• Amyloidosis is a heterogenic group of diseases which are caused by amyloid deposited in various body tissues and organs.
• The aetiology of amyloidosis may be hereditary or acquired, and the amyloid deposits may be either localised or systemic.
• The clinical manifestations of amyloid accumulation are manifold and their recognition may be difficult.
• The progression of some types of amyloidosis can be delayed by medication but, for the time being, the treatment of several types of amyloidosis is symptomatic.

• 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 different types of amyloidosis are classified, to the extent possible, based on the biochemical composition of the amyloid fibrils.
• There are nearly 40 amyloid-forming proteins known. The most common proteins causing systemic amyloidosis are immunoglobulin light chains, transthyretin, and serum amyloid A.

• AL amyloidosis is caused by a clonal plasma cell dyscrasia. At the time of diagnosis, about 10% of patients can be diagnosed as having myeloma and a significantly smaller share as having lymphoma or chronic lymphocytic leukaemia.
• 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.

Symptoms and findings

• 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 (AL amyloidosis in the eyelids)), petechiae, ecchymosis
  • Papules
• Carpal tunnel syndrome, usually bilateral, in 20% of cases
• Enlarged tongue in 10% of cases (picture (Macroglossia in a patient with AL amyloidosis))
• Cardiac amyloidosis is common and usually manifests itself as restrictive cardiomyopathy, most typically causing symptoms of right heart failure. Once congestive cardiac failure manifests, it will often progress quickly.
  • Typical ECG changes include low QRS complexes and a chest lead Q wave pattern which mimics anterior myocardial infarction (Picture (ECG of a patient with AL amyloidosis)). Conduction disturbances and arrhythmias are common.
  • Troponin (TnT, TnI) and proBNP concentrations are usually increased.
  • The findings of echocardiography are usually characteristic, thick walls with clear echo.
• 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 occurs 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 with AL amyloidosis 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.
• In cardiac manifestations, troponin (TnT, TnI) and proBNP concentrations are increased.

• Transthyretin amyloidosis is a systemic disease where misfolded transthyretin (TTR) mostly produced in the liver is deposited in the body.
• The disease occurs most commonly in the heart or the peripheral nervous system.
• Transthyretin may be structurally abnormal due to a gene defect (ATTRm, mutant) or in association with ageing (ATTRwt, wild type, previously called senile amyloidosis).
• The mean age of patients with ATTRwt exceeds 70 years, with most of them men, whereas ATTRm occurs in both sexes nearly equally often, and the patients are younger, on average.
• ATTRm is dominantly inherited but there is great interindividual variation in its manifestation, and de novo mutations also occur.
• In cardiac ATTR amyloidosis, transthyretin is deposited in the myocardium, leading to thickening and stiffening of the muscle.
• See also https://www.orpha.net/en/disease/detail/85447/.

Symptoms and findings

• In ATTRwt, gradually worsening dyspnoea on exertion is a common initial symptom. ATTRwt is an underdiagnosed cause of heart failure in the elderly. Atrial fibrillation and atrioventricular blocks are also typical.
• As the disease progresses, dyspnoea gets worse and oedema in lower limbs, ascites and ventricular arrhythmias develop.
• Of extracardiac findings, carpal tunnel syndrome is the most common. It may occur as long as 10 years before cardiac manifestations. In addition, there may be spinal stenosis and intestinal symptoms.
• In ATTRm, the initial symptom is most typically autonomic and peripheral neuropathy. In addition, there may be intestinal symptoms and vitreous opacity.

• AA amyloidosis is due to a prolonged inflammatory reaction that may be associated with
  • a chronic infection, such as tuberculosis, osteomyelitis or bronchiectasis
  • a chronic inflammatory disease, such as rheumatoid arthritis or inflammatory bowel disease
  • certain hereditary diseases, such as familial Mediterranean fever.
• The amyloid fibrils are composed of the AA protein which is a part of 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 as renal failure.
• Amyloid is also deposited in other organs but often causes no symptoms (intestines, heart, liver, spleen, thyroid gland, adrenal glands).
• Due to decreasing chronic infections and better control of inflammatory diseases, the incidence of AA amyloidosis has decreased in western countries.
• See also https://www.orpha.net/en/disease/detail/85445/.

• AGel amyloidosis, or Meretoja disease 3 https://www.orpha.net/en/disease/detail/85448/, is a dominantly inherited form of amyloidosis belonging to the Finnish disease heritage.
• The amyloidogenic protein is mutated gelsolin.
• The typical symptom triad consists of corneal degeneration, facial nerve palsy and loose skin (cutis laxa).
• Cardiac and renal symptoms are rare.

• Patients who have undergone dialysis for a long time 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, painful large joints, bony cysts and fractures.
• A-beta-2-M-amyloidosis is nowadays nearly extinct.

• 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.
• Suspicion of cardiac ATTR amyloidosis arises based on symptoms, abnormal ECG (low QRS amplitudes, pathological Q waves) and increased troponin and proBNP concentrations.
• The most common reason to suspect AA amyloidosis is proteinuria in a patient with chronic infection or inflammatory disease. Persistently or repeatedly high serum CRP is a risk factor for the development of amyloidosis.
• In order to diagnose amyloidosis, a biopsy should be taken of the affected organ (kidney, rectum, liver, heart). If AL or AA amyloidosis is suspected, a fine-needle aspiration biopsy of subcutaneous abdominal tissue is usually sufficient to confirm the diagnosis.
  • If staining with Congo red dye confirms that there is amyloid, immunohistochemical typing of a tissue biopsy should be performed.
• In AL amyloidosis further investigations are warranted to exclude or establish myeloma.
• Echocardiography and MRI will provide further information on the severity of cardiac manifestations.
• ATTRwt cardiomyopathy can be confirmed either non-invasively by gammography or invasively by myocardial biopsy.
• ATTRm can be diagnosed based on a gene test provided that the patient has first been found to have a clinical manifestation of the disease.

• The treatment of amyloidosis should be carried out by specialist units (haematology, cardiology, neurology).
• The treatment of AL amyloidosis targets the causative plasma cell clone; usually with combinations of bortezomib, cyclophosphamide, melphalan, dexamethasone and the CD38 antibody daratumumab, or, in carefully selected patients, cytostatic chemotherapy supported by stem-cell transplantation.
• Cardiac manifestations are treated with diuretics, anticoagulants and antiarrhythmic agents and, as necessary, by implanting a pacemaker.
• For ATTR amyloidosis, there is a drug delaying the course of the disease (tafamidis) that can be used for certain patients with exact prerequisites.
• The cornerstone in the treatment of AA amyloidosis that has already evolved is the good management of the underlying inflammatory disease.
• The treatment of AGel amyloidosis is symptomatic.

• The average life expectancy after diagnosis is 2 years in AL amyloidosis and 4–6 years in ATTRwt amyloidosis and 4–8 years in AA amyloidosis but the prognosis of amyloidosis shows great interindividual variation.
• In AL and ATTR amyloidosis, the extent of cardiac damage is the most crucial prognostic factor.