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UNIT №1: DIABETES MELLITUS & THYROID DISEASES

Internal Medicine — Endocrinology

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PART I: DIABETES MELLITUS

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1. DEFINITION OF DIABETES MELLITUS

• Absolute insulin deficiency (Type 1) → autoimmune destruction of pancreatic β-cells
• Relative insulin deficiency + insulin resistance (Type 2) → progressive β-cell failure in the setting of peripheral resistance
• End result in both: impaired glucose uptake by cells, hepatic glucose overproduction, and hyperglycemia

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2. CLASSIFICATION OF DIABETES MELLITUS (WHO/ADA)

A. Type 1 Diabetes Mellitus (T1DM)

• Immune-mediated (Type 1A): Autoimmune destruction of pancreatic β-cells by T-lymphocytes; associated with HLA-DR3 and HLA-DR4 alleles; autoantibodies present (anti-GAD65, anti-islet cell, anti-insulin, anti-IA2)
• Idiopathic (Type 1B): No evidence of autoimmunity; strong insulin deficiency; more common in African and Asian populations
• Absolute insulin deficiency; prone to diabetic ketoacidosis (DKA)
• Onset typically in childhood/young adulthood (though can occur at any age)

B. Type 2 Diabetes Mellitus (T2DM)

• Most common form — 90–95% of all diabetes
• Progressive insulin resistance + relative insulin secretory defect
• Strong genetic predisposition + environmental triggers (obesity, sedentary lifestyle)
• Usually develops in adults >40 years; increasingly common in younger individuals due to obesity epidemic
• Patients are NOT prone to spontaneous DKA (though it can occur under severe stress)
• Often associated with metabolic syndrome: central obesity, hypertension, dyslipidemia (↑ triglycerides, ↓ HDL), hyperglycemia

C. Gestational Diabetes Mellitus (GDM)

• Any degree of glucose intolerance first recognized during pregnancy
• Occurs in 2–5% of pregnancies
• Mechanism: placental hormones (human placental lactogen, estrogen, cortisol) cause progressive insulin resistance during 2nd and 3rd trimester
• Most resolves post-partum, but 50% will develop T2DM within 10 years
• Risks: macrosomia, neonatal hypoglycemia, shoulder dystocia, polyhydramnios, preeclampsia

D. Other Specific Types of DM

1. Genetic defects of β-cell function (MODY — Maturity-Onset Diabetes of the Young):
   • Monogenic forms; autosomal dominant
   • MODY 1 (HNF-4α), MODY 2 (glucokinase), MODY 3 (HNF-1α) — most common
   • Typically mild hyperglycemia; often misdiagnosed as T1DM or T2DM
2. Genetic defects in insulin action: Lipoatrophic diabetes, Type A insulin resistance
3. Diseases of the exocrine pancreas: Pancreatitis, cystic fibrosis, hemochromatosis, pancreatic carcinoma → "Pancreatogenic diabetes"
4. Endocrinopathies:
   • Acromegaly (↑ GH antagonizes insulin)
   • Cushing syndrome (↑ cortisol → peripheral insulin resistance)
   • Glucagonoma (↑ glucagon → hepatic glucose production)
   • Pheochromocytoma (↑ catecholamines → inhibit insulin secretion)
   • Primary hyperaldosteronism (hypokalemia impairs insulin secretion)
   • Hyperthyroidism
5. Drug/chemical-induced:
   • Glucocorticoids (most common)
   • Thiazide diuretics
   • Atypical antipsychotics (olanzapine, clozapine)
   • Tacrolimus/cyclosporine (post-transplant diabetes)
   • Pentamidine, diazoxide, β-agonists, phenytoin
6. Infections: Congenital rubella, CMV, coxsackievirus B → β-cell destruction
7. Uncommon immune-mediated forms: Stiff-man syndrome, anti-insulin receptor antibodies
8. Other genetic syndromes: Down syndrome, Turner syndrome, Klinefelter syndrome, Wolfram syndrome, Friedreich's ataxia, myotonic dystrophy

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3. CLINICAL MANIFESTATIONS

Classic Symptoms ("The 3 Polys + 1")

Additional Symptoms

• Fatigue, weakness, lethargy
• Blurred vision (osmotic changes in the lens)
• Recurrent infections: skin (furuncles, Candida), UTI, vaginal candidiasis, poorly healing wounds
• Nocturia
• Pruritus vulvae / pruritus ani
• Paresthesias (early peripheral neuropathy)
• Abdominal pain, nausea, vomiting (especially in DKA)

Differences in Presentation by Type

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4. DIAGNOSIS & DIAGNOSTIC CRITERIA (ADA Standards of Care)

Diagnostic Criteria — ANY ONE of the following confirms diabetes:

Key Rule: In the absence of symptoms, any single abnormal test must be confirmed on a separate day by repeat testing with the same or a different test (except the random glucose + symptoms criterion).

Fasting Definition

• No caloric intake for at least 8 hours prior to FPG testing

HbA1c

• Reflects average glucose over past 2–3 months (reflects glycosylation of hemoglobin)
• Not affected by acute illness or meal timing
• Limitations: falsely low in hemolytic anemia, sickle cell disease, pregnancy; falsely high in iron-deficiency anemia, thalassemia
• Target for treatment: <7.0% for most patients; <8.0% for elderly/high-risk

OGTT (Oral Glucose Tolerance Test)

• Gold standard for GDM diagnosis
• Patient fasts overnight, drinks 75g glucose solution (100g for GDM screening)
• Blood drawn at 0, 1, and 2 hours
• More sensitive than FPG for diagnosing early T2DM and IGT
• GDM criteria (Carpenter-Coustan, ADA): Any 2 of: Fasting ≥92, 1-hr ≥180, 2-hr ≥153 mg/dL (75g load); or Fasting ≥95, 1-hr ≥180, 2-hr ≥155, 3-hr ≥140 mg/dL (100g load)

Screening Recommendations

• T2DM: Screen all adults ≥45 years every 3 years; earlier if BMI ≥25 + ≥1 risk factor (family history, HTN, dyslipidemia, GDM history, polycystic ovary syndrome, ethnicity — Hispanic, Black, Native American, Asian)
• GDM: Screen all pregnant women at 24–28 weeks gestation

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5. DIFFERENTIAL DIAGNOSIS

T1DM vs T2DM vs LADA (Latent Autoimmune Diabetes in Adults)

• LADA: Autoimmune diabetes presenting in adults (>35 yrs); initially appears like T2DM; anti-GAD antibodies positive; slow progression to insulin dependence; low C-peptide

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6. TYPE 1 DIABETES MELLITUS — FULL DETAIL

Epidemiology

• Prevalence ~0.3% globally; highest in Finland and Sardinia
• Peak onset at 5–7 years and at puberty (10–14 years)
• Equal sex distribution

Pathogenesis

1. Genetic susceptibility: HLA-DR3, HLA-DR4 (>90% of T1DM patients carry these alleles); HLA-DQ8 also implicated
2. Environmental trigger: Viral infection (enterovirus, Coxsackievirus B4), dietary factors (cow's milk protein in infancy?), gut microbiome alterations
3. Autoimmune destruction:
   • T-cell mediated attack on β-cells (insulitis — lymphocytic infiltration of islets)
   • Autoantibodies: anti-GAD65, anti-IA-2 (islet tyrosine phosphatase), anti-insulin (IAA), anti-ZnT8
   • Progressive loss of β-cell mass over months-years before clinical onset
4. Result: Absolute insulin deficiency → hyperglycemia + unopposed glucagon → ketogenesis → DKA

Honeymoon Period

• Transient partial remission shortly after diagnosis; residual β-cells still produce some insulin
• Lasts weeks to months; insulin requirements decrease
• Should not be mistaken for cure

DKA (Diabetic Ketoacidosis)

• Life-threatening complication of T1DM (also occurs in T2DM under stress)
• Triad: Hyperglycemia (usually >250 mg/dL) + ketonemia + metabolic acidosis (pH <7.3, HCO3 <18)
• Precipitants: Infection (50%), missed insulin dose, new-onset T1DM, surgery, trauma, MI, pancreatitis
• Symptoms: Nausea, vomiting, abdominal pain, polyuria/polydipsia, Kussmaul respiration (deep, rapid breathing — compensatory respiratory alkalosis), fruity (acetone) breath, dehydration, altered consciousness, coma
• Labs: ↑ glucose, ↑ ketones (β-hydroxybutyrate, acetoacetate), ↓ pH, ↓ HCO3, ↑ anion gap, ↑ BUN/creatinine, hyponatremia (pseudohyponatremia), potassium often normal or ↑ on admission but depleted
• Treatment (ABCDEF):
  • IV fluids (0.9% NaCl first, then 0.45% NaCl with dextrose when glucose <250)
  • Insulin infusion (regular insulin 0.1 U/kg/hr; do NOT give insulin until K+ >3.5)
  • Potassium replacement (critical — insulin drives K+ into cells)
  • Bicarbonate (only if pH <6.9)
  • Monitor glucose hourly, electrolytes every 2–4 hours

Insulin Therapy in T1DM

• Multiple Daily Injections (MDI): Basal insulin (glargine/detemir once daily) + rapid-acting bolus (aspart/lispro/glulisine) before meals
• Insulin pump (CSII — Continuous Subcutaneous Insulin Infusion): Gold standard; delivers basal + bolus doses
• Target: HbA1c <7% (most patients); avoid hypoglycemia

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7. TYPE 2 DIABETES MELLITUS — FULL DETAIL

Epidemiology

• ~450 million people worldwide; fastest-growing disease globally
• WHO projects >600 million by 2045
• 90–95% of all DM cases; predominantly adults but increasingly adolescents
• Strongly associated with obesity, physical inactivity, Western diet

Pathogenesis (The "Ominous Octet" — DeFronzo)

1. ↓ Insulin secretion (β-cell dysfunction) — progressive, irreversible
2. ↑ Insulin resistance (muscle, adipose tissue, liver)
3. ↑ Hepatic glucose production (gluconeogenesis/glycogenolysis)
4. ↓ Incretin effect (impaired GLP-1 and GIP secretion from gut)
5. ↑ Glucagon secretion from α-cells (hyperglucagonemia)
6. Neurotransmitter dysfunction in brain (altered satiety, glucose metabolism)
7. ↑ Lipolysis (free fatty acids worsen insulin resistance and are lipotoxic to β-cells)
8. Renal glucose reabsorption ↑ (SGLT2 upregulation in hyperglycemia)

Risk Factors

• Obesity/overweight (BMI ≥25; BMI ≥23 in Asians)
• Abdominal/visceral adiposity (waist >40" men, >35" women)
• Physical inactivity
• Family history (first-degree relative with T2DM)
• Age ≥45
• Prediabetes (IFG or IGT)
• GDM history or delivery of baby >9 lbs
• Hypertension (≥140/90 mmHg)
• Dyslipidemia: HDL <35 mg/dL or TG >250 mg/dL
• Polycystic ovary syndrome (PCOS)
• Acanthosis nigricans
• Metabolic syndrome
• Ethnicity: Hispanic, African American, Native American, Asian, Pacific Islander

Complications of Diabetes (Chronic)

Macrovascular:

• Coronary artery disease (CAD): DM is a "CAD risk equivalent" — patients with DM and no prior MI have the same cardiovascular risk as non-diabetics with prior MI. Nearly 80% of DM patients die from CVD.
• Peripheral arterial disease (PAD): Claudication, rest pain, gangrene, amputation
• Cerebrovascular disease: Stroke, TIA (2–4× increased risk)
• Diffuse atherosclerosis driven by: endothelial dysfunction, advanced glycation end products (AGEs), dyslipidemia (↑ small dense LDL, ↓ HDL, ↑ TG), hypertension, oxidative stress

Microvascular:

Diabetic Foot:

• Combination of neuropathy + PAD + impaired immunity → non-healing ulcers → infection → osteomyelitis → amputation
• Screen annually with monofilament test (10g Semmes-Weinstein)
• ABI (Ankle-Brachial Index) for PAD

Diabetic Autonomic Neuropathy:

• Gastroparesis (delayed gastric emptying → erratic glucose control)
• Orthostatic hypotension
• Sexual dysfunction (erectile dysfunction)
• Cardiac autonomic neuropathy (resting tachycardia, loss of heart rate variability, sudden cardiac death)
• Bladder dysfunction (neurogenic bladder)
• Hypoglycemia unawareness

Treatment of T2DM

Lifestyle Modifications (First-Line):

• Dietary counseling: Mediterranean or low-glycemic diet; reduce refined carbohydrates; increase fiber
• Weight loss (5–10% of body weight significantly improves glycemic control)
• Physical activity: 150 min/week of moderate-intensity aerobic exercise + resistance training
• Smoking cessation

Pharmacological Treatment:

1. Metformin (first-line unless contraindicated):
   • Mechanism: Reduces hepatic glucose production; improves insulin sensitivity; activates AMPK
   • Benefits: Cardiovascular protective; weight-neutral; low hypoglycemia risk; inexpensive
   • Contraindications: eGFR <30, iodinated contrast (hold 48h), hepatic failure, alcoholism, severe hypoxia
   • Side effects: GI upset (take with food), lactic acidosis (rare)
   • Dose: Start 500 mg BID with meals; max 2550 mg/day
2. GLP-1 Receptor Agonists (semaglutide, liraglutide, dulaglutide, exenatide):
   • Mechanism: Stimulate glucose-dependent insulin secretion, suppress glucagon, delay gastric emptying, reduce appetite
   • Benefits: Weight loss (2–5 kg), CV protection (LEADER, SUSTAIN-6 trials), reduce MACE
   • Preferred in: ASCVD, HFrEF (semaglutide), obesity
   • Side effects: Nausea/vomiting, pancreatitis risk, contraindicated in thyroid C-cell tumor history
3. SGLT2 Inhibitors (empagliflozin, dapagliflozin, canagliflozin):
   • Mechanism: Block SGLT2 in proximal tubule → glucosuria + natriuresis + osmotic diuresis
   • Benefits: Weight loss, BP reduction, heart failure reduction (EMPA-REG, CANVAS, DAPA-HF), renal protection
   • Preferred in: Heart failure with reduced EF, CKD, ASCVD
   • Side effects: UTI, genital mycotic infections, DKA (rare, even euglycemic), volume depletion
   • Hold before surgery
4. Sulfonylureas (glipizide, glimepiride, glyburide):
   • Mechanism: Stimulate β-cell insulin secretion by closing K+ATP channels
   • Side effects: Hypoglycemia (main risk), weight gain
   • Avoid glyburide in elderly (long-acting, more hypoglycemia risk)
5. DPP-4 Inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin):
   • Mechanism: Inhibit DPP-4 enzyme → increase endogenous GLP-1 → glucose-dependent insulin release
   • Benefits: Weight-neutral, low hypoglycemia risk, renal-dose adjustments needed (except linagliptin)
   • Side effects: Nasopharyngitis, pancreatitis (rare), heart failure risk (saxagliptin)
6. Thiazolidinediones / TZDs (pioglitazone, rosiglitazone):
   • Mechanism: PPAR-γ agonists → improve insulin sensitivity in adipose/muscle
   • Side effects: Weight gain, fluid retention, CHF exacerbation, bone fractures, bladder cancer risk (pioglitazone)
   • Avoid in heart failure
7. Insulin Therapy in T2DM:
   • Start when: HbA1c >10–12%, symptomatic hyperglycemia, contraindications to oral agents, failure of combination therapy
   • Basal insulin first (NPH, glargine, detemir, degludec): Add to oral agents at bedtime; titrate by 2U every 3 days targeting fasting glucose 80–130 mg/dL
   • Prandial insulin if fasting glucose at goal but post-meal glucose elevated
   • Basal-bolus regimen for most intensive control
8. Incretin Mimetics (Amylin analog): Pramlintide — adjunct to mealtime insulin

Treatment Targets:

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8. GESTATIONAL DIABETES MELLITUS (GDM)

Screening & Diagnosis

• Universal screening at 24–28 weeks gestation
• Two-step approach (US standard): 50g non-fasting glucose challenge test (GCT); if 1-hour glucose ≥140 mg/dL, proceed to 3-hour 100g OGTT
• One-step approach (ADA/WHO): 75g OGTT; diagnose if any value meets: Fasting ≥92, 1-hr ≥180, 2-hr ≥153 mg/dL
• First-trimester screening for overt DM: FPG, HbA1c, or random glucose if risk factors present (obesity, prior GDM, strong family history)

Management

1. Medical Nutrition Therapy (MNT): 1800–2500 kcal/day; 40–45% carbohydrates; avoid simple sugars; distribute meals evenly across 3 meals + 3 snacks
2. Glucose monitoring: Fasting + 1- or 2-hour post-prandial glucose daily
3. Insulin (preferred pharmacological agent — does not cross placenta in significant amounts):
   • NPH + regular insulin, or basal-bolus with analogs
   • Start if dietary measures fail: Fasting >95 or 1-hr post-meal >140 or 2-hr >120 mg/dL
4. Metformin/Glyburide (second-line; glyburide may cross placenta)
5. Postpartum: OGTT at 6–12 weeks postpartum; annual FPG or HbA1c thereafter
6. Fetal monitoring: NST (non-stress test), BPP, growth ultrasound for macrosomia

Maternal and Fetal Risks

• Maternal: Preeclampsia, polyhydramnios, operative delivery, postpartum hemorrhage, future T2DM
• Fetal/Neonatal: Macrosomia, shoulder dystocia, birth trauma, neonatal hypoglycemia, neonatal hyperbilirubinemia, respiratory distress syndrome, NICU admission, intrauterine fetal death (late, if uncontrolled)

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9. HYPOGLYCEMIA

Definition

• Symptomatic hypoglycemia: Glucose <70 mg/dL (3.9 mmol/L) with symptoms
• Severe hypoglycemia: Requires assistance from another person
• Whipple's Triad: (1) Symptoms of hypoglycemia + (2) Low plasma glucose + (3) Relief with glucose administration

Symptoms

• Adrenergic (early): Tremor, palpitations, anxiety, diaphoresis, pallor, hunger — from catecholamine surge
• Neuroglycopenic (severe): Confusion, slurred speech, abnormal behavior, seizure, coma — from CNS glucose deprivation

Treatment

• Conscious patient: 15g fast-acting carbohydrate (4 glucose tablets, 4 oz juice) → recheck in 15 min → repeat if glucose still <70
• Unconscious/unable to swallow: Glucagon 1 mg IM/SC, or IV dextrose (D50W 25–50 mL)

Hypoglycemia Unawareness

• Repeated hypoglycemia blunts adrenergic counterregulatory response
• No warning symptoms before neuroglycopenic symptoms develop
• Management: Relax glucose targets temporarily; avoid hypoglycemia for 2–3 weeks to restore awareness

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10. HYPEROSMOLAR HYPERGLYCEMIC STATE (HHS)

• Predominantly in T2DM; typically elderly patients with reduced fluid intake
• Glucose >600 mg/dL, serum osmolality >320 mOsm/kg, NO significant ketoacidosis (pH >7.3, HCO3 >18), altered mental status
• Precipitants: Infection, dehydration, dialysis, hyperalimentation, medications
• Mortality higher than DKA (~10–15%)
• Treatment: Aggressive IV hydration (0.9% then 0.45% NaCl), insulin infusion (after fluids initiated), electrolyte replacement, treat underlying cause

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PART II: THYROID DISEASES

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1. THYROID PHYSIOLOGY & ANATOMY BASICS

Anatomy

• Butterfly-shaped gland in anterior neck, weighing 20–25 g
• Two lobes connected by isthmus; 10% of people have pyramidal lobe
• Supplied by superior thyroid artery (from external carotid) and inferior thyroid artery (from thyrocervical trunk)
• Closely related to recurrent laryngeal nerve (important in thyroid surgery)

Thyroid Hormone Synthesis

1. Iodide trapping: Active uptake of iodide (I⁻) by sodium-iodide symporter (NIS) in follicular cells
2. Iodide oxidation: Thyroid peroxidase (TPO) + H₂O₂ oxidizes I⁻ → I₀ (active iodine)
3. Organification: I₀ attached to tyrosine residues on thyroglobulin → MIT (monoiodotyrosine) and DIT (diiodotyrosine)
4. Coupling: MIT + DIT → T3; DIT + DIT → T4
5. Secretion: Thyroglobulin endocytosed → proteolysis → T4 (85%) and T3 (15%) released into blood
6. Peripheral conversion: T4 → T3 (active form) by deiodinase enzymes (D1, D2, D3) in liver, kidney, and other tissues

Regulation — HPT Axis

• Hypothalamus: TRH (thyrotropin-releasing hormone) → stimulates pituitary
• Pituitary: TSH (thyroid-stimulating hormone) → stimulates thyroid
• Thyroid: T4/T3 → negative feedback on pituitary and hypothalamus
• TSH is the most sensitive indicator of thyroid function

Thyroid Hormone Actions

Key Laboratory Tests

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2. HYPOTHYROIDISM

Definition

Classification

• Primary hypothyroidism: Thyroid gland failure; TSH ↑, FT4 ↓ (most common)
• Secondary hypothyroidism: Pituitary failure (↓ TSH, ↓ FT4); TSH may be inappropriately normal or low
• Tertiary hypothyroidism: Hypothalamic failure (↓ TRH)
• Subclinical hypothyroidism: TSH slightly elevated (>4.0 mIU/L), FT4 normal, patient asymptomatic or minimally symptomatic

Etiology

Clinical Features of Hypothyroidism (Hypometabolic State)

Myxedema Coma

• Extreme, life-threatening manifestation of hypothyroidism
• Precipitants: Cold exposure, infection, sedatives, trauma
• Features: Hypothermia, altered mental status, bradycardia, hypoventilation, hyponatremia, hypoglycemia, coma
• Mortality: 20–50%
• Treatment: IV T4 (levothyroxine 300–500 μg loading dose, then 50–100 μg/day) + IV T3 (controversial) + IV hydrocortisone (to cover possible adrenal insufficiency) + warming + supportive care

Hashimoto's Thyroiditis (Chronic Autoimmune Thyroiditis)

• Most common cause of hypothyroidism in the US and developed world
• Autoimmune disorder: anti-TPO and anti-thyroglobulin antibodies → lymphocytic infiltration of thyroid → progressive fibrosis
• May initially present with transient hyperthyroidism ("Hashitoxicosis") as stored thyroid hormone is released
• Goiter is usually present (diffusely firm and rubbery)
• Diagnosis: Elevated TSH + low-normal to low FT4 + positive TPO antibodies; ultrasound shows heterogeneous, hypoechoic pattern
• Association: Other autoimmune diseases (T1DM, rheumatoid arthritis, vitiligo, Addison's disease, celiac disease)
• Increased risk of thyroid lymphoma (rare)

Treatment of Hypothyroidism

• Levothyroxine (LT4): Drug of choice
  • Dose: 1.6 μg/kg/day (full replacement); start low in elderly/cardiac patients (25–50 μg/day)
  • Absorb on empty stomach 30–60 min before breakfast (avoid calcium, iron, antacids — they reduce absorption)
  • Monitor TSH every 6–8 weeks after dose change; every 6–12 months when stable
  • Goal TSH: 0.5–2.5 mIU/L in young adults; 1–3 mIU/L in elderly; 0.5–2.5 mIU/L in pregnancy
• Subclinical hypothyroidism treatment: Treat if TSH >10 mIU/L; consider treatment if TSH 4–10 mIU/L with symptoms, positive TPO Ab, pregnancy, or cardiovascular risk
• Combination T4+T3 (LT4 + liothyronine): Occasionally used for persistent symptoms despite normal TSH; controversial

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3. HYPERTHYROIDISM & THYROTOXICOSIS

Definitions

• Hyperthyroidism: Overproduction of thyroid hormone by the thyroid gland
• Thyrotoxicosis: Clinical syndrome from excess thyroid hormone (any cause — including exogenous intake)
• Distinction: Subacute thyroiditis causes thyrotoxicosis from hormone release (not overproduction) → radioiodine uptake (RAIU) is LOW

Diagnosis

• sTSH <0.1 mIU/L (often <0.01 in Graves disease, which may be unmeasurable) + elevated FT4 and/or FT3
• Determination of etiology requires further testing (see below)

Clinical Features (Hypermetabolic State)

Common Causes of Hyperthyroidism

Graves Disease — Full Detail

• Most common cause of hyperthyroidism
• Autoimmune: TSH-receptor stimulating antibodies (TRAb/TSI) bind TSH receptors → mimic TSH → continuous thyroid stimulation → ↑ T3/T4 → suppressed TSH
• TSH usually <0.01 mIU/L (unmeasurable); TSH >0.05 mIU/L makes Graves diagnosis suspect
• Diagnosis requires absent goiter AND absent ophthalmic signs to be questioned
• Classic triad: Hyperthyroidism + diffuse goiter + exophthalmos (Graves ophthalmopathy)
• Graves Ophthalmopathy (Orbitopathy):
  • Proptosis (exophthalmos), periorbital edema, diplopia, chemosis, corneal ulceration, visual loss
  • Mechanism: Autoimmune attack on orbital fibroblasts expressing TSH receptors → glycosaminoglycan accumulation → inflammation and edema
  • Independent of thyroid status; may worsen with radioiodine treatment
  • Treatment: Mild — lubricant eye drops, selenium; Moderate-severe — IV glucocorticoids; orbital decompression surgery
• Pretibial Myxedema: Brawny non-pitting plaques on shins; orange peel texture; caused by glycosaminoglycan accumulation
• Acropachy: Digital clubbing + periosteal new bone formation; rare, specific to Graves

Treatment of Graves Disease — Three Options:

1. Antithyroid drugs (ATDs):
   • Methimazole (MMI): Preferred; once daily; inhibits TPO → blocks thyroid hormone synthesis; also has immunosuppressive effects
   • Propylthiouracil (PTU): Preferred in first trimester of pregnancy (MMI teratogenic — aplasia cutis, choanal atresia) and thyroid storm; also blocks peripheral T4→T3 conversion
   • Duration: 12–18 months; remission ~30–40% with Graves
   • Side effects: Agranulocytosis (0.5% — check CBC if fever/sore throat), hepatotoxicity (PTU > MMI), rash, arthralgia, vasculitis
   • Symptomatic control while awaiting euthyroid state: β-blockers (propranolol preferred — also blocks T4→T3 conversion; atenolol/metoprolol also used)
2. Radioiodine therapy (¹³¹I ablation):
   • Preferred definitive treatment in US; given orally; concentrated by thyroid → local radiation → follicular destruction
   • Results in hypothyroidism in 80–90% of patients (expected, then replaced with LT4)
   • Contraindications: Pregnancy, breastfeeding, confirmed/suspected thyroid cancer, coexisting moderate-severe ophthalmopathy (worsens eye disease)
   • Pre-treat with ATDs if severe symptoms; stop ATDs 5–7 days before ¹³¹I
3. Thyroidectomy (near-total or total):
   • Preferred if: Large goiter, suspected malignancy, severe ophthalmopathy, pregnancy (second trimester), patient preference, failure/allergy to ATDs
   • Pre-operatively: Make euthyroid with MMI; add Lugol's iodine 10 days prior (reduces vascularity of gland)
   • Complications: Hypoparathyroidism (↓ PTH → hypocalcemia), recurrent laryngeal nerve injury (hoarseness), bleeding, hypothyroidism

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4. THYROID STORM (THYROTOXIC CRISIS)

• Life-threatening emergency: Mortality up to 75% if unrecognized
• Severe exacerbation of thyrotoxicosis — organs decompensate
• Clinical diagnosis (not defined by TSH or T4 levels)
• Precipitants: Infection (most common — ~50%), surgery, trauma, MI, abrupt cessation of ATDs, radioiodine therapy, iodinated contrast, childbirth
• Clinical Features:
  • Hyperpyrexia (>38.5–40°C / >102°F) — high fever disproportionate to apparent illness
  • Tachycardia out of proportion to temperature
  • GI: Nausea, vomiting, diarrhea, jaundice (hepatic dysfunction)
  • CNS: Agitation, hyperirritability, anxiety, confusion, apathy, coma
  • Cardiovascular: High-output failure, shock
  • Any patient with goiter + fever + marked tachycardia → treat as thyroid storm
• Treatment (Burch-Wartofsky scoring system used for diagnosis):
  1. β-blockers: Propranolol 60–80 mg orally q4h or IV — controls tachycardia, reduces T4→T3 conversion
  2. Antithyroid drugs (PTU preferred — blocks T4→T3): PTU 200–250 mg q4-6h PO/NG; MMI if PTU unavailable
  3. Iodine (Lugol solution or SSKI): Given AFTER ATDs (to block hormone release, not synthesis); inhibits thyroid hormone release (Wolff-Chaikoff effect); 5–10 drops q8h
  4. Glucocorticoids: Hydrocortisone 300 mg IV then 100 mg q8h — blocks T4→T3 conversion and prevents relative adrenal insufficiency; also has immunosuppressive effect
  5. Antipyretics: Paracetamol (NOT aspirin — displaces T4 from binding proteins)
  6. Aggressive IV fluids — replace fluid losses
  7. Identify and treat precipitating illness (e.g., antibiotics for infection)
  8. ICU admission + endocrinologist consultation

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5. SUBCLINICAL THYROID DISEASE

Subclinical Hypothyroidism

• TSH 4.0–10.0 mIU/L with normal FT4 and minimal/no symptoms
• Prevalence: ~5–10% of women; 3% of men
• Risk of progression to overt hypothyroidism: ~2–5%/year (higher if TPO Ab positive)
• Cardiovascular risk: Modest increase in CV events when TSH >10
• Treatment indications: TSH >10, symptoms, positive TPO Ab, pregnancy or planning pregnancy, age <65, dyslipidemia, cardiac disease

Subclinical Hyperthyroidism

• TSH <0.1 mIU/L (some define <0.4) with normal FT4 and FT3 and no symptoms
• Causes: Excess thyroid hormone replacement, autonomous nodule, early Graves, TMNG
• Risks: Atrial fibrillation (3-fold increase in elderly), osteoporosis
• Treatment: Consider if TSH <0.1 mIU/L, especially in patients >65 years OR with any of: heart disease, osteoporosis, postmenopausal, hyperthyroid symptoms

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6. THYROIDITIS

Subacute (De Quervain's) Thyroiditis — Key Points

• Most common cause of painful thyroid gland
• Preceded by upper respiratory infection
• Three phases:
  1. Thyrotoxic phase (2–8 weeks): Hormone released from destroyed follicles → thyrotoxicosis + suppressed TSH; RAIU very low
  2. Hypothyroid phase (weeks to months): Depleted hormone stores → hypothyroidism
  3. Recovery: Most (90%) regain normal function
• Labs: ↑ ESR (often >50, can be >100), ↑ CRP, ↑ T4, ↓ TSH in toxic phase, leukocytosis (mild)
• Treatment: NSAIDs for mild pain; aspirin; high-dose prednisone (40 mg/day) for severe cases; β-blockers for thyrotoxic symptoms; no ATDs (not over-producing hormone)

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7. THYROID NODULES

Epidemiology

• Thyroid nodules palpable in 5% of women, 1% of men
• Incidental nodules on ultrasound ("incidentalomas") very common (up to 50% of adults)
• Malignancy risk in palpable nodule: ~5–15%
• Nodules <1 cm have <0.5% malignancy risk

Evaluation

1. History: Risk factors for malignancy: prior head/neck radiation, family history of thyroid cancer/MEN2, rapid growth, hoarseness, dysphagia, age <14 or >65, male sex
2. TSH + FT4: Suppressed TSH → autonomous (toxic) nodule → ¹²³I scan first; normal/elevated TSH → FNA
3. Thyroid ultrasound: Modality of choice; features suggesting malignancy: hypoechogenicity, microcalcifications, irregular margins, taller-than-wide shape, central vascularity, cervical adenopathy
4. Fine-needle aspiration biopsy (FNA/FNAB): Gold standard for evaluation of ≥1 cm nodules with concerning features; guided by ultrasound
   • Bethesda classification: I (Non-diagnostic), II (Benign), III (AUS/FLUS), IV (Follicular neoplasm), V (Suspicious for malignancy), VI (Malignant)
5. ¹²³I or ⁹⁹mTc radionuclide scan: Used when TSH is suppressed; "hot" nodule = autonomous functioning = almost never malignant; "cold" nodule = 10–15% risk of malignancy

Management

• Benign nodule (Bethesda II): Monitor with ultrasound at 6–12 months, then every 1–2 years; repeat FNA if grows >50% volume or >20% in 2 dimensions
• Hot nodule: ¹³¹I ablation or surgery if symptomatic
• Malignant/suspicious: Surgical resection (near-total or total thyroidectomy)

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8. THYROID CANCER

• MEN2A: Medullary thyroid cancer + pheochromocytoma + hyperparathyroidism; RET mutation
• MEN2B: Medullary thyroid cancer + pheochromocytoma + marfanoid habitus + mucosal neuromas; RET mutation
• FMTC: Familial medullary thyroid cancer only; RET mutation
• Cowden syndrome: PTEN mutation; papillary/follicular thyroid cancer + breast cancer + hamartomas

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9. GOITER

Definition

• Enlargement of the thyroid gland (>25 g); may be diffuse or nodular

Classification

• Simple/non-toxic goiter: Normal thyroid function; diffuse; iodine deficiency most common cause worldwide; goitrogens (thiocyanates in brassica vegetables)
• Toxic multinodular goiter (TMNG / Plummer's disease): Multiple autonomous nodules producing excess hormone; commonest cause of hyperthyroidism in iodine-deficient areas and in elderly
• Toxic adenoma: Single autonomously functioning nodule; suppresses TSH; warm/hot on scan

Complications of Large Goiter

• Tracheal compression/deviation → dyspnea, stridor, choking
• Esophageal compression → dysphagia
• SVC compression → SVC syndrome
• Recurrent laryngeal nerve compression → hoarseness
• Pemberton's sign: Elevation of arms → facial congestion/plethora (from substernal goiter)

Treatment

• Iodine deficiency: Iodine supplementation; iodized salt programs
• Non-toxic goiter: Monitor; ¹³¹I for large multinodular goiter; surgery if compressive symptoms
• TMNG/Toxic adenoma: ¹³¹I ablation (preferred) or hemithyroidectomy (if solitary toxic adenoma)

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10. DIFFERENTIAL DIAGNOSIS — THYROID DISORDERS

Sick Euthyroid Syndrome (Non-Thyroidal Illness Syndrome)

• Any severe non-thyroidal illness → altered thyroid function tests mimicking hypothyroidism
• ↓ T3 (most common), ↓ T4 in severe illness, TSH may be low/normal/mildly elevated
• Mechanism: ↓ deiodinase activity → ↓ T4→T3 conversion; ↑ reverse T3 (rT3, biologically inactive)
• Do NOT treat with thyroid hormone — resolves as underlying illness improves

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SUMMARY TABLE: DM Types at a Glance

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SUMMARY TABLE: Key Thyroid Tests

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KEY CLINICAL PEARLS FOR EXAMS

1. DM diagnosis requires confirmation on a separate day unless classic symptoms + random glucose ≥200 mg/dL
2. HbA1c is affected by RBC lifespan — falsely low in hemolytic anemia, sickle cell; falsely high in iron deficiency
3. Microalbuminuria (30–300 mg/day albumin in urine) is the earliest marker of diabetic nephropathy
4. ACE inhibitors or ARBs are renoprotective in diabetic nephropathy — first-line antihypertensives in DM + microalbuminuria
5. DKA treatment: Never give insulin before checking and repleting potassium (insulin drives K+ into cells → fatal hypokalemia)
6. Aspirin is contraindicated in thyroid storm (displaces T4 from TBG → worsens toxicosis)
7. TSH is the single best screening test for thyroid disease (most sensitive)
8. Graves disease diagnosis suspect if TSH >0.05 mIU/L or if no goiter or ophthalmic signs present
9. Radioiodine is contraindicated in pregnancy; PTU is preferred in first trimester (methimazole is teratogenic)
10. Papillary thyroid cancer is the most common thyroid cancer; spread is lymphatic; overall prognosis excellent (>95% 10-year survival)
11. Medullary thyroid cancer secretes calcitonin; associated with MEN2; RET mutation screening required in all cases
12. LADA — adult-onset autoimmune DM initially mimicking T2DM; check anti-GAD antibodies
13. Subclinical hypothyroidism with TSH <10 + negative TPO Ab in non-pregnant adult = watchful waiting, not treatment
14. De Quervain's thyroiditis = painful goiter + ↑ ESR + viral prodrome + LOW radioiodine uptake; treat with NSAIDs/steroids, not ATDs
15. Empagliflozin and dapagliflozin reduce heart failure hospitalizations and CKD progression independent of glucose control

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