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Amyloidosis

Generality

Amyloidosis is the term used to define a group of diseases characterized by the accumulation, often in the extracellular area, of a fibrillar protein material, defined as amyloid . Insoluble amyloid fibrils form particularly stable deposits in many organs.

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The symptoms and severity of the disease depend on the organ mainly affected by the accumulation of amyloid and the type of amyloidosis. However, most cases are systemic. In other words, fibrillar deposits are widespread and can potentially compromise the function of many tissues and organs of the body. Diagnosis is defined by biopsy, examining a small sample of tissue under a microscope. Potential etiological factors vary according to the variant of amyloidosis. The treatments available help to manage the symptoms and limit the production of amyloid.

Characteristics of amyloid deposits

Amyloidosis derives from disorders of the secondary structure of proteins (with a β-folded leaflet configuration). In normal conditions, in fact, the proteins are synthesized in a linear string of amino acids, which, by folding, assumes a specific spatial conformation (protein folding). Thanks to its structure, therefore to the correct protein folding, the protein is able to perform the physiological functions for which it is deputed. The? Amyloid proteins derive from a precursor processed by the cells incorrectly (due to the "misfolding"). The fibril-forming proteins are diversified according to size, amino acid sequence and native structure, but they become insoluble aggregates that are similar in structure and properties. The fibril precursors are represented by primary molecules (for example: immunoglobulin light chain, β2-microglobulin, apolipoprotein A1 etc.) or from products that reflect an alteration in the amino acid sequence. The aberrant secondary structure predisposes to the formation of fibrils, which can be deposited locally in tissues and organs and lead to the impairment of their normal physiological function. More than 20 different protein precursors have been identified that can take on an amyloid conformation, which is why there are many different types of amyloidosis.

Based on the location of amyloid deposits, the disease can be distinguished into:

  • Localized form: confined to a particular organ or tissue (heart, kidneys, gastrointestinal tract, nervous system and dermis) and is usually less severe than systemic (diffuse) forms. For example, amyloidosis can only affect the skin, causing depigmentation and / or itching. A particular type of amyloid protein has also been found in the brains of patients with Alzheimer's disease. Localized amyloidosis is typical of senescence and of patients with type 2 diabetes (where protein accumulates in the pancreas).
  • Systemic form: amyloid deposits are present in various organs and generally recognize the neoplastic, inflammatory, genetic or iatrogenic origin. Systemic amyloidosis is often very severe: it commonly damages the heart, kidneys, intestines and nerves, causing progressive organ failure.

Classification

There are many forms of amyloidosis, classified according to the nature of the proteins that make up fibrillar deposits.

The most common variants are:

  1. Primary amyloidosis (also called light chain amyloidosis, AL);
  2. Secondary amyloidosis (also called acquired amyloidosis, AA);
  3. Hereditary amyloidosis;
  4. Amyloidosis associated with aging (or senile systemic amyloidosis).

AL amyloidosis

See also: Amyloidosis symptoms

The most common form of systemic amyloidosis is the primary (AL). AL amyloidosis is caused by the accumulation of fibrils containing light chains of immunoglobulins derived from monoclonal plasma cells. The disease is often a consequence of monoclonal gammopathies and can be associated with multiple myeloma or other lymphoproliferative disorders of the B chain.

In AL amyloidosis, fibrillar deposits can gradually settle at the level of the organs many years before the clinical presentation. The symptoms are variable and, in addition to the general manifestations (fatigue, edema and weight loss), depend on the organ mainly affected and on the size of the amyloid deposits. For example, if these are deposited in the kidneys, they can cause chronic kidney failure, while if they are localized in the heart they can compromise the ability to supply adequate blood to the whole body. The amyloid is typically localized in the kidney, heart, liver, peripheral nervous system and autonomic nervous system. Other districts that may be affected are: lungs, skin, tongue, thyroid, bowel and blood vessels.

AL amyloidosis can potentially cause the following symptoms:

  • Weakness and significant weight loss;
  • Fluid retention with edema (as a result of heart failure or nephrotic syndrome);
  • Dizziness;
  • Shortness of breath;
  • Numbness or a tingling sensation in the hands and feet;
  • Carpal tunnel syndrome (disturbance of the median nerve function);
  • Skin lesions: petechiae and ecchymoses;
  • Purple around the eyes;
  • Macroglossia (volumetric growth of the tongue.).

Secondary, senile and hereditary amyloidosis

The less common forms of systemic amyloidosis are briefly described below:

  • Secondary amyloidosis (AA) : it is also known as acquired amyloidosis and can develop as a complication of various diseases that cause a persistent inflammatory condition (such as tuberculosis, rheumatoid arthritis, leprosy and familial Mediterranean fever) and certain forms of cancer (example: cell carcinoma kidney). In these processes, the intervention of pro-inflammatory cytokines (IL-1, IL-6 and TNF) stimulates hepatic production of serum amyloid A (SAA). SAA can be found in high concentrations in the serum of patients with rheumatoid arthritis, Chron's disease and in hereditary forms of periodic fever, at least until the inflammatory phase of these chronic conditions is attenuated. Typical places of amyloid accumulation are spleen, liver, kidneys, adrenal glands and lymph nodes. Secondary amyloidosis, in fact, presents in a characteristic way proteinuria and / or hepatosplenomegaly, to show the involvement of these organs. Treating the underlying condition often prevents amyloidosis from getting worse.
  • Senile systemic amyloidosis (cardiac) : amyloidosis associated with the normal aging process is generally found in patients over 60 years of age. The deposits, in this form, are deposited at the cardiac level. The causes are not yet known and new diagnostic tests and treatments are currently under development.
  • Hereditary amyloidosis : has been noted in some families as the result of a genetic defect. These mutations affect specific blood proteins (such as the transthyretin protein, TTR) and can be inherited in an autosomal dominant fashion. Hereditary amyloidosis mainly involves the nervous system: patients develop a characteristic symmetrical sensorimotor neuropathy in their lower limbs. Other amyloid deposits can be located at the level of the heart, blood vessels and kidneys.

Possible effects of fibrillar deposits in amyloidosis

Affected organ or systemPossible consequences
BrainAlzheimer's disease
Digestive systemMacroglossia, difficulty swallowing, diarrhea or constipation, intestinal obstruction and poor absorption of nutrients
HeartCardiac rhythm abnormalities (arrhythmias) and heart failure
KidneysAccumulation of fluid in the tissues and edema, proteins in the urine (detected by the urine test) and renal failure
LiverHepatomegaly (enlarged liver)
LungsDifficulty breathing
lymph NodesSwollen lymph nodes
Nervous systemCarpal tunnel syndrome, numbness, tingling or lack of sensation in the feet and on their plant or burning sensation in these regions
SkinPapules, purpura and ecchymoses
ThyroidThyroid enlargement (thyroid goiter)

Who is most at risk?

People with the following profile have an increased risk of developing amyloidosis:

  • Male sex: amyloidosis predominantly affects male subjects;
  • Patients over the age of 60;
  • Disorders affecting plasma cells (multiple myeloma, lymphoma, monoclonal gammopathy or Waldenström's macroglobulinemia);
  • Chronic infectious or inflammatory disease (such as rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever or ankylosing spondylitis);
  • Long-term dialysis;
  • Genetic mutations that influence the conformation of proteins.

Diagnosis

The accumulation of large amounts of amyloid can alter the normal functioning of many organs. The diagnosis of amyloidosis can be very challenging, as the symptoms are often generic. However, doctors may suspect amyloidosis when:

  • Several organs present a functional deficit;
  • Fluid retention occurs, with consequent edema, at the level of the tissues;
  • An unexplained bleeding occurs, particularly in the skin (ecchymosis, purpura, etc.).

In order to rule out other conditions, the doctor can start by conducting:

  • Physical examination (to detect the clinical signs of organ involvement);
  • Blood and urine tests (to find the fibrillar protein involved).

The diagnosis can be definitively confirmed by biopsy and microscopic examination of the sample taken and processed with Congo red color. In some patients, where amyloidosis is suspected, a biopsy can be performed at the periombelical fat pad. Alternatively, doctors can perform the same procedure by taking a renal, rectal or cutaneous sample. After the diagnosis, the doctor may schedule further periodic examinations to check the levels of related substances, the size and location of amyloid deposits, the course of the disease and the effects of the treatment.

Prognosis and therapy

The therapy must be adapted to the various forms of amyloidosis, taking into consideration the basic conditions and those secondary to the pathology. Unfortunately, therapeutic protocols to reduce or control the symptoms and complications of the disease are only modestly successful for most people. No treatment aimed at amyloid deposits is still available and the therapy is therefore destined to the repression of the underlying plasma cell dyscrasia, with supportive measures to support and possibly preserve the function of the organ.

Primary amyloidosis, whether or not associated with multiple myeloma, presents a poor prognosis and survival is approximately 2-4 years. Most people who suffer from both diseases die within 1-2 years. The most frequent causes of death are represented by pictures of cardiac, renal and respiratory failure, bleeding from the gastrointestinal tract and infections. In the case of primary amyloidosis the main objective is to inherit the pathological clone. For this purpose, chemotherapy may be considered. As in the classical forms of monoclonal gammopathies, melphalan or cyclophosphamide (chemotherapeutic agents also used to treat some neoplasms) and dexamethasone, a corticosteroid used for its anti-inflammatory effects, are administered. The combination of these drugs inhibits abnormal bone marrow cells, so it can lead to a gradual reduction in the amount of amyloid in the body and prevent organ damage. Researchers are studying other chemotherapy regimens suitable for the management of amyloidosis. Several drugs used in the treatment of multiple myeloma (bortezomib, thalidomide and lenalidomide) have also been tested to evaluate their efficacy in the treatment of amyloidosis.

Stem cell transplantation may represent a therapeutic option, in some cases. Selected patients can be effectively treated with high-dose intravenous administration of melphalan, followed by transfusion of peripheral stem cells, ie immature blood cells previously collected to replace the damaged or damaged bone marrow (hematopoietic tissue).

In the case of secondary amyloidosis (AA), the treatment of basic inflammatory disease (inflammatory conditions, chronic infections or carcinoma), usually slows down or reverses the course of the disease. The prognosis of secondary amyloidosis depends on how the underlying condition is treated and the survival is approximately 5-10 years.

Organ transplantation (kidney, heart, etc.) can prolong the survival of a limited number of patients with organ failure secondary to amyloidosis. However, the disease continues to progress and even the transplanted organ can accumulate amyloid deposits (it can be avoided, if possible, by suppressing chemotherapy of the bone marrow). The exception is represented by liver transplantation, which can limit the progression of hereditary amyloidosis (often, the protein that causes this form of amyloidosis is synthesized in the liver). The perspective for the latter form varies depending on the type of gene mutation and the degree of progress at the time of diagnosis. Amyloid deposits located in a specific area of ​​the body can sometimes be removed surgically.