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Genetic signatures & hereditary ATTR amyloidosis
Amyloidosis is a rare protein misfolding disease in which proteins change shape and then bind together to form amyloid fibrils, which are deposited in tissues and organs. As a result, the function of these tissues and organs is affected.
There are several different proteins that can cause amyloidosis, and ATTR amyloidosis is a form of the disease that involves the protein ‘transthyretin’ (TTR), made by the liver and helps carry thyroid hormones and vitamin A in the blood. There are two types of ATTR amyloidosis – hereditary, also known as familial ATTR amyloidosis, or wild-type ATTR amyloidosis.1
Hereditary ATTR amyloidosis involves a mutation in the DNA of TTR, causing the body to produce a mutant form of the protein. This mutated form can be passed on through generations and due to its unstable nature, is more likely to form into amyloid fibrils.2
The genetic forms of the disease are relatively uncommon, except in endemic areas such as Portugal or Japan, where a single mutation is dominant and relatively common in the population. Worldwide, African American’s have been identified as the most common population, with hereditary ATTR amyloidosis present in about 3.5% of African American’s.
Joel Buxbaum, MD, Scripps Research, La Jolla, CA, discusses in detail the genetic signatures associated with hereditary ATTR amyloidosis. The notion in ATTR amyloidosis is that the autosomal dominant diseases are largely a reflection of the particular mutation – of which there are many, more than 120. Like most autosomal dominant diseases, the mutation establishes the general pattern of disease, but the pattern of penetrance seems to be dependent on a small number of genes, around 20-30.
Dr. Buxbaum explains how what researchers decide to review determines the clinical pattern of the autosomal dominant diseases and their penetrance, and the parameter that has been easiest to look at is age of onset. Age of onset is seen to be most discrete in the V30M mutation, found endemically in the northern parts of Sweden, and in regions in Portugal and Japan. Patients carrying the TTR V30M mutation commonly show a mixed phenotype but with substantial variation in disease manifestations and age at onset in different geographical locations.3
There are half a dozen genes that have been described in the Portuguese population that seem to have an effect on age of onset, for instance the gene that encodes retinol-binding protein (RBP) which interacts with TTR, with an association having been made between the binding protein and age of onset.
The value of screening biopsies in AL & ATTR amyloidosis
Immunoglobulin light chain (AL) & transthyretin (ATTR) amyloidosis generally requires a histological diagnosis of some description. Histological diagnosis is often achieved via a biopsy sample taken from a critical organ; however, this can be high-risk and costly – especially in the era of COVID-19.
Dr Oliver Charles Cohen, MD, University College London Hospitals NHS Foundation Trust, London, UK, discusses the recent effort investigating the value of screening biopsies in AL and ATTR amyloidosis.4 Screening biopsies represent a far lower risk approach to histological diagnosis, they include the use of abdominal fat aspiration (AFA), bone marrow (BM) and gastrointestinal (GI) biopsies.
In this study, the diagnostic sensitivity of screening biopsies and their concordance with patients (n = 471) with AL (n = 321) and TTR (n = 150) amyloidosis was analyzed. Results demonstrated that diagnosis sensitivity of AL and ATTR amyloidosis, respectively, was 73.2% and 27.3% for AFA, 59.7% and 42.2% for BM and 74.6% and 44.6% for GI biopsy. Across all screening biopsies, AL amyloidosis was easier to detect and in ATTR, specifically wild-type was much harder to detect than hereditary. In AL amyloidosis, when AFA and BM biopsy were combined, a sensitivity of 82.9% was obtained.
Furthermore, I-SAP scintigraphy was used to identify a strong association between whole body amyloid burden and sensitivity of each screening biopsy method. Finally, patients with organ involvement, such as cardiac, renal and hepatic amyloidosis, all had a higher diagnostic sensitivity then those without visceral deposits.
In summary, this study suggests that patients with AL amyloidosis would benefit from both AFA and BM screening biopsies, as the vast majority, almost 90%, will get a diagnosis in one of these screening methods, meaning that the patient will not require critical organ biopsy.
Burning questions: ASCT in AL amyloidosis
Vaishali Sanchorawala, MD, Boston University School of Medicine, Boston, MD, discusses the outcomes from a panel discussion at the International Society of Amyloidosis, examining the role of autologous stem cell transplantation (ASCT) in immunoglobulin light chain (AL) amyloidosis. The panel discussion was held in view of recent advances in novel agents, as well as recent results from the ANDROMEDA (NCT03201965) clinical trial.
Results of ANDROMEDA saw high response rates achieved with daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD). However, panelists concluded that ASCT does have a role in a number of small, highly selective patients with AL amyloidosis. These patients would need to meet the eligibility criteria, which was also discussed. Patients with renal dysfunction and severe hypoalbuminemia are at an increased risk of developing acute kidney injury in the peritransplant setting.
Furthermore, the role of induction therapy was also debated, and the majority of the panelists found that induction therapy should be performed in patients with bone marrow plasmacytosis of >10%. Consolidation and maintenance therapy were not widely recommended in standard use unless they were based on clinical trial results.
The final point that was discussed was the reduction in treatment related mortality over the last 20 years and what this can be attributed to. It was concluded that this was owed to a combination of factors, such as better patient selection, early recognition and improved characterization of cardiac involvement, improvement in post-transplant supportive care, as well as increased number of ASCTs performed resulting in more experienced healthcare professionals.
AL amyloidosis during the pandemic
COVID-19 has become a major global challenge causing a worldwide healthcare crisis. The current pandemic presents a greater challenge for patients with chronic conditions, Efstathios Kastritis, MD, University of Athens School of Medicine, Athens, Greece, outlines the challenges associated with the management of patients with AL amyloidosis during the COVID-19 pandemic.5
Immunoglobulin light chain (AL) amyloidosis is a multi-systemic disease that can affect multiple different organ systems, including the heart, kidneys, liver and lungs. Although COVID-19 is associated with respiratory tract infection, it may also affect and cause complications in numerous organs. Treatment options for patients with AL amyloidosis often involve chemotherapy, leaving the patients with immunosuppression, and therefore, a higher risk of infection.
COVID-19 is also associated with cytokine storm syndrome, an increase in inflammatory mediators and cytokines, which can cause deregulation in tissue homeostasis. For patients with AL amyloidosis, especially those with severe organ involvement, it may be extremely difficult to manage and survive this cytokine storm syndrome.
The other challenge that clinicians face in the context of the pandemic is patients not seeking medical advice for symptoms that manifest, due to the fear of going to the hospital and putting themselves at risk of COVID-19 infection. This will lead to a delay in diagnosis in many patients, which is especially concerning as delayed diagnosis can be detrimental for AL amyloidosis patient’s health and survival.
The final challenge presented is that patients who need to receive their therapy face difficulties with attending appointments, either because of lockdowns, the overwhelmed healthcare systems leading to restricted resources or patient fear. It’s evident that physicians and patients need to discuss how treatment can be adjusted in light of the pandemic.
References
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- Cleveland Clinic. Amyloidosis: ATTR (transthyretin). Available from: https://my.clevelandclinic.org/health/diseases/17855-amyloidosis-attr (Last accessed 24/9/20).
- Stanford Health Care. Familial ATTR Amyloidosis. Available from: https://stanfordhealthcare.org/medical-conditions/blood-heart-circulation/amyloidosis/types/familial-attr-amyloidosis.html (Last accessed 24/9/20).
- Arvidsson S, Pilebro B, Westermark P, et al. Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis – Impact of Sex and Amyloid Fibril Composition. PLoS One. 2015:10(suppl 11):1-11.
- Cohen O, Sharpley F, Gilbertson J, et al. The value of screening biopsies in light-chain (AL) and transthyretin (ATTR) amyloidosis. Eur J Haematol. 2020;105:352-356.
- Kastritis E, Wechalekar A, Schonland S, et al. Challenges in the management of patients with systemic light chain (AL) amyloidosis during the COVID-19 pandemic. British J Haematology. 2020;190:346-357.
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Written by Frankie Lewns
Edited by Tom Southgate
