stools once in 5-7days

no newborn screen report

Case report

Persistent jaundice, puffy coarse facies, large tongue, large anterior and posterior fontanelle, floppy, umbilical hernia, short arms, large pudgy hands

Parents are extremely happy with the baby and want you to prescribe prune juice for constipation. They are confident that investigations are unnecessary. What will you do?

Will you -Reassure the parents and see the patient again in two months OR will you investigate?

Knee & Skull XR-

Our patient

They agree for X rays but no blood tests

What will you tell them? 1. X rays are normal and no further investigation needed now2. Immediate blood tests are needed

Another 2 month old healthy infant

Blood tests done!

CBC Hematocrit 40%, WBC 9.8k, Platelet 202k

Serum Na141, K 4.6, Cl 105, HCO3- 25, Ca 9.8mg/dl

TSH-76 µIU/mL(Normal0.5 - 4.70 µIU/mL)

T4 and T3 – not detected What is the diagnosis?

Parathyroid glands

• Thyroxine (T4, tetraiodothyronine)• Liothyronine (T3, triiodothyronine)

• Iodinated diphenyl ether structure• Built and stored on thyroglobulin• >99% protein bound in plasma• Only free form has physiologic effects

• T3 more potent; T4 longer lasting– Peripheral deiodination

Hypothyroid Euthyroid Hyperthyroid

• Increases transcription (nuclear)• Increases mitochondrial metabolism• Net effects are target dependent

– Oxygen consumption– Heat production– Metabolism, growth, differentiation– Promotes effects of hormones

• Steroids, catecholamines

Physiological Effects

Congenital Hypothyroidism

1 in 4000 newborns 90% Thyroid agenesis maternal T4 crosses the placenta, entering

fetal blood well before the fetal thyroid is secreting its own T4

So early protection but in second trimester high demand for T4 not met by transfer- so signs of hypothyroidism sets in

Treatment- T4 ie Thyroxine supplementation

Other causes

-Primary Idiopathic Autoimmune Traumatic Iatrogenic

-Secondary Pituitary dysfunction Increased protein binding

• estrogen; HIV; liver dysfunction; heroin

Case Report38 y/o computer professional lady reports

over phone seeking an immediate appointment

palpitations, tremulousness for 6 months weight loss, heat intolerance of 12 weeks

duration Menstrual periods have been scanty for

6months She used to be a regular in Chicago

marathon until last year and wants to be tested for uterine problems because of lack of periods

She is now walking into your office

PE reveals HR = 120 bpm BP = 170/90 fine tremor of

outstretched hands and

... …..

Lab reports free T4 = 40 pmol/L, free T3 = 10.6 pmol/L

TSH – undetectable elevated thyroid-stimulating

globulins confirming a Dx of ?

Hyperthyroidism

• Causes– Grave’s disease (TSHR autoantibodies)

• 0.1% to 1% prevalence, higher in women

– Thyroiditis– Toxic adenoma

• Non-pharmacologic treatments– Subtotal thyroidectomy– Radioiodine– Arterial embolization (2005)

Grave’s Disease

Pharmacologic Treatments• Thionamides (thiourelynes)

Hyperthyroidism

• Methimazole (Tapazole)– Typical dose 15 – 30 mg QD– Rapidly absorbed (Cmax < 2 hours)– Half-life 13 – 18 hours

• Propylthiouracil (PTU)– Typical dose 50– 600 mg BID– Good bioavailability– Half-life 2 – 4 hours– Blocks peripheral T4 -> T3 conversion

Thionamide MOA

Coupling is also highly sensitive to drug

• Rash/itch• Fever• Rarely:

– Liver dysfunction– Leucocytopenia

Thionamide Side Effects

Cooper DS. N Engl J Med 005;352:905-917.

Other Antithyroid Options

Iodide loading• High doses can inhibit iodide formation• Effect transient• May be useful prior to RAI or surgery

Debulk and devascularize gland• Side effects

Rash, hypersalivation, oral ulcers CI in pregnancy (may cause fetal goiter)

Other Antithyroid Options

Beta Blockers• Adjunctive treatment• May reduce T4 -> T3 conversion• Control HR and palpitations, sweats• Rapid action

Corticosteriods• Reduce T4 -> T3 conversion• May reduce TSHR antibody effect in Grave’s

Algorithm for the Use of Antithyroid Drugs among Patients with Graves' Disease.

Thyroid Storm

Potentially life threatening Combined treatment strategy

• High dose PTU Give 1st; iodide will reduce drug uptake in gland

• Iodide loading (IV Lugol’s solution)• Beta blockers• Corticosteriods

Chief cells-Small dark numerous -produce Parathyroid hormone (PTH)

Oxyphil cells -No known physiological function-May produce PTH related protein

Parathyroid Basics

Parathyroid Basics

Parathyroid Hormone• Small molecule (34 amino acids)• Activity based on amino terminal• No disulfide linkages• Encoded on chromosome 11• Half-life only 2 – 4 minutes• Secreted by chief cells

Case reportA 17 year old male was admitted with history of generalized seizures for 8 years

& involuntary movements for 2 months short statured (138 cm),had hypoplastic

dentition, thick dystrophic nails. The patient demonstrated tetany, a

positive Chvostek's sign and generalized hyper-reflexia. Systemic examination was normal.

Labs: hypocalcaemia, hyperphosphataemiaEyes- Posterior subcapsular cataract CT Brain- basal ganglial calcification

Dx: ?

Hypoparathyroidism

Causes• Surgical (most common)• Idiopathic

Genetic familial forms Circulating receptor antibodies

• Functional Due to hypomagnesemia

• Mg2+ necessary for PTH release

Hypoparathyroidism Decreased bone resorption & osteocytic activity Hypocalcemia

• Increased neuromuscular excitability• Tetanic muscle contractions/spasms• Seizure• Prolonged QT interval• Cataract• Trousseau Sign• Chvostek Sign

Low or absent iPTH

Psuedohypoparathyroidism

Target organs resistant to PTH• Congential defect of PTHR1

Plasma Ca2+ low Plasma phosphate high Renal phosphatase activity high

Hypoparathyroidism

Maintenance Treatment• Combined oral calcium + Vitamin D• Phosphate restriction may be used

Acute Treatment• Tetany or Hungry Bone Syndrome

Parenteral calcium followed by vitamin D supp + oral calcium

Hyperparathyroidism Primary

•Excess PTH high calcium, low phosphate Tumor, adenoma, hyperplasia

•More common in women•Marrow fibrosis•Osteitis fibrosa cystica•Metabolic acidosis•Increased Alk Phos •Kidney stones

Hyperparathyroidism

Primary – Diagnosis• Multiple elevated Ca2+ serum tests• Elevated iPTH• Alk Phos typically low• Corticosteroid suppression test

Prednisolone reduces serum Ca2+• Indicates non-parathyroid origin

Sarcoid, vitamin D intoxication, etc.

Hyperparathyroidism

Treatment• Acute Severe forms

Adequate hydration, forced diuresis• Other Agents

Corticosteroids – Blood malignancies Mythramycin

• Toxic antibiotic used to inhibit bone resorption – hematologic and solid neoplasms

Hyperparathyroidism

Treatment• Other Agents

Calcitonin• Inhibits osteoclast activity and bone resorption

Biphosphonates• Given IV or orally to reduce bone resorption

Estrogen• Can be given to postmenopausal women with 1°

hyperparathyroidism as medical therapy

Hyperparathyroidism

Treatment• Surgery

Definitive treatment

2° Hyperparathyroidism

Adaptive & unrelated to intrinsic disease of glands

Due to chronic stimulation of glands by low serum Ca2+ levels

2° Hyperparathyroidism

Causes• Dietary deficiency of vitamin D or Ca2+• Decreased intestinal absorption of vitamin D

or Ca2+• Drugs such as phenytoin, phenobarbital• Renal Failure

Decreased activation of vitamin D3• Hypomagnesemia