Systemic amyloidoses: What an internist should know

European Journal of Internal Medicine 24 (2013) 729–739

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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim

Systemic amyloidoses: What an internist should know☆,☆☆ Giovanni Palladini, Giampaolo Merlini ⁎ Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy Department of Molecular Medicine, University of Pavia, Pavia, Italy

a r t i c l e

i n f o

Available online 18 November 2013 Keywords: Amyloidosis Diagnosis Treatment

a b s t r a c t Systemic amyloidoses are rare, complex diseases caused by misfolding of autologous proteins. Although these diseases are fatal, effective treatments exist that can alter their natural history, provided that they are started before irreversible organ damage has occurred. The cornerstones of the management of systemic amyloidoses are early diagnosis, accurate typing, appropriate risk-adapted therapy, tight follow-up, and effective supportive treatment. Internists play a key role in suspecting the disease, thus allowing early diagnosis, starting the diagnostic workup and selecting patients that should be referred to specialized centers, judiciously titrating supportive measures, and following patients throughout the course of the disease. Here we review the pathogenesis, diagnosis and treatment of the most common forms of systemic amyloidoses. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction

2. Pathogenesis

Systemic amyloidoses are caused by conformational changes and aggregation of autologous proteins that deposit in tissues in the form of fibrils [1]. This process causes functional damage of the organs involved, and eventually leads to death, if left untreated. With an estimated incidence of 9 cases per million person-year [2], systemic amyloidoses are listed among rare diseases. Nevertheless, their annual rate is comparable to that of chronic myelogenous leukemia and Hodgkin's disease [3], which are well known to internists despite their relative rarity. In recent years, our understanding of the pathogenesis of systemic amyloidoses and our ability to treat these diseases have much improved. The most common forms of systemic amyloidoses are now treatable, patients' survival can considerably improve, and quality of life can be restored, provided the disease is diagnosed at early stages and appropriately managed [4–7]. Thus, it is vital that physicians in general, and particularly internists, to whom patients with multiorgan dysfunction are most often referred for diagnosis, are aware of these diseases and are able to recognize their early clinical manifestations timely, when organ damage is still amenable to improve.

Almost 15 forms of systemic amyloidoses are known and classified according to the different amyloidogenic precursor proteins [8]. However, 5 types of amyloidosis account for more than 99% of the patients referred to our center (Table 1). The molecular mechanisms through which different soluble proteins become prone to undergo an irreversible transition from their native conformation into highly ordered aggregates sharing the unique structural features of amyloid fibrils are diverse [1]. They involve increased synthesis, as in the amyloidosis reactive to chronic inflammation, mutations increasing the propensity to form amyloid in the hereditary amyloidoses, and aging in senile systemic amyloidosis. Immunoglobulin light chain (AL) amyloidosis is the most common form of systemic amyloidosis in Western countries and accounts for almost three fourths of patients with systemic amyloidosis referred to our center. In AL amyloidosis the pathogenic protein is a monoclonal light chain produced by a usually small-sized bone marrow plasma cell clone [9]. Both the concentration of the light chain and mutations increasing their amyloidogenic propensity are involved in the pathogenesis of AL amyloidosis. The mechanisms of organ damage are still debated. The observations that the infusion of light chains from patients with cardiac AL amyloidosis increases end-diastolic pressure in isolated rat hearts, well before amyloid deposits can form [10], and that in patients in whom chemotherapy succeeds in reducing the concentration of the circulating light chain, cardiac dysfunction improves despite amyloid deposits remain unaltered [11,12] indicate that cardiac damage is caused primarily by a direct toxic effect of circulating light chains. More recent experimental evidence, showing that amyloidogenic light chains cause cardiotoxicity and early mortality in zebrafish, further supports this hypothesis [13].

☆ This work was supported by grants from the Ministry of Health (Ricerca Finalizzata Malattie Rare), “Istituto Superiore di Sanità” (526D/63); Ministry of Research and University (2007AESFX2_003);and “Associazione Italiana per la Ricerca sul Cancro” Special Program Molecular Clinical Oncology 5 per mille n. 9965. ☆☆ The authors have no conflicts of interest to disclose. ⁎ Corresponding author at: Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Viale Golgi, 19, 27100 Pavia, Italy. Tel.: +39 0382 502994; fax: +39 0382 502990. E-mail address: [email protected] (G. Merlini).

0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.10.007

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Table 1 Most common forms of systemic amyloidosis. Amyloid type

AL amyloidosis

Precursor protein (main synthesizing organ)

Immunoglobulin light chain (bone marrow) Hereditary ATTR Mutated transthyretin amyloidosis (liver) Hereditary Mutated apolipoprotein AApoAI AI (liver, Gastrointestinal amyloidosis tract) AA (reactive) Serum amyloid A protein amyloidosis (liver) Senile systemic Wild type transthyretin amyloidosis (liver)

Table 2 Conditions associated with AA amyloidosis. Organ involvement Heart Kidney Liver PNS

ANS ST

++

++

+

+

+

+

++

±

−

++ +

−

++

+

++

−

−

−

±

++

+

−

+

−

++

−

−

−

−

−

Conditions

Diseases

Inflammatory arthritides

•Rheumatoid arthritis •Ankylosing spondylitis •Adult Still's disease •Juvenile idiopathic arthritis •Psoriatic arthritis •Gout •Crohn's disease •Ulcerative colitis •Behcet's disease •Polyarteritis nodosa •Giant cell arteritis •Takayasu's arteritis •Polymyalgia rheumatica •Familial Mediterranean fever •Tumor necrosis factor receptor associated periodic syndrome (TRAPS) •Muckle–Wells syndrome •Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurological, cutaneous and articular (CINCA) syndrome •Hyper-IgD syndrome •Castleman's disease •Hodgkin's lymphoma •Waldenström's macroglobulinemia •Hairy cell leukemia •Hepatocellular adenoma •Renal cell carcinoma •Adenocarcinoma of the lung •Adenocarcinoma of the gut •Mesothelioma •Schnitzler syndrome •Osteomyelitis •Tuberculosis •Pyelonephritis •Leprosy •Whipple's disease •Bronchiectasis •Chronic cutaneous ulcers •Cystic fibrosis •Epidermolysis bullosa •Injection drug users •Jejuno-ileal bypass •Paraplegia •Common variable immunodeficiency •Hypogammaglobulinemia •X-linked agammaglobulinemia •Cyclic neutropenia •HIV infection/acquired immunodeficiency syndrome •Obesity •Sarcoidosis •Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome

Inflammatory bowel diseases Systemic vasculitides

ANS, autonomic nervous system; ST, soft tissues; and PNS, Peripheral nervous system.

Specific structural features of the pathogenic light chains play a role in organ tropism. Three Vλ genes, IGLV2-14, IGVL6-57 and IGLV3-1 contribute to encoding almost 60% of amyloidogenic λ light chains [14–16], light chains of the λVI family are almost invariably associated with amyloidosis most often involving the kidney [17,18], and the Vλ gene IGLV1-44 is preferentially associated with cardiac involvement [19]. The most common form of hereditary systemic amyloidosis is caused by mutated transthyretin (TTR), a 127-amino acid protein that forms tetramers transporting thyroxin and holoretinol binding protein in plasma. The amyloid process initiates with the dissociation of the tetramer into monomers which misfold and aggregate into amyloid fibrils. More than 110 mutations in the TTR gene are known to promote the amyloid process. The age of onset and pattern of organ involvement of hereditary TTR amyloidosis (ATTR) is influenced by different TTR mutations, ranging from isolated cardiac amyloidosis to forms exclusively characterized by peripheral neuropathy, through mixed cardiac and neuropathic phenotypes [20]. Wild-type TTR has an intrinsic amyloidogenic propensity and, given enough time, can cause cardiac amyloid deposits in senile systemic amyloidosis (SSA), affecting men as young as 60 years and reaching a 15% prevalence in men over 80 years old [21]. Mutated apolipoprotein A–I (ApoAI) can cause amyloidosis (AApoAI) most frequently manifesting with asymptomatic cholestatic hepatopathy, renal failure, and testicular involvement with hypogonadism [22]. Certain mutations can cause progressive cardiomyopathy, leading to heart failure [23]. Proteolytic remodeling plays an important role in determining the amyloidogenic propensity of ApoAI variants [24]. In reactive amyloidosis (AA), the amyloid fibrils are formed by proteolytic fragments of the acute-phase protein serum amyloid A (SAA). Reactive amyloidosis is a long-term complication of chronic inflammatory disorders listed in Table 2 [25]. Inflammation triggers the production of cytokines, particularly IL-1, IL-6, and TNF-α, which, in turn, increase liver synthesis of SAA. A persistently elevated concentration of SAA is necessary for AA amyloidosis to develop; however, not all the patients with chronic inflammation eventually present this complication. This indicates that disease-modifying factors must also play a role in the pathogenesis of AA amyloidosis. The best characterized of these factors is SAA1 genotype: SAA1.1 in Caucasians and SAA1.3 in Japanese are associated with higher incidence and earlier onset of AA amyloidosis in subjects with chronic inflammation [25].

3. Clinical presentation and prognosis The clinical presentation of systemic amyloidoses is protean and mainly contingent upon organ involvement (Table 1).

Hereditary autoinflammatory diseases

Neoplasms

Chronic infections

Conditions predisposing to chronic infections

Hereditary and acquired immunodeficiencies

Other

3.1. Cardiac involvement Amyloid heart involvement presents as a typical restrictive cardiomyopathy. The echocardiographic features of advanced cardiac amyloidosis are distinctive, with non-dilated ventricles showing marked thickening of the left and right ventricular walls, as well as of the interventricular and interatrial septa. Amyloid infiltration gives a characteristic aspect to the myocardial texture that has been described as “granular sparkling”. The electrocardiography limb lead voltages tend to decrease as the ventricle wall thickens, resulting in a decreased ratio of voltage to echo-derived left ventricular mass, a finding that strongly suggests an infiltrative cardiomyopathy [26]. Importantly, it should be kept in mind that low voltages are not observed in SSA, rendering more difficult the differential diagnosis with cardiac hypertrophy secondary to hypertension in the elderly. Beyond allowing further insights into cardiac diastolic dysfunction, pulsed tissue Doppler imaging can demonstrate the presence of longitudinal

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systolic impairment before the ejection fraction becomes abnormal [27–29]. Long-axis dysfunction might be demonstrated by strain and strain rate imaging that may also have potential for evaluating the prognosis in AL amyloidosis [27,28,30–34]. At comparable left ventricular wall thickness, myocardial velocity gradient during systole and early diastole is in fact depressed in cardiac amyloidosis when compared with hypertensive heart disease and hypertrophic cardiomyopathy [35]. Cardiac magnetic resonance imaging (MRI) in patients with advanced cardiac amyloidosis shows an unusual pattern characterized by global subendocardial late gadolinium enhancement and associated abnormal myocardial and blood-pool gadolinium kinetics [36–39]. In patients with endomyocardial biopsyproven cardiac AL amyloidosis, late gadolinium enhancement shows good sensitivity (80%) and excellent specificity (94%), being strongly correlated with symptoms of heart failure, as well as with B-type natriuretic peptide (BNP) and troponin concentrations [40–42]. However, a recent study showed that the prognostic value of cardiac MRI is not independent from clinical assessment of heart failure [39]. Although echocardiographic and MRI features are indistinguishable between the different types of amyloidosis involving the heart, the progression of cardiac dysfunction is faster in AL amyloidosis, and prognosis is worse compared to hereditary ATTR amyloidosis and SSA [43]. It has been shown that radiolabeled bone tracers, 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) and 99mTc-pyrophosphate (99mTc-PYP), avidly localize in the heart of patients with TTR amyloidosis, either wild-type or mutated, and scintigraphy with this tracer represents a useful complement to diagnosis, helping differentiating these forms from AL amyloidosis [44–47]. Heart involvement, its presence and degree, is the most important predictor of survival in patients with AL amyloidosis. Among 1399 patients with this disease evaluated at the Pavia Amyloidosis Research and Treatment Center, the heart was involved in 70% of cases, and cardiac involvement was responsible for 85% of deaths. Severe heart involvement at presentation precludes aggressive treatment of the underlying clonal disease and often results in death before therapy has a chance to alter the course of the disease. Indeed, although in the past 20 years the proportion of patients surviving 5 years increased from 30 to 60%, no improvement was made in subjects who present with advanced cardiac involvement [48]. Thus, the early detection of cardiac amyloidosis and the accurate assessment of its severity are of paramount importance. The most practical and useful metrics of cardiac organ damage in AL amyloidosis are the cardiac biomarkers. They provide relevant measures of early cardiac involvement, prognosis and response to therapy. We showed that the serum concentration of N-terminal pro BNP (NT-proBNP) is a sensitive marker of cardiac involvement in AL amyloidosis and is a powerful prognostic determinant, independent of clinical assessment of heart failure, wall thickness and ejection fraction [11]. All patients with cardiac AL amyloidosis have an elevated concentration of NT-proBNP, indicating 100% sensitivity [11,49]. However, caution should be taken in interpreting NT-proBNP values, since NT-proBNP is not a specific marker and can be elevated in non-amyloid cardiac disease, particularly in the presence of atrial fibrillation, as well as in renal failure, which is not uncommon in patients with amyloidosis. In patients with renal failure, BNP is a more specific marker of cardiac dysfunction than NT-proBNP, but its sensitivity in the overall population is lower (89%) [49]. Also the concentration of cTn portends a poor outcome in AL amyloidosis, independently from classical echocardiographic features [50]. These two biomarkers can be combined in a very simple yet accurate staging system that allows discrimination of patients at low, intermediate and high risk, guiding the choice of therapy in single subjects and allowing patients' stratification in clinical trials [51]. While low-risk patients can survive long time even if they fail to respond to first-line treatment, the median survival of high-risk patients is only 3.5 months

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[51]. A European study showed that extremely elevated NT-proBNP concentrations (N8500 ng/L) and low systolic blood pressure (b 100 mmHg) identify a subset of patients with very advanced cardiac disease who survive only few weeks [52]. Recently, a revised staging system including the concentration of circulating free light chains discriminated between four groups with significantly different survival [53]. Refinement of prognostic stratification in AL amyloidosis has also been attempted with novel cardiac biomarkers. Cardiac TnT measured with a high-sensitivity assay (hs-cTnT) proved to be the single most powerful prognostic determinant [54,55]. More recently, midregional pro-adrenomedullin (MR-proADM) was shown to be an additional strong prognostic marker in AL amyloidosis [56]. While standard echocardiographic features, such as wall thickness and ejection fraction, are of little value in prognostic assessment compared to biomarkers, other, more refined, echocardiographic parameters, in particular longitudinal left ventricular function, have been shown to add relevant prognostic information [34]. Arrhythmia is also a prominent feature of cardiac amyloidosis. Approximately one fourth of patients die suddenly. Holter electrocardiography can be of help in the initial assessment of patients with AL amyloidosis: subjects in whom complex ventricular arrhythmias are detected are at high risk of sudden death independently from echocardiographic variables [57]. Recently, it has been shown that fragmented QRS at standard electrocardiogram has an independent prognostic factor in AL amyloidosis and can help refining patient staging [58]. Cardiac involvement in AL amyloidosis is also associated with conduction disturbances, such as prolonged PQ, QRS, QT and QTc intervals and intraventricular blocks that are associated with a poorer prognosis [59]. 3.2. Renal involvement Involvement of the kidney can manifest with proteinuria evolving to overt nephrotic syndrome, renal failure progressing to end-stage renal disease, or both. The kidney is involved in almost all the patients with AA amyloidosis and in 70% of those with AL amyloidosis, and albuminuria is the initial finding in these forms. In ApoAI amyloidosis with renal involvement, a slowly progressing reduction in glomerular filtration rate (GFR) without significant proteinuria is observed [60]. A recent study showed that the estimation of GFR at baseline, serum albumin concentration, and the quality of hematologic response to treatment independently predicted progression of renal damage in AL amyloidosis. The latter two variables were also independently associated with improvement of renal involvement [61]. More recently, it has been reported that profound decreases in proteinuria (N95%) 1 year after treatment initiation are associated with improved survival in AL amyloidosis [62]. In AA amyloidosis, progression to end-stage renal disease and survival are independently affected by SAA concentration and by the presence of end-stage renal disease at presentation [63]. Patients with periodic fever have a better outcome than those with chronic sepsis or Crohn's disease [63]. 3.3. Liver involvement Hepatic amyloidosis manifests with hepatomegaly and cholestasis. However, hepatomegaly can also occur in patients with cardiac amyloidosis and congestive heart failure in the absence of amyloid infiltration of the liver. Slowly progressing cholestasis is the hallmark of a form of hereditary ApoAI amyloidosis which is endemic in northern Italy [22]. In AL amyloidosis the liver is involved in approximately one fifth of patients. In a series of 98 patients with hepatic AL amyloidosis diagnosed by liver biopsy, hepatomegaly was found in 81% of cases, alkaline phosphatase was elevated in 86% of patients, aspartate aminotransferase in 80%, total bilirubin in 21%, and 35% of subjects had a prolonged prothrombin time [64]. Liver biopsy was associated with a small (4%) risk of bleeding [64]. Patients with elevated bilirubin had a very poor outcome, with a median survival of only one month

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[64]. Kappa clones are more frequently found in subjects with liver involvement, being responsible for 30–40% of cases [64,65]. However, lambda light chains causing liver involvement seem to be associated with more aggressive disease, more advanced cardiac involvement and worse outcome [65]. 3.4. Peripheral and autonomic nervous system involvement Peripheral neuropathy is a feature of both AL and hereditary ATTR amyloidosis. However, several TTR mutations give rise to amyloidosis involving almost exclusively the peripheral nervous system, as in the prototypical and most common form of familial amyloid polyneuropathy caused by the Val30Met TTR variant, whereas in AL amyloidosis neuropathy is seldom isolated (2% of cases in our series of 1399 patients). The involvement of the peripheral nervous system is assessed clinically in the presence of symmetric lengthdependent ascending sensorimotor peripheral neuropathy, initially affecting sensitivity to pain and temperature [66]. Electromyography and nerve conduction velocity studies frequently give negative results, because amyloid initially involves small fibers [67]. Autonomic neuropathy manifests with postural hypotension, impotence and bladder and bowel dysfunction, ranging from severe diarrhea to constipation. However, multiorgan damage makes it difficult to clinically evaluate autonomic nervous system involvement. For instance, reduced cardiac output and hypoalbuminemia resulting in contraction of plasma volume can also play a role in the genesis of hypotension. When confirmation of GI involvement is needed, direct biopsy is required, keeping in mind that the finding of amyloid deposits only in the vascular walls on an endoscopic biopsy is very common and often asymptomatic and is not evidence of GI involvement [66]. Asymptomatic involvement of the autonomic nervous system is also very common in patients with AL amyloidosis, with deregulation of arterial baroreflex and autonomic modulation of the heart rate [68]. 3.5. Soft tissue involvement In AL amyloidosis, soft tissue involvement is found in 12% of patients and can include macroglossia, submandibular swelling,

lymphadenopathy, vascular deposits manifested as purpura or claudication of the jaw, muscular pseudohypertrophy, articular deposits, the shoulder pad sign and carpal tunnel syndrome. When present, these signs strongly suggest AL amyloidosis, since they are only exceptionally found in other forms of systemic amyloidosis (Fig. 1). Differently, carpal tunnel syndrome can be found both in AL and in ATTR amyloidosis and can precede by several years the other manifestation of the disease. 3.6. General manifestations of systemic amyloidosis Besides symptoms and signs of specific organ involvement, systemic amyloidoses are often accompanied by manifestations that cannot be directly linked to any organ dysfunction. These include profound fatigue and anorexia. In AL amyloidosis, malnutrition is best assessed by measuring the serum concentration of prealbumin and independently affects survival and quality of life [69–72]. Also in ATTR amyloidosis the nutritional status, best assessed as modified body mass index (mBMI), and gastrointestinal dysfunction strongly affect patients' survival [73]. 4. Diagnosis Systemic amyloidoses are progressive diseases leading to irreversible organ dysfunction and death. However, therapies are available that can halt, and many times reverse, the course of the disease [4]. Thus, timely diagnosis is vital. The early clinical manifestations that should raise the suspicion of systemic amyloidosis, the so-called “red flags”, are reported in Table 3. Early identification of cardiac AL amyloidosis is of particular importance, because this disease progresses rapidly, and, although cardiac function can be restored, this is possible only at early stages. Since amyloidoses are rare diseases population screening is unfeasible. However, it is reasonable to screen patients who are at particularly high risk of developing amyloidosis. For instance, subjects with monoclonal gammapathies of undetermined significance, who have an altered free light chain (FLC) κ/λ ratio should have cardiac biomarkers and albuminuria included in their periodic workup, in order to timely detect the onset of cardiac and/or renal AL amyloidosis

Fig. 1. Soft tissue involvement in AL amyloidosis.

G. Palladini, G. Merlini / European Journal of Internal Medicine 24 (2013) 729–739 Table 3 Early “red flags” of the most common types of systemic amyloidoses. Organ or syndrome

Amyloidosis Early red flags types

Heart

AL

Kidney Liver Soft tissues ANS/PNS

AL, AA AL, AApoAI AL, ATTR AL, ATTR

NT-proBNP N332 ng/L (sensitivity 100%) or BNP N73 ng/L (sensitivity 89%) in patients with monoclonal gammapathy and elevated FLC κ/λ ratio Proteinuria N0.5 g/day (predominantly albumin) Elevation of ALP or γGT in the absence of other causes Carpal tunnel syndrome Neuropathic pain and loss of sensitivity to temperature Erectile dysfunction Onset of hypotension or resolution of hypertension

ALP, alkaline phosphatase; ANS, autonomic nervous system; γGT, γ-glutamyl transpeptidase; NT-proBNP, N-terminal pro-natriuretic peptide type B; PNS, peripheral nervous system; and FLC, free light chain.

[6,7]. Also, it is advisable to periodically look for albuminuria in patients suffering from chronic inflammatory diseases, who can develop renal AA amyloidosis. The diagnosis of systemic amyloidosis requires a tissue biopsy showing amyloid deposits that are effectively detected by their green birefringence under polarized light when stained with Congo red [66]. Subcutaneous abdominal fat aspiration is the simplest and least invasive diagnostic procedure. Its sensitivity is above 80% in AL and AA amyloidosis (with the exception of amyloidosis secondary to familial Mediterranean fever), but is lower in ATTR [74]. Labial salivary gland biopsy is also simple and yields a high diagnostic sensitivity in AL, AA, and ATTR amyloidoses [75,76]. Amyloid deposits are found in the labial salivary glands of almost 60% of patients with systemic amyloidosis and negative abdominal fat aspirate, and the sequential biopsy of these two sites has a negative predictive value of 91%, thus limiting the need for an organ biopsy to less than 10% of patients [77]. The biopsy of the involved organs can be performed if amyloidosis is still suspected but biopsies of alternative sites are negative. The small, but significant, risk of hemorrhage should be taken into account. Rectal biopsy has a good sensitivity in AL, AA, and ATTR amyloidosis [78,79], however, abdominal fat aspirate should be preferred. Gastro-duodenal biopsy can be as informative as rectal biopsy, at least in AA amyloidosis [80,81]. It should be kept in mind that amyloid deposits are more frequently found in the submucosa than in the muscularis mucosae and in the mucosa, therefore biopsies should be deep enough to provide the highest sensitivity [82]. Different types of amyloidosis require different therapeutic approaches. Incorrect amyloid typing results in catastrophic therapeutic consequences, such as exposing to useless and toxic chemotherapy subjects with hereditary or senile amyloidosis. It must be kept in mind that identifying amyloid deposits in a patient with a monoclonal component is not conclusive evidence of AL amyloidosis, due to the high prevalence of monoclonal gammapathies particularly in the elderly [83–87]. Given the substantial overlap in disease manifestations of the most common types of systemic amyloidosis, clinical evaluation is of little help in differential diagnosis. Also, the absence of a family history does not exclude the hereditary amyloidoses, due to the variable penetrance of these diseases. However, in some instances the clinical picture including typical macroglossia, periorbital purpura and/or the shoulder pad sign, as well as the coexistence of cardiac and renal involvement in a patient with a monoclonal gammapathy, strongly suggest AL amyloidosis. In these cases, if cardiac dysfunction requires the prompt initiation of chemotherapy, treatment can be started while waiting for amyloid typing [88]. Light microscopy immunohistochemistry can consistently identify AA amyloidosis. However, conventional immunohistochemistry, as well as immunofluorescence on renal biopsies, is unreliable in AL, when performed with commercial antibodies [89]. Nevertheless, at referral centers using custom-made antibodies, light microscopy immunohistochemistry can be a valuable tool for amyloid

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characterization [90]. At our center we routinely rely on immuno electron microscopy performed on abdominal fat aspirates and organ biopsies [91]. This technique co-localizes the antibody and the amyloid fibril, thus increasing specificity, and could correctly identify the amyloid type in more than 99% of cases in a series of 537 patients referred to our center for suspected systemic amyloidosis [74]. Modern proteomics makes typing of amyloid a direct matter, and several proteomic approaches based on two-dimensional electrophoresis [92,93], laser capture microdissection [94], and Multidimensional Protein Identification Technology [95] have been developed by our group and by Mayo Clinic investigators. The results of tissue typing are confirmed by DNA analysis in the hereditary amyloidoses, and by the demonstration of a monoclonal component of the same isotype as that of the light chain forming the amyloid fibrils in AL amyloidosis. The latter is not trivial endeavor because of the small size of the plasma cell clone, and requires the combination of different high-sensitivity techniques. The sensitivity of standard serum and urine immunofixation in AL amyloidosis ranges from 79% to 96% [96–101]. Immunofluorescence on bone marrow aspirates can detect the amyloidogenic plasma cell clone in 84% of cases [102]. The possibility of measuring circulating FLC offered a most useful complement for the diagnosis of AL amyloidosis. Clonality can be inferred by an altered FLC κ/λ ratio with a sensitivity ranging from 75% to 98% [96–101]. However, only the combination of immunofixation of both serum and urine with the quantification of circulating FLC grants a 98–100% diagnostic sensitivity [101,103,104]. 5. Treatment The mainstay of treatment of systemic amyloidoses is the suppression of the synthesis of the amyloid protein. Alternative strategies include reducing the amyloidogenic propensity of the precursor and targeting the amyloid deposits. Supportive therapy, including organ transplant also plays a major role in improving the patients' symptoms and quality of life and supporting organ function while specific treatment has time to take effect [105]. 5.1. Reducing the supply of the amyloidogenic precursor In AL amyloidosis reducing the concentration of the circulating FLC translates in the improvement of organ dysfunction and prolonged survival [12,96,106–108]. This is obtained by targeting the amyloidogenic plasma cell clone with chemotherapy [109]. The treatment regimens used in AL amyloidosis are adapted from those employed in multiple myeloma. However, AL amyloidosis is not only a hematologic malignancy, but its clinical manifestations and prognosis are dictated by multiorgan dysfunction [110]. Thus, treating these patients is a challenging undertaking even for the hematologists experienced in the care of patients with multiple myeloma, as indicated by the high treatment related mortality and morbidity observed in multicenter studies. This, combined with the need for sophisticated diagnostic techniques, facilitated the creation of a few highly specialized referral centers, where physicians can evaluate and treat the hundreds of patients necessary to develop adequate skills. Yet, the need to travel to referral centers to be administered chemotherapy causes a significant discomfort to patients and is often unfeasible. To overcome these difficulties, more than 25 years ago, we established a network of clinical centers dedicated to the treatment of AL amyloidosis coordinated by our institution and sharing a common, annually updated, therapeutic and diagnostic protocol [111]. The cornerstones of chemotherapy for AL amyloidosis are risk stratification and frequent assessment of hematologic and cardiac response, allowing for a rapid switch to second-line treatment in case of suboptimal efficacy of first-line therapy. Both risk stratification and response assessment are based on measurements of cardiac biomarkers and FLC [112]. Response should be evaluated every two cycles, or three

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months after autologous stem cell transplantation, using the recently updated criteria for hematologic and cardiac response (Table 4) [5,113]. Very few randomized clinical trials exist to guide the choice of treatment in AL amyloidosis; however, thanks to international cooperation and validated response criteria several large trials are ongoing that will eventually define a standard of care [114]. Awaiting the results of the ongoing studies, some indications can be derived from smaller uncontrolled trials and case series. Autologous stem cell transplantation (ASCT), when performed with full dose (200 mg/m2) melphalan, induces a hematologic response in approximately three fourths of patients with complete responses (CR) in about 40% [115]. In the past two decades the mortality related to ASCT has progressively decreased, thanks to improved patient selection based on cardiac biomarkers [116,117]. Currently, ASCT is offered only to highly selected patients, younger than 65 years, with cTnT b0.06 ng/mL and NT-proBNP b6000 ng/L, GFR N 50 mL/min, performance status 0 to 2, ejection fraction N 45%, systolic blood pressure N 90 mmHg (standing), and CO diffusion capacity N 50%, who represent approximately 15% of patients [6,118]. Patients who are not eligible for ASCT are usually offered the oral combination of melphalan and dexamethasone (MDex). This regimen grants a hematologic response in two thirds of patients, with CR in one third of cases [119]. The durability of response to MDex is comparable to that reported with ASCT [120]. Moreover, a randomized trial failed to demonstrate the superiority of ASCT over MDex in terms of both response rate and survival [121]. An alternative to MDex, which has the advantage of sparing stem cells, is a combination of cyclophosphamide, thalidomide and dexamethasone [122]. Currently, the dyad ASCT/MDex is being challenged by the availability of bortezomib. Bortezomib, the first in class proteasome inhibitor, is thought to be particularly effective against amyloidogenic plasma cells relying on proteasome activity to cope with the proteotoxicity posed by the misfolded light chain they synthesize [123,124]. Indeed, both a large retrospective series [125] and a prospective trial [126–128] showed a high rate of rapid responses to this drug in previously treated patients, and suggested moving bortezomib to first-line therapy. Recently, two independent small retrospective case series showed an unprecedented rate of hematologic response (81–94%, with CR in 42–71%) to the combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) [129,130]. Since CyBorD is a stem cell sparing regimen it has been proposed to treat with this combination patients eligible to ASCT, actually performing transplant only in subjects who do not attain a CR [113]. Bortezomib can also be used after ASCT in order to increase the rate of CR [131]. A large, international, randomized trial (NCT01277016) is ongoing comparing MDex vs. MDex with the addition of bortezomib (BMDex). The treatment of high-risk patient is yet an unsolved problem, since it must conjugate maximum tolerability with rapid action. High-dose

Table 4 Criteria for hematologic response and cardiac response and progression in AL amyloidosis. Definition

Criteria

Hematologic response

CR: negative serum and urine immunofixation and normal FLC κ/λ ratio VGPR: dFLC b40 mg/L PR: dFLC decrease N50% compared to baseline NR: all other patients NT-proBNP decrease N30% and 300 ng/L in patients with baseline NT-proBNP ≥650 ng/L or Decrease by at least 2 NYHA classes in patients with baseline NYHA class III or IV NT-proBNP increase N30% and 300 ng/L or cTn increase ≥33% compared to baseline or Decrease of at least 10% of ejection fraction

Cardiac response

Cardiac progression

CR, complete response; dFLC, difference between involved (amyloidogenic) and uninvolved free light chain concentration; FLC, free light chain; NR, no response; NT-proBNP, N-terminal pro-natriuretic peptide type B; NYHA, New York Heart association; PR, partial response; and VGPR, very good partial response.

dexamethasone is poorly tolerated in these patients, since it can precipitate heart failure and cause severe arrhythmias [132,133], and MDex cannot overcome their poor prognosis also when combined with thalidomide [134–137]. Patients who fail to respond to first-line therapy can effectively be rescued with dexamethasone associated with thalidomide [138], lenalidomide, either alone [139–141] or combined with alkylators [142–147], or pomalidomide [148]. Reduction of the supply of the precursor has been also the mainstay of treatment of hereditary ATTR amyloidosis. This was obtained by liver transplantation, replacing the production of the mutated TTR with the wild type protein, beginning in 1990 [149]. Surgical outcome is generally excellent, since patients are not in liver failure at the time of transplant, and three fourth of subjects survive at least 5 years [150]. Factors associated with poor prognosis are an mBMI b600, disease duration N7 years, non Val30Met mutations, and severe peripheral and autonomic neuropathy at the time of transplant [150–152]. The greatest benefits of liver transplant are stabilization and in some instances improvement of neurological symptoms [150,151,153,154] and amelioration of nutritional status, possibly secondary to rapid improvement of gastrointestinal motility [155,156]. The benefit for patients with significant cardiac involvement is less clear. Indeed, it has been shown that cardiac amyloidosis can progress after liver transplant, due to the deposition of wild-type TTR triggered by preexisting amyloid fibrils primarily composed of the mutated protein [153,156–160]. Combined heart and liver transplant can extend the eligibility to patients with advanced cardiac amyloidosis [161]. Progressive amyloid deposits following liver transplantation have been documented also in the eye [162] and in the leptomeninges, leading to intracranial hemorrhage [163], caused by production of mutant TTR by the choroid plexus. Of interest, because the synthetic function of the liver is intact in patients with ATTR amyloidosis, the explanted liver can be transplanted into another individual in a domino transplant. However, the occurrence of symptomatic amyloid deposits in recipients has been reported [164,165]. Lowering TTR concentration by small interfering RNA is an alternative promising strategy which has been proven feasible in a phase I trial [166]. Also in AA amyloidosis, it has been shown that reduction of the amyloidogenic precursor, SAA, results in improvement of organ dysfunction and extended survival [167]. This goal is reached with aggressive treatment of the underlying inflammatory disease. The type of treatment depends on the nature of the inflammatory condition. Attention should be paid to even temporary relapses with increasing SAA concentration, that can be associated with rapid worsening of previously recovered renal damage [25]. Early intervention with anti-TNFα agents is recommended in AA amyloidosis secondary to rheumatoid arthritis that seems able to induce improvement of renal dysfunction in spite of suboptimal control of SAA [168]. However, use of these agents is associated with a higher frequency of infections, including fatal sepsis [169]. Familial Mediterranean Fever (FMF) is effectively treated by colchicine in more than 95% of cases. Other autoinflammatory diseases, as well as FMF cases resistant to colchicine, can be effectively controlled by means of anti-interleukin agents [170]. 5.2. Interfering with precursor protein aggregation and targeting the amyloid deposits In the early nineties we demonstrated for the first time that a small molecule, the anthracycline 4′-iodo-4′-deoxy-doxorubicin (I-DOX), inhibited amyloidogenesis in vitro and could improve the clinical status and promote resorption of amyloid deposits in patients with AL amyloidosis [171,172]. Subsequently, it was reported that I-DOX could disrupt the fibrillar structure of ATTR amyloidosis [173] and induce “disaggregation” of pre-fibrillar oligomers [174]. A compound whose molecular structure closely resembles that of I-DOX, the antibiotic doxycycline, was also shown to disrupt amyloid fibrils in vitro and in a

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transgenic mouse model [175,176]. More recently it has been reported that tauroursodeoxycholic acid (TUDCA) acts synergistically with doxycycline in lowering TTR deposition [177]. Doxycycline and TUDCA have the advantage of being marketed drugs that can be “repurposed” for the treatment of ATTR amyloidosis. A trial evaluating the combination of doxycycline and TUDCA in ATTR amyloidosis, both hereditary and senile, showed that this therapy can stabilize the disease for at least 1 year in the majority of patients [178]. The use of polyphenols as anti-amyloid compounds is also being considered with interest [179,180]. Following the observations that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces cerebral amyloidosis in Alzheimer's transgenic mice [181], and inhibits amyloid fibril formation [182], its action is being explored in systemic amyloidosis. Ferreira and coworkers showed that EGCG inhibits TTR aggregation in vitro, in a cell culture system, and in a ATTR mouse model [183]. Subsequently, Dr. Werner Hunstein, former professor of hematology at the University of Heidelberg, who had been suffering from AL amyloidosis, observed an improvement in his cardiac symptoms while he was purposely drinking high amounts of green tea [184]. The clinical activity of EGCG was then confirmed in retrospective case series both in AL and in ATTR amyloidosis [185,186]. More recently, Ferreira et al. showed that EGCG has a dual effect on TTR amyloidogenesis in a mouse model, both as TTR aggregation inhibitor and amyloid fibril disruptor [187]. A randomized clinical trial is ongoing at our center to evaluate the ability of EGCG in promoting regression of residual cardiac damage in patients with AL amyloidosis who have completed chemotherapy (NCT01511263). Pepys et al. investigated the possibility of promoting resorption of amyloid deposits by depleting serum amyloid P component (SAP), a common constituent of amyloid deposits thought to protect them from resorption, with a palindromic compound, CPHPC, a competitive inhibitor of SAP binding to amyloid fibrils [188]. A pilot clinical study of CPHPC, showed promising results in subjects with hereditary fibrinogen amyloidosis [189]. More recently, the same group showed that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers resorption of visceral amyloid deposits [190]. The University of Tennessee group is also exploring immunotherapy of systemic amyloidosis. They showed that infusion of an anti-light-chain monoclonal antibody having specificity for an amyloid-related epitope caused the resolution of amyloidomas generated in mice by injection of amyloid proteins extracted from the spleens or livers of patients with AL amyloidosis [191]. Similar activity was observed in a mouse model of AA amyloidosis [192]. Two small molecules, diflunisal, an anti-inflammatory drug marketed in the USA, and tafamidis, a specifically designed novel compound, are able to stabilize the TTR tetramer, preventing its dissociation in monomers and hence the amyloidogenic process. Early data from the diflunisal trial indicate that the drug can be safely administered also in patients with cardiac dysfunction [193,194]. Early results suggest that tafamidis slows disease progression in patients with TTR familial amyloid polyneuropathy and improves mBMI [195]. Tafamidis has been approved by the European Medicines Agency in 2011. Eprodisate, a small sulfonated molecule resembling heparan sulfate interferes with the interaction between amyloidogenic proteins and glycosaminoglycans and inhibits the development of amyloid deposits in a mouse model of AA amyloidosis [196]. A randomized, placebocontrolled trial showed the eprodisate can slow progression of renal failure in AA amyloidosis [197]. A larger international trial is underway to ascertain its efficacy (NCT01215747). 5.3. Supportive therapy Supportive treatment is a fundamental part of the management of AL patients. It is aimed at maintaining the quality of life and prolonging survival, while specific therapy has time to take effect.

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The mainstay of the treatment of congestive heart failure and nephrotic syndrome are salt restriction and judicious diuretic use. Cardiac function in amyloidosis is often preload dependent, and reduction of intravascular volume should be avoided, particularly in patients with hypoproteinemia and postural hypotension [105]. Many patients have asymptomatic involvement of the autonomic nervous system [68], and symptomatic hypotension can easily ensue after treatment with angiotensin-converting enzyme inhibitors that should be used with great caution and at the lowest effective dose. Heart failure and hypoproteinemia can contribute in lowering blood pressure. Patients with hypotension can benefit from fitted elastic leotards and midodrine. Patients with recurrent syncope may benefit from pacemaker implantation. The utility of implantable cardioverterdefibrillators (ICD) is controversial [198]. Neuropathic pain can benefit from gabapentin or pregabalin treatment. Diarrhea due to gastrointestinal and/or autonomic nervous system involvement can be controlled with octreotide [199–202]. Maintenance of a good nutritional status is a vital part of supportive treatment for systemic amyloidosis, since in AL and ATTR amyloidosis malnutrition independently affects prognosis and quality of life, and limits eligibility to effective therapies [69,70,150,203]. In AA amyloidosis a tight control of blood pressure can improve renal response to treatment aimed at reducing SAA concentration [204]. Transplantation of the organs involved by amyloidosis may prolong survival, improve quality of life, and render patients with advanced disease eligible for aggressive specific treatment. The main concerns with organ transplantation are recurrence of amyloidosis in the graft and progression in other organs. In AL amyloidosis, organ transplant can be considered in patients who attain CR, but have irreversible end-stage organ damage. The role of renal transplant in this setting has been recently reviewed [205]. Available data indicate that kidney transplant can be offered to patients with AL amyloidosis with sustained CR. Heart transplant followed by ASCT or other effective chemotherapy can be the only effective option for young patients with isolated, severe cardiac involvement [206–211]. Ventricular assist devices have been used in patients with terminally compromised cardiac function with disappointing results mostly due to high morbidity [212]. In ATTR amyloidosis combined liver and heart transplant allows extending the benefits of liver transplant therapy to subjects with heart involvement, who would otherwise be ineligible due to the likely progression of cardiac dysfunction despite liver transplant [161]. Renal transplantation can be offered to carefully selected patients with AA amyloidosis and end-stage renal disease, in whom a steady control of SAA concentration has been achieved [213]. In AApoAI amyloidosis with cardiac involvement, given the slow pace of the disease, heart transplant can prolong survival by several years [214].

6. Conclusion The cornerstones of the management of systemic amyloidoses are early diagnosis, accurate typing, appropriate risk-adapted therapy, tight follow-up, and supportive treatment. Systemic amyloidoses are complex diseases, and most patients need to be referred to specialized centers for diagnosis and for designing the therapeutic approach. Nevertheless, internists play a key role in the care of patients suffering from these diseases, in that they are often the first seeing these subjects once early organ dysfunction manifests, therefore having the priceless opportunity of making an early diagnosis. It is their responsibility to recognize the disease, start the diagnostic workup and select patients to be referred to amyloid centers. Moreover, internists have the multidisciplinary background which is needed to provide these patients with continuous, careful support during treatment and follow-up. Whatever the advances amyloid researcher will make in the future to better understand and possibly cure systemic amyloidoses, they will always rely on internists to transfer them in everyday clinical practice.

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Learning points • Systemic amyloidoses are caused by conformational changes aggregation and deposition of autologous proteins in tissues, leading to organ dysfunction, which is fatal if left untreated. • Early diagnosis is the prerequisite for effective therapy, allowing reversal of organ damage and extending survival. • The different types of amyloidosis are treated differently, and accurate identification of amyloid type is mandatory, if necessary referring patients to specialized centers for diagnosis. • Therapy should be guided by risk-stratification and frequent assessment of response based on biomarkers. • Careful supportive treatment can improve patients' quality of live and grant time for specific therapy to exert its action.

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