Amyloidosis

What amyloid is

Normally, proteins fold into precise shapes. In amyloidosis, a particular protein misfolds, sticks to other copies of itself and forms rigid fibrils. These deposits accumulate between cells, where the body cannot clear them. Over time they thicken and stiffen organs.

Amyloidosis can be systemic (affecting many organs) or localized (confined to one site, such as the bladder, larynx or skin). The type is named after the protein that forms the deposits, and the type determines treatment.

Types of amyloidosis

Other rare hereditary forms involve proteins such as fibrinogen, apolipoprotein and lysozyme. Dialysis-related amyloidosis (beta-2 microglobulin) occurs after many years of dialysis.

The amyloid plaques in Alzheimer's disease are a different, brain-only process and are not usually grouped with systemic amyloidosis.

Symptoms by organ

Symptoms are often vague and develop slowly, so diagnosis is frequently delayed.

Heart (cardiac amyloidosis)

• breathlessness, fatigue and leg swelling from heart failure
• a thickened, stiff heart muscle (a restrictive cardiomyopathy)
• low blood pressure, often after previously high blood pressure
• irregular heart rhythms, especially atrial fibrillation, and fainting

Kidneys

• protein leaking into the urine, causing foamy urine
• swelling of the legs and around the eyes (nephrotic syndrome)
• gradually declining kidney function

Nerves

• numbness, tingling and burning in the feet, spreading upward
• carpal tunnel syndrome in both wrists, often years before heart symptoms in ATTR
• autonomic problems: dizziness on standing, diarrhea alternating with constipation, erectile dysfunction, bladder problems

Other features

• enlarged tongue, sometimes with tooth indentations (AL)
• purple bruising around the eyes ("raccoon eyes") after coughing or straining (AL)
• enlarged liver and spleen
• unexplained weight loss and fatigue
• spinal stenosis and biceps tendon rupture (ATTR)

Diagnosis

1. Suspicion: the most important step. Clues include heart failure with a thick heart wall but low ECG voltages, protein in the urine with no diabetes, and carpal tunnel syndrome in both wrists.
2. Blood and urine tests: serum free light chains and immunofixation of blood and urine to look for an abnormal light chain (which suggests AL). Kidney function, urine protein and heart markers (NT-proBNP and troponin).
3. Heart imaging: echocardiogram with strain imaging, and cardiac MRI.
4. Bone scintigraphy (technetium PYP or DPD scan): strong uptake in the heart, together with no abnormal light chain, can diagnose cardiac ATTR without a biopsy.
5. Biopsy: fat pad, bone marrow, or affected organ tissue. Amyloid shows apple-green birefringence under polarized light with Congo red stain.
6. Typing: mass spectrometry identifies the precise protein, which is essential for treatment.
7. Genetic testing for the TTR gene in ATTR, with family screening if a variant is found.

Treatment

AL amyloidosis

AL is treated by eliminating the abnormal plasma cells, using regimens similar to myeloma treatment: daratumumab with bortezomib, cyclophosphamide and dexamethasone is a standard first-line approach. Selected patients have high-dose chemotherapy with autologous stem cell transplant. Hematologists track the light chain level to judge response.

ATTR amyloidosis

• Stabilizers (tafamidis, acoramidis) hold the transthyretin protein in its normal shape and reduce deaths and hospital stays in cardiac ATTR.
• Silencers (patisiran, vutrisiran, inotersen, eplontersen) reduce production of transthyretin in the liver. They are used for hereditary ATTR neuropathy, and vutrisiran is also approved for cardiac ATTR.
• Liver transplant was historically used for some hereditary forms.

AA amyloidosis

Controlling the underlying inflammation or infection, for example with biologic drugs for rheumatoid arthritis or colchicine for familial Mediterranean fever, can stop progression and sometimes allow deposits to regress.

Supportive care

• diuretics and careful fluid and salt management for heart failure
• some standard heart failure medicines are poorly tolerated, so a cardiologist experienced in amyloidosis guides treatment
• anticoagulation for atrial fibrillation, and pacemakers or defibrillators when needed
• dialysis or kidney transplant for kidney failure
• compression stockings and medicines for low blood pressure on standing
• nerve pain medicines and carpal tunnel surgery

Outlook

The outlook depends on the type and how much the heart is involved at diagnosis. Untreated AL amyloidosis with advanced heart involvement progresses quickly, but modern treatment has greatly improved survival, especially when it is caught early. ATTR progresses more slowly, over years, and stabilizers and silencers now slow or stop progression for many people. Care at a specialized amyloidosis center is recommended.

Frequently asked questions

What is amyloidosis?

Amyloidosis is a group of diseases in which misfolded proteins form deposits called amyloid in organs and tissues. These deposits stiffen and damage organs such as the heart, kidneys and nerves. The type depends on which protein is involved, and each type has different causes and treatments.

What are the first signs of amyloidosis?

Early signs are often vague: fatigue, breathlessness, leg swelling, foamy urine, numbness or tingling in the feet, carpal tunnel syndrome in both wrists, dizziness on standing, unexplained weight loss, a large tongue or bruising around the eyes. Because these are nonspecific, diagnosis is often delayed.

Is amyloidosis a form of cancer?

AL amyloidosis is not cancer, but it is caused by a plasma cell disorder closely related to multiple myeloma and is treated by hematologist-oncologists using similar drugs. ATTR and AA amyloidosis are not related to cancer.

Is amyloidosis hereditary?

Some types are. Hereditary ATTR amyloidosis is caused by inherited TTR gene variants, and relatives can be tested. AL, wild-type ATTR and AA amyloidosis are not inherited, though some inflammatory conditions that cause AA can run in families.

Can amyloidosis be cured?

Most forms cannot be fully cured, but they can be controlled. Effective AL treatment can stop new deposits and allow organs to recover partly. ATTR drugs slow or halt progression. Controlling the inflammation in AA amyloidosis can stabilize it. Earlier treatment gives better results.