Staging for cardiac burden is a critical part of the initial evaluation since the prognosis in AL amyloidosis is a function of the extent of cardiac involvement [2–4, 13, 14, 16]. In the case of hereditary amyloidoses, significant cardiac involvement may require combined liver and cardiac transplantation (please see below) [15]. Serum troponins (I or T) and B-type natriuretic peptides (either BNP or NT-proBNP) are highly sensitive markers for cardiac involvement and normal values exclude clinically significant cardiac amyloid [2–4, 13, 14, 16]. Electrocardiography and echocardiography should be performed to evaluate for arrhythmias and restrictive cardiomyopathy. Consideration should be given to cardiology consultation in cases where any abnormalities are found. Cardiac MRI is also an emerging modality for the evaluation of amyloid infiltration. Cardiac biomarkers are prognostic for survival in AL patients and can also be used to monitor the effect of treatment. Post-therapy, patients with a greater than 30 % reduction and a greater than 300 ng/L decrease in the NT-proBNP level, from baseline, are correlated with improved survival; increases of the same amount are associated with a reduced survival rate [2–4, 13, 14, 16].

Systemic AL amyloidosis is caused by free light chains produced by clonal plasma cells, or rarely (2 % of the time), by mature B-cell lymphomas (please see Chap. 26; [2–4, 17]). In contrast to multiple myeloma, AL amyloid patients may have significant end organ damage with <10 % plasma cells found on bone marrow examination (please see Chap. 2) [17]. The cytogenetics and FISH studies that have prognostic value in myeloma are not yet well validated for amyloid. Please see also Chaps. 26 and 27.

Appropriate treatment for amyloidosis differs based on the amyloid protein type and the staging, highlighting the importance of an accurate diagnosis at presentation [1–4]. Localized disease is generally managed with local treatments or, in select cases, by observation with planned reevaluations. Although localized amyloidosis, if diagnosed correctly, is felt to progress rarely to a systemic process, these patients require periodic reevaluation to exclude recurrences or progression, which may take years to develop (please see Chap. 25). Recurrences may also occur. Various risk-adapted therapies, including personalized targeted therapies, are currently being used for the treatment of multifocal disease associated with MALT lymphoma [5, 6]. Other amyloidoses, including AA, hereditary, and senile forms, are not responsive to cytotoxic therapies and their management involves evaluation for organ transplantation and/or pharmacologic therapies (see below and Chaps. 37 and 38). The most critical step in the management of patients with a newly diagnosed amyloidosis is distinction between systemic AL versus other amyloidoses [1–4, 10].

The goal of therapy in patients with AL amyloidosis is to reduce the production of abnormal free light chains to as low a level as possible, for as long as possible, and as soon as possible [2–5]. Patients with amyloidosis associated with CLL or non-Hodgkin’s lymphoma should have their therapy directed against the specific associated disease. It is important to recognize that eliminating the source of the damaging light chains can reverse AL-related organ damage and improve the functional status of these patients [2–5, 7, 16, 17]. Despite improvements in diagnosis and staging, the effective treatment of AL amyloidosis remains a challenge. The median survival from diagnosis is mainly driven by the degree of cardiac involvement [2–4, 16, 17]. Thus, in patients with scores ranging from 0 to 3 median survival ranges from 94.1 to 5.8 months, respectively [3]. Delayed/late diagnosis continues to play a major role in early mortality while undergoing treatment [2–4, 16]. Failure to achieve a 50 % reduction in involved free light chain has been associated with a significantly reduced survival [2–4, 16]. Increasing evidence supports the notion that it is the pre-fibrillar monomers, rather than the actual amyloid fibrils, that are the toxic entity [17]. Hence, a rapid reduction in the level of circulating light chains is an important issue.

A broad range of therapies are available for patients who have plasma cell disorders underlying their amyloidosis. We will briefly summarize some of the most common current and emerging therapies. There is abundant literature pertaining to this subject and a more detailed review is beyond the scope of this chapter. The choice of therapy for an individual patient is dependent on their comorbidities, their overall condition, and, particularly, the cardiac staging, referred to as “risk-adapted” therapies. The most significant independent prognostic determinants are cardiac involvement and response to therapy [2–4, 16, 17].

Not all systemic amyloidoses are, at present, treatable, but new possibilities are emerging. Modern therapies for AA amyloidosis and emerging therapies for other amyloidoses are discussed in Chaps. 37 and 38. The role of solid organ transplantation in the management of patients with various systemic amyloidoses, hereditary as well as non-hereditary, is also increasing [38–46].

For several hereditary amyloidoses, the liver is the predominant (transthyretin), exclusive (fibrinogen), or partial (apolipoprotein AI) source of abnormal protein. Based on this, liver transplantation was offered to affected patients as a form of “surgical” gene therapy, where replacement of the variant gene with a normal gene is achieved by replacement of the liver [38]. Thus, in the early 1990s, the first patients with familial amyloid polyneuropathy (FAP) due to a mutation in the ATTR gene were treated by liver transplantation and there is now a worldwide registry of such transplantations (please see www.​fapwtr.​org; [38]). Currently, liver transplantation is an acceptable treatment option, halting progress of the disease; however, long-term outcomes are variable. The results appear to be better in younger patients who are affected by the most prevalent variant of transthyretin (Met30), and who are at the early stages of the disease, with mild symptoms [40, 42, 43]. Thus, regression of visceral amyloid deposits has been reported, as well as improvements in autonomic and, to a lesser extent, peripheral nerve function. Unexpectedly, however, some patients, who were affected by certain mutations, experienced a rapid progression of cardiac amyloidosis after liver transplantation, even though the deposits elsewhere had stabilized or regressed [43, 44]. It is proposed that this is due to enhanced deposition of wild-type TTR on a template of amyloid derived from the variant TTR [38, 44]. This phenomenon appears to be mutation dependent. In sum, it appears that the outcome of liver transplantation in patients with FAP depends on many variables, including the type of mutation, severity of neuropathy and the degree of cardiac amyloid involvement, as well as nutritional status and age; thus, early diagnosis and transplantation is critical. Unfortunately, given the variability of penetrance and the late onset of disease in many mutations, a family history is often missing. De novo mutations are also possible. For these reasons, the diagnosis is often delayed.

With the exception of being a source of abnormal protein, which causes systemic disease, livers from patients with ATTR are otherwise structurally and functionally normal. Usually, the livers contain only microscopic amyloid deposits in hilar vessels and nerves and are otherwise uninvolved [44, 47]. Thus, given the shortage of livers available for transplantation, since 1995, such explanted livers have been used sequentially as donor grafts for recipients with liver malignancies or conditions that make them unacceptable (or low priority) candidates for conventional cadaveric liver transplantation (“marginal recipients”). This type of dual, sequential transplantation has been named “domino” liver transplantation [47–53]. The domino surgery has not been found to add additional risk to the FAP-liver donor or recipient. However, importantly, domino surgery increases the organ pool, allowing the transplantation of marginal recipients who would not otherwise be eligible to receive a deceased donor liver [48, 51–53].

Since the penetrance of the disease varies substantially and amyloid deposition and symptoms occur in affected persons only in adulthood, it was considered that the danger of de novo disease in the recipient was minimal. Indeed, hundreds of patients have benefited from domino transplants. However, with longer survival times post-domino liver transplantation, rare patients were found to develop polyneuropathy. The first such reported case was a patient who developed polyneuropathy associated with ATTR amyloid deposits, in his peripheral nerves, 8 years post-domino liver transplantation [54]. More recent reports suggest that overt polyneuropathy may be preceded by subclinical gastrointestinal transthyretin amyloid deposits [55, 56]. Thus, it appears that polyneuropathy symptoms may appear 3 or 4 years after the histological demonstration of amyloid deposition elsewhere in the body. Even earlier, non-fibrillar deposits of transthyretin may also be detected in the skin [55]. Hence, at the present time, long-term monitoring of domino FAP recipients, using annual abdominal fat or gastroduodenal mucosal biopsies, is recommended in order to detect amyloid deposits at an early stage of disease. Nerve biopsy is required to diagnose de novo amyloid polyneuropathy and to consider retransplantation. Pharmacologic therapies, some of which are currently in clinical trials, are also becoming available [57, 58]. Further, nonsteroidal anti-inflammatory drugs have been shown to stabilize the native tetramer of TTR molecules, to inhibit transthyretin amyloidogenesis, and to reduce the risk of posttransplant amyloid polyneuropathy [39].

In individuals with a TTR gene mutation, it takes >20 years before the onset of amyloid deposition in their organs and several more years before FAP symptoms develop. While it is difficult to explain why some recipients of FAP livers develop TTR amyloidosis within a much shorter incubation period (in comparison with genetically determined FAP patients), the age factor may play a role. In this regard, recipients of domino livers have typically been older and, hence, subject to age-related amyloidogenesis. The TTR molecule, being composed largely of beta-sheet structure, is inherently amyloidogenic. In older individuals, even the wild-type molecule may promote amyloidogenesis, in particular affecting the heart (please see also Chaps. 5 and 7). Thus, in older patients, who are recipients of domino livers, amyloidogenesis may be accelerated due to older age [54–56]. The Familial Amyloidotic Polyneuropathy World Transplant Registry also collects data on domino liver transplants (The Domino Liver World Transplant Registry at: http://​www.​fapwtr.​org/​ram1.​htm; [47]).

Variants of fibrinogen A alpha-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and possibly also in the United States [59, 60]. This type of hereditary amyloidosis appears to target primarily the kidney, leading to the development of nephrotic syndrome, hypertension, and kidney failure as the main clinical manifestations. Initially, kidney transplantation was offered to affected patients, but solitary renal allografts were found to fail within 1–7 years as a consequence of recurrent amyloidosis. Since the variant fibrinogen is solely produced in the liver, currently, a combined liver and kidney transplantation is performed. Moreover, data published recently by Stangou et al. [59] even encourage the consideration of a preemptive solitary liver transplantation, early in the course of amyloid nephropathy, in order to obviate the need for subsequent hemodialysis and kidney transplantation. These authors also propose that early solitary liver transplantation may also prevent significant cardiovascular amyloidosis. This is based on their evidence that AFib is a systemic and serious disorder, affecting more organs than just the kidneys, and that, therefore, renal transplantation can be compromised by ongoing damage to other tissues and to the new renal graft (Fig. 36.3; [59, 60]).

Thus, similar to FAP, patients affected by AFib are considered for transplantation at the earlier stages of the disease. However, issues associated with the clinical management of asymptomatic carriers of a potentially amyloidogenic mutation are still largely unresolved [59]. In general, due to variable penetrance, aggressive treatments are delayed until onset of the disease is clinically apparent, a situation that may occur quite late in some patients. This may change, however, in view of the data presented by Stangou et al. suggesting that, even in clinically healthy carriers of a mutation, damage to the systemic vasculature may already have occurred (Fig. 36.3; [59, 60]). The development of pharmacologic gene therapy should alleviate some of the issues associated with transplantation in hereditary amyloidoses. Conventional pharmacologic therapies for overt ATTR disease are also in clinical trials (please see also Chap. 37).

Apolipoprotein AI (AApoAI), which can cause hereditary amyloidosis, is secreted by the liver and intestine [61]. Here, amyloid disease progression may be very slow and the natural history of the condition can be favorably altered in patients who receive a liver transplant. Moreover, it has been advocated that, in hereditary AApoAI amyloidosis, failing organs should be replaced, since graft survival is excellent and transplantation confers substantial survival benefit [61]. In Apolipoprotein AII (AApoAII) hereditary amyloidosis, the major morbidity is associated with renal failure. Hence, kidney dialysis and renal transplantation are, presently, the only two therapeutic options. Renal transplantation is an effective therapy for apolipoprotein AII amyloidosis, since recurrence of amyloid in the graft and progression of other organ involvement may be very slow [62].