Amyloidosis

Incidence

A rare disease with an incidence 1- 5 cases per 100,000 people per year i.e. as common as chronic myeloid leukaemia or Guillain-Barré syndrome.¹

Risk factors

Family history of unexplained neuromuscular disease.

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

• Cases formerly called primary amyloidosis and in myeloma-associated amyloidosis, the fibril protein is an immunoglobulin light chain or light chain fragment (abbreviated L); thus, patients with these amyloidoses are now said to have light chain amyloidosis (AL).
• Cases previously termed senile cardiac amyloidosis the fibrils consist of the transport protein transthyretin (TTR); these diseases are now termed ATTR.

The cause of amyloid production and its deposition in tissues is unknown. Potential aetiological factors vary according to the subtype of amyloid.²

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.²

Systemic AL amyloid

• Formerly known as primary amyloidosis.
• In AL the fibril is monoclonal immunoglobulin light chain produced by plasma cell dyscrasia:
  • There is no associated disease.
  • The heart, lung, skin, tongue, thyroid gland, and intestinal tract may be involved.
  • Localised amyloid "tumours" may be found in the respiratory tract or other sites. Parenchymal organs (liver, spleen, kidney) and the vascular system, especially the heart, are involved frequently.
• Amyloid A protein is produced from an acute phase reactant in response to chronic diseases, either infectious e.g. tuberculosis, or inflammatory e.g. rheumatoid arthritis.
• The fibril associated with familial and senile cardiac amyloidosis is produced from an inherited variant protein - transthyretin.

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 are 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, postural hypotension.

Signs

• Unexplained renal disease may be observed, especially with nephrotic syndrome or restrictive cardiomyopathy (especially if both together):³
  • 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.⁴
• Vitreous opacities or involvement of other major organs suggest hereditary amyloidosis.
• Subtle signs of autonomic disturbance:
  • Postural hypotension or early satiety
• GI amyloid may cause:
  • Oesophageal motility abnormalities, gastric atony, motility abnormalities of the small and large intestine and pseudo-obstruction
  • Malabsorption
  • Bleeding
  • Macroglossia 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 may result from amyloidosis of the thyroid gland.

• 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

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 & E's - raised creatinine
• Liver function tests - raised alkaline phosphatase
• Clotting – there is abnormal clotting in 50% of cases - raised international normalised ratio, factor X deficiency⁵
• Inflammatory markers – raised 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
• Radionuclide – amyloid P labelled with 123-iodine (amyloid P scan)
• Biopsy of affected organ, or simple subcutaneous aspiration of abdominal fat - stains red with Congo red stain giving red-green birefringence under polarised light. Diagnosis established in 80% of cases³
• Immunofixation electrophoresis to establish form of amyloidosis.

General principles

Treat symptoms – e.g. diuretics for renal failure, alpha-blocker for postural hypertension, erythropoietin for anaemia.

AL amyloidosis

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.The objective is to eradicate the supply of monoclonal Ig light chains. This leads to stabilisation and regression of the amyloid:

• Chemotherapy is based on the treatment of multiple myeloma and is tailored to the patient.⁶
• Where suitable, patients should receive vincristine, adriamycin and dexamethasone as first-line therapy.

ATTR

It has been shown that in amyloidosis due to transthyretin mutations, liver transplantation, which removes the site of 90% synthesis of the mutant protein, is effective.⁷ However, progression of the disease has been observed.⁸

AA amyloidosis

Treatment of underlying inflammatory condition is paramount.

Dialysis related amyloidosis

• 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

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.³
• 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.