Transthyretin Amyloidosis: Symptoms, Causes, Treatment

What are the symptoms of transthyretin amyloidosis?

Transthyretin amyloidosis (ATTR amyloidosis) has a range of symptoms that can vary depending on the type and the organs affected. The symptoms generally involve the nervous system, heart, and other organs.

General Symptoms

• Peripheral Neuropathy: Tingling, numbness, burning pain, or weakness, typically starting in the hands and feet and progressing upwards (often known as a “glove and stocking” distribution).
• Autonomic Neuropathy: Dizziness upon standing (due to low blood pressure), gastrointestinal issues like diarrhea or constipation, bladder control problems, and sexual dysfunction.

Cardiac Symptoms

• Heart Failure: Shortness of breath, fatigue, and fluid retention (edema), particularly in the legs.
• Arrhythmias: Irregular heartbeats, which can feel like palpitations.
• Thickened Heart Walls: Leading to restrictive cardiomyopathy, which makes it harder for the heart to pump blood effectively.

Gastrointestinal Symptoms

• Weight Loss: Unintentional weight loss is common due to poor nutrient absorption.
• Nausea and Vomiting: Especially after meals.
• Diarrhea or Constipation: Alternating bowel habits are frequent.

Other Symptoms

• Carpal Tunnel Syndrome: Numbness, tingling, or pain in the hands due to nerve compression.
• Eye Problems: In some cases, patients may develop vision changes or have small yellow deposits (vitreous opacities) in the eye.
• Fatigue: Chronic tiredness and weakness.

Wild-Type ATTR (Non-Hereditary)

• Predominantly Cardiac Symptoms: This form mainly affects the heart and is more common in older adults.
• Less Neurological Involvement: Neuropathy is less frequent compared to hereditary forms.

Hereditary ATTR

• Mixed Symptoms: This form often involves both significant neurological and cardiac symptoms.
• Onset in Middle Age: Symptoms usually start in mid-life but vary depending on the specific genetic mutation.

The progression and severity of symptoms can differ widely among individuals. Early diagnosis is key to managing the condition effectively.

What are the causes of transthyretin amyloidosis?

Transthyretin amyloidosis (ATTR amyloidosis) is caused by the misfolding and aggregation of the transthyretin (TTR) protein. Normally, TTR is produced in the liver and transports thyroid hormone and vitamin A in the blood. However, in ATTR amyloidosis, the protein becomes unstable, leading to misfolding and deposition as amyloid fibrils in tissues, impairing their function.

Hereditary (familial) ATTR amyloidosis occurs due to inherited mutations in the TTR gene, which destabilize the protein. This form is passed down in an autosomal dominant pattern, where inheriting one copy of the mutated gene from a parent can lead to the condition.

Wild-type (senile) ATTR amyloidosis is age-related and occurs when normal TTR protein becomes unstable with aging, forming amyloid deposits, particularly in the heart. This form is not associated with a genetic mutation and more commonly affects older males.

Environmental factors, lifestyle, and aging can influence the progression of both hereditary and wild-type forms. The specific TTR mutation in hereditary cases often determines the organ involvement and the age of symptom onset. Genetic testing and counseling are essential for families with a history of this condition.

What is the treatment for transthyretin amyloidosis?

The treatment for transthyretin amyloidosis (ATTR) focuses on managing symptoms, slowing disease progression, and addressing complications. ATTR is a rare, progressive condition caused by the buildup of amyloid fibrils derived from misfolded transthyretin (TTR) protein, leading to organ damage, particularly in the heart, nerves, and other tissues.

1. Medications to Stabilize TTR Protein

• Tafamidis (Vyndamax, Vyndaqel): This drug stabilizes the TTR protein, preventing it from breaking apart and forming amyloid deposits. It is approved for use in hereditary and wild-type ATTR with cardiomyopathy.
• Diflunisal: An anti-inflammatory medication, which also has TTR-stabilizing properties, is sometimes used off-label for ATTR.

2. Gene-Silencing Therapies

These therapies target the production of abnormal TTR protein at the gene level, reducing amyloid formation:

• Patisiran (Onpattro): An RNA interference (RNAi) therapy that reduces the production of TTR protein by targeting its mRNA. It is mainly used for hereditary ATTR with polyneuropathy.
• Inotersen (Tegsedi): An antisense oligonucleotide therapy that also targets TTR mRNA to reduce TTR protein production. It is approved for hereditary ATTR with polyneuropathy.

3. Heart-Related Treatments

• Heart Failure Management: For patients with cardiomyopathy, standard heart failure treatments such as diuretics, beta-blockers, and ACE inhibitors may be used, although their effectiveness can be limited due to amyloidosis-specific issues.
• Pacemakers and Implantable Cardioverter Defibrillators (ICDs): In cases where ATTR affects the heart’s electrical system, devices like pacemakers or ICDs may be needed.

4. Liver Transplant

• For Hereditary ATTR: Since the liver produces most of the TTR protein, liver transplantation can be an option in hereditary cases to reduce the production of mutated TTR. However, this approach is less common today due to advances in gene-silencing therapies.

5. Organ-Specific Support

• Peripheral Neuropathy: Pain management, physical therapy, and supportive devices can help manage nerve-related symptoms such as pain, numbness, and weakness.
• Gastrointestinal Issues: Dietary modifications, medications, and other strategies can be used to manage digestive symptoms common in ATTR.
• Kidney Support: For ATTR-related kidney damage, management may involve medications, dietary changes, or even dialysis if kidney function is severely affected.

6. Emerging and Experimental Treatments

Research is ongoing into new drugs and therapies for ATTR. Clinical trials may be an option for some patients, providing access to novel treatments.

7. Supportive and Palliative Care

• Multidisciplinary Care: ATTR is a complex disease that often requires coordinated care from cardiologists, neurologists, geneticists, and other specialists.
• Palliative Care: For advanced cases, palliative care focuses on improving quality of life by managing symptoms and providing psychological support.

Treatment plans for transthyretin amyloidosis are highly individualized and depend on the type of ATTR (hereditary or wild-type), the organs affected, and the overall health of the patient. Early diagnosis and intervention are crucial to managing the disease and improving outcomes.