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Staging and Progression of AL Amyloidosis

Posted on April 20, 2021
Medically reviewed by
Todd Gersten, M.D.
Article written by
Maureen McNulty

  • The signs and symptoms of amyloid light-chain (AL) amyloidosis often grow worse over time.
  • AL amyloidosis stages are estimated based on heart or kidney biomarkers.
  • Doctors use different staging systems to estimate the amount of heart or kidney damage and to predict prognosis.

Amyloid light-chain (AL) amyloidosis symptoms may become increasingly serious as the disease progresses, or gets worse. When AL amyloidosis affects multiple organs, it is called primary systemic amyloidosis. In primary systemic amyloidosis, parts of antibody proteins build up within various tissues and organs. The more these amyloid proteins accumulate, the more they can impair organ function and cause severe symptoms.

It is important to know the signs of AL amyloidosis progression so you can recognize how this disease is affecting your body. If your AL amyloidosis begins causing new problems, your doctor may recommend you change your treatment plan.

AL Amyloidosis Disease Progression

Doctors use various tests to monitor AL amyloidosis progression and check for disease signs — measurable characteristics, such as an enlarged tongue or swelling in the legs, that can be seen by another person. These signs are often accompanied by symptoms — internal sensations, such as pain, that can only be felt by the person experiencing them.

Different cases of AL amyloidosis can progress at different rates. For many people, amyloidosis gets worse quickly. AL amyloidosis most often affects the kidneys and the heart, and it causes these organs to progressively become more damaged. It can also affect other tissues, such as those in the digestive system, liver, and nervous system. Eventually, affected organs can completely shut down. Understanding signs of amyloidosis progression can clarify why you experience certain symptoms or why your doctor recommends specific tests.

Read more about how AL amyloidosis can affect the organs.

AL Amyloidosis and the Bone Marrow

Amyloidosis starts in the bone marrow, where a type of white blood cell called a plasma cell is often found. When these cells develop abnormalities, they begin producing amyloid proteins. People with AL amyloidosis develop two signs of disease before they start experiencing symptoms:

  • Monoclonal gammopathy — Abnormal antibody proteins appear in the blood.
  • Signs of organ involvement — Tests show signs of organ damage.

Your doctor may want to test you for amyloidosis if you have these signs. If left untreated, amyloid protein levels will continue to rise, amyloid deposits will build up in one or more organs, and you will start noticing symptoms. Disease progression may look different depending which organs are affected.

Read about the connection between AL amyloidosis and blood cell cancers.

Kidney-Related Disease Progression

Kidneys filter toxins and proteins in the blood. When amyloid deposits form in the kidneys, it affects their ability to efficiently filter toxins, and waste products build up. Nephrotic syndrome is a condition that occurs when the kidneys leak protein into the urine. Signs of nephrotic syndrome include:

  • Albuminuria — An increased amount of albumin protein in the urine
  • Hypoalbuminemia — Decreased levels of albumin in the blood
  • Hyperlipidemia — Abnormally high amounts of fats and cholesterol in the blood

Your doctor may look for these signs using blood and urine tests. You may not realize you have these problems, or you may notice symptoms like edema — swelling in the legs, feet, or ankles.

When amyloid deposits prevent the kidneys from purifying blood, renal failure can result. In these cases, end-stage kidney disease occurs, and kidney dialysis becomes necessary.

Progression of Heart Symptoms

When amyloid deposits form in the heart, the walls of this critical organ become thickened and stiff. Amyloid deposits make the heart unable to efficiently function. As amyloidosis progresses, people may experience heart problems including:

  • Diastolic heart failure — The heart can’t fill with enough blood
  • Systolic heart failure — The heart can’t pump enough hard enough
  • Arrhythmias — Abnormal heart rhythms
  • Conduction disturbances — Problems with electrical signaling in the heart
  • Embolic events — Dangerous blood clots
  • Sudden death

Cardiac amyloidosis often progresses quickly. To monitor heart health, your doctor may use imaging tests, such as an echocardiogram or magnetic resonance imaging (MRI). Tests may show that the heart has become larger or that it is not beating correctly.

AL Amyloidosis Progression in the Digestive System

Complications associated with protein accumulation in the gastrointestinal system can be quite dangerous. Some symptoms, like acid reflux or nausea, may be a direct result of amyloid deposits. Other symptoms, like diarrhea and weight loss, may actually be caused by other issues — such as nerve damage — that can appear as amyloidosis progresses.

Progression of Nervous System Symptoms

Amyloid light-chain proteins can collect in the nerves, blocking them from carrying signals back and forth between the brain and various tissues in the body. This can lead to neuropathy, or nerve damage. Neuropathy often starts with mild symptoms, such as feelings of “pins and needles” in the feet. These feelings are a sign that amyloid deposits are collecting in smaller nerves. As amyloidosis progresses, amyloid proteins begin to affect bigger nerves. This can lead to symptoms like numbness and feelings of muscle weakness.

Staging of AL Amyloidosis

If you have AL amyloidosis, your doctor may try to determine your disease stage. The stage of amyloidosis, expressed as a number, describes how advanced the amyloidosis is. Your amyloidosis stage can help you and your care team understand the severity of organ damage and what your prognosis may look like.

There are several staging systems for AL amyloidosis. Specialists don’t currently all agree on one system, so different doctors may stage the disease differently. Some staging systems describe the severity of heart damage, while others focus on kidney damage. The amyloidosis stage is determined using biomarkers — molecules that can act as a sign of disease. Biomarkers are often measured using blood or urine tests.

Mayo Clinic Staging System

Researchers from the Mayo Clinic first came up with a staging system to measure amyloidosis-related heart damage in 2004. The most recent version of this system, designed in 2012, uses three different biomarkers to assess heart disease:

  • N-terminal pro-brain natriuretic peptide (NT-proBNP) — The heart makes NT-proBNP when changes in heart pressure cause it to start to fail.
  • Cardiac troponin T (cTnT) — This molecule is produced when heart cells are damaged.
  • Difference between involved and uninvolved free light chains (dFLC) — This number is a measure of how many of the body’s light-chain proteins are abnormal amyloid proteins.

The higher each of these numbers is, the higher your amyloidosis stage and the more heart damage you probably have. In healthy individuals, levels of these biomarkers will usually be:

  • NT-proBNP — Less than 1,800 nanograms per liter
  • cTnT — Less than 0.025 nanograms per milliliter
  • dFLC — Less than 180 milligrams per liter

To use the Mayo Clinic staging system, your doctor will measure levels of these cardiac biomarkers. If any biomarker levels are higher than the above cutoffs, you will be diagnosed with a higher amyloidosis stage:

  • Stage 1 — All biomarkers are below the cutoffs.
  • Stage 2 — One biomarker is above its cutoff.
  • Stage 3 — Two biomarkers are above their cutoffs.
  • Stage 4 — All biomarkers are above their cutoffs.

People with higher-stage amyloidosis are likely to have more severe heart damage and not to live as long. In one study, people with stage 1 AL amyloidosis lived an average of 7.8 years after diagnosis, while people with stage 4 disease lived an average of 5.8 months.

Other Cardiac Staging Systems

Other researchers have since developed systems to stage AL amyloidosis. One of them came from a group of European studies and is sometimes called “Mayo2004/European” or the “European modification.” This staging system is similar to the above revised Mayo Clinic system. However, the European system separates stage 3 amyloidosis into two groups, “a” and “b.” Both groups have NT-proBNP and cTnT levels above certain cutoffs. However, people with stage 3b amyloidosis have extremely high levels of NT-proBNP:

  • Stage 3a — NT-proBNP levels are less than 8,500 nanograms per liter. People at this stage live an average of 15 months after diagnosis.
  • Stage 3b — NT-proBNP levels are higher than 8,500 nanograms per liter. People at this stage live an average of four months after diagnosis.

NT-proBNP is a useful biomarker, but it can be hard to test for. Many laboratories find it easier to test for a related molecule, brain natriuretic peptide (BNP). Therefore, another staging system was developed using BNP instead. Additionally, rather than testing for cTnT, this system uses a similar molecule called cardiac troponin I (cTnI). This staging system looks like:

  • Stage 1 — BNP is less than 81 picograms per milliliter, and cTnI is less than 0.1 nanograms per milliliter.
  • Stage 2 — BNP is greater than 81 picograms per milliliter, or cTnI is greater than 0.1 nanograms per milliliter.
  • Stage 3 — BNP is greater than 81 picograms per milliliter, and cTnI is greater than 0.1 nanograms per milliliter.
  • Stage 3b — BNP is greater than 700 picograms per milliliter, and cTnI is greater than 0.1 nanograms per milliliter.

Using this BNP-based staging system, people with stage 3b amyloidosis also usually have a worse disease outlook and a shorter life span than people with lower-stage disease.

Kidney Staging Systems

Kidney staging is often performed using two prognostic factors. One is proteinuria, or protein in the urine. The other is estimated glomerular filtration rate (eGFR), which measures how well your kidneys are working. A lower eGFR usually means that you have worse kidney function.

Kidney staging often follows this system:

  • Stage 1 — eGFR is greater than 50 milliliters per minute per 1.73 square meters, and proteinuria is less than 5 grams in 24 hours.
  • Stage 2 — eGFR is less than 50 milliliters per minute per 1.73 square meters, or proteinuria is greater than 5 grams in 24 hours.
  • Stage 3 — eGFR is less than 50 milliliters per minute per 1.73 square meters, and proteinuria is greater than 5 grams in 24 hours.

Kidney stages tell you how likely you are to need dialysis. Dialysis is a treatment people need when they have kidney failure. People with renal stage 1 amyloidosis have a 1 percent chance of needing dialysis within two years of diagnosis. People with stage 3 disease, on the other hand, have a 48 percent chance of needing dialysis within two years of diagnosis. If you have higher-stage amyloidosis, your doctor may want to more closely monitor your kidney health over time.

Talk With Others Who Understand

MyAmyloidosisTeam is the social network for people with amyloidosis and their loved ones. On MyAmyloidosisTeam, members come together to ask questions, give advice, and share their stories with others who understand life with amyloidosis.

Are you living with amyloidosis? Share your experience in the comments below, or start a conversation by posting on your Activities page.

References
  1. Light-Chain (AL) Amyloidosis: Diagnosis and Treatment — Clinical Journal of the American Society of Nephrology
  2. Signs and Symptoms — Nature Research
  3. AL Amyloidosis — Amyloidosis Foundation
  4. Management of AL Amyloidosis in 2020 — Blood Journal
  5. Renal-Limited AL Amyloidosis — A Diagnostic and Management Dilemma
  6. Novel Pathologic Scoring Tools Predict End-Stage Kidney Disease in Light Chain (AL) Amyloidosis — Amyloid: The Journal of Protein Folding Disorders
  7. Amyloidosis — National Organization for Rare Disorders
  8. Cardiac Amyloidosis: Updates in Diagnosis and Management — Archives of Cardiovascular Diseases
  9. Amyloidosis of the Gastrointestinal Tract: A 13-Year, Single-Center, Referral Experience — Haematologica
  10. Amyloid Neuropathies — Mount Sinai Journal of Medicine
  11. Staging of Multiple Myeloma and AL Amyloidosis — Tufts Medical Center
  12. Biomarker — National Cancer Institute Dictionary of Cancer Terms
  13. Predicting Survival in Light Chain Amyloidosis — Haematologica
  14. NT-proB-Type Natriuretic Peptide (BNP) — Cleveland Clinic
  15. Troponin — Lab Tests Online
  16. Appraisal of Immunoglobulin Free Light Chain as a Marker of Response — Blood
  17. Prognosis and Staging of AL Amyloidosis — Acta Haematologica
  18. Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements — Journal of Clinical Oncology
  19. Development and Validation of a Survival Staging System Incorporating BNP in Patients With Light Chain Amyloidosis — Blood
  20. Estimated Glomerular Filtration Rate (eGFR) — National Kidney Foundation
  21. Dialysis — National Kidney Foundation
All updates must be accompanied by text or a picture.
Todd Gersten, M.D. is a hematologist-oncologist at the Florida Cancer Specialists & Research Institute in Wellington, Florida. Review provided by VeriMed Healthcare Network. Learn more about him here.
Maureen McNulty studied molecular genetics and English at Ohio State University. Learn more about her here.

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