Sandbox: hyperthyroid

Sandbox: hyperthyroid Microchapters
Overview
Classification
Differentiating hyperthyroidism from other diseases
Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Ahmed Younes M.B.B.CH [2]

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Overview

Thyroid hormones are responsible for regulating the basal metabolic rate of the body. Over secretion of thyroid hormones can lead to a wide variety of syndromes depending on the cause of the hyperthyroidism. Hyperthyroidism can be due to hyperactivity of the thyroid gland itself (primary hyperthyroidism) or due to abnormalities in the pituitary gland or the hypothalamus causing irregularities in the upper control of the gland. Hyperthyroidism can also be classified according to the results of iodine uptake study into high uptake, low uptake, and high or normal uptake.

Classification

According to the origin of the abnormality

Hyperthyroidism is classified according to the origin of the lesion into

Primary hyperthyroidism:

Excess thyroid production from thyroid gland

• Grave’s disease
• Toxic thyroid nodule
• Thyroid adenoma
• Multinodular goiter

Secondary hyperthyroidism:

Excess thyroid production due to disorders of the pituitary:

• Pituitary adenoma
• Intracranial tumors pressing pituitary gland

Tertiary hyperthyroidism:

• Excess thyroxin production due to disorders of the hypothalamus which may be due to intracranial tumors or masses.

According to iodine uptake

Hyperthyroidism can be classified according to the results of iodine uptake test into

High iodine uptake

• Graves' disease
• Toxic multinodular goiter
• Toxic thyroid adenoma

High or normal uptake:

• Iodine caused hyperthyroidism
• Hashitoxicosis
• Germ cell tumors (choriocarcinoma in males and testicular germ cell tumors)
• Pituitary TSH producing adenoma

Low uptake:

• Subacute thyroiditis
• Hyperthyroidism due to ectopic thyroid tissue
• Factitious thyrotoxicosis
• Struma ovarii
• Painless thyroiditis
• Amiodarone induced thyroiditis-Type 1
• Amiodarone induced thyroiditis-Type 2

Differentiating hyperthyroidism from other diseases

Disease	Prominent clinical features	Lab findings	Images
Hyperthyroidism	The main symptoms include: Palpitations Insomnia Anxiety Weight loss Heat intolerance Diarrhea Depending on the underlying diagnosis, the patient might have exophthalmus or goiter	The patient usually has elevated T3 and T4 TSH might be increased or decreased depending on the underlying cause Thyroid stimulating antibodies (TSI) might be increased in cases of Graves’ disease	By Jonathan Trobe, M.D. - University of Michigan Kellogg Eye Center - The Eyes Have It, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=16115992
Essential hypertension	Most patients with hypertension are asymptomatic at the time of diagnosis. Common symptoms are listed below: Headache Blurry vision Dyspnea Epistaxis Tinnitus Fatigue Drowsiness	JNC 7 recommends the following routine laboratory tests before initiation of therapy for hypertension: 12-Lead electrocardiogram (ECG) Urinalysis, including urinary albumin excretion or albumin/creatinine ratio Blood glucose Blood hematocrit Serum electrolytes, especially potassium Serum calcium Lipid profile: Total cholesterol, LDL, HDL, triglycerides Creatinine or estimated GFR	-
Generalized anxiety disorder	DSM-V Diagnostic Criteria for Generalized Anxiety Disorder “ A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance). AND B. The individual finds it difficult to control the worry. AND C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms having been present for more days than not for the past 6 months); Note: Only one item is required in children. 1. Restlessness or feeling keyed up or on edge. 2. Being easily fatigued. 3. Difficulty concentrating or mind going blank. 4. Irritability. 5. Muscle tension. 6. Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep). AND D. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. AND E. The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g.,hyperthyroidism). AND F. The disturbance is not better explained by another mental disorder (e.g., anxiety or worry about having panic attacks in panic disorder, negative evaluation in social anxiety disorder social phobia, contamination or other obsessions in obsessive-compulsive disorder, separation from attachment figures in separation anxiety disorder, reminders of traumatic events in post traumatic stress disorder, gaining weight in anorexia nervosa, physical complaints in somatic symptom disorder, perceived appearance flaws in body dysmorphic disorder, having a serious illness in illness anxiety disorder, or the content of delusional beliefs in schizophrenia or delusional disorder). ”	-	-
Menopausal symptoms	The perimenopause symptoms are caused by an overall drop, as well as dramatic but erratic fluctuations, in the levels of estrogens, progestin, and testosterone. Some of these symptoms such as formication etc may be associated with the hormone withdrawal process. Vasomotor instability Hot flashes, hot flushes, including night sweats Sleep disturbances Urogenital atrophy Itching Dryness Bleeding Watery discharge Urinary frequency Urinary urgency Urinary incontinence Skeletal Osteoporosis gradually developing over time Joint pain, muscle pain Back pain Skin, soft tissue Breast atrophy Skin thinning Decreased elasticity Formication, a sensation of pins and needles, or ants crawling on or under the skin Psychological Mood disturbance Irritability Fatigue Memory loss Depression Sexual Decreased libido Vaginal dryness Problems reaching orgasm Dyspareunia	B-HCG should always be done first to rule out pregnancy especially in women under the age of 45 years FSH can be measured but it can be falsely normal or low TSH, T3 and T4 to rule out thyroid abnormalities Prolactin can be measured to rule out prolactinoma as a cause of menopause	-
Opioid withdrawal disorder	DSM-V Diagnostic Criteria for Opioid Withdrawal “ A. Presence of either of the following; 1. Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e.,several weeks or longer). 2. Administration of an opioid antagonist after a period of opioid use. AND B. Three (or more) of the following developing within minutes to several days after Criterion A: 1. Dysphoric mood. 2. Nausea or vomiting. 3. Muscle aches. 4. Lacrimation or rhinorrhea. 5. Pupillary dilation, piloerection, or sweating. 6. Diarrhea. 7. Yawning. 8. Fever. 9.Insomnia. AND C. The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. AND D. The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance. ”	Urine drug screen to rule out any other associated drug abuse Routine blood work such as electrolytes and hemoglobin to rule out any associated disease explaining the symptoms	-
Pheochromocytoma	The hallmark symptoms of a pheochromocytoma are those of sympathetic nervous system hyperactivity, symptoms usually subside in less than one hour and they may include: Palpitations especially in epinephrine producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered by incidence screening especially MEN patients. Please note that not all patients with pheochromocytoma experience all classical symptoms.	Diagnostic lab findings associated with pheochromocytoma include: Elevated plasma and urinary catecholamines and metanephrines Elevated urinary vanillyl mandelic acid	Left sided pheocromocyroma - Case courtesy of Dr Bruno Di Muzio, Radiopaedia.org, rID: 44813

Cause of thyrotoxicosis	TSH receptor Antibodies	Thyroid US	Color flow Doppler	Radioactive iodine uptake/Scan	Other features
Graves' disease	+	Hypoechoic pattern	↑	↑	Ophthalmopathy, dermopathy, acropachy
Toxic nodular goiter	-	Multiple nodules	-	Hot nodules at thyroid scan	-
Toxic adenoma	-	Single nodule	-	Hot nodule	-
Subacute thyroiditis	-	Heterogeneous hypoechoic areas	Reduced/absent flow	↓	Neck pain, fever, and elevated inflammatory index
Painless thyroiditis	-	Hypoechoic pattern	Reduced/absent flow	↓	-
Amiodarone induced thyroiditis-Type 1	-	Diffuse or nodular goiter	↓/Normal/↑	↓ but higher than in Type 2	High urinary iodine
Amiodarone induced thyroiditis-Type 2	-	Normal	Absent	↓/absent	High urinary iodine
Central hyperthyroidism	-	Diffuse or nodular goiter	Normal/↑	↑	Inappropriately normal or high TSH
Trophoblastic disease	-	Diffuse or nodular goiter	Normal/↑	↑	-
Factitious thyrotoxicosis	-	Variable	Reduced/absent flow	↓	↓ serum thyroglobulin
Struma ovarii	-	Variable	Reduced/absent flow	↓	Abdominal RAIU

Disease		Findings
Thyroiditis	Direct chemical toxicity with inflammation	Amiodarone, sunitinib, pazopanib, axitinib, and other tyrosine kinase inhibitors may also be associated with a destructive thyroiditis.
	Radiation thyroiditis	Patients treated with radioiodine may develop thyroid pain and tenderness 5 to 10 days later, due to radiation-induced injury and necrosis of thyroid follicular cells and associated inflammation.
	Drugs that interfere with the immune system	Interferon-alfa is a well known cause of thyroid abnormality. It mostly leads to the development of de novo antithyroid antibodies.
	Lithium	Patients treated with lithium are at a high risk of developing painless thyroiditis and Graves' disease.
	Palpation thyroiditis	Manipulation of the thyroid gland during thyroid biopsy or neck surgery and vigorous palpation during physical examination may cause transient hyperthyroidism.
Exogenous and ectopic hyperthyroidism	Factitious ingestion of thyroid hormone	The diagnosis is based upon the clinical features, laboratory findings, and 24-hour radioiodine uptake.
	Acute hyperthyroidism from a levothyroxine overdose	The diagnosis is based upon the clinical features, laboratory findings, and 24-hour radioiodine uptake.
	Struma ovarii	Functioning thyroid tissue is present in an ovarian neoplasm.
	Functional thyroid cancer metastases	Large bony metastases from widely metastatic follicular thyroid cancer cause symptomatic hyperthyroidism.
Hashitoxicosis		It is an autoimmune thyroid disease that initially presents with hyperthyroidism and a high radioiodine uptake caused by TSH-receptor antibodies similar to Graves' disease. It is then followed by the development of hypothyroidism due to the infiltration of thyroid gland with lymphocytes and the resultant autoimmune-mediated destruction of thyroid tissue, similar to chronic lymphocytic thyroiditis.
Toxic adenoma and toxic multinodular goiter		Toxic adenoma and toxic multinodular goiter are results of focal/diffuse hyperplasia of thyroid follicular cells independent of TSH regulation. Findings of single or multiple nodules are seen on physical examination or thyroid scan.
Iodine-induced hyperthyroidism		It is uncommon but can develop after an iodine load, such as administration of contrast agents used for angiography or computed tomography (CT), or iodine-rich drugs such as amiodarone.
Trophoblastic disease and germ cell tumors		Thyroid-stimulating hormone and HCG have a common alpha-subunit and a beta-subunit with considerable homology. As a result, HCG has weak thyroid-stimulating activity and high titer HCG may mimic hyperthyroidism.

Pathophysiology

Rgulation of thyroxin secretion - By CFCF; slightly modified by Geo-Science-International - This file was derived fromThyroid vector.svg:, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=47043638

• Thyroid hormones (T3 and T4) are regulating basal metabolic rate, influence oxygen consumption by tissues. They are crucial for normal development of the brain and growth of the body, especially in prepubertal period.
• Secretion of thyroid hormones follows upper control from the hypothalamus and the pituitary. Thyroid releasing hormone (TRH) acts on thyrotropes releasing cells in the pituitary causing them to release thyroid stimulating hormone (TSH).
• TSH acts on thyroid gland by binding to specific membrane receptors and activating an intracellular pathway involving cAMP that ends in formation and secretion of thyroid hormones.
• Iodine is essential for the synthesis of thyroid hormones. The daily iodide need is about 100mcg / day. Iodide is uptaken through a special Na/I transporter found in the membrane of thyroid follicular cell. After uptaking iodide, it goes through a series of organic reactions ending in the formation of the two forms of thyroid hormones: T3 and T4. T3 and T4 remain stored in the thyroglobulin of the follicles and are released in response to further stimulation by TSH to the thyroid follicles.
• While T3 is 3 to 5 times more potent than T4, it represents only one fourth of the total hormone secretion. T3 is thought to be the biologically active form of the of the two forms of the hormone. Most of the circulating T3 is due to peripheral conversion of T4 in the liver and peripheral tissues while only a small percentage is secreted directly from the thyroid gland itself.
• T3 and T4 act on nuclear receptors (DNA binding proteins) and cause the regulate the transcription of many proteins to regulate the metabolic rate of the body.
• The higher regulation of thyroxin secretion follows the negative feedback role, meaning that high levels of T3 and T4 will suppress TRH and TSH secretion and vice versa (Low levels of thyroxins will stimulate TRH and TSH secretion). This is useful in diagnosing the cause of hyperthyroidism (in secondary hyperthyroidism where the pituitary or the hypothalamus are the sources of the disease. TSH will be high, while in primary hyperthyroidism where the gland is the source of the excess hormones, TSH will be low).
• In graves' disease, the most common cause of hyperthyroidism. The disorder lies in the secretion of thyroid stimulating antibodies (TSI) that work on thyroid follicular cells causing an excessive uncontrolled release of the thyroxins. TSI responsible for many other aspects of the disease such as ophthalmopathy and the skin manifestations. This is thought to be due to the epitopic similarity between antigens on the surface of these cells and the thyroid receptors.
• Toxic nodular goiter involves the growth of a various number of nodules (ranging from one to tens). These nodules either bleed and undergo degeneration and fibrosis followed by calcification or they might have autonomous activity producing excess thyroxin.
• The majority of circulating T3 and T4 are bound to plasma proteins and thus not active (T4 is mostly bound to thyroxine binding globulin and T3 is mostly bound to transthyretin). Conditions that impair the production of thyroid binding globulins (such as pregnancy, liver failure, and certain drug administration) cause a change in the total serum thyroxins but the free T3 and T4 remain normal and the patient remains euthyroid (this carries only laboratory significance).