Toxic Goiter - المنصورة

• Thyrotoxicosis is due to hyperthyroidism, which causes high thyroid hormone levels, but it is not responsible for all manifestations of the disease.

Clinical Types of Toxic Goiter

• Includes diffuse toxic goiter (Graves' disease)
• Toxic nodule
• Toxic nodular goiter
• Hyperthyroidism due to rarer causes

Diffuse Toxic Goiter (Graves' Disease)

• A primary form of thyrotoxicosis
• A diffuse vascular goiter appears at the same time as the hyperthyroidism
• Frequently presents with eye signs
• More common in younger women
• Pathology involves all functioning thyroid tissue with hypertrophy & hyperplasia due to abnormal thyroid stimulating antibodies binding to TSH receptor sites
• Prolonged effect of stimulation
• Family history shows 55% of patients have autoimmune endocrine diseases

Toxic Nodular Goiter

• A secondary form of thyrotoxicosis
• A simple nodular goiter is present for a long time
• Very infrequent eye signs
• Affects middle-aged or elderly individuals
• Many cases have inactive nodules and overactive internodular thyroid tissue
• Some cases feature overactive nodules, with autonomous hyperthyroidism, like in a toxic adenoma

Toxic Nodule

• Defined as a solitary overactive nodule
• May be part of generalized nodularity or a true toxic adenoma
• Autonomous in function
• Normal thyroid tissue around the nodule is suppressed and inactive

Hyperthyroidism due to Rarer Causes

• Thyrotoxicosis factitia (drug-induced): Intake of L-thyroxine more than normal
• Jod Basedow thyrotoxicosis: Large doses of iodides given to a hyperplastic endemic
• Autoimmune thyroiditis/De Quervain's thyroiditis: Inflammation of thyroid cells causing inappropriate hormone release, subsides in 3–4 weeks
• Neonatal thyrotoxicosis: TsAb titers fall in the baby's serum
• Struma Ovarii: Ovarian tumors with ectopic hormone production
• Drugs like amiodarone (antiarrhythmic agent): Rich in iodine, structurally similar to T4, causing thyrotoxicosis
• Very rarely, well-differentiated carcinoma can cause thyrotoxicosis of metastatic type and high beta-HCG in hydatidiform mole or choriocarcinoma, which can stimulate TSH receptors

Histology of Thyroid Gland

• Thyroid gland consists of acini
• Normal thyroid gland has a normal number of acini filled with homogenous colloid, lined by flattened cuboidal epithelium
• Toxic goiter features hyperplasia with high columnar epithelium, many acini are empty
• Others contain vacuolated colloid with ‘scalloped’ pattern adjacent to the thyrocytes

Clinical Features of Thyrotoxicosis

• Thyrotoxicosis is 8 times more common in women
• Can occur at any age

Symptoms of Thyrotoxicosis

• Tiredness
• Emotional lability
• Heat intolerance
• Weight loss
• Excessive appetite
• Palpitations

Signs of Thyrotoxicosis

• Tachycardia
• Hot, moist palms
• Exophthalmos
• Eyelid lag/retraction
• Agitation
• Thyroid goiter and bruit
• Arrhythmia

Cardiac Rhythm

• A fast heart rate that persists during sleep is characteristic
• Cardiac arrhythmias are superimposed on sinus tachycardia
• More common in older patients

Myopathy

• Weakness of proximal limb muscles
• May present with severe muscular weakness (thyrotoxic myopathy)
• Recovery proceeds as hyperthyroidism is controlled

Eye Signs

• Some degree of exophthalmos is common and may be unilateral
• True exophthalmos: Proptosis of the eye due to retrobulbar tissue infiltration with fluid & round cells
• Spasm of the upper eyelid leads to widening of palpebral fissure with the sclera seen above the iris and cornea
• Weakness of extraocular muscles, particularly elevators, leads to diplopia
• Severe cases can cause papilledema, corneal ulceration, and potential eye destruction (malignant exophthalmos)

Treatment of Eye Issues

• Hyperthyroidism control reduces spasm & retraction
• Beta-blockers can improve the condition
• Exophthalmos tends to improve with time
• Graves' ophthalmopathy is an autoimmune disease
• Eye signs are common in primary thyrotoxicosis
• Lid lag and spasm can occur in secondary thyrotoxicosis

Thyroid Dermopathy

• Also known as pretibial myxedema
• Rare condition
• Involves thickening of skin, usually in areas of trauma, with delayed onset
• Mechanism: Deposition of hyaluronic acid in the dermis & subcutis
• Treatment: Topical steroids with treatment of the underlying thyroid disorder

Primary vs Secondary Thyrotoxicosis

• Primary (Grave's disease) typically affects young adults aged 20-30 and occurs on top of a normal gland
• Sudden or gradual onset with a severe course, remission, and potential thyrotoxic crises
• Secondary (Plummer's disease) typically affects elderly individuals aged 40-50 and occurs on top of a nodular gland
• Slow or insidious onset with a mild to moderate course, generally without relapse
• Metabolic manifestations are more marked in primary, while nervous symptoms are more marked in primary
• Ocular manifestations are present in primary but absent in secondary
• Thyroid enlargement is slight in primary but huge in secondary
• Primary is symmetrical, while secondary is asymmetrical

Degree of Toxicity

• Degree of toxicity: High in primary, low in secondary
• Treatment: Always medical for primary, often surgical after control for secondary
• Better response to antithyroid drugs (ATDs) in primary and gives a lesser response in secondary
• Recurrence after surgery: Higher in primary (10-20%) and lower in secondary (1-2%)

Clinical Investigations for Toxic Goiter

• Sleeping Pulse: Counting pulse during sleep indicates degree of toxicity
• Mild: 80-90 b/m
• Moderate: 90-110 b/m
• Severe: >110 b/m
• BMR (Basal Metabolic Rate): Elevated in hyperthyroidism
• ECG
• Body weight

Laboratory Investigations

• Non-specific:
  • CBC: Check for side effects of antithyroid drugs (Agranulocytosis)
  • Liver Function Tests: Monitor for liver toxicity
  • Blood Glucose & Urine Glucose: Look for glucosuria
  • Lipid Metabolism: Note hypocholesterolemia and decreased triglycerides
  • Serum Creatinine: Increased in hyperthyroidism and decreased in hypothyroidism
• Specific:
  • Serum TSH:
    • If the level is normal no need to measure T3 and T4 levels
    • In euthyroid state, T3, T4 levels and TSH levels are within normal range
    • In thyroid failure, T3, T4 levels are Low, with Gross elevation of TSH
    • In incipient/developing thyroid failure, T3, T4 levels are Low/normal with Elevation of TSH
    • In toxic states, T3, T4 levels are increased, while TSH is Suppressed & undetectable

Thyroxine (T4) and Tri-iodothyronine (T3)

• Total hormone assays are obsolete due to protein level interference from estrogen and nutrition
• Highly accurate radioimmunoassay measures free T3 and T4, as routine
• T3 toxicity (with a normal T4) is a distinct entity, diagnosed by measuring the serum T3
• Suppressed TSH with normal T4 may suggest the diagnosis

Thyroid Autoantibodies

• Significant indicators include:
• Thyroid peroxidase antibody (TPO): above 25 units/mL
• Anti-thyroglobulin: titers greater than 1:100
• TSH receptor antibodies often present in Graves' disease

Thyroglobulin Estimation

• Normal value: 0.5–50 μg/L
• Raised thyroglobulin antibodies render the test useless
• Produced only by thyroid tissue, reducing levels after thyroidectomy
• Ideal follow-up marker for well-differentiated thyroid carcinoma, especially follicular carcinoma

Radioactive Studies

• Using I¹³¹ or Tcm⁹⁹.
• Uptake by the Gland (Rarely Used Nowadays):
• Not done routinely
• Differentiates between:
  • Hyperthyroidism in Grave's disease showing high uptake
  • Hyperthyroidism in De Quervain thyroiditis showing low uptake
• Toxic patient:
  • Localization differentiates between a toxic nodule (with gland suppression)
  • Toxic multinodular goiter (with multiple increased uptake areas), implying important implications for therapy
• Whole body scanning:
  • Used to demonstrate metastases
  • Inappropriate for distinguishing benign from malignant lesions, as most ‘cold’ swellings are benign

Thyroid Scanning

• After oral dose of I¹²³
• Radioactivity of gland assessed by gamma camera
• Detects Anatomy of gland location and size, Retrosternal extension, Ectopic thyroid, Functioning thyroid metastases and tracer distribution

Findings of Thyroid Scanning

• Hot nodule presents 10% of the time, overactive and suppresses the rest of the gland
• Warm nodule appear 20% of the time, active in the nodule and gland when it takes up I¹²³
• Cold nodule appear 70% of the time, inactive and doesn't take up I¹²³ with the rest of the gland being euthyroid, may be malignant (15-20%), adenoma, cyst, hemorrhage, degeneration or calcification

Imaging Investigation: Ultrasound (US)

• Advantages: Shows good anatomical images of thyroid & surrounding structures as well as Identifies nodules (number, size, vascularity, echogenicity), to do USG-guided FNAC, identifies neck lymph nodes and finds out solid or cystic nature
• Single or multiple nodules: 50% of clinically solitary thyroid nodules appear multiple on US
• Benign vs Malignant lesions: Benign lesions are Hyperechoic, are Often cystic with well-defined margin and present peripheral eggshell calcification with sonolucent rim (halo)
• Malignant lesions are Hypoechoic, have Poorly defined margin and Microcalcification without any halo

Additional Imaging Investigations

• B. Plain X-Ray on neck and chest shows retrosternal goiter and degrees of tracheal deviation/compression as well as pulmonary metastases
• C. CT, MRI & PET scans are reserved for assessment of known malignancy, retrosternal and recurrent goiters
• D. Bone Survey: Used in malignancy for bone metastasis
• Pathological Investigation: FNAC (Fine needle aspiration cytology)

Fine Needle Aspiration Cytology

• The investigation of choice for most thyroid diseases
• Useful for diagnosing papillary, anaplastic, medullary, and colloid carcinomas and lymphomas as well as thyroiditis
• Suspicious solitary/multiple nodules/dominant nodules should be aspirated and it has Specificity of 85%
• Aspiration is graded as:
  • THY1: Non-Diagnostic
  • THY2: Non-Neoplastic
  • THY3: Follicular
  • THY4: Suspicious of Malignancy
  • THY 5: Malignancy
• May be less reliable in a cyst
  • If the cyst recurs after 3 aspirations, surgery is needed
• Malignancy rate is 5% in a simple cyst but 75% in a complex cyst
• FNA is not reliable at present in follicular carcinoma of the thyroid
  • Newer techniques may identify the differences

Benign vs Malignant

• Benign tumors are Polyploidy and Monoclonal
• Malignant lesions are Aneuploidy and Polyclonal and FNNAC is more reliable

Additional Biopsy Information

• Tru-cut Biopsy: Needs anesthesia and may cause pain, hemorrhage, and injury to trachea/nerves
• Open Biopsy: Least biopsy in thyroid cases is hemithyroidectomy

Endoscopic and Tumor Marker Investigations

• Direct & Indirect Laryngoscopy: Used for visualization of vocal cords, it shows 3% asymptomatic cord paralysis
• Tumor Markers: Measuring calcitonin for medullary carcinoma and thyroglobulin for papillary carcinoma

Principles of Treatment of Thyrotoxicosis

• Medical Uses
  • For 1ry toxic goiter, mild cases, preoperative preparation of severe cases
  • For pregnant females in the 1st trimester, a small dose of PTU is given
  • Use for children & young ages, with a high recurrence in young ages
  • Preoperative preparation of 2ry toxic goiter and when treating progressive exophthalmos as well as for patients who refuse operation or is unfit for operation/recurrent thyrotoxicosis after surgery
• Surgical Uses
  • For 1ry toxic goiter that is Failure of medical treatment/Recurrence/Complications
  • For 2ry toxic goiter and to remove a solitary toxic nodule, retrosternal goiter or in cases of suspicion of malignancy
• Radioiodine Therapy
  • Used for patients unfit for medical treatment, or surgery
  • Used for recurrent toxicity after surgery

Contraindications for Medical Treatment

• Pregnancy after 12 weeks or pressure manifestation as antithyroid drugs increase size of gland
• Retrosternal goiter or a suspension of malignancy is present

Advantages of Medical Treatment

• No surgery needed
• No Radioactive iodine given to body

Disadvantages of Medical Treatment

• Prolonged treatment with a failure rate of at least 50%
• Impossible to predict which patient will go to remission and produces side effects

Contraindications for Surgical Treatment

• 1st trimester of pregnancy requiring Abortion
• Severe exophthalmos "must first be controlled"
• For young patient before 20 there is high incidence of recurrence
• After recurrence of surgery there is an ↑↑ incidence of injury to RLN
• If patient has Thyrocardiac, "must be controlled first!”
• Radio-Iodine Therapy is relatively contraindicated for age <45 as it increases risk of thyroid carcinoma. Secondary thyrotoxicosis, sever exophthalmos, iodine/pregnancy/lactation allergies are absolutely contraindicated

Advantages of Surgical Treatment

• The goiter is removed completely
• The cure is rapid
• The cure rate is high if surgery is adequate

Disadvantages of Surgical Treatment

-  Recurrence can occur
-  Postoperative hypothyroidism (20-45%) and Parathyroid Insufficiency/risk of permanent hypoparathyroidism and nerve injury can occur
-  Cosmesis can be affected due to scarring

Advantages to Radioiodine Therapy

-  No surgery required
-  No prolonged drug therapy needed

Disadvantages to Radioiodine Therapy

-  Isotope facilities must be available for use
-  The patient must be quarantined to avoid close physical contact with children
-  Pregnancy must be avoided
-  Eye signs may be aggravated and thyroid failure can occur
-  Long-life follow up is essential

Medical Treatment

• Control Toxic symptoms with mental & physical rest as well as dietary intake of proteins, vitamins, & minerals as well as administering drugs
• Beta Blocker: Propranolol to Control cardiac symptoms & Block peripheral conversion of T4 to T3, administer 10-40mgs three times a day, orally, up to 240mgs/day
• Antithyroid Drugs: Carbimazole & Propylthiouracil Block oxidation, iodination & coupling and may produce Immunosuppressive action
  • Neomercazole dose for 4-6 weeks until patient is in euthyroid state and then the dose is decreased. (5mg)
  • Propyl and methyl are alternatives (100/200 to 50/100)

Side Effects

• Allergic reaction
• Aplastic anemia
• Agranulocytosis: If occurs, stop drug, inject Penicillin and perform + Fresh blood transfusion + Vit B6
• Increase size & vascularity of goiter
• Cretinoid goiter
• Hypothyroidism with over dosage/ Intrahepatic cholestasis & Jaundice

Surgical Treatment

• Operative Preparation includes Sedatives, Beta Blockers, Antithyroid drugs except if it is Retrosternal goiter, as well as Potassium Iodides to reduce vascularity
• Operation used in Solitary toxic nodule removal is Hemithyroidectomy or removing Multiple toxic nodules by Subtotal, Near total or Total thyroidectomy
• Total thyroidectomy is indicated in severe ophthalmopathy, coexisting thyroid cancer, MEN II syndrome or the patient refuses RAI (radio ablation iodine) therapy.

After Subtotal Thyroidectomy vs Total Thyroidectomy

• In subtotal procedures, the plan is to return the patient to a euthyroid state, but there risk of recurrence
• In near-total/total procedures there is accepts immediate thyroid failure & lifelong thyronine replacement in order to eliminate risk of recurrence

Post-Operative Care

• Continue Inderal for 2 weeks as well as antithyroid drugs for 1 week
• Administer L-thyroxine 0.1 mg/day for 6-12 month to prevent hypothyroidism & recurrence

Radioiodine Action and Uses

• Function: Destroys the thyroid cells
• Action: In thyroidectomy, reduces the mass of functioning thyroid tissue to below a critical level
• Restriction: There is no age or gender restriction preferred in children after growth completion and adults after family
• Completion of conception must be avoided for four months

Management Problems

• Pregnancy:
  • Radioactive iodine is contraindicated
  • PTU in minimum doses together with B-blocker
• Surgery after short of antithyroid & Propranolol is safe during the second and third trimesters
• Propylthiouracil is recommended during lactation
• Thyro-cardiac:
  • The cardiac condition takes the priority in management
  • Thyroidectomy is ideal after control of the cardiac status
  • If it is not permissible, radioiodine is used followed by antithyroid drugs until the effect of the former appears
• Thyrotoxicosis in children
  • Antithyroid drugs are preferred till late teen age
  • Conventional Surgery has a high recurrence rate or hypothyroid state which affects later the growth
  • Radioactive iodine can be used to treat small gland problems