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Amyloidosis

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Description: Amyloidosis is a rare condition characterized by the abnormal deposition of amyloid proteins in various tissues and organs, leading to their dysfunction.
Type: Amyloidosis is a group of diseases characterized by abnormal deposits of amyloid protein in tissues and organs. There are several types of amyloidosis, including:

1. AL (Primary) Amyloidosis: Caused by the deposition of light chains produced by plasma cells. It is not typically inherited and usually occurs sporadically.
2. AA (Secondary) Amyloidosis: Occurs due to chronic inflammatory conditions such as rheumatoid arthritis or chronic infections. It is also not inherited.
3. Hereditary (Familial) Amyloidosis: Caused by genetic mutations, primarily in the transthyretin (TTR) gene, but can also affect other proteins. This type follows an autosomal dominant pattern of inheritance.
4. Dialysis-Related Amyloidosis: Occurs in patients undergoing long-term dialysis and is due to the deposition of beta-2 microglobulin. This type is not inherited.
5. Wild-Type (Senile) Systemic Amyloidosis: Occurs in older adults due to the accumulation of wild-type transthyretin protein. It is not inherited.

The genetic transmission of Hereditary (Familial) Amyloidosis is primarily autosomal dominant, meaning that a single copy of the mutated gene inherited from one parent can cause the disease.
Signs And Symptoms: The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved.
Prognosis: Prognosis varies with the type of amyloidosis and the affected organ system. Prognosis for untreated AL cardiac amyloidosis is poor, with a median survival of six months. More specifically, AL amyloidosis can be classified as stage I, II or III based on cardiac biomarkers like Nt-proBNP and cardiac troponin. Survival diminishes with increasing stage, but recent advancements in treatments have improved median survival rates for stages I, II, and III, to 91.2, 60, and 7 months respectively.Outcomes in a person with AA amyloidosis depend on the underlying disease, organ(s) affected, and correlate with the concentration of serum amyloid A protein.People with ATTR, mutant ATTR and wild-type ATTR have a better prognosis when compared to people with AL and may survive for over a decade. Survival time is not associated with gender or age, however, some measures of reduced heart function are associated with a shorter survival time.Senile systemic amyloidosis was determined to be the primary cause of death for 70% of people over 110 who have been autopsied.
Onset: The onset of amyloidosis can vary widely depending on the type and underlying cause. Symptoms may develop slowly over many years or appear more rapidly, particularly in cases triggered by conditions like multiple myeloma. It often remains undiagnosed until it significantly affects organ function.
Prevalence: The prevalence of amyloidosis varies depending on the type. For example, light-chain (AL) amyloidosis, the most common form in developed countries, affects approximately 8 to 13 people per million annually. Transthyretin (ATTR) amyloidosis, which includes both hereditary and wild-type forms, has a prevalence of about 50 per million for hereditary ATTR in some populations, while the prevalence of wild-type ATTR is less well-defined but considered more common in the elderly.
Epidemiology: Amyloidosis has a combined estimated prevalence of 30 per 100,000 persons with the three most common forms being AL, ATTR, and AA. The median age at diagnosis is 64.AL has the highest incidence at approximately 12 cases per million persons per year and an estimated prevalence of 30,000 to 45,000 cases in the US and European Union.AA amyloidoses is the most common form in developing countries and can complicate longstanding infections with tuberculosis, osteomyelitis, and bronchiectasis. AA amyloidosis is caused by an increase in extracellular deposition of serum amyloid A (SAA) protein. SAA protein levels can rise in both direct and indirect manners, through infection, inflammation, and malignancies. The most common causes of AA amyloidosis in the West are rheumatoid arthritis, inflammatory bowel disease, psoriasis, and familial Mediterranean fever.People undergoing long-term hemodialysis (14–15 years) can develop amyloidosis from accumulation of light chains of the HLA 1 complex which is normally filtered out by the kidneys.Wild-type transthyretin (ATTR) amyloidosis is found in a quarter of elderly at postmortem. ATTR is found in 13–19% of people experiencing heart failure with preserved ejection fraction, making it a very common form of systemic amyloidosis.
Intractability: Amyloidosis can be considered intractable in many cases since there is no definitive cure for the disease. Treatment primarily focuses on managing symptoms, slowing disease progression, and addressing organ damage. The prognosis varies depending on the type of amyloidosis and the organs involved. Some patients respond well to current therapies, while others may have a more challenging course.
Disease Severity: Amyloidosis is a group of diseases in which amyloid proteins build up in organs and tissues, potentially leading to organ dysfunction. The severity can vary widely depending on the type of amyloidosis and the organs affected. Some forms are less severe and may progress slowly, while others can be life-threatening and require urgent treatment. Commonly affected organs include the heart, kidneys, liver, and nervous system.
Healthcare Professionals: Disease Ontology ID - DOID:9120
Pathophysiology: Amyloidosis is characterized by the abnormal deposition of amyloid fibrils in tissues and organs. Amyloids are insoluble proteins that aggregate into fibrils with a beta-pleated sheet structure. These fibrils disrupt the normal function of affected tissues and organs, leading to a variety of clinical manifestations depending on the locations of deposition. The process typically involves misfolding of a normally soluble protein, which then becomes insoluble and prone to accumulation. The exact pathophysiological process may vary depending on the specific type of amyloidosis, such as AL (light chain), AA (secondary), or hereditary forms like ATTR (transthyretin).
Carrier Status: Amyloidosis is not typically discussed in terms of carrier status as it is not a simple Mendelian inherited condition. Instead, it is a group of diseases caused by abnormal protein deposits (amyloid) in tissues and organs. Some types of amyloidosis, such as hereditary amyloidosis, are genetic and can be inherited in an autosomal dominant pattern. Others are acquired and related to chronic inflammatory diseases or conditions like multiple myeloma.
Mechanism: Amyloidosis is a group of diseases characterized by the abnormal deposition of amyloid proteins in various tissues and organs. The mechanism and molecular mechanisms involved in amyloidosis are as follows:

**Mechanism:**
1. **Protein Misfolding:** Proteins normally fold into specific three-dimensional shapes essential for their function. In amyloidosis, proteins misfold and adopt an abnormal conformation.
2. **Aggregation:** Misfolded proteins aggregate into insoluble fibrils that can self-assemble into larger amyloid deposits.
3. **Deposition:** These amyloid fibrils are deposited in extracellular spaces within tissues, leading to organ dysfunction and damage.

**Molecular Mechanisms:**
1. **Protein Precursors:** Different types of amyloidosis are associated with different precursor proteins, such as immunoglobulin light chains in AL amyloidosis, serum amyloid A protein in AA amyloidosis, and transthyretin in ATTR amyloidosis.
2. **Beta-Sheet Structure:** The misfolded proteins typically form beta-sheet-rich structures, which are stabilized by hydrogen bonding and become resistant to proteolytic degradation.
3. **Nucleation:** The initial formation of amyloid fibrils often involves a nucleation process where a small number of misfolded protein molecules form a stable nucleus that seeds further fibril growth.
4. **Seeding:** Once a nucleus is formed, it can act as a template, recruiting additional misfolded proteins and promoting the elongation of fibrils.
5. **Cellular and Molecular Stress:** The accumulation of amyloid fibrils can induce stress responses in cells and extracellular matrix alterations, leading to inflammation, apoptosis, and tissue damage.

Understanding these mechanisms is crucial for developing targeted therapies to inhibit amyloid formation or promote the clearance of amyloid deposits to treat amyloidosis effectively.
Treatment: Treatment depends on the type of amyloidosis that is present. Treatment with high dose melphalan, a chemotherapy agent, followed by stem cell transplantation has shown promise in early studies and is recommended for stage I and II AL amyloidosis. However, only 20–25% of people are eligible for stem cell transplant. Chemotherapy treatment including cyclophosphamide-bortezomib-dexamethasone is currently the recommended treatment option for people with AL Amyloidosis not eligible for transplant.In AA, symptoms may improve if the underlying condition is treated. In people who have inflammation caused by AA amyloidosis, tumour necrosis factor (TNF)-alpha inhibitors such as infliximab and etanercept are used for an average duration of 20 months. If TNF-alpha inhibitors are not effective, Interleukin-1 inhibitors (e.g., anakinra, canakinumab, rilonacept) and interleukin-6 inhibitors (e.g., tocilizumab) may be considered.Management of ATTR amyloidosis will depend on its classification as wild type or variant. Both may be treated with tafamidis, a low toxicity oral agent that prevents destabilization of correctly folded protein. Studies showed tafamidis reduced mortality and hospitalization due to heart failure. Previously, for variant ATTR amyloidosis, liver transplant was the only effective treatment. New therapies include diflunisal, inotersen, and patisiran.
Diflunisal binds to misfolded mutant TTR protein to prevent its buildup, like how tafamidis works. Low-certainty evidence indicates that it mitigates worsening of peripheral neuropathy and disability from disease progression.Inotersen blocks gene expression of both wild-type and mutant TTR, reducing amyloid precursor. Moderate-certainty evidence suggests that it mitigates worsening of peripheral neuropathy. Long-term efficacy and safety of inotersen use in people with mutant TTR-related amyloidosis is still be evaluated in a phase-III clinical trial as of 2021. Both diflunisal and inotersen may also mitigate declines in quality-of-life, though the evidence for this effect is unclear. For people with cardiac ATTR the effect of inotersen use is inconclusive and requires further investigation. In 2018, inotersen was approved by the European Medicines Agency to treat polyneuropathy in adults with hereditary transthyretin amyloidosis. It has since been approved for use in Canada, the European Union and in the USA.Patisiran functions similarly to inotersen. Moderate-certainty evidence suggests that patisiran mitigates worsening of peripheral neuropathy and disability from disease progression. Additionally, low-certainty evidence suggests that patisiran mitigates decreases in quality-of-life and slightly reduces the rate of adverse events versus placebo. There is no evidence of an effect on mortality rate. A review of early data from use of patisiran in people with variant cardiac ATTR suggests that it may reduce mortality and hospitalization, however this is still being investigated and requires further investigation. In 2018, patisiran was not recommended by NICE in the UK for hereditary transthyretin-related amyloidosis. As of July 2019 further review however is occurring. It was approved for this use in the United States, however.The roles of inotersen and patisiran in cardiac ATTR amyloidosis are still being investigated.In 2021, in a clinical trial using the CRISPR gene-editing technique, several participants had an "80% to 96% drop in TTR levels, on par or better than the average of 81%" who were given patisiran.Vutrisiran was approved by the U.S. Food and Drug Administration (FDA) in June 2022, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults.
Compassionate Use Treatment: For amyloidosis, several experimental treatments and therapies used under compassionate use or off-label include:

1. **Daratumumab**: Originally approved for multiple myeloma, daratumumab has shown promise in treating AL amyloidosis by targeting plasma cells that produce amyloid protein.

2. **CAEL-101**: An investigational monoclonal antibody designed to target amyloid fibrils.

3. **Patisiran and Inotersen**: Approved for hereditary transthyretin amyloidosis with polyneuropathy, these RNA interference therapies are being studied for broader applications in other forms of amyloidosis.

4. **Tafamidis**: Initially approved for transthyretin amyloid cardiomyopathy, it stabilizes the transthyretin protein and prevents amyloid fibril formation.

5. **Bortezomib**: Though primarily used for multiple myeloma, this proteasome inhibitor has been used off-label for AL amyloidosis due to its ability to decrease amyloid precursor protein production.

6. **CRISPR-Cas9 Gene Editing**: Experimental treatments aiming to correct genetic mutations causing amyloidosis are under investigation.

It is crucial to consult with a healthcare provider for the most current and personalized treatment options.
Lifestyle Recommendations: For amyloidosis, lifestyle recommendations include:

1. **Dietary Adjustments**: Adopt a balanced diet low in sodium to help manage fluid retention and reduce strain on the heart and kidneys.

2. **Regular Exercise**: Engage in moderate physical activity as tolerated, which can help maintain muscle strength and cardiovascular health.

3. **Avoid Alcohol and Smoking**: These can exacerbate symptoms and negatively impact overall health.

4. **Stay Hydrated**: Proper hydration is crucial, but must be balanced to prevent fluid overload, especially with cardiac or renal involvement.

5. **Manage Stress**: Use stress-reduction techniques such as meditation, yoga, or counseling, as chronic stress can worsen symptoms.

6. **Monitor Weight**: Regularly check your weight to identify fluid retention early.

7. **Follow Medical Advice**: Keep regular appointments with healthcare providers and adhere to prescribed treatments and medications.

8. **Heart-Healthy Lifestyle**: If cardiac amyloidosis is present, follow guidelines for heart health, including managing cholesterol, blood pressure, and avoiding strenuous activity.

Implementing these lifestyle changes can help in managing symptoms and improving quality of life for those with amyloidosis. Always consult with healthcare providers before making significant changes to your lifestyle or treatment plan.
Medication: Amyloidosis treatment typically involves the use of medications aimed at reducing the production of the amyloid protein and managing symptoms. Commonly used medications include:

1. Chemotherapy drugs: such as melphalan, especially in AL amyloidosis, to reduce the abnormal plasma cells producing amyloid protein.
2. Corticosteroids: like dexamethasone or prednisone, to reduce inflammation and immune activity.
3. Proteasome inhibitors: such as bortezomib, to target plasma cells more effectively.
4. Immunomodulatory drugs: such as lenalidomide or thalidomide, which help in reducing the abnormal plasma cells.
5. Diflunisal and Tafamidis: for ATTR amyloidosis, to stabilize the transthyretin protein and prevent its aggregation.

Patients should always consult a healthcare provider to determine the most appropriate treatment plan for their specific type of amyloidosis.
Repurposable Drugs: For amyloidosis, the following repurposable drugs have shown potential in treatment:

1. **Doxycycline**: An antibiotic that has shown promise in preventing amyloid aggregation and promoting fibril clearance.
2. **Diflunisal**: A non-steroidal anti-inflammatory drug (NSAID) that can stabilize transthyretin and reduce amyloid deposits.
3. **Tafamidis**: Initially developed for other conditions, it stabilizes transthyretin and has been repurposed for treating transthyretin amyloidosis (ATTR).

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Metabolites: Amyloidosis is characterized by the abnormal deposition of amyloid proteins in various tissues and organs. Specific metabolites related to amyloidosis can vary depending on the type of amyloid protein involved (e.g., light chain (AL), amyloid A (AA), or transthyretin (ATTR) amyloidosis). Generally, altered levels of the precursor proteins and their cleavage products can be involved in disease pathology. Monitoring these metabolites can aid in diagnosis and management.
Nutraceuticals: There is limited evidence on the direct role of nutraceuticals specifically in treating amyloidosis. However, some nutraceuticals with anti-inflammatory and antioxidant properties may support overall health. Examples include curcumin (found in turmeric), resveratrol (found in red grapes), and green tea extracts. It's crucial to consult with healthcare professionals before using nutraceuticals for amyloidosis.
Peptides: Amyloidosis is characterized by the abnormal accumulation of amyloid fibrils, which are insoluble protein aggregates, in various tissues and organs. These fibrils are formed from misfolded peptides or proteins that aggregate and deposit extracellularly. This buildup can disrupt normal function and lead to organ damage. Different types of amyloidosis are classified based on the specific precursor protein involved, such as light chain (AL) amyloidosis, which involves immunoglobulin light chains, or transthyretin (ATTR) amyloidosis, which involves the transthyretin protein. Diagnosis often involves tissue biopsy, and treatment may include addressing the underlying cause and managing symptoms. Nanotechnological approaches, such as using nanoparticles for targeted drug delivery or diagnostic imaging, are being explored to improve the management and treatment of amyloidosis.