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

• Autoimmune Amyloidosis
• Inflammatory Amyloidosis
• Secondary Amyloidosis

What is AA 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 amyloid proteins build up secondary to a chronic disease, it is known as AA Amyloidosis
• The ‘AA’ proteins are the product of partial breakdown of serum amyloid A (SAA) protein. SAA proteins are formed during an inflammatory response, and are broken down during the recovery process
• However, in response to a chronic infection or inflammatory disease, SAA levels remain elevated and their breakdown is incomplete. Such chronic conditions may include diabetes, tuberculosis, inflammatory bowel disease, and rheumatoid arthritis
• AA Amyloidosis typically affects the kidneys, although the amyloid protein build-up may occur in other tissues and organs as well, including the heart, liver, spleen, GI tract, and the nervous system
• An effective management of the underlying condition that result in AA Amyloidosis and the severity of its signs and symptoms, determines the overall prognosis. In case of major organ involvement, the prognosis is usually guarded

Who gets AA Amyloidosis? (Age and Sex Distribution)

• AA Amyloidosis is considered the most common form of amyloidosis, especially in certain developing countries
• AA Amyloidosis can affect individuals of all age groups and both genders; no racial or ethnic bias is noted
• Although amyloidosis can affect individuals of any age, most cases are noted in the age group of 50-70 years

What are the Risk Factors for AA Amyloidosis? (Predisposing Factors)

Some known risk factors for AA Amyloidosis include:

• Chronic inflammatory conditions such as:
  • Arthritis, including rheumatoid arthritis, juvenile inflammatory arthritis, psoriatic arthritis and ankylosing spondylitis
  • Inflammatory bowel disease (IBD) such as ulcerative colitis
• Chronic infections that include:
  • Tuberculosis
  • Leprosy
  • Bronchiectasis
  • Osteomyelitis
  • Skin infections (especially in drug abusers, who use needles to inject themselves)
  • Chronic infection in skin with burns
  • Chronic kidney infections (pyelonephritis)
  • Whipple’s disease
• Poorly-controlled diabetes
• Infectious diseases such as HIV/AIDS
• Cystic fibrosis; individuals with this condition are prone to repeat infections
• Certain cancers such as Hodgkin’s lymphoma and renal cell carcinoma
• Family history of certain hereditary disorders that may include:
  • Familial Mediterranean fever (FMF)
  • Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS)
  • Hyperimmunoglobulin D syndrome and periodic fever syndrome (HIDS)
  • Cryopyrin-associated periodic syndrome (CAPS)
  • Majeed syndrome

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 AA Amyloidosis? (Etiology)

AA Amyloidosis is caused by a partial breakdown of serum amyloid A (SAA) protein. SAA is generated by the liver, as a reaction to inflammation.

• Normally, SAA is broken down and recycled following an acute inflammatory reaction, during the recovery phase
• However, with long-term inflammatory conditions and infections, SAA levels remain elevated and the protein is not completely broken down
• This partial breakdown leads to the formation and accumulation of the aberrant amyloid A protein (AA protein) that gets deposited in tissues causing symptoms

What are the Signs and Symptoms of AA Amyloidosis?

The signs and symptoms of AA Amyloidosis may vary among the affected individuals, in terms of organs and tissues affected, as well as in severity. These may be present in addition to manifestations of the underlying condition that caused AA Amyloidosis.

The signs and symptoms of AA Amyloidosis begin in the kidneys, which may include:

• Anemia
• Fatigue
• Unintended weight loss
• Excess protein (albumin) in urine; decreased amounts of albumin protein in blood
• Low blood pressure
• Hyperlipidemia, or increased amount of fat (cholesterol) in blood 
• Edema, or swelling, is observed in hands, feet, legs and face
• Joint stiffness
• Bone cysts
• Tingling sensation; numbness 
• Carpal tunnel syndrome (resulting in weak grip)
• Blood clot (thrombosis) in the renal vein
• Recurrent kidney problems including kidney failure

In addition, the following general signs and symptoms may be present:

• 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
• Rash around the eyes
• Eyes that appear puffy
• Clay-colored stools
• Bleeding disorders; problems with proper clotting of blood

In some cases, AA Amyloidosis may affect organs other than the kidneys. The following are some organ-specific symptoms:

Signs and symptoms related to the heart:

• Decreased urine output; increased urge to urinate at night time
• Shortness of breath with physical exertion or while lying down
• Irregular heartbeats
• Chest pain
• Enlargement of heart; fluid build-up around the heart
• Excess cholesterol in blood
• Unintended weight loss
• Edema, or swelling, in abdomen, hands, feet, legs and face

Signs and symptoms related to respiratory tract:

• Hoarseness in voice
• Cough, which may contain blood
• Wheezing
• Grating noise while breathing (stridor)
• Labored breathing, which may mimic asthma symptoms
• Shortness of breath
• Repetitive infections in the respiratory tract, which may mead to pneumonia
• Night sweats

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

General signs and symptoms of thyroid gland amyloidosis: 

• Sore throat, hoarseness
• Swallowing difficulties

Signs and symptoms of hypothyroidism:

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

Signs and symptoms of hyperthyroidism:

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

Signs and symptoms of thyroiditis:

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

Signs and symptoms of goiter:

• Visible swelling in throat
• Cough
• Difficulty breathing
• Feeling of tightness in throat

Signs and symptoms related to nervous system:

• Generalized pain in the body (including muscle spasm)
• Bone abnormalities
• Changes in the skin, nails, and hair
• Numbness and tingling sensation in the limbs
• Unusual sensations (parasthesia) that may be painful
• Insensitivity to extreme temperatures
• Sweating
• Extreme drop in blood pressure while standing up from a seated position
• Lightheadedness
• Loss of voluntary muscle control
• Involuntary urination; inability to empty urinary bladder
• Lack of appetite; feeling of fullness after eating a little food
• Constipation
• Loss of sensation (such as in the hands and feet)
• Loss of coordination and balance
• Inability to respond to emotional inputs
• Having trouble with sleep 
• Problems with sexual performance (erectile dysfunction in men)
• Heart-related abnormalities that may lead to a heart attack
• Stomach-related signs and symptoms that include vomiting and diarrhea
• Headache (in some specific areas)
• Confusion
• Double vision
• Abnormal position of eyelids; drooping eyelids
• Change in the position of eyeballs
• Drowsiness
• Seizures
• Paralysis 

Signs and symptoms related to the lymphatic system:

• Swelling of lymph nodes, which may or may not be painful
• Obstruction of lymph nodes, causing lymphedema, leading to
  • Fluid accumulation in the body, causing generalized swelling
  • Ascites or fluid accumulation in the peritoneal cavity that causes swelling of the abdomen
  • Pleural effusion, which is the accumulation of fluid in the lining between the lungs and chest. This can lead to chest pain, cough, and difficulty breathing

Signs and symptoms related to gastrointestinal system:

• Thickening of tongue (macroglossia)
• Difficulty in swallowing
• Acid reflux (gastroesophageal reflux disease or GERD)
• Sluggish peristaltic movement (process that moves food in the GI tract by involuntary muscle contractions)
• Nausea
• Loss of appetite; feeling of fullness after eating a small amount of food
• Gastric polyps (nodules on the stomach wall)
• Slowing of stomach emptying (gastrointestinal atony) 
• Pseudo-obstruction of intestines; a sense of blocked intestines without any actual physical blockage
• Abdominal bloating and distension; abdominal pain
• Constipation or diarrhea that may contain blood
• Clay-colored stools; or, fatty and foul-smelling stools (steatorrhea)

Signs and symptoms related to the liver:

• Enlarged liver (hepatomegaly)
• Enlarged spleen (splenomegaly)
• Upper abdominal pain; abdominal swelling
• Possible changes in the levels and function of liver enzymes

Signs and symptoms related to the spleen:

• Enlarged spleen
• Abdominal swelling; left abdominal pain
• Left shoulder pain

Signs and symptoms related to skin

• Small, red blood spots on skin
• Round or irregularly shaped flat spots that may be red, purple, or blue in color
• Raised spots (papules) or plaques near eyelids, neck and genital area
• Dark skin patches, which may be distributed symmetrically on the body
• Skin rashes; nodules on skin
• Itching 
• Brittle nails
• Loss of hair in patches across the skin

Signs and symptoms related to the adrenal glands (in rare cases):

• Fever, headache
• Loss of appetite and weight loss
• Low blood pressure that worsens when the individual stands from a sitting or lying position; this results in lightheadedness
• Muscle weakness and muscle spasms
• Behavioral changes, irritability, anxiety, or depression
• Darkening of the skin, especially in pressure areas such as belt regions, nail, gums, and nipples
• Decreased body hair
• Nausea and vomiting
• Anorexia
• Abdominal pain, chest pain
• Joint pain and neck pain
• Problems with one’s gait
• Problems with intellect
• Decrease in sex drive

How is AA Amyloidosis Diagnosed?

AA Amyloidosis is diagnosed on the basis of the following tests and exams:

• A thorough physical examination
• Evaluation personal and family medical history
• Assessment of the presenting signs and symptoms
• Blood tests: 
  • For complete blood count (CBC)
  • To check for serum albumin levels
  • To measure cholesterol levels
  • To assess abnormal antibodies 
  • To check heart function (cardiac biomarkers for stress on the heart)
  • For measuring immunoglobulin by immunofixation electrophoresis
  • For measuring levels of an enzyme known as alkaline phosphatase
• Urine tests: 
  • Check for excess protein (a 24 hour urine test is usually performed)
  • Measure immunoglobulin by immunofixation electrophoresis
• Electrocardiography and echocardiography for checking heart function
• 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 the case of AA Amyloidosis, 
  • Immunohistochemical analysis of tissue samples using anti-AA serum may be performed, to identify the type of amyloidosis an individual has
  • Biopsy of affected tissue, such as organ tissue, bone, muscle, or fat, may be necessary
  • 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)
• Molecular testing to type AA proteins in the amyloid deposits through mass spectrophotometry 
• Molecular genetic testing for certain inherited diseases (such as familial Mediterranean fever, TNF receptor associated periodic syndrome, hyperimmunoglobulin D syndrome and periodic fever syndrome, cryopyrin-associated periodic syndrome, and Majeed syndrome) that are known to cause AA Amyloidosis

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of AA Amyloidosis?

The potential complications of AA Amyloidosis include:

• Increased susceptibility to infections
• Kidney failure, resulting in end-stage kidney disease (ERSD)
• Stiffness and pain in joints leading to difficulty with movement
• Dizziness and risk of fall, if one stands up too quickly from a seated position
• Heart failure

How is AA Amyloidosis Treated?

Currently, there are no treatment options available to cure AA Amyloidosis. There are, however, treatments available to ease the symptoms and slow disease progression. The treatment measures are also unique to each individual and depend on the organs affected.

The treatment measures for AA Amyloidosis may include:

• Adequate management of an underlying disease or condition that result in AA Amyloidosis
• Dialysis, in case of kidney failure
• Kidney transplantation for kidney failure
• Blood transfusions for anemia
• Diet: Having frequent and small meals through the day, with reduced fat content
• Removal of spleen
• Pacemaker implantation to improve heart function
• Heart transplantation for severe dysfunction of heart
• Liver transplantation for those with familial amyloidosis (since, the aberrant amyloid protein in inherited Amyloidosis is generated in the liver)
• A drug under clinical investigation known as eprodisate, which interferes with the formation of amyloid aggregates

How can AA Amyloidosis be Prevented?

• Currently, there are no specific methods or guidelines available to prevent AA Amyloidosis
• Seeking medical attention for pre-existing conditions that can lead to AA Amyloidosis is advisable, in order to delay the onset of symptoms
• 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 AA Amyloidosis? (Outcomes/Resolutions)

• The prognosis for AA Amyloidosis may be determined by a number of factors, such as whether the medical condition causing AA Amyloidosis is well-managed, the extent of disease, organs affected, overall health of the affected individual, and his/her response to treatment
• However, if the function of major organs, such as the heart and kidney, is compromised, the prognosis is guarded
• Individuals with AA Amyloidosis are known to survive 5-10 years following diagnosis of the condition

Additional and Relevant Useful Information for AA 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