Gastrointestinal amyloidosis is a rare condition characterized by the deposition of abnormal proteins, called amyloid, within the tissues of the digestive system. These protein deposits can interfere with the normal functioning of the affected organs.
What is Gastrointestinal Amyloidosis?
Amyloidosis involves the abnormal folding and accumulation of proteins into insoluble amyloid fibrils that deposit in various tissues and organs throughout the body. When these deposits occur in the gastrointestinal (GI) tract, they can lead to a range of issues. This infiltration of misfolded proteins can affect different layers of the GI tract, including the mucosal lining, muscles, or nerves, and even the arteries supplying the GI tract.
The accumulation of amyloid fibrils can cause affected tissues to thicken, leading to impaired organ function. This can manifest as malabsorption, where nutrient absorption is problematic, or motility disorders, affecting food movement through the digestive tract. These deposits can progressively damage the GI system, leading to severe complications.
Causes and Forms of the Condition
Gastrointestinal amyloidosis can arise from various underlying causes, with several distinct forms commonly affecting the digestive system. These forms are classified based on the specific precursor protein that misfolds and accumulates.
AL (Light Chain) amyloidosis
AL (Light Chain) amyloidosis, also known as primary amyloidosis, is the most common type of systemic amyloidosis with GI involvement. This form is caused by the deposition of abnormal immunoglobulin light chain proteins, which are produced by plasma cells in the bone marrow. AL amyloidosis is often associated with plasma cell disorders, such as multiple myeloma.
AA (Secondary) amyloidosis
AA (Secondary) amyloidosis results from the accumulation of serum amyloid A (SAA) protein, an acute-phase reactant produced by the liver during inflammation. This type is a complication of chronic inflammatory or infectious diseases, including rheumatoid arthritis, inflammatory bowel disease (such as Crohn’s disease and ulcerative colitis), and long-standing infections.
Hereditary amyloidosis
Hereditary amyloidosis, also known as familial amyloidosis, is caused by inherited genetic mutations that lead to the production of abnormal proteins. One prominent example is hereditary transthyretin (ATTRm) amyloidosis, where mutations in the transthyretin (TTR) gene result in misfolded TTR proteins. Other genetic mutations involving proteins like apolipoprotein AI (ApoAI), fibrinogen Aα chain, and lysozyme (ALys) can also cause hereditary forms that may affect the GI tract.
Wild-type ATTR (ATTRwt) amyloidosis
Wild-type ATTR (ATTRwt) amyloidosis, previously known as senile systemic amyloidosis, occurs in older adults without a known genetic mutation or chronic inflammatory cause. This form involves the deposition of normal, unmutated transthyretin protein that becomes unstable with age. GI symptoms like diarrhea and weight loss can occur due to autonomic neuropathy.
Localized amyloidosis
Localized amyloidosis is a less common form where amyloid deposits are confined to a single organ, such as the GI tract, without evidence of systemic involvement. In these cases, the amyloid is produced at or near the site of deposition. Localized GI amyloidosis can affect various parts of the digestive system, including the stomach, small bowel, and colon.
Identifying Symptoms
The symptoms of gastrointestinal amyloidosis can be varied and non-specific, making the condition challenging to identify. The manifestations depend on which part of the GI tract is affected and the extent of amyloid deposition. Many patients with GI amyloidosis experience symptoms such as weight loss, fatigue, light-headedness, and anorexia.
Common gastrointestinal symptoms include nausea, vomiting, diarrhea, and constipation. Patients may also experience abdominal pain, bloating, and early satiety, which is the feeling of fullness after eating only a small amount of food. These symptoms can be caused by amyloid deposits interfering with the normal muscular contractions of the digestive tract, leading to dysmotility.
More severe manifestations include malabsorption, where the intestines struggle to absorb nutrients, leading to nutritional deficiencies and weight loss. Gastrointestinal bleeding can also occur from any site of amyloid deposition, often due to fragile blood vessels or mucosal lesions like erosions or ulcers. This bleeding may appear as black stools or bright red blood. Pseudo-obstruction, a condition mimicking a bowel obstruction without a physical blockage, and protein-losing enteropathy, characterized by excessive protein loss from the GI tract leading to edema and diarrhea, can also develop.
Diagnosis and Management
Diagnosing gastrointestinal amyloidosis can be challenging due to its non-specific symptoms, which often overlap with other common digestive disorders. The definitive method for confirming amyloid deposits is a tissue biopsy, which can be taken from affected areas such as the rectum, stomach, or duodenum.
Once a tissue sample is obtained, specialized laboratory techniques are used. The biopsy is stained with Congo Red, which causes amyloid deposits to appear red under normal light and exhibit a distinctive apple-green birefringence when viewed under polarized light. Immunohistochemistry is then performed to identify the specific type of amyloid protein, which is important for guiding treatment. Imaging studies, such as CT scans, MRI, or endoscopy, can help assess the extent of organ involvement. Blood and urine tests are also conducted to evaluate organ function and identify any underlying conditions that might be causing the amyloidosis.
Management of gastrointestinal amyloidosis primarily focuses on addressing the underlying cause of the amyloidosis and providing symptomatic relief.
For AL amyloidosis
For AL amyloidosis, treatment aims to suppress the production of abnormal light chains, often involving chemotherapy regimens that may include drugs like melphalan, cyclophosphamide, bortezomib, and dexamethasone. High-dose chemotherapy followed by autologous stem cell transplantation may be considered for eligible patients.
For AA amyloidosis
For AA amyloidosis, treatment is directed at controlling the chronic inflammatory or infectious condition that is driving SAA protein production. This may involve anti-inflammatory medications, biologic agents that target specific cytokines like TNF-alpha or IL-6, or antibiotics for chronic infections.
Hereditary forms of ATTR amyloidosis
Hereditary forms of ATTR amyloidosis can be managed with therapies that stabilize the TTR protein, such as tafamidis or diflunisal, or gene-silencing drugs that reduce the production of the abnormal protein.
Symptomatic management is a part of care for all types of GI amyloidosis. This can include medications to alleviate nausea, vomiting, diarrhea, or constipation. Nutritional support is necessary, and procedures like balloon dilation for esophageal narrowing or Botox injections for stomach spasms may be considered. A multidisciplinary approach, involving specialists in hematology, gastroenterology, cardiology, and neurology, is beneficial for comprehensive care.