A Call to Increase Awareness About AL Amyloidosis

The systemic disorder AL amyloidosis (light chain amyloidosis) is highly treatable when detected early, yet it often takes patients upwards of two years to receive a diagnosis. To address this challenge, the American Society of Hematology (ASH) convened a panel of experts to develop guidelines that foster prompt diagnosis of this life-threatening disease.

Background

AL amyloidosis is a protein misfolding disorder that starts with the presence of abnormal plasma cells in the bone marrow. The disease may mimic other conditions given its systemic nature and often nonspecific symptoms. By the time patients are diagnosed, they often have irreversible organ damage.

Many primary care and family medicine providers may not consider AL amyloidosis when working up a patient with suggestive symptoms due to its rarity. Between 1,275 to 3,200 new cases are diagnosed each year in the U.S. Patients often present with non-specific symptoms such as fatigue, making it challenging to diagnose.

In addition, the systemic nature of the disease adds another layer of complexity to diagnosis. Accumulation of abnormal light chain proteins can affect any number of organs, including the heart and kidneys.

“There’s decreased awareness about this disease in many clinical settings, so we wanted to develop simple, practical guidelines to empower and support clinicians to diagnose it rapidly,” says Jack Khouri, MD, a member of the guideline panel and a hematologist/oncologist with Cleveland Clinic Cancer Institute.

Simple screenings are highly accurate

Dr. Khouri and his fellow panelists urge clinicians to order blood and urine immunofixation and serum free light chain assays for any patient experiencing symptoms such as fatigue and unexplained weight loss. These simple tests have a high negative predictive value. A negative result will virtually rule out AL amyloidosis. “Protein electrophoresis alone in the serum and urine is not really helpful,” explains Dr. Khouri. “Clinicians should obtain immunofixation and serum free light chains and not just electrophoresis to screen for AL amyloidosis.”

Leveraging biopsies earlier

For cases where a patient tests positive for protein in their blood and/or urine and the clinical scenario is suggestive of AL amyloidosis, an immediate biopsy is needed to quickly make a diagnosis. “If treatment is instituted early, you can reverse cardiac damage but the longer it takes to diagnose and treat, the greater the chance of losing cardiac tissue,” says Dr. Khouri. “We want to help clinicians be more proactive in recognizing signs to look for — and to order tests rapidly instead of sending patients to specialists before they start the workup.”

In some cases, patients may have signs of organ involvement, such as:

• Elevated cardiac biomarkers
• Autonomic dysfunction
• Peripheral neuropathy
• Proteinuria

If the clinician doesn’t have access to a subspecialist who can perform a target organ biopsy, they can order a bone marrow biopsy and a fat pad biopsy. The sensitivity of these surrogate tissue biopsies for diagnosis is close to 90%. These methods spare patients from the risk of a more involved procedure such as a cardiac or kidney biopsy and can expedite diagnosis in resource-limited settings.

“If you practice at a large center where your patient could get seen by a skilled specialist quickly, a target organ biopsy may be the appropriate first step, but in cases where there's a long wait or the patients do not have access to the latter, order a fat pad sampling and bone marrow biopsy to make a quick diagnosis,” explains Dr. Khouri.

The case for cardiac MRI

Clinicians often believe they’ll need a cardiac MRI to increase suspicion for cardiac AL amyloidosis. However, positive monoclonal blood and/or urine testing, evidence of potential cardiac amyloidosis on an echocardiogram and positive serum cardiac biomarkers (NT pro BNP and/or troponins) are sufficient to proceed to tissue biopsy and skip further cardiac imaging. A cardiac MRI may be beneficial if the latter testing is equivocal and more testing is needed before proceeding to a biopsy.

In cases where a patient has heart failure but is negative for monoclonal protein in their blood and urine, a bone scintigraphy may be used to screen for ATTR amyloidosis. This progressive disease involves ATTR proteins depositing in the heart and other organs. Bone scintigraphy is generally only useful in cases where blood and urine tests are negative for monoclonal proteins.

In both AL amyloidosis and ATTR amyloidosis, it’s important to gauge the type and severity of organ involvement to identify appropriate supportive care. For example, cardiac biomarkers and imaging are used when heart involvement is suspected.

Key takeaways

It may be hard to discern what’s happening when a patient presents with vague symptoms. The ASH panel shared several takeaways in those cases.

Have a high degree of suspicion for plasma cell disorders. “Often when clinicians see patients with weight loss and fatigue they think of endocrine problems or cancer but we also want them to screen for plasma cell disorders,” says Dr. Khouri.

Order the right series of tests. If you’re seeing a patient with non-specific symptoms such as fatigue and weight loss, order blood and urine immunofixation and serum-free light chain assays. There’s a very low burden on patients to have these tests.

Recognize the utility of surrogate tissue biopsies. These procedures are often the best option to minimize risk and accelerate time-to-diagnosis.