Amyloidosis: Interference With Organ Structure and Function

Amyloidosis is considered a group of conditions caused by the accumulation of amyloid protein in tissues and organs, resulting in their compromised function.¹ The cause of amyloidosis is unknown; however, a tendency to accumulate amyloid protein is found in individuals with certain disorders such as arthritis, chronic renal failure, and multiple myeloma (MM).² Amyloid may accumulate locally, in which case relatively few symptoms manifest, or widely (i.e., systemically), in which case multiple organ involvement is seen, resulting in severe multiorgan failure (TABLE 1).³ While symptoms of amyloidosis vary, depending on the organ(s) affected, this disease has the potential to be disabling or life-threatening.⁴

Although amyloid deposits do not exert metabolic effects, they interfere with the structure and function of organs.³ Evidence supports the notion that underlying the disease in most patients is some degree of derangement in their immune system.⁵ While it is a result of neither too little immunity nor too much immunologic activity, amyloidosis is a disease in which abnormal protein is deposited in tissues; in some cases, the protein is derived from fragments of immunoglobulins.⁵ The most common type of amyloidosis, referred to as primary amyloidosis (AL), may be due to either aberrant synthesis or processing of immunoglobulin light chains.⁴ AL affects only about eight individuals per million annually; two-thirds of patients with this disease are men.⁴  

Classification of Amyloidosis

The hypothesis regarding a single amyloid substance predominated prior to 1970, after which amyloid has been classified chemically.⁶ Abbreviations are used based on the classification, starting with a capital A--for amyloid--followed by an abbreviation for the type of fibril protein.⁶ As can be noted from the example above, primary amyloidosis is referred to as AL, where the A represents amyloidosis and the L represents an immunoglobulin light chain or light chain fragment.^4,6 

AL: In normal immune function, plasma cells in bone marrow help form antibody proteins used to protect against infection and disease; antibodies are recycled after use in healthy individuals.⁴ In the case of AL, the abnormal protein involved is an immunoglobulin causing a monoclonal plasma cell disorder in which excess antibody proteins are produced and recycling does not properly occur.^3,4 These proteins can form a meshwork in body tissues, accumulating amyloid.^1,3,4 Deposition of amyloid is commonly found in the nerves, skin, heart, kidney, liver, gastrointestinal (GI) tract, spleen, and blood vessels.^3,7 In the bone marrow, mild plasmacytosis is noted, and while suggestive of MM--a malignancy of bone marrow--most patients do not have true MM, which is associated with anemia, lytic bone lesions, and renal tubular casts.³ Of those patients with a diagnosis of MM, 10% to 15% also develop amyloidosis.⁷ 

Secondary Amyloidosis (AA): Patients with AA develop the disorder secondary to various infections (e.g., osteomyelitis, tuberculosis), inflammatory conditions (e.g., rheumatoid arthritis, Crohn's disease), or malignancy (myeloma conditions). ^3,4 This form of amyloidosis generally affects the kidneys, spleen, liver, and lymph nodes, although other organs may be involved.⁴ This condition may be ameliorated with treatment of the underlying disease.⁴ 

Familial Amyloidosis: Inherited (familial) metabolic defects cause rare cases of amyloidosis resulting from accumulation of a plasma protein that has been mutated (e.g., transthyretin [TTR], in which case it is referred to as amyloid transthyretin [ATTR]), and is mostly produced by the liver.³ Familial amyloidosis typically affects the nerves, kidneys, and heart.⁴ Peripheral sensory neuropathy and motor neuropathy, often accompanied by autonomic neuropathy, are caused by ATTR.^3,8 Accumulation of amyloid in and around nerves interferes with their functioning; often causes numbness, tingling, and pain in the hands and feet; and is referred to as amyloid neuropathy.² ATTR commonly produces carpal tunnel syndrome when amyloid deposits affect the nerves in the hands and arms.² As ATTR progresses, the heart and kidneys are usually affected.³ A variety of local and systemic effects can be seen with other very rare hereditary amyloidoses.³ 

A beta₂-Microglobulin Amyloidosis: Dialysis-related amyloidosis, occurring in patients with chronic renal failure who have endured long-term (i.e., often >8 years) hemodialysis or peritoneal dialysis (and, rarely, in patients with renal failure who are not on dialysis), is caused by amyloid deposits consisting of beta₂-microglobulin.^3,6 While these deposits are normally eliminated by the kidney, they are unable to be removed via dialysis membranes.³ Their deposition is found most often in and adjacent to bones and joints and the carpal tunnel, although they have been detected in the GI tract and other organs, as well.³ 

A beta-Protein Amyloidosis: While the definitive cause of Alzheimer's disease (AD) has not yet been determined, neuritic plaques and neurofibrillary tangles are the pathologic hallmarks of this disease.⁹ While plaques and tangles can be found in normal aging, as well as in  other diseases, they appear in much higher concentrations in individuals with AD.⁹ Neuritic plaques, which are also termed amyloid plaques, are comprised of beta-protein fragment of beta-amyloid precursor protein.^3,9 These plaques are found in the brain; when found around blood vessels, they are thought to be a cause of nonhypertensive cerebral hemorrhage (i.e., cerebral amyloid angiopathy).^3,9 

Diagnosis

Diagnosis of amyloidosis is based on the presence of amyloid deposits in organs or other body tissues detected via biopsy.⁴ While the best biopsy sites are subcutaneous abdominal fat (i.e., via aspiration) and rectal mucosa, other sites include gingiva, skin, nerve, liver, and kidney.³ On occasion, a biopsy may be taken from the liver, nerve, heart, or kidney using local anesthetic and sedation; hospitalization is rarely required.⁴ Only tissue biopsies and bone marrow tests can positively determine a diagnosis and classification of type of amyloidosis.⁴ Pathologic diagnosis involves Congo red dye staining and immunohistochemistry; if immunostaining a biopsy specimen is not done to identify the type of deposited protein, a misdiagnosis may result and can lead to ineffective or harmful interventions since different types of amyloidosis require different approaches to treatment.⁶ This concept may be illustrated by the fact that carpal tunnel syndrome can be attributed to AL, ATTR, and A beta₂-microglobulin amyloidosis; however, each has a different etiology and requires a different treatment.⁶

Prognosis

The prognosis for patients with amyloidosis greatly depends on the organ and tissue involvement and the extent to which amyloid accumulates.² For example, if involvement is limited to the nerves in the arms and legs, life expectancy is not shortened.² Generally, however, with any type of amyloidosis that involves the kidneys or the heart, particular concern is warranted; AL  has a poor prognosis and significantly increased mortality as a result of frequent cardiac involvement.^3,10 AL with MM has the poorest prognosis, with death commonly occurring within 1 year.³ If ATTR amyloidoses are left untreated, death is usual within 10 to 15 years.³ 

Treatment

While there is no cure for amyloidosis, treatment of the underlying cause may, in fact, arrest the disorder.^2,3 In general, the management of amyloidosis is aggressive symptomatic treatment.^3,4 Treatments vary, depending on the following: 1) which type of amyloid protein is present; 2) the location of the deposits; 3) in what way the amyloid deposits affects organ(s) and other tissues (TABLE 2).¹¹

A combination of medications and diet is recommended, based on the organs involved; for example, if the heart or kidneys are affected, a low-sodium diet in conjunction with diuretics may reduce fluid retention.⁴ Since dietary protein intake is not linked to amyloidosis, provision of a well-balanced diet is recommended to supply the patient with adequate energy.⁴ Appropriate treatment of comorbidities may also be helpful in managing this disorder.² Surgical removal of amyloid is sometimes warranted.²

For the most common type, AL, the foundation of the treatment is chemotherapy, including peripheral stem cell transplantation (TABLE 2).⁴ The treatment philosophy involves targeting the cells that make the amyloid protein to potentially limit further production and improve quality of life.¹¹ In cardiac amyloid patients, especially the AL type, and in those with atrial fibrillation, intracardiac thrombosis frequently occurs.¹¹ Feng et al have found that risk for thrombosis increases if left ventricular diastolic dysfunction and atrial mechanical dysfunction are present; anticoagulation therapy appears to be protective.¹¹ The researchers recommend timely screening in high-risk patients to allow for early detection of intracardiac thrombus. It is suggested that anticoagulation therapy should be carefully considered.¹¹ 

Conclusion

While amyloidosis is rare, the primary form of the disorder is more prevalent in individuals over 40 and among men. It frequently affects multiple organs, including the heart, kidneys, liver, spleen, nervous system, and GI tract. Pharmacists should be aware of the classifications and ramifications of this disorder, and appropriate symptomatic management. 

REFERENCES

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