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Guidelines on the diagnosis and management of AL amyloidosis

2004; Wiley; Volume: 125; Issue: 6 Linguagem: Inglês

10.1111/j.1365-2141.2004.04970.x

1365-2141

Chronic Myeloid Leukemia Treatments

British Journal of HaematologyVolume 125, Issue 6 p. 681-700 Free Access Guidelines on the diagnosis and management of AL amyloidosis First published: 20 May 2004 https://doi.org/10.1111/j.1365-2141.2004.04970.xCitations: 92 Dr Jenny Bird, Avon Haematology Unit, Bristol Haematology and Oncology Centre, Horfield Road, Bristol BS2 3ED, UK. E-mail: jenny.bird@ubht.swest.nhs.uk AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Methods These guidelines have been compiled by members of the Guidelines Working Group of the UK Myeloma Forum on behalf of the British Committee for Standards in Haematology (BCSH). They are intended to set out key areas in the effective diagnosis and clinical management of AL amyloidosis. A Medline search for literature published between January 1975 and January 2003 was performed using PubMed. A search was made for clinical trials involving AL (primary) amyloidosis and papers or reviews where AL amyloidosis was the major focus. Abstracts from relevant meetings held between 1998 and 2003 were also included. The Cochrane database was searched but did not include any relevant information. Recommendations were made based on literature review and consensus of expert opinion in consultation with representatives of other specialities and patient advocate groups. Levels of evidence and grades of recommendation are shown in Table I. Table I. Levels of evidence and grades of recommendation. Levels of evidence Ia Evidence obtained from meta-analysis of randomized controlled trials Ib Evidence obtained from at least one randomized controlled trial IIa Evidence obtained from at least one well-designed, non-randomized study, including phase II trials and case–control studies IIb Evidence obtained from at least one other type of well-designed, quasi-experimental study, i.e. studies without planned intervention, including observational studies III Evidence obtained from well-designed, non-experimental descriptive studies. Evidence obtained from meta-analysis or randomized controlled trials or phase II studies which is published only in abstract form IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities Grades of recommendation Grade A, evidence level Ia, Ib Recommendation based on at least one randomized controlled trial of good quality and consistency addressing specific recommendation Grade B, evidence level IIa, IIb, III Recommendation based on well conducted studies but no randomized controlled trials on the topic of recommendation Grade C, evidence level IV Evidence from expert committee reports and/or clinical experiences of respected authorities The draft guidelines were reviewed by the UK Myeloma Forum Executive, members of the BCSH and a panel of approximately 60 UK haematologists. The British Society of Blood and Marrow Transplantation also reviewed the document. The planned date for full revision of these guidelines by the Guidelines Working Group of the UK Myeloma Forum is January 2007. Interim updates will be on the UK Myeloma Forum and BCSH websites. AL amyloidosis: the context Systemic AL amyloidosis, formerly known as primary amyloidosis, is a protein conformation disorder associated with a clonal plasma cell dyscrasia (Falk et al, 1997). Multiple organ disease results from the extracellular deposition of monoclonal immunoglobulin light chain fragments in an abnormal insoluble fibrillar form. Amyloid fibrils associate in vivo with the normal plasma protein serum amyloid P component (SAP), and this phenomenon is the basis for the use of SAP scintigraphy for imaging and monitoring amyloid deposits (Hawkins et al, 1990). Accumulation of amyloid progressively disrupts the normal tissue structure and ultimately leads to organ failure, frequently including the kidneys, heart, liver and peripheral nervous system (Kyle & Gertz, 1995). Amyloid deposits appear to evoke little or no local reaction in the tissues and there is a poor correlation between the amount of amyloid and the degree of impairment of organ function, particularly in the kidneys. The natural history of AL amyloidosis is that it is progressive and fatal within 2 years in about 80% of patients (Kyle et al, 1999). However, treatments that substantially reduce the supply of monoclonal immunoglobulin light chains frequently result in the stabilization or regression of existing amyloid deposits, and are often associated with preservation or improvement in the function of organs infiltrated by amyloid (Gillmore et al, 1997). Pathophysiology and relationship with other B-cell disorders AL amyloidosis may be associated with myeloma or other B-cell malignancy, but in most cases the underlying plasma cell dyscrasia is subtle and non-proliferating, analagous to monoclonal gammopathy of undetermined significance (MGUS). The cytogenetic abnormalities that commonly occur in multiple myeloma and MGUS, such as 14q translocations and 13q deletion, have also been observed in AL amyloidosis (Harrison et al, 2002). A concurrent diagnosis of myeloma or other B-cell malignancy is made at diagnosis in patients with AL amyloidosis when the diagnostic criteria for these conditions are fulfilled. Coexistent AL amyloid deposits are identified either at presentation or at some time during the course of the disease in approximately 10–15% of patients with myeloma and more rarely in Waldenström's macroglobulinaemia and other lymphoid malignancies. AL amyloid deposits that are demonstrated histologically during the course of investigations in patients with these disorders may not be clinically significant but this can only be determined following comprehensive clinical and laboratory evaluation. It is rare for AL amyloidosis to progress to overt myeloma (Rajkumar et al, 1998), probably because of the short survival of patients with AL amyloidosis. AL amyloid fibrils are derived from the N-terminal region of monoclonal immunoglobulin light chains and consist of the whole or part of the variable (VL) domain. Intact light chains may rarely be found, and the molecular weight therefore varies between about 8000 and 30 000 Da. All monoclonal light chains are unique and the propensity for certain ones to form amyloid fibrils is an inherent property related to their particular structure. Monoclonal light chains that can form amyloid are able to exist in partly unfolded states, involving loss of tertiary or higher order structure. These readily aggregate with retention of β-sheet secondary structure into protofilaments and fibrils. Once the process has started, 'seeding' may also play an important facilitating role, so that amyloid deposition may progress exponentially as expansion of the amyloid template 'captures' further precursor molecules. Only a small proportion of monoclonal light chains are amyloidogenic, but it is not possible to identify these from their class or abundance. Incidence and epidemiology The incidence of AL amyloidosis is difficult to define precisely. The age-adjusted incidence of AL amyloidosis in the United States is estimated to be between 5·1 and 12·8 per million persons per year (Kyle et al, 1992), which is equivalent to approximately 600 new cases per year in the UK. AL amyloidosis is estimated to be the cause of death in 1/1500 deaths in the UK. Among 474 patients seen at the Mayo Clinic (Kyle & Gertz, 1995), 60% patients were between 50 and 70 years old at diagnosis and only 10% were less than 50 years. Similarly, among 800 UK patients with AL amyloidosis, who have been evaluated at the National Health Service (NHS) National Amyloidosis Centre (NAC), 66% were aged between 50 and 70 years old at diagnosis, and 17% were aged less than 50; 30 of these patients (4%) were aged less than 40 years, and three were aged less than 30 years (NAC database, unpublished data). The male:female ratio was equal. The relatively lower fraction of patients older than 70 years, when compared with the age incidence of myeloma and MGUS, probably reflects referral practice to tertiary centres and undiagnosed disease in the elderly. Clinical features The most common clinical features at diagnosis are (Kyle & Gertz, 1995): (i) nephrotic syndrome with or without renal insufficiency; (ii) congestive cardiomyopathy; (iii) sensorimotor and/or autonomic peripheral neuropathy; and (iv) hepatomegaly. Fatigue and weight loss are extremely common presenting symptoms but the diagnosis is rarely made until symptoms referable to a particular organ appear. Although multiple organs are generally affected, dysfunction of one particular organ is usually predominant. Patients are said to have dominant renal or cardiac involvement, for example, when the relevant organ is either the only organ involved or that most severely affected. Some patients will also have the features of associated myeloma. Renal amyloid. Nearly one-third of patients have dominant renal amyloid at diagnosis. Renal amyloidosis is mainly a glomerular lesion causing marked proteinuria, which often results in nephrotic syndrome. Evidence of mild renal dysfunction is frequently found but AL amyloidosis rarely presents as progressive renal failure. Symptoms include ankle swelling, fatigue and loss of energy. There is often peripheral oedema and there may be evidence of a pleural effusion. Occult pericardial effusion can occur. Orthostatic hypotension may be a feature of autonomic neuropathy and/or cardiac involvement but is also a feature of volume depletion, which may occur as a result of diuretic treatment. Cardiac amyloid. About 20% of patients have dominant symptomatic cardiac amyloid at diagnosis. Abnormalities on an electrocardiogram (ECG), notably low voltages in the standard leads, may precede clinical congestive cardiac failure. Clinical signs are mainly of right-sided heart failure (raised jugular venous pulse, right-sided third heart sound, peripheral oedema and hepatomegaly) or those associated with a low cardiac output, including orthostatic hypotension. In severe cases, atrial thrombi may be present in sinus rhythm (Dubrey et al, 1995); the onset of atrial fibrillation may be associated with an abrupt deterioration in cardiac performance and a high risk of thromboembolism. The cardiomyopathy in amyloidosis is restrictive in nature. Hence, the cardiac silhouette on chest X-ray is often not enlarged and the clinical differential diagnosis may include pericardial disease or tamponade. Peripheral and autonomic neuropathy. AL polyneuropathy may give rise to a wide range of symptoms. Up to 20% of patients present with symptoms of peripheral neuropathy, most commonly parasthesiae, numbness and muscle weakness (Rajkumar et al, 1998). Sensory neuropathy is usually symmetrical, usually affecting the lower extremities, and may be painful; motor neuropathy is rare. Carpal tunnel syndrome is common and may predate other symptoms by over a year. There is frequently a long delay between onset of symptoms and diagnosis when neuropathy is the presenting manifestation of AL amyloidosis. Autonomic neuropathy is a far more serious feature, which can give rise to postural hypotension, impotence and disturbed gastrointestinal (GI) motility and is usually associated with some degree of peripheral neuropathy. The clinical manifestations of autonomic disorders are protean and should be specifically sought through enquiry about erectile and ejaculatory failure in men, symptoms relating to poor bladder emptying, altered bowel habit, early satiety, anhidrosis or gustatory sweating, and symptoms relating to postural hypotension. The last is confirmed by demonstrating a fall in systolic blood pressure of at least 20 mmHg when a patient has been standing for 3–5 min after spending at least 5 min supine. GI and hepatic involvement. Involvement of the GI tract may be focal or diffuse and symptoms relate to its site and extent. Macroglossia occurs in about 10% of patients and is virtually pathognomonic; it can be marked causing airway obstruction, difficulty in eating and sleep apnoea. Other features include early satiety, diarrhoea, chronic nausea, malabsorption and weight loss. GI amyloid may also present with gut perforation or frank rectal bleeding. Certain symptoms, notably early satiety and explosive post-prandial diarrhoea, often reflect disturbed GI motility due to autonomic neuropathy. Hepatomegaly is present in approximately one quarter of patients at diagnosis; in the presence of heart failure, it may not be possible to clinically differentiate amyloid infiltration from venous congestion. Haemostatic abnormalities. Haemorrhage is a frequent manifestation of amyloidosis and can be a serious problem. It occurs at some time in about one-third of patients, and an abnormal clotting screen is present in about half (Mumford et al, 2000). The most common manifestation of bleeding is purpura due to vascular fragility as a result of endothelial amyloid deposits, but life-threatening bleeding is also well described and may follow liver or renal biopsy. Peri-orbital purpura ('raccoon eyes') is particularly characteristic. Other organ systems. These include the following. • Skin and soft-tissue thickening. • Painful seronegative arthropathy. • Bone involvement is demonstrated by SAP scan in approximately 30% of patients but, in contrast to myeloma, bone pain, lytic lesions or pathological fracture are not common. There are no characteristic radiological appearances. Lytic lesions and vertebral collapse may occur, but multiple lytic lesions are suggestive of myeloma. X-rays may be normal even when there is substantial amyloid involvement of bone. • Vocal cord infiltration may produce a hoarse voice, although this is most frequently a manifestation of localized AL amyloidosis. • Adrenal gland or thyroid infiltration occasionally results in hypoadrenalism or hypothyroidism. • Lymphadenopathy and pulmonary infiltration can be features of systemic or localized AL amyloidosis. • Any organ other than the brain can be involved. Localized AL amyloidosis. AL amyloidosis can occur in a localized form that is most often identified in the upper respiratory, urogenital and GI tracts, the skin and the orbit. In such circumstances the amyloidogenic light chains are produced by a subtle focal infiltrate of clonal lymphoplasmacytoid cells in proximity to the amyloid deposits. This type of amyloid is frequently nodular in character, but can occur quite diffusely throughout a particular tissue when it is associated with a more contiguous infiltrate of clonal cells. The AL nature of localized amyloid can often be confirmed immunohistochemically or by sequencing the fibril protein but it may not be possible to characterize the associated clonal cells due to their scanty nature. Monoclonal immunoglobulin cannot be detected in the serum or urine of most patients with localized AL amyloidosis, even when using highly sensitive assays. The phenotype of hereditary systemic amyloidosis associated with certain apolipoprotein A1 variants can mimic localized laryngeal AL amyloidosis. The course of the disease is relatively benign in most patients, but severe damage to the affected organ can ultimately occur. Treatment is generally confined to local surgical intervention according to symptoms. Diagnosis and investigation Many patients with AL amyloidosis have multi-system involvement at diagnosis. Patients in whom the diagnosis is made at a relatively early stage have the broadest options for treatment, and are more likely to be eligible for dose-intensive chemotherapy regimens. Diagnosis requires a high index of suspicion. AL amyloidosis should be considered in any patient who presents with nephrotic range proteinuria with or without renal insufficiency, non-dilated cardiomyopathy, peripheral neuropathy, hepatomegaly or autonomic neuropathy whether or not a paraprotein can be detected in the serum or urine. Particular vigilance should be maintained in patients with multiple myeloma or MGUS. If suspicion of the diagnosis is based on symptoms in one organ system, evidence for involvement at other sites should be sought, e.g. low voltage ECG, proteinuria or hepatomegaly, but multiple organ biopsies are potentially hazardous and are not recommended. Diagnostic investigations Initial investigation should confirm the diagnosis of amyloidosis on tissue biopsy and this should be followed by investigations to establish the type of amyloid present and the extent of organ involvement (Table II). It is not always easy to be certain that amyloidosis is of AL type because immunohistochemical staining for immunoglobulin light chains in amyloidosis is unreliable and the presence of a paraprotein does not per se confirm a diagnosis of AL amyloidosis; hereditary forms of amyloidosis are more common than previously thought and may co-exist with MGUS. This can lead to misdiagnosis (Lachmann et al, 2002a). In cases of doubt DNA analysis and/or amyloid fibril sequencing may be necessary. Imaging using SAP scanning may be helpful because demonstration of bone marrow involvement is strongly correlated with amyloidosis of AL type. Table II. Investigations required in suspected AL amyloidosis. Confirmation of amyloid Determination of amyloid type Evaluation of organ involvement Investigation of underlying plasma cell dyscrasia Monitoring Pathology Biopsy and histology of screening tissue (e.g. fat aspirate or rectal biopsy or affected organ. Congo red staining of marrow biopsy Immunohistochemical staining of tissue biopsy with a panel of antibodies to amyloid fibril proteins Tissue biopsy of affected organ, but once the diagnosis is known, organ biopsies merely to determine extent of amyloid involvement not recommended Bone marrow aspirate and biopsy with light chain immunophenotyping Follow-up tissue biopsies and bone marrow examinations are usually not helpful Haematology/chemical pathology/immunology Routine electrophoresis and immunofixation of serum and urine. Quantifiable serum free light (FLC) assay Urea, electrolytes, creatinine, albumin 24-h total protein, liver function test, coagulation screen, creatinine clearance (measured or calculated) FBC, urea and electrolytes, creatinine, calcium, albumin. Quantification of serum and urine paraprotein. Levels of normal immunoglobulins Paraprotein level, serum FLC assay Imaging SAP scanning SAP scanning (evidence of marrow involvement) SAP scanning Skeletal survey SAP scanning Other DNA analysis, amyloid fibril sequencing ECG; echocardiogram chest X-ray Organ function assessments Histology. Amyloid deposits stain with Congo red and produce pathognomonic red-green birefringence under cross-polarized light microscopy. Biopsy of an affected organ is usually diagnostic but less invasive alternatives are possible, e.g. subcutaneous fat aspirate (Libbey et al, 1983). Abdominal fat aspirate and rectal and labial salivary gland biopsies yield positive results in up to 80% of cases in reported studies (Duston et al, 1987; Kyle & Gertz, 1995), but are non-diagnostic in up to 50% of patients in routine clinical practice. Bone marrow biopsy should also be stained with Congo red for the presence of amyloid, and involvement of the bone marrow is strongly suggestive of AL type. Evaluation of adequate specimens in experienced laboratories is necessary to maintain high diagnostic sensitivity and specificity. Both false-positive and false-negative interpretations are not uncommon. Immunohistochemistry. Antibodies are available against most known amyloid fibril proteins but definitive results are obtained in less than 50% of patients with AL amyloid due to the presence of background normal immunoglobulin, and because light chain epitopes that are recognized by antisera to kappa or lambda light chains may be lost during fibril formation and tissue fixation. In contrast, immunohistochemistry in experienced hands can confirm or exclude amyloidosis of AA type in virtually all cases. DNA analysis. This is principally used to distinguish AL amyloidosis from hereditary forms of amyloid. Hereditary amyloidosis is an autosomal dominant disorder caused by mutations in the genes for transthyretin, fibrinogen A α-chain, lysozyme or apolipoprotein AI, but a family history is often masked due to incomplete penetrance. The clinical features may be indistinguishable from AL amyloidosis. Hereditary transthyretin and fibrinogen A α-chain amyloidosis are much more common than previously thought, and 31 of the 34 patients in whom hereditary amyloidosis was misdiagnosed as AL amyloidosis in a British series of 350 cases had amyloid of either variant transthyretin or fibrinogen A α-chain type (Lachmann et al, 2002a). Hereditary transthyretin amyloidosis presented with polyneuropathy and/or amyloid cardiomyopathy in each case, and there should be a low threshold for sequencing the gene for transthyretin in patients with this phenotype. Features suggestive of variant fibrinogen A α-chain amyloidosis are its almost exclusively renal presentation coupled with a distinctive appearance on renal biopsy. This type of amyloid accumulates very selectively and substantially within the glomeruli, but is characteristically absent from blood vessels and the interstitium. DNA analysis is available at the NAC, based in London. Amyloid fibril protein sequencing. Amyloid fibrils can be isolated from tissue biopsy samples and characterized by amino acid sequencing. This is the only uniformly definitive method for determining the amyloid fibril type, and can be performed to identify the type of amyloidosis when other methods have failed. This is the method by which the genes associated with hereditary amyloidosis have been identified, and is available at the NAC. Evaluation of plasma cell dyscrasia. While the presence of a paraprotein does not necessarily mean that amyloidosis is of AL type, evidence of a plasma cell dyscrasia would be supportive evidence for a diagnosis of AL amyloidosis. Relevant investigations are as follows. Serum and urinary protein electrophoresis and immunofixation. A paraprotein is detectable in the serum or urine by routine electrophoresis in approximately 50% of patients. When an intact whole monoclonal immunoglobulin is present in serum the concentration is less than 10 g/l in 30% of patients, less than 20 g/l in over 70% of patients and above 30 g/l in less than 10% (Kyle & Gertz, 1995). It is therefore essential to perform immunofixation, as the level of paraprotein in AL amyloidosis is usually very low and routine electrophoresis is often negative. However, even on immunofixation no paraprotein is detectable in serum or urine in 20% of cases. Serum free light chain (FLC) estimation. A new immunoassay can detect and quantify FLCs in serum with remarkable specificity and sensitivity (Bradwell et al, 2001). The assay gives a positive result (raised level of either kappa or lambda together with an altered ratio of free kappa to free lambda light chain) in 98% of patients with systemic AL amyloidosis (Lachmann et al, 2003), including those in whom a monoclonal immunoglobulin cannot be demonstrated by conventional means. This assay is not specific for AL amyloidosis, and monoclonal FLC are present in about one half of patients with uncomplicated MGUS, and in virtually all patients with multiple myeloma. Bone marrow aspirate and trephine. Bone marrow aspirate and trephine is usually reported to be normal or to show only a small increase in the percentage of plasma cells, unless the patient has overt myeloma. Immunophenotyping may help to establish clonality when only small numbers of plasma cells are present. Differential diagnosis The possibility of the following alternative diagnoses should be considered in all patients: • Systemic non-AL amyloidosis including hereditary forms and AA amyloidosis. Note that patients with AA amyloidosis may not have an overt underlying inflammatory disorder, and that non-AL amyloidosis may co-exist with MGUS. • Localized AL amyloidosis. • Other paraprotein-associated diseases including peripheral neuropathy and immunoglobulin deposition diseases. Evaluation of organ involvement Once a diagnosis of AL amyloidosis has been made, investigations are required to evaluate the extent and severity of organ involvement, along with further evaluation of the underlying monoclonal plasma cell dyscrasia to exclude a diagnosis of myeloma or other lymphoid malignancy. Recommended investigations are listed in Table II. Frequent laboratory findings on routine investigation include glomerular proteinuria (predominantly albuminuria) in 90% of patients. Hypercholesterolaemia is common in patients with nephrotic syndrome. Generalized abnormalities of liver function tests are unusual until liver amyloidosis is very advanced. The most common abnormality is isolated elevation of alkaline phosphatase. Anaemia is uncommon unless the amyloidosis is associated with myeloma, bleeding or chronic renal failure. An abnormal clotting screen is relatively common. A prolonged thrombin time is the most frequent abnormality, but this has no clinical association with a bleeding diathesis (Mumford et al, 2000). A prolonged prothrombin time is the only coagulation abnormality associated with bleeding. SAP scintigraphy. This investigation is available at the NAC, and is performed routinely in most patients who are referred for evaluation of proved or suspected amyloidosis. Radiolabelled SAP component localizes rapidly and specifically to amyloid deposits in proportion to the quantity of amyloid present. This enables the diagnosis and quantification of deposits by whole body scintigraphy, although cardiac amyloid is poorly visualized (Hawkins et al, 1990; Hawkins, 2002). It is useful in assessing the extent and distribution of organ involvement by amyloid, and for evaluating the effects of treatment and it is recommended that it be performed in all patients when feasible. It can also be used as supporting evidence for a diagnosis of amyloidosis when tissue biopsy is not possible. ECG and echocardiography. Cardiac amyloid is poorly visualized by SAP scintigraphy but ECG and echocardiography provide essential information about the extent of involvement, cardiac function and prognosis. Characteristic features of cardiac amyloid on ECG include low voltages and a pattern suggestive of myocardial infarction without evidence of ischaemic damage on echocardiography. The echocardiographic features of amyloid include concentrically thickened ventricles, normal or small cavities, thickened valves and dilated atria. The ejection fraction is frequently normal, or even increased. Doppler flow studies are required to identify diastolic dysfunction, which is frequently missed in routine studies, and tissue Doppler imaging may provide further useful information. There is a poor correlation between echocardiographic and ECG findings, one or other of which may occasionally appear normal in the presence of clinically significant cardiac amyloidosis. The World Health Organisation (WHO) has described a grading system for cardiac amyloid and the New York Heart Association (NYHA) has developed a functional classification for patients with cardiac disease that can be applied to patients with cardiac amyloid (see Appendices A and B). Chest X-ray. Chest X-ray in patients with pulmonary amyloidosis may show reticulo-nodular shadowing and there may be impaired CO diffusion on pulmonary function testing. Nerve conduction studies. These may be required where neuropathy is the dominant presenting symptom. Nerve biopsy may be required to establish the diagnosis. Criteria for defining organ involvement. There are no universally agreed or validated criteria for defining organ involvement. Most groups use similar but not identical criteria and only two have reported these in detail (Comenzo et al, 1998; Dispenzieri et al, 2001; see Table III). Table III. Non-invasive diagnostic criteria of amyloid-related major organ involvement.* Organ involvement Comenzo et al (1998) Dispenzieri et al (2001) Heart Mean left ventricular wall thickness on echocardiography >11 mm with no history of hypertension or valvular heart disease (or) unexplained low voltage ( 12 mm and/or infiltrative cardiomyopathy and/or diastolic dysfunction determined by echocardiography Kidney Proteinuria >0·5 g/24 h Proteinuria >0·5 g/24 h Liver Hepatomegaly with an alkaline phosphatase >200 U/l Hepatomegaly (>4 cm below costal margin) with an alkaline phosphatase >1·5 times normal levels Nerve Based on clinical history, autonomic dysfunction with orthostasis, gastric atony by gastric emptying scan and abnormal sensory and/or motor findings on neurological examination Peripheral neuropathy (other than carpal tunnel syndrome) or autonomic neuropathy *In both these series, non-invasive diagnostic criteria were used only in patients in whom a positive diagnosis had been made by tissue biopsy. Prognostic factors Prognosis is variable but is generally poor if AL amyloidosis is untreated. Patients with systemic AL amyloidosis have a median survival of 1–2 years (Kyle & Gertz, 1995). Few studies have specifically a