What are the other Names for this Condition? (Also known as/Synonyms)

• Amyloid Goiter
• Amyloid Tumor of Thyroid Gland
• Amyloidosis of Thyroid Gland

What is Thyroid Gland Amyloidosis? (Definition/Background Information)

• Amyloidosis is a group of disorders in which the ‘amyloid protein’ builds up in many organs and tissues of the body. The term “amyloid” is used for protein molecules of any type that stick together owing to misfolding (or incorrect formation of the proteins)
• These protein aggregates are abnormally-formed and arranged into fibrils (slender fibers). An amyloid build-up can occur locally in only one organ or may occur throughout the body. When the amyloid proteins get deposited in the thyroid gland, the resulting condition is known as Thyroid Gland Amyloidosis
  • The thyroid gland is a large gland situated in the front of the neck
  • The gland secretes hormones that regulate metabolism, and consequently, growth and development
• There are 5 major types of amyloidosis including amyloid light amyloidosis, AA amyloidosis, hereditary amyloidosis, wild-type ATTR amyloidosis, and dialysis-related amyloidosis
• Thyroid Gland Amyloidosis may be associated with medullary thyroid carcinoma and systemic AA amyloidosis. Thyroid Gland Amyloidosis can also occur in AL subtype of amyloidosis
• The deposition of amyloid proteins in Thyroid Gland Amyloidosis can lead to an enlargement of the organ, known as “amyloid goiter”. Older adults are more prone to developing this condition
• Thyroid Gland Amyloidosis may be asymptomatic, or present with symptoms of a visible lump in the throat, and increased or (rarely) decreased production of hormones
• The prognosis of Thyroid Gland Amyloidosis is dictated by factors, such as whether thyroid gland dysfunction has occurred, the underlying condition causing amyloidosis, involvement of major organs, the affected individual’s overall health, and his/her response to treatment

Who gets Thyroid Gland Amyloidosis? (Age and Sex Distribution)

• Thyroid Gland Amyloidosis is detected in about 80% of those with AA subtype, and 50% of AL subtype of amyloidosis. Nevertheless, it is an extremely rare condition
• Individuals of any age with an underlying chronic condition may develop Thyroid Gland Amyloidosis; however, the condition is more common in adults, especially elderly adults
• In adolescents, Thyroid Gland Amyloidosis may form in association with juvenile arthritis or familial Mediterranean fever (FMF)
• Males are more prone to developing the disorder than females
• Thyroid Gland Amyloidosis may occur in all races and ethnicities

What are the Risk Factors for Thyroid Gland Amyloidosis? (Predisposing Factors)

The following are some known risk factors for developing Thyroid Gland Amyloidosis:

• Medullary thyroid carcinoma
• Any condition that affects the antibody-producing cells in the body: These conditions include benign monoclonal gammopathy, malignant lymphoma, and multiple myeloma
• Chronic infections or inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, and tuberculosis
• Long-term kidney dialysis
• Certain chronic inflammatory conditions such as:
  • Arthritis - including rheumatoid arthritis, juvenile inflammatory arthritis, psoriatic arthritis, and ankylosing spondylitis
  • Inflammatory bowel disease and ulcerative colitis
• Uncontrolled diabetes
• Chronic infections such as:
  • Leprosy
  • Bronchiectasis
  • Osteomyelitis
  • Skin infections (in drug abusers who use needles to inject themselves)
  • Chronic infection in skin with burns
  • Chronic kidney infections (pyelonephritis)
  • Whipple’s disease
  • Tuberculosis
• Infectious diseases such as HIV infection and AIDS
• Cystic fibrosis (individuals with this disease are prone to repeated infections)
• Certain malignancies such as Hodgkin’s lymphoma and renal cell carcinoma
• Having a family history of certain hereditary disorders:
  • Familial Mediterranean fever (FMF)
  • Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS)
  • Hyper immunoglobulin D syndrome and periodic fever syndrome (HIDS)
  • Cryopyrin associated periodic syndrome (CAPS)
  • Majeed syndrome
• A family history of amyloidosis

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Thyroid Gland Amyloidosis? (Etiology)

Thyroid Gland Amyloidosis is caused as a manifestation of systemic amyloidosis of AA and AL subtypes. It can develop from the following factors:

• Medullary thyroid cancer, either sporadic or owing to mutation(s) in the RET gene
  • The RET gene codes for a protein that is involved in cellular signaling
  • This gene also causes multiple endocrine neoplasia (MEN)
  • The gene is inherited in an autosomal dominant pattern

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Thyroid Gland Amyloidosis may be caused as a consequence of medullary thyroid cancer containing calcitonin in the amyloid deposits:

• Irrespective of the events leading to Thyroid Gland Amyloidosis, there is abnormal protein misfolding, which results in amyloid protein formation
• The amyloid protein fibrils circulate in the bloodstream and get deposited in the thyroid gland
• The deposition of amyloid protein may increase the size of the thyroid gland to result in a condition called goiter

What are the Signs and Symptoms of Thyroid Gland Amyloidosis?

In a majority of cases, Thyroid Gland Amyloidosis is not known to cause any significant symptoms. The signs and symptoms that may occur can vary among the affected individuals in type and severity.

The signs and symptoms may include decreased hormone synthesis (hypothyroidism) or increased hormone synthesis (hyperthyroidism), as well as inflammation and swelling of the thyroid gland.

General signs and symptoms may include:

• Sore throat
• Hoarseness
• Swallowing difficulties

Hypothyroidism may result in:

• Weight gain
• Feeling cold
• Dry skin
• Constipation
• Weakness

Hyperthyroidism may result in:

• Rapid heartbeat
• Sweating
• Weight loss
• Mood swings including irritability

Thyroiditis may result in:

• Swollen thyroid gland
• Fever
• Rapid heartbeat
• Weakness
• Trembling
• Changes in menstruation
• Reduced sex drive

Goiter may result in:

• Visible swelling in the throat
• Cough
• Difficulty breathing
• A feeling of tightness in the throat

If Thyroid Gland is present as a manifestation of systemic amyloidosis, other signs and symptoms pertinent to specific organ systems may be present. The following are some general symptoms associated with systemic amyloidosis:

• Fatigue
• Swelling in the ankles and legs
• Unintended weight loss
• Pain in hands and feet
• Joint pain
• Skin rashes, which may be purple or red spots
• Rashes around the eyes
• Eyes that appear puffy
• Tingling sensation
• Numbness
• Anemia
• Clay-colored stools
• Bleeding disorders; problems with proper clotting of blood
• Carpal tunnel syndrome (resulting in weak grip)

The signs and symptoms of underlying medullary thyroid cancer (if present) that may lead to Thyroid Gland Amyloidosis may include:

• Swelling of the thyroid gland
• Hoarseness
• Difficulty swallowing
• Breathing difficulty
• Cough, which may contain blood
• Diarrhea

How is Thyroid Gland Amyloidosis Diagnosed?

The diagnosis of Thyroid Gland Amyloidosis may include general tests so as to:

• Ascertain the subtype of amyloidosis (and its underlying cause),
• Check for medullary thyroid cancer
• To assess damage to the structure and function of thyroid glands

The following methods may be employed for an accurate diagnosis of Thyroid Gland Amyloidosis:

• A thorough physical examination
• Evaluation of personal and family medical history
• Assessment of the presenting signs and symptoms
• Blood tests to assess:
  • The levels of sodium, potassium, cortisol, and adrenocorticotropic hormone (ACTH)
  • Complete blood count (CBC) that may show decreased neutrophils and increased eosinophils and lymphocytes
  • Thyroid antibodies
  • Levels of various thyroid hormones, such as T3, T4, free T4 and TSH
  • Heart function (cardiac biomarkers for stress on the heart)
  • Perform “Freelite assay”, a measurement of light chain immunoglobulins
  • Immunoglobulin by immunofixation electrophoresis
  • Levels of alkaline phosphatase enzyme
• Urine tests to check function of kidneys:
  • To check for excess protein (a 24-hour urine test is usually done)
  • To measure immunoglobulin by immunofixation electrophoresis
• Electrocardiography and echocardiography for checking heart functions
• Imaging tests, to assess amyloid deposits in the body/organs, and to assess damage to the organs, tissues, and bones, which include:
  • X-rays
  • Ultrasound imaging
  • Computed tomography scanning
  • Magnetic resonance imaging
  • Serum amyloid protein (SAP) scintigraphy scan: In this procedure, a small amount of radiolabeled (radioactive iodine) SAP is introduced through injection into the body. After several hours, individuals are scanned with a whole body gamma scanner to check for amyloid deposits in the tissues and organs. Individuals undergoing this procedure ingest potassium iodide before and after the procedure, to prevent the thyroid glands from absorbing the radioactive iodine
• Tissue biopsy: A biopsy of an affected organ or tissue is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy sample under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy sample under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis. In case of Thyroid Gland Amyloidosis,
  • Immunohistochemical analysis of tissue samples using anti-AA serum may be performed, to identify the type of amyloidosis an individual has
  • Amyloid deposit from affected tissue is detected using a staining procedure. When stained with Congo red stain, the amyloid protein deposits appear green under a special type of microscope (polarizing microscope)
• Bone marrow aspiration for checking the type of abnormal immunoglobulin light chains
• Molecular genetic testing to check for mutation(s) in genes that are known to cause hereditary amyloidosis or cause conditions that may result in Thyroid Gland Amyloidosis (such as AA amyloidosis and medullary thyroid carcinoma)
• Molecular testing to check the type of proteins in amyloid deposits (AL, AA, or calcitonin proteins) through mass spectrophotometry

What are the possible Complications of Thyroid Gland Amyloidosis?

The potential complications of Thyroid Gland Amyloidosis may include:

• Increased susceptibility to infections
• Respiratory distress
• Secondary complications due to thyroid gland dysfunction in the body

How is Thyroid Gland Amyloidosis Treated?

Currently, there are no treatment options to cure Thyroid Gland Amyloidosis. However, treatment is available to ease the symptoms and slow disease progression. The treatment measures are unique to each affected individual and are dictated by the extent of thyroid gland damage. These include:

• Thyroid hormone replacement for hypothyroidism
• Radioactive iodine, anti-thyroid agent, or surgical treatment for hyperthyroidism
• Radioactive iodine, anti-thyroid agent, or surgical treatment for goiter

It must be noted that Thyroid Gland Amyloidosis does not occur in isolation and can be systemic, affecting multiple organs at the same time. Therefore, additional treatments pertaining to the subtype of amyloidosis and its underlying cause are often necessary.

The following treatments may be considered in individuals with medullary thyroid cancer:

• Surgical excision of the thyroid gland tumor, followed by radioactive iodine treatment or radiation therapy
• Thyroid hormone replacement therapy

How can Thyroid Gland Amyloidosis be Prevented?

• Currently, there are no specific methods or guidelines to prevent Thyroid Gland Amyloidosis
• If there is a family history of amyloidosis, then genetic counseling will help assess risks, before planning for a child
• Seeking medical attention for pre-existing conditions that can lead to Thyroid Gland Amyloidosis, such as medullary thyroid cancer and systemic amyloidosis, is advisable
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

What is the Prognosis of Thyroid Gland Amyloidosis? (Outcomes/Resolutions)

The prognosis for Thyroid Gland Amyloidosis may be determined by a number of factors, such as the extent of the condition, underlying condition that caused Thyroid Gland Amyloidosis, overall health of the affected individual, and their treatment response.

• If Thyroid Gland Amyloidosis develops due to medullary thyroid cancer, the overall prognosis is based on the underlying condition (including whether the cancer is a recurrent or not)
• Damage to major organs, such as the heart and kidneys (along with the thyroid glands), in systemic amyloidosis can also lead to a poorer prognosis

Additional and Relevant Useful Information for Thyroid Gland Amyloidosis:

• Approximately, 30 different proteins with a tendency to form amyloids have been identified. These are known as precursor proteins or amyloidogenic proteins
• The misfolding of proteins can occur due to a number of reasons, including aberrant formation, improper breakdown, or accumulation beyond a critical concentration in serum