Discussion
Amyloidoses are a typology of rare diseases characterized by the accumulation of protein fibrillary aggregates in heart, kidney, gastrointestinal tract, peripheral and autonomic nerves, skin, joints and blood vessels of all tissues1.The proteins typically are antiparallel β-sheets, which show X-Ray diffraction, orange-red appearance under light microscopy and apple-green birefringence under polarized light2. Primary or light chain (AL) amyloidosis is the most frequent type of systemic amyloidosis. AL is caused by abnormal proliferation of resident bone marrow monoclonal plasma cells producing unstable light chains. Lambda subtype accounts for 75% of all cases. Those amyloidogenic free light chains can then accumulate in tissues evolving in progressive organ dysfunction. Typically, plasma cells are less than 10% at the bone marrow biopsy3. Symptoms depend on the organ involvement, ranging from heart failure with preserved ejection fraction, nephrotic syndrome, organomegaly (mainly tongue and salivary glands) to peripheral neuropathies and unspecific symptoms such as fatigue, asthenia and body weight loss. The most common cause of the death in patients with amyloidosis is heart failure4. Clinical suspicion of AL amyloidosis will require biopsy of the involved organs, preferably the fat pad or, more rarely, kidney, salivary gland, heart and liver5. Currently, there are no clear guidelines on systemic AL amyloidosis treatment. However, since both AL amyloidosis and multiple myeloma (MM) are monoclonal plasma cell dyscrasias, AL amyloidosis treatment strategies and medications are derived from the anti-plasma cell therapy used for MM6,7.
In our case report, the patient presented non-specific symptoms and signs (hypotension, severe asthenia, limitation in ordinary activity due to fatigue and dyspnea, itching, recurrent low-grade fever, DVT). Laboratory tests showed nephrotic-range proteinuria and monoclonal IgA lambda. The first clinical suspicion of infiltrative disease arose from the low QRS voltage in V1-6 and limb leads. Amyloidosis EKG often shows QRS voltage less than 0,5 mm in the peripheral leads and less than 1 mm in precordial leads; the Sokolow/Lyon index which represents the sum of the S wave in V1 and R wave in V5 and V6 (SV1+RV5/6) is usually < 1.5 mV and is typically found in 30-70% of patients with AL amyloidosis8. Echocardiography usually documents hypertrophic cardiomyopathy, with no prior history of hypertension9. Cardiac MRI was suggestive of amyloid accumulation (Figure 2 ). Myocardial scintigraphy and genetic exams were even performed to rule out transthyretin (ATTR) amyloidosis. Despite cardiac MRI sensitivity and specificity is 85-90%9, the gold standard exam to diagnose amyloidosis is histological evidence of amyloid deposition in the tissues10. In our case, given the negativity of fat pad aspiration (58% sensitivity and 100% specificity in AL amyloidosis), cardiac involvement and high clinical suspicion, renal biopsy was mandatory to confirm diagnosis.
HBV and HIV are typically associated with AA amyloidosis11. Only few studies describe development of AL amyloidosis after HBV and HIV infection and there is no unique consensus about the etiopathogenesis12. The main hypotheses are that HBV is responsible for chronic immunological stimulation, while HIV antigens act like superantigens and stimulate B cell proliferation determining immunoglobulins production; on the other hand HIV infection causes CD4+ T cell depletion which induces immunodeficiency13. Immunoglobulins can misfold and accumulate as amyloid fibrils and lead to amyloidosis. Moreover, some studies correlate monoclonal proliferation of plasma cells and HIV13,14. In particular, the prevalence of MGUS in HIV patients is higher compared to the general population, especially at younger age (from 3-4% to 26%). In these patients, MGUS usually recover after receiving antiviral therapy15.
Conclusion Our clinical case represents a rare case of HIV and HBV-associated AL amyloidosis with IgA Lambda monoclonal component. Physiopathological links between HIV, HBV and AL amyloidosis need to be accurately studied. Our case report suggests that HIV-associated immune dysregulation might be critical for pathogenesis of plasma cell dyscrasias and then AL amyloidosis. Thus, we hypothesize that early immune restoration in our patient is important to remodulate the activity of HIV-induced immune system and, hopefully, to respond to anti-plasma cell neoplasm therapy.
We believe that this unusual observation presented as clinical case might be important for infectious disease specialist, general practitioners, cardiologists, and nephrologists to rapidly recognize risk factors for AL amyloidosis and thus facilitate the diagnosis and to start specific treatment.
AUTHOR CONTRIBUTIONS A.P., G.C, and O.M collected data, A.P., G.C, O.M and M.P. interpreted data and wrote the manuscript, all authors reviewed and approved the final version of the manuscript.
KEY MESSAGE Chronic viral infections as potential risk factor for AL amyloidosis
FUNDING INFORMATION This article was produced without any funding.
CONFLICT OF INTEREST STATEMENT The Authors declare that there are no potential conflicts of interest.
DATA AVAILABILITY STATEMENT Not applicable.
ETHICS STATEMENT This article does not contain any studies with human participants or animals performed by any of the authors.
PATIENT CONSENT STATEMENT The patient provided informed consent for the use of his clinical data.
ORCID Mariangela Palladino https://orcid.org/0000-0001-5993-8034