Background

• Amyloidosis is a group of rare diseases characterized by the abnormal accumulation of misfolded protein fragments called amyloids in various tissues and organs of the body.  
• Amyloids are insoluble fibers that can build up in organs such as the heart, kidneys, liver, spleen, and nervous system, disrupting their normal function. 
• The term “amyloid” refers to the abnormal protein aggregates that form fibrils and deposit in tissues. 
• The most common types of amyloidosis involve proteins such as amyloid beta (associated with Alzheimer’s disease) or various forms of immunoglobulin light chains (associated with systemic amyloidosis). 
• Different types of Amyloidosis as follows:  
• Primary (AL) Amyloidosis: Results from the abnormal production of immunoglobulin light chains by plasma cells in the bone marrow. 
• Secondary (AA) Amyloidosis: It is associated with chronic inflammatory conditions, infections, or inflammatory arthritis. 
• Hereditary (ATTR) Amyloidosis: Caused by mutations in specific genes, leading to the production of abnormal transthyretin (TTR) protein. 
• Localized Amyloidosis: Involves the deposition of amyloid in a specific organ or tissue, without systemic involvement. 

Epidemiology

• Primary amyloidosis is the most common type of systemic amyloidosis. It is a rare disease, with an estimated annual incidence of about 6 to 10 cases per million people. Men are slightly more affected than women. 
• Secondary amyloidosis is associated with chronic inflammatory conditions, such as rheumatoid arthritis and inflammatory bowel disease. 
• The incidence of secondary amyloidosis has decreased in recent years, possibly due to better management of the underlying inflammatory conditions. 
• Hereditary amyloidosis is caused by genetic mutations, and its prevalence can vary based on the specific mutation and population. 
• ATTR amyloidosis has different forms, including familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). 

Anatomy

Pathophysiology

• Amyloidosis is characterized by the misfolding of specific proteins. The misfolded proteins adopt a beta-sheet conformation instead of their normal functional structure. 
• Misfolded proteins tend to aggregate, forming oligomers and eventually mature amyloid fibrils. These aggregates are resistant to normal protein degradation mechanisms. 
• The aggregated proteins, now in the form of amyloid fibrils, are deposited extracellularly in various tissues and organs. Amyloid fibril deposition leads to tissue damage and dysfunction.

Etiology

• Hereditary amyloidosis, such as transthyretin (TTR) amyloidosis, is caused by genetic mutations. Mutations in the TTR gene lead to the production of abnormal transthyretin protein, which can form amyloid fibrils.  
• Localized forms of amyloidosis can occur without systemic involvement. The deposition of amyloid fibrils in specific tissues or organs may be idiopathic or associated with chronic inflammatory conditions or neoplastic processes in the affected organ. 
• The normal aging process can lead to the accumulation of wild-type transthyretin in tissues, particularly in the heart. 

Genetics

Prognostic Factors

• Amyloid deposits in vital organs such as the heart, kidneys, or nervous system can significantly impact overall survival and quality of life. 
• Cardiac involvement is a critical prognostic factor in amyloidosis, particularly in AL amyloidosis and ATTR amyloidosis. 
• Cardiac amyloidosis can lead to heart failure and is associated with a poorer prognosis. 
• Renal involvement is common in amyloidosis and can affect prognosis. Chronic kidney disease due to amyloid deposition may impact overall survival. 

Clinical History

• Age Group:  
• AL amyloidosis is more commonly diagnosed in older adults. It is relatively rare in younger individuals. 
• The age of onset can vary, but it is more likely to occur in adults. 
• Senile Systemic Amyloidosis is typically affecting older individuals, with an increased prevalence in those over 70 years of age. 

Physical Examination

• General Examination: Check blood pressure, heart rate, respiratory rate, and temperature. 
• Cardiovascular Examination: Listen for abnormal heart sounds, such as a third heart sound (S3) or murmurs. 

Evaluate for signs of heart failure, including jugular venous distension, peripheral edema, and hepatomegaly. 

• Respiratory Examination: Listen for crackles or other abnormal lung sounds, which may indicate pulmonary involvement. 
• Neurological Examination: Evaluate for signs of peripheral neuropathy, including sensory deficits, weakness, and impaired reflexes. 
• Gastrointestinal Examination: Palpate the abdomen for hepatomegaly or splenomegaly. Assess for tenderness or signs of gastrointestinal involvement. 

Age group

Associated comorbidity

• Cardiac amyloidosis, common in AL and ATTR amyloidosis, can lead to restrictive cardiomyopathy and heart failure. 
• Amyloid deposits in the heart may contribute to arrhythmias. Present in certain types of amyloidosis, such as familial amyloid polyneuropathy (FAP). 
• Amyloid deposition in the GI tract can lead to malabsorption, motility issues, and bleeding. 

Associated activity

Acuity of presentation

• AL amyloidosis often has a chronic and insidious onset. Symptoms may develop gradually, and patients may initially present with nonspecific complaints such as fatigue, weight loss, and peripheral neuropathy.  
• Familial amyloid polyneuropathy (FAP) may present with a gradual onset of peripheral neuropathy, while familial amyloid cardiomyopathy (FAC) may involve a slow progression of cardiac symptoms. 
• Secondary amyloidosis is often associated with chronic inflammatory conditions, and its presentation can be subacute.  
• Patients may have a history of inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease. 

Differential Diagnoses

• Peripheral Neuropathies: Peripheral neuropathy associated with diabetes can mimic the neurological manifestations seen in some types of amyloidosis. 
• Systemic Lupus Erythematosus (SLE): SLE and other autoimmune diseases may present with a variety of clinical features that overlap with those of amyloidosis. 
• Multiple Myeloma: Multiple myeloma, a plasma cell dyscrasia, can present with monoclonal gammopathy like primary (AL) amyloidosis. 
• Rheumatoid Arthritis (RA): RA can be associated with secondary amyloidosis, and its symptoms may overlap with systemic manifestations of amyloidosis. 
• Inflammatory Bowel Disease (IBD): Chronic inflammation in conditions like Crohn’s disease or ulcerative colitis can lead to secondary amyloidosis. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

• Heart Failure Management: Standard heart failure management may be implemented, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and other cardiac medications. 
• Radiation Therapy: Localized forms may be managed with surgery or localized radiation therapy to reduce amyloid deposits in specific organs. 
• Hemodialysis Modification: Modification of hemodialysis procedures to reduce beta-2 macroglobulin levels. 
• Supportive Care: Symptomatic treatment of complications and supportive care to maintain quality of life. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

use-of-non-pharmacological-approach-for-amyloidosis

• Low-Sodium Diet: For those with heart involvement, a low-sodium diet can help manage fluid retention and reduce the burden on the heart. 
• Adaptive Equipment: For individuals with peripheral neuropathy, the use of adaptive equipment such as handrails, braces, or orthopedic devices can enhance mobility and prevent falls. 
• Physical Therapy: Physical therapy may help maintain or improve mobility and function. 
• Renal Diet Care: A diet low in protein and potassium may be recommended for individuals with kidney involvement. 
• Fluid Management: Monitoring fluid intake may be necessary to prevent excessive fluid retention. 
• Dietary Modifications: Depending on the gastrointestinal symptoms, dietary modifications such as a soft or easily digestible diet may be recommended. 
• Orthostatic Precautions: Individuals with autonomic neuropathy may benefit from taking precautions to avoid sudden changes in position, such as rising slowly from sitting or lying down. 

Use of drugs for treating hereditary transthyretin (ATTR) amyloidosis

• Patisiran: It is a small interfering RNA (siRNA) molecule that works by targeting and inhibiting the production of abnormal transthyretin (TTR) protein in the liver. 
• Inotersen: It is an antisense oligonucleotide that modulates the production of TTR protein by binding to the mRNA, preventing its translation into the abnormal protein. 

Inotersen is used to reduce the production of abnormal TTR protein, thereby addressing the underlying cause of the disease. 

• Tafamidis: It is a TTR stabilizer that binds to the protein, preventing its misfolding and subsequent aggregation into amyloid fibrils. 

Tafamidis is used to stabilize the TTR protein, preventing its misfolding and reducing the formation of amyloid deposits in tissues. 

use-of-intervention-with-a-procedure-in-treating-amyloidosis

• Tissue Biopsy: A definitive diagnosis of amyloidosis often requires a tissue biopsy, typically from an affected organ. The biopsy specimen is stained with Congo red and examined under polarized light for characteristic apple-green birefringence. 
• Liver Transplantation: In hereditary ATTR amyloidosis, especially when there is significant cardiac involvement, liver transplantation may be considered to replace the mutant transthyretin-producing liver with a healthy one. 
• Renal Biopsy: A renal biopsy may be performed to assess the extent of renal involvement and guide treatment decisions. 

use-of-phases-in-managing-amyloidosis

• Diagnosis Phase: Thorough clinical assessment and evaluation of symptoms. 

Laboratory tests, imaging studies, and specific diagnostic procedures such as biopsy for confirmation of amyloidosis and determination of the type. 

• Treatment Phase: Developing a treatment plan based on the type of amyloidosis, organs affected, and the patient’s overall health. 
• Disease-Modifying Therapies: Utilizing specific therapies to target the underlying cause of amyloidosis, reduce amyloid production, or stabilize amyloid fibrils. 
• Multidisciplinary Care: Involving specialists from various fields, including cardiology, nephrology, neurology, and others. 
• Palliative Care: Addressing the physical, emotional, and psychosocial needs of the patient. 
• Monitoring and Follow-up: Ongoing monitoring through clinical evaluations, laboratory tests, imaging studies, and other procedures to assess disease progression and treatment response. 

Medication

Future Trends

Media Gallary

References

• Amyloidosis – StatPearls – NCBI Bookshelf (nih.gov) 
• Amyloidosis – NHS (nhs.uk)