Clinical approach of patients with systemic amyloidosis

Hazenberg BPC. Clinical approach of patients with systemic amyloidosis Amyloidosis is the name of diseases characterised by deposition of protein fibrils with a beta-sheet structure. This beta-sheet structure generates affinity of amyloid for Congo red dye and is resistant to proteolysis. The main three types of systemic amyloidosis are AA (related to underlying chronic inflammation), AL (related to underlying monoclonal light chain production), and ATTR amyloidosis (related to old age or underlying hereditary mutations of transthyretin). Signs and symptoms vary among the three types and the treatment is different for each type. If a patient is suspected to have systemic amyloidosis, proof of the presence of amyloid in tissue must be obtained first and systemic involvement should be unequivocal. Determination of the precise type of amyloid is extremely important and one should start to detect the particular amyloid precursor. Assessment of size and function of vital organs and tissues is essential in the clinical work-up of a patient with systemic amyloidosis. A fast and thorough clinical evaluation is necessary to obtain all relevant information for prognosis and choice of treatment. The treatment is based on the “precursor-product” concept, in which the supply of amyloid precursor is the rate limiting step for further accumulation of amyloid. Effective therapy quickly and completely stops ongoing supply of precursor. In this respect, investigations such as serum amyloid P component (SAP) scintigraphy may help not only to investigate organ involvement but also response to treatment. The effects of therapy on both underlying disease and amyloidosis should be monitored frequently during follow-up. Tijdschr Nucl Geneesk 2011; 33(4):778-784 Introduction Amyloidosis is the name of a group of diseases characterised by deposition of proteinaceous fibrils with a molecular ß-sheet structure (1). This structure of the fibrils is responsible for its insolubility, resistance to proteolysis, and binding affinity for Congo red dye and the consequent green birefringence with polarised light. Amyloid fibrils are derived from a variety of protein precursors. The extracellular deposition of amyloid Bouke P.C. Hazenberg, MD, PhD Department of Rheumatology & Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands fibrils in organs and tissues results in loss of function and often causes prominent swelling of the affected organ or tissue. Deposition of amyloid can be localised (produced in and limited to one organ or site of the body) or systemic (deposition in various organs and tissues throughout the body). The precursor protein is used for typing amyloid in the current classification of amyloidosis (2). Signs and symptoms of systemic amyloidosis differ among the various types of amyloidosis (1-3). The aim of this article is to provide a clinical overview of systemic amyloidosis: an approach to diagnosis, clinical evaluation, and background of therapy. Systemic amyloidosis Localised deposition of amyloid plays a still unresolved role in widespread diseases such as Alzheimer’s disease (ß-protein in the plaques) and diabetes mellitus type II (amylin in the islands of Langerhans). Systemic deposition of amyloid, however, is directly related to the grim prospects of systemic amyloidosis. Three major types can be distinguished (1-3). AA amyloidosis is caused by longstanding inflammation. Serum amyloid A protein (SAA), an acute phase reactant, is the precursor. Signs of kidney disease, such as proteinuria (progressing to nephrotic syndrome) and loss of renal function (progressing to renal failure), are observed most frequently (in about 90% of cases). Less frequent manifestations are autonomic neuropathy, splenomegaly, hepatomegaly, goiter, and cardiomyopathy. AL amyloidosis is caused by an, often low-grade, plasma cell dyscrasia. Lambda or kappa immunoglobulin light chain is the precursor of this type of amyloid. Clinical manifestations are diverse, such as cardiomyopathy, hepatomegaly, splenomegaly, nephrotic syndrome, renal failure, orthostatic hypotension, diarrhea, peripheral and autonomic neuropathy, arthropathy, carpal tunnel syndrome (CTS), and glossomegaly. The diversity of disease manifestations is related to severity of deposition in the various organs and tissues. ATTR amyloidosis is caused by many autosomal dominantly inherited point mutations of the precursor protein transthyretin (TTR). Transthyretin is the acronym of transport protein of thyroid hormone and retinol binding protein. About 100 of these TTR mutations have been described, but the so-called TTR-Met30 mutation is seen most frequently. Prominent clinical manifestations are familial peripheral and autonomic neuropathy, but cardiomyopathy, renal failure, and eye involvement (vitreous opacities) are also often observed in the course of the disease. Severe cardiomyopathy is the