Amyloidosis: An Overview for Patients
Amyloidosis: Causes are Abnormal Proteins
The causes of amyloidosis are diverse. These can include certain cancers, chronic inflammation, or hereditary factors. What they all have in common, however, is that abnormally folded proteins clump together and deposit in tissues. These deposits consist of insoluble protein fibers, known as amyloid fibrils. The body produces them faster than it can break them down. The abnormal proteins disrupt the metabolism and function of various organs.
Either the amyloids form in only one place and deposit exclusively there (localized amyloidosis), or they are produced in one area and then deposit in various regions throughout the body (systemic amyloidosis). There are many different forms of amyloidosis, depending on the amyloid-triggering protein. Here is an overview of the most important ones.
AL Amyloidosis (Light Chains)
This involves the deposition of subunits of proteins in the tissue that play an essential role in immune defense. They are called immunoglobulin light chains. Abnormally altered immune cells in the bone marrow or lymph nodes (plasma or lymph cells) produce these abnormal light chains. The development of AL amyloidosis is closely related to and partially linked with cancers of the bone marrow and lymph nodes, such as multiple myeloma or non-Hodgkin lymphoma.
ATTR Amyloidosis
Genes are less commonly involved in amyloidosis. In various regions of the world, such as Japan, Sweden, and Portugal, hereditary amyloidosis occurs frequently, but not in Switzerland.
In familial transthyretin amyloidosis (familial or hereditary ATTR amyloidosis = ATTRv amyloidosis), the cause lies in a genetic defect affecting the so-called transthyretin gene. Due to this mutation, the liver primarily produces a defective transport protein called transthyretin. It is responsible for transporting the thyroid hormones thyroxine and retinol. The proteins deposit particularly in the nerves, heart, intestines, and eyes.
AA Amyloidosis
The causes are chronic inflammations that have been present for about 20 years (and sometimes significantly shorter). These can include lung and skin infections (such as tuberculosis), inflammatory rheumatic diseases (such as rheumatoid arthritis), chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis), and more rarely hereditary fever conditions (such as familial Mediterranean fever = FMF).
The chronic inflammation causes the liver to permanently produce excessive amounts of the protein serum amyloid A (SAA). These can transform into AA fibrils, which predominantly deposit in the spleen and later in the kidneys. The liver and gastrointestinal tract can also be affected. The heart is rarely involved. AA amyloidosis itself is not inherited but can occur in the context of certain hereditary diseases.
Symptoms: Amyloidosis Causes Various Complaints
As diverse as amyloidosis types are, so are the symptoms they can cause. The complaints are not the same for every patient and are not equally severe. The type of amyloidosis and the organs in which the insoluble proteins deposit play a role. In systemic amyloidosis, multiple organs are usually affected simultaneously. In localized amyloidosis, protein deposits are found only locally, such as in the skin.
The first symptoms of amyloidosis are often very non-specific. General complaints such as fatigue, exhaustion, or decreased physical performance can occur. However, these also accompany many other diseases, which is why many people misinterpret them.
Warning signs for systemic amyloidosis can include:
- Heart: for example, shortness of breath during physical exertion, water retention (edema), cardiac arrhythmias (such as racing heart, palpitations), fainting spells
- Kidney: for example, water retention (such as eyelids, ankles, feet, lower legs), foamy urine due to increased protein excretion, kidney failure
- Liver: for example, enlarged and stiffened liver, water retention in the abdominal cavity (ascites)
- Gastrointestinal tract: for example, swallowing disorders, loss of appetite, weight loss, nausea, feeling of fullness, bloating, diarrhea, constipation, bleeding in the digestive tract
- Eyes: for example, dry eyes, vitreous opacity, increased intraocular pressure (glaucoma)
- Nervous system: for example, pain and numbness in the hands and feet, disorders of intestinal movements and bladder emptying, erectile dysfunction
- Soft tissues and other areas: for example, swollen and enlarged tongue (macroglossia), hoarseness, skin hemorrhages - such as in the eyelids (raccoon eyes), carpal tunnel syndrome, swollen joints, enlarged spleen, muscle weakness, fatigue
Amyloidosis: Diagnosis
In many patients, amyloidosis is only diagnosed after some time. One reason is that the symptoms are often too atypical. Studies show that approximately 20 percent of patients with AL amyloidosis receive the diagnosis only after more than two years. In about 42 percent of patients with ATTRwt amyloidosis, we find the disease only more than four years after the onset of symptoms.
Diagnosis always begins with a discussion of your medical history, the anamnesis. You will be asked questions such as:
- What symptoms do you have exactly?
- When did they first appear?
- Where do the complaints particularly show?
- How intense are they?
- Are there known diseases in your history?
- Are there diseases in your family?
- Are you undergoing treatments?
- Do you regularly take medications?
Your answers help with an initial assessment. This is followed by a physical examination, in which the body is thoroughly examined and palpated. This helps detect changes. Additionally, the heart and lungs are auscultated.
Further Examinations
If amyloidosis is suspected, further examinations follow to detect deposited amyloid in the tissue:
Tissue sample (biopsy): The tissue is usually taken from the abdominal fat or rectal mucosa. Less commonly, due to potential risks, the tissue sample is obtained from the organ where we suspect protein deposits (such as the heart, kidney). In some cases, a bone marrow biopsy is additionally necessary.
Important for diagnosis is not only the pure detection of amyloids but also the determination of the amyloidosis type. We need to know what kind of protein has deposited because the treatment depends on it. The following further examinations are used, for example:
- Urine analysis, for example, determination of protein quantity in urine, ratio of albumin/creatinine
- Blood tests, for example, blood count, electrolytes, liver values such as alkaline phosphatase and gamma-GT, immunoglobulins
- Immunohistochemical examinations: We stain the removed tissue with the dye Congo red and subsequently examine it. The amyloid binds the Congo red. Under polarized light, the deposits then glow greenish.
- Genetic testing, for instance, if familial ATTR amyloidosis is suspected
- Ultrasound examination (sonography)
- X-ray examination
- Electrocardiography (ECG) and heart ultrasound (echocardiography)
- Computed tomography (CT)
- Magnetic resonance imaging (MRI)
- Lung function testing, for example, spirometry
- Endoscopy
- Electromyography (EMG) - a test to check muscle function
- Electroneurography (ENG) - it shows how well the nerves function
- Skeletal scintigraphy - a nuclear medicine procedure that can detect increased metabolic activity
Source: www.usz.ch
Amyloidosis: Frequency and Age
The exact frequency of the different amyloidosis types is difficult to determine. Some estimates are:
- AL amyloidosis: In North America, annually 5 to 13 out of one million people newly develop AL amyloidosis. The frequency increases with age, and men are more commonly affected than women. AL amyloidosis is one of the most common forms of amyloidosis.
- Hereditary ATTR amyloidosis: Worldwide, about 5,000 to 10,000 people are affected. This form belongs to the rare diseases (orphan diseases).
- Wild-type transthyretin amyloidosis: This age-related form is increasingly being diagnosed. Approximately 25 percent of those over 80 and about 13 percent of those over 60 with heart failure (with preserved left ventricular ejection fraction) are likely affected. The actual frequency is probably underestimated.