SECONDARY (AA) AMYLOIDOSIS: SYMPTOMS, CAUSES, COMPLICATIONS, AND TREATMENT

Medically Reviewed by Dr. Sony Sherpa (MBBS) - September 23, 2024

Secondary AA Amyloidosis is a pressing health concern that exacerbates the symptoms of inflammatory conditions and contributes to all-cause mortality.

The following discussion explores what AA amyloidosis is, how it is caused, and how it compares to other types. Current diagnosis, treatment options, and prevention strategies are also briefly detailed below.

What is AA Amyloidosis?

Amyloidosis refers to a group of diseases in which pathogenic proteins known as amyloids or amyloid fibrils are deposited across various tissues of the body. The proteins are malformed, either during their assembly or degradation, and are often difficult for the body to remove once deposited as insoluble amyloid. Some forms of amyloidosis may be genetic, as seen in familial transthyretin-associated amyloidosis, where gene mutations cause suboptimal protein assembly.

Secondary AA Amyloidosis is a subtype of amyloidosis that is associated with dysfunctional serum amyloid alpha (AA or SAA) protein. SAA protein is a lipoprotein of HDL cholesterol and is released in large quantities from the liver in response to inflammation. Chronic inflammatory diseases, infections, or injuries can eventually promote the long-term development of secondary AA amyloidosis. It can be considered a rare complication of these conditions. Secondary amyloidosis is also known as inflammatory amyloidosis and reactive amyloidosis. Like all types of amyloidosis, secondary amyloidosis may be localized or systemic.

Primary AL Amyloidosis vs. Secondary AA Amyloidosis. There is a big difference between primary and secondary amyloidosis. In Primary Amyloidosis, carcinogenic or faulty plasma cells in the bone marrow produce malformed antibodies or antibody fragments called light chains (Amyloid Light chain or AL amyloidosis). These form fibrils like AA proteins and are deposited into different organs and tissues.[1]

Prevalence. The prevalence of amyloidosis is not well understood and is estimated to affect roughly 5-20 million patients annually. Of these, secondary amyloidosis is the least common subtype of the most frequently encountered amyloid diseases. It has a prevalence of roughly 6%, while primary amyloidosis constitutes up to 78% and genetic types between 10-20%.[2] As AA amyloidosis arises from causes that are more common to the general population than other types and tools for its diagnosis are limited, its incidence may be more frequent than currently understood.

Symptoms

AA amyloidosis symptoms can vary depending on the trigger, the chronic levels of circulating SAA, and the degree of amyloidosis. Secondary amyloidosis most frequently affects the liver, spleen, kidneys, digestive tract, and vascular system. While uncommon, systemic AA amyloidosis may affect the nervous system and heart. It may increase the severity of inflammatory symptoms of a comorbid condition.

Those with secondary AA amyloidosis may suffer from symptoms pertaining to these organs, especially the kidneys.[3] These include:

• Low blood pressure, orthostasis (low blood pressure when shifting between laying down or sitting and standing positions), and POTS
• Proteinuria
• Edema
• Enlarged liver, spleen, or kidneys
• Gastrointestinal complaints
• Nausea and vomiting
• General muscle stiffness
• Anxiety
• Joint pain
• Neuropathy

Is AA Amyloidosis Terminal? If systemic, AA Amyloidosis can be a terminal condition and is often associated with fatal diseases. Severe AA amyloidosis can present with kidney failure, heart failure, and gastrointestinal bleeding. Patients with amyloidosis that display cardiac and/or kidney involvement may have anywhere between a 2 and 8-fold risk of mortality 5 years after diagnosis.[4] [5]

Amyloidosis Causes and Underlying Mechanisms

Secondary AA amyloidosis is caused when SAA is chronically elevated in an unbound form for a prolonged period of time.

Biologic Functions of Serum Amyloid A. Serum AA is released as part of the acute phase response, which is a systemic response to injury, infection, trauma, or other triggers of acute inflammation. It serves two main functions within the acute phase response:

• HDL-Associated Fat Clearance. HDL cholesterol is considered a group of apolipoproteins that help clear the blood vessels of larger cholesterol particles (LDL and VLDL) and triglycerides. The lipoproteins in HDL bind to these fatty substrates and transport them back to the liver for processing. Serum amyloid A has a high affinity for HDL cholesterol and is classified as a type of apolipoprotein that is chaperoned by HDL in the bloodstream. During the acute phase response, LDL is released more, and since healthy HDL is larger, it is able to recruit more fatty molecules. SAA is upregulated and tends to displace other lipoproteins (ApoA-I) from HDL. Due to the anti-inflammatory properties of HDL plus SAA, SAA may play a role in aiding HDL to clear the bloodstream of excess fatty substrates during the acute phase response.
• Innate Immune Defence. Under normal circumstances, elevated SAA in the acute phase response helps the body resolve a problem by acting as an inflammatory signal. When unbound, SAA triggers the release of inflammation from surrounding cells, which attracts the attention of immune cells like macrophages. It can bind to pathogens[6], reactive proteins, or cells, serving to act as a homing beacon that gets them removed by immune cells. SAA is also released from local tissues when similar problems are detected. When chronically elevated, SAA contributes to the destruction of tissues and perpetuates inflammation. [7] [8]

Amyloid Formation and Deposition. When disassociated, SAA is known to be an inherently disorderly protein with a high predisposition for becoming malformed under the right conditions, enabling it to form amyloid. Despite this, moderate concentrations of free SAA often get removed as waste from the body without forming amyloid or with forming very little. The following points describe how chronic inflammation and SAA can cause amyloid deposition and amyloidosis:

• Precursor Production. The liver is the primary site for intensive systemic amyloid A production and causes its levels to rapidly rise 1000-fold in the body during the acute phase response to injury, infection, or similar causes of inflammation. Amyloid A protein elevations increase the risk for depositions that can contribute towards the development of full-blown amyloidosis. Most cell types, including immune cells, blood cells, and stem cells, also produce serum AA amyloid proteins in response to inflammation or harmful stimuli.
• Amyloid Fibril Formation. Free AA gets taken up into cells, where it gets sent to the cell’s lysosome in order to be broken down. Under healthy circumstances, AA is removed as waste. In states of disease, heightened states of inflammation, bodily acidity[9], temperature, and faulty cellular metabolism interfere with lysosome function and protein degradation. Under these conditions, AA in the lysosome undergoes structural changes that cause it to elongate and become malformed. If the cell becomes damaged, deformed AA gets released along with cell debris, binds with other proteins, and creates AA fibrils.
• Deposition. AA fibrils are dumped in cell lesions, create vascular plaques, or fuse with other cell wall proteins or fats to form amyloid deposits.

Other Problems Associated with Free SAA. Besides increasing the risk for becoming fibrillated and forming plaques, unbound SAA can increase amyloid formation in a number of other ways that contribute towards the development of amyloidosis:

• HDL Deformation and LDL Deposition. Excessive SAA, inflammation, and other acute phase proteins are known to change the structure, and function of HDL, which promotes its clearance from the bloodstream.[10] SAA removes other lipoproteins from HDL, which, if excessive and chronic, can cause HDL to eventually shrink, become dysfunctional, and reduce its ability to remove large cholesterol molecules from the bloodstream.[11] When HDL is dysfunctional, LDL levels can increase. In this scenario, excess SAA binds with LDL and promotes cardiovascular conditions through binding to or fusing with cell membrane proteins, enabling the deposition of LDL into tissues or plaques.[12]
• Unbalanced Coagulation. Besides unbalancing cholesterol, SAA directly affects the coagulant system. It can bind to coagulant proteins, such as fibrinogen, create blood clots, and promote platelet activation, all of which increase thrombosis risk[13]. It can also bind to blood platelets and entirely deactivate them.
• Increased Cell Protein Production. Proteoglycans are important cell wall proteins that have been shown to trap clotting factors, calcium, amyloid, cholesterol, and lipoproteins in vascular lesions.[14] SAA elevations can increase the production and chain length of proteoglycans in cells, which enhances their ability to bind to substrates and contributes to amyloidosis and cardiovascular conditions.

Risk Factors

Most risk factors for secondary AA amyloidosis increase and prolong SAA production and blood concentrations.

• Inflammation. Many cytokines (inflammatory signaling compounds), including interleukin 6 and tumor necrosis factor (TNF), can cause the liver and other cells to produce more serum amyloid AA proteins.
• Faulty HDL and Dyslipidemia. When bound to HDL, the negative effects of SAA appear to remain contained, and together, SAA plus HDL may even have anti-inflammatory effects. HDL helps to keep SAA levels in check and reduces atherosclerosis risk, as documented in mice[15]. Impaired liver metabolism, dyslipidemia, or high LDL cholesterol levels that detract from HDL levels can increase the blood levels of SAA when expressed. Over time, this can increase its deposition across tissues.
• Cardiovascular Risk Factors. Microvascular injuries and plaques have been shown to accumulate amyloid AA protein. Thus, all risk factors pertaining to increasing vascular problems apply to AA amyloidosis as well.
• AGEs Formation. Advanced Glycation End Products (AGEs) were found in higher quantities in AA amyloid deposits than in other types of amyloid.[16] AGEs and amyloids form as a result of similar mechanisms, due to the oxidation of proteins and sugars that cause them to merge together and become increasingly more difficult to break down. A diet high in AGEs is known to increase their systemic levels, which can increase the risk of developing AA amyloid deposits.
• Autoimmune conditions and chronic infections tend to increase the risk, particularly due to the type of inflammation expressed. Some reviews suggest that up to 40% of those with secondary AA amyloidosis have rheumatoid arthritis.[17] 
• Pollution. Ozone (O3)[18], woodsmoke[19], and heavy metals can increase the expression of SAA and inflammation. Manganese (toxic in higher concentrations) is able to promote the formation of amyloid plaques by enhancing the aggregation abilities of SAA.
• High Estrogen Levels. Estrogen therapy is known to increase SAA levels, as are states indicative of estrogen elevation, such as obesity. This contrasts with the rise in estrogen seen in pregnancy, which is likely to be a protective factor.
• Low Albumin Levels. Albumin is a protein that can bind to excess SAA and remove it from the body. During the acute phase response, albumin levels may become temporarily depleted due to the active disposal of several waste products, including excess SAA. Healthy individuals with low albumin levels are at an increased risk for developing SAA. However, boosting serum albumin in patients with amyloidosis has not been shown to improve symptoms or inhibit disease progression.[20]

Complications

Complications of secondary AA amyloidosis are often systemic and depend on the organs and tissues involved. A few common complications include:

• Cardiovascular Complications. Besides amyloidosis, chronically elevated SAA levels are connected to an increased risk for cardiovascular diseases, such as thromboembolism[21] and atherosclerosis. In vitro, studies suggest that SAA is also involved in promoting the blood clotting issues seen in patients with COVID-19.[22]
• Cancer Metastasis. Amyloidosis and cancer metastasis are closely linked. Metastatic cancers increase the expression of both inflammation and SAA, while inflammation and circulating SAA promote metastases. Amyloid deposits may also contribute by forming convenient locations for circulating tumor cells to embed within, and amyloid fibrils may also fuse with them to contribute towards their development. Secondary AA amyloidosis is mainly associated with renal carcinoma metastases.[23]
• Gastrointestinal Abnormalities. Secondary AA amyloidosis can lead to irregular growth in the gastrointestinal tract, characteristic of an enlarged tongue (macroglossia), swollen throat, and narrowing of the intestines. This can slow down digestive processes and increase the risk of cuts, abdominal pain, internal bleeding, and colon cancer.[24] AA amyloidosis is occasionally seen to exacerbate symptoms of Crohn’s Disease.[25]
• Respiratory. Very rarely, amyloidosis can increase respiratory problems by causing stiffening of the lungs and airways.[26]
• Decreased Fetal Growth and Pregnancy Complications. Amyloid A protein is seen to be higher in pregnancy and may count as a signal of danger during pregnancy that may interfere with optimal development. A small group of women with secondary amyloidosis due to familial Mediterranean fever were shown to give birth to preterm infants with low birth weight, as well as being more prone to Preeclampsia.[27] Despite these findings, animal studies suggest that pregnancy is capable of inhibiting amyloid formation[28], possibly due to the way in which female reproductive hormones enhance cell repair (able to lower cell debris and suboptimal protein degradation) and lower inflammation.

Diagnosis

AA amyloidosis is often only diagnosed when other types have been ruled out.

If suspected by a healthcare practitioner after a physical examination with history, the patient will undergo a series of tests to confirm amyloidosis and to ascertain which type:

• Biopsy of fatty tissue, lymphatics, or the liver is used to diagnose primary amyloidosis.
• Blood and Urine Testing can often detect light chain antibody amyloid or transthyretin (seen in familial and age-related amyloidosis).
• Genetic Testing may be required to rule out familial amyloidosis.

If other types are not indicated, and the patient shows signs of kidney impairment and neuropathy, then they are diagnosed with AA amyloidosis.

Prevention and Treatment

Both prevention and AA treatment usually consists of tackling the underlying inflammatory condition. This helps to lower the level of circulating inflammation and AA protein in the bloodstream, which then prevents the formation of more amyloid from its precursor and the contributions of dead cell debris. In this regard, treatment often consists of comorbid medications and therapeutics in tandem with antibiotics (if necessary), anti-inflammatories such as aspirin, and blood-thinning agents such as warfarin.

Additional medical treatments are currently being investigated to clear amyloid fibrils from the body and target amyloid tissue deposits.

A focus on the following aspects of health may help to improve the prevention of amyloidosis as well as enhance outcomes for those with the condition:

• Keeping Inflammation in Check. Most of the suggestions below serve to keep inflammation in check. Immune support, constant physical activity, stress management, getting enough sleep and sunlight, as well as consuming a nutritionally balanced diet (low in AGEs) all help to reduce the production of amyloid by preventing and regulating various types of inflammation. Avoiding injuries, minimizing infection risk, resting properly when unwell, and opting for adequate medical treatment are also important. Those with amyloidosis may not be able to exert themselves or consume a diet containing any animal products or refined foods.
• Fat and Cholesterol Balance. Healthy HDL is vital for keeping systemic SAA levels balanced, even during inflammatory conditions. This involves maintaining the health and functioning of the liver and, by extension, the digestive tract. The diet should include a moderate amount of good-quality fats in order to keep the HDL:LDL ratio in check and lower the burden on the liver with respect to fat metabolism. Post-prandial hyperglycemia and refined carbohydrates ought to also be minimized where possible, as these can substantially detract from fat metabolism and liver function.
• Antioxidants, Anti-inflammatories, and Anticoagulants. A diet high in nutrients often contains many antioxidant compounds capable of inhibiting inflammation, as well as those that thin the blood. This is especially true of teas, herbs, and spices such as garlic, clove, ginger, green tea, and more. Several preclinical studies have also shown that propolis[29] and many phytochemicals (plant-based nutrients) are capable of improving lysosome protein degradation, inhibiting amyloid fibril formation, and possibly even promoting the removal of amyloid deposits in the absence of SAA excess.[30]

Conclusion

AA amyloidosis is a complication of chronic inflammatory illnesses that may be more prevalent than previously thought. It is usually only detected in severe stages of inflammatory diseases, such as kidney or heart failure, yet tends to be very common in those with Rheumatoid Arthritis and other autoimmune conditions. Persistent inflammation and infection are the most common risk factors, coupled with dyslipidemia and impaired protein degradation. Treatment mainly comprises treating the primary condition and may also include anti-inflammatory or anticoagulant prescriptions. Lifestyle and dietary approaches that lower inflammation can help to prevent its development and improve the quality of life for those with the condition.

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