Hypothyroidism: Diagnosis and Manifestations

Endocrine Pathology - Thyroid and Parathyroid

• The course is Endocrine Pathology II, focusing on thyroid and parathyroid pathology.
• The class is Year 2.
• The course is Pathology.
• The lecturer is Dr Helen Barrett.
• The date of the lecture is January 10, 2025.

Learning Outcomes

• Identify the histological features of a normal thyroid gland.
• List the causes of hypothyroidism and hyperthyroidism.
• Describe and illustrate the pathological features of neoplastic and non-neoplastic thyroid lesions (including thyroiditis).
• Explain the usefulness and limitations of thyroid fine-needle aspiration (FNA).
• Classify thyroid tumors and outline key clinical features and presentation.
• List the etiological factors in the development of thyroid carcinoma.
• Identify the histological features of a normal parathyroid gland.
• List the causes of hypoparathyroidism and hyperparathyroidism.

Endocrine System

• Pure endocrine organs: pituitary, thyroid, parathyroid, adrenal.
• Endocrine components in mixed organs: pancreas, ovary, testis.

Disease in Endocrine Organs

• Diseases often present via hyperfunction, hypofunction, or enlargement/mass effect.

Thyroid Gland

• Develops via the thyroglossal duct.
• Typical weight is 20-25g.
• Composed of two large lateral lobes joined by an isthmus.
• Potential developmental anomalies: aplasia/hypoplasia (rare), heterotopic thyroid tissue, and thyroglossal duct cyst (hyoid bone region).

Thyroid and Parathyroid Glands (Histology)

• Diagrams and micrographs are presented to show the structure.

Thyroid Gland (Histology)

• Histologically, follicular cells produce thyroid hormones.
• Parafollicular (C) cells produce calcitonin.
• Active form of thyroid hormones is T3 (triiodothyronine).
• Thyroid function tests include T4, T3, TSH, and antibodies (to thyroid and thyroglobulin).

Thyroid System (Diagram)

• Explains the hypothalamic-pituitary-thyroid axis.
• Shows the hormones and feedback loops involved.

Symptoms of Thyroid Disease

• Symptoms of hyperthyroidism: heat intolerance, weight loss despite increased appetite, tachycardia, palpitations, hypermotile symptoms, tremor, irritability, often proximal muscle weakness.
• Symptoms of hyperthyroidism (elderly): "apathetic" hyperthyroidism, worsening cardiac insufficiency.
• 'Thyroid storm': abrupt, severe hyperthyroidism, medical emergency, usually in underlying Graves' disease.
• Symptoms of hypothyroidism: apathy, mental sluggishness, cold intolerance, edema of face and tongue, hoarseness, myxedema, including the elderly.
• Enlarged thyroid gland: Generalized (goitre), or localized (nodule).
• Euthyroid: normal thyroid status.

Graves' Disease

• Autoimmune disorder with hyperthyroidism.
• M:F ratio is 1:5.
• Age range: 15-40 years.
• Familial tendency exists.
• Marked by IgG autoantibodies to the TSH receptor, mimicking TSH's effect, leading to increased thyroid hormone release.
• Macro features: diffuse enlargement.
• Micro features: star-shaped follicles, little colloid, increased lymphocytes.
• Clinical features: hyperthyroidism and exophthalmos (swelling of retro-orbital tissues, leading to protruding orbits), lid lag, pretibial myxedema (dermophathy).

Thyroiditis

• A group of disorders involving thyroid inflammation.
• Common types: autoimmune thyroiditis (e.g., Graves' disease, Hashimoto's thyroiditis), De Quervain's (subacute granulomatous) thyroiditis.
• De Quervain's: subacute (subacute granulomatous) thyroiditis, F>M, common age range: 30-50 years, often viral etiology, upper RTI preceding onset.
• Micro features: focal acute inflammation, granulomatous.
• Most patients return to euthyroid state in 6–8 weeks.
• Clinical: sudden painful enlargement and fever.

Thyroid Enlargement

• Simple/multinodular goiter: diffuse involvement of the gland, often bordering on low function states, generally does not cause abnormal function.
• Nodules: can be neoplasms (hyperplastic nodule, thyroid cyst) or some cases of thyroiditis.
• Goitre: enlarged thyroid gland.

Simple and Multinodular Goiter

• Diffuse involvement of the gland.
• Often bordering on too low function, but usually not associated with abnormal function.
• Endemic: low iodine ("goitrogens").
• Non-endemic: low iodine synthesis problems (F>M).
• Decreased T3/T4 output → increased TSH → hypertrophy/hyperplasia of thyroid.
• Simple goitre → involution, TSH ↓, T3/T4 return to normal.
• Multinodular goitre → fibrosis, haemosiderin, atrophy, hypertrophy/hyperplasia.

Thyroid Nodules

• Common.
• Differential diagnosis: hyperplastic nodule, neoplasms (benign/malignant (primary/metastasis), rarely thyroiditis).
• Approach to evaluation: Clinical history and examination, blood tests, radiology (ultrasound: solid vs cystic, calcifications, size, vascularity; radionuclide imaging: classify as cold, warm, hot; less common CT or MRI).
• Pathology: fine needle aspiration biopsy (FNAB).

Thyroid FNA

• Diagnostic tool of choice for evaluating thyroid nodules.
• Performed under ultrasound guidance.
• Safe, accurate, cost-effective.
• Categories: Thy1 (non-diagnostic), Thy2 (non-neoplastic), Thy3 (possible neoplasm), Thy4 (suspicious malignancy), Thy5 (malignant).

Thyroid Neoplasms

• Benign: follicular adenoma, others (e.g., lipoma).
• Malignant: papillary, follicular, medullary, anaplastic carcinoma, other (e.g., lymphoma, metastases).

Follicular Adenoma

• Any age, F > M.
• Clinical: euthyroid, sometimes toxic.
• Macro: encapsulated, firm, usually <5 cm.
• Micro: follicles of rather uniform size, variable colloid, can show cytological atypia.
• No capsular or vascular invasion.

Malignant Thyroid Tumors

• 0.5% of all cancer deaths.
• F>M
• Risk factors: ionizing radiation exposure, iodine-rich diet, genetic issues (e.g., MEN 2a or 2b), nodules.
• Types: papillary, follicular, medullary, or anaplastic.

Papillary Carcinoma

• Most common (85% of thyroid cancers).
• Any age, 20-40 years, F: M=4:1.
• Good prognosis (98% 5-year survival).
• Favourable factors include female sex and age <20 years and confined to the thyroid.
• Well-differentiated cytologic morphology and often multifocal; small whitish nodule, +/- cystic spaces.
• Micro (histology): papillary architecture, pale/optically clear nuclei, overlapping nuclei, nuclear inclusions, nuclear grooves, psammoma bodies.
• Invade lymphatics, leading to regional lymph node metastases.

Papillary Carcinoma Variants

• Follicular, oncocytic, columnar, diffuse sclerosing, tall-cell variant.
• Papillary microcarcinoma (<1 cm): common incidental finding.

Follicular Carcinoma

• 10-15% of thyroid cancers.
• 50-60 years, F:M=3:1.
• Slowly enlarging painless thyroid nodule.
• Often haematogenous spread (bone marrow).
• Micro: capsular/vascular invasion.
• Prognosis related to invasion degree: minimally invasive (95% survival), widely invasive (30–70% 5-year survival).
• Treatment: total thyroidectomy, radioactive iodine, thyroid hormone after surgery.

Medullary Carcinoma

• Up to 5% of thyroid cancers.
• 50-60 years.
• Neuroendocrine neoplasm of parafollicular C-cells (secrete calcitonin).
• Distinctive amyloid stroma.
• 30%: Familial, e.g., MEN2A or MEN2B.
• Macro: variable: single to multiple nodules.
• Micro: variable solid and glandular; often spindled cells.
• Prognosis varies, related to familial status; familial (often good, screened/asymptomatic), sporadic (worse, usually present with a lump).

Anaplastic Carcinoma

• <5% of thyroid cancers.
• Elderly.
• Rapid growth into adjacent neck structures.
• Macro: hard, gritty.
• Micro: undifferentiated, giant cells.
• Poor prognosis (usually fatal within 1 year).

Parathyroid Glands

• Derived from pharyngeal pouches.
• Location not limited to the thyroid.
• Contains chief cells and oxyphil cells.
• Normal size: 35-40mg.
• 10% of individuals may have only 2 or 3 glands instead of typical 4.

Parathyroid Hormone Function (Diagram)

• Diagram showing how the parathyroid hormone regulates calcium levels in the body.

Parathyroid Hyperfunction

• Primary, secondary, tertiary categories.

Hyperparathyroidism

• Primary: overproduction of parathyroid hormone (PTH) leading to hypercalcaemia.
• Important cause of hypercalcaemia.
• Types: adenoma (75-80%), primary hyperplasia (10-15%), parathyroid carcinoma (<5%).
• Adenoma: solitary, 0.5–5 g, well circumscribed, delicate capsule, other glands normal size or shrunken.
• Primary hyperplasia: diffuse or nodular; occur sporadically, or as component of MEN syndromes.
• Diagnosis: invasion of surrounding tissue and metastasis.

Hyperparathyroidism (Secondary)

• Chronic decreased calcium levels leading to compensatory overactivity of parathyroid glands.
• Most common cause is renal failure.
• Chronic renal insufficiency leads to PO4 excretion decrease, hyperphosphataemia, depressing Ca levels, and stimulating parathyroid gland activity and PTH secretion, keeping the serum calcium level near normal.

Hyperparathyroidism (Tertiary)

• In a minority of patients, parathyroid activity becomes autonomous and excessive.
• Resulting in hypercalcaemia.
• Treated with parathyroidectomy.

Hypercalcemia (Symptoms)

• "Painful bones, renal stones, abdominal groans, psychic moans."
• Osteoporosis, osteitis fibrosa cystica.
• Chronic renal insufficiency, renal stones.
• Constipation, anorexia, nausea, vomiting, pancreatitis, peptic ulcer disease.
• Altered concentration, depression, confusion, seizures.
• Weakness and fatigue.
• Aortic/Mitral valve calcifications (cardiac manifestations).

Features of Hyperparathyroidism (Diagram)

• Diagram depicting bone, kidney, and gastrointestinal involvement.

Parathyroid Hypofunction

• Surgical removal (inadvertently) during thyroidectomy.
• Mistaken for lymph nodes.
• Congenital absence (DiGeorge syndrome).
• Primary idiopathic atrophy (autoimmune).
• Antibodies against Ca sensing receptors in parathyroid gland.
• Familial hypoparathyroidism (condition present in childhood).

Hypocalcemia (Symptoms)

• Numbness and tingling in extremities and perioral region.
• Muscle cramps, bronchospasm, laryngospasm, seizures.
• Chvostek's sign (muscle spasms).
• Trousseau's sign (carpal spasm).
• Intracranial manifestations (parkinsonian-like movement).
• Cardiovascular manifestations (conduction defect with prolonged QT interval).

Multiple Endocrine Neoplasia (MEN)

• Familial diseases associated with neoplasia or hyperplasia in several endocrine glands.
• Disorders inherited as autosomal dominant traits.
• Types: MEN type 1 (Wermers syndrome), MEN type 2A, MEN type 2B.

MEN Type 1 (Wermer's Syndrome)

• Hyperplasia or neoplasia of parathyroid glands, pituitary glands (prolactinomas), and pancreatic islet cells.
• Commonly manifests as primary hyperparathyroidism.
• Genetic defect: MEN1 gene (tumour suppressor gene) located at chromosome 11q13.

MEN Type 2

• Two distinct groups, activating mutations of the RET proto-oncogene at chromosome 10q11.2.
• MEN type 2A (Sipple syndrome): characterised by medullary carcinoma, pheochromocytoma, and parathyroid hyperplasia.
• MEN type 2B: includes medullary thyroid carcinoma, pheochromocytoma, and ganglioneuromas of mucosal sites and Marfanoid habitus and long axial bones.

MEN Syndromes (additional aspects)

• Tumours occur at a younger age than sporadic neoplasms.
• Arise in multiple endocrine organs, often multifocal.
• Tumours are preceded by an asymptomatic stage of endocrine hyperplasia.
• More aggressive and have a higher chance of recurrence compared to sporadic tumours.
• RET gene mutations indicate prophylactic thyroidectomy is needed.

Learning Outcomes (Review)

• The learning outcomes for the course are reiterated, highlighting the topics covered.

This quiz explores hypothyroidism, covering symptoms, lab results, and age-related manifestations. It also covers the underlying causes and patterns of thyroid dysfunction, including Hashimoto's thyroiditis.