Amyloidosis

What is Amyloidosis?

Amyloidosis is a varied disease in which harmful, insoluble protein clusters settle in several tissues of the body. It can be either passed down (hereditary) or occur independently (acquired), and it can impact specific areas (localized) or many parts of the body (systemic). Amyloid, the substance causing the disease, can build up in various organs like the liver, heart, kidneys, nerves, and blood vessels all leading to a range of health issues including heart disease, enlarged liver, protein in urine, swollen tongue, autonomic dysfunction, skin discoloration, neuropathy, kidney failure, high blood pressure, and abnormalities in the cornea and vitreous (parts of the eye).

There have been several systems in the past to categorize the different types of Amyloidosis. However, today it is typically classified based on the chemical analysis of the amyloid found in the body. The disease can be classified as systemic, inherited, affecting the central nervous system, affecting the eyes, or localized. The most frequently seen types are AL, AA, ATTR (amyloid transport protein transthyretin), and dialysis-related amyloidosis (beta2M type).

In the case of AL amyloidosis, the ‘A’ stands for amyloid and ‘L’ stands for light chain fragment or immunoglobulin light chain, which is the associated protein. In AA amyloidosis, the additional ‘A’ represents the serum amyloid A protein.

What Causes Amyloidosis?

Amyloidosis has several common causes, like immunoglobulin-light-chain related amyloidosis (AL), ATTR amyloidosis, and reactive amyloidosis (AA). These last type largely happens due to long-term inflammatory diseases such as persistent infections and rheumatoid arthritis. AL amyloidosis is a condition you develop, not one you’re born with. It happens when a type of white blood cell produces wrongly shaped proteins that deposit in various organs and tissues.

AA amyloidosis is often seen in people with different long-term inflammatory conditions and in those with long-term or local infections. It can sometimes occur due to cancer, though that’s rare. AA is the most frequent kind of systemic amyloidosis, but its occurrence can vary within different ethnic groups.

Risk Factors and Frequency for Amyloidosis

AL amyloidosis is a condition that is typically found in Western countries, with approximately 1 case for every 100,000 people each year. In the U.S. alone, it accounts for about 1275 to 3200 new cases annually. It should be noted that 78% of all new cases each year are identified as AL amyloidosis.

Then there is familial transthyretin-associated amyloidosis (ATTR). It’s a less widespread type of amyloidosis, and its exact frequency is not known. However, in hospitals and medical centers, it makes up around 10 to 20% of all diagnosed cases. Of these cases, 7% are inherited due to a mutation in the transthyretin protein (ATTRm), and roughly 6% are acquired with age, known as wild-type ATTRwt amyloidosis. This latter kind is most commonly found in males and was earlier referred to as senile systemic amyloidosis.

Last but not least, secondary or AA amyloidosis forms about 6% of all diagnosed amyloidosis cases each year. This type is acquired and is generally a reaction to chronic inflammation in the body.

Signs and Symptoms of Amyloidosis

Amyloidosis is a condition that can manifest differently according to the type of amyloid proteins involved. When it affects multiple parts of the body (systemic amyloidosis, or AA), symptoms can potentially include heart failure, liver enlargement, kidney problems, a swollen tongue, low blood pressure when standing up, skin bruising, nerve damage, and disorders like carpal tunnel syndrome. Secondary amyloidosis (also AA), can present with an enlarged liver and spleen, protein in urine, kidney failure, and low blood pressure. ATTR amyloidosis develops around middle age and might cause peripheral and autonomic nerve damage, heart disease, and clouding in parts of the eye. Finally, amyloid beta-amyloidosis is focused in the brain and often appears as Alzheimer’s disease in older individuals.

Additional physical symptoms that might suggest amyloidosis include increased muscle size around the shoulders, skin discoloration, and “raccoon eyes” due to certain deficiencies. Excessive clotting or bleeding can also occur, which can be identified in lab tests.

• Heart failure
• Liver enlargement
• Kidney problems
• Swollen tongue
• Low blood pressure when standing up
• Skin bruising
• Nerve damage
• Carpal tunnel syndrome
• Enlarged liver and spleen
• Protein in urine
• Kidney failure
• Peripheral and autonomic nerve damage
• Heart disease
• Clouding in parts of the eye
• Increased muscle size around the shoulders
• Skin discoloration
• “Raccoon eyes”
• Excessive clotting or bleeding

Testing for Amyloidosis

When a doctor suspects amyloidosis – a rare disease that happens when abnormally folded proteins called amyloids build up in organs – they will use a range of tests to confirm it. These include a close look at your family history and tissue samples.

Taking tissue samples (also called biopsy) from different parts of the body can be a key step. One way to do this is by taking a sample of abdominal fat just under the skin. This is a simple and safe procedure that can identify the disease 81% of the time in one type of amyloidosis, called AL, using a special stain test.

If this fat tissue test doesn’t provide any answers, a biopsy of the minor salivary glands (those in your mouth) can be done. This helps diagnose systemic amyloidosis in 60% of those cases where the fat tissue test came up negative. Liver biopsies should be done very carefully as the liver might bleed excessively if it is filled with amyloids.

If doctors still have suspicions after these biopsies, they will perform extra tests like serum and urine electrophoresis accompanied by immunofixation and tests for free light chains (FLC). These tests are used to rule out another condition called plasma cell dyscrasia, which has similarities with amyloidosis. If no light chains are found, a bone marrow biopsy can help confirm the diagnosis.

If no hints of plasma cell dyscrasia are found, the next step is to consider other types of amyloidosis. Several techniques like mass spectrometry, immune electron microscopy, or immunohistochemistry can be used to identify the type of amyloids in the tissue samples. There is also a technique to detect a protein called transthyretin.

Gene sequencing is performed when hereditary amyloidosis – those passed on by families – needs to be ruled out based on symptoms.

Even if no transthyretin is found, and the person has symptoms like an enlarged tongue and other organ issues, they might still have AL amyloidosis, despite no indications of plasma cell dyscrasia. In such cases, a cardiac biopsy can be helpful in making a diagnosis. Other scanning techniques can help distinguish between different types of the disease, potentially avoiding the need for a heart biopsy.

AA amyloidosis is another type of the disease. If no transthyretin or AL amyloids are found after all these tests, but kidney damage and nerve disease are present, AA amyloidosis is tested for. Immunohistochemistry tests can be used for this.

Finally, to plan the best treatment, the extent of the amyloidosis and which organs are involved should be established. Various checks on cardiac function such as an echocardiogram, ECG, Holter ECG, and cardiac MRI are recommended. Kidney function can be assessed by evaluating 24-hour urinary protein and eGFR. Liver function can be checked using a set of blood tests and imaging methods like ultrasound, MRI, or a CT scan.

Treatment Options for Amyloidosis

AL amyloidosis is often treated in the context of clinical trials and the treatment approach is based on a risk assessment system called the Standard Mayo Clinic staging system.

Patients classified as low-risk generally have specific indicators, such as NT-proBNP less than 5000ng/L, troponins less than 0.06ng/ml, eGFR more than 50 ml/min per 1.73m, etc. These patients usually undergo a procedure known as an autologous stem cell transplant with Melphalan 200mg/m2. If the patient’s condition includes more than 10% bone marrow, plasma cell infiltration, or if the patient declines the transplant process, a treatment with cyclophosphamide, bortezomib, and dexamethasone is considered. If a complete cure is not accomplished, a combination of bortezomib and dexamethasone is administered.

Patients assessed as intermediate risk, who are not suitable for autologous stem cell transplants and are at stages I-IIIa, are treated with Melphalan and Dexamethasone, particularly if they have neuropathy. Patients with renal problems or those showing 1q21 gain are provided with a combination of Cyclophosphamide, Bortezomib, and dexamethasone.

Patients classified as high-risk may be provided with bortezomib due to its rapid effect, or are treated with low-dose combination regimens. An alternative for patients with a specific translocation, t(11;14), or those with an FLC above 180 mg/l is a combination of bortezomib, melphalan, and dexamethasone.

ATTR amyloidosis treatment involves targeting Transthyretin, a protein mainly produced in the liver. Liver transplant often results in the disappearance of mutant Transthyretin from the blood and improvement in neuropathy.

Supportive therapy in treating systemic amyloidosis aims at improving the quality of life and preventing the functions of organs from being impaired. Patients waiting for a heart transplant should receive low-dose chemotherapy as it significantly enhances their lifespan.

Splenectomy, or spleen removal, is considered a treatment option for severe factor-X deficiency, which is present in about 2.5% of patients with AL amyloidosis and can lead to bleeding disorders. This operation is usually effective for patients with an enlarged spleen, but not typically for those with normal-sized spleens.

What else can Amyloidosis be?

Amyloidosis, a condition where abnormal proteins build up in your tissues and organs, has connections to chronic inflammatory and body-wide conditions. Often, this disorder occurs alongside conditions linked to Immunoglobulin M – a type of antibody in your body.

When diagnosing this condition, doctors need to rule out other diseases that may display similar symptoms, such as:

• Inherited Kidney Amyloidosis
• Immunoglobulin-Linked Amyloidosis
• A type of kidney disease known as “Membranous Glomerulonephritis”
• Kidney Vein Clots brought on by amyloid
• Thickened folds on the scalp known as “Cutis Verticis Gyrata”
• Mastocytosis, overproduction of certain immune cells
• Localized bumps of Amyloidosis on the skin
• A skin condition making it appear cracked or loose, known as “Pseudoxanthoma Elasticum”

To make an accurate diagnosis, doctors would appropriately examine these possibilities.

What to expect with Amyloidosis

The outlook for patients with amyloidosis, a type of disease where harmful proteins called amyloids build up in the body, depends on the exact type of amyloidosis they have and how well they respond to treatment. If systemic amyloidosis, which affects the whole body, is left untreated, it can be life-threatening.

Progression of the disease can speed up if the doctors do not detect and address a chronic inflammatory condition causing amyloidosis or if this condition is wrongly diagnosed. The survival rate varies, depending on which organs are affected by the disease. If the heart becomes involved, patients face significant risk of heart-related complications, which can significantly increase their chances of serious illness or even death.

Possible Complications When Diagnosed with Amyloidosis

Amyloidosis is a condition that impacts various organs in the body. One of the severe outcomes of this disease is restrictive cardiomyopathy, resulting from a long-term buildup of amyloidosis. At first, when the heart is affected, it may lead to chest pain, lightheadedness upon standing, or abnormal heart rhythms. It’s important to note that about 40% of people with systemic amyloidosis end up passing away due to heart failure.

Beyond the heart, amyloidosis can create other complications. For instance, if it causes an enlarged tongue, this can lead to difficulty swallowing, which can be not only a nuisance but also painful. If amyloidosis infiltrates the blood vessels, it can lead to leg or jaw claudication, which means the legs or jaw muscles get insufficient blood flow. Hair loss can occur if amyloid is lodged in the skin, and on top of all that, bleeding can occur when the disease infiltrates the digestive system, leading to poor nutrient absorption or even death.

Common symptoms of Amyloidosis include:

• Chest pain
• Lightheadedness upon standing
• Abnormal heart rhythms
• Enlarged tongue causing difficulty in swallowing
• Leg or jaw muscle discomfort due to inadequate blood flow
• Hair loss
• Bleeding in the digestive system