As amyloidosis is a remarkably heterogenous disease it may present to a variety of different medical specialties. There are numerous reasons for patients with amyloidosis to present to the respiratory physician. Chronic pulmonary conditions can themselves give rise to systemic amyloidosis, most commonly of AA sub-type. While these patients rarely present with symptomatic involvement of the lung the underlying pulmonary disease is the driver of the amyloidogenic protein production and it is therefore important to recognise those patients at risk. Patients with systemic amyloidosis may also present with respiratory symptoms as a consequence of amyloidosis itself whereby amyloid deposits are found in the lung as a component of a more systemic process. Localised, isolated pulmonary and respiratory tract amyloid deposits are also well-described and may either present with symptoms or be detected incidentally on chest radiography or biopsy. Lastly, it is important to recognize that, especially in the context of AL amyloidosis, pulmonary complications may also arise from treatment.

The key first step in diagnosis is obtaining tissue evidence of amyloid fibril deposition. The diagnostic gold-standard for the presence of amyloid is histological confirmation by Congo red staining, producing red-green birefringence under crossed polarised light [3] (Fig. 7.1a, c). Most tissue specimens, ranging from needle biopsies to open surgical resections, can be studied although small biopsies are open to sampling error given the often focal nature of the deposits. Standard formalin fixation of the biopsy specimen is appropriate in the majority of cases. Samples can then be embedded in paraffin for cutting. These samples are suitable for the Congo red stain as well as subsequent immunofixation. It is also appropriate for laser capture microdisection and mass spectrometry described later in the chapter. Biopsy of any organ can be hazardous in amyloidosis as there is an increased risk of haemorrhage. Significant bleeds having been reported in 5 % of liver biopsies [21], although more recent data from renal biopsies is reassuring [22]. A case report from 1987 described fatal lung haemorrhage following transbronchial biopsy in a patient with amyloidosis. The post mortem findings showed the biopsied blood vessels infiltrated with amyloid [23]. A further case series by Utz et al. published in 1996 reported no major complications in 11 patients following transbronchial lung biopsies however 2 of the 11 cases were reported to have 100 mL blood loss [24]. A less invasive alternative in suspected disease is fine needle aspiration and this has been used successfully in the respiratory tract [25, 26]. The increased risk of haemorrhage in amyloidosis is multifactorial. There is often increased fragility in involved blood vessels as well as reduced elasticity of amyloidotic tissues. Very occasionally in AL type amyloid an acquired deficiency of clotting factors IX or X is seen [27–29]. Interestingly the factor deficiencies are most often due to sequestering of the circulating factor in the liver and spleen. It is not generally due to deficient factor production or the development of an inhibitor as is sometimes seen in other clonal lymphoproliferative disorders.

Once amyloid is identified immunohistochemical stains are then used to determine the fibril protein type as this ultimately guides further therapeutic interventions (Fig. 7.1b, d) [30]. Suitable antibodies for most of the common amyloid subtypes are widely available. This includes antibodies to kappa and lambda light chains, SAA and transthyretin. It should be noted that although immunohistochemistry is usually definitive in AA amyloidosis, it is non-diagnostic in about 20 % of AL deposits [31, 32]. Expertise in the immunohistochemical typing of hereditary amyloid is restricted, and definitive immunohistochemical typing of amyloid deposits cannot always be achieved [33]. Laser capture micro-dissection and mass spectrometry is fast being established as the new gold-standard in fibril typing. The technique involves micro-dissection of a suspected amyloid deposit, identified by positive Congo red staining, from a cut specimen on a microscope slide. The microscopic protein deposit is removed from the slide and then analyzed by mass spectrometry to identify the fibril sub-type, this technique is successful in the vast majority of cases. It is especially useful in those patients who cannot be confidently diagnosed through immunohistochemical typing however the technique is currently limited by availability [34]. If Congo red positivity is not demonstrated but the clinical suspicion of a clonal lymphoproliferative disorder being the source of the symptoms is still high one should consider Nonamyloidotic Monoclonal Immunoglobulin Deposition Disease (NMIDD). This may be due to either heavy chain or light chain deposition within the tissues but without amyloid fibril formation. This is a rare entity but the presentation can be very similar to more typical AL amyloid of the lung. The diagnosis is again dependent on tissue biopsy often requiring special pathology expertise. Clinically, management is very similar to that of AL amyloid given that the underlying etiology is a clonal disorder.

If a genetic variant is suspected one should pursue more detailed analyses examining for mutations in the gene giving rise to the amyloidogenic fibril. In general sequencing is the preferred modality and ideally samples should be sent to a reference lab with expertise in this area. A web-based repository reviewing all currently known mutations in genes with amyloidogenic potential has been recently made available to help guide these investigations (http://​amyloidosismutat​ions.​com).

Once histological confirmation of amyloid has been obtained the extent of the organ deposition and dysfunction needs to be established. In respiratory tract amyloidosis this can be challenging and the optimum imaging technique can vary depending upon the distribution of deposits. In many cases however, it may be normal. Plain radiography as an initial assessment can be helpful with findings ranging from local amyloidomas presenting as intrathoracic mass lesions (Fig. 7.2a), to non-specific reticular interstitial infiltrates (Fig. 7.2b). Computed tomography (CT) scanning is particularly useful in further defining interstitial disease (Fig. 7.2c). In combination with positron emission tomography (PET) imaging it can also help to better define the metabolic activity of a solid lesion thus aiding differentiation from more typical intrathoracic malignancy or metastases as well as rare entities such as plasmacytomas [35]. In addition magnetic resonance imaging (MRI) and bronchoscopy may also be useful in combination with comprehensive pulmonary function tests (PFTs). PFTs are an important objective tool to formally establish the severity of clinically relevant disease and are useful in guiding therapeutic decisions. Evidence of extra-pulmonary systemic disease should be sought clinically and by performing relevant serologic and radiographic investigations. A diagnostic algorithm is presented in Fig. 7.3.

If AL amyloid is suspected it is important to identify the underlying clonal disease process. The plasma cell clones that underlie systemic AL amyloidosis are often subtle and may not be detected by bone marrow examination or immunofixation of serum and urine. In recent years, the use of the serum free light chain assay has increased the diagnostic sensitivity in testing for clonal disease [36, 37]. Immunoglobulin gene rearrangement studies may identify subtle clones in either the bone marrow or, in the case of localised AL, within the amyloidotic tissue itself [38]. A number of other non-invasive techniques are available to assess the overall amyloid burden. Radiolabelled ¹²³I-human SAP localises specifically to amyloid deposits in vivo in proportion to the quantity of amyloid present and thereby enables diagnosis, quantification and monitoring of amyloid [11]. SAP scintigraphy is useful in visualising amyloid in the major organs of the abdomen (Fig. 7.4a). Localisation to the lungs is poor thus it is not routinely used for identifying or monitoring amyloid deposits in the respiratory tract however dense fibril deposits as seen in large amyloidomas may occasionally show distinct tracer uptake (Fig. 7.4b). In combination with single photon emission computed tomography (SPECT)-CT imaging SAP uptake can be better delineated; better characterizing the degree of uptake within an organ or lesion (Fig. 7.4c). It is also important to note that while it is a very specific test for the presence of amyloid, alone it cannot reliably differentiate the fibril sub-type. Cardiac amyloidosis is best evaluated by a combination of echocardiography and ECG [39–41]. Two-dimensional Doppler echocardiography classically reveals concentric biventricular wall thickening with a restrictive filling pattern [42]. Amyloid primarily causes diastolic dysfunction with a decline in the ejection fraction occurring generally in the latter stage of the disease [40]. The ECG may be normal but in advanced disease commonly shows small voltages, pathological ‘Q’ waves (pseudo-infarct pattern) in the anterior chest leads and conduction abnormalities. Cardiac magnetic resonance imaging (CMR) is being used more frequently and is extremely useful in identifying cardiac amyloid. Typical appearances are of homogenous late gadolinium enhancement [43]. ^99mTc-3, 3-diphosphono-1,2-propanodicarboxylic acid (^99mTc-DPD) scintigraphy is fast becoming a powerful imaging tool in the investigation of cardiac amyloid. It is a specific test indicative of fibril deposition within the heart with newly emerging data suggesting that the degree of uptake and pattern of distribution in the extra-cardiac soft tissue may even be specific for ATTR amyloid [44–46]. If these studies are confirmed prospectively then this may evolve as a tool whereby a non-invasive diagnostic test can be used to confirm fibril sub-type. Elevation of N terminal Pro brain naturetic peptide (NT-Pro BNP) and cardiac troponins can also be helpful in establishing whether a patient has cardiac amyloid. Together they have become key markers to risk stratify patients and guide therapy [47]. It is important to recognize that these enzymes are not always specific and can be elevated for many reasons such as renal impairment and other forms of cardiomyopathy; however a normal NT-Pro BNP can often exclude clinically significant cardiac involvement [48, 49].

First described by Lesser in 1877, localised amyloidosis of the respiratory tract ranges from asymptomatic pulmonary nodules to diffuse parenchymal deposits. Presenting symptoms can mimic a variety of lung pathology and depends on the location of the amyloid fibrils. Initial investigations with routine imaging can be unhelpful in confirming the diagnosis. A number of classifications have been proposed based upon radiographic or bronchoscopic findings but have not been widely adopted [24, 87]. In general amyloidosis is best classified by the fibril protein (Table 7.1), and then by the sites of clinical involvement.

Localised amyloid deposition is not uncommon although often goes undiagnosed. It results either from local production of fibril precursors [88, 89], or from properties inherent to the particular microenvironment, which favour fibril formation from a widely distributed precursor protein [90]. The vast majority of localised amyloid deposits are of AL type [91, 92] with symptomatic deposits occurring most frequently in the eye [93], skin [94], respiratory [24, 95] or urogenital tracts [96, 97]. They are often associated with extremely subtle focal monoclonal B cell proliferation confined to the affected site. Surgical resection of these localised ‘amyloidomas’ can sometimes be curative if the underlying clonal are removed [97]. Symptomatic apparently localised amyloid deposits can rarely be manifestations of systemic disease and patients should always be fully investigated to exclude more generalised amyloid deposition [30].

Thorough evaluation of respiratory tract amyloidosis and biopsy confirmation is required to determine the need for treatment and the most suitable modality based on fibril sub-type. However, the paucity of controlled clinical trials means that management decisions have to be made on an individual basis. Broadly speaking, systemic chemotherapy is usually indicated for systemic AL amyloidosis and local intervention, according to symptoms for its localised forms.