Amyloidosis

Essentials

  • Amyloidosis is a heterogenic group of diseases which are caused by amyloid deposited in various body tissues and organs.
    • Amyloid is a protein-containing fibrillar material deposited in the extracellular space. Amyloid has an affinity for Congo red dye and appears green when viewed in polarised light.
  • The aetiology of amyloidosis may be hereditary or acquired, and the amyloid deposits may be either localised or systemic. These clinical forms are further classified according to the biochemical composition of the amyloid fibrils.
  • The clinical manifestations of amyloid accumulation are manifold and their recognition may be difficult.

AL (amyloid light chain) amyloidosis

  • AL amyloidosis is associated with plasma cell dyscrasia, and can be further classified as being either idiopathic (primary) or myeloma associated. In AL amyloidosis the amyloid fibrils are composed of the kappa or lambda (more common) light chains of monoclonal immunoglobulin molecules.
  • The annual incidence is approximately 1/100,000 inhabitants. The average age at diagnosis is approximately 60 years.
Signs and symptoms

  • Symptoms are diverse and difficult to detect, which is why diagnosis is often delayed.
  • General symptoms
    • Weakness, tiredness
    • Weight loss
  • Cutaneous manifestations
    • Periorbital purpura (picture (1)), petechiae, ecchymosis
    • Papules
  • Carpal tunnel syndrome, usually bilateral, in 20% of cases
  • Enlarged tongue in 10% of cases (picture (2))
  • Cardiac amyloidosis is common and usually manifests itself as restrictive cardiomyopathy. The patient will gradually develop congestive cardiac failure. Typical ECG changes include low voltage complexes and a chest lead QS complex pattern which mimics anterior myocardial infarction. Conduction disturbances and arrhythmias are common. The findings of echocardiography may be characteristic.
  • Renal amyloidosis is common and typical manifestations include proteinuria, nephrotic syndrome or renal failure.
  • Intestinal involvement is common but often has few symptoms. A motility disorder (diarrhoea) is more common than an absorption disorder.
  • Enlarged liver or spleen
  • Sensorimotor peripheral neuropathy may occur in 10% of cases. Orthostatic hypotension and diarrhoea are symptoms of autonomic neuropathy.
  • Pulmonary amyloidosis may manifest itself as cough or dyspnoea.
  • Amyloidosis involving the joints is rare. Its signs and symptoms include chronic, symmetrical, non-erosive, seronegative arthropathy which involves shoulders (shoulder pad sign), wrists, knees and fingers. Joint swelling and stiffness are the dominating symptoms.

Laboratory findings

  • Almost all patients test positive for the M-component in the serum or urine.
  • ESR may be elevated.
  • Proteinuria is possible and plasma creatinine concentration may be increased.

Reactive AA (amyloid A) amyloidosis (secondary)

  • Amyloidosis associated with chronic infection or inflammatory disease. In Finland, the most common causative illness is rheumatic arthritis.
  • The amyloid fibrils are composed of the AA protein which is derived from a precursor protein, the serum amyloid A (SAA) protein, which is an acute phase protein.
  • The most common clinical manifestation is proteinuria or nephrotic syndrome. The disease may also manifest itself as renal failure.
  • Amyloid is also deposited into other organs but often causes no symptoms (intestines, heart, liver, spleen, thyroid gland, adrenal glands).

A-beta-2-M amyloidosis, i.e. dialysis-related amyloidosis

  • Patients who have undergone dialysis for a long time (7–10 years) may develop amyloidosis as a result of serum beta2-microglobulin being deposited in the tissues.
  • A-beta-2-M-amyloidosis causes musculoskeletal symptoms: carpal tunnel syndrome, pain of the large joints, bony cysts and fractures.
  • A-beta-2-M-amyloidosis is nowadays very rare.

Senile amyloidosis

  • ATTR amyloidosis is seen in the elderly. It may cause heart failure.

Hereditary amyloidoses

  • The AGel amyloidosis seen in Finland (Meretoja's syndrome) causes corneal degeneration and facial nerve palsy.
  • ATTR amyloidosis manifests itself as peripheral and autonomic neuropathy, enteropathy and cardiomyopathy.

Diagnosis

  • A suspicion of AL amyloidosis is based on the clinical picture (nephrotic syndrome, cardiomyopathy, enlarged liver or peripheral neuropathy) and presence of the M-component in the serum or urine.
  • The most common reason to suspect AA amyloidosis is proteinuria in a patient with rheumatoid arthritis. Persistently or repeatedly high serum CRP is a risk factor for the development of amyloidosis.
  • In order to diagnose amyloidosis, either a fine-needle aspiration biopsy of subcutaneous abdominal tissue or a tissue biopsy of the affected organ (kidney, rectum, liver, heart) is obtained.
    • A 10 or 20 ml syringe and a 0.9 × 38 mm needle are recommended for the fine-needle aspiration. Use of a syringe holder makes the aspiration a lot easier. The aspirate is syringed on a clean glass slide and spread with another clean slide. The sample is representative if it contains fat tissue fragments that are visible to the naked eye, and not only a thin fat film.
    • If staining with Congo red dye confirms the diagnosis of amyloidosis immunohistochemical typing should be attempted.
  • In AL amyloidosis further investigations are warranted to exclude or establish myeloma.

Treatment

  • The treatment of amyloidoses is carried out by specialist units.
  • The treatment of AL amyloidosis targets the causative plasma cell clone; usually intermittent treatment with a combination of either melphalan and dexamethasone and different cytotoxic agents, or, in carefully selected patients, cytotoxic chemotherapy supported by stem-cell transplantation.
  • The cornerstone in the treatment of AA amyloidosis that has already evolved is the good management of the underlying inflammatory disease.

Prognosis

  • The average life expectancy after diagnosis is 2 years in AL amyloidosis and 4–8 years in AA amyloidosis. In AL amyloidosis, the extent of cardiac damage is the most crucial prognostic factor.
  • The prevalence of AA amyloidosis has decreased due to the improved treatment of inflammatory rheumatic diseases.

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