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Summary Table

Feature	Details
Risk Factors	Female sex (F:M ratio approximately 10:1), age 30 to 60 years, family history of autoimmune disease, personal history of other autoimmune conditions (type 1 diabetes, celiac disease, pernicious anemia, vitiligo), Down syndrome, Turner syndrome
Etiology	Autoimmune destruction of thyroid follicular cells mediated by anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies
Patient Presentation	Gradual onset of fatigue, weight gain, cold intolerance, constipation, dry skin, menstrual irregularities (menorrhagia), depression, cognitive slowing
Classic Physical Exam	Painless, nontender, diffuse, firm (rubbery) goiter; periorbital edema; delayed relaxation of deep tendon reflexes; bradycardia; diastolic hypertension; coarse/dry skin; thinning hair
Key Diagnostic Results	Elevated TSH, low free T4, positive anti-TPO antibodies (most sensitive and commonly tested marker), positive anti-thyroglobulin antibodies
Management	Oral levothyroxine (T4) replacement, dose titrated to normalize TSH
Keywords	"Painless goiter," "rubbery thyroid," "anti-TPO positive," "hypothyroid woman with goiter," "lymphocytic infiltration on biopsy," "Hurthle cells"

1. Pathophysiology

Hashimoto's thyroiditis is the most common cause of hypothyroidism in iodine-sufficient regions. The disease is driven by a cell-mediated and humoral autoimmune response directed against thyroid tissue. CD4+ T-helper cells recognize thyroid antigens and recruit CD8+ cytotoxic T-lymphocytes, which directly destroy thyroid follicular cells. Simultaneously, B-lymphocytes produce anti-TPO antibodies and anti-thyroglobulin antibodies, which fix complement and contribute to follicular cell death through antibody-dependent cell-mediated cytotoxicity (ADCC).

The progressive destruction of thyroid parenchyma leads to a gradual decline in T4 and T3 production. In response, the anterior pituitary increases TSH secretion through loss of negative feedback. This sustained TSH elevation drives residual thyroid tissue to hypertrophy, which explains the goiter seen early in the disease. Over time, as more follicular tissue is replaced by lymphocytic infiltrate and fibrosis, the gland may actually shrink, and the patient transitions into overt hypothyroidism.

The cold intolerance and weight gain result from decreased basal metabolic rate due to insufficient thyroid hormone. Constipation reflects decreased gastrointestinal motility. Menorrhagia occurs because hypothyroidism disrupts the hypothalamic-pituitary-gonadal axis and can also impair clotting factor metabolism. Delayed deep tendon reflex relaxation is a classic exam finding that reflects slowed muscle metabolism. The myxedema (nonpitting edema of the skin, especially periorbital) is caused by accumulation of glycosaminoglycans (particularly hyaluronic acid) in the dermis and subcutaneous tissue, a direct consequence of reduced thyroid hormone signaling on connective tissue metabolism.

An important concept: some patients initially experience a transient thyrotoxic phase ("Hashitoxicosis") early in the disease course. This occurs when inflammatory destruction of follicular cells releases preformed thyroid hormone stores into the bloodstream. This is self-limited and is followed by the expected hypothyroid state. On exam, the critical distinction from Graves disease is that Hashitoxicosis presents with a low radioactive iodine uptake (RAIU), because the thyroid is being destroyed, not stimulated.

2. Classification and Clinical Manifestation

Phase	Mechanism	Clinical Features	Labs
Early / Euthyroid	Subclinical autoimmune infiltration, gland compensates	Painless goiter, no systemic symptoms	Normal TSH and free T4, anti-TPO positive
Hashitoxicosis (transient)	Follicular destruction releases stored T4/T3	Palpitations, anxiety, tremor, transient weight loss, heat intolerance	Low TSH, elevated free T4, low RAIU
Subclinical Hypothyroidism	Declining thyroid reserve, pituitary compensates	Often asymptomatic or mild fatigue	Elevated TSH, normal free T4, anti-TPO positive
Overt Hypothyroidism	Extensive gland destruction	Fatigue, weight gain, cold intolerance, constipation, dry skin, bradycardia, menorrhagia, depression, myxedema	Elevated TSH, low free T4
Atrophic (late stage)	Complete fibrotic replacement of thyroid	Hypothyroid symptoms without goiter (gland atrophied)	Elevated TSH, low free T4, anti-TPO may decline

Additional associations worth noting:

Association	Details
Primary thyroid lymphoma	Hashimoto's disease carries an increased risk of thyroid MALT lymphoma (B-cell, non-Hodgkin). A rapidly enlarging, firm thyroid mass in a patient with longstanding Hashimoto's should raise suspicion.
Other autoimmune conditions	Part of autoimmune polyendocrine syndromes. Commonly co-occurs with type 1 diabetes, Addison disease, pernicious anemia, vitiligo, celiac disease.
Papillary thyroid carcinoma	Some data suggest a modestly increased risk; a dominant nodule in Hashimoto's still warrants evaluation with fine-needle aspiration.

3. Diagnostic Workup

Test	Role	Expected Finding
TSH	Best initial test	Elevated (primary hypothyroidism)
Free T4	Confirms overt hypothyroidism	Low in overt disease, normal in subclinical
Anti-TPO antibodies	Most sensitive serologic marker, confirms autoimmune etiology	Positive in over 90% of Hashimoto's cases
Anti-thyroglobulin antibodies	Supportive, less sensitive than anti-TPO	Positive in approximately 60 to 80%
Radioactive Iodine Uptake (RAIU)	Used when thyrotoxicosis is present to differentiate from Graves	Diffusely low uptake (destruction, not synthesis)
Ultrasound	Not routinely needed for diagnosis, but useful if nodules are palpated	Diffusely heterogeneous, hypoechoic gland; may show pseudonodules
Fine-Needle Aspiration (FNA)	Gold standard for histology, but rarely needed for diagnosis	Lymphocytic infiltration with germinal centers, Hurthle cells (oxyphilic metaplasia of follicular cells)

TSH is the single best initial test for evaluating thyroid function. In primary hypothyroidism, the thyroid gland is failing, so TSH rises as the pituitary attempts to drive more hormone production. If TSH is elevated, the next step is to check free T4 to determine whether the patient has subclinical (normal free T4) or overt (low free T4) hypothyroidism.

To establish that the hypothyroidism is autoimmune in origin, order anti-TPO antibodies. This is the most sensitive serologic test for Hashimoto's and is positive in over 90% of cases. Anti-thyroglobulin antibodies add supportive evidence but are less sensitive and less commonly tested in isolation.

Radioactive iodine uptake is not part of the routine workup for hypothyroidism. It becomes relevant when the patient presents with thyrotoxic symptoms and you need to distinguish Hashitoxicosis from Graves disease. Both may show diffuse goiter and elevated free T4, but the RAIU will be low in Hashitoxicosis (gland is being destroyed and is not actively trapping iodine) versus diffusely elevated in Graves (gland is hyperstimulated by TSH receptor antibodies).

Thyroid ultrasound is helpful when there is a palpable nodule or asymmetry. The classic sonographic appearance of Hashimoto's is a diffusely hypoechoic, heterogeneous gland, sometimes described as having a "Swiss cheese" or micronodular pattern. If a dominant or suspicious nodule is identified, proceed to FNA biopsy to rule out papillary carcinoma or lymphoma.

FNA in Hashimoto's classically reveals a background of dense lymphocytic infiltration with germinal center formation and the presence of Hurthle cells (large, eosinophilic, granular follicular cells representing oxyphilic metaplasia). This is the histologic gold standard, but in practice the diagnosis is usually made clinically with TSH, free T4, and anti-TPO, without requiring biopsy.

4. Management and Treatment

Clinical Scenario	Treatment	Details
Overt hypothyroidism	Levothyroxine (T4)	Starting dose: 1.6 mcg/kg/day in young, healthy adults; start lower (25 to 50 mcg/day) in elderly or cardiac patients; take on empty stomach, 30 to 60 minutes before breakfast
Subclinical hypothyroidism (TSH > 10)	Levothyroxine	Treat, as progression to overt disease is likely
Subclinical hypothyroidism (TSH < 10)	Consider treatment	Treat if symptomatic, pregnant, planning pregnancy, or anti-TPO positive (higher risk of progression); otherwise, monitor TSH every 6 to 12 months
Pregnant patients	Levothyroxine	Target TSH in the lower range (trimester-adjusted); dose requirements typically increase by 25 to 50% during pregnancy; inadequate treatment risks fetal neurodevelopmental impairment
Hashitoxicosis (transient)	Symptomatic: beta-blockers (propranolol)	Do not use thionamides (methimazole, PTU), as the thyrotoxicosis is from hormone release, not overproduction; resolves spontaneously in weeks to months
Myxedema coma	IV levothyroxine + IV hydrocortisone	This is an endocrine emergency; give hydrocortisone before or with T4 to prevent adrenal crisis (coexisting adrenal insufficiency must be assumed until ruled out)

Levothyroxine is the standard of care for all patients with overt hypothyroidism from Hashimoto's. The goal is to normalize TSH to within the reference range (approximately 0.5 to 4.5 mIU/L in nonpregnant adults). After initiating or adjusting the dose, recheck TSH in 6 to 8 weeks, as this is the time required for TSH to reach a new steady state. Once stable, monitoring is done annually.

Important medication interactions: levothyroxine absorption is reduced by calcium supplements, iron supplements, proton pump inhibitors, cholestyramine, and aluminum-containing antacids. Patients should be counseled to take levothyroxine on an empty stomach, ideally 30 to 60 minutes before eating, and to separate it from these medications by at least 4 hours.

In elderly patients or those with coronary artery disease, start with a low dose (25 mcg/day) and titrate slowly. Rapid correction of hypothyroidism in these patients can precipitate angina, myocardial infarction, or arrhythmias because thyroid hormone increases myocardial oxygen demand.

In pregnancy, adequate thyroid hormone is critical for fetal brain development, particularly in the first trimester before the fetal thyroid is functional. TSH targets are trimester-adjusted and generally lower than in nonpregnant patients. Women with known Hashimoto's who become pregnant should have their levothyroxine dose increased early (a common approach is to increase by approximately 30% as soon as pregnancy is confirmed) and should be monitored frequently throughout gestation.

Myxedema coma is a life-threatening decompensation of severe hypothyroidism, characterized by altered mental status, hypothermia, bradycardia, and hypoventilation. Treatment requires IV levothyroxine loading (200 to 400 mcg IV bolus, then 50 to 100 mcg IV daily) combined with IV hydrocortisone (50 to 100 mg every 8 hours). The rationale for steroids is that hypothyroidism may coexist with adrenal insufficiency (Schmidt syndrome / autoimmune polyendocrine syndrome type 2), and giving T4 alone can accelerate cortisol metabolism, precipitating adrenal crisis.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Looks Similar	Key Discriminator
Graves disease	Both cause goiter; Hashitoxicosis phase mimics Graves with elevated T4 and low TSH	Graves: diffusely increased RAIU, positive TSH receptor antibodies (TRAb), exophthalmos, pretibial myxedema. Hashitoxicosis: low RAIU, anti-TPO positive, no eye findings, self-limited
Subacute (de Quervain) thyroiditis	Can also present with transient thyrotoxicosis followed by hypothyroidism, low RAIU	de Quervain: painful, tender thyroid, preceded by viral illness, elevated ESR. Hashimoto's goiter is painless and nontender
Riedel thyroiditis	Hard, fixed thyroid gland	Riedel: "rock-hard," fixed to surrounding structures, may cause compressive symptoms (dysphagia, stridor); biopsy shows dense fibrosis replacing thyroid, not lymphocytic infiltration
Thyroid lymphoma	Rapidly enlarging neck mass in a patient with Hashimoto's	Suspect lymphoma if a previously stable goiter suddenly enlarges rapidly; diagnosed by FNA or core biopsy showing monoclonal B-cell population
Iodine deficiency goiter (endemic)	Goiter with hypothyroidism	History of living in iodine-deficient region, anti-TPO negative, no lymphocytic infiltration on biopsy
Drug-induced hypothyroidism	Elevated TSH, low free T4	History of amiodarone, lithium, interferon-alpha, tyrosine kinase inhibitors, or immune checkpoint inhibitors; anti-TPO may or may not be positive depending on whether the drug triggered autoimmunity
Central (secondary) hypothyroidism	Fatigue, weight gain, low free T4	TSH is low or inappropriately normal (not elevated) because the problem is at the pituitary or hypothalamus, not the thyroid. Hashimoto's always has elevated TSH.

6. Traps and High-Yield Pearls

The single most tested concept in Hashimoto's is recognizing the transient thyrotoxic phase (Hashitoxicosis) and distinguishing it from Graves disease. Both present with thyrotoxic symptoms and a diffuse goiter, but the test-writer will embed the key differentiator in the workup: RAIU is low in Hashitoxicosis and high in Graves. Many students reflexively associate thyrotoxicosis with Graves and select thionamide therapy, but this is a trap. Thionamides block new hormone synthesis and are useless when the problem is uncontrolled release of preformed hormone from a gland being destroyed. The correct answer is beta-blockers for symptom control and watchful waiting.

Another common trap involves subclinical hypothyroidism. Students often want to treat every elevated TSH, but the decision depends on the clinical context. The two strongest indications to treat subclinical hypothyroidism are pregnancy (or intent to conceive) and TSH above 10 mIU/L. Outside of these, treatment is considered but not mandatory, and the vignette will often test whether you can identify who needs treatment versus monitoring.

Be alert for the vignette describing a longstanding Hashimoto's patient whose goiter suddenly and rapidly enlarges. This is not just worsening autoimmune disease. The answer the test-writer is looking for is concern for primary thyroid lymphoma (MALT lymphoma), which has a well-established association with Hashimoto's. The next step is biopsy, not simply increasing levothyroxine.

Finally, remember the myxedema coma management sequence: give IV hydrocortisone before or simultaneously with IV levothyroxine. The test-writer may present a severely hypothyroid patient with altered mental status and ask for the next best step. Students who jump straight to T4 replacement without addressing potential concurrent adrenal insufficiency will select the wrong answer.

The core competency being tested across Hashimoto's questions is the ability to integrate serologic markers (anti-TPO, TSH, free T4) with clinical context (goiter characteristics, presence or absence of pain, RAIU pattern) to correctly identify the etiology of thyroid dysfunction and sequence the appropriate management.

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