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.¹

Classification

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

• A amyloidosis (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. AA occurs in various chronic inflammatory disorders, e.g. rheumatoid arthritis, chronic local or systemic microbial infections, e.g. tuberculosis, and occasionally with neoplasms, e.g. renal cell carcinoma.
• Light chain amyloidosis (AL) is a monoclonal plasma cell disorder very similar to multiple myeloma producing a fibril of monoclonal immunoglobulin (Ig). Organs involved include the heart, kidney, peripheral nerve, gastrointestinal tract, respiratory tract and nearly any other organ. AL was formerly known as primary amyloidosis.
• Heavy chain amyloidosis has only been reported in a few patients
• Transthyretin amyloidosis (TTR) has a precursor transport protein synthesised in the liver and choroid plexus. Normal-sequence TTR forms amyloid deposits in the cardiac ventricles of elderly people.
• Beta₂-microglobulin amyloidosis precursor protein is the light chain component of the major histocompatibility complex. It is associated with dialysis and, rarely, renal failure in the absence of dialysis.
• 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

A rare disease with an incidence of 1-5 cases per 100,000 people per year.

Aetiology

The cause of amyloid production and its deposition in tissues is unknown. Potential aetiological factors vary according to the subtype of amyloid - see above.¹

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, e.g. 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):²
  • Massive proteinuria with normal or only slightly enlarged kidneys.
  • Hypertension is rare.
• Marked hepatomegaly with kidney disease:
  • Hepatic amyloid disease produces hepatomegaly, but rarely jaundice.
  • Massive hepatomegaly has been reported.
  • Liver function test results usually are normal, but elevated alkaline phosphatase may be observed.
  • Occasionally, portal hypertension may occur with oesophageal varices and ascites.
• Mainly right-sided, rapidly progressive heart failure can be seen:
  • This often occurs without chest pain.
  • There is a characteristic low-voltage pattern ECG.
  • In the elderly there may be an infiltrative cardiomyopathy.
• Sensory glove- and stocking-type polyneuropathy:
  • Especially carpal tunnel syndrome, which may significantly predate the diagnosis.
  • 20% of cases have a peripheral neuropathy.³
• Vitreous opacities or involvement of other major organs suggest hereditary amyloidosis.
• Subtle signs of autonomic disturbance:
  • Postural hypotension or early satiety.
• 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, nontender goitre resembling Hashimoto's thyroiditis may result from amyloidosis of the thyroid gland.

Differential diagnosis

• Renal failure (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 biopsy.

• Urinalysis - proteinuria/light chain on electrophoresis.
• Full blood count - anaemia - often mild, thrombocytopenia.
• Blood film - Howell-Jolly bodies (from splenic dysfunction).
• U&Es - raised creatinine.
• Liver function tests - raised alkaline phosphatase.
• Clotting - there is abnormal clotting in 50% of cases - raised international normalised ratio, factor X deficiency.⁴
• Inflammatory markers - raised erythrocyte sedimentation rate (ESR), normal C-reactive protein.
• Bone marrow - colonial dominance of plasma cells (gamma greater than kappa).
• ECG - characteristic low-voltage pattern with poor R way 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.²
• 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, e.g. diuretics for renal 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, betablockers, and digoxin are contra-indicated in cardiac amyloidosis, because they may cause toxicity at therapeutic levels.

Underlying condition

Treat any underlying causes, e.g. inflammatory conditions, chronic infection or carcinoma.

Specific therapy

As AL 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 prednisone were compared with no therapy or therapy with colchicine alone.⁵ 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 3 organs involved. However, the benefits of transplantation for amyloidosis have not been consistently proven.⁶

Surgical

• Liver transplantation is effective for some subtypes.⁷ However, progression of the disease has been observed.⁸
• 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.⁹
  • Amyloid will ultimately recur in a donor kidney, but several recipients have done very well and have lived up to 10 years.¹⁰

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.

• AL amyloidosis is fatal in 80% of cases.¹¹
• Median survival is 1-2 years.²
• Amyloidosis associated with multiple myeloma has the poorest prognosis, and death within 1 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.

Document references

1. Holmes RO et al; Amyloidosis, Overview, eMedicine, Jul 2009
2. Kyle RA, Gertz MA; Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995 Jan;32(1):45-59.
3. Rajkumar SV, Gertz MA, Kyle RA; Prognosis of patients with primary systemic amyloidosis who present with dominant neuropathy. Am J Med. 1998 Mar;104(3):232-7. [abstract]
4. Mumford AD, O'Donnell J, Gillmore JD, et al; Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis. Br J Haematol. 2000 Aug;110(2):454-60. [abstract]
5. Kyle RA, Gertz MA, Greipp PR, et al; A trial of three regimens for primary amyloidosis: colchicine alone, melphalan N Engl J Med. 1997 Apr 24;336(17):1202-7. [abstract]
6. Mhaskar R, Kumar A, Behera M, et al; Role of high-dose chemotherapy and autologous hematopoietic cell transplantation Biol Blood Marrow Transplant. 2009 Aug;15(8):893-902. Epub 2009 Apr 2. [abstract]
7. Adams D, Samuel D, Goulon-Goeau C, et al; The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. Brain. 2000 Jul;123 ( Pt 7):1495-504. [abstract]
8. Liepnieks JJ, Benson MD; Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid. 2007 Dec;14(4):277-82. [abstract]
9. Kilicturgay S, Haberal M; Transplantation for renal amyloidosis. Ren Fail. 1993;15(5):629-33. [abstract]
10. Ozdemir BH, Ozdemir FN, Sezer S, et al; Among therapy modalities of end-stage renal disease, renal transplantation improves survival in patients with amyloidosis. Transplant Proc. 2006 Mar;38(2):432-4. [abstract]
11. Kyle RA, Gertz MA, Greipp PR, et al; Long-term survival (10 years or more) in 30 patients with primary amyloidosis. Blood. 1999 Feb 1;93(3):1062-6. [abstract]

Internet and further reading

• Centre for amyloidosis and acute phase proteins, University College London
• Nyirady J et al; Amyloidosis, primary systemic, eMedicine, Apr 2009
• DermNet NZ. Amyloidosis.

Acknowledgements