Amyloidosis

Amyloidosis is a clinical disorder caused by extracellular and/or intracellular deposition of insoluble abnormal amyloid fibrils that alter the normal function of tissues.

Proteins that form amyloid fibrils differ in size, function, amino acid sequence and native structure but become insoluble aggregates that are similar in structure and in properties.

Pathogenesis

In humans there are approximately 23 different unrelated proteins that are known to form amyloid fibrils in vivo. All types of amyloid consist of a major fibrillar protein that defines the type of amyloid (approximately 90%) plus various minor components.

Classification

Amyloid is classified chemically. The amyloidoses are referred to with a capital A (for amyloid) followed by an abbreviation for the fibril protein:

AA amyloidosis¹

• AA is a normal-sequence serum amyloid A protein which is an acute-phase reactant produced mainly in the liver in response to multiple cytokines. Only a minority of patients with elevated serum amyloid A levels develop amyloidosis².

• Systemic AA amyloidosis is a long-term complication of several chronic inflammatory disorders - eg, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, malignancies and conditions predisposing to recurrent infections.

• The incidence of AA in rheumatoid arthritis and other chronic arthritides has decreased as a result of the use of more effective anti-inflammatory and immunosuppressive therapies.

• Organ damage results from the extracellular deposition of proteolytic fragments of the acute-phase reactant serum amyloid A (SAA) as amyloid fibrils.

• Only a minority of patients with long-standing inflammation actually present with AA amyloidosis.

• The kidneys, liver and spleen are the main target organs of AA amyloid deposits. In more than 90% of patients, proteinuria, nephrotic syndrome and/or renal dysfunction dominate the clinical picture at the onset.

• If not effectively treated, end-stage kidney disease develops and renal replacement therapy is required. The prognosis, even with treatment, is poor.

AL amyloidosis³

• Organs involved include the heart, kidney, peripheral nerve, gastrointestinal tract, respiratory tract and nearly any other organ. AL was formerly known as primary amyloidosis.

• AL amyloidosis results from extra-cellular deposition of fibril-forming monoclonal immunoglobulin light chains (most commonly of lambda isotype). Most patients have evidence of isolated monoclonal gammopathy or asymptomatic myeloma, and the occurrence of AL amyloidosis in patients with symptomatic multiple myeloma or other B-cell lymphoproliferative disorders is unusual.

• AL amyloidosis is the most common type of systemic amyloidosis in developed countries with an estimated incidence of nine cases/million/year. The average age of diagnosed patients is 65 years and fewer than 10% of patients are under 50.

• The clinical presentation is very varied because of the wide number of tissues or organs that may be affected. The most common presenting symptoms are weakness and dyspnoea.

• Renal manifestations are the most frequent, affecting two thirds of patients at presentation, with heavy proteinuria, nephrotic syndrome and impaired renal function in half of the patients.

• Heart involvement is present at diagnosis in more than 50% of patients and leads to restrictive cardiomyopathy.

• The diagnosis relies on histological examination of an involved site showing Congo red-positive amyloid deposits, with typical apple-green birefringence under polarised light, that stain positive with an anti-LC antibody by immunohistochemistry and/or immunofluorescence.

• Due to the systemic nature of the disease, non-invasive biopsies, such as abdominal fat aspiration, should be considered before taking biopsies from involved organs, in order to reduce the risk of bleeding complications.

• Treatment of AL amyloidosis is based on chemotherapy. Standard treatment options include high-dose melphalan followed by autologous haematopoietic stem cell transplantation or oral melphalan with dexamethasone⁴.

• The use of an alkylating agent with high-dose dexamethasone has proven to be effective in two thirds of patients. New agents used in the treatment of multiple myeloma are under investigation. Symptomatic measures and treatment for organ failure are also required.

• Amyloid heart disease should be treated with diuretics. Amiodarone and pacemaker implantation should be considered in patients with rhythm or conduction abnormalities. Heart and kidney transplantation may be considered.

• Survival in AL amyloidosis depends on the nature and severity of organ involvement, and the response to treatment. The presence and severity of amyloid heart disease is the main adverse prognostic factor.
  

Transthyretin amyloidosis (ATTR)⁵

• ATTR is the most frequent inherited systemic form of amyloidosis. ATTR is an autosomal-dominant disease but is associated with at least 100 different transthyretin (TTR) mutations.

• Each variant has a different organ involvement. Peripheral neuropathy and cardiomyopathy may occur as well as kidney impairment and proteinuria.

• Nephropathy affects patients with late-onset neuropathy, low penetrance in the family, and cardiac dysrhythmias.

• Microalbuminuria can be the disorder's first presentation, even before the onset of neuropathy.

• Amyloid renal deposits commonly occur, even in the absence of urinary abnormalities.

• The need for haemodialysis is associated with poor survival.

• The primary treatment for neuropathy is liver transplantation⁶.

• Heart or kidney transplantation may also be considered.

Other forms of amyloidosis

• Heavy-chain amyloidosis has only been reported in a few patients.

• Beta₂-microglobulin amyloidosis precursor protein is the light chain component of the major histocompatibility complex. It is associated with chronic kidney diasease.

• Cryopyrin-associated periodic syndrome-associated amyloidosis (CAPS) includes familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Patients with CAPS have chronically elevated levels of acute-phase reactants, especially high-sensitivity C-reactive protein due to increased interleukin levels.

• Hereditary renal amyloidoses are a group of conditions that are each related to mutations in a specific protein. They should be considered when a renal biopsy demonstrates amyloid deposition and when the family history suggests an autosomal-dominant disease.

• Central nervous system amyloid includes beta protein amyloid (found in Alzheimer's dementia) and prion protein amyloidosis (found in Creutzfeldt-Jakob disease).

Epidemiology

Amyloidosis is a rare disease. However, systemic amyloidosis continues to be fatal and is responsible for about 1 in 1,500 deaths per year in the UK⁷.

Systemic light chain (AL) amyloidosis is the most common of systemic amyloidosis, but wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly being diagnosed⁸.

Aetiology

The cause of amyloid production and its deposition in tissues is unknown. Potential aetiological factors vary according to the subtype of amyloid - see 'Classification', above.

Risk factors

Family history of unexplained neuromuscular disease.

Presentation

Symptoms

These are largely determined by the organ or system affected and the picture is often confused by the underlying disease, which may be fatal before amyloidosis is suspected.

Typically, in amyloidosis there is a combination of symptoms affecting more than a single system - eg, fatigue, weight loss, easy bruising, breathlessness, peripheral oedema, sensory change, carpal tunnel syndrome, and postural hypotension.

Signs

• Unexplained renal disease may be observed, especially with nephrotic syndrome or restrictive cardiomyopathy (especially if both together):
  

  • Massive proteinuria with normal or only slightly enlarged kidneys.

  • Cardiac amyloidosis causes an infiltrative restrictive cardiomyopathy leading to progressive heart failure⁹.

• Marked hepatomegaly with kidney disease:
  

  • Hepatic amyloid disease produces hepatomegaly, but rarely jaundice.

  • Massive hepatomegaly has been reported.

  • LFT results usually are normal, but elevated alkaline phosphatase may be observed.

  • Occasionally, portal hypertension may occur with oesophageal varices and ascites.

• Cardiac amyloid deposition, causing an infiltrative/restrictive cardiomyopathy, is a frequent feature of amyloidosis¹⁰.

• Sensory glove- and stocking-type polyneuropathy:
  

  • Especially carpal tunnel syndrome, which may significantly predate the diagnosis.

  • 20% of cases have a peripheral neuropathy.

• Vitreous opacities or involvement of other major organs suggest hereditary amyloidosis.

• Subtle signs of autonomic disturbance:
  

  • Postural hypotension or early satiety.

• Pulmonary amyloidosis¹¹.

• Gastrointestinal amyloid may cause:
  

  • Oesophageal motility abnormalities, gastric atony, motility abnormalities of the small and large intestine and pseudo-obstruction.

  • Malabsorption.

  • Bleeding.

  • Macroglossia, which is common in primary and myeloma-related amyloidoses.

• Skin lesions:
  

  • Spontaneous periorbital purpura - racoon eye sign.

• A firm, symmetrical, non-tender goitre resembling Hashimoto's thyroiditis may result from amyloidosis of the thyroid gland.

Differential diagnosis

• Chronic kidney disease (with normal-sized kidneys).

• Diabetes mellitus.

• Sarcoidosis.

• Lymphoma.

• Multiple myeloma.

• Fragile capillaries - scurvy or Ehlers-Danlos syndrome.

• Macroglossia.

• Down's syndrome.

• Neoplasia - lymphangioma, hypothyroidism, acromegaly.

Investigations

Amyloidosis is suspected on the basis of symptoms and signs described above, but can be diagnosed only by biopsy¹².

• Urinalysis - proteinuria/light chain on electrophoresis.

• FBC - anaemia - often mild, thrombocytopenia.

• Blood film - Howell-Jolly bodies (from splenic dysfunction).

• U&Es - raised creatinine.

• LFTs - raised alkaline phosphatase.

• Clotting - there is abnormal clotting in 50% of cases - raised INR, factor X deficiency.

• Inflammatory markers - raised ESR, normal CRP.

• Bone marrow - colonial dominance of plasma cells (gamma greater than kappa).

• ECG - characteristic low-voltage pattern with poor R-wave progression across the limb leads.

• Echocardiography - ventricular thickening with reduced ventricle size.

• Serum amyloid P (SAP) scintigraphy - this shows the distribution and amount of amyloid within the body's organs without the need for biopsies

• Biopsy of an affected organ, or simple subcutaneous aspiration of abdominal fat - stains red with Congo red stain giving red-green birefringence under polarised light. Diagnosis is established in 80% of cases.

• Immunofixation electrophoresis to establish the form of amyloidosis.

Management

No treatment is yet available that specifically targets the amyloid deposits, and therapy is therefore aimed at suppressing the underlying plasma cell dyscrasia along with supportive measures to support and possibly preserve organ function.

Supportive

Treat symptoms - eg, diuretics for kidney failure, erythropoietin for anaemia. Congestive heart failure may respond to diuretics, but larger doses are often required as the disease progresses. The use of calcium-channel blockers, beta-blockers, and digoxin are contra-indicated in cardiac amyloidosis, because they may cause toxicity at therapeutic levels.

Underlying condition

Treat any underlying causes - eg, inflammatory conditions, chronic infection or carcinoma.

Specific therapy¹³

Alkylator-based chemotherapy is effective to some degree in almost two thirds of patients. Trials with novel agents such as thalidomide, lenalidomide, pomalidomide and bortezomib have shown promising results.

As AL amyloidosis is very similar to multiple myeloma, the chemotherapy regimes used for myeloma have been also tried in AL. Different regimens of intermittent oral melphalan and prednisolone were compared with no therapy or therapy with colchicine alone. The response rate was low, with an increased survival from a median of approximately 7-9 months in patients who did not receive chemotherapy to approximately 12-18 months in those receiving chemotherapy.

Stem cell transplantation

Patients who are considered for this are usually less than 70 years old, have minimal heart failure, have serum creatinine ≤177 μmol/L and have fewer than three organs involved. However, the benefits of transplantation for amyloidosis have not been consistently proven¹⁴.

Surgical

• Liver transplantation is effective for some subtypes. However, progression of the disease has been observed¹⁵.

• Kidney transplantation has been performed in patients with renal amyloid:
  

  • Long-term survival is comparable to that in other renal diseases, but mortality is higher in the early years.

  • Amyloid will ultimately recur in a donor kidney, but several recipients have done very well and have lived up to 10 years¹⁶.

Prognosis

Ultimately some people with amyloidosis continue to deteriorate and develop terminal complications. Aggressive treatment may no longer be appropriate, and care should focus on relieving pain and suffering.

• Survival in AL amyloidosis has improved markedly as novel chemotherapy agents have become available. Early diagnosis is a key to better outcomes⁸.

• Median survival is 1-2 years.

• Amyloidosis associated with multiple myeloma has the poorest prognosis, and death within one year is common.

• All forms of renal amyloidosis have a poor prognosis, but patients may remain stable and even improve with supportive therapy.

• Dialysis and kidney transplantation have further improved the prognosis.

• Myocardial amyloidosis is the most common cause of death, primarily due to arrhythmias or intractable heart failure.