Amyloidosis

Amyloidosis is a collective term for the extracellular deposition of abnormal proteins, either in a single organ (localized amyloidosis) or throughout the body (systemic amyloidosis). The different subtypes of amyloidosis are categorized according to the origin of the deposited proteins (e.g., AA, AL). These abnormal proteins are produced as a result of various diseases. The most common form of systemic amyloidosis in developed nations is light chain amyloidosis (AL deposition), which is caused by plasma cell dyscrasias such as multiple myeloma. The second most common systemic form – reactive amyloidosis (AA deposition) – is secondary to chronic inflammation and typically presents with nephrotic syndrome. Depending on which organs are affected, amyloidosis may also present with hepatomegaly, macroglossia, cardiac conduction abnormalities, and symptoms of restrictive cardiomyopathy. Abdominal fat or rectal mucosa biopsies are used to diagnose systemic amyloidosis. When stained with a Congo red dye, amyloid deposits exhibit an apple green birefringence under polarized light. No definitive therapy for amyloidosis exists. Instead, the underlying disease should be treated. If amyloidosis progresses rapidly, melphalan and corticosteroids can be used to control the underlying disease.

Systemic amyloidosis

Light-chain amyloidosis (AL-amyloidosis)

• Most common form of amyloidosis in developed nations
• Etiology: associated with plasma cell dyscrasias (e.g., multiple myeloma, Waldenström macroglobulinemia)
• Pathophysiology: increased production of the light chains of immunoglobulins → deposition of AL (amyloid light chain) protein in various organs
• Clinical presentation: rapidly progressive clinical course
  • Heart: restrictive cardiomyopathy, atrioventricular block
  • Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
  • Tongue: macroglossia → obstructive sleep apnea
  • Autonomic nervous system: autonomic neuropathy
  • Gastrointestinal tract: malabsorption
  • Bleeding disorders

Reactive amyloidosis (AA-amyloidosis)

• Etiology: secondary disease
  • Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis, SLE, vasculitis, familial Mediterranean fever)
  • Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, osteomyelitis)
  • Certain tumors (e.g., renal cell carcinoma, lymphomas)
• Pathophysiology: chronic inflammatory process → increased production of acute phase reactant SAA (serum amyloid-associated protein) → deposition of AA (amyloid-associated) protein in various organs
• Clinical features
  • Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
  • Adrenal glands: primary adrenal insufficiency
  • Liver and spleen: hepatomegaly, splenomegaly
  • Gastrointestinal tract: malabsorption

Amyloidosis should always be considered in a patient with a long-standing inflammatory and/or infectious disease who presents with kidney, liver, or GI involvement.

Overview of systemic amyloidosis

Type of systemic amyloidosis		Amyloid protein	Underlying cause	Age of onset	Organs most commonly affected	Additional information
Light-chain amyloidosis		Light chains of immunoglobulins → AL amyloid protein	Plasma cell dyscrasias (e.g., multiple myeloma)	> 40 years	Heart Kidney Tongue Autonomic nervous system Gastrointestinal tract	Most common form of amyloidosis in the western world Rapidly progressive clinical course
Reactive amyloidosis		Serum amyloid-associated protein (SAA) AA amyloid protein	Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis, SLE) Chronic infectious diseases (e.g., tuberculosis, osteomyelitis) Certain tumors (e.g., renal cell carcinoma, lymphomas)	Any age	Kidney Adrenal glands Liver and spleen Gastrointestinal tract	Most common form of amyloidosis in the developing world The progression of the disease can be slowed by controlling the underlying condition.
Hemodialysis-associated amyloidosis		β2-microglobulin → Aβ2M amyloid protein	Long-term hemodialysis	∼10 years after starting hemodialysis	Joints and tendons	Almost all individual on long-term hemodialysis will develop amyloidosis at some point

Localized amyloidosis

Affected organ		Amyloid protein	Associated condition
Senile cardiac amyloidosis		Normal (wild-type) transthyretin (ATTR)	Old age
Isolated atrial amyloidosis		ANP → increased risk of atrial fibrillation	Old age
Cerebral amyloidosis		Aβ	Alzheimer disease
		APrP	Prion diseases
Endocrine amyloidosis		Islet amyloid polypeptide (IAPP) → amylin deposition in pancreatic islet	Type 2 diabetes mellitus
		Amyloid at insulin injection site (AIns)	Subcutaneous insulin injection in diabetes mellitus
		Procalcitonin (ACal)	Medullary carcinoma of the thyroid

Hereditary amyloidosis

Condition	Amyloid protein	Pattern of inheritance	Age of onset	Affected sites	Additional information
Familial amyloid cardiomyopathy	Mutated transthyretin (ATTR)	Autosomal dominant disease (most common)	> 20 years	Ventricular endomyocardium → restrictive cardiomyopathy, arrhythmia	Common in African Americans
Familial amyloid polyneuropathy (FAP)				Peripheral and autonomic nerves	Common in Portugal, Sweden, Japan, and among people of Irish descent
Familial Mediterranean fever (FMF)	AA amyloid protein	Autosomal recessive disease	< 20 years	Kidney Liver and spleen Adrenal glands	Common among individuals of Mediterranean descent (e.g., Sephardic Jews, Arabs, Turks) Two types of FMF: Type 1 FMF Type 2 FMF

References:^{[1][2][3][4][5][6][7]}

• Biopsy of abdominal fat or rectal mucosa with Congo red stain
  • Pink to reddish appearance
  • Apple-green birefringence under polarized light
• Tests to diagnose the underlying disease
  • Light chain amyloidosis
    • Serum electrophoresis: monoclonal gammopathy
    • Urine test for Bence-Jones proteins (see multiple myeloma)
  • Reactive amyloidosis: ESR, CRP, chest x-ray

References:^[8][9]

• No definitive therapy exists
• Adequate treatment of the underlying disease may stall disease progression.
• If amyloidosis progresses rapidly (e.g., light chain amyloidosis): corticosteroids, melphalan
• Prevention of AA-amyloidosis and consequent renal failure in patients with FMF: colchicine ^[10]

References:^[6][11]