Transthyretin amyloidosis (TTA) is a systemic disease characterized by the deposition of amyloid proteins derived from transferrin. This leads to disruption of normal tissue and organ function, which can cause serious clinical manifestations in various body systems. The heart, nerves, kidneys and gastrointestinal tract are most often affected. Depending on the type of amyloids and the underlying mechanism of their formation, transthyretin amyloidosis can be hereditary or acquired. The classic form of the disease is associated with mutations in the TTR (transthyretin) gene, which leads to the formation of stable amyloid fibrils, while the senile form is often associated with polymerization of normal, non-mutated protein.
History of the disease and interesting historical facts
The history of transthyretin amyloidosis goes back more than a century. In 1901, the era of amyloidosis research began with August Ladegard’s discovery of a disease associated with amyloid protein deposits. However, it was in the 1980s, thanks to research conducted in the context of specific gene mutations, that it was discovered that amyloidosis can be hereditary. Notably, in the 1990s, clinical cases associated with TTR gene mutations were described, which contributed to the development of genetic testing and understanding of the disease. In addition, among historical facts, it is worth noting that the first successful use of liver transplantation in the treatment of the hereditary form of TTA occurred in 1990.
Epidemiology
Transthyretin amyloidosis is a rare disease, but its prevalence varies among populations. The hereditary form of TTA has been reported to occur with a frequency of approximately 1 in 1000 in populations of Portuguese or Scandinavian descent, while in patients over 60 years of age with no genetic predisposition, the incidence of the senile form may reach 10-25%. In recent decades, there has been an increase in the number of reported cases, due to increased awareness and improved diagnostic methods. It is also important to consider that the disease may be underdiagnosed or misclassified, making it difficult to accurately assess its epidemiology.
Genetic predisposition to this disease
Transthyretin amyloidosis, as a hereditary disease, is often associated with certain mutations in the TTR gene, which is located on chromosome 18. The most well-known mutations include V30M, V122I, and I68L, each of which is associated with different clinical manifestations and disease outcomes. The V30M mutation, which is widespread in the Swedish and Portuguese population, is characterized by high permeability among carriers, while V122I manifests itself predominantly in older people and often leads to cardiac complications. Genetic testing for these mutations allows not only to confirm the diagnosis, but also to predict the risk of developing the disease in family members.
Risk factors for the development of this disease
Risk factors that contribute to the development of transthyretin amyloidosis include both genetic and exogenous factors. The main ones include:
- Age - the risk increases in older people (especially those over 60 years of age) who develop the senile form of TTA.
- Genetic predisposition - the presence of mutations in the TTR gene, which are passed on by inheritance.
- Gender - men are more susceptible to the disease than women, especially in the hereditary form.
- Certain ethnic groups - The prevalence of hereditary TTA is higher among Portuguese, Scandinavians, and people from some African countries.
- Chronic inflammatory diseases—such as chronic infections or inflammatory conditions—may contribute to the development of amyloidosis.
Diagnosis of this disease
Diagnosis of transthyretin amyloidosis requires a multi-step approach and includes:
- Key symptoms to look out for include:
- convulsions;
- numbness and weakness in the limbs;
- heart problems (arrhythmia, heart failure);
- changes in the gastrointestinal tract (diarrhea or constipation).
- Laboratory tests:
- blood test for transthyretin levels;
- cytological analyses of biopsies (usually from adipose tissue or organs);
- PET-CT for visualization of amyloid deposits.
- Radiological tests, including MRI and cardiac ultrasound, may be used to assess the extent of organ damage.
- Other diagnostic tests include genetic testing for TTR mutations.
- Differential diagnosis is required to exclude other forms of amyloidosis, which may be associated with various diseases (eg, multiple myeloma amyloidosis).
Treatment
Treatment of transthyretin amyloidosis is multi-level and includes:
- General treatment:
- Supportive therapy to manage symptoms;
- Physical rehabilitation to restore function after neuropathy.
- Pharmacological treatment:
- Drugs that reduce transthyretin levels and prevent fibril formation (eg, tazemetistat);
- Corticosteroids in case of inflammatory manifestations.
- Surgical treatment:
- Liver transplant for the inherited form of the disease.
- Other treatments, such as targeted therapies and new experimental drugs in clinical trials.
List of medications used to treat this disease
Among the main drugs used to treat transthyretin amyloidosis are:
- Tazemetistat (Tafamidis) - reduces transthyretin levels.
- Patirisoparin (Patisiran) is an RNA interference drug to reduce transthyretin production.
- Ivoserdin (Inotersen) is an antiglobulin drug.
- Corticosteroids - used to reduce inflammation.
Disease monitoring
Monitoring of transthyretin amyloidosis is important to assess the patient's clinical status and adjust treatment. Key aspects include:
- Regular tests to assess heart and kidney function, including echocardiography and blood tests.
- The prognosis depends on the form of the disease, the presence of cardiac and organ complications, and the speed of initiation of therapy.
- Complications may include progression of heart failure, neuropathy, and organ failure.
Age-related features of the disease
Transthyretin amyloidosis may present differently in different age groups:
- Young patients with the hereditary form experience more aggressive manifestations, often accompanied by neuropathy.
- In older people, the senile form often progresses more slowly, but cardiac complications can develop quickly.
- Children are generally at low risk for the inherited form, but may be carriers of the TTR gene, which requires future monitoring.
Questions and Answers
- What are the first symptoms of transthyretin amyloidosis? Initial symptoms may include numbness or tingling in the limbs, fatigue, and abnormal heart rhythms.
- How is TTA diagnosed? Diagnosis includes clinical examination, laboratory tests, biopsy, and genetic testing for TTR mutations.
- Is liver transplantation possible for treatment? Yes, liver transplantation is a treatment option for patients with the inherited form of the disease.
- Is there an influence of age on the manifestations of TTA? Yes, younger patients often suffer from more severe symptoms, while older people may have a less aggressive form of the disease.
- What is the prognosis for patients with transthyretin amyloidosis? The prognosis depends on the form of the disease and the speed of treatment; early diagnosis and timely treatment significantly improve the outcome.
