ENDOCRINE MODULE

Thyroid & Parathyroid

Disorders
Academic Circle
MFSU Ragama
 Contents
Thyroid Disorders ............................................................................................................................ 2

Hypothyroidism ........................................................................................................................... 3

Thyroid disorders in children ...................................................................................................... 7

Pathology - THYROIDITIS ........................................................................................................... 10

Hyperthyroidism........................................................................................................................ 15

Parathyroid disorders ................................................................................................................... 28

Calcium Metabolism.................................................................................................................. 28

Parathyroid Gland Introduction & Development...................................................................... 29

Hyperparathyroidism ................................................................................................................ 31

Hypoparathyroidism.................................................................................................................. 38

1
 Thyroid Disorders
X Function related ʹ hypothyroidism, hyperthyroidism

X Goiter (enlargement) ʹdiffuse, nodular

X Carcinoma

Actions of Thyroid Hormones

‡ CVS ʹј,ZΘK

‡ Bone ʹјƚƵƌŶŽǀĞƌΘƌĞƐŽƌƉƚŝŽŶ

‡ RS ʹmaintain normal hypoxic & hypercapnic drive in resp center

‡ GIT ʹјŐƵƚŵŽƚŝůŝƚLJ

‡ Blood ʹfacilitate O2 release to tissues

‡ NMS ʹјƐƉĞĞĚŽĨŵƵƐĐůĞĐŽŶƚƌĂĐƚŝŽŶͬƌĞůĂdžĂƚŝŽŶΘ

‡ CHO metabolism ʹјŚĞƉĂƚŝĐŐůƵĐŽŶĞŽŐĞŶĞƐŝƐͬŐůLJĐŽůLJƐŝƐΘ

glucose absorption

‡ Lipid Metabolism ʹјĐŚŽůĞƐƚĞƌŽůƐLJŶƚŚĞƐŝƐΘĚĞŐƌĂĚĂƚŝŽŶ

‡ Sympathetic NS ʹјĐĂƚĞĐŚŽůĂŵŝŶĞƐĞŶƐŝƚŝǀŝƚLJΘďĞƚĂ
-adrenergic receptor numbers in heart,
skeletal muscle, adipose tissue & lymphocytes

2
 Hypothyroidism
Types

‡ Primary ʹdisease of thyroid, common

‡ Secondary ʹdisease of hypothalamic-ƉŝƚƵŝƚĂƌLJĂdžŝƐ;љd^,Ϳ͕ƌĂƌĞ

Causes of Primary Hypothyroidism

‡ Iodine deficiency

‡ Autoimmune hypothyroidism (Hashimoto thyroiditis)

‡ Post ablative: Surgery, radioiodine therapy, or external irradiation

‡ Drugs (lithium, iodides, p-amino salicylic acid)

‡ Developmental (thyroid dysgenesis)

‡ Thyroid hormone resistance syndrome (THRB mutations)

‡ Congenital biosynthetic defect (dyshormonogenetic goiter)

Causes of Secondary Hypothyroidism

Pituitary failure Hypothalamic failure

• Tumors • Tumors

• Postpartum pituitary • Trauma

• necrosis /Trauma • Radiation therapy

• Nonpituitary tumors • Infiltrative diseases

3
Symptoms Signs
• Female>Male • Goiter
• Tiredness • Dry skin & hair
• Weight gain • Bradycardia
• Deep voice • Slow relaxing reflexes
• Depression / psychosis • Peripheral edema
• Constipation • Over-weight / obesity
• Menstrual disturbances • Anemia
• Cold intolerance • Mental slowness

Investigations
• TSH high, fT4 low

• Auto antibodies ʹthyroid & other

• Non-specific ʹanemia

high CPK

high AST

hypercholesterolemia

low sodium

Treatment
X Replacement with thyroxine for life

X 100 mcg daily initially (elderly 50 mcg, IHD 25 mcg) Pregnancy ʹincrease dose

Myxoedema Coma
• Rare presentation of severe hypothyroidism

• More likely in elderly

• Confusion, coma, hypothermia, cardiac failure, pericardial effusion, hypoventilation,

hypoglycaemia, hyponatraemia

4
 Thyroxin preparations
‡ 2 naturally occurring active forms

-T3 --- tri-iodo-L-thyronine

-T4 --- tetra-iodo-L-thyronine

T4 is the precursor of T3

T3 ʹ
most active form

Levothyroxine (T4) Liothyronine(T3)

-Drug of choice to treat hypothyroidism -More potent than T4.
-T1/2 -7d in euthyroid -T1/2 2 days

-Rapid onset of action-can induce heart failure

not routinely used

Clinical improvement in 2 weeks

Full resolution of symptoms in about 6 months

Treatment of hypothyroidism-monitoring
• Taken on an empty stomach upon waking in the morning
• spaced out from meals, tea, coffee, by at least ½-1-hour duration.
• Evaluate clinically and with FT4 6-8 weekly till FT4 and TSH are normalized.
• Once the thyroid functions have normalized, patient can be reviewed every 6 to 12
months.
• Avoid overtreatment -----Osteoporosis /atrial fibrillation may result

*Thyroid suppressive therapy -- In thyroid carcinoma patients, aim of levothyroxine therapy is to achieve
appropriate TSH suppression

*In central hypothyroidism replace cortisol deficiency prior to starting levothyroxine

(thyroxine enhance cortisol clearance and precipitate adrenal crisis)

5
 Causes of failure to normalize TSH during treatment
• Non-compliance
• Factors affecting absorption

* Taking levothyroxine close to a meal

* Drug interfering in absorption e.g. cholestyramine, ferrous sulfate

*Malabsorption

• Drugs accelerating metabolism e.g. phenytoin, carbamazepine

Treatment of hypothyroid coma

‡ severe hypothyroidism

‡ Slow rise of core temperature

‡ Warm humidified oxygen

‡ Monitoring of vitals

‡ High dose of levothyroxine 300-500ʅg via NG

‡ Hydrocortisone IV

6
 Thyroid disorders in children
Congenital hypothyroidism
• Deficient production of thyroid hormones and manifesting from birth

• Causes

• Thyroid dysgenesis (85%)

• aplasia, hypoplasia or ectopia - not hereditary

• female: male = 2:1

• Dyshormonogenesis (15%)

• defect in one of the several hormones of thyroid synthesis ʹautosomal

recessive

Presentation
• Detected at Newborn screening ʹ

➢ Clinically asymptomatic at birth due to trans-placental passage of maternal T4

• If not screened/detected at birth diagnosis is delayed

Early clinical features of untreated CH Late clinical features of untreated CH

• Widely open AF and PF • Short stature

• Prolonged jaundice ʹindirect • Developmental delay

• Feeding difficulties • Large head/ short neck

• Lethargy/sluggishness • Broad hands / short fingers

• Large tongue/ respiratory difficulties • Dry scaly skin/ coarse scanty hair

• Constipation • Hoarse voice

• Large abdomen/ umbilical hernia • Hypotonia

• Hypothermia • Myxedema

• Bradycardia • Delayed sexual maturation

• Macrocytic anemia • Delayed osseous maturation (bone age)

7
Untreated CH
• Physical and mental development retarded

• Develop obvious clinical features by 3-6 months

Laboratory findings
• TSH ʹelevated

• Serum T4 and Free T4 ʹlow

• Thyroid US scan

• Thyroid Scintigraphy - 123I-sodium iodide

• X-ray left knee joint

➢ Absent distal femoral and proximal tibial epiphysis / epiphyseal dysgenesis

• ECG- low voltage P and QRS complexes

Newborn screening
✓ Heel Prick blood sample before discharge OR Venous blood sample between day 3-5

• If Initial TSH is >6mU/L

✓ Do venous TSH/FreeT4 urgently

Treatment
• Indications to start treatment

➢ TSH >20 mU/L (even if free T4 is normal)

➢ TSH between 6-20mU/L and low free T4

➢ TSH between 6-20mU/L and small/ectopic thyroid gland (even if free T4 is normal)

• Levothyroxine (L-T4)

➢ Should be started as early as possible

➢ 10-15 micrograms/kg/d

8
Follow-up and monitoring
• Monitor treatment with

➢ TSH and freeT4

❖ Free T4 ʹupper half of the reference range

❖ TSH- in the reference range

➢ Undertreatment ʹPersistent hypothyroidism

➢ Overtreatment- craniosynostosis, temperament problems

• Thyroid re-evaluation

➢ To identify transient hypothyroidism

➢ At 3 years ʹgradually reduce and omit LT4

9
 Pathology - THYROIDITIS
‡ Mostly due to non-infective causes

‡ Classified on the basis of onset and duration of disease

± Acute

‡ Infective or radiation induced

± Sub-acute

‡ Granulomatous thyroiditis/ de Quervain thyroiditis

(Acute inflammation followed by a granulomatous response)

± Chronic

‡ Autoimmune thyroiditis

‡ ZĞŝĚĞů͛ƐƚŚLJƌŽŝĚŝƚŝƐ

Chronic autoimmune thyroiditis

‡ Hashimotos thyroiditis / chronic lymphocytic thyroiditis

‡ Most common cause of hypothyroidism in non-endemic areas

‡ Disease of older women, can occur in children

‡ Most prevalent 45 - 65 years of age

‡ Women > men

‡ Major cause of non- endemic goiter in the pediatric population.

‡ Strong genetic predisposition

‡ Characterized autoimmune destruction of glandular tissue gradual thyroid failure

‡ Painless symmetric and diffuse enlargement of the thyroid
‡ Hypothyroidism develops gradually

‡ Preceded by transient thyrotoxicosis

‡ јƌŝƐŬĨŽƌĚĞǀĞůŽƉŝŶŐŽƚŚĞƌĂƵƚŽŝŵŵƵŶĞĚŝƐĞĂƐĞƐ
adrenalitis) and nonendocrine (SLE, myasthenia gravis, and Sjogren syndrome).

‡ јƌŝƐŬƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨ
-cell NHL (MALT)

10
 Pathogenesis of chronic autoimmune thyroiditis
Caused by a breakdown in self-tolerance to thyroid auto-antigens.

Autoantibodies against variety of thyroid antigens (TG and TP) / anti thyroglobulin anti thyroperoxidase

Depletion of thyrocytes by apoptosis and replacement of the thyroid parenchyma by mononuclear cell
infiltration and fibrosis.

Initiating event is sensitization of auto reactive CD4+ T-helper cells to thyroid antigens

Death of thyroid follicular cell by multiple immunologic mechanisms

1. CD8+ cytotoxic T cellʹ

mediated cell death

2. Cytokine - mediated cell death

3. Antibody - dependent cell-mediated cytotoxicity (ADCC)

Macroscopy
‡ Classic form
✓ Diffuse, symmetrical firm enlargement
✓ Cut surface is fleshy and lobulated
(Could be Nodular enlargement, Solitary nodule in thyroid)

Microscopy
✓ Extensive mononuclear cell infiltration of the parenchyma: small
lymphocytes, plasma cells, macrophages and well-developed germinal
centers
✓ Follicular atrophy
✓ Follicular destruction
✓ Hürthle cell metaplasia; abundant eosinophilic, granular cytoplasm
✓ Interstitial fibrosis
✓ Formation of lymphoid follicles

11
Subacute (Granulomatous/Dequervain) Thyroiditis
Clinical features

‡ Thyroid pain
‡ Majority have history of an URTI

‡ Variable enlargement of the thyroid

‡ Nearly all patients have transient thyrotoxicosis

‡ RI uptake is diminished

‡ Thyroid function returns to normal, generally in 6 to 8 weeks

Pathogenesis of subacute thyroiditis

‡ Triggered by a viral infection (Immune response is virus-initiated)

‡ Seasonal incidence - peak in the summer

‡ association with coxsackievirus, mumps, measles, adenovirus

Macroscopy
‡ Enlarged (unilateral/ bilateral)
‡ Firm
‡ Intact capsule
‡ Slightly adherent to surrounding structures
‡ C/S Firm and yellow-white involved areas stand out from the more rubbery, normal
brown thyroid substance.

Microscopy:
‡ Changes are patchy and depend on the stage of the disease.
‡ Acute: Entirely disrupted scattered follicles replaced by neutrophils forming micro
abscesses
‡ Subacute: Damaged thyroid follicles surrounded by aggregates of lymphocytes,
activated macrophages, and plasma cells
‡ Multinucleate giant cells enclose pools or fragments of colloid
‡ Chronic: Chronic inflammatory infiltrate and fibrosis replace the foci of injury
‡ Different histologic stages may find in the same gland

12
Riedel thyroiditis
‡ Extensive fibrosis involving the thyroid and contiguous neck structures

‡ Hard and fixed thyroid mass

‡ Associated with idiopathic fibrosis in other sites in the body-retroperitoneum

Goiter
‡ an enlargement of thyroid gland.

‡ Goiter: thyroid enlargement due to compensatory hypertrophy & hyperplasia of the follicular
epithelium in response to thyroid hormone deficiency.

‡ End result is generally euthyroid state, but at various stages hyperthyroidism and
hypothyroidism can result.

‡ 2 morphological forms

‡ diffuse non-toxic goiter (simple/colloid goiter)

‡ Diffuse enlargement of thyroid gland unaccompanied by hyperthyroidism

‡ Try to maintain euthyroid state through stages of hypothyroidism

‡ Could be

‡ Endemic

‡ sporadic

‡ Nodular goiter (multinodular goiter/adenomatous goiter)

‡ End stage of long-standing simple goiter

‡ Tumor like enlargement

‡ Could give rise to hyperthyroidism

13
 Pathogenesis of simple & multinodular goiter

Iodine lack goitrogen

Deficiency of thyroid hormone production s

Excess TSH stimulation

Cyclic hyperplasia and involution of thyroid gland
Diffuse goiter
Repeated hyperplasia and involution of thyroid gland

Growth of Fibrosis of
hyperplastic areas Nodular goiter involuted areas

Diffuse goiter
‡ Moderate enlargement of the gland

‡ Symmetrical and diffuse

‡ Microscopically

± in hyperplastic stage

‡ Tall columnar epithelium forming papillary infoldings

± In involution stage

‡ Flattened cells lining large follicles

Multinodular goiter
Macroscopy Microscopy
‡ Asymmetrical enlargement ‡ Nodule formation

‡ Nodularity ‡ Follicles of varying size

‡ Fibrous scarring ‡ Hemorrhage

‡ Hemorrhage ‡ Fibrosis

‡ Calcification ‡ Calcification
‡ Cystic degeneration ‡ Cystic change

14
 Hyperthyroidism
Hyperthyroidism and Thyrotoxicosis

ͻ Thyrotoxicosis- Hypermetabolic state caused by јĐŝƌĐƵůĂƚŝŶŐůĞǀĞůƐŽĨ

ͻ Hyperthyroidism ʹHyper function of the thyroid gland
ͻ Thyrotoxicosis is commonly due to Hyperthyroidism
ͻ May be due to excessive release of preformed thyroid hormone (thyroiditis)
ͻ 1ry thyrotoxicosis - arising from an intrinsic thyroid abnormality
ͻ 2ry thyrotoxicosis- processes outside of the thyroid
ͻ Female: male =5:1 (MCQ)

Thyrotoxicosis causes

Common

• 'ƌĂǀĞƐ͛ĚŝƐĞĂƐĞ;ĂƵƚŽŝŵŵƵŶĞͿ
• Toxic multinodular goiter
• Solitary toxic nodule/adenoma
• Drugs ʹamiodarone, immunotherapy (ipilimumab, pembrolizumab, nivolumab)
• Thyrotoxicosis factitia (secrete T4 consumption)

Uncommon

• Acute thyroiditis
o sŝƌĂů;Ğ͘Ő͘ĚĞYƵĞƌǀĂŝŶ͛ƐͿ
o Autoimmune
o Post-irradiation
o Postpartum
• Gestational thyrotoxicosis (HCG-stimulated)
• Neonatal thyrotoxicosis (maternal thyroid antibodies)
• Exogenous iodine
• TSH-secreting pituitary tumors
• Metastatic differentiated thyroid carcinoma
• HCG-producing tumors
• Hyperfunctioning ovarian teratoma (Struma ovarii)

15
Graves’ Disease
✓ Most common cause of hyperthyroidism (MCQ)
✓ Auto-immune process ʹIgG Abs (TSHR-ďͿďŝŶĚŝŶŐƚŽd^,ƌĞĐĞƉƚŽƌ
production
✓ Mostly 30-50-year-old females (MCQ)
✓ Diffuse thyroid enlargement
✓ Ophthalmopathy
✓ Pre-tibial myxedema, dermopathy, thyroid acropachy
✓ Associated with other auto-immune disorders ʹVitiligo, Myasthenia gravis (MCQ)
✓ 40% have single episode
✓ Most have relapses & remissions ʹeventually many become hypothyroid (MCQ)

Symptoms Signs
ͻ Weight loss despite increased appetite ͻ Tremor
ͻ Irritability & restlessness ͻ Tachycardia / atrial fibrillation
ͻ Tremor ͻ High volume pulse with warm,
ͻ Breathlessness & palpitations vasodilated peripheries
ͻ Heat intolerance ͻ Systolic hypertension
ͻ Diarrhea ͻ Goiter (bruit)
ͻ Itching ͻ Lid lag & stare
ͻ Oligomenorrhoea ͻ Proximal myopathy
ͻ Sweating
Eye signs, pretibial myxedema, thyroid acropachy only in Graves (MCQ)
Graves’ Ophthalmopathy
✓ >ŝĚůĂŐΘ͚ƐƚĂƌĞ͛
✓ Grittiness, increased tearing
✓ Exophthalmos
✓ Proptosis & lid retraction cause corneal ulceration
✓ Ophthalmoplegia, diplopia
✓ Papilledema
✓ Loss of vision
• ŚĂƌĂĐƚĞƌŝƐƚŝĐŽĨ'ƌĂǀĞƐ͛ĚŝƐĞĂƐĞ
• јǀŽůƵŵĞŽĨƚŚĞƌĞƚƌŽ
-orbital connective tissues and extraocular muscles
1. Infiltration of the retro-orbital space by mononuclear cells
2. Inflammatory edema and swelling of extraocular muscles
ϯ͘јĞdžƚƌĂĐĞůůƵůĂƌŵĂƚƌŝdžĐŽŵƉŽŶĞŶƚƐ
4. Fatty infiltration

16
Pathogenesis
• Due to breakdown in self-tolerance to thyroid autoantigens - TSH receptor
• Production of multiple autoantibodies
ŶƚŝďŽĚŝĞƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚ'ƌĂǀĞƐ͛ĚŝƐĞĂƐĞ
✓ Thyroid- stimulating immunoglobins (TSI) ʹBinds to TSH receptor-increase release of
thyroid hormones ʹRelatively specific
✓ Thyroid growth-stimulating immunoglobins (TGI) ʹStimulate proliferation of thyroid
epithelium
✓ TSH binding inhibitor immunoglobins (TBII) ʹInhibitory to binding of TSH to its own
receptors
• Depending upon its action as inhibitory or stimulatory to follicular epithelium gets episodes of
hyper or hypothyroidism

Pathology of Graves’ disease

Macroscopy

ͻ Diffuse and Symmetrically enlarged gland

ͻ Increases in weight

ͻ Cut surface is red- brown due to vascularity

ͻ Fleshy and homogenous

Microscopy

ͻ Increased vascularity

ͻ Lymphocytic infiltration of the stroma with germinal centers

ͻ Epithelial hyperplasia and hypertrophy

ͻ The follicles are lined by tall columnar epithelium and heaped up into papillary infoldings

ͻ Colloid is markedly scanty, pale

ͻ Colloid resorption

17
 Investigations
✓ TSH suppressed
✓ Free T4 & T3 elevated
✓ TSH receptor Abs ʹnot routinely tested
✓ TPO & anti-thyroglobulin Abs in Graves

Management
• Anti-thyroid drugs
• Radio iodine
• Surgery

Choice of Therapy

ͻ dĨŽƌϭϴŵŽŶƚŚƐ͙͙
͙͘͘͘
watch

ͻ dĨŽƌϭϴŵŽŶƚŚƐ͙͙
͙͘͘͘
surgery

ͻ I131
dĨŽƌϭϴŵŽŶƚŚƐ͙͙
͙͘͘͘

ͻ I 131 at presentation

Antithyroid Drugs
ͻ Carbimazole (or Methimazole) or Propylthiouracil ʹboth equally effective

ͻ Inhibit formation of thyroid hormones (CBZ is immuno-suppressive)

ͻ Gradual dose titration or Block & Replace

ͻ Clinical benefits take 10-20 days due to long half-life of T4

CBZ 20-40 mg daily for 4-6 weeks

Review ʹclinical, T3/T4 levels ʹadjust dose

Review in 2-3 months ʹadjust dose

Reduce to 5 mg daily over 6-24 months

Stop CBZ when euthyroid on 5 mg

18
 Block and replace regimen

ͻ Full doses of ATD is given (40mg carbimazole)

ͻ Suppress the thyroid completely

ͻ Replace the thyroid activity with 100mcg of levothyroxine daily once euthyroid state is achieved

ͻ This is continued usually for 18 months

Antithyroid drugs ʹ
mechanism of action

✓ inhibit thyroid hormone synthesis by interfering with thyroid peroxidase mediated

iodination of tyrosine residues in thyroglobulin, an important step in the synthesis of
thyroxine and triiodothyronine
✓ Propylthiouracil can also block the conversion of T4 to T3. (MCQ)
✓ antithyroid drugs may have clinically important immunosuppressive effects, CBZ has
high than PTU
✓ PTU is preferred in T1 and CBZ is preferred T2 and T3, Both safe in lactation, (MCQ)

Antithyroid drugs Adverse effects

Minor

• urticaria and other rashes

• arthralgia
• gastrointestinal upset

Major

• Agranulocytosis, in CBZ (MCQ)

Immediate medical attention if fever or sore throat (MCQ)
• Hepatotoxicity
• Vasculitis

Antithyroid drugs in pregnancy and lactation

• Both carbimazole and PTU are NOT considered 100% safe

but PTU preferred in pregnancy as carbimazole causes fetal malformations (aplasia cutis) (MCQ)

• Both are safe in lactation

19
Beta Blockers

ͻ For rapid symptom control

ͻ Propranolol 40-80 mg every 6-8 hours
ͻ Avoid in asthma, caution in heart failure
ͻ Stop when clinically euthyroid
ͻ NOT to be used alone
Iodides (NaI, KI)

ͻ Inhibition of T3 & T4 release and synthesis

ͻ Decrease of size & vascularity of the hyperplastic gland
Indications 1. Hyperthyroidism

2. Thyroid crisis.

Indications for Surgery or Radioiodine Therapy

• Patient choice
• Persistent drug side effects
• Poor compliance with drugs
• Recurrent hyperthyroidism after drugs
• Large goiter (surgery)

Radioactive Iodine I131

ͻ Destroys functioning thyroid cells

ͻ Takes several months to be fully effective

ͻ Must be euthyroid with drugs before RAI

ͻ Majority become hypothyroid ʹlong term follows up essential

ͻ Contra-indicated in pregnancy & breast feeding

ͻ Ophthalmopathy may worsen with I131

20
 Toxic Multinodular Goiter
✓ Female > 60 years
✓ CVS features (AF, heart failure) predominate
✓ I131 large doses + partial thyroidectomy
✓ Antithyroid drugs rarely induce remission

Solitary Toxic Adenoma

✓ Rest of the gland atrophies due to suppression of TSH Female >40yr
✓ Radio isotope scanning useful for diagnosis
✓ Rx are hemi-thyroidectomy, I131

Thyroid storm
• A medical emergency - abrupt onset of severe hyperthyroidism
• Patients with underlying 'ƌĂǀĞƐ͛ disease
• Results from an acute elevation in catecholamine levels
• During any form of stress - infection, surgery, cessation of anti-thyroid medication
• Febrile and present with tachycardia out of proportion to the fever
• Untreated - die of cardiac arrhythmias

Thyroid storm ʹ
management

✓ Thermal regulation
✓ Treatment of arrhythmias
✓ Treatment of precipitating cause e.g. -. antibiotics
✓ Propylthiouracil (to block thyroid hormone synthesis and T4 to T3 conversion)
✓ Potassium iodide therapy (Lugol solution) -to inhibit thyroid hormone release
✓ Beta blockers
✓ Intravenous hydrocortisone 100mg 6 hourly (to inhibit T4 to T3 conversion)

21
 Thyroid Tumors

Thyroid tumors- general facts

▪ All thyroid tumors are common in females > men
▪ Usually present as a solitary nodule
▪ Majority of clinically detected solitary nodules are a dominant nodule of a multi-nodular goiter
▪ dƵŵŽƌƐĂƌĞ͚ĐŽůĚ͛ŽŶƚŚLJƌŽŝĚƐĐĂŶ
▪ Benign tumors are commoner than the malignant
▪ In young age and in men, a solitary nodule is regarded with more suspicion than in a middle-aged
woman

Features favor neoplastic nodule

▪ Solitary nodules
▪ Younger patients
▪ Gender - Males
▪ History of radiation treatment to the head and neck region
▪ Cold nodules MCQ

Thyroid Tumors
MCQ

Follicular cell derived Para follicular derived Other

Medullary carcinoma Lymphoma

Benign Malignant
Sarcoma

Follicular adenoma Follicular carcinoma

Papillary carcinoma

Poorly differentiated

Anaplastic carcinoma

22
 Follicular adenoma
MCQ
• Commonest of all thyroid tumors
• Rarely can cause hyperthyroidism -͚ƚŽdžŝĐĂĚĞŶŽŵĂ͛
• Encapsulated and compress the surrounding thyroid tissue
• No invasion of the capsule is the key difference from follicular carcinoma
• Not the precursors of follicular carcinoma
SEQ

Macroscopy
✓ Solitary
✓ Spherical
✓ Encapsulated
✓ Well demarcated from surrounding thyroid
✓ ǀĞƌĂŐĞϯĐŵŝŶĚŝĂŵĞƚĞƌ;ƐŽŵĞůĂƌŐĞƌшϭϬĐŵͿ
✓ Cut surface bulges MCQ
✓ Color : gray-white to red-brown
✓ Areas of hemorrhage, fibrosis, calcification, and cystic change +

Microscopy
✓ Well-formed intact capsule encircling the tumor
✓ Follicular growth pattern
✓ Uniform-appearing follicles that contain colloid
✓ Distinct from the adjacent non-neoplastic thyroid
✓ Follicular epithelial cells little variation in cell and nuclear morphology
✓ Mitotic figures are rare
✓ Occasionally Hürthle cell change
✓ No capsular and/or vascular invasion

• Extensive mitotic activity

• Necrosis
• High cellularity warrants careful examination of the capsule and the
nuclear features

SEQ

Follicular carcinoma

• These are also composed of small /large follicles

• Essential feature is infiltration across its capsule or invasion of the
vessels.
• Composed of closely packed follicular structures
• Distant blood borne metastasis occurs to bone and lung
• Prognosis is worse than that of papillary carcinoma
Minimally invasive Widely invasive

Papillary thyroid carcinoma

Follicular Adenoma Follicular Carcinoma

Thin capsule Thick capsule

No Capsular invasion Capsular invasion present

Compressed normal thyroid May have vascular invasion usually present external
to capsule

Papillary thyroid carcinoma

• Accounts for about 60-70% of all thyroid cancers. (commonest cancer)
• Has the best prognosis of all thyroid cancers MCQ
• Occurs in young
• 3 times more commoner in females than men.
• Lymphatic infiltration and metastasis is the way of spread.
• Can present with cervical lymphadenopathy without thyroid enlargement
SEQ
Macroscopy
✓ Small to larger size
✓ Single lesion or multifocal
✓ Solid or cystic
✓ Papillary excrescences may be seen
✓ Could be
ʹwell encapsulated ʹgood prognosis
ʹwidely infiltrative ʹ
bad prognosis
 SEQ

Microscopy
✓ Fronds of tissue with papillary pattern
✓ Papillae have a thin fibro-vascular cores
✓ Papillae are lined by optically clear nuclei (Orphan Annie Nuclei)
✓ Cells show,
MCQ
Nuclear grooving
Nuclear overlapping
Intranuclear inclusions (pseudo inclusions)
✓ Psammomatous calcifications are seen in about 50 % of cases.

Papillae with fibrovascular cores

Psammomatous
calcifications
Nuclear
inclusions
Clear nuclei Nuclear
grooves

Poorly differentiated thyroid carcinoma

• Malignant follicular cell neoplasm with limited evidence of follicular cell differentiation
• Intermediate clinical behavior between well differentiated (FTC & PTC) and anaplastic carcinoma
• Diagnostic criteria (Turin consensus )
• Solid / trabecular / insular growth pattern
• No nuclear features of papillary carcinoma
• Presence of at least one of following:
convoluted nuclei
шϯŵŝƚŽƚŝĐĨŝŐƵƌĞƐͬϭϬ,W&
tumor necrosis

Solid / trabecular / insular growth pattern Tumor necrosis Brisk mitoses

Anaplastic carcinoma
• Undifferentiated tumors of the thyroid follicular epithelium
• Aggressive tumors
• Mortality rate approaching 100%
• Fewer than 5% of all thyroid cancers
• Mean Age = 65 yrs
• 50% of the patients have a history of multinodular goiter

Microscopy MCQ
✓ Composed of highly anaplastic cell
➢ Large , pleomorphic cells, including occasional osteoclast-like multinucleate giant
cells
➢ spindle cells with a sarcomatous appearance
➢ small cells

Medullary carcinoma of thyroid

ͻArise from the parafollicular C cells in the thyroid MCQ
ʹFamilial medullary thyroid carcinomas
• Occur in multiple endocrine neoplasia type 2 (MEN-2) and are associated
with germ-line RETprotooncogene mutations (multiple endocrine neoplasia
syndrome)
• Bilateral
• Occurs in young
ʹSporadic medullary thyroid carcinomas
• Unilateral
• Middle age
Therefore if a medullary CA is identified it is important to screen the family members with
serum calcitonin assay
• Amyloid stroma of the medullary thyroid carcinoma has been stained with congo red.

Macroscopy
✓ Solid pattern of growth
✓ Do not have connective tissue capsules
MCQ
Microscopy
✓ Composed of polygonal to spindle-shaped cells
ʹmay form nests, trabeculae, and even follicles
✓ Acellular amyloid deposits, derived from altered calcitonin molecules, are present in the
adjacent stroma in many cases

26
 Amyloid stains red with congo red Immunohistochemical anti-
Amyloid deposits calcitonin antibody stain showing
strong red positivity

Clinical approach in thyroid problems

MCQ
Tumors are diagnosed by USS guided FNAC
➢ Papillary thyroid carcinoma
➢ Medullary carcinoma of thyroid

Follicular lesions in cytology (FNAC)

Could be
ͻFollicular adenoma
ͻFollicular carcinoma
ͻHyperplastic nodule in a multinodular goiter

Histology is essential for further identification

27
 Parathyroid disorders

Calcium Metabolism
ͻŽŶƚƌŽůůĞĚďLJWd,ΘsŝƚĂŵŝŶ

ͻ,LJƉĞƌĐĂůĐĞŵŝĂŵŽƌĞĐŽŵŵŽŶƚŚĂŶ
hypocalcaemia

ͻĞƚĞĐƚŝŽŶŽĨĂƐLJŵƉƚŽŵĂƚŝĐŚLJƉĞƌĐĂůĐĞŵŝĂŝƐďĞĐŽŵ

28
Parathyroid Gland Introduction & Development
• The parathyroid glands are small endocrine glands in the neck, usually located behind the
thyroid gland.
• They produce Parathormone (PTH) which is the Regulator of calcium homeostasis

Parathyroid glands
• Developmentally, the parathyroid gland is derived from the pharyngeal pouch endoderm
• Develops from the 3rd & 4th Pharyngeal Pouches

• 4 Glands
• Superior are constant in position
• Inferior NOT constant
• Blood supply
The inferior thyroid arteries supply the parathyroid glands via its branches (supplying both the
inferior and superior parathyroid in most cases). Collaterals via the superior thyroid artery,
thyroid ima artery

• When blood Calcium levels drop below a certain point, Calcium sensing receptors in the
parathyroid gland are activated to release hormone into the blood.
• Parathyroid Hormone (PTH, also known as Parathormone) is a small protein that Controls
Calcium and Phosphate Homeostasis, as well as bone physiology.
• Parathyroid Hormone has effects antagonistic to those of Calcitonin.
• It increases blood calcium levels by stimulating osteoclasts to break down bone and release
calcium.
• PTH also increases gastrointestinal calcium absorption by activating vitamin D, and promotes
calcium uptake by the kidneys.

29
Investigation of Parathyroid

Assessment of Function

✓ Serum Calcium
✓ Serum Phosphate
✓ PTH
Visualization

✓ US scan
✓ Sestamibi Scan - isotope Scan (Methoxy-IsoButyl-Isonitrile)
✓ CECT/ 4D CT

Parathyroid Diseases Introduction

Parathyroid Disorders are mainly

• Excess Hormone Secretion Hyperparathyroidism

ͻWƌŝŵĂƌLJ
- (Commonest)
ͻ^ĞĐŽŶĚĂƌLJ- Secondary to Renal Disease
ͻdĞƌƚŝĂƌLJ
• Decreased Hormone Secretion ʹHypoparathyroidism

30
 Hyperparathyroidism
• May be
✓ primary
✓ secondary
✓ tertiary

Primary Hyperparathyroidism
• Common cause of hypercalcemia
• Due to abnormality in the gland/glands
✓ Single parathyroid adenoma (>80%)
✓ Diffuse hyperplasia (15-20%)
✓ Rarely ʹparathyroid carcinoma (<1%)
• ĂƵƐĞƐј^͘ĐĂůĐŝƵŵΘљ^͘ƉŚŽƐƉŚĂƚĞ
јϮϰ-hour urinary calcium excretion

Secondary Hyperparathyroidism
• Physiological compensatory hypertrophy of all parathyroid glands due to persistent
hypocalcaemia
• Due to ʹ
✓ Vitamin D deficiency
✓ Chronic kidney disease (early)
• When cause of hypocalcaemia is corrected PTH becomes normal

Tertiary Hyperparathyroidism
• >ŽŶŐƐƚĂŶĚŝŶŐƐĞĐŽŶĚĂƌLJŚLJƉĞƌƉĂƌĂƚŚLJƌŽŝĚŝƐŵї
onomy of
parathyroid due to hypertrophy)
• Due to
✓ chronic kidney disease (advanced)
• ĂƵƐĞƐјƐ͘ĐĂůĐŝƵŵΘјƐ͘ƉŚŽƐƉŚĂƚĞ

31
Causes of Hypercalcemia
• Excess PTH ʹprimary, tertiary, ectopic
• Malignancy ʹmyeloma, bone secondaries
• Excess Vitamin D ʹoral, granuloma, lymphoma
• Excess Calcium ʹoral
• Other endocrine disease (mild) ʹƚŚLJƌŽƚŽdžŝĐŽƐŝƐ͕ĚĚŝƐŽŶ͛ƐĚŝƐĞĂƐĞ
• Drugs ʹthiazides, Vitamins A & D analogues, Lithium
• Long term immobility
• Severe hypercalcemia (> 3 mmol/L) malignant disease hyperparathyroidism advanced CKD
vitamin D toxicity
• Common primary tumors - bronchus, breast, myeloma, esophagus, thyroid, prostate,
lymphoma, renal cell carcinoma

Clinical Features of Hypercalcemia

• Mild - usually asymptomatic
• Tiredness, malaise, dehydration, depression
• Renal colic (stones), polyuria, nocturia, hematuria, hypertension
• ŽŶĞƉĂŝŶ͕ďŽŶĞĐLJƐƚƐΘ͚ďƌŽǁŶƚƵŵŽƌƐ͛
• Abdominal pain
• Chondrocalcinosis & ectopic calcification
• Corneal calcification

32
Differential Diagnosis
• protein electrophoresis ʹmyeloma
• serum TSH ʹhyperthyroidism
• 0900 h cortisol and/or ACTH test - Addison's disease
• serum ACE ʹsarcoidosis
• hydrocortisone suppression test - sarcoidosis, vitamin D mediated hypercalcemia, some
malignancies

Investigations – Biochemistry
• Fasting serum calcium & phosphate
• Serum PTH
• Arterial blood gas - hyperchloremic acidosis
• Renal functions ʹusually normal
• 24-hour urinary calcium ʹlook for hypocalciuric hypercalcemia
• ј>W ʹsevere parathyroid bone disease

Investigations – Imaging
• X-ray abdomen ʹrenal calculi, nephrocalcinosis
• X-ray hands ʹsubperiosteal erosions in middle & terminal phalanges
• DXA bone density scan
• Parathyroid imaging - ultrasound scan, high resolution CT or MRI, radio-isotope scan

33
Treatment
• Treatment of Acute Severe Hypercalcemia
✓ Presentation ʹdehydration, nausea & vomiting, nocturia, polyuria, drowsiness, altered
consciousness
✓ Hydrate adequately 4-6 L N. Saline on D1, 3-4 L/day thereafter
✓ IV Pamidronate ʹtreatment of choice
✓ Calcitonin - short duration of action
✓ Prednisolone - 30-60 mg daily
✓ Oral Phosphates - causes diarrhea

• Treatment of Primary Hyperparathyroidism

✓ high fluid intake
✓ avoid high calcium & Vitamin D intake
✓ agents that target calcium sensing receptors(e.g. cinacalcet)
✓ Medical treatment may be considered in
o Unfit patients
o Mild disease
o Asymptomatic disease (detected by routine screening)
✓ Medical treatment controls the effects esp. on bones - Does NOT treat the pathology

34
 ✓ Surgical Removal ʹindications are,
o renal stones
o impaired renal function
o ďŽŶĞŝŶǀŽůǀĞŵĞŶƚŵĂƌŬĞĚљŝŶ cortical bone density
o marked hypercalcemia
o <50 yrs. of age
o previous episode of acute severe hypercalcemia
✓ 4 gland exploration - Requires General Anesthesia
✓ Minimally invasive Parathyroidectomy (MIP) -Requires General Anesthesia -Uses an
endoscope
✓ Focused Parathyroidectomy (also called MIP) - Local Anesthesia - Localize accurately and
small incision

• Treatment for Secondary hyperparathyroidism -treat cause

• Treatment for Tertiary hyperparathyroidism -parathyroid resection surgery

35
Normocalcemic hyperparathyroidism

36
Familial Hypocalciuric Hypercalcemia
• Caused by inactivating mutation of calcium sensing receptors
• Sensitivity of receptors to calcium decreases, requiring higher calcium levels to suppress PTH
secretion.
• Fractional excretion of calcium is lower than 1%, despite hypercalcemia.
• Hypercalcemia in FHH has a generally benign course and is resistant to medications, except for
some cases successfully treated with the calcimimetic agent calcinet.

MCQ points
• Primary hyperparathyroidism is mainly due to parathyroid adenoma.
• In primary hyperparathyroidism; Ca2+ is elevated & PO43- is reduced.
• Early CKD – secondary hyperparathyroidism.
• Advanced CKD – tertiary hyperparathyroidism
• Brown tumors are a feature of severe hyperparathyroidism
• Secondary hyperparathyroidism is due to persistent hypocalcaemia.
• Chondrocalcinosis occurs due to hypercalcemia.
• Hypercalcemia causes osteopenia in trabecular bones.
• IV pamidronate is the treatment of choice for acute severe hypercalcemia.

37
 Hypoparathyroidism

PRIMARY HYPOPARATHYROIDISM
‡ љ^͘ĐĂůĐŝƵŵǁŝƚŚј^͘ƉŚŽƐƉŚĂƚĞ
‡ Associated with other autoimmune disorders in Polyglandular Autoimmune Syndrome ʹ
vitiligo, cutaneous candidiasis

PSEUDO HYPOPARATHYROIDISM
‡ End organ resistance to
PTH

‡ Short stature
‡ Short metacarpals
‡ Subcutaneous
calcification

‡ Intellectual impairment

PSEUDO- PSEUDO HYPOPARATHYROIDISM

Its phenotype is similar to those with pseudo hypoparathyroidism.

But calcium metabolism is normal.

38
 OTHER CAUSES OF HYPOCALCAEMIA

ͻ/ŶĐƌĞĂƐĞĚƉŚŽƐƉŚĂƚĞůĞǀĞůƐ
Chronic kidney disease (common)
Phosphate therapy
ͻsŝƚĂŵŝŶĚĞĨŝĐŝĞŶĐLJ
Osteomalacia/ rickets, Vitamin D resistance
ͻƌƵŐs - Calcitonin, bisphosphonates
ͻDŝƐĐ͘
- Acute pancreatitis (common)
Citrated blood in massive transfusion (common)
Low plasma albumin (malnutrition, CLCD)
Malabsorption (coeliac disease)

Symptoms of Hypoparathyroidism
‡ Paresthesia of hands and feet
‡ Circumoral numbness
‡ Cramps, anxiety & tetany
‡ Convulsions
‡ Laryngeal stridor
‡ Dystonia
‡ Psychosis

39
Signs of Hypoparathyroidism
‡ Chvostek’s sign ʹTwitching of the facial muscles when the facial nerve is gently tapped in
the pre-auricular region

‡ Trousseau’s sign

40
 ‡ Papilledema
‡ Cataracts
‡ (prolonged QT on ECG)

Investigations in hypocalcemia
• Serum calcium and phosphate
• PTH- absent / low in hypoparathyroidism, high in other causes of hypocalcemia
• Serum creatinine
• Serum 25- hydroxy vitamin D -low in vit. D deficiency
• Serum magnesium
• X Ray of hands- short 4th metatarsal in pseudo hypoparathyroidism

Management of hypoparathyroidism

• Alpha hydroxylated derivates of vitamin D (eg: alfa calcidol)

• Calcium supplements
• Regular monitoring of Serum calcium/urine calcium: creatinine ratio

41