Amyloidosis is the deposition of amyloid proteins in body tissues leading to tissue damage. Amyloidosis is classified as either primary or secondary. The former results from multiple myelomaor an idiopathic disease, while the latter is a sequela of a chronic or inflammatory disease process. These classifications are based on the type of fibrillar protein deposited. The primary form usually affects the skin, heart, tongue, and GI tract, while the secondary form, although more common, has no cutaneous manifestations.

Systemically, patients with primary amyloid light chain amyloidosis present with fatigue, weight loss, and symptoms specific to the organs involved. The kidneys and heart are the most common organs involved, demonstrating renal failure and aggressive congestive heart failure. CNS manifestations are absent, but peripheral neuropathies are common.

The most common oral manifestation of amyloidosis is macroglossia, which occurs in 20% of patients. The enlarged tongue demonstrates lateral ridging due to teeth indentation.Although pain is not usually present, enlargement, firmness, and loss of mobility are common. Grossly, the tongue may be firm and appear relatively normal or it may have yellow nodules on the lateral surface. Macroglossia is virtually pathognomonic of systemic AL amyloidosis and can cause numerous complications including dysphagia, dysarthria and, very occasionally, airway obstruction. Macroglossia is present in 10–23% of patients with systemic AL amyloidosis.Interference with taste has also been reported in some patients, and hyposalivation may result from amyloid deposition in the salivary glands. Involvement of the salivary glands can result in xerostomia, which mimics the symptoms of Sjogren syndrome. Submandibular swelling occurs subsequent to tongue enlargement and can lead to respiratory obstruction. Rarely, oral ulceration may present.

Microscopic examination of a biopsy sample from an enlarged tongue reveals the characteristic amorphous fissured appearance of amyloid in the tissues; a green negative birefringence is depicted when polarized light is shone on tissue stained with Congo red. The most common protein type deposited in the oral cavity is amyloid. The detection of AL in a patient warrants further evaluation for possible multiple myeloma. Of patients with multiple myeloma, 7-20% have amyloid deposition. The presence of myeloma yields a poor prognosis for the patient.

Treatment of systemic amyloidosis

The prognosis of systemic amyloidosis has improved markedly over the past few decades. In the absence of specific antiamyloid therapy, the principle of treatment is to reduce the abundance of the amyloidogenic pre cursor protein. This approach can lead to regression of amyloid deposition and result in stabilization or improvement of organ function. Initial therapeutic efficacy is indicated by a reduced concentration of the relevant precursor protein, which may then be followed by regression of amyloidosis and improvement in amyloidotic organ dysfunction. Treatment of AL amyloidosis is with hematological stem cell transplantation or with myelomatype chemotherapy, although important differences in treatment of myeloma and AL amyloidosis exist. The plasma cell dyscrasias that are usually present in patients with AL amyloidosis tend to be subtle and low grade. A complete hematological response is not the universal goal in the treatment of AL amyloidosis, since a partial response can be sufficient to lead to improvement in organ function.

Toxicity of therapy is often substantial in patients with amyloidosis, particularly in those whose affected organs might have reduced functional reserve. The aim of therapy for patients with AA amyloidosis is to reduce the production of SAA. Survival of the patient, amyloidotic organ survival and change in amyloid load are directly influenced by SAA concentration. In addition to specific anti-inflammatory or immuosuppressive therapies for any given underlying inflammatory condition, biological agents that target pivotal inflammatory cytokines, such as tumor necrosis factor, have had an immense effect on the treatment of a variety of conditions that underlie AA amyloidosis.

For patients with hereditary systemic amyloidosis in whom the amyloidogenic precursor protein is produced solely by the liver, treatment has been revolutionized by liver transplantation as a form of ‘surgical gene therapy.’ Liver transplantation has been used most successfully for treatment of FAP. The mainstay of therapy for patients with β2microglobulin amyloidosis is supportive, but kidney transplantation is associated with very rapid and marked relief of musculoskeletal symptoms.

 

Classification of amyloidosis

Type of amyloidosis	Abnormal amyloidogenic   precursor Protein	Clinical syndrome
AA	Serum amyloid A protein	Reactive systemic amyloidosis   associated with chronic inflammatory diseases
AL	Monoclonal immunoglobulin   light chains	Systemic amyloidosis associated   with monoclonal plasma cell dyscrasias
Aβ2M	β2‑microglobulin	Periarticular and,   occasionally, systemic amyloidosis associated with long‑term   dialysis
ATTR	Normal plasma transthyretin	Senile systemic amyloidosis   with prominent cardiac involvement
ATTR	Genetically variant   transthyretin	Autosomal dominant systemic   amyloidosis Familial amyloid   polyneuropathy
ACys	Genetically variant cystatin   C	Hereditary cerebral   hemorrhage with cerebral and systemic amyloidosis
AGel	Genetically variant gelsolin	Autosomal dominant systemic   amyloidosis Predominant cranial nerve   involvement with lattice corneal dystrophy
ALys	Genetically variant lysozyme	Autosomal dominant systemic   amyloidosis Non‑neuropathic   with prominent visceral involvement
AApoAI	Genetically variant   apolipoprotein AI	Autosomal dominant systemic   amyloidosis Predominantly non‑neuropathic with prominent visceral involvement
AApoAII	Genetically variant   apolipoprotein AII	Autosomal dominant systemic   amyloidosis Non‑neuropathic   with prominent renal involvement
AFib	Genetically variant   fibrinogen A α chain	Autosomal dominant systemic   amyloidosis Non‑neuropathic   with prominent renal involvement