Article Text

Systemic disorders in heart disease
Amyloid diseases of the heart: assessment, diagnosis, and referral
  1. S W Dubrey1,
  2. P N Hawkins2,
  3. R H Falk3
  1. 1Department of Cardiology, Hillingdon Hospital, Uxbridge, Middlesex, UK
  2. 2National Amyloidosis Centre, Department of Medicine, Royal Free and University College Medical School, London, UK
  3. 3Brigham and Women's Hospital-Harvard Vanguard Cardiac Amyloidosis Program, Harvard Vanguard Medical Associates, Boston, Massachusetts, USA
  1. Correspondence to Dr Simon W Dubrey, Department of Cardiology, Hillingdon Hospital, Pield Heath Road, Uxbridge, Middlesex UB8 3NN, UK; simon.dubrey{at}thh.nhs.uk

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The amyloidoses are a group of diseases in which amyloid, a proteinaceous substance, deposits in one or more organs. As many as 23 different precursor proteins to the formation of amyloid have been described in man. These may deposit themselves in a fibrillar matrix within selected tissues. Fibrils are formed when normally soluble constituents undergo transformational change and misfold to become relatively insoluble. A variety of mechanisms promote these changes, which result in the final common pathway of the deposition of non-branching fibrils that can be visualised by electron microscopy and which are seen on light microscopy as a homogenous extracellular material (figure 1).

Figure 1

Myocardial biopsy from a patient with congestive cardiac failure and echocardiographic appearances of amyloid deposition. The myocytes appear yellow with the amyloid staining turquoise (sulfated Alcian blue stain). Immunostaining subsequently confirmed transthyretin as the constituent protein.

In the developed world, cardiologists predominantly encounter three main types of amyloidosis that affect the heart; light chain (AL) amyloidosis, senile systemic amyloidosis (SSA), and familial amyloidosis (FAP); the latter most commonly results from a mutation in transthyretin. In the developing world, secondary amyloid (AA) is more prevalent, due to chronic infections and inadequately treated inflammatory conditions. Occurring worldwide and later in life, a further amyloid type to affect the heart is isolated atrial amyloid (IAA).w1 w2 Finally, and much less common, are the non-transthyretin variants, including mutations of fibrinogen, apoprotein, and gelsolin. These rarer types can cause significant cardiac compromise.

Cardiac involvement in amyloidosis is usually part of a systemic disease. The heart is frequently the predominant organ affected but, in some forms of the disease, isolated heart involvement can occur. In patients with a non-cardiac biopsy showing amyloid deposition, cardiac involvement has been defined—by a consensus opinion from the 10th International Symposium on Amyloidosis1—as either a positive heart biopsy and or/increased left ventricular wall thickness (interventricular septal thickness >12 mm) in the absence of hypertension or other potential causes of true left ventricular hypertrophy.

Making an early diagnosis of amyloidosis is critical because, once clinically significant heart disease is present, the prognosis is extremely poor. Amyloid deposition can be a very rapidly progressive disease. Untreated, myocardial wall thickening can progress at rates of between 1.45–2.16 mm/month in patients with AL amyloid.2 With the development of congestive cardiac failure, death can ensue within 6 months.w3 Delay in diagnosis may result in patients being unsuitable for the most intensive forms of treatment, because they are too unwell to survive these treatment programmes. Such treatments include intensive chemotherapy with stem cell transplantation and solid organ transplantation of the heart, liver or kidney. Accurate typing of the amyloid deposits is of utmost importance as the wrong diagnosis may result in withholding appropriate therapy, or giving inappropriate treatment, potentially with catastrophic consequences. Lachmann et al showed that 34 of 350 patients (9.7%) with systemic amyloidosis who were considered to have AL amyloidosis possessed mutations for fibrinogen (18 patients) or transthyretin (13 patients), and hence had familial forms of the disease. Of the remaining three patients, two possessed mutations for apolipoprotein-AI and one a mutation encoding a lysozyme variant.3

The management of amyloidosis is often very complex, in many cases involving and combining chemotherapy, transplantation, and research protocols. The type of amyloid, extent of organ involvement, and the individual mutation will determine treatment options, which can only be formulated within a specialist unit with the appropriate expertise. In this article, we outline the different types of amyloidosis that affect the heart and describe the diagnostic pathway for determining both the presence of the disease and the type of amyloid causing it. Mindful of the audience, we have emphasised the facilities that are available for patients in the UK (appendix 1), but major amyloid centres are also to be found in the USA and continental Europe (appendix 2).

Amyloid types affecting the heart

Light chain (AL) amyloidosis

AL amyloidosis occurs approximately equally in men and women, usually presenting in those over 50 years of age. The disorder is a plasma cell dyscrasia in the same disease family as, but distinct from, multiple myeloma. Myeloma may co-exist with AL amyloid in around 10–15% of cases and portends a poorer prognosisw4; this is not multiple myeloma with secondary amyloidosis, but the co-existence of two separate but overlapping diseases of the plasma cell. In AL amyloidosis a monoclonal plasma cell population produces an abnormal paraprotein which misfolds to produce amyloid. The organs involved include kidneys (74%), heart (60–90%), liver (27%), peripheral nervous system (22%), and autonomic nervous system (18%). Carpal tunnel syndrome occurs in 20% and may pre-date other disease manifestations by over a year (figure 2A).4 In the majority of patients (69%) more than one organ is compromised.5 About 20% of patients have dominant symptomatic cardiac amyloid at diagnosis, but clinically isolated heart involvement is seen in <5% of cases.6 When amyloid involves the vasculature, and particularly small vessels in the myocardium, patients may present with classical exertional angina. The presence of cardiac amyloidosis is indicative of the worst prognosis compared to other organ involvement7; this can frequently prevent application of the most effective therapies.

Figure 2

Schematic diagrams illustrating organ involvement and extent of deposition for four types of amyloid: ‘A’, AL (light chain amyloidosis); ‘B’, SSA (senile systemic amyloid); ‘C’, FAP-TTR (familial amyloidosis due to transthyretin); ‘D’, IAA, isolated atrial amyloid. A darker shade of colour indicates increased likelihood of organ involvement by amyloid. In the AL image (A), note the macroglossia, carpal tunnel (syndrome) involvement, shoulder pad deposition, peri-orbital and muzzle region involvement, thyroid and adrenal but overwhelmingly kidney, heart and liver involvement. In SSA (B), the deposition is largely in the heart, lungs and gastrointestinal tract. Carpal tunnel involvement can occur. In TTR amyloid (C), renal disease is much less prevalent than in the other hereditary amyloidoses, while gastrointestinal dysfunction is common due to the significant autonomic nervous system involvement. Around 20% of TTR mutations are associated with vitreous opacities (‘cotton wool inclusions’) derived from amyloid. In IAA (D), organ involvement is unique to the heart. ANS, autonomic nervous system; BM, bone marrow; CT, carpal tunnel; GIT, gastrointestinal tract; H, heart; K, kidney; L, liver; L's, lungs; PNS, peripheral nervous system; S, spleen; T, tongue enlargement (macroglossia); TH, thyroid.

Bone marrow biopsy is useful in order to determine the percentage of plasma cells and the presence of multiple myeloma. In AL amyloidosis they usually comprise 5–10% of marrow cellularity (normal ≤4%), although up to 20% is sometimes seen.8 9 Plasma cells express a clonal dominance of either κ or λ isotype and this can be recognised in up to 92% of patients. There is a predominance of λ over κ light chains in a ratio of 1:3 in AL amyloidosis; this is the reverse of the ratio usually seen in myeloma (3:2).8 w5 In AL amyloid, the plasma cell number, degree of clonality, the quantity of light chain, and the light chain isotype are related to survival.w4 w6 w7

Senile systemic amyloid

Wild-type (non-mutant) transthyretin is the precursor protein of senile systemic amyloid (SSA) and is deposited predominantly in the heart in SSA. It is almost exclusively a disease of men older than 65 years. As the name suggests, this form of amyloid does have systemic distribution, although clinically for this to be evident (other than carpal tunnel syndrome, which is common), or to cause any compromise, is very unusual. Outside the heart, lung involvement predominates but SSA is also found in the gastrointestinal tract, liver, spleen, and endocrine glands (figure 2B). Autopsy studies have revealed amyloid in the bone marrow and tongue.w8 Kidney involvement is less common, but impaired renal function may occur late in the disease when cardiac output is very low.10 As the presenting feature is almost invariably congestive heart failure, myocardial involvement is usually pronounced.w9 A small number of patients, usually in whom the disease has occurred at a younger age, has undergone successful cardiac transplantation.11 Autopsy studies suggest that up to 22–36% of individuals older than 80 years will have demonstrable amyloid deposits in cardiac tissue,10 but these are generally not severe enough to affect cardiac function.

The disease should be suspected in an elderly male patient with unexplained ventricular wall thickening noted on echocardiography and clinical biventricular heart failure. ECG voltage may be normal. Atrial fibrillation or flutter commonly occur, and conduction system disease requiring a permanent pacemaker is a frequent finding.

Hereditary systemic amyloidoses

The hereditary systemic amyloidoses (also termed familial amyloidoses) are a group of autosomal dominant diseases. A family history of neurological disease, heart failure or early death may be helpful in establishing a diagnosis, although spontaneous cases are frequent and the disease may often have been misdiagnosed or missed in earlier generations.

Transthyretin variants

Transthyretin is the most common protein in this category of amyloidosis. It is predominantly synthesised in the liver with smaller amounts from the choroid plexus. Around 100 different mutations have now been identified, most resulting in clinical disease in middle or old age.12 Possessing the mutation does not guarantee that the disease will develop, and penetrance depends on the mutation and the kindred or ethnic group affected. Of the 75 mutations currently known to express a clinical phenotype, around 44 (59%) involve the heart to a greater or lesser degree (figure 2C). Two of the most common mutations encountered are methionine for valine at position 30 (Val 30 Met), which is encountered almost worldwide, and isoleucine for valine at position 122 (Val 122 Ile), which is present in almost 4% of the black population.13 An interesting feature is that amyloid, derived from wild-type transthyretin, coexists with that derived from mutated forms in the amyloid deposits of TTR (tabulation of human transthyretin) amyloidosis.w10

Fibrinogen, apolipoprotein, and gelsolin variants

Variants of fibrinogen, apolipoprotein-AI (apo-AI) and apolipoprotein AII (apo-AII) can also cause amyloid heart disease.w11 w12

Several mutations of fibrinogen have now been identified which almost universally present with renal involvement. Gillmore et alw13 have shown that even after a median follow-up of 4 years in fibrinogen amyloidosis, significant extrarenal disease is uncommon (figure 3A). Furthermore, a family history was frequently absent in this large series which makes the diagnosis more difficult. These patients usually present with proteinuria and progressive renal impairment. However, cardiac involvement can occur and, if present, can be severe enough to necessitate cardiac transplantation.11

Figure 3

Schematic diagrams illustrating organ involvement and extent of deposition for four further types of amyloid: ‘A’, fibrinogen; ‘B’, apoprotein AI (apo-AI); ‘C’, gelsolin; ‘D’, AA (secondary) amyloid. In fibrinogen amyloidosis there is almost exclusive accumulation in the kidneys although heart involvement can be very significant (A). Amyloid of this type is absent from the blood vessels. In apo-AI, the predominant organ involved is kidney (B). In some kindreds the heart is significantly involved as may be the peripheral nervous system. In gelsolin related amyloid the conduction system of the heart is the primary cardiac target (C). Dermatological involvement presents as cutis laxa, in which the skin is inelastic and hangs in folds. In AA (secondary) amyloid, the predominant organ involved is the kidney. Liver and/or spleen involvement is seen in around 10%. Cardiac involvement is rare. ANS, autonomic nervous system; BM, bone marrow; CT, carpal tunnel; GIT, gastrointestinal tract; H, heart; K, kidney; L, liver; L's, lungs; PNS, peripheral nervous system; S, spleen; T, tongue enlargement (macroglossia); TH, thyroid.

Mutations of apo-AI also cause renal disease, which presents with progressive renal failure. In contrast to AL amyloid renal involvement, where proteinuria reaches nephrotic proportions (>3 g/24 h), apo-AI renal disease can occur in the absence of proteinuria. In a proportion of these patients a progressive cardiomyopathy and heart failure occurs (figure 3B). Similar to the situation in which non-mutated transthyretin may form amyloid deposits,14 non-mutated wild type apo-AI also has a tendency to form amyloid fibrils. This type tends to be localised within intravascular atherosclerotic plaques.w14

A rare form of hereditary amyloidosis includes variant gelsolin type (also termed Finnish hereditary amyloidosis or Meretoja amyloidosis).w15 Gelsolin mutations are endemic in Finland, but occur sporadically worldwide. Phenotypes reflect the systemic nature of this amyloid type and include cranial neuropathies, skin involvement (cutis laxa), distal peripheral neuropathy, renal involvement, and lattice corneal dystrophy of the eye.w16

Cardiac involvement by gelsolin amyloidosis is usually restricted to the conduction system (figure 3C).w17 This can be severe, and death related to renal and cardiac involvement has been reported.w18

Non-AL and non-hereditary amyloidoses

Isolated atrial amyloid

In contrast to the pronounced male predominance in SSA, isolated atrial amyloid (IAA) is more common in older women. The reason for these gender distributions remains unexplained. The precursor protein in IAA is atrial natriuretic peptide, which is deposited in the atria (figure 2D). There is no systemic component to this type of amyloid. Although very prevalent in the elderly population and also found in patients with chronic heart failure, it is of little clinical significance, except perhaps being associated with the development of atrial fibrillation.

Secondary amyloid

Worldwide, secondary amyloid (AA amyloid) is one of the most common systemic amyloidoses. It usually occurs in association with chronic inflammatory conditions such as rheumatoid arthritis or chronic infective conditions including leprosy, tuberculosis, and bronchiectasis. The precursor monomer is the inflammatory protein serum amyloid A (SAA) and the kidney is a major target. An overt underlying inflammatory disorder is not, however, obligatory in AA amyloid. A recent large autopsy study on rheumatoid patients has shown that amyloid deposition is often clinically occult and that subclinical heart involvement is as frequent as renal involvement (figure 3D).w19 In the UK, AA amyloidosis is unusual and cardiac involvement is rarely seen.w20 The 5 year survival in patients with cardiac amyloidosis of rheumatic aetiology compared to those without heart involvement was reported as 31.3% and 63.3%, respectively.w21

Diagnosis of amyloid heart disease

The diagnosis of cardiac involvement by amyloid is a three stage process. The initial stage (stage I) is suspicion of the disease and histological confirmation that amyloidosis is present. The initial suspicion may be hampered by the multiple and often non-specific presenting features of amyloidosis—symptoms which, while frequently systemic in character, may be vague.1 8 Stage II involves confirmation that the heart is involved by amyloid deposition. Finally, one must define the exact type of amyloid (stage III) so that treatment can be matched to amyloid type and prognosis determined.

Stage I: determination of the presence of amyloid deposition disease

Identifying that amyloidosis is the cause of a collection of seemingly unrelated symptoms is the first challenge. Classic ‘stigmata’ (figure 4) may point towards a diagnosis of amyloid disease. Macroglossia is virtually pathognomonic of AL amyloid (in the absence of conditions such as acromegaly and myxoedema), but only occurs in around 10% of cases.15 Periorbital purpura (‘racoon’ or ‘panda’ eyes) occurs as a result of vascular fragility along with more serious bleeding issues that are seen in around a third of patients with AL amyloid.w22 More common are recurrent petechial lesions of the eyelids and periorbital area, which may be caused by rubbing the area, or coughing and sneezing. The multisystem nature of AL amyloidosis may cause a patient to seek initial help for a variety of unrelated disorders, but the recognition that several organ systems are involved should raise the possibility of amyloidosis (figure 3).

Figure 4

Symptoms, clinical signs and investigations involved in the diagnosis of amyloidosis. AL, immunoglobulin light chain amyloid; FAP, familial amyloid polyneuropathy; FLC, free light chains; SSA, senile systemic amyloid. *Infiltration of the thyroid and adrenals can cause a cascade of systemic symptoms due to dysfunction of these endocrine glands.

Initial investigations in suspected amyloidosis should include the analysis of serum and urine for the presence of a monoclonal immunoglobulin, in addition to standard blood tests such as full blood count, urea and electrolytes, liver function tests, clotting screen, and glucose and thyroid function tests. Although commonly performed by local hospitals as part of routine screening, standard serum protein electrophoresis will fail to detect a monoclonal band in a significant number of cases, owing to the small amount of circulating paraprotein or its fragment.16 Immunofixation is much more sensitive and should be performed whenever amyloidosis is suspected; the reported sensitivity for AL amyloidosis is 71% (serum) and 84% (urine), respectively.1 However, even with immunofixation, up to 20% of cases will show no detectable paraprotein.15

As a corollary, one should be cautious about concluding that monoclonal gammopathy (MGUS) in a patient with suspicious symptoms indicates the presence of AL amyloid; MGUS is not infrequent in an elderly population (5–10%),w23 and can co-exist in patients with non-AL amyloid.w24 w25 Recently, quantitative measurement of serum κ and λ free light chains (FLCs) has become an established standard in the diagnosis, prognosis and follow-up of AL amyloidosis.w26 The sensitivity of FLC testing for detecting a paraprotein is 10-fold that of immunofixation electrophoresis, and is usually abnormal even when immunofixation is negative. Although an abnormality of this assay is not specific for AL amyloidosis, as monoclonal FLCs are present in around 50% of patients with MGUS and in virtually all patients with myeloma, normal FLCs make AL amyloidosis an unlikely diagnosis.

Once AL amyloidosis is suspected, a bone marrow biopsy is obligatory to determine the plasma cell percentage. A monoclonal plasma cell population has been reported in around 84% of AL patients when immunofluorescence techniques have been used, and a significant elevation of plasma cells (>20% cellularity) suggests coexisting myeloma.

If the FLC assay and bone marrow biopsy are normal, particularly in the absence of a monoclonal band on immunofixation, a search for other forms of amyloidosis should commence. At this point in the diagnostic pathway it would be useful to seek advice from a specialised amyloid centre. In the UK, this is the National Amyloidosis Centre, which is located at the Royal Free Hospital, London (details in appendix 1).

A formal diagnosis of amyloid requires a biopsy specimen which stains with Congo red dye to produce an apple-green birefringence when viewed under polarised light (figure 5). A screening biopsy should be taken from an easily accessible, safe, and likely site of involvement. Details on slide preparation are shown in appendix 3. In practice this is frequently an abdominal fat aspiration (capillaries in the subcutaneous fat are often involved),w27 but can be from kidney, heart, peripheral nerve, salivary gland, stomach, liver or bone marrow. Occasionally, the initial finding of amyloid deposition is incidental, as for example in tissue from a carpal tunnel decompression procedure or on a bone marrow performed for a non-specific haematological abnormality. In such cases a careful search for systemic disease is mandatory.

Figure 5

Slide showing myocardium stained with Congo Red and viewed under cross-polarised light (×200 magnification). The vascular and interstitial amyloid deposition manifests as red–green birefringence.

Antibodies are now available to identify most known amyloid fibril proteins. This is sensitive for AA amyloid, but less so in AL where light chain epitomes usually recognised by κ and λ antisera may be lost during fibril assembly and tissue fixation.15

An assessment of the extent of amyloid deposition, of any type, can be made by serum amyloid P component (SAP) scintigraphy (figure 6).17 Currently, this test is only available within the UK at the National Amyloidosis Centre in London. SAP is a normal plasma glycoprotein which binds reversibly to amyloid deposits. Quantifying the whole body amyloid load, primarily in the liver, kidneys, and spleen, is the main indication. Bone marrow involvement on SAP scanning is also strongly correlated with AL amyloidosis type and is present in around 30% of cases.15 An additional benefit is being able to follow response to treatments. Unfortunately, it is not useful for identifying amyloid in the heart, due to blood pool uptake and the slow passage of the tracer across myocardial capillary endothelia.

Figure 6

Whole body scintigram: an iodine-123 labelled serum amyloid P (SAP) scan which in this case demonstrates tracer uptake in the liver and spleen. A small amount is taken up by the axial skeleton. A, anterior view; B posterior view. Reproduced with permission from: Dubrey SW, Falk RH. Amyloid heart disease Br J Hosp Med 2010;71:76–82.

Stage II: determination of the presence of cardiac amyloid

In some cases of cardiac amyloidosis the heart is the predominant target (SSA) and in others the only target (IAA). In the rare examples of gelsolin mutations it is the conduction system of the heart that is uniquely affected (figure 7).

Figure 7

Symptoms, clinical signs and investigative features suggestive or diagnostic of heart involvement by amyloid. AS, aortic stenosis; BNP, B-type natriuretic peptide; BP, blood pressure; CM, cardiomyopathy; ECG, electrocardiogram; EF, ejection fraction; JVP, jugular venous pressure; LV, left ventricle; MV, mitral valve; QTc, corrected QT interval.

Patients with suspected cardiac involvement from any of the aforementioned amyloid types are likely to have symptoms and signs of heart failure, initially right sided with raised jugular venous pressure, peripheral oedema, and liver congestion. Despite the stiff ventricle, a fourth heart sound is rarely present, due to atrial dysfunction. Potential pitfalls with differential diagnoses that may cause thick walled hearts are listed in table 1.

Table 1

Differential diagnoses for amyloid heart disease

The ECG shows low voltage (all limb leads <0.5 mV) in around 46–71% cases of AL amyloid and frequently in familial forms of the disease (figure 8).6 w28 A pseudo-infarction pattern is most common in AL amyloid and usually involves the precordial ECG leads (V1–V3), but can also occur in the inferior leads (II, III, and aVF). Surprisingly, the rhythm is often sinus, although atrial fibrillation and conduction system disease do occur as the disease progresses. This may be because the extensive atrial involvement leaves inadequate atrial myocardium to sustain atrial fibrillation. In severe involvement, atrial thrombi may be present even when sinus rhythm is present due to atrial electromechanical dissociation with consequent atrial standstill. The onset of atrial fibrillation may cause rapid clinical deterioration with an escalation of thromboembolic risk. Ventricular rhythm disturbance, prolongation of the QT interval, and abnormalities on signal averaged ECGs are also well described.w29–w31 Biomarkers recently identified as useful for prognosis include N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin measurements.w32 w33 In common with the use of NT-proBNP in heart failure, generally it is best used as a ‘rule out’ test. Palladini et al reported that no patients with AL amyloid heart disease had an NT-proBNP concentration <55 pmol/l.w33 Detectable troponin T or I has been described as being associated with a reduced survival when compared to patients in whom no troponin elevation was found.w34 However, high sensitivity troponin assays may result in detection of troponin in a higher proportion of patients and lessen the clinical significance of this finding.

Figure 8

Resting 12 lead ECG showing extreme low voltage limb leads (mean voltage <0.2 mV) and Q waves in the anterior chest leads C1 through C3. Both features are highly characteristic of AL (light chain) amyloid heart disease. Reproduced with permission from: Dubrey SW, Falk RH. Amyloid heart disease Br J Hosp Med 2010;71:76–82.

A chest radiograph may not suggest the diagnosis, even when amyloid deposits have been found in other organs, because the heart size can be normal, particularly in early cardiac amyloidosis. The presence of a pleural effusion is not uncommon and can be due to pleural disease or heart failure. The mainstay of cardiac screening is the appearance on two dimensional echocardiography (figure 9). The left ventricle (and often the right) is thick walled (due to infiltration with amyloid, rather than caused by myocyte hypertrophy), and the left ventricle is rarely dilated. Atria are often large and immobile with what has been labelled as ‘owl's eyes’ appearance. Thrombi may be present within any cardiac chamber but most frequently the atria. Small pericardial effusions are often seen. The valves, papillary muscles, and intra-atrial septum are also thickened. Mild valvular dysfunction is quite common, but severe dysfunction is rare. It is not possible to distinguish between AL, FAP, non-transthyretin FAP, senile amyloid or the rare secondary (AA) amyloid by echocardiography.18 w9 w20 Doppler echocardiography shows characteristic restrictive filling patterns with rapid left ventricular inflow deceleration times and low ‘A’-wave velocity (figure 10). Serial studies show a progression of diastolic dysfunction with disease progression.w35 Pulsed tissue Doppler interrogation of long axis function now provides information on ventricular dysfunction before any changes in ejection fraction occur.w36 No echocardiographic characteristics are specific for amyloid heart disease; combining these features with the clinical signs and usually a low voltage ECG is the best way to distinguish amyloidosis from other diagnoses.4 However, an ECG may have normal voltage in senile amyloid. Preserved ECG voltage, and very occasionally voltage that suggests ‘true hypertrophy’, can occasionally be seen in the presence of significant amyloid infiltration.w28 In some patients this may be due to pre-existing left ventricular hypertrophy caused by previous hypertension.

Figure 9

Echocardiogram showing a four chamber view in end diastole (A) and end systole (B) from an elderly male with senile systemic amyloid. Note the bi-atrial dilatation and normal internal ventricular chamber dimensions.

Figure 10

Transmitral Doppler. The E-wave (E) is prominent, often with a rapid deceleration time indicative of restrictive filling. The A-wave (A) is small and characteristic of atrial failure in a patient with AL (light chain) cardiac amyloid infiltration.

Cardiac magnetic resonance (CMR) imaging has now established a role in the diagnosis of amyloid heart involvement. Features include global gadolinium late enhancement (GLE) in a subendocardial distribution (figure 11).w37 w38 Recent work has shown that, for AL amyloid, CMR with GLE is highly sensitive and specific for the identification of cardiac involvement. However, it does not predict survival simply by its presence.19 w39

Figure 11

Magnetic resonance scan of the heart. Four chamber view. Late gadolinium enhancement (white arrows) is seen in a global endocardial distribution. LA, left atrium; LV, left ventricle: RA, right atrium; RV, right ventricle.

Myocardial biopsy is valuable when amyloidosis is suspected from non-invasive testing, but non-cardiac tissue stains negative for amyloid deposition. It is also useful in the occasional case in which a definite diagnosis of systemic amyloidosis has been made, but where coexistent cardiac disease such as aortic stenosis or severe hypertension may have caused true left ventricular hypertrophy. We do not recommend endomyocardial biopsy in the majority of cases with non-cardiac biopsy proven amyloidosis, as ventricular thickening seen on echocardiography makes cardiac involvement highly likely and normal wall thickness with normal ejection fraction is a prognostically good sign, even if a small amount of cardiac amyloid is detected at biopsy.

The World Health Organization has now developed a grading system to describe the extent of compromise due to heart involvement by amyloid (table 2).

Table 2

World Health Organization staging system for cardiac amyloid

Stage III: determination of the exact type of cardiac amyloid

Establishing the precursor protein determines amyloid type. Free κ and λ light chains in the serum or urine combined with a plasma cell dyscrasia indicate AL amyloid; however, this can also occur in MGUS and myeloma. If an abnormal FLC ratio is absent immunohistochemical confirmation of transthyretin derived amyloid on biopsies would be the next step.w40 DNA analysis is available at the National Amyloidosis Centre and is principally used to distinguish more ‘diagnostically occult’ AL amyloid from hereditary forms.w41 In the context of normal wild type transthyretin being found (no mutation identified) then the diagnosis shifts to one of senile systemic amyloid (figure 12).

Figure 12

Diagram illustrating fundamental diagnostic tests in establishing a specific type of amyloid involvement of the heart. AA, secondary amyloidosis; AL, light chain amyloid; FLC, free light chains; SSA, senile systemic amyloidosis. *AL amyloid may co-exist with myeloma and free light chains may also be present in monoclonal gammopathies of unknown significance.

Finally, amyloid fibril protein sequencing can unravel the amino acid sequence of the fibril and is the method by which the actual genes associated with hereditary amyloidosis have been identified.

Management of amyloid diseases

The detailed management of the precursor protein abnormality leading to amyloidosis disease states is outside the remit of this article.4 16 w5 AL amyloidosis can be treated using high dose intravenous melphalan chemotherapy.9 The aim is to eliminate the responsible plasma cell clone. This therapy requires preliminary stem cell ‘harvesting’ followed by, post-chemotherapy, autologous stem cell transplantation (ASCT). Unfortunately, patients in whom the heart is significantly compromised by amyloid infiltration tolerate ASCT very poorly. However, a small number of highly selected patients have undergone sequential orthotopic heart transplantation followed by ASCT, in order to treat the underlying disease process.w42 In patients considered to be at too high a risk for high dose chemotherapy with ASCT, combinations of dexamethasone with oral melphalan, lenalidomide or bortezomib may produce a haematologic and clinical response. All these therapies need to be administered by a haematologist skilled in treating AL amyloidosis, in conjunction with a skilled cardiologist who can follow the patient carefully.

In the case of the familial amyloidoses caused by transthyretin, fibrinogen, and apolipoprotein, treatment involves liver transplantation to remove the source of the mutant protein. In all cases, consideration may need to be given to transplantation of additionally involved organ targets, including the heart and kidney.

In SSA, IAA, and AA amyloidoses, no proven specific disease modifying therapy exists, although clinical trials of promising compounds are in progress. In AA amyloidosis, treatment of the underlying inflammatory or infective aetiology is the only way to suppress the disease state. From a purely cardiac point of view, management involves conventional heart failure therapies with particular caution in the use of any negative inotropic agents. Diuretics are the mainstay of treatment, and angiotensin converting enzyme inhibitors and angiotensin II receptor blockers must be used carefully to avoid hypotension and problems with underfilling of ‘stiff’ hearts. Hypotension with these drugs is particularly prevalent in AL amyloidosis. Permanent pacing should be used if indicated for conduction disease, and full length support stockings and the α agonist midodrine may help with postural hypotension due to autonomic neuropathy. Digoxin is of no value except in the uncommon case with atrial fibrillation and a rapid ventricular response.

Conclusion

Heart involvement is the predominant feature in some types of amyloidosis while in others it is rare. In the majority of cases cardiac involvement is very detrimental, reducing therapeutic options and survival.

Diagnosis is paramount to the management of the spectrum of the amyloidoses. Cardiologists are likely to have their suspicions first aroused by echocardiographic two dimensional images. These are now increasingly likely to be supported by CMR scanning with gadolinium enhancement. These techniques do not currently possess the sensitivity to distinguish different amyloid types, and in cases of familial amyloid the exact mutation and phenotype for that family will be necessary to predict a likely clinical outcome. In some cases, the diagnosis requires a cascade of advanced techniques and considerable expertise to tease out the responsible protein. However, the correct typing of the amyloid, once a diagnosis of amyloidosis has been made, is critical for the correct, and potentially life-saving, treatment of the patient and should be pursued with appropriate vigour.

Important points in the diagnostic pathway

  • Amyloidosis must be suspected when systemic features are present.

  • The classic stigmata (panda eyes, macroglossia, and skin features) should be sought, but are often not present.

  • Patients must be identified as early as possible to allow all treatment options.

  • The type of amyloid must be correctly identified.

  • Family history should be enquired about.

  • The ECG and echocardiogram are integral to the initial diagnosis, indicated by the low voltage to mass ratio.

  • A histological diagnosis is ultimately required.

  • Expert opinion from a specialist amyloid unit should be sought.

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Acknowledgments

We thank Dr M Burke for supplying the image and legend for figure 5.

Appendix

The National Amyloidosis Centre for the UK

The National Amyloidosis Centre (NAC) is based at the Royal Free Hospital, London, NW3 2PF (telephone number 020 7433 2725 for general enquiries). A large amount of information on all the amyloidoses, and the services offered by the NAC, is available on the website: http://www.ucl.ac.uk/medicine/amyloidosis/nac/.

Transport of samples to the UK National Amyloidoses Centre—Slides, which should be unstained (see appendix 3), or the tissue block can be sent to the NAC. Biopsy samples (blocks) should contain as much tissue as is available and be embedded in wax. Formaldehyde preservation should be avoided as transportation is problematic due to toxicity issues. When sending blood samples for hereditary amyloid testing, this should include a 2–5 ml EDTA sample as well as serum or clotted blood and a completed request form (obtained from NAC). Samples can be sent at room temperature by first class post and should arrive in 3 days or less. Urine is sent as a fresh aliquot from part of a 24 h collection with the total volume recorded.

Appendix

Major amyloid treatment and research centres

1. Boston Medical Centre Treatment and Amyloid Research Program

Contact: Dr Martha Skinner MD

Boston University School of Medicine

72 East Concord Street, Boston, MA 02118, USA

Tel (617) 638-4317, fax (617) 638 4493; email amyloid{at}bu.edu

2. Brigham and Women's Hospital-HVMA Cardiac Amyloidosis Program

Contact: Rodney H Falk MD

Harvard Vanguard Medical Associates

133 Brookline Ave, Boston, MA 02459, USA

Tel (617) 421 6088; email rfalk{at}partners.org

3. Mayo Clinic (Rochester) Haematology and Amyloidosis Program

Contact: Dr Morie Gertz MD

Mayo Clinic

200 First Street SW, Rochester, MN 55905, USA

Tel (507) 538 3270

4. Indiana University School of Medicine

Contact: Dr Merrill Benson MD

Department of Medical and Molecular Genetics

Medical Research and Library Building 130,

975W Walnut St, Indianapolis, IN 46202-5251, USA

Tel (317) 635 7401

5. Amyloidosis Research and Treatment Centre

Contact: Dr Giampaolo Merlini MD

University of Pavia, Pavia, Italy

Tel 0382-502994; fax 0382 502990; email centro.amiloidosi{at}smatteo.pv.it

Appendix

Slide preparation

If sending slides, the following requirements are requested:

  1. 22 serial sections on polysine slides or equivalent, dried overnight at 37°C, and cut as follows:

  2. Sections 1–9, 6 μm thick

  3. Sections 10–21, 2 μm thick

  4. Section 22, 6 μm thick, on the same slide as section 1

  5. Sections placed near the top of the slide if possible

If only a small amount of material is available please supply only sections 1–9.

References

  1. An important consensus statement concerning the definitions for organ involvement which also defines thresholds for whether an organ system has responded to treatment.

  2. This paper highlights the issues that we address in our article concerning the ease with which patients can be misdiagnosed and, as a result, receive not only inappropriate but harmful treatment.

  3. A large review that details the presenting features and clinical findings in light chain (AL) amyloid heart disease.

  4. This is the largest published series that summarises the clinical features of patients with AL amyloid.

  5. A comprehensive and extensive review of the major amyloid diseases.

  6. This paper describes the characteristics, various types of amyloid, and the outcome of patients who have undergone heart transplantation for amyloid cardiomyopathy.

  7. An important contribution, indicating that up to 4% of African American patients carry a gene for one particular type of transthyretin mutation, that may result in amyloid heart disease.

  8. This paper not only identified wild type (non-mutant) transthyretin as the protein sub-unit in senile systemic amyloidosis, but contributes to our understanding of disease progression (with wild type transthyretin) following theoretical curative liver transplantation in some forms of hereditary amyloidosis.

  9. One of the most recent comprehensive reviews of the management of patients with amyloid heart disease. Well illustrated and extensively referenced.

  10. This paper details one of the most useful screening tools available for determining the whole body load of amyloid deposition. Its disadvantage is that technical reasons prevent it being used to assess heart involvement.

View Abstract

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

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Footnotes

  • Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The authors have no competing interests.

  • Provenance and peer review Commissioned; not externally peer reviewed.