Guidelines on the diagnosis and investigation of AL amyloidosis

Abstract

The following recommendations are all Grade 1 level C evidence. This guideline has 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). The objective of this guideline is to provide healthcare professionals with clear guidance on the management and investigation of patients with AL amyloidosis. A Medline search for literature published between 1975 and May 2014 was performed using PubMed. The search included clinical trials in AL amyloidosis and papers or reviews where AL amyloidosis was the major focus. Abstracts from relevant meetings held between 1998 and 2014 were also included. The Cochrane database did not include any relevant information. Levels of evidence and grades of recommendation are based on the GRADE system (http://www.gradeworkinggroup.org/index.htm). The draft guideline was reviewed by the UK Myeloma Forum Executive and members of the BCSH and British Society of Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and comments incorporated where appropriate. The guidance may not be appropriate to all patients with AL amyloidosis and, in all cases, individual patient circumstances may dictate an alternative approach. The NAC (www.ucl.ac.uk/medicine/amyloidosis/nac/index.html) was commissioned directly by the Department of Health to provide a diagnosis and management advisory service for the national caseload of patients with amyloidosis. The clinical unit is based in the Royal Free Hospital Campus, University College London. The Centre developed scintigraphic imaging (serum amyloid P component [SAP] scanning) of amyloid as a quantitative diagnostic procedure and provides various specialized clinical services for patients with acquired and hereditary systemic amyloidosis, including: Physicians at the NAC offer telephone advice and will arrange specialist laboratory investigations that are not available locally. Some investigations may be performed on peripheral blood samples following discussion. In the UK there is a move to develop a UK Amyloidosis Network, to include a number of regional centres throughout the UK in which there is expertise in clinical management of patients with systemic amyloidosis. The aim is to develop an expanding network of regional ‘Amyloidosis Treatment Centres’ characterized by a multi-disciplinary approach that includes input from a haematologist, cardiologist, nephrologist and specialist nurse with expertise in amyloidosis. Systemic AL amyloidosis (formerly primary amyloidosis) is a disorder of protein folding in which there is extracellular accumulation as β-pleated fibrillar deposits of monoclonal immunoglobulin light chain fragments (Falk et al. 1997) that ultimately leads to organ failure, most commonly of the kidneys, heart, liver and peripheral nervous system (Kyle & Gertz 1995). There is considerable clinical heterogeneity in AL amyloidosis due to the variable organ involvement and poor correlation between the amount of amyloid and the degree of impairment of organ function, particularly in the kidneys. Although the natural history of AL amyloidosis is that it is fatal within 2 years in about 80% of patients (Kyle et al. 1999), treatments that reduce the supply of amyloidogenic monoclonal immunoglobulin light chains can result in stabilization or regression of existing amyloid deposits leading to preservation or improvement in the function of organs and improved survival (Gillmore et al. 1997). AL amyloidosis may be associated with myeloma or other B-cell malignancy, such as Waldenström macroglobulinaemia, but in most cases the underlying plasma cell dyscrasia would be classified as monoclonal gammopathy of undetermined significance (MGUS) if it were not for the presence of amyloid deposition. 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. Importantly, the International Myeloma Working Group (2003) and, more recently, the World Health Organization (WHO), included AL amyloidosis as a symptomatic myeloma-defining condition (McKenna et al. 2008). Although coexistent AL amyloidosis is diagnosed in approximately 10–15% of patients who present with overt myeloma, the AL amyloid deposits demonstrated histologically during the course of investigations in patients with these disorders may not be clinically significant. It is rare for AL amyloidosis to progress to overt myeloma (Rajkumar et al. 1998a), probably because of the short survival of patients with AL amyloidosis. AL amyloidosis can also complicate certain B-cell malignancies, such as Waldenstrom macroglobulinaemia, or indolent lymphomas, such as marginal zone lymphoma. AL amyloid fibrils are derived from the N-terminal region of monoclonal immunoglobulin light chains and consist of the whole or, more usually, just a part of the variable (VL) domain (molecular weight therefore varies between about 8000 and 30 000 Da). All monoclonal light chains are structurally unique with only a small proportion of monoclonal light chains being amyloidogenic; however, lambda light chains are more commonly associated with amyloid than kappa in approximately a 3:1 ratio. The propensity for certain light chains to form amyloid fibrils is an inherent property related to their particular structure. Once amyloid deposition has started, ‘seeding’ may occur leading to exponential amyloid accumulation (Booth et al. 1997). The genetic abnormalities that commonly occur in multiple myeloma and MGUS, such as 14q translocations and 13q deletion, are also a feature of AL amyloidosis. However, the t(11;14) translocation is significantly more common in AL amyloidosis (39–55%) than in myeloma (15%) and, unlike in myeloma, may carry an adverse prognosis (Harrison et al. 2002, Bochtler et al. 2008, Bryce et al. 2009, Bochtler et al. 2011). Hyperdiploidy (Bochtler et al. 2011) and the poor-risk myeloma genetic abnormalities, namely the t(4;14) and deletions of 17p (TP53), are rare in AL amyloidosis. Increased frequency of gain of 1q21 may be associated with AL amyloidosis, usually in the context of progression to myeloma (Bochtler et al. 2008). As yet, none of the cytogenetic abnormalities are known to influence the pattern and severity of organ involvement. The incidence of AL amyloidosis, although hard to calculate, is estimated to be ~0·8/100 000 population and the cause of death in ~1 per 1500 deaths in the UK (Pinney et al. 2013). The age-adjusted incidence of AL amyloidosis in the United States is 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 and the male:female ratio is equal. Among 474 patients seen at the Mayo Clinic (Kyle & Gertz 1995), 60% of patients were between 50 and 70 years old at diagnosis and only 10% were aged under 50 years. Similarly, among 2700 patients with AL amyloidosis who have been evaluated at the UK NAC (NAC), 28% were aged over 70 years at diagnosis, 62% were aged between 50 and 70 years at diagnosis, and 10% were aged under 50 years; 2% were aged under 40 years at diagnosis (NAC database, unpublished data). However, referrals to specialized tertiary centres under-represent the very elderly population, patients with very poor performance status and patients who are reluctant to travel. The most common clinical features at diagnosis are (Kyle & Gertz 1995): Fatigue and weight loss are extremely common presenting symptoms but the diagnosis of amyloidosis is rarely made until symptoms referable to a particular organ appear. Although AL amyloid deposits generally affect multiple organs, dysfunction of one particular organ often predominates. Certain patterns of organ involvement (macroglossia) may be pathognomonic of AL amyloidosis; however, the pattern of organ involvement is frequently non-diagnostic and overlaps with other (non-AL) forms of amyloid. Nearly one half of patients have dominant renal amyloid at diagnosis, which is predominantly a glomerular lesion causing nephrotic syndrome. Substantial albuminuria in the context of myeloma, as opposed to isolated Bence Jones proteinuria, should alert the physician to the possibility of AL amyloid. Loss of renal excretory function is common in AL amyloidosis although presentation with progressive renal failure in the absence of substantial proteinuria is rare (Pinney et al, 2011). Symptoms include ankle swelling, fatigue, loss of energy, peripheral oedema, pleural effusions and occult pericardial effusions. Orthostatic hypotension may be a feature of autonomic neuropathy and/or cardiac involvement by amyloid but may also result from intravascular volume depletion in association with diuretic treatment for nephrotic syndrome. About 25% of patients have dominant symptomatic cardiac amyloidosis at diagnosis, which confers a poor prognosis. Abnormalities on electrocardiography (ECG), notably reduced QRS voltages in the standard leads, may precede clinical congestive cardiac failure. The cardiomyopathy in amyloidosis is restrictive in nature with thickened cardiac walls but often a normal cardiac silhouette on chest X-ray, and the clinical differential diagnosis may include pericardial disease or tamponade. Clinical signs are mainly of right-sided heart failure (raised jugular venous pressure, right-sided third heart sound, peripheral oedema and hepatomegaly), arrhythmias or signs associated with a low cardiac output, including orthostatic hypotension. In severe cases atrial thrombi may be present despite sinus rhythm (Dubrey et al. 1995) and atrial fibrillation may be associated with an abrupt deterioration in cardiac performance and a high risk of thromboembolism. AL polyneuropathy may give rise to a wide range of symptoms and there is frequently a long delay from presentation to diagnosis. Up to 15% of patients present with symptoms of an axonal length-dependent peripheral neuropathy, most commonly a peripheral symmetrical sensory neuropathy with paraesthesiae, numbness, possibly pain and muscle weakness although motor neuropathy is rare (Rajkumar et al. 1998b). Carpal tunnel syndrome is common and may predate other symptoms by over a year. Autonomic neuropathy is a more serious feature, which typically gives rise to postural hypotension, impotence, weight loss and disturbed gastro-intestinal motility, often in association with some degree of peripheral neuropathy. The clinical manifestations of autonomic disorders are protean and should be specifically sought through enquiry about erectile 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. Involvement of the gastrointestinal 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 of AL amyloidosis and can cause airway obstruction, difficulty eating and sleep apnoea. Features of gastrointestinal amyloid include early satiety, diarrhoea, chronic nausea, malabsorption, weight loss, gut perforation and frank rectal bleeding. Certain symptoms, notably early satiety and explosive post-prandial diarrhoea, often reflect disturbed gastrointestinal motility due to autonomic neuropathy. Hepatomegaly is present in approximately one quarter of patients at diagnosis and, in the presence of heart failure from amyloid cardiomyopathy, it may not be possible clinically to differentiate hepatic amyloid infiltration from venous congestion. Haemorrhage is a frequent manifestation of amyloidosis and can be a serious problem. It occurs at some stage during the course of the disease in about one-third of patients, and an abnormal clotting screen is present in about one half (Mumford et al. 2000). The mechanism is often multifactorial but may include vascular fragility as a result of endothelial amyloid deposits and/or loss of vitamin K-dependent clotting factors through binding to amyloid deposits, typically in the spleen, thus leading to a warfarin-like effect (Furie et al. 1981, Choufani et al. 2001). The most common manifestation of bleeding is purpura but life-threatening bleeding is also well described and may follow liver or renal biopsy. Peri-orbital purpura (‘raccoon eyes’) is particularly characteristic. These include the following: AL amyloidosis can occur in a localized form that is most often identified in the upper respiratory, urogenital and gastrointestinal tracts, the skin and the orbit. In such circumstances the amyloidogenic light chains are produced by a subtle focal infiltrate of clonal lymphoplasmacytoid cells within the same tissue as the amyloid deposits. This type of amyloid is frequently nodular in character, but can occur throughout a particular tissue when it is associated with a more infiltrate of clonal The AL nature of localized amyloid can often be confirmed or by but it may not be possible to the associated clonal cells due to their immunoglobulin be in the or of most patients with localized AL amyloidosis, when using The course of the disease is in most patients, but severe to the organ can ultimately Treatment is generally to to Systemic AL amyloidosis is clinically with organ or involvement and diagnosis a high of AL amyloidosis should be in any patient who with nephrotic range proteinuria, cardiomyopathy, peripheral or autonomic neuropathy, or not a can be in the or for of amyloid related organ dysfunction should be in patients with multiple myeloma or known of the diagnosis is based on symptoms in one organ evidence for involvement by amyloid within other organs should be sought low N-terminal proteinuria or organ are and are not generally because of amyloid deposits within one organ and a search for dysfunction of other organs usually Amyloidosis is a diagnosis. amyloid is investigations to the type and the of organ involvement should be for immunoglobulin light chains in AL amyloidosis has only and the presence of a not per a diagnosis of AL amyloidosis. Amyloidosis is therefore often diagnosed as AL type only after of and by and hereditary by genetic Importantly, hereditary and amyloidosis are more common than and may with MGUS, which can to et al. following of or may be in amyloid that of involvement by is virtually diagnostic of AL and of a particular pattern of abnormal including in the heart, by is of cardiac amyloidosis. of tissue in where genetic should be in all cases of amyloidosis in cases of should be by amyloid or et al. is usually diagnosed by of an organ and with the amyloid deposits pathognomonic when under the diagnosis may be confirmed in cases with by by a low risk procedure et al. or which are low risk et al. & Gertz 1995). the low of a not amyloid and should be by of an organ the clinical should be with for the presence of amyloid. of amyloid is and is not is when from are available most known amyloid but are in of patients with AL amyloid due to the presence of normal and because light chain that are by to kappa or lambda light chains may be during and tissue In in can or amyloidosis of and of the amyloid protein by is rarely possible from a and renal and/or gastrointestinal are for this amyloid may be improved by the same tissue with and et al. This is to AL amyloidosis from hereditary forms of amyloidosis. dominant hereditary systemic amyloidosis is by in the for A C and A history of amyloidosis may be due to The clinical features in hereditary systemic amyloidosis may be from in AL amyloidosis. and A amyloidosis are more common than and of patients in hereditary amyloidosis was as AL amyloidosis in a British of cases amyloid of or A chain type et al. amyloidosis with polyneuropathy and/or amyloid cardiomyopathy, and there should be a low for the in patients with this A amyloidosis should be in any patient with an renal presentation and has a on renal with glomerular involvement in the absence of amyloid. is available at the Health NAC available at fibrils can be isolated from tissue samples and characterized by This is the only for the amyloid type and can associated with hereditary amyloidosis. can amyloid from tissue samples et al. 2008, et al. and with of amyloid type in most cases et to may also amyloid from samples et investigations are as The light chain et al. gives a result (raised level of kappa or lambda with an altered ratio of kappa to lambda light in of patients with systemic AL amyloidosis, including in a monoclonal immunoglobulin be demonstrated by et al. This is not for AL amyloidosis in that monoclonal are in patients with other B-cell malignancies, particularly in the of myeloma patients and approximately of In patients with chronic disease the of kappa and lambda is with the and, the range for a normal ratio with progressive renal failure et al. 2008). The between the amyloidogenic and has as being in the component and is to patients with renal failure et al. 2008, et al, 2011). It is to that 10–15% of AL patients have only abnormal and for these patients be for A between the and of at diagnosis has been as being for using in as a disease et al. and this includes about of patients with diagnosed systemic AL amyloidosis. The is well and to have some for have not been 15% of patients with abnormal the on there being a which has been as et al. A of patients an of A is in the or by in approximately of patients with AL amyloidosis. an whole monoclonal immunoglobulin is present in the is in of patients, in over of patients and very rarely 30 (Kyle & Gertz 1995). patients with myeloma are than 10% AL amyloidosis patients have a of unpublished data). It is therefore to because the level of in AL amyloidosis is usually very low and is often However, on is in or in of is when for AL amyloidosis because rare clonal may be using The possibility of the following alternative should be in all patients with The possibility of the following alternative should be in all patients with amyloidosis who have a plasma cell Once a diagnosis of AL amyloidosis has been investigations are to the and severity of organ with of the underlying monoclonal plasma cell dyscrasia to a diagnosis of myeloma or other criteria for amyloid organ involvement were in and form the for and including clinical trials et al. The criteria were and the criteria are in 2 & on other cause in the absence of renal failure or atrial fibrillation Hepatomegaly with liver in the absence of heart failure upper of normal symmetrical peripheral neuropathy Autonomic postural hypotension, erectile dysfunction dysfunction to organ infiltration with symptoms pattern of infiltration laboratory in patients with AL amyloidosis include glomerular proteinuria in of patients and impairment of renal excretory function abnormalities are until liver amyloidosis is and are most commonly in heart failure due to amyloid cardiomyopathy may cause liver function in the absence of liver involvement by amyloid. is amyloidosis is associated with myeloma, bleeding or chronic abnormal clotting screen is a is the most frequent but is of clinical A is the only associated with bleeding (Mumford et al. 2000). of and cardiac are seen in a wide of cardiac conditions and in chronic However, AL amyloidosis is by an of unpublished et al. This investigation is available at the and is performed in patients who are for of or amyloidosis. fibrils in with the normal plasma protein and this is the for the of for imaging and amyloid deposits et al. and specifically to amyloid deposits in proportion to the of amyloid This diagnosis and of deposits by whole although cardiac and amyloid is et al. It is in the and of organ involvement by and for the of treatment and it is that it be performed in all patients when It can also be as evidence for a diagnosis of amyloidosis when tissue is not amyloid is by but and provide about the of cardiac function and prognosis. of is very in this context the of AL amyloidosis. features of cardiac AL amyloidosis on include reduced QRS voltages and a pattern of evidence of a regional on The features of amyloid include thickened walls with normal or small thickened and The is frequently although and imaging may a in systolic in early stage cardiac amyloidosis et al. There is a poor correlation between and one or other of which may normal in the presence of clinically cardiac amyloidosis. dysfunction is common in the elderly population and in chronic disease however, and it may be to a patient with AL amyloidosis has cardiac involvement. The of the of and cardiac in with in this context has not been The criteria for cardiac involvement in AL amyloidosis in the absence of an are a on of with other cardiac cause et al. The for patients with cardiac disease may be to patients with cardiac amyloidosis. provides and on cardiac amyloid in a to the is for and of is in tissue subtle abnormalities et al. et al. but based on provide information. The of is of cardiac amyloid et al. and with prognosis et al. 2008). is in patients with other of because it can differentiate amyloidosis from the of which may not be possible by after of a which to be in certain although not in the to be for cardiac amyloid deposits et al. 2008, et al. et al. in the diagnostic of or amyloid to be in patients with amyloidosis may and there may be on function These may be where neuropathy is or present and an axonal neuropathy. may be to the diagnosis. is variable but is generally poor if AL amyloidosis is survival has improved from a of years in the and to more than 5 years in (Kyle & Gertz et al. et al. probably a of and more The natural history varies with the and nature of organ involvement but only of all AL amyloidosis patients or more years from the of diagnosis (Kyle et al. & 2008). and have predominantly on cardiac or et al. et al. et al. 2011). The most system for AL amyloidosis to is based on the and et al. The of disease and to prognosis are as recently, a system cardiac and a of over patients, identified based on a system that 1 for the presence of of the following and et al. There is a to and particularly in cardiac the system by et al. the at As well as the a poor prognosis is associated A prognosis is associated of appropriate treatment in AL amyloidosis on and of organ involvement. are in the 2014 AL amyloidosis Treatment et al. Clinical presentation and in AL amyloidosis is by the immunoglobulin light chain variable region of the clonal cells et al. et al. the advice and in these is to be and at the of to the the British Society of the UK Myeloma Forum the any for the of these