Amyloidosis

What is amyloidosis?

The group of amyloidoses comprises various clinical pictures and subgroups. To date, just over 30 proteins are known that can form such amyloids. Assignment to a group depends on which protein is responsible for amyloid formation. Common forms are AL amyloidosis and ATTR amyloidosis (of which there is an inherited and age-related acquired form), AA amyloidosis is rarer.

Experts also differentiate between localized amyloidosis, in which the proteins only accumulate in one place in the body, for example the skin. In systemic amyloidosis, however, the defective proteins are found in several organs.

There are major differences between the forms of amyloidosis and the deposition patterns of the proteins. Not every person with amyloidosis has the same health symptoms and limitations. The symptoms depend on where in the body the proteins are deposited. In principle, any organ can be damaged by the amyloids. However, they often affect the heart, kidneys, liver, gastrointestinal tract or nervous system.

Some amyloidoses can be traced back to a fault in the genes. Parents can then pass the disease on to their children. One example is familial ATTR amyloidosis. However, hereditary factors do not play a role in the majority of amyloidoses. The cause of AL amyloidosis is often a bone marrow or lymph gland disease. AA amyloidosis, on the other hand, is triggered by long-standing inflammatory diseases, such as rheumatoid arthritis or the chronic inflammatory bowel diseases Crohn’s disease and ulcerative colitis.

Amyloidosis usually progresses further and further. The organs on which the proteins are deposited gradually lose their function. The treatment of amyloidosis depends on the type of amyloid-forming protein. There are various ways to slow down the disease. But amyloidosis is not yet curable.

Amyloidosis – frequency and age

The frequency of the different types of amyloidosis cannot be precisely quantified. Some figures, although these are only estimates:

• For AL amyloidosis, data from North America show that 5 to 13 out of every million inhabitants are newly diagnosed with the disease each year. The frequency increases with age. Men seem to be affected by AL amyloidosis more often than women. AL amyloidosis is one of the most common forms of amyloidosis.
• Inherited (hereditary) ATTR amyloidosis (ATTRv amyloidosis) affects only around 5,000 to 10,000 people worldwide. It therefore falls into the category of orphan diseases.
• We are diagnosing age-related wild-type transthyretin amyloidosis (ATTRwt amyloidosis) more and more frequently. Around 25 percent of patients over 80 years of age and around 13 percent of patients over 60 years of age with heart failure (with preserved left ventricular ejection fraction) are probably affected by the disease. We therefore assume that the frequency has been underestimated to date.

Amyloidosis: Causes are abnormal proteins

The causes of amyloidosis vary. This can be caused by certain cancers, chronic inflammation or hereditary factors. What they all have in common, however, is that abnormally folded proteins accumulate and are deposited in the tissue. These deposits consist of insoluble protein fibers, the so-called amyloid fibrils. The body produces them faster than it can break them down again. The abnormal proteins disrupt the metabolism and the function of various organs.

The amyloids either form in only one place and are deposited exclusively there (local amyloidosis) or they are produced in one place and are then deposited in various regions of the organism (systemic amyloidosis). There are many different forms of amyloidosis, depending on the amyloid-triggering protein. The most important at a glance.

AL amyloidosis (light chains)

Subunits of proteins that play an important role in the immune defense are deposited in the tissue. They are called immunoglobulin light chains. Pathologically altered immune cells in the bone marrow or the lymph glands (plasma or lymph cells) produce these abnormal light chains. The development of AL amyloidosis is closely related and partly linked to cancers of the bone marrow and lymph glands, for example plasma cell myeloma or non-Hodgkin’s lymphoma.

ATTR amyloidoses

Genes are less frequently involved in amyloidosis. Inherited amyloidosis is more common in various regions of the world, such as Japan, Sweden and Portugal, but not in Switzerland.

Familial transthyretin amyloidosis (familial or inherited ATTR amyloidosis = ATTRv amyloidosis) is caused by a genetic defect that affects the transthyretin gene. This mutation causes the liver in particular to produce a defective transport protein called transthyretin. It is responsible for transporting the thyroid hormones thyroxine and retinol. The proteins are particularly deposited on the nerves, heart, intestines and in the eyes.

More than 100 changes in the transthyretin gene are now known. The mode of inheritance is autosomal dominant. This means that the offspring of those affected have a 50 percent probability of inheriting the defective gene:

• Familial amyloid neuropathy (FAP): The most common genetic mutation is the Val50Met mutation in the transthyretin gene(TTR gene). In Portugal and Japan, FAP occurs most frequently between the ages of 30 and 40, in Sweden in 50 to 60-year-olds. Typical symptoms of FAP are damage to the nerves (neuropathy) and the heart. But the gastrointestinal tract and the eyes can also be affected. The kidneys are only affected in around ten percent of patients, the liver never.
• Familial amyloid cardiopathy (FAC): The most common mutations of the TTR gene are Leu111Met and Val122Ile. In FAC, the abnormal protein transthyretin is deposited almost exclusively in the heart. The first symptoms usually appear from the age of 60. Sometimes the heart disease is preceded by carpal tunnel syndrome. The metacarpal nerve is trapped in the wrist tunnel (carpal tunnel).

ATTR amyloidosis can also occur as a result of a spontaneous change in the transthyretin gene (acquired or wild-type ATTR amyloidosis = ATTRwt amyloidosis). In this case, inheritance does not play a role. Experts used to call the disease “senile systemic amyloidosis” because it is age-related. In contrast to familial ATTR amyloidosis, there is no underlying mutation, but the normal transthyretin folds incorrectly. The amyloidosis deposits mainly affect the heart muscle. The first symptoms do not appear until the age of 70 and upwards. Most people experience symptoms of heart muscle weakness (heart failure). Doctors conclude from autopsies that the diagnosis of ATTRwt amyloidosis is often not made during the patient’s lifetime. The number of people affected could therefore be higher than previously assumed.

AA amyloidosis

The causes are chronic inflammations that have been present for around 20 years (and sometimes much less). These can be lung and skin infections (e.g. tuberculosis), as well as inflammatory rheumatic diseases (e.g. rheumatoid arthritis). B. rheumatoid arthritis), chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis) and, more rarely, hereditary fevers (e.g. familial Mediterranean fever = FMF).

The chronic inflammation ensures that the liver permanently produces excessive amounts of the protein serum amyloid A (SAA). These can transform into AA fibrils, which are mainly deposited 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 occurs as part of some hereditary diseases.

Symptoms: Amyloidosis causes various symptoms

As different as amyloidoses are, they can also cause different symptoms. The symptoms are not the same for every patient, nor are they equally severe. The type of amyloidosis and the organs in which the insoluble proteins are deposited play a role. In systemic amyloidosis, several organs are usually affected at the same time. In localized amyloidosis, however, the protein deposits are only found locally, for example in the skin.

The first symptoms of amyloidosis are often very uncharacteristic. General complaints such as tiredness, fatigue or a decrease in physical performance can occur. However, they also accompany many other diseases, which is why many people misinterpret them.

Warning signs of systemic amyloidosis can be, for example

• Heart: e.g. shortness of breath and shortness of breath during physical exertion, water retention (edema), cardiac arrhythmia (e.g. palpitations, palpitations), fainting spells
• Kidney: e.g. water retention (e.g. eyelids, ankles, feet, lower legs), foamy urine due to increased excretion of proteins, kidney failure
• Liver: e.g. enlarged and stiffened liver, water retention in the abdomen (ascites)
• Gastrointestinal tract: e.g. difficulty swallowing, loss of appetite, weight loss, nausea, bloating, flatulence, diarrhea, constipation, bleeding in the digestive tract
• Eyes: e.g. dry eyes, vitreous opacity, increased intraocular pressure (glaucoma)
• Nervous system: e.g. pain and numbness in the hands and feet, disorders of bowel movements and bladder emptying, erectile dysfunction
• Soft tissue and other areas: e.g. swollen and enlarged tongue (macroglossia), hoarseness, bleeding in the skin – e.g. in the eyelids (“raccoon eyes”), carpal tunnel syndrome, swollen joints, enlarged spleen, muscle weakness, fatigue

Always consult your doctor promptly if you notice any unusual symptoms for which you cannot find an explanation.

Amyloidosis: Diagnosis with us

In many patients, we only discover amyloidosis after some time. One reason is that the symptoms are often so atypical. Studies show that around 20 percent of patients with AL amyloidosis are only diagnosed after more than two years. In around 42 percent of patients with ATTRwt amyloidosis, we only find the disease more than four years after the onset of symptoms.

The diagnosis always begins with a discussion of your medical history, the anamnesis. For example, we ask you the following questions:

• What exactly are your symptoms?
• When did they first appear?
• Where do the symptoms particularly manifest themselves?
• How intensively are they pronounced?
• Do you have any known diseases?
• Are there any illnesses in your family?
• Do you undergo treatments?
• Do you take medication regularly?

Your answers will help us to make an initial assessment. This is followed by a physical examination, during which we thoroughly examine and palpate the body. This allows changes to be detected. We also listen to the heart and lungs.

Amyloidosis: Further examinations

If amyloidosis is suspected, further examinations are carried out to detect the deposited amyloid in the tissue:

• Tissue sample (biopsy): We usually take the tissue from the abdominal fat or the rectal mucosa. Less frequently, we obtain the tissue sample from the organ in which we suspect the protein deposits (e.g. heart, kidney) due to the potential risks. In some cases, a bone marrow biopsy is also necessary.

However, not only the pure detection of amyloids is important for the diagnosis, but also the determination of the amyloidosis type. We need to know what type of protein has been deposited. Because the treatment is based on this. The following further examinations are used, for example:

• Urine examination, B. Determination of the amount of protein in the urine, ratio of albumin/creatinine
• Blood test, e.g. blood count, electrolytes, liver values such as alkaline phosphatase and gamma-GT, immunoglobulins
• Immunohistochemical examinations: We stain the removed tissue with Congo red dye and then examine it. The amyloid binds the Congo red. Under polarized light, the deposits then glow greenish.
• Genetic test, for example in cases of suspected familial ATTR amyloidosis
• Ultrasound examination (sonography)
• X-ray examination
• Electrocardiography (ECG) and cardiac ultrasound (echocardiography)
• Computed tomography (CT)
• Magnetic resonance imaging (MRI = magnetic resonance imaging)
• Pulmonary function test, e.g. 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 be used to detect increased metabolic activity

Amyloidosis: prevention, early detection, prognosis

Amyloidosis can have many different causes. They range from chronic inflammation to diseases of the bone marrow or lymph glands to altered genes.

Have underlying diseases such as familial Mediterranean fever, plasma cell myeloma, chronic inflammatory bowel disease and rheumatoid arthritis treated consistently and adequately. In this way you can prevent amyloidosis to a certain extent. However, you have no influence on the genes and protection against amyloidosis is not possible in this case. For some forms of amyloidosis, medication is available to prevent the formation of further protein deposits.

Special measures for the early detection of amyloidosis in the doctor’s office are also not known. Due to the uncharacteristic symptoms, many patients are diagnosed late, years after the onset of the first symptoms. Therefore, always consult your doctor if you experience symptoms that you cannot classify.

Course and prognosis of amyloidosis

Amyloidosis is a very serious disease. However, the course and prognosis of amyloidosis cannot be generally predicted. They vary from person to person and also depend on the type of amyloidosis. Some forms of the disease affect several organs – heart, liver, lungs, kidneys, gastrointestinal tract or the nervous system. As a rule, amyloidosis gradually worsens within a few years because the organs lose more and more of their function. It is currently incurable.

Amyloidosis is sometimes associated with chronic inflammatory diseases. Amyloidosis can often be slowed down by the correct and sufficient treatment of the underlying disease.

Amyloidosis: treatment means slowing down the disease

The treatment of amyloidosis belongs in our hands, as we have a lot of experience with the therapy. We work closely with various specialist areas. These include, for example, specialists in cardiology, nephrology, gastroenterology, hematology and neurology. We discuss each case individually on an interdisciplinary basis and plan the treatment together.

Amyloidosis is not curable. Treatment is therefore aimed at alleviating the symptoms and slowing down the progression of the disease. We want to prolong life and maintain a good quality of life for as long as possible.