Toxic Goiter - MU

Definition

• Thyrotoxicosis → Symptoms because Hyperthyroidism is a raised level of circulating thyroid hormones.
• It is not responsible for all manifestations of the disease.

Clinical Types

• Clinical types are:
• Diffuse toxic goiter (Graves' disease)
• Toxic nodular goiter
• Toxic nodule
• Hyperthyroidism due to rarer causes

Diffuse Toxic Goiter (Graves’ Disease)

• Primary thyrotoxicosis
• A diffuse vascular goiter appears at the same time as hyperthyroidism
• Frequently associated with eye signs
• More commonly found in younger women
• Pathology: involves the whole of the functioning thyroid tissue.
• Hypertrophy & hyperplasia are due to abnormal thyroid stimulating antibodies (TSH-RAb) that bind to TSH receptor sites → produce a disproportionate and prolonged effect.
• Family history: 55% of patients have a family history of autoimmune endocrine diseases.

Toxic Nodular Goiter

• Secondary thyrotoxicosis
• A simple nodular goiter is present for a long time prior to hyperthyroidism
• Very infrequently associated with eye signs
• Middle-aged or elderly individuals more commonly affected
• The nodules are inactive in many cases
• It is the internodular thyroid tissue that is overactive
• One or more nodules are overactive in some cases
• The hyperthyroidism is due to autonomous thyroid tissue, as in a toxic adenoma

Toxic Nodule

• A toxic nodule - a solitary overactive nodule
• Types:
• May be part of a generalized nodularity
• Or a true toxic adenoma
• It is autonomous (its hypertrophy and hyperplasia are not due to TSH-RAb)
• The normal thyroid tissue surrounding the nodule is itself suppressed and inactive

Hyperthyroidism Due to Rarer Causes

• Thyrotoxicosis factitia (drug induced) due to intake of L-thyroxine more than normal
• Jod-Basedow thyrotoxicosis is due to large doses of iodides given to a hyperplastic endemic
• Autoimmune thyroiditis OR de Quervain's thyroiditis - inflammation/destruction of the thyroid cells → inappropriate release of thyroid hormone; it subsides in 3–4 weeks as TsAb titers fall in the baby's serum
• Neonatal thyrotoxicosis - as TsAb titers fall in the baby's serum
• Struma ovarii - ectopic hormone production due to a type of ovarian tumors → symptoms of hyperthyroidism
• Drugs like amiodarone (antiarrhythmic agent:)
• Rich in iodine
• Causing thyrotoxicosis due to its structural similarity to T4
• Very rarely - well-differentiated carcinoma can cause thyrotoxicosis-metastatic type, patients with hydatidiform mole or choriocarcinoma with high levels of ß HCG, can stimulate TSH receptor and can cause thyrotoxicosis

Histology

• Thyroid gland consists of acini
• Normal Thyroid Gland
• Number: Normal
• Lining cells: Flattened cuboidal epithelium
• Content: Filled with homogeneous colloid
• Toxic Goiter
• Number: Hyperplasia
• Lining cells: High columnar epithelium
• Content: Many of them are empty. Others contain vacuolated colloid with a characteristic ‘scalloped' pattern adjacent to the thyrocytes

Clinical Features

• Type of Patient:
• Sex: Thyrotoxicosis is 8 times more common in women than in men.
• Age: May occur at any age
• Symptoms & Signs of thyrotoxicosis:
• Symptoms:
• Tiredness
• Emotional lability
• Heat intolerance (prefers cold weather)
• Weight loss (despite a good appetite)
• Excessive appetite
• Palpitations
• Signs:
• Tachycardia
• Hot, moist palms
• Exophthalmos
• Eyelid lag/retraction
• Agitation
• Thyroid goiter and bruit
• Cardiac arrhythmia

Cardiac Rhythm

• Characters:
• A fast heart rate, which persists during sleep is characteristic
• Cardiac arrhythmias are superimposed on the sinus tachycardia as the disease progresses
• Arrythmia أنواع ، ممكن تكون Sinus) منشأها الSA) Node) أو Pathological لأي سبب آخر.
• Age: more common in older patients

Myopathy

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

Eye Signs

• Some degree of exophthalmos is common. It may be unilateral
• Characters:
• True exophthalmos: Proptosis of the eye, caused by infiltration of the retrobulbar tissues with fluid & round cells with a varying degree of retraction or spasm of the upper eyelid, which results in "widening of the palpebral fissure" due to seeing the sclera clearly above the upper margin of the iris & cornea (above the 'limbus')
• Weakness of the extraocular muscles, particularly the elevators (inferior oblique) → diplopia
• In severe cases, papilledema & corneal ulceration occur, when severe & progressive, it is known as [Malignant exophthalmos] and the eye may be destroyed.
• Treatment:
• Spasm & retraction usually disappear when hyperthyroidism is controlled.
• Beta-adrenergic blocking drugs can improve the condition.
• Exophthalmos tends to improve with time.
• Notes:
• Graves' ophthalmopathy is an autoimmune disease in which there are antibody-mediated effects on the ocular muscles.
• Eye signs are common in primary thyrotoxicosis.
• Lid lag, lid spasm can occur in secondary thyrotoxicosis also.

Thyroid Dermopathy (Pretibial Myxoedema)

• It's a rare condition

Characters

• Thickening of the skin
• Usually in areas of trauma
• Has a delayed onset

Mechanism

• Deposition of hyaluronic acid in dermis & subcutis

Treatment

• Treat the underlying thyroid disorder
• Use topical steroids

1ry (Grave's Disease)

• Age: Patients are usually young adults, 20–30 years old.
• History: occurs on top of normal gland, sudden or gradual onset, severe course, remission and relapse, thyrotoxic crisis more liable to occur
• Metabolic: More marked
• Nervous: More marked
• Cardiac: Rare
• Ocular: Present
• Thyroid enlargement: slight enlargement smooth, diffuse, and symmetrical
• Investigations: high degree of toxicity
• Treatment: always medical and responds to antithyroid drugs (ATDs) better
• Recurrence after surgery: Higher (10–20%)

2ry (Plummer's Disease)

• Age: usually elderly 40-50
• History: occurs on top of the nodular gland, slow or insidious onset, mild or moderate course, no relapse, thyrotoxic crisis less liable to occur
• Ocular: absent
• Thyroid enlargement: includes huge enlargement nodular, asymmetric enlargements
• Investigations: presents low degree of toxicity
• Treatment: always surgical after control, responds to antithyroid drugs (ATDs) less
• Recurrence after surgery: Lower is 1-2%

Investigations

Clinical Investigation

• Sleeping Pulse
• Counting of pulse during sleep to avoid psychological stress
• Indicates degree of toxicity:
• 80-90 b/m is mild
• 90-110 b/m is moderate
• > 110 b/m is severe
• BMR (Basal Metabolic Rate): Normal = 40 K cal/m²/body surface. Elevated in hyperthyroidism
• ECG (ElectroCardioGram)
• Body weight

Laboratory Investigation (Non-Specific)

• CBC for side effects of antithyroid (Agranulocytosis)
• Liver function tests to monitor for liver toxicity caused by antithyroid drugs
• Blood glucose & Urine glucose: Glucosuria in severe cases
• Lipid metabolism: presence of hypocholesteremia and decreased triglycerides
• Serum Creatinine:
• Elevated in hyperthyroidism
• Decreased in hypothyroidism

Specific (Thyroid Function Tests)

• Serum TSH:
• If serum TSH level is in the normal range → no need to measure T3 and T4 levels
• Euthyroid state: T3, T4 levels are within the normal range and TSH level is within the normal range too
• Thyroid failure: T3, T4 levels are low and TSH level shows the gross elevation
• Incipient or developing thyroid failure: T3, T4 levels are low normal values and TSH level shows the elevation
• Toxic states: T3, T4 levels show increase and TSH level is suppressed & undetectable
• Thyroxine (T4) & tri-iodothyronine (T3):
• TOTAL hormone assays for both are now OBSOLETE because of the confounding effect of circulating protein concentrations, which is influenced by the level of circulating estrogen & nutritional state
  • Total serum = Free active hormone (constant) + Bound (changeable by change of plasma proteins)
  • If plasma proteins increase ---> increase total (e.g., Pregnancy - Steroids)
  • If plasma protein decrease---> decrease total (e.g., LCF - Nephrotic syndrome) Highly accurate radioimmunoassay of free T3 and free T4 are now routine. Total ممنوع أطلب
• T3 toxicity (with a normal T4) is a distinct entity and it may only be diagnosed by measuring the serum T3 and if a suppressed TSH level with a normal T4, it may suggest the diagnosis
• An appropriate combination to establish the functional thyroid status at initial assessment is serum TSH and assay of antithyroid antibodies, Supplemented by free T4 and T3 evaluation when TSH is abnormal.
• Thyroid Autoantibodies:
• Include the following as significant:
• For Thyroid peroxidase antibody (TPO): Levels above 25 units/mL
• For Anti-thyroglobulin: titers of greater than 1 : 100
• TSH receptor antibodies (TSH-Rab or TRAB) are often present in Graves' disease, largely produced within the thyroid itself

Thyroglobulin Estimation

• Normal value is 0.5–50 μg/L
• If thyroglobulin antibodies are raised in a patient, then it is of no use
• Thyroglobulin is produced only by the thyroid tissue, so after total thyroidectomy → its level drastically reduces
• It is the ideal follow-up marker in well-differentiated thyroid carcinoma (especially in follicular carcinoma) after thyroidectomy

Radioactive Studies

• Using ¹³¹I, ¹²³I or ⁹⁹Tcm
• Uptake by the gland (Rarely used nowadays): not done routinely
• Its main value is to differentiate between:
• Hyperthyroidism in Grave's disease with high uptake
• Hyperthyroidism in De Quervain thyroiditis with low uptake
• Its principal value is for the toxic patient
• Localization of overactivity in the gland → will differentiate between:
• A toxic nodule: with suppression of the remainder of the gland
• Toxic multinodular goiter: with several areas of increased uptake With important implications for therapy
• Whole-body scanning:
• Used to demonstrate metastases, in patients have all normally functioning thyroid tissue ablated either by surgery or radioiodine because metastatic thyroid cancer tissue cannot compete with normal thyroid tissue in the uptake of iodine
• Inappropriate for distinguishing benign from malignant lesions, because:
• The majority (80 %) of ‘cold' swellings are benign
• Some (5%) functioning or 'warm' swellings will be malignant

Thyroid Scanning

• After oral dose of ¹²³I
• Radioactivity of gland is assessed by gamma camera Used to detect:
• Anatomy of gland (Site - Size - Shape)
• Retrosternal extension
• Ectopic thyroid
• Functioning thyroid metastases
• Distribution of the tracer
• Findings:
• Hot nodule: 10% showing overactivity where the rest of the gland is suppressed
• Warm nodule (20%) "Does not show in scan": active nodule where the nodule & gland takes up ¹²³I
• Cold nodule: 70% showing inactive nodule where it does not take up ¹²³I

Ultrasound (US)

• Advantages:
• Gives good anatomical images of the thyroid and surrounding structures
• To identify nodules, number, size, vascularity, echogenicity
• To do USG-guided FNAC
• To identify neck lymph nodes
• To find out solid or cystic nature
• Single or multiple nodules:
• 50% of clinically apparent solitary thyroid nodules ---→ By US: appear multiple nodules with prominent one
• Benign lesion VS Malignant lesion:
• Benign lesion: presents hyperechoic with often cystic with well-defined margin, showing peripheral eggshell calcifcation with sonolucent rim (halo) around nodule
• Malignant lesion - presents hypoechoic with poorly defined margin showing Microcalcifcation without any halo around with high vascularity

Plain X-Ray on Neck & Chest

• It can show:
• Retrosternal goiter: the chest and thoracic inlet x-ray will rapidly & economically confirm: the presence of significant retrosternal goiter & clinically important degrees of tracheal deviation and compression, though chest x-ray tends to underestimate the extent of retrosternal extensions
• Pulmonary metastases may also be detected

CT, MRI & PET-Scan on chest especially those with a substernal component

• Not done routinely, but reserved for assessment of known malignancy and to assess the extent of retrosternal & occasionally recurrent goiters measured w/ Positron emission tomography (PET)/CT scanning

Pathological Investigation - FNAC

• The investigation of choice in most of thyroid diseases to conclude pathological diagnosis
• It is useful in:
• Papillary carcinoma
• Anaplastic carcinoma
• Colloid nodules
• Medullary (amyloid) carcinoma
• Lymphomas
• Thyroiditis
• Suspicious solitary/multiple nodules/dominant nodules should be aspirated
• Diagnostic accuracy of FNAC:
• Sensitivity: 95%
• Specificity: 85%
• Aspiration is graded as:
• Thy 1 - Non-diagnostic
• Thy 2 - Non-neoplastic.
• Thy 3 - Follicular.
• Thy 4 - Suspicious of malignancy.
• Thy 5 - Malignancy
• FNAC may be less reliable in a cyst
• If the cyst recurs after 3 aspirations → surgery is needed
• Malignancy rate:
• In a simple cyst is 5%
• In a complex cyst 75%

FNAC In Follicular Carcinoma

• FNAC isn’t reliable at present as capsular and vascular invasions cannot be found
• However, by newer techniques it is possible to identify the differences:
• Benign tissue is polyploidy and monoclonal
• Malignant tissue is aneuploidy and polyclonal
• Also, MR spectroscopy and thyroid-immunoperoxidase estimation are useful to differentiate
• FNAC (fine needle non-aspiration cytology) is said to be more reliable

Open biopsy

• Least biopsy in the thyroid is hemithyroidectomy

Other Investigations

• Direct & indirect laryngoscopy for visualization of vocal cords ➜ 3% asymptomatic cord paralysis

Tumor markers

• Calcitonin in medullary carcinoma
• Thyroglobulin in papillary carcinoma

6 Principles of Treatment of Thyrotoxicosis

• Medical indications include treating: A) Mild cases of 1ry toxic goiter B) Preoperative preparation of sever cases of 1ry toxic goiter C) Pregnant females with 1ry toxic goiter using small dose of PTU, especially during the 1st trimester D) 1ry toxic goiter in children & young ages despite its high recurrence after surgery
• Preoperative preparation
• Progressive exophthalmos for 6 months till becomes stable to avoid more progression if toxic status is terminated suddenly by surgery or radio-iodine Patient refuses operation or is unfit for operation, and recurrent thyrotoxicosis after surgery
• Surgical indications include treating: A) Failure of medical treatment of 1ry toxic goiter B) Recurrence after successful treatment of 1ry toxic goiter C) Development of complications of with 1ry toxic goiter
• Indications of radio-iodine therapy: A) Unfit for medical treatment - idiosyncrasy to antithyroid drugs B) patients unfit for surgery or refuses surgery and C) recurrent toxicity after surgery

Medical treatment Contraindications

1. Pregnancy after 12 weeks.
2. Pressure manifestation - as antithyroid drugs ↑↑ size of gland ---→ more pressure manifestations
3. Retrosternal goiter
4. Suspension of malignancy

Advantages

1. No surgery
2. No radioactive iodine

Disadvantages

1. Prolonged treatment.
2. Failure rate at least 50%
3. Impossible to predict which patient will go to remission.
4. Side effects of drugs.

Surgical Therapy

• Indications include
  1. 1st trimester of pregnancy: Abortion
• Sever exophthalmos "must be controlled first" (If not controlled ---→ Malignant exophthalmos)

2. Young patient before 20 y: it carries high incidence of recurrence
3. Recurrence after surgery: ↑↑ incidence of injury of R.L.N if redo surgery is required
4. Thyrocardiac "must be controlled first”

Surgical Advantages

1. Goiter is removed
2. Cure is rapid
3. Cure rate is high if surgery is adequate

Radio-Iodine Therapy

Contradindications:

• 1st trimester of pregnancy: Abortion
• Sever exophthalmos "must be controlled first" (If not controlled ---→ Malignant exophthalmos)
• Young patient before 20 y: it carries high incidence of recurrence
• Recurrence after surgery: ↑↑ incidence of injury of R.L.N if redo surgery is required
• Thyrocardiac "must be controlled first” Contraindications:

Radio-Iodine

• Relative:
• Age <45 years (Risk of inducing thyroid carcinoma)
• 2ry thyrotoxicosis (Irradiation ineffective due to fibrosis)
• Severe exophthalmos
• Absolute:
  • Iodine allergy
• Pregnancy (Teratogenicity)
• Lactation (Excreted in milk)

Radio-Iodine Advantages

• No surgery
• No prolonged drug therapy

Radio-Iodine Therapy

• Isotope facilities must be available
• Patient must be quarantined
• Avoid:
• Pregnancy
• Close physical contact, particularly with children.
• Eye signs may be aggravated
• Thyroid failure
• Follow-up is essential

Medical Treatment

Aim is to:

1. Control toxic symptoms.
2. Maintain patient euthyroid till remission.

Lines

1. Mental & physical rest.
2. Diet: Rich in proteins, vitamins & minerals.

Medical Drugs

• Beta-blockers:
• Propranolol (Inderal)
• Control cardiac features of hyperthyroidism.
• Block peripheral conversion of T4 to T3
• Dose 10-40 mg orally up to 240mg/day
• Antithyroid drugs- Carbimazole, and Propylthiouracil Actions: Block oxidation, iodination & coupling and immunosuppressive action on Ts.Abs, and in addition, PTU block peripheral conversion of T4 to T3 Carbimazole 10mg for 4-6weeks than reduce to 5mg for 12-18months Propyl thiouracil 100mg reduces up to 50mg

Medical Drugs Side Effects

• Allergic reaction.
• Aplastic anemia.
• Agranulocytosis (Sore throat & fever): Stop drug + Penicillin + Fresh blood transfusion + Vit B6.
• Up size & vascularity of goiter (Due to # TSH) -If retrosternal goiter ---→ will result in mediastinal syndrome.
• Cretinoid goiter (If they are taken after the 1st trimester or lactation (PTU safe during pregnancy).
• Hypothyroidism with over dosage.
• Intrahepatic cholestasis & Jaundice.

Surgical Treatment - Preoperative Preparation

1. Sedatives (Barbiturates).
2. Beta Adrenergic blockers (Inderal in full dose)

• Used to block the cardiovascular effects of the elevated T4

3. Antithyroid drugs in full dose except in Retrosternal goiter Those in common use are carbimazole and propylthiouracil.
4. Potassium iodides (e.g., Lugol's iodine):

• Used as immediate preoperative preparation in the 10 days before surgery
• Reduce the vascularity, block oxidation, blocks release of thyroid hormones, blocks stimulant effect of TSH,

Dose and effect

• Take drops t.d.s. gradually increased to 15 drops t.d.s and maximum effect reached is within 10-15 days
• However, its effect decreases afterwards (tolerance) as the gland uses iodine causing aggravation of thyrotoxicosis making it is a temporary relief so it should be used for long term therapy and used only in preoperation and crisis

Types of operations In Cases Of

• Operation (A) Solitary toxic nodule: Hemithyroidectomy
• (B) Multiple toxic nodules:

1. Subtotal thyroidectomy
2. Near total thyroidectomy
3. Hartley- Dunhill procedure
4. Total thyroidectomy

• Indicated if patient has severe ophthalmopathy, coexisting thyroid cancer, MEN II syndrome, the patient refuses RAI therapy or has life threatening reactions to antithyroid medications such as agranulocytosis or liver failure
• After subtotal thyroidectomy: the patient should return to a euthyroid state However, there is at long-term risk of recurrence and eventual thyroid failure After total/near total thyroidectomy:

Postoperative

• Continue Inderal for 2 weeks
• Continue antithyroid drugs for 1 week- Half-life of thyroid hormone is 1 week
• L-thyroxine 0.1 mg/day for 6-12 month
• Prevent (hypothyroidism and increased Recurrence)

Radioiodine

Radioiodine destroys thyroid cells:

• And, as in thyroidectomy, reduces the mass of functioning thyroid tissue . Important Notes in the Use of Radioiodine Therapy:

1. Today, there are no restrictions with age and gender of the person for radioiodine in treatment.
2. Use is preferred in children only after completion of growth and in adults, only after family is complete.
3. Conception should be avoided for 4 months after radioiodine therapy.

Management Problems

• Special Problems Concerning Management of Toxic Goiter (A) Pregnancy: Radioactive iodine is contraindicated; antithyroid drugs (PTU) in minimum doses together with B. blocker; or surgery after a short course of antithyroid & Propranolol might be safe during the second and third trimesters; however, giving lactating pt propylthiouracil is recommended
• B) Those Whose Hearts Can't Stand It (tyrocardiac patients): in these patients, the heart is set to take a priority in management of the pt where a thyroidectomy is ideal after their cardiac health has been controlled to give radioiodine followed by antithyroid drugs if a thyroidectomy is somehow impermissible in the case
• C) Toddlers, Little Ladies (tyrotoxicosis in children): use antithyroid drugs with these patients as the preferable option as they make it to late teenager with a need for conventional surgery which might either be followed by a recurrence fate or hypothyroid state to affect the young pts during growth with also radioiodine be useful if the case needs to take it if it is in a small gland and after completion of growth.