Amyloidosis : Recent Trends and Updates in Diagnosis and Treatment

Abstract

Amyloidosis is a generic term that signifies the aggregation of abnormal extracellular tissue deposition of heterogenic, misfolded, proteinaceous substances composed of one of a family of biochemically unrelated proteins in the form of insoluble oligomeric and polymeric protein fibrils in various tissues leading to architectural and functional changes of tissue. The term (amyloid) was firstly use by Rudolph Virchow, in 1854, for this amorphous hyaline change in tissue. In 1859, Friedreich and Kekule showed that amyloid is composed of proteins instead of carbohydrates. And after that in 1959 Alan Cohen and Evan Calkins set the concept of amyloid fibrillar structure when they studied amyloid with electron microscope. The idea of a single amyloid substance predominated until 1968-1969, when Mordechai Pras had introduced a method to extract proteins from fibrils with water, this method turned out to be a big step forward in the chemical characterization of amyloid proteins in the following years. The modern era of amyloidosis classification started in the late 1960s with the development of methods to make amyloid fibrils soluble wich permitted the study of the chemical properties of amyloids. To date, there are 31 known extracellular fibril proteins in humans. Identifying the type of amyloidosis became crucial to determine clinical management, prognosis, and treatment. Thus, the actual nomenclature of amyloid disorders is based on the biochemical nature of amyloid. The reasons for amyloid association disease are unclear. the protein misfolding and amyloid deposits disrupt tissue architecture with cellular damage and tissue injury consequently cause organ dysfunction mainly by prefibrillar intermediates rather than mature amyloid fibers which causing cell death, which, in systemic amyloidoses, ultimately lead to failure of vital organs and to the patient death. Amyloid is a tissue-based diagnosis and based on detecting of amyloid presence in tissue which proved by a tissue specimen taken either from a clinically involved organ or clinically uninvolved organ which is known to contain amyloid deposits in the systemic forms. Nowadays, three first-line types of biopsy are commonly performed: Biopsy of the gastrointestinal tract (gastroduodenal or rectal), Labial salivary gland (LSG) biopsy and Subcutaneous abdominal fat aspiration biopsy (AFA). There are other types of biopsy such as: Bone marrow, Nerve, Liver , heart and kidney biopsies which may have a greater risk of bleeding.Biopsy of classical mucocutaneous lesions should be the procedure of first choice. Tissue specimen showing amyloid as an amorphous, eosinophilic, hyaline substance under light microscopy, stained with Congo-red stain which known as king of dyes” in the diagnosis of amyloid fibrils histologically, it also able to bind fibrils in vitro giving the brick-red staining reaction and positive characteristic “apple-green birefringence” under polarization which is specific for amyloid and distinguishes it from collagen. recently the “anomalous colors” is the more accurate phenomenon should be present which means examined the stained amyloid between crossed polarizer and analyzer, shows anomalous colors. However, negative Congo red staining does not exclude macular or lichen amyloidosis. Many Other stains can demonstrate amyloid deposits in the skin. Cutaneous Amyloidosis CA reflect the cutaneous appearances of the deposits and underlying pathogenesis. It is classified to localized cutaneous amyloidosis and cutaneous involvement in systemic amyloidosis, which caused by an abnormal amyloidogenic protein produced at a non-cutaneous site and mainly deposit in the blood vessel walls in the dermis and around lymphatic vessels causing wall fragility and bleeding in the skin and mucous membranes spontaneously or by minor trauma. This deposits are derived from a different precursor protein in each case, so there is a clinicopathological classification of CA based on the causative protein. While, localized cutaneous amyloidosis LCA may be either primary (idiopathic) PLCA which is clinically classified into keratinic primary localized amyloidosis kPLCA with 2 major types, more common macular MA and papular (lichen) LA type, and the rare nodular localized primary cutaneous amyloidosis NLPCA. Or secondary to localized inflammatory, autoimmune, infection and neoplastic skin disorders, which lead to local production of the amyloidogenic protein. There is another classification of PLCA based on the type of amyloid precursor. Apart from these 2 main types, rare variants include biphasic amyloidosis presented with both pigmented ripped plaques of MA and the pigmented papules of LA, which suggests a common etiology for the two forms, also poikiloderma-like cutaneous amyloidosis, amyloidosis cutis dyschromia (ACD), bullous, vitiliginous, eczematous and anosacral forms are a rare variants. The kPLCA is more common in South America, Southeast Asia and China. There are several etiologic factors implicated in the pathogenesis of kPLCA such as: racial, genetic mutations (OSMR, IL31RA ), environmental factors, sex (female), female hormones, exposure to sunlight, friction (long term abrasion) and atopy. Therapies continue to develop treatment of amyloidosis, The goal of pharmacotherapy for amyloidosis is to reduce morbidity. It is a two-part process, manage symptoms to elevate the survival rate and patient’s well-being, quality of life and clear the supply of amyloid proteins which lead to improvement of the organ function.It based on the organs affection, the type of amyloidosis, the patient’s status, his age and personal priority. The current basis of the treatment is precursor-product concept, which aiming to reduce the levels of proteins precursor in serum to undetectable or normal values. Coming clinical research aiming to target protein conformationstopping the amyloid deposition and rising clearance of amyloid by Interferes with the precursor production which the most common treatment, Stabilizing the normal structure and preventing the misfolding of the protein precursor by drug which is the second strategy and directe destabilization of the amyloid fibrils and can no longer remain misfolded. The conventional treatments of AL amyloidosis includes oral or intravenous chemotherapy (immunotoxins) which forms the cornerstone of treatment for AL amyloidosis. Various new approaches of therapy under evaluation includes bone marrow-derived dendritic cells (DCs) vaccination through induction of antibodies against epitopes of amyloid, anti tumor necrosis factor alpha (TNF-α) agents like Enbrel and 4′-iodo-4′-deoxydoxorubicin, vitamin C, vitamin E and vitamin D3 which