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Advances in Systemic Amyloidosis: A Spotlight on New Disease-Modifying Therapies Across the Clinical Spectrum
  • CME
  • CE

Beth Faiman, PhD, MSN, APRN-BC, AOCN
Shaji K. Kumar, MD
Released: October 21, 2021

Systemic Amyloidosis


Shaji K. Kumar, MD:
Systemic amyloidosis represents a family of disorders that is characterized by the deposition of amyloid fibrils in different organs.1 Multiple proteins that can form amyloid fibrils have been identified, leading to systemic amyloidosis with consequent clinical manifestations. 

Systemic Amyloidosis: Pathogenesis

Shaji K. Kumar, MD:
These protein aggregates have some common characteristics, including x-ray diffraction patterns, fibril size, and the way the fibrils are structured in the amyloid deposits.2 Their appearance on electron microscopy is fairly consistent across the group of amyloid diseases. Likewise, the appearance of amyloid deposits is similar using polarized light microscopy and other detection techniques that will be discussed.

Systemic Amyloidosis: Classification

Shaji K. Kumar, MD:
Many different proteins that can result in amyloidosis have been identified. This table shows common precursor proteins, some of which can lead to systemic amyloidosis, whereas others are limited to localized manifestations.3 Multiple organ systems can be affected by the different types of amyloid, including the heart, kidneys, and nerves. The clinical manifestations depend entirely on the organs that are affected, as well as the severity of the involvement.

Systemic Amyloidosis: Organ Involvement

Shaji K. Kumar, MD:
The most commonly affected organs in amyloidosis are the heart, kidneys, liver, lungs, peripheral nerves (specifically autonomic nerves), and gastrointestinal tract.3 The level of involvement of different organs depends on the underlying type of amyloid protein, with immunoglobulin G AL-related amyloid and ATTR amyloid commonly affecting multiple organs.

Other types of amyloid, such as ALECT2, may be more often seen in the context of kidney involvement or with liver involvement. Others, such as gelsolin-related amyloid, may primarily affect nerves.

Amyloidosis: Clinical Presentation

Shaji K. Kumar, MD:
Clinical presentation may help determine which type of amyloid is responsible for the patient’s disease. Again, the 3 most common amyloid types encountered in the clinic are light-chain–related amyloid, wild-type transthyretin (TTR), or TTR with genomic variants.4 It is important to note that light-chain amyloid is associated with monoclonal gammopathy and tends to present with symptoms involving multiple organ systems.

The figure shown here depicts common symptoms associated with specific organs. Cardiac involvement can lead to arrhythmias, as well as symptoms consistent with congestive heart failure, hypotension, and chest pain.5 Renal involvement may present with significant proteinuria or slowly progressing renal failure. Gastrointestinal involvement can lead to weight loss, dysmotility, and malabsorption.

Amyloidosis: Tissue Diagnosis

Shaji K. Kumar, MD:
Although clinical presentation varies by organ involvement and the type of amyloid, all amyloid types can be detected through various approaches, with tissue analysis being the most essential to diagnosis. Shown here are several examples of biopsies of different tissues.3 The amyloid deposits are predominantly extracellular, exhibit an apple-green birefringence under polarized light, and display an affinity for the Congo red stain. It is possible to perform immunohistochemistry to look for the specific protein of origin, as shown in the lower middle and lower right panels, where a fat aspirate is exhibiting strong positivity for λ light chain but not κ light chain—suggesting that this is λ light-chain–associated amyloid.

Later, we will discuss how approaches such as mass spectrometry have made identification of amyloid types and thus diagnosis much easier than historical methods.

Amyloidosis: Identifying the Protein of Origin

Shaji K. Kumar, MD:
Because amyloid fibers can be derived from different proteins, it is critical to identify the culprit protein, as treatments can be quite different depending upon the origin of the amyloid.6-8 The most common initial test is Congo red staining of a tissue biopsy. If positive, this indicates that amyloid is indeed present. The question then is: What kind of protein is making the amyloid fibrils? To answer this, we can perform laser microdissection of the amyloid deposits and subject them to tandem mass spectrometry. Using various bioinformatic techniques, we can determine the type of protein that is most abundant in the deposit based on the amino acid sequences.

Amyloidosis: Mass Spectrometry

Shaji K. Kumar, MD:
Shown here are the proteomic diagnostic signatures for 21 amyloid types determined using mass spectrometry analysis of 16,175 amyloidosis specimens.9 Although these signatures are unique to each type, it is important to note that mass spectrometry also will identify proteins common across amyloid types, such as serum amyloid P component and several apolipoproteins.

Distribution of New Cases of Amyloidosis at Mayo Clinic Rochester (2012-2017)

Shaji K. Kumar, MD:
The etiology and epidemiology of amyloidosis are important because diagnosis, treatment, and patient outcomes depend on the type of amyloid. Although the variety and frequency of amyloid types can vary between studies, shown here are data from our experience at the Mayo Clinic Rochester. In a population of 7676 patients seen at our clinic from 2012-2017, the most common amyloid was immunoglobulin light chain or heavy chain. The next most frequent group consisted of age-related amyloid and then the hereditary/transthyretin amyloidosis. Localized amyloidosis, which can arise from different proteins, was observed in a small but steady number of patients over the years.

Systemic Amyloidosis: Diagnostic Approach

Shaji K. Kumar, MD:
Bearing in mind that AL and ATTR are the most common forms of systemic amyloidosis, the initial approach toward diagnosis can be based on clinical presentation. Thus, if a patient presents with cardiac-specific signs of amyloidosis, such as diastolic heart failure or infiltrative cardiomyopathy identified on imaging, the first step would be to do a technetium 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) or 99mTechnetium (Tc) pyrophosphate (PYP) scan.4 The results can help point toward a diagnosis of ATTR amyloidosis.

By contrast, if a patient presents with noncardiac signs such as nondiabetic proteinuria, nondiabetic neuropathy, hepatomegaly, or monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma, the initial approach would be to screen for the presence of monoclonal protein. If monoclonal protein is detected, that makes the diagnosis more likely to be AL amyloidosis, in which case an SC fat aspirate or a bone marrow biopsy should be performed.

If the tissue sample exhibits deposits that are Congo red positive, the next step is to determine the amyloid type using immunohistochemistry or proteomic approaches. In these patients, additional testing to better characterize the extent of organ involvement also can be undertaken.

If the tissue sample is negative by Congo red staining, consider doing a cardiac MRI and an endomyocardial biopsy, which then can be used for typing analyses. Of course, if the endomyocardial biopsy is negative, that mostly rules out amyloid as a cause of the symptoms.

If a patient has normal immunoglobulin but a PYP scan suggests ATTR amyloidosis, the next step is to perform germline DNA sequencing to characterize the variant ATTR and then proceed with the therapy and genetic counseling, as appropriate.

We will next focus on the initial workup, treatment approaches, and patient outcomes specific to AL and ATTR amyloidosis.

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