Complications and Comorbidities

Transthyretin (ATTR) amyloidosis is a complex disease. It happens when a protein called transthyretin, or TTR, misfolds. These misfolded proteins build up as amyloid fibrils in different parts of the body. This buildup can damage organs and tissues over time. ATTR amyloidosis is a systemic disease. This means it can affect many body systems.^1-3

There are 2 main types of ATTR amyloidosis:^1-3

• Hereditary (hATTR) amyloidosis – caused by a gene mutation passed down in families
• Wild-type (ATTRwt) amyloidosis – usually affects older adults and is not inherited

Both types can lead to serious health problems. This article explores the common complications and related conditions (comorbidities) for both types of ATTR amyloidosis.^1-3

How ATTR amyloidosis causes damage

The TTR protein is made mostly in the liver. When it is functioning as it is supposed to, it delivers vitamin A and a thyroid hormone to the rest of the body through the blood. In ATTR amyloidosis, this protein becomes unstable. It breaks apart and forms clumps called amyloid fibrils. These fibrils travel through the bloodstream and deposit in organs.^1-3

This buildup makes tissues stiff and stops them from working correctly. This process leads to organ dysfunction and the symptoms of the disease.^1-3

Complications of hereditary (hATTR) amyloidosis

Hereditary ATTR amyloidosis is caused by a mutation in the TTR gene. There are over 120 different mutations. The specific mutation often determines which complications are most severe. Some mutations primarily cause nerve damage. Others, like the V122I mutation, primarily cause heart damage.^1,3,4

Nervous system complications

Damage to the nerves, or polyneuropathy, is a classic sign of hATTR.^1,3

Peripheral neuropathy
This involves damage to the nerves in the feet, legs, hands, and arms. Early symptoms usually include pain, numbness, or tingling that starts in the feet and moves up the body. It can lead to muscle weakness and difficulty walking.^1,3

Autonomic neuropathy
This is damage to the nerves that control automatic body functions. This can cause a wide range of problems. These include orthostatic hypotension, which is severe dizziness or fainting when standing up. It also includes serious gastrointestinal (GI) issues.^1,3

Gastrointestinal (GI) complications

GI problems are very common in hATTR and are usually caused by autonomic neuropathy. Symptoms can be severe and may include:^1,3

• Chronic diarrhea or constipation
• Nausea and vomiting
• Feeling full after eating very little
• Unexplained weight loss

Heart complications

The heart is a common target in hATTR amyloidosis. For some people with hATTR, heart issues are their very first sign of the disease.^3,4

Cardiomyopathy
The reason hATTR causes heart problems is that amyloid fibrils build up in the heart muscle. This makes the heart walls thick and stiff. This condition is called cardiomyopathy (CM). When cardiomyopathy is a complication of ATTR, it is often called ATTR-CM.^3,4

Heart failure
A stiff heart cannot pump blood effectively. This leads to heart failure. Many people develop a type of heart failure called heart failure with preserved ejection fraction. Symptoms include shortness of breath, feeling very tired, and swelling in the legs or feet.⁴

Atrial fibrillation (Afib)
The amyloid deposits can also damage the heart's electrical system. This causes irregular heart rhythms, known as arrhythmias. Atrial fibrillation (Afib) is a very common arrhythmia in ATTR.⁴

Conduction system disease
Amyloid can also damage the heart’s natural pacemaker. This is when electrical signals move too slowly through the heart, leading to a very slow heart rate. A person may need a permanent pacemaker to keep their heart beating correctly.⁴

Complications of wild-type (ATTR-wt) amyloidosis

Wild-type ATTR amyloidosis (ATTRwt) is most common in men over the age of 60 and primarily affects the heart. However, it often involves other tissues, especially in the musculoskeletal system.^4,5

Heart complications

The heart is the main organ damaged in ATTRwt. The complications are similar to those in hATTR and can include:^4,5

• Heart failure
• Cardiomyopathy
• Arrhythmias like Afib
• Conduction disease

Musculoskeletal complications

In many people with ATTRwt, other conditions appear years before heart problems start. These are often seen as signs of aging.⁶

Carpal tunnel syndrome
This is a very common early sign. It causes numbness, tingling, and pain in both hands and wrists. It often occurs 5 to 10 years before heart symptoms.⁶

Lumbar spinal stenosis
This is a narrowing of the spinal canal in the lower back. It can cause back pain and leg pain when walking. Amyloid deposits have been found in the ligaments of the spine.⁶

Tendon rupture
People with ATTRwt may experience spontaneous ruptures. The most common is the biceps tendon in the upper arm.⁶

Other systems affected by ATTR amyloidosis

Both hATTR and ATTRwt can damage other organs as the disease progresses.^1,3

Kidney complications

Amyloid can build up in the kidneys. This may cause protein to leak into the urine (proteinuria). Over time, this can lead to kidney dysfunction or kidney failure.^1,3

Eye complications

Amyloid deposits can form inside the eyes. This can cause problems like:^1,3

• Blurry vision or seeing “floaters”
• Increased pressure in the eyes (glaucoma)

Living with ATTR amyloidosis

ATTR amyloidosis is a multisystem disease. It can cause a wide range of complications. These can include heart failure, nerve damage, joint problems, and kidney issues.

Managing these complications is a key part of treatment. This often requires a team of doctors, including specialists in heart, nerve, and kidney health.

It is important to tell your doctor about any new symptoms you have. This is true even if they seem unrelated to your main condition. Early recognition of complications can help your healthcare team create the best plan for you.