Amyloidosis: Types and Manifestations

Basically, this is a group of disorders where there is extracellular tissue deposition of fibrils of various proteins. 

Types:

1. AL Amyloidosis (Primary) – protein is derived from immunoglobulin light chain fragments, due to plasma cell dyscrasias.  Occurs alone, or with multiple myeloma, less frequently Waldenstrom’s macroglobulinemia or Non-Hodgkins Lymphoma. 
2. AA Amyloidosis (Secondary) – protein is derived from fragmenets of the acute phase reactant serum amyloid A.  Occurs in diseases with chronic inflammation, e.g Rheumatoid Arthritis, Infections such as Tuberculosis, Spondyloarthropathies, Inflammatory Bowel Disease, Periodic fever syndromes.
3. Dialysis-Related Amylodosis – from fibrils of Beta-2 microglobulin which accumulates in ESRD patients on dialysis. 
4. Heritable Amylodosis – due to various mutations in different proteins, with heterogeneous phenotypes.  As an example, mutation in Transthyretin leads primarily to neuropathic and cardiac amyloidosis.
5. Age-related (Senile) Systemic Amylodisis – due to deposition of otherwise normal transthyretin in the myocardium and other sites leading to primarily cardiac disease. 
6. Organ-specific Amyloidosis - most common = Alzheimer's disease (amyloid deposition in the brain).

Manifestions:  not all types have the same organ involvement, but systemic AL amyloid (the most common type in the developed world) can affect all systems as below:

• NEURO – peripheral neuropathy, autonomic dysfunction.  CNS involvement is unusual.
• CV – cardiomyopathy, much more common with AL (and transthyretin) vs AA.  Clinically, usually present with signs of right-sided heart failure.  EKG often shows low voltages and conduction abnormalities.  Patients are prone to ventricular arrhythmias as well.  Echo will usually show wall thickening and diastolic dysfunction, and later evidence of a restrictive cardiomyopathy, and thickening of the valves.  Sometimes you can see increased echogenicity with a granular, sparkling appearance, but this is insensitive and often not found with more modern echo technology. 
• PULM – can get infiltration of the trachea and bronchi, leading to hoarseness, stridor, airway obstruction.  Also, parenchymal nodules and pleural effusions.
• RENAL – most common organ to be affected, usually presents with proteinuria à nephrotic syndrome.  Less commonly presents with frank renal failure.
• GI – often nonspecific symptoms such as diarrhea, malabsorption, protein loss.  Often get GI bleeding due to vascular fragility.  Liver involvement with hepatomegaly and often splenomegaly is common.  Macroglossia, when found, is pathognomonic for AL form amyloidosis.
• HEME – can get Factor X deficiency with AL due to binding of amyloid fibrils.
• MSK – infiltration of muscle à pseudohypertrophy.  Also, arthropathies and carpal tunnel syndrome.
• SKIN – waxy thickening, easy bruising, subcutaneous nodules and plaques.  Purpura in a periorbital distribution (raccoon eyes) is highly characteristic of AL amyloid (present in a minority of patients).

(Chanu Rhee MD, 12/14/10)