I recently saw a 78-year-old gentleman who came in with an unusual complaint—his tongue had gradually become so enlarged that it was interfering with speech and swallowing. Known as macroglossia, this isn’t a common symptom in most conditions, but it’s one that should immediately raise suspicion for amyloidosis. Laboratory tests were consistent with amyloidosis, as I suspected.

Amyloidosis is a group of diseases caused by the abnormal buildup of proteins, called amyloids, in various organs. These misfolded proteins disrupt normal function, and because they can deposit almost anywhere in the body, the symptoms can vary widely. The challenge with amyloidosis is that it often masquerades as other, more common conditions, leading to delays in diagnosis.

Recognizing the Signs: When to Suspect Amyloidosis

The symptoms of amyloidosis depend on which organs are affected, but certain red flags should prompt further investigation:

• Macroglossia (enlarged tongue) – Seen in about 10-20% of cases of primary (AL) amyloidosis, it can cause difficulty speaking, swallowing, and even breathing.
• Nephrotic syndrome – Protein in the urine (proteinuria), swelling in the legs (edema), and declining kidney function can suggest amyloid deposits in the kidneys.
• Restrictive cardiomyopathy – Heart involvement can lead to heart failure with preserved ejection fraction (HFpEF), arrhythmias, and thickened heart walls seen on echocardiogram.
• Peripheral neuropathy – Tingling, numbness, and weakness in the hands and feet can indicate amyloid infiltration of nerves.
• Orthostatic hypotension – A drop in blood pressure upon standing, leading to dizziness or fainting, may suggest autonomic nervous system involvement.
• Unexplained weight loss and fatigue – Often vague but persistent, these symptoms should prompt consideration of systemic diseases like amyloidosis.

The Subtypes of Amyloidosis

Understanding the different types of amyloidosis is critical for proper treatment. The three most common subtypes are:

• AL (Immunoglobulin Light Chain) Amyloidosis – The most common form, AL amyloidosis is caused by misfolded light chains produced by abnormal plasma cells, similar to multiple myeloma. It can affect multiple organs, including the heart, kidneys, nerves, and liver.
• ATTR (Transthyretin) Amyloidosis – This form results from misfolded transthyretin proteins, either due to a genetic mutation (hereditary ATTR) or aging (wild-type ATTR). It frequently affects the heart and nerves.
• AA Amyloidosis – A result of chronic inflammation from conditions like rheumatoid arthritis or infections, AA amyloidosis primarily affects the kidneys, leading to proteinuria and renal failure.

How Is Amyloidosis Diagnosed?

Given its protean manifestations, amyloidosis requires a high index of suspicion. The diagnostic process typically includes:

• Serum and Urine Protein Electrophoresis (SPEP/UPEP) and Free Light Chain Assay – Helps identify AL amyloidosis.
• Cardiac Imaging – Echocardiography and cardiac MRI can reveal characteristic patterns of amyloid infiltration.
• Biopsy – Tissue samples from affected organs or fat pad aspirates can confirm the presence of amyloid deposits. Congo red staining under polarized light shows the classic apple-green birefringence.
• Genetic Testing – Important in distinguishing hereditary ATTR amyloidosis from the wild-type variant.

Treatment: Targeting the Underlying Cause

Treatment depends on the type of amyloidosis and the organs involved:

• AL Amyloidosis – Treated similarly to multiple myeloma, often with chemotherapy (bortezomib, cyclophosphamide, dexamethasone) and, in eligible patients, autologous stem cell transplant.
• ATTR Amyloidosis – Medications like tafamidis can stabilize transthyretin to prevent further misfolding. Patisiran and inotersen (RNA-targeting therapies) help reduce transthyretin production in hereditary cases.
• AA Amyloidosis – Requires controlling the underlying inflammatory condition, often with biologics or immunosuppressive therapy.

Why Early Detection Matters

Amyloidosis is progressive, and delays in diagnosis can result in irreversible organ damage. Physicians should maintain a high level of suspicion when encountering patients with unexplained heart failure, neuropathy, nephrotic syndrome, or macroglossia. If amyloidosis is suspected, prompt referral to a specialist, typically a hematologist or cardiologist, is essential for confirmation and treatment initiation.

Final Thoughts

This 78-year-old gentleman’s case was a classic example of how subtle yet critical findings can lead to a life-altering diagnosis. Amyloidosis, though rare, should always be on the differential when faced with unexplained multi-organ dysfunction. The sooner we recognize and treat it, the better the patient’s chances of maintaining quality of life.

References:

1. Falk RH, Alexander KM, Liao R, Dorbala S. “AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy.” J Am Coll Cardiol. 2016;68(12):1323-1341.
2. Maurer MS, Schwartz JH, Gundapaneni B, et al. “Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.” N Engl J Med. 2018;379(11):1007-1016.
3. Gertz MA, Dispenzieri A, Sher T. “Pathophysiology and Treatment of AL Amyloidosis.” Mayo Clin Proc.2020;95(11):2674-2696.