Thyroid Pathology Lecture (1).pdf

Thyroid Pathology BMS 200 Today’s Outcomes Describe the pathophysiological process involved in the formation of goiter in both hyperthyroidism and hypothyroidism Predict the clinical features and complications of a) over-section and b) under- section of thyroid hormones Describe...

Thyroid Pathology BMS 200 Today’s Outcomes Describe the pathophysiological process involved in the formation of goiter in both hyperthyroidism and hypothyroidism Predict the clinical features and complications of a) over-section and b) under- section of thyroid hormones Describe the pathophysiology of hypothyroidism due to iodine deficiency Critique theories of pathogenesis of autoimmune thyroid diseases (Grave's and Hashimoto's), including gut-thyroid-axis, infectious triggers, pregnancy and environmental pollutants Describe relationship between viral infections and thyroiditis Describe the pathophysiology of myxedema Describe the pathophysiology of thyroid cancers and relate to clinical features and complications Describe the pathogenesis, clinical features, and complications of thyroglossal duct cysts and congenital hypothyroidism Relate the known mechanism of action of anti-thyroid medications and levothyroxine to the pathophysiology of Graves disease and hypothyroidism, respectively Describe the pathogenesis of thyroid storm and toxic multinodular goiters and relate to clinical features and complications Overview of Thyroid Disease Hypothyroidism or reduced Hyperthyroidism and thyroid function*: thyrotoxicosis: ▪ Autoimmune hypothyroid ▪ Graves disease syndromes: ▪ Toxic multi-nodular goitre, Hashimoto’s thyroiditis toxic nodules Subacute thyroiditis ▪ Thyroid neoplasms (DeQuervain thyroiditis) Follicular and papillary ▪ Iodine deficiency & non-toxic adenomas and goiter adenocarcinomas ▪ Less common causes: Medullary and anaplastic congenital hypothyroidism, carcinomas hypopituitarism, hypothalamic disease, infiltrative disorders ▪ Iatrogenic (i.e. treatment for hyperthyroidism) Hashimoto’s thyroiditis One of the most common endocrine diseases: ▪ Incidence ~ 4/1000 in women, 1/1000 in men (per year) Pathological findings: ▪ Lymphocytic infiltration of the thyroid with germinal centre formation, atrophy of follicles, loss of colloid T and B cells present ▪ Mild – moderate fibrosis ▪ Over time, some will progress to what is known as atrophic thyroiditis More fibrosis, follicles almost completely disappear, lymphocyte infiltration more limited ▪ So… your adaptive immune system has attacked your thyroid Hashimoto’s thyroiditis Pathophysiology - basic ▪ Some have genetic susceptibility that is presumed to be linked to particular HLA haplotypes or polymorphisms in CTLA-4 HLA-DR3, DR4, DR5 in Caucasians Association between T1DM, Addison’s disease, pernicious anemia, vitiligo ▪ Damage to T-cells thought to be mediated primarily by cytotoxic T-cells Local production of inflammatory cytokines may contribute (TNF, IL-1, IFN-gamma) Although anti-thyroid antibodies are produced, they likely are not as important in damaging the follicular cells ▪ Antibodies are diagnostically useful, though – anti-TPO and anti-thyroglobulin antibodies mainly ▪ Can also have antibodies that block the TSH receptor (not stimulate it) Which mechanism is more prominent in Hashimoto’s? OR  Hashimoto thyroiditis - pathology Rubin’s Pathology: Mechanisms of Human Disease ▪ Fig. 27-19 Massive number of leukocytes, germinal centers prominent, atrophic thyroid follicles are noted ▪ Gland is still enlarged Hashimoto’s thyroiditis Clinical features: ▪ Fatigue, cold intolerance, “slowing” of mental and physical performance, presence of a goitre ▪ Dermatology - Skin and connective tissue – macroglossia, hoarseness, facial puffiness, periorbital edema Skin is often cool and rough, with some degree or carotenemia present Skin (dermis) often thickens but does not pit – known as myxedema Hair is often dry and coarse, with loss of lateral 1/3 of eyebrows ▪ Neurological - Paresthesias, cramps, and delayed deep tendon reflexes are common Carpal tunnel syndrome is more likely Hashimoto’s thyroiditis Clinical features cont…: ▪ Cardiovascular - Bradycardia, usually mild hypotension, hypercholesterolemia In those with more severe disease, worsening CHF + angina, pericardial effusions (fluid in the pericardial space) Enlargement of the heart can also occur (interstitial edema “myofibrillary swelling”) ▪ Respiratory - Hypoventilation, decreased exercise capacity ▪ Reproductive - Impacts on menstruation can include menorrhagia or amenorrhea Erectile dysfunction may be reported in men ▪ GI - Constipation, weight gain, and poor appetite  Facial appearance in Hashimoto’s Eyes, face are puffy Skin appears thickened Note that in this patient, lateral eyebrows seem to be preserved Hashimoto’s thyroiditis Assorted details ▪ Progresses insidiously and patients don’t even know “how bad it is” until they receive thyroxine ▪ A significant proportion will have an early phase where excessive thyroid hormone is released due to autoimmune destruction of the gland Thyroxic phase This resolves and progresses to hypothyroidism as the gland is further compromised ▪ Hashimoto’s disease is likely the best model to understand how hypothyroidism “looks clinically” Iodine deficiency states are quite variable Subacute thyroiditis AKA de Quervain’s thyroiditis, granulomatous thyroiditis, viral thyroiditis… ▪ Viruses: mumps, coxsackie, influenza, adenoviruses, and echoviruses, SARS-CoV-2 Pathology: ▪ Early stages: patchy, inflammatory infiltrate, multi-nucleate giant cells (derived from macrophages) ▪ Initially neutrophilic → lymphocytic infiltration ▪ Usually the inflammation subsides → resolution of symptoms, lab abnormalities… however long-term hypothyroidism in some (15%)  Subacute thyroiditis Rubin’s Pathology: Mechanisms of Human Disease ▪ Fig. 27-20 Note the arrows indicating the multi-nucleate giant cells Subacute thyroiditis Clinical Features: Destruction of the thyroid sometimes leads to transient thyrotoxicosis Neck pain can mimic pharyngitis ▪ The inflammation can be accompanied by fever, and there may be symptoms of an URTI in the preceding weeks ▪ Thyroid is typically tender on palpation Could be signs of hypothyroidism or thyrotoxicosis – depending on the phase of the disease  Subacute thyroiditis Harrison’s Principles of Internal Medicine, 21st ed. Fig 384-3 See notes below for text “Silent” thyroiditis Occurs in patients with underlying autoimmune thyroid disease ▪ Brief period of (usually) mild thyrotoxicosis (2-4 weeks) ▪ Mild (usually) hypothyroidism for 4-12 weeks ▪ Resolution – most resolve, but some will, over time, develop permanent hypothyroidism (follow-up recommended) Goitre is painless, no fever, no ESR elevations ▪ The “silent” refers to the lack of thyroid pain Occurs in up to 5% of women 3-6 months after pregnancy ▪ Associated with the emergence of TPO antibodies prior to delivery ▪ 3X more common in pregnant women with T1DM Goiter – Enlarged Thyroid Gland Can occur with thyrotoxic or hypothyroid states… why? Conditions that cause (noticeable) goiters: ▪ Autoimmune conditions: Hashimoto’s thyroiditis, Graves’ disease ▪ Nodular thyroid diseases & iodine deficiency ▪ Thyroid neoplasms Iodine deficiency is uncommon in North America, but there are areas of the world where iodine deficiency is much more common Global distribution of iodine intake Endotext: The Iodine deficiency disorders https://www.ncbi.nlm.nih.gov/books/NBK285556/ Diffuse non-toxic goiter Diffuse enlargement of the thyroid, no nodules, no thyrotoxicosis (hence non-toxic) – also known as simple goiter Usually caused by iodine deficiency worldwide ▪ Can occur with sufficient iodine – in this case cause is unknown (idiopathic) Iodine deficiency → decreased ability to iodinate thyroglobulin → modestly decreased thyroid hormone production → increased TSH from pituitary→ stimulation of colloid production ▪ Often TSH is only mildly increased or normal, but total T4 is decreased ▪ Follicles that are uniformly enlarged with lots of colloid Sometimes a simple goiter can cause compression of underlying structures (thoracic outlet, trachea) Non-toxic multinodular goiter It is common for a normal-sized thyroid to have nodules – when thyroid is normal size, not classified as a goiter ▪ Up to 12% of adults MNG is more common in areas of thyroid deficiency, but can also occur elsewhere ▪ about 1% in North America, usually not huge goiters Nodules tend to be widely variable in size, with a wide range of histologies: ▪ Cystic areas filled with colloid, or hypercellular, hyperplastic regions with less colloid ▪ Fibrosis is common Likely a wide range of pathogenetic factors ▪ In regions with iodine deficiency, there may be an evolution from simple goiter → localized nodules that are hyperplastic and “stop listening” to factors (TSH) that promote normal growth – they “decide” to continually grow… some may be overtly neoplastic Clinical Features – non-toxic goiters Common for thyroid function to be relatively preserved (euthyroid) ▪ Patients can also be hypothyroid – depends on Mass effects ▪ Simple goiters can be quite large, but unusual for them to cause significant compressive effects compressive effects can be exacerbated by raising the arms when a substernal goiter is present Esophageal compression (dysphagia) or tracheal compression can also occur Hypothyroidism & Iodine Deficiency Thyroid gland increases the ratios of MIT to DIT within thyroglobulin (TG). Increase in the proportion of T3 secreted relative to T4. ▪ T3 is the more active form of thyroid hormone, so this shift may be a way to maximize the effects of the limited hormone production. Low T3 & T4 → Increased TRH → Increased TSH secretion & development of a goiter Cretinism: mental and physical developmental delays due to the lack of thyroid hormones during critical periods of growth. Myxedema coma – what is it? Complication of long-term hypothyroidism PLUS another precipitating factor: ▪ Infection (pneumonia, UTI/urosepsis, sepsis in general) ▪ Burns, severely impaired pulmonary function, GI hemorrhage, stroke, trauma, surgery ▪ Hypoglycemia, hypothermia ▪ Lots of medications A rare and very serious complication of hypothyroidism ▪ 0.22/million/year, more common in women ▪ Much more likely in an elderly hypothyroid patient Specificity in terminology – sometimes the term “myxedema” is used to describe the non-pitting edema in hypothyroid dermopathy ▪ Sometimes it refers to myxedema coma Treasure Island (FL): StatPearls Publishing; 2023 Jan: Myxedema https://www.ncbi.nlm.nih.gov/books/NBK545193 Thyroid Emergency - Myxedema coma Clinical Features: Cardiovascular: ▪ Hypotension → shock Hypothyroid patients are hypothermic and decreased peripheral oxygen consumption → peripheral vasoconstriction This causes those with hypothyroidism to have elevated diastolic pressures Those with myxedema coma often lose this somewhat protective vasoconstriction → inability to maintain BP ▪ Dysrhythmias that are very dangerous Heart block, torsades de pointes (these are FYI) ▪ Bradycardia in the setting of low blood pressure is also very dangerous Treasure Island (FL): StatPearls Publishing; 2023 Jan: Myxedema https://www.ncbi.nlm.nih.gov/books/NBK545193 Myxedema coma Clinical Features: Neurologic: ▪ Neurologic progression is typically slow: lethargy/apathy + depression → disorientation + decreased reflexes → coma Some will present with overt psychosis Very rare – seizures Respiratory ▪ Hypoventilation due to decreased central sensitivity to carbon dioxide, diaphragmatic weakness ▪ Obstructive sleep apnea – macroglossia, vocal cord swelling Treasure Island (FL): StatPearls Publishing; 2023 Jan: Myxedema https://www.ncbi.nlm.nih.gov/books/NBK545193 Myxedema coma Clinical Features: GI: ▪ Ileus, nausea and vomiting, abdominal pain ▪ Anorexia, constipation ▪ Sometimes ascites (rare), also increased risk of GI bleeding (coagulopathy, presumably due to liver dysfunction) Renal ▪ Hyponatremia → this can be serious enough to contribute to mental status changes Increased ADH, decreased GFR → increased water retention with less sodium retention Treasure Island (FL): StatPearls Publishing; 2023 Jan: Myxedema https://www.ncbi.nlm.nih.gov/books/NBK545193  Thyrotoxicosis Great table: Harrison’s Principles of Internal Medicine, 21st ed. Table 384-2 Graves’ disease Most common cause of thyrotoxicosis Up to 2% of women, 10X less common in men, 60 – 80% of cases of thyrotoxicosis Usually between ages 20 and 50, but can also occur in the elderly ▪ Why might it be particularly dangerous in an older population? Pathogenesis: Pathophysiology → TSH receptor-stimulating immunoglobulins (TSIs) stimulate the TSH receptor and are not responsive to negative feedback from increases in thyroid hormone production ▪ TSIs can be measured Graves’ disease Pathogenesis: Immune factors: polymorphisms in immunoregulatory genes ▪ CTLA-4, PTPN22, CD25 (alpha-chain of high-affinity IL-2 receptor) Non-specific stresses and smoking seem also to be environmental risk factors Sudden increases in iodine intake seem to precipitate Graves’ disease Ophthalmopathy of Graves’ is unique: ▪ Orbital tissues express the TSH-R → autoimmune attack → increased fibrosis ▪ As well, some pro-inflammatory cytokines increase activation of fibroblast and GAG secretion (extraocular muscles swell) ▪ There may also be aberrant IGF-1 signaling involved Graves’ disease Clinical Features: See table – all are present Additional features include: ▪ Ophthalmopathy – clinically observable in 1/3 of patients, but most will have findings on CT Begins as eye grittiness, excess tearing, and lid retraction Longer-term disease progresses to proptosis – this is where eye findings of Graves-disease diverge from other causes of thyrotoxicosis Interestingly, many patients will have eye findings prior to other thyrotoxicosis features ▪ Thyroid dermopathy - < 5% of patients, usually moderate or severe ophthalmopathy is present Anterior and lateral plaques that look orangey-red Clubbing of the fingers is usually associated  Thyrotoxicosis - generalities Great table: Harrison’s Principles of Internal Medicine, 21st ed. Table 384-2 Graves’ disease FIGURE 384-1 Features of Graves’ disease. A. Ophthalmopathy in Graves’ disease; lid retraction, periorbital edema, conjunctival injection, and proptosis are marked. B. Thyroid dermopathy over the lateral aspects of the shins. C. Thyroid acropachy. Toxic multinodular goitre Pathogenesis of toxic MNG is similar to non-toxic MNG Less common than non-toxic MNG, but second most common cause of thyrotoxicosis (15 - 30% of cases in North America) Difference → some of the nodules in toxic MNG become autonomous (operate independently of TSH and produce TH) ▪ Nodules can be monoclonal or polyclonal Clinical features: Hyperthyroidism is usually mild, and could also be subclinical ▪ Subclinical hypo- or hyperthyroidism = laboratory evidence of thyroid hormone abnormalities with no or very few clinical manifestations ▪ Often see abnormalities in TSH secretion but T4 is within the normal range The level of TSH in the blood is typically low; uncombined T4 levels may be normal or only slightly elevated; T3 levels are often elevated to a greater degree than T4. Toxic multinodular goitre Clinical features: Patients are often elderly and presents with the following: ▪ Atrial fibrillation +/- palpitations, tachycardia ▪ Nervousness, tremor, weight loss ▪ Could be a history of recent iodine supplementation Toxic adenoma Uncommon disorder where a single nodule has gained an activating mutation of the TSH-R Thyrotoxicosis is usually mild no previous history of iodine deficiency or a non-toxic MNG This can also be a cause of toxic MNG Thyroid Emergency – Thyroid storm Life-threatening exacerbation of hyperthyroidism ▪ Usually occurs in previously hyperthyroid patients that have experienced an acute illness Stroke, infection, trauma, diabetic ketoacidosis, surgery (especially thyroid surgery), radioioidine therapy for hyperthyroidism ▪ Due to rapid release/increase in thyroid hormone levels (less due to long-term elevations and absolute levels)? Thankfully rare complication of hyperthyroidism – mortality can approach 30%, even with treatment Unclear pathophysiology ▪ May be due to magnified, “overactivation” of the sympathetic nervous system ▪ May also be due to increased global oxygen (and therefore blood flow) requirements Thyroid Emergency – Thyroid storm Clinical Features ▪ Hyperthermia (fever of 40-41.1 °C) and diaphoresis ▪ CV: Tachycardia (sometimes extreme) Dysrhythmias, heart failure Can start out with hypertension, but as cardiac function further deteriorates → hypotension and shock Can cause cardiac arrest ▪ CNS: impaired level of consciousness Agitation, delirium, anxiety, psychosis, coma ▪ GI: nausea, vomiting, diarrhea, abdominal pain Hepatic failure in some ▪ Can also see signs and symptoms of thyrotoxicosis (long- term, background) Congenital Hypothyroidism Incidence: 1 in 2000 to 4000 newborns ▪ neonatal screening done in all newborns Neonatal hypothyroidism may be transient, due to maternal factors that cross the placenta However, permanent hypothyroidism is more common and occurs in the majority of newborns with congenital hypothyroidism ▪ Lifelong thyroid hormone support Causes: ▪ Gland dysgenesis, TSH-R antibody from mother ▪ Mutations: central hypothyroidism (secondary or tertiary), gland dysgenesis, abnormal TH synthesis Transplacental TH support to treat if discovered in utero Congenital Hypothyroidism Clinical features: ▪ feeding problems, hypotonia, enlarged tongue ▪ delayed bone maturation and growth, umbilical hernia, prolonged jaundice ▪ Importantly, permanent neurologic damage results if treatment is delayed. ▪ Typical features of adult hypothyroidism may also be present. ▪ Other congenital malformations, especially cardiac, are four times more common in congenital hypothyroidism Thyroid neoplasms Could be non-malignant neoplasms – adenomas ▪ Most common neoplastic thyroid tumours – most common adenoma is a follicular adenoma Usually do not secrete thyroid hormone, may be present in up to 5% of the population (larger ones less common, usually hard to detect) Could be malignant ▪ Papillary carcinoma (70 – 80%) ▪ Follicular carcinoma (5 – 10%) ▪ Medullary carcinoma (derived from calcitonin-secreting C-cells) ▪ Anaplastic carcinoma Note – hyperplasia is not neoplasia ▪ Hyperplasia is responsible for the development of MNGs, for example Growth is stimulated by some sort of stimulus/signal ▪ Neoplasias grow despite the absence of external stimuli/signals Thyroid neoplasms Could be non-malignant neoplasms – adenomas ▪ Most common neoplastic thyroid tumours – most common adenoma is a follicular adenoma Usually do not secrete thyroid hormone, may be present in up to 5% of the population (larger ones less common, usually hard to detect) Could be malignant (15/100,000/year – most common endocrine malignancy) ▪ Papillary carcinoma (70 – 80%) ▪ Follicular carcinoma (5 – 10%) ▪ Medullary carcinoma (derived from calcitonin-secreting C-cells) ▪ Anaplastic carcinoma Note – hyperplasia is not neoplasia ▪ Hyperplasia is responsible for the development of MNGs, for example Growth is stimulated by some sort of stimulus/signal ▪ Neoplasias grow despite the absence of external stimuli/signals Thyroid neoplasms Papillary – most common thyroid cancer ▪ Cells with large, clear nuclei that are arranged in papillary or follicular structures (many subtypes) ▪ Most are well-differentiated, but some have an increased risk of metastasis, which is magnified when they have the capability to invade vessels (angioinvasion) Typical sites of metastasis: bone and lung ▪ Most are identified in earlier stages and have a very good survival (minimal impact on mortality) Only about 1% present with stage IV cancer Thyroid neoplasms Follicular carcinoma ▪ More common in iodine-deficient regions of the world (only 5% in North America) ▪ Difficult to diagnose because non-malignant adenomas and follicular carcinoma “look” very similar Carcinoma when it invades the capsule, vessels ▪ If vascular invasion and metastasis to distant sites (bone lung, central nervous system) then survival is much more poor than non-invasive cancer Poor prognosis also indicated by larger tumour size Thyroid neoplasms Well-differentiated tumours like follicular and papillary carcinoma do respond somewhat to TSH suppression therapy… ▪ How would you suppress TSH pharmacologically? ▪ Higher TSH associated with poorer outcomes You can also fight a well-differentiated thyroid cancer by administering radioactive iodide.. ▪ What pharmaceutical would make sense to optimize radioactive iodide uptake? Thyroid neoplasms Anaplastic thyroid cancer ▪ Rare, but extremely aggressive due to its rapid metastases Most patients die within 6 months Don’t take up iodine well or respond to TSH Medullary thyroid carcinoma ▪ Derived from C-cells, secretes high levels of calcitonin (useful lab for diagnosis) ▪ Better survival than anaplastic, usually worse than well- differentiated thyroid tumours (5 year survival about 90%) With metastasis, 5-year survival is 38% Genetic factors in thyroid cancer Some thyroid nodules have activating mutations of the TSH receptor and the GSα subunit. 70% of PTCs show activation of the RET-RAS-BRAF signalling pathway ▪ Receptor tyrosine kinase = RET (specific gene = RET/PTC) ▪ RAS mutations, which stimulate the MAPK signalling cascade, are found in around 20-30% of thyroid neoplasms Poorly differentiated cancers also involve mutations in the RET-RAS-BRAF pathway… ▪ However p53 mutations are much more common in these malignancies ▪ Often mutations in the beta-catenin gene (CTNNB1) are present as well Assorted risk factors for thyroid cancer Radiation: ▪ Radioactive isotope uptake during nuclear waste release into the atmosphere (radioactive iodine) ▪ Generalized radiation Sometimes radiation to ablate hyperthyroidism can increase risk of later cancer development Children seem more vulnerable to harm through radiation Basic thyroid pharmacology – mechanisms of action Propylthiouracil (PTU) – anti-thyroid drug ▪ Inhibits thyroid peroxidase (major effect) ▪ Also inhibits de-iodination of T4 – T3 in the thyroid (minor effect) ▪ What would you use this drug for? Methimazole – anti-thyroid drug ▪ Inhibits the activity of thyroid peroxidase, no effect on deiodinases ▪ May also reduce inflammatory mediators within the thyroid (IL-2, ICAM-1, anti-thyrotropin receptor antibodies) ▪ What would you use this drug for? To note, methimazole often chosen over PTU due to liver toxicity of PTU Basic thyroid pharmacology – mechanisms of action Levothyroxine – synthetic T4 ▪ What would we use this for? Radioactive iodine – used for well-differentiated thyroid cancers ▪ Uptake destroys the thyroid gland ▪ Can be used for Graves’ disease if resistant to other anti- thyroid medications