Primary Amyloid

Synonyms: AL, light chain amyloidosis, primary amyloidosis, primary systemic amyloidosis, myeloma associated amyloidosis, immunoglobulin-related amyloidosis.

• Amyloidosis is a condition caused by extracellular deposition of abnormal protein fibrils that damage the tissue in which they are deposited.
• Primary amyloid is now better known as systemic AL amyloidosis.¹
• There are more than 20 different proteins which accumulate in a misfolded state, insoluble state and share certain characteristics. A fairly distinct clinical picture is associated with each type of fibril. These fibrils share certain properties such as their uptake of hematoxylin and eosin and appearence under the microscope.
• The term primary amyloid has been used to describe amyloidosis with no associated clinical condition (sometimes termed 'idiopathic amyloidosis'). Such descriptive classifications have fallen out of favour as they do not identify aetiological factors. However the term is still used and it is useful to consider the classification of amyloid to put it in context.
• It is important to correctly identify the type of amyloidosis as treatments differ. AL may particularly benefit from chemotherapy unlike other varieties of amyloidosis.

• During the 1970s it was assumed that amyloid was a single substance. Classifications were developed which took into account the organs affected and the clinical findings. Primary amyloid was the term used to describe amyloid which was not secondary to associated chronic inflammatory conditions.
• However it became apparent in the 1960s that amyloid is not a single substance but comprises more than 20 distinct fibrillar proteins. Amyloid is now classified according to what the particular protein is. The different types are now abbreviated to the letter A (for amyloid) followed by an abbreviation for the particular protein (for example 'L' for 'light chain fragment').
• In most cases of what used to be called primary amyloidosis and myeloma- associated amyloidosis the particular protein is an immunoglobulin light chain or light chain fragment (abbreviation 'L').

Before the discovery that the protein fibril was made up of immunoglobulin fragments (light chain type) patients with AL were described as having primary amyloid or myeloma- associated amyloidosis (when the burden of monoclonal plasma cells was large). Now it is known that the fibrils come from immunoglobulin fragments it is easy to understand the continuum which exists between AL produced in multiple myeloma (high burden of monoclonal plasma cells) and monoclonal gammopathy of undetermined significance (MGUS with a lower burden of monoclonal plasma cells). Most patients with AL amyloidosis have a subtle non-proliferating type of plasma cell dyscrasia (MGUS).¹ 20% of patients with MGUS will progress to multiple myeloma within 10 years. The following points are worthy of note:

• The AL fibrils usually come from the lamda light chains.
• All deposits in most patients are a mixture of intact L chains and L chain fragments.
• AL deposits can develop in any organ system. The most common are:
  • Kidneys
  • Heart
  • Gastrointestinal tract
  • Liver
  • Peripheral nerves
• There is a poor correlation between the degree of organ impairment and the extent of amyloid deposition.¹
• Factors affecting the deposition of and particular organ distribution in particular patients are poorly understood.
• In a very small number of AL patients amyloid may be deposited in localised sites (or even amyloid masses) without any systemic involvement.

• The incidence is1-5 cases per 100,000 per year or between 5.1 and 12.8 per million people per year.¹
• AL amyloidosis occurs in about a third of patients with multiple myeloma.
• AL amyloidosis has been found to be more common in men in some studies³ but usually equally in both sexes.¹
• AL amyloidosis presents usually at about age 65, with most between 50 and 70 years old at diagnosis. Only 10% of patients are below 50 years at presentation.¹

The clinical presentation varies widely according to which organs are affected by amyloid deposition.The organ affected determins the particular clinical consequences and complaints, rather than the type of amyloid. Hence AL affecting the kidney may present like any other form of amyloidosis affecting the kidney. The most common clinical features at diagnosis are:

• Nephrotic syndrome
• Congestive cardiomyopathy
• Peripheral neuropathy (sensory or autonomic)
• Hepatomegaly

History

A wide variety of complaints may be forthcoming. Fatigue and weight loss are very common.¹Typical examples include:

• Kidney:
  • Peripheral oedema
  • Nephrotic syndrome
  • Renal failure
• Heart (20% of patients have mainly cardiac symptoms at presentation):
  • Postural hypotension
  • Generalised weakness
  • Palpitations
  • Shortness of breath
  • Peripheral oedema
  • Angina
• Peripheral nerves:
  • Disorders of sensation
  • Weakness
  • Symptoms worse in legs
• Gastrointestinal tract:
  • Commonly involved but often no symptoms
  • Change in bowel habit
  • Symptoms akin to irritable bowel syndrome
• Carpal tunnel syndrome:
  • Typical symptoms in up to a fifth of patients with AL

Examination³

The findings may be widespread or very localised. Unusual combinations of findings should alert suspicion.

• General features. The most common are:
  • Peripheral oedema
  • Purpura (amyloid deposition subendothelium causing fragile capillaries)
  • Enlarged liver
  • Postural hypotension
  • Peripheral neuropathy
  • Macroglossia
  • Carpal tunnel syndrome
• Cardiac findings:
  • Nothing unique to cardiac amyloidosis
  • Usually diastolic dysfunction (for example atrial fibrillation)
  • Congestive cardiac failure
  • Arrhythmias
• Bleeding disorders:
  • From capillary fragility
  • Deficiency factor X (gets bound to amyloid)
• Neuropathy:
  • 20% of AL patients get peripheral neuropathy
  • Autonomic neuropathy may occur
• Postural hypotension:
  • May be severe
  • Can be caused by cardiac involvement or autonomic neuropathy
  • May result from treatments such as diuretics
• Macroglossia:
  • Seen more often in late presentation
  • May cause difficulty with swallowing or breathing
• Musculoskeletal findings:
  • Can resemble seronegative arthritis
  • AL deposits found in joints
• Localised respiratory tract AL:
  • Localised AL occurs most commonly in the respiratory tract
  • Skin nodules do occur
  • Mediastinal and retroperitoneal amyloidomas can occur
  • Bladder involvment may present as haematuria

The diagnosis may initially be difficult and AL can be mistaken for organ specific diseases. Once the broad pathological process is identified it is necessary to differentiate from:

• Other paraprotein associated diseases and immunoglobulin deposition diseases
• Other forms of amyloidosis
• Multiple myeloma
• Monoclonal gammopathies of uncertain origin
• Anderson-Fabry Disease

Blood and urine testing

• Full blood count. Usually normal but there may be thrombocytosis reflecting asplenism.
• Serum protein electrophoresis. Monoclonal immumoglobulin L chain is the cardinal finding in up to 90% of patients. With a sensitive enough assay it should be detectable in all patients.
• Urine protein electrophoresis
• Prothrombin time and activated partial thromboplastin time
• Urinary protein and 24-hour urinary protein levels. Proteinuria is invariably present when AL involves the kidneys. Serial 24 hour protein levels can be monitored to assess response to chemotherapy.
• Liver function tests (LFTs). Even with extensive liver involvement the LFTs are usually normal.
• Renal function studies. Mild elevation of creatinine is a common finding.
• Bone marrow examination. About 40% of patients will have at least 10% plasma cells in their bone marrow.

Imaging

• Cardiac imaging:
  • Echocardiography is the most useful noninvasive test for cardiac amyloidosis (increased thickness ventricle walls).
  • CT scans are not usually as useful as echocardiograms.
• Bone imaging:
  • Skeletal surveys are required as for multiple myeloma.
  • Plain x-rays may be used for localised areas of bone pain.
• Chest X-ray. This may reveal a reticular nodular pattern of involvement or an interstitial pattern.

Other investigations

• ECG. The classic finding is low voltage QRS complex. Different arrhythmias may result from deposition in conducting pathways.
• Biopsy and staining of tissue affected by amyloid deposition can determin the specific type of amyloidosis. Immunostaining can be done using commercially available kits. It is essential to confirm the diagnosis using direct testing as incorrect diagnosis of the amyloidosis could lead to inappropriate and harmful treatment.

The varied and widespread nature of the amyloid deposition can produce many different manifestations of disease in different organs. These have been outlined above.

Management should be undertaken by a consultant haematologist who is part of an approved Cancer Network in accordance with UK NHS strategy.¹ The aim of treatment is to reduce the production of the precursor monoclonal immunoglobulin. Supportive treatments are also important. Information is available from the National Amyloidosis Centre and the patients and their families will need information and support. Treatments include:

• Chemotherapy. Treatments are similar to those used for multiple myeloma. Combination treatments are used and may be low, intermediate or high dose.¹ Examples include:
  • Melphalan and prednisolone- the only combination shown to improve survival.
  • Melphalan or cylophosphamide (with or without prednisolone).¹
  • Vincristine, carmustine, melphalan, cyclophosphamide and prednisolone. This combination is still being evaluated, but appears no more effective than the above and is not now recommended.^1,3
  • High dose chemotherapy (HDT) with intravenous melphalan followed by autologous bone marrow rescue. This may be tried in selected patients (under 70, no heart failure, no autonomic neuropathy, no more than 2 organ systems involved). Unfortunately the plasma cell clone can almost never be completely eradicated thus limiting the scope of this approach.
  • Thalidomide with or without dexamethasone and other agents is also used.¹ The mode of action is unclear. The response rate is over 30% alone and 60% if combined with dexamethasone.
  • Therapies to 'dissolve' the amyloid fibrils have been tried.
• Radiation therapy. This may be used to treat localised disease.
• Surgery may also be used:
  • To treat localised disease
  • Carpal tunnel release
  • Organ transplantation (particularly renal transplantation)
• Supportive treatments. These can be applied depending on organ involvement. For example:
  • Cardiac:
    • Diuretics
    • Digoxin
    • Calcium channel blockers
    • Pacemakers
  • Renal:
    • Peritoneal dialysis
    • Haemodialysis

The complications are a function of organ involvement. Cardiac complications have the highest mortality and cause death in more than half of patients.³

Generally the disease is progressive and fatal in 80% of patients within 2 years if untreated.¹

• Prognosis is poor if untreated but few studies have looked at prognostic variables.¹
• Patients with cardiac involvement have the worst prognosis.³
• Patients with disease limited to peripheral nerves have the longest survival.
• Normal renal function is a good prognostic factor.