Amyloid

Amyloidosis is a clinical disorder caused by the deposition of insoluble abnormal fibrils in the extracellular space composed of low molecular weight subunits that range from 5 to 25 kiloDaltons. These abnormal extracellular fibrils are formed by the aggregation of misfolded, soluble proteins that are found normally within the extracellular matrix and plasma. The precursor proteins involved undergo transformation to a beta-pleated configuration.

Amyloid Proteins

There is a total of 25 different human amyloid fibrils. The classification of amyloidosis is through a capital A for amyloid, followed by another letter for the fibril protein. There are numerous, however the most common are serum amyloid A protein, termed AA, light chain amyloidosis termed AL, heavy chain amyloidosis AH, and procalcitonin. Moreover, there is a familial form of amyloidosis, which is hereditary, termed ATTR to denote transthyretin, the abnormal fibril protein.

AL = (primary amyloid)
AA = amyloid (secondary amyloidosis)

Primary Amyloidosis

Primary amyloidosis is a disease of plasma cells, including multiple myeloma, Waldenstrom's macroglobulinemia, and MGUS in which a clonal expansion of plasma cells begin producing monoclonal light chain fibrils at high levels that are subsequently deposited in tissues, most commonly in the kidney through the circulation.

Considering the light chain, 75% are lambda chain, and 25% are kappa light chain.

Clinical Manifestations of Amyloid

The different forms of amyloidosis are important to define, as the type of precursor protein dictates the clinical manifestations. In addition, the amount of amyloid deposition and its distribution is crucial. For example, amyloid deposition in cardiac or kidney tissue, can lead to heart failure or renal failure respectively, as the normal functioning cells are replaced with this abnormal, nonfunctioning substance.

Amyloid deposition produces:

Nephrotic syndrome when found in the kidney.
Restrictive cardiomyopathy and congestive heart failure when found in the heart.
Hepatosplenomegaly when in the liver and spleen.
Macroglossia when affecting the oropharynx and tongue.
Peripheral neuropathy, Carpal tunnel syndrome when depositing in the nerves.

Organs Affected in Amyloidosis

Heart, Liver, Kidneys, but can involve any tissue. In highly dissiminated disease, amyloid can be deposited almost everywhere.

Different Presentations of Amyloidosis

AL = (primary amyloid)
AA = amyloid (secondary amyloidosis)

Cardiomyopathy – AL, hereditary, rare in AA
Systolic or diastolic dysfunction, arrhythmia, heart block, angina, infarction (amyloid in coronary arteries)

Pulmonary disease – AL, AA
Involvement of the trachobronchial tree leading to hoarseness, stridor, airway obstruction, dysphagia, persistent pleural effusions, pulmonary hypertension

Gastrointestinal – AL, AA,
Enlarged liver and/or spleen, bleeding (vascular fragility), gastroparesis, constipation, bacterial overgrowth, pseudo-obstruction due to dysmotility

Renal disease – AL, AA, hereditary
Asymptomatic proteinuria, nephritic syndrome, renal failure

Neurological – hereditary, neuro
Sensory and motor peripheral neuropathy and autonomic neuropathy, autonomic neuropathy, Alzheimer’s, Carpal tunnel, intracranial bleeding

Musculoskeletal disease – AL, dialysis
Pseudohypertrophy, macroglossia, arthropathy, jaw claudication, shoulder pad sign = visible enlargement of the anterior shoulder due to fluid in the glenohumeral joint and amyloid infiltration of the synovial membrane through AL amyloid and dialysis related amyloidosis

Hematologic abnormalities
Bleeding due to factor X deficiency which binds to amyloid fibrils and liver dysfunction or infiltration of blood vessels, anemia and thrombocytopenia due to bone marrow infiltration

Skin manifestations – AL, AA
Infiltration of subcutaneous fat

Diagnosis

Detection of monoclonal protein in the serum and urine of patients. Bone marrow aspirate and biopsy can also reveal monoclonal plasma cells, as found with plasma cell dyscrasias, however this is rarer. Immunoassays for abnormal serum light chains can also be performed if your centre offers these assays. If there is a family history of amyloid, transthyretin should be screened for. Immunofluorescence or immunohistochemistry for these light chains can also be done and is the gold standard for diagnosis. Abdominal subcutaneous fat pad biopsy or rectal biopsy can show apple-green birefringence on Congo red stain. Biopsy of the kidney or liver is the norm if there are clinical manifestations. Abdominal fat pad is also aspirated often. Moreover, bone marrow, skin and rectal biopsy's can also be done. SPEP, UPEP, SIEP, bone marrow biopsy, Echocardiography for cardiac changes, looking for biventricular thickening with “granular sparkling appearance”. Genetic testing for hereditary forms, such as TTR.

Amyloidosis Treatment

AL amyloid - uses melphalan + prednisone. If these fail, the use of autosomal stem cell transplant as a last resort to remove the plasma cells producing the abnormal fibrils.
AA amyloid - treat underlying condition
Hereditary – liver transplant
Local amyloid - the most easily treated, with surgical excision

Prognosis

AL – median survival = 12-18 months; if cardiac involvement – median survival 6 months