What Is Amyloidosis?
Amyloidosis is a systemic disorder characterized by the extracellular deposition of amyloid (proteinaceous substance) in the body. The amyloid buildup in the body leads to the malfunctioning of the organs. Organs affected are the heart, liver, kidneys, spleen, nervous system, and digestive tract.
What Is Amyloid?
Amyloid is an insoluble, fibrous, extracellular, and proteinaceous substance found in organs and tissues. It is mainly associated with pathology and does not play a structural and supportive role like the other protein components in the body. The term used to describe the pathology related to amyloid is amyloidosis. A few diseases associated with amyloid deformity are Alzheimer’s (a brain disorder that destroys memory), type 2 diabetes (the body does not use insulin properly, leading to the increased glucose level in the body), and spongiform encephalopathies (brain damage caused by a protein prion and is a fatal condition). Amyloid fibrils are soluble proteins that aggregate together to become insoluble masses resistant to degradation. They deposit extracellularly and are pathogenic. The most common types of amyloid forms are:
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AL (amyloid light form).
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AA (amyloid associated).
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AB protein (beta-amyloid protein).
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Transthyretin (TTR).
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Misfolded prion protein.
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Serum amyloid component.
What Are the Types of Amyloidosis?
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Clinical Classification:
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Systemic or Generalized - When the amyloid deposits involve several organs.
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Localized - When the amyloid deposits are limited to a single organ like the heart or kidney.
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Classification Based on the Biochemical Nature of the Protein Fibrils:
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AL (primary) amyloidosis.
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AA (secondary) amyloidosis.
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Familial hereditary ATTR amyloidosis.
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Wild type (senile) ATTR amyloidosis.
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What Is Hereditary Amyloidosis?
Hereditary amyloidosis is a systemic disorder due to a genetic mutation, and the amyloid protein produced is abnormal in shape. In addition, the amyloid proteins deposit in the organs and nerves of the body. Once it accumulates in the body, it affects tissues and causes organ dysfunction. In most cases, no signs and symptoms are evident until adulthood. There are two main types of hereditary amyloidosis:
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ATTR (Amyloid Transthyretin) - These diseases are more common in hereditary amyloidosis disorders. It is related to the mutations in the TTR (transthyretin) protein.
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Non-TTR (Non-Transthyretin) - These diseases are rarer than the ATTR (transthyretin) variations. Non-TTR amyloidosis is an inherited condition. The gene mutation causes significant symptoms and affects health adversely. The proteins involved are fibrinogen Aa, Apo lipoprotein, lipoprotein All, gelsolin, and cystatin C. The treatment modality and symptoms are similar to ATTR (amyloid transthyretin) amyloidosis.
What Is Hereditary Amyloidosis ATTR (Amyloid Transthyretin)?
In ATTR amyloidosis, A stands for amyloid, and TTR stands for transthyretin (a protein that transports thyroid hormone (thyroxine) and retinol-binding protein to retinol). Most hereditary amyloidosis types are related to transthyretin (TTR) mutations. Mutation in the TTR gene causes transthyretin instability and misfolding of the protein. As a result, the mutated amyloid fibrils are deposited, which damages the organs. The type of TTR (transthyretin) mutation decides organ damage due to amyloid deposition. Transthyretin synthesizes in the liver, the retinal pigment, and the choroid plexus and is secreted into the blood, cerebrospinal fluid (CSF), and the eye. The symptoms appear only in adulthood, and the disease's severity varies depending on the individual. Hereditary amyloidosis ATTR mainly involves the nerve and heart. Hence, it is also known as familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC).
What Are the Symptoms of Hereditary Amyloid Transthyretin (ATTR) Amyloidosis?
The symptoms depend on the type of TTR (transthyretin) variant and the organ affected due to amyloid deposits. The most common sites of amyloid deposits in hereditary ATTR amyloidosis are the heart, nerves, kidneys, and eyes.
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Heart - Amyloid deposits in the heart cause cardiomyopathy (disease of the heart muscle that makes it difficult for the heart to pump blood to the body). Nausea, dizziness, shortness of breath, edema (swelling) of the leg, arrhythmia (irregular heartbeat), inability to sleep, atrial fibrillation (palpitations and abnormal heart rhythms), and chest pain are some of the symptoms.
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Nerves - Amyloid deposits in the nerves cause both peripheral and autonomic neuropathy (nerve dysfunction resulting in numbness or weakness of the nerves). Peripheral neuropathy in hereditary ATTR amyloidosis results in numbness and tingling, commonly in the hands, feet, and lower legs. Few patients also experience increased sensitivity to pain and temperature. Sensorimotor (loss of combination of sensory and motor functions) impairment also occurs. Autonomic neuropathy results in damage to the nerves that assist in organ functioning. Muscles lose their ability to contract and expand due to nerve damage resulting in poor digestion, constipation, diarrhea, glaucoma, and impaired erectile function.
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Kidney - Amyloid deposits in the kidney significantly impact the kidneys' ability to filter toxins in the blood resulting in nephrotic syndrome and excess protein in the urine. It also causes swelling of the body, especially the legs. Sometimes amyloid deposits can result in renal (kidney) failure.
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Both sensorimotor and autonomic neuropathy cause the involvement of visceral organs also. Ophthalmopathy (vitreous opacities, glaucoma), cardiomyopathy (cardiac failure, arrhythmia), and central nervous system (CNS) manifestations (intracerebral hemorrhage, subarachnoid hemorrhage) changes are usually seen in the later stages of the disease.
How Is Hereditary ATTR Amyloidosis Diagnosed?
The patient's family history is vital as the signs and symptoms do not occur in adulthood. Once amyloidosis is confirmed, it is crucial to establish the ATTR variant. In addition, it helps to curate the treatment plan. The main diagnostic tests are blood and urine tests and tissue biopsy.
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Blood And Urine Tests - These tests help diagnose amyloidosis, the organs involved, and the extent of damage to the organ.
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Biopsy - Tissue biopsy uses Congo red stain. Amyloid deposits show yellow-green birefringence under polarized light.
Once the hereditary transthyretin amyloidosis is diagnosed, deoxyribonucleic acid and genome sequencing is done to identify the protein involved.
What Is the Management for Hereditary ATTR Amyloidosis?
Treatment is planned as follows:
- Supportive Treatment - It aims to treat problems related to organ damage and its symptoms.
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Peripheral neuropathy is treated with medication for pain relief and nerve damage.
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Heart problems are managed by frequent tests like echocardiogram and ECG (electrocardiogram). The patient is also provided with all the necessary medication.
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Kidney problems are managed by medicine and dialysis.
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Gastrointestinal problems include treatment for poor nutritional health, diarrhea, constipation, and vomiting.
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Source Treatment - It aims at slowing or stopping the overproduction of amyloid at the source of the disease. Amyloid synthesizes in the liver; however, the liver is seldom affected by amyloid deposits. Therefore, a liver transplant will help reduce or stop the amyloid deposit. However, it will not improve the conditions of cardiomyopathy (a disease involving heart muscles). Research is ongoing to understand this treatment modality.
Conclusion:
Many genetic variations of hereditary amyloidosis have been identified and studied. Ongoing research and studies can identify other variants. Familial onset has its pattern related to age onset, the organ involved, and associated symptoms. Family history is a crucial indicator in determining familial hereditary amyloidosis because of similar symptoms, organs affected, and causes of illness identified.
