Micro Classroom No. 14 Prof. Min Yang: Early diagnosis of AL amyloidosis

Fig.
1 Prevalence (A) and incidence of AL amyloidosis in real-world studies in the United States (B)

Patients with AL amyloidosis have a low 5-year overall survival (OS) rate, ≥with a median OS of only 2.
2 years in patients aged 70 years and a median OS of 2.
6 years in patients with cardiac involvement4
.

Early diagnosis of AL amyloidosis is difficult, and one of the very important reasons is that AL amyloidosis affects almost all organs
except the brain.
Common organs involved include heart, liver, kidneys, etc.
, and soft tissue involvement may cause periorbital purpura and carpal tunnel syndrome; and even lead to abnormal blood clotting function; Focal amyloidosis of the lungs causes dry cough; Gastrointestinal involvement leads to gastric paralysis, indigestion, and affects the nervous system, and the diversity of clinical manifestations makes the early diagnosis of AL amyloidosis very difficult
.

According to a retrospective exploration of the data of 1313 AL amyloidosis patients in the US commercial insurance database from 2006 to 20185, the average time from the first symptom to diagnosis of AL amyloidosis is 2.
5 years, and the most common non-specific clinical manifestations such as fatigue, edema, dyspnea and abdominal pain are easy to cause missed diagnosis and misdiagnosis
。 Patients with arrhythmias, cardiac hypertrophy, and cardiomyopathy often consult the Department of Cardiology; Most patients with symptoms such as chronic kidney disease and edema present to a nephrologist
.
Therefore, from the first symptom onset to the diagnosis, more than 90% of patients have at least 5 visits, and only one-quarter of patients have M protein testing 1 year before diagnosis, but the diagnosis
is not clear.

According to the results of a US ^study6, only 28.
2% of patients with AL amyloidosis are diagnosed in time within 6 months of symptom onset, and multidisciplinary collaboration is expected to further deepen clinicians' understanding of the disease and improve the diagnosis rate
of AL amyloidosis.
Delayed diagnosis (> 6 months) may result in more organ involvement, while patients with cardiac involvement have a worse prognosis, with the heart as the primary organ involved in 34.
7% of patients with delayed diagnosis, compared with 18.
8%
of patients with early diagnosis (< 6 months).

In terms of diagnosis, the current gold standard is that tissue biopsy pathologically confirms amyloid deposition, and the precursor protein of amyloid is immunoglobulin light chain or heavy light chain, specifically positive Congo red staining, apple green birefringence under polarized light
.
In addition, the presence of monoclonal immunoglobulins/free light chains in blood or urine, or the presence of monoclonal plasma cells/B cells on bone marrow examination, is also strong supporting evidence
.

Regarding the prognostic value of bone marrow plasma cells, a study of 79 patients with AL amyloidosis7 found that higher bone marrow plasma cell infiltration in patients with AL amyloidosis was associated with systemic organ damage, with a higher degree of heart and kidney involvement as bone marrow plasma cells increased, and higher bone marrow plasma cell infiltration (>10%) associated with shorter progression-free survival (PFS) and OS ⁸ (Figure 2).

Fig.
2 Effect of bone marrow plasma cell infiltration level on PFS and OS

In addition to bone marrow plasma cells, serum free light chain (sFLC) testing is also important for the diagnosis and prognosis of patients with AL amyloidosis
.
sFLC detection can not only be used to judge the clonality of immunoglobulins, but also have a good indication for the quantitative detection of micro M
proteins.
For primary AL amyloidosis, the sFLC level is an indicator of tumor burden in the patient and an important prognostic indicator
for patients.
A retrospective study of 126 patients with primary AL amyloidosis from 2009 to 2015 at Peking Union Medical College ^Hospital9 showed that sFLC detection significantly improved the M protein detection rate (81%) in patients with primary AL amyloidosis, and multivariate analysis found that the free light chain difference (dFLC) ≥130mg/L was an independent risk factor
affecting the prognosis of patients with primary AL amyloidosis.

In contrast, low levels of sFLC at diagnosis predict a good prognosis
.
A retrospective study of 783 patients with newly diagnosed AL amyloidosis10 showed that low levels of dFLC (<⁵⁰ mg/L) meant less myeloplasma cell proliferation and fewer organ involvement, and a lower proportion and less
severe cardiac involvement.
A significantly higher proportion of patients with dFLCs < 50 mg/L achieve complete remission after first-line therapy to help patients realize OS benefit
.

To better diagnose patients with AL amyloidosis, attention must be paid to cardiac and kidney-related markers (Table 1
).
In Mayo 2012 staging ^system11, patients are classified as stages I-IV based on N-terminal natriuretic peptide precursors (NT-proBNP), cardiac troponin (cTnT), and dFLC according to cardiac function, with a median OS of only 6 months for stage IV patients and more than 10 years
for stage I patients.
At the same time, it is not difficult to find that these three indicators have important value
for the judgment of heart function.

Table 1 Development of cardiac staging system

As the second most commonly affected organ of AL amyloidosis, the kidneys also have an important impact on
patient survival and treatment options.
Establishing a renal staging system based on glomerular filtration rate and urine protein levels can be used to determine renal prognosis, and criteria for renal response and progression can also be used to predict dialysis progression
.

For patients with renal and cardiac involvement, the Nanjing prognostic staging system ¹² formulated by Academician Liu Zhihong's team also included dFLC as a prognostic index, and when the stage IV was staged, the median OS was only 15 months
.

In addition, growth differentiation factor 15 (GDF-15) as a new detection marker is strongly associated
with patient OS and renal remission.
GDF-15 is a member of transforming growth factor β (TGF-β), which is a marker reflecting oxidative stress and inflammation in cardiomyocytes, and has anti-inflammatory
, inhibition of apoptosis, improvement of myocardial remodeling and ventricular hypertrophy, and improvement of kidney disease.
A study exploring the importance of serum GDF-15 levels to patient prognosis in two separate ^cohorts13 of Pavia and Athens found that GDF-15>7575pg/mL was associated with shorter survival (Figure 3), and GDF-15>4000pg/mL significantly increased the risk of
progression to dialysis within 2 years.
GDF-15 is a predictor
of independent Mayo stratification and renal stratification.

Fig.
3 Impact of GDF-15 level on patient survival

summary 

AL amyloidosis can involve multiple organs, and the clinical manifestations are diverse;

Early diagnosis is currently the most important clinical unmet need for AL amyloidosis;

sFLC detection is of great significance for the diagnosis and prognosis of patients with AL amyloidosis.

The heart and kidneys are the two most commonly affected organs of AL amyloidosis and play an important role in the clinical course;

More exploration of new markers is needed for early diagnosis
of AL amyloidosis.