The meta-analysis entitled “Diagnostic Role of NT-proBNP in Patients with Cardiac Amyloidosis Involvement: A Meta-Analysis” brings us an important review of the usefulness of NT-proBNP measurement in patients with cardiac involvement by amyloidosis. The demonstration of good sensitivity and specificity of this biomarker reinforces its usefulness in the diagnosis of cardiac amyloidosis (CA).

Cardiac amyloidosis has been increasingly diagnosed, especially in patients with the heart failure phenotype of preserved ejection fraction. Just over half of the patients with symptoms of heart failure have preserved ejection fraction, especially elderly individuals. This finding is usually considered only as age-related diastolic dysfunction and associated comorbidities. However, this factor should be one of the warning signs for diagnosing CA, especially when associated with high levels of biomarkers. A great variability in the frequency of diagnosis of CA in the general population has been described, ranging from 5 to 74% between the various studies. This variability may be related to factors such as low clinical suspicion or difficulties accessing complementary exams necessary for diagnosing cardiac involvement in amyloidosis. The diagnostic flowchart in patients with suspected cardiac involvement by amyloidosis is mainly based on imaging tests.^– These tests can be expensive, such as myocardial scintigraphy, strain echocardiography and cardiac magnetic resonance, and, often, they are only available at cardiology referral centers, making the diagnosis of CA more difficult and delayed. In addition, it is important to note that the late diagnosis of these patients can directly influence the prognosis by delaying the start of treatment, leading to a median of 6 months of survival after the development of symptoms in the AL form of amyloidosis for example.

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Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly and multiple-organ failure. It consists of two different conditions that may be difficult to distinguish: a primary form is mostly seen in children and is caused by various mutations with genetic inheritance and a secondary HLH may be secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus without an identifiable underlying genetic trigger.^,

The hyperinflammatory immune state is caused by the absence of normal downregulation by activated macrophages and lymphocytes. Most patients with HLH have impaired cytotoxic function of natural killer (NK) cells and cytotoxic lymphocytes (CTLs), coupled with excessive activation of macrophages. Lack of feedback regulation results in excessive macrophage activity and high levels of interferon gamma and other cytokines. Excessive cytokine production by macrophages, NK cells, and CTLs is a primary mediator of tissue damage.

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