Subtypes and clinical features of systemic Amyloidosis

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Amyloidosis refers to a group of disorders in which normally soluble proteins become insoluble, fibrous proteins, referred to as amyloids. In humans there are 25 different proteins which can take up this fibrillar conformation in vivo (Gillmore and Hawkins, 2013). Amyloids are deposited in the extracellular space of almost any organ or tissue (Murakami T. et al, 2014). Extracellular amyloid deposits are associated with disruption of the organ function and leads to development of clinical syndromes, whose classification depends on the causative fibril protein precursor. Amyloids form due to a disorder in the secondary structure of proteins which cause the protein to assume an aggregated, β-pleated sheet conformation (Elsevier's Global Clinical Reference, 2012). If amyloid accumulation occurs in a single organ, amyloidosis is localized. In systemic amyloidosis amyloid deposits are widespread throughout the body and ordinarily accumulate in a progressive fashion (Gillmore and Hawkins, 2013). All amyloid accumulations contain pentraxin serum amyloid P (SAP) and glycosaminoglycans. At least 24 such proteins have been recognized as causative of amyloidosis. Diagnosis depends on identification of amyloid accumulation in biopsy or autopsy tissue. Treatment aims at reducing the production and extracellular deposition of amyloids, promoting lysis of existing amyloids as well as treatment for dysfunction of the underlying organ. Systemic amyloidosis is usually a progressive disease. If untreated, 80% of patients die within 2 years of diagnosis (Elsevier's Global Clinical Reference, 2012).

Figure 1. Amyloidodis-associated periorbital purpura (Gertz, 2013)

Figure 2. Massive enlargement of the tongue caused by amyloid infiltration (Mayanka et al., 2010)

Figure 3. Amyloid fibrils stain blue. Amyloid deposits are seen everywhere and encircle each heart cell (Stanford Hospital & Clinics, 2014)

Figure 4. Heart ultrasound from a normal patient and one with amyloid deposits in the heart. The thickness in the patient with amyloidosis is not due to extra heart muscle, but rather from deposits of amyloid fibrils (Stanford Hospital & Clinics, 2014)

Figure 5. Sural nerve biopsy for amyloid involvement of PNS. The nodular deposit of pink amorphous material in the bottom center is the amyloid (Gertz, 2013)

Figure 6. Amyloid deposits in the kidney (Gertz, 2013)

Systemic Amyloidosis - Subtypes and Clinical Features

Systemic amyloidosis is divided to three major subtypes depending on the causative protein:

A. Primary amyloidosis (AL). Occurs when bone marrow produces excessive amounts excess production of immunoglobulins by plasma cells that build up in the bloodstream and deposit in tissues. It accounts for more than 80% of all cases. The causative protein is Immunoglobulin light chains. The clinical features of primary amyloidosis are variable since it may affect any organ other than the CNS (Gillmore and Hawkins, 2013). This form is associated with an underlying plasma-cell dyscrasia (a group of diseases identified by proliferation of a single clone of cells producing a monoclonal immunoglobulin or immunoglobulin fragment: multiple myeloma, Waldenström macroglobulinemia, the heavy chain disease, benign monoclonal gammopathy). AL consistently affects the kidneys, heart, and peripheral nervous system (PNS). More than 60% of affected individuals present with renal dysfunction which causes proteinuric renal failure. Half of the affected individuals also develop stage 1 or 2 chronic kidney disease (CKD) while 16% develops stage 5 CKD (Gillmore and Hawkins, 2013). This form exhibits the broadest spectrum of organ involvement. AL may lead to carpal tunnel syndrome, cardiomyopathy and congestive heart failure, intestinal malabsorption, liver swelling, kidney failure, nephrotic syndrome, neuropathy and orthostatic hypotension. Symptoms depend on the organs in which amyloids have accumulated. They include abnormal heart rhythm, swollen tongue, fatigue, numbness of hands or feet, shortness of breath, skin changes, swallowing problems, swelling of extremities and weight loss (Gertz, 2011). Treatment aims to reduce plasma cell dyscrasia. It involves high-dose melphalan chemotherapy together with dexamethasone, then peripheral stem cell tranplantation. Additional measures are taken to treat dysfunction of the underlying damaged organ (Elsevier's Global Clinical Reference, 2012).

B. Familial amyloidosis (ATTR). Familial amyloidoses are autosomal dominant inherited diseases. The amyloid is being synthesized from birth but deposits occur mid-life (Amyloidosis Foundation, 2011). Hereditary amyloidoses include amyloidoses ALys, AApoA1, AFib and amoloidosis associated with apolipoprotein A­ II-(AApoA2) (Gillmore and Hawkins, 2013), with ATTR being the most common. ATTR accounts for approximately 5% of systemic amyloidosis cases. It's caused by inherited mutations of particular protein groups which form fibrils, typically transthyretin (TTR) which is produced in the liver (Elsevier's Global Clinical Reference, 2012). Renal dysfunction in familial amyloidoses is common, while ATTR predominantly affects the heart and less frequently the PNS, causing cardiomegaly and peripheral neuropathy. Symptoms of ATTR are common to AL.For this type of amyloidosis there is no specific pharmacotherapy available, only supportive therapy. In cases of extended liver involvement, liver transplantation is required (Elsevier's Global Clinical Reference, 2012) to remove the part of the tissue where mutant TTR is produced and replace it with healthy tissue with normal TTR production. This prevents progression of autonomic and peripheral neuropathy but exacerbates cardiomyopathy. Patients with extensively affected kidneys may be also benefited from following a dietary regimen with limited protein, sodium, potassium and phosphorus (Amyloidosis Foundation, 2011).

C. Secondary amyloidosis (AA). A form that develops simultaneously with a chronic infectious or inflammatory disease, for example tuberculosis, rheumatoid arthritis, osteomyelitis et.c. It accounts for about 5% of all cases. The causative protein is serum amyloid A protein (SAA). Approximately 97% of patients with AA present with proteinuric kidney dysfunction and more than 50% have nephrotic syndrome. Eventually 40% advance to end-stage renal disease (ESRD). AA amyloids consistently infiltrate the spleen and in 33% of the cases the adrenal glands. This results in hepatosplenomegaly in 9% of individuals (Gillmore and Hawkins, 2013). Heart is not commonly affected (only 10% of cases) (Elsevier's Global Clinical Reference, 2012). Patients with extensively affected kidneys may be also benefited from following a dietary regimen with limited protein, sodium, potassium and phosphorus (Amyloidosis Foundation, 2011). Symptoms include bleeding in the skin, fatigue, irregular heartbeat, numbness of extremeties, rash, shortness of breath, swallowing difficulties, swollen arms or legs, swollen tongue and weight loss. Treatment involves treating the coexisting inflammatory disease as well as the dysfunctioning organs. Renal transplantation may be a necessity (Elsevier's Global Clinical Reference, 2012).

Aetiology and Pathogenesis - Molecular Basis of Systemic Amyloidosis

A change in a protein's secondary structure results in a misfolded protein, the amyloid. Amyloids tend to cluster with other amyloids to form fibrils, which accumulate in the interstitium and distort organ function. Factors contributing to this tendency include:

  1. Protein Concentration is pathologically increased e.g. serum amyloid A protein in chronic inflammatory diseases in ESRD.
  2. A protein which has an inherent tendency for misfolding and aggregation e.g. inherited proteins in familial amyloidoses.
  3. A protein which is proteolytically remodeled e.g. cleavage of integral mem­brane protein 2B by furin protease and release of amyloid­ β peptides by secretases.
  4. Age, e.g. wild-type TTR is amyloidogenic and is associated with age­ related amyloid deposition.

The occurrence, timing, extend and effects of amyloid amyloid accumulation are not only dependent on these factors but also on environmental and genetic components. For instance, the amyloidogenic Val30Met variant of TTR exhibits variable patterns in infiltration and clinical features amongst different ethnic groups (Gillmore and Hawkins, 2013).

Amyloid structure. Electron microscopy and X­ray diffraction analyses have shown that amyloid deposits are composed of rigid, nonbranching fibrils with an average dia meter of 7.5–10 nm and a cross­-β-­sheet supersecondary structure (Gillmore and Hawkins, 2013).

Constituents of amyloid deposits. Serum amyloid P­ component (SAP) -a circulating glycoprotein of the pentraxin family- is bound by all types of fibrils through a specific Ca2+ -dependent interaction which fractionally protects the fibrils from proteolysis. Amyloid deposits also typically contain numerous proteoglycans. For instance, heparan sulphate was shown to be involved in formation of amyloid deposits since degradation of heparan sulphate by heparanase inhibits induction of AA. Heparan sulphate hastens the transition of serum amyloid A (SAA) from its native into the amyloidogenic conformation and also accelerates the formation of fibrils by amyloidogenic SAA, TTR, immunoglobulin light chains and amyloid­ β through selective binding to a basic motif. Amyloid deposits also include laminin and type IV collagen (ECM components) as well as chaperone proteins e.g. apolipoprotein E and clusterin (Gillmore and Hawkins, 2013).

Kinetics of fibril formation. Studies in vitro demonstrated that formation of amyloid fibrils proceeds via nucleated growth similar to crystallization. Originally a lag phase occurs in monomeric proteins. A critical nucleus is generated and fibril formation begins and proceeds very fast. Amyloidogenic proteins with a conformation prone to aggregation is incorporated into the growing fibrils. The rate of fibril formation is much faster than the natural clearance of amyloid. Amyloid traces in tissues may remain even after an optimal response to therapy. In case of disease relapse, these residues can rapidly restore amyloid deposits. These in vitro findings are relevant in cases of AA in which control of SAA production and progessive reduction in proteinuria, if followed by a short increase in SAA levels, results in deteriorated renal function (Gillmore and Hawkins, 2013).

Organ tropism. Certain misfoded proteins have a propensity for deposition in certain organs. One example is leuko­cyte chemotactic factor 2­ (ALECT2) deposits in the kidney in AA. Another one is TTR's preference for peripheral nerves in ATTR. The exact mechanism of organ tropism is unclear though factors that contribute may include cellular receptors, pH, local protein concentrations, tissue­-specific glycosaminoglycans, interactions with collagen or specific local proteolytic enzymes (Gillmore and Hawkins, 2013).

Mechanisms of tissue damage. The precise mechanism of tissue damage by amyloid deposits is not fully understood. Some evidence sug­gests potential cytotoxicity of pre-fibrillar oligomeric species, such as TTR, Ig light chains, amyloid ­β protein and prions. Clinical evidence of such cytotoxicity was best observed in cardiac AL; After chemotherapy-induced suppression of amyloidogenic light chains, the serum concentration of a marker of cardiac dysfunction, N ­terminal pro-brain natriuretic peptide (NT­proBNP), may considerably and promptly decrease (Gillmore and Hawkins, 2013).


Systemic amyloidosis is responsible for approximately 1 in 1,500 deaths annually in the UK and seemingly also in other developed coun­tries. Amyloidoses principally manifest mid to late life but typically AA can occur in children too. About 4% of adult renal biopsies reveal renal amyloidosis. The disease develops in ~2% of individuals with monoclonal B ­cell dyscrasias. AA amyloidosis may convolute almost any chronic inflammatory condition and the reported prevalence in patients with chronic arthritides is 3–6%. Incidence of AA is higher in Europe than the USA. Worldwide, AA incidence is gravitating for unknown reasons. Between onset of inflammation and diagnosis of AA, the duration of latency exhibits a median of 17 years. In the UK, the prevalence of hereditary non­-neuropathic amyloidosis, including AFib, apolipoprotein A­I- ­associated and lysozyme-­associated (ALys) amyloidoses, is about 1.5 cases per million (Gillmore and Hawkins, 2013).


(Years from Diagnosis)

Figure 7. Overall survival seen in MayoClinic of patients with Amyloidodis (Gertz, 2013)


Systemic AL amyloidosis. AL treatment depends on age, cardiac staging, and regimen toxicities. Currently, the universally applied treatment regimens for AL include combining: 1. bortezomib, cyclophosphamide and dexamethasone, 2. melphalan and dexamethasone, 3. cyclophosphamide, thalidomide and dexamethasone and 4. lenalidome and dexamethasone (Gillmore and Hawkins, 2013).

Figure 8. A small plasma cell clone produces amyloidogenic light chains which misfold and form amyloid fibrils (A). Inside the plasma cell, increased protein load induces ER stress and rapid elimination of these protein is required to maintain homeostasis. The degradation of these proteins depends on proteasome activity. Bortezomib blocks proteasome degradation of proteins and increases poor quality protein load within ER thus inducing ER stress beyond the capacity of the control mechanisms and resulting in plasma cell apoptosis (B) (Dimopoulos & Kastritis, 2011)

AA amyloidosis. Treatment aims in suppressing the underlying inflammatory disease to the highest possible degree by decreasing production of SAA. SAA concentration is a strong predictor of survival and renal outcome. Completely and incessantly suppressed inflammation achieved together with establishment of normal SAA levels (<4 mg/l) correlates with an 18­-fold lower mortality risk compared to SAA levels ≥155 mg/l. About 40% of patients with AA eventually require renal replacement therapy, with a median time to dialysis from diagnosis of about 6 years (Gillmore and Hawkins, 2013).

Familial amyloidosis. Hereditary non-­neuropathic amyloidosis tends to be "inert" for several decades. In apolipoprotein A­I- ­associated and lysozyme-­associated types, kidney transplantation for ESRD is usually decidedly successful and grafts are functioning for decades. In the case of AFib, amyloid deposits reappear and lead to graft loss after about 7 years. Another possible route is combined hepatorenal transplantation since fibrinogen is syn­thesised exclusively in the liver but this option poses increased mortality risk. ATTR is generally fatal within 5­-15 years. A placebo­-controlled trial in 125 patients with early ­stage ATTR (Val30Met variant of TTR) suggested that tafamidis -a small molecule which converts circulating TTR into its stable conformation- therapy might slow disease progression (Gillmore and Hawkins, 2013).


(Time, Months)

Figure 9. Survival of 55 patients with amyloidosis treated with high dose dexamethasone (Gertz, 2013). Dexamethasone is a glucocorticoid agonist which crosses cell membranes and binds with high affinity to specific cytoplasmic glucocorticoid receptors. The complex binds DNA elements, leading to modification of transcription and protein synthesis to inhibit leukocyte infiltration at the site of inflammation, block mediators of inflammatory response and reduce edema (Drugbank, 2013).


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