LYMPHOPROLIFERATIVE DISORDERS

AL amyloidosisMajid Kazmi

AbstractAmyloidosis is a rare group of disorders with protean manifestations char-

acterized by the deposition in tissue of misfolded protein. The body’s ca-

pacity to remove such deposits is poor, resulting in progressive

accumulation of amyloid deposits and disruption of organ function.

Among patients with systemic amyloidosis, AL type is more common

than AA type (secondary amyloidosis), which is caused by a chronic infec-

tion or chronic inflammatory disease.

The familial types of amyloidoses are rare, with an estimated incidence

of less than 1 per 100,000. They are autosomal dominant inherited dis-

eases with manifestations of amyloid deposition not developing until

mid-life. The most common form is caused by mutations in the transthyr-

etin (TTR) protein.

This chapter will focus on AL amyloidosis, formerly known as primary

amyloidosis, which most frequently affects the kidneys, heart, liver and

peripheral nervous system. Fatigue and weight loss are common but

the diagnosis is rarely made until symptoms referable to a particular

organ appear. Untreated, it is progressive and fatal within two years in

about 80% of patients. There is a three-step approach to diagnosis and

investigation of AL amyloid, which involves establishing the diagnosis;

assessing the extent of organ involvement; and excluding a plasma cell

dyscrasia or lymphoma. Treatment is directed towards reducing the pro-

duction of amyloidogenic light chains and stabilizing organ function.

New drugs such as bortezomib show real promise in rapidly reducing

light chain burden whilst being well tolerated. Future developments will

focus on reducing the amyloid load by interfering with the misfolding

of the proteins or interaction with serum amyloid P protein.

Keywords AL amyloid; amyloidosis; chemotherapy; SAP scan; stem cell

transplantation

Introduction

Amyloidosis is a rare group of disorders with protean manifes-

tations characterized by the deposition in tissue of misfolded

protein. The body’s capacity to remove such deposits is poor

resulting in a progressive accumulation of amyloid deposits and

disruption of organ function.

Awareness of amyloidosis has increased in recent years but

most diagnoses are still made at an advanced stage of disease. It

is important to differentiate the different types of amyloidosis as

their treatments are very different. There are over 20 different

types of amyloid in man. Among patients with systemic

amyloidosis, AL type is most common, followed by AA type;

hereditary amyloidosis accounts for about 10% of cases.

Majid Kazmi FRCP FRCPath is a Consultant Haematologist at Guy’s and ST

Thomas’ NHS Foundation Trust, UK. Competing interests: none

declared.

MEDICINE 41:5 299

AL amyloidosis

Systemic AL amyloidosis occurs where there is extracellular

accumulation of amyloidogenic monoclonal immunoglobulin

light chain fragments1 in association with the normal plasma

protein serum amyloid P (SAP). AL amyloidosis affects most

frequently the kidneys, heart, liver and peripheral nervous sys-

tem.2 Untreated, it is progressive and fatal within 2 years in

about 80% of patients.3 The age-adjusted incidence of AL

amyloidosis in the USA is estimated to be between 5.1 and

12.8 per million persons per year4; 60% of patients are between

50 and 70 years old at diagnosis and only 10% are aged under

50 years.2 There is equal male:female incidence. AL amyloidosis

may be associated with myeloma or other B-cell malignancy, but

in most cases the underlying plasma cell dyscrasia is subtle.

Clinical features

Fatigue and weight loss are common but the diagnosis is rarely

made until symptoms referable to a particular organ appear.

The most common clinical features at diagnosis are listed in

Table 1.2 It is important to recognize however that AL

amyloidosis can affect almost any organ or tissue in the body

other than the brain.

Diagnosis and investigation

The approach to diagnosis and investigation is a three-stage

process. In the UK it is recommended that all cases of amy-

loid are referred to, or at least discussed with, the National

Amyloidosis Centre (www.ucl.ac.uk/medicine/amyloidosis/

nac)

1. Establish the diagnosis of AL amyloid. Amyloid deposits

stained with Congo red produce red-green birefringence

when viewed under cross-polarized light. Amyloid is usually

diagnosed by biopsy of an affected organ, although less

invasive alternatives may be considered (e.g. subcutaneous

fat aspirate).6 Bone marrow involvement with amyloid is

strongly suggestive of AL amyloid [Figures 1 and 2]. Owing

to poor sensitivity of immunohistochemical staining for light

chains (60%), AL amyloidosis is often diagnosed after

exclusion of AA and hereditary types by immunohisto-

chemistry and genetic sequencing, respectively.7 In cases of

doubt, amyloid fibril gene sequencing or mass spectrometry

should be undertaken.8,9

2. Search for evidence for involvement by amyloid within other

organs. (Table 2).

3. Evaluation of plasma cell dyscrasia/lymphoma.

It is important to exclude a diagnosis of myeloma or other

lymphoid malignancy.

Prognostic factors

Patient survival has steadily improved from a median of

1e2 years in the 1980s to more than 5 years in recent se-

ries,2,11,12 probably reflecting a combination of better sup-

portive care and more successful treatment strategies. A poor

prognosis has been associated with symptomatic cardiac

disease.13

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Most common organ-specific manifestations of AL amyloid

Affected organ Approximate incidence Clinical features

Renal amyloid 33% Proteinuria and nephrotic syndrome with or without renal insufficiency.

Orthostatic hypotension

Cardiac involvement 20% Reduced QRS complexes on ECG.

Restrictive cardiomyopathy, orthostatic hypotension

Neurological involvement 20% C Sensory most commonly symmetrical

C Motor rare

C Carpal tunnel syndrome

C Autonomic peripheral neuropathy with gastrointestinal dysmotility, severe

orthostatic hypotension, weight loss, sexual dysfunction, bladder

dysfunction, abnormal sweating

Organ enlargement 25%

10%

Hepatomegaly

Macroglossia

Haemostatic involvement 50%

(5 Mumford et al 2000.)

Abnormal clotting screen

Bleeding diathesis including peri-orbital purpura (‘raccoon eyes’)

Table 1

LYMPHOPROLIFERATIVE DISORDERS

Treatment

Localized AL amyloid (non-vital organ)

The course of the disease is relatively benign in most patients. In

some cases local surgical intervention is appropriate.

Systemic AL amyloid including vital organ involvement

No treatment is yet available that removes specifically amy-

loid deposits, and therapy is aimed at suppressing the pro-

duction of clonal light chains to slow or halt ongoing amyloid

deposition, along with supportive measures for organ

function.

Numerous case series have shown that patients who achieve

complete or near-complete clonal responses have better out-

comes in terms of both patient survival14,15 and improvement in

amyloidotic organ dysfunction.16,17

Figure 1 AL amyloid in the bone marrow (interstitial).

MEDICINE 41:5 300

Myeloma-based conventional chemotherapy has been used

to treat AL amyloidosis.18 Relatively low rates of response and

delayed time to response prompted use of high dose melphalan

and autologous peripheral blood stem cell transplantation

(HDM and PBSCT).19 The risk of such a procedure in patients

with AL amyloid is significantly higher than in patients with

myeloma, with mortality rates running as high as 21% often

due to poor patient selection. Such treatments are now confined

to low-risk patients (defined by low-risk of transplant-related

mortality).

The advent of novel agents in myeloma treatment has seen

significant suppression of light-chain production and higher

complete response rates compared to conventional chemotherapy.

Although there are no prospective comparative trials, the

emerging data from the USA and Europe suggest that bortezomib-

containing regimens achieve rapid and deep clonal responses and

Figure 2 AL amyloid in the bone marrow (vessel wall).

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Evaluation of organ involvement with AL amyloid

Organ involved Tests

Generic Full blood count, clotting screen, skeletal

survey, chest X-ray, SAP scana

Renal Renal function tests, Quantification of

proteinuria e 24-hour urine collection or

protein/creatinine ratio calculation.

Liver Liver function tests

Cardiac ECG/echocardiogram/NT-proBNP and cardiac

troponin, cardiac MRI.

Respiratory Pulmonary function tests

Neurological Nerve conduction studies and autonomic

function tests

BNP, brain natriuretic peptide; ECG, electrocardiography; MRI, magnetic reso-

nance imaging; SAP, serum amyloid P.a SAP scintigraphy. This investigation is available only at the NHS National

Amyloidosis Centre, allows diagnosis and quantification of deposits,10 and

is useful in assessing the extent and distribution of organ involvement and

for evaluating the effects of treatment.

Table 2

LYMPHOPROLIFERATIVE DISORDERS

are generally well tolerated.20, 21 Such regimens may become the

first-line treatment of choice in AL amyloidosis. A

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