Amyloidosis describes a heterogeneous group of diseases, all characterized by the extracellular deposition of fibrillar, proteinaceous material in organs and tissues, either locally or systemically. The following four major classes of systemic amyloidosis are differentiated by the nature of the precursor plasma proteins that form the fibril deposits:

• Immunoglobulin light chain or "primary" amyloidosis (AL) (associated with monoclonal plasma cell dyscrasias; the most common form of systemic amyloidosis; also known as primary idiopathic amyloidosis)
• Reactive or secondary amyloidosis (AA) (associated with chronic inflammatory disease)
• Hereditary amyloidosis (an autosomal dominant group of diseases, each associated with gene mutations producing different proteins)
• Beta₂-microglobulin amyloidosis (associated with long-term dialysis for chronic renal failure)

Localized amyloid deposits are restricted to specific tissues in certain diseases. These include:

• Polypeptide hormone-derived amyloidosis (seen in over 90% of type II diabetes mellitus patients; also seen in the case of medullary carcinoma of the thyroid and other endocrine tumors; approximately 80% of adults over age 80 have this type of deposition in the sarcolemma)
• Amyloidosis associated with Alzheimer's disease and Down's syndrome as well as hereditary cerebral hemorrhage with amyloidosis (all caused by a beta-amyloid protein, betaAP)
• Diseases caused by scrapie-associated prion proteins (Creutzfeldt–Jakob disease, kuru, and Gerstmann–Straussler syndrome)

Isolated deposits may be seen in any organ or tissue site.

The common pathogenesis in all forms of amyloidosis is the production of amyloid fibrils and their deposition in the extracellular matrix. However, the process by which precursor proteins produce fibrils is multifactorial and differs among the various types of amyloid. Sixteen biochemically diverse proteins have been identified as fibrillar constituents of amyloid deposits. Amino-acid mutations of the precursor molecules may play a role in destabilizing proteins in both AL and ATTR amyloidosis, in the presence of local physical and chemical forces. (ATTR is a hereditary protein mutation; see section entitled Risk Factors below.) In addition, because of the age-related nature of the disease, there may be an age-related trigger involved in oxidation and free radical production. In vivo precipitation of amyloid fibrils by "seeding" suggests that amyloid deposition is a self-perpetuating process. Dysfunction of the immune system, particularly macrophage function, favors amyloid formation. The cause of associated diseases should also be taken into consideration and may be of therapeutic significance.

The role of dietary factors in the pathogenesis of amyloidosis may be important. An agent called amyloid enhancing factor (or AEF), for example, has been extracted from mammalian tissues and tested in animal models; see section entitled Nutrition, subsection Meat Products below. The role of AEF in promoting amyloidogenesis in humans needs further investigation.

• Male gender. In AL amyloidosis, males are more highly represented (60% to 65%) than women (35% to 40%) in referred groups.
• Age over 50 years. Amyloidosis is generally diagnosed in older individuals. However, cases in younger adults and children are seen, usually in association with inflammatory conditions, e.g., juvenile rheumatoid arthritis. Even in hereditary protein mutations, clinically significant amyloid deposits are not detected until later in life and are rapidly progressive at that time.
• Plasma cell dyscrasias (e.g., multiple myeloma, malignant lymphoma, benign monoclonal gammopathy, Waldenström's macroglobulinemia)
• Chronic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, ankylosing spondylitis) are associated with AA
• Long-term dialysis. Almost all patients with end-stage renal disease who are maintained on hemodialysis for more than 5 years develop amyloid deposits composed of beta₂-microglobulin.
• Hereditary mutations of proteins: transthyretin (ATTR—the most common form), apolipoprotein A1, gelsolin, fibrinogen A alpha, lysozyme, and cystatin C
• Long-term infections such as leprosy, tuberculosis, or osteomyelitis may be the inciting condition for AA.

Clinical presentation depends on the location and extent of the amyloid deposits.

AL amyloidosis manifestations are protean as any tissue may be involved and include:

• Restrictive cardiomyopathy with right ventricular failure; arrhythmias due to involvement of the conduction system
• Abnormal voltage and MI pattern on EKG (heart disease is the most common cause of death); proteinuria and the nephrotic syndrome, leading to renal failure
• Gastrointestinal disturbances of motility disturbances (often secondary to autonomic neuropathy), perforation, hemorrhage, and obstruction
• Hepatomegaly
• Hyposplenism
• Hypoadrenalism and other endocrine deficiencies
• Peripheral neuropathy
• Autonomic neuropathy leading to orthostatic hypotension, impotence, and GI dysfunction
• Carpal tunnel syndrome
• Skin disorders (papules, nodules, plaques, purpura resulting in "raccoon eyes," easy bruising)
• Macroglossia (pathognomonic) with or without submandibular swelling and respiratory obstruction as well as sleep apnea
• Pulmonary involvement occurs and may be localized and mild or diffuse and more severe
• Articular amyloid deposits ("shoulder pad" sign)
• Serious acquired bleeding diatheses
• Most patients die of heart failure, uremia or other complications within one year of diagnosis

Hereditary (ATTR) amyloidosis presents a clinical picture which differs from the AL form, but enough overlap occurs to make clinical differentiation inaccurate. The manifestations tend to be the same for each mutation and include:

• Peripheral and autonomic neuropathies predominate
• Renal disease is less prevalent
• Macroglossia does not occur
• Gastrointestinal dysfunction (diarrhea, weight loss) may be prominent and reflects autonomic dysfunction
• Cardiac disease manifestations vary with the mutation and are either conduction defects (e.g., sinus node dysfunction, bundle-branch block, atrioventricular block, heart failure) or involve infiltration of the myocardium that is indistinguishable from AL disease. The transthyretin Met 30 variant often requires pacing.

AA amyloidosis generally presents with renal disease, including proteinuria or frank nephrotic syndrome leading to renal failure (the cause of death in 40% to 60%). Hepatomegaly and splenomegaly are also common. Cardiac involvement is rare and less severe. Associated inflammatory disease has usually been present for a decade or more.

Beta₂-microglobulin amyloidosis is usually seen with end-stage renal disease requiring chronic hemodialysis, but can be seen with ambulatory peritoneal dialysis. Deposits are frequently osteoarticular and associated with carpal tunnel syndrome, large joint pain and stiffness, soft tissue masses, bone cysts, and pathologic fractures.

Amyloidosis may mimic a variety of chronic systemic or localized diseases in all organ systems. Unfortunately, it is either an incidental finding at autopsy, diagnosed histologically in its late stages, or misdiagnosed. Because of the recent advances in understanding of pathophysiology and in treatment strategies, increased effort is required for early detection and differentiation of the underlying causes. Amyloidosis has an incidence similar to that of Hodgkin's disease and chronic granulocytic leukemia. The diagnosis should be considered in any patient with unexplained nephrotic-range proteinuria, heart failure, peripheral neuropathy, or hepatomegaly, especially in the presence of a monoclonal protein.

The physician should be alert to the clinical features of systemic amyloidosis, particularly when patients present with multisystem abnormalities. Signs of heart and/or renal failure, arrhythmias, hepatosplenomegaly, macroglossia, and peripheral and autonomic neuropathies should alert the physician to consider the diagnosis.

• All amyloid deposits contain the serum amyloid P component (SAP), a pentagonally structured plasma protein (pentraxin), which is used for diagnostic and prognostic purposes.
• AL amyloidosis: The subunit or precursor protein derived from either the lambda (most commonly) or kappa light chain is formed from the immunoglobulin of a monoclonal plasma cell dyscrasia.
• AA amyloidosis: The subunit protein AA is the degradation product of serum amyloid A (SAA); SAA protein levels rise in response to inflammatory processes; this response is thought to be controlled by interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF), and other cytokines; there are multiple forms of SAA which are all apolipoproteins and become part of the HDL fraction in plasma; when SAA production is elevated, the apolipoprotein may compete with the binding of HDL.
• Hereditary amyloidosis: Genes coding for normal plasma proteins such as transthyretin (commonest), apolipoprotein A1, gelsolin, fibrinogen A alpha, lysozyme, and cystatin C are mutated, producing precursor proteins.
• Beta₂-microglobulin amyloidosis: Excess beta₂-microglobulin, the light chain portion of the major histocompatibility complex (MHC) class I molecules not removed by kidney dialysis, is incorporated into amyloid fibrils and deposited in articular structures.

• Congo red staining of biopsy tissues (abdominal fat pad, rectal mucosa, or affected organs) and observation of classic yellow/green birefringence on polarized microscopy—to make the diagnosis. This test will be positive in 85% of patients with AL amyloidosis.
• Immunofixation electrophoresis of serum or urine—to detect monoclonal immunoglobulins or light chains (in 90% of AL amyloidosis)
• Bone marrow immunohistochemical staining or other cellular studies that use labeled antibodies specific for human light chains
• DNA testing with polymerase chain reaction and restriction fragment length polymorphism analysis—to determine the specific protein mutation in hereditary amyloidosis

• Electron microscopy—to distinguish the structure of amyloid fibrils
• X-ray diffraction studies—to distinguish the beta-pleated sheet structure of amyloid fibrils

• Echocardiography—to determine ventricular wall thickness and ventricular function changes due to amyloid deposits
• Quantitative scintigraphy with iodine 123 (serial labeled SAP)—to diagnose and assess progression or regression of disease
• Electrocardiography—to determine the typical amyloid pattern (i.e., healed myocardial infarction [83%] and low voltage [63%]). Misdiagnosis can occur with the presence of healed MI pattern.
• Miscellaneous testing to access other organ involvement, e.g., urine and renal function tests and GI motility studies

Therapy is supportive except in selected patients. Treatment involves the reduction of subunit proteins that act as precursors of amyloid fibrils. Chemotherapy is the current treatment for AL amyloidosis. There is no treatment for AA amyloidosis except to treat the inflammatory condition. Renal transplantation to remove excess beta₂-microglobulin may cure dialysis-related amyloidosis. Liver transplantation to lower transthyretin levels is the current treatment for hereditary amyloidosis.

• Melphalan and prednisone with or without colchicine, or alternatively, cyclophosphamide and prednisone, have been used in combination to treat multiple myeloma and AL amyloidosis in selected cases. These combinations, while effective for multiple myeloma, increase morbidity and mortality in patients with amyloidosis and have not been shown to increase survival.
• Colchicine alone has been used effectively to prevent AA amyloidosis in patients with familial Mediterranean fever.
• Other experimental protocols are underway including evaluation of new dialysis systems and placement of antioxidants in dialysate.

Supportive therapy includes:

• Diuretics—to treat nephrotic syndrome and congestive heart failure
• Antiarrhythmics—to treat cardiac arrhythmias
• Metoclopramide—to speed delayed gastric emptying
• Antibiotics—to relieve diarrhea and malabsorption related to bacterial overgrowth

Transplantation surgery may be necessary for different organs:

• Kidneys—to return beta2-microglobulin levels to normal and to treat renal failure
• Liver—to eliminate mutant serum transthyretin
• Heart—to treat heart failure
• Bone marrow—autologous stem cell bone marrow transplantation with high dose chemotherapy can result in improvement in AL amyloidosis patients, but toxicity is high owing to impaired organ function.

Other surgical procedures may be necessary as well:

• Splenectomy—to correct bleeding episodes associated with splenic amyloid
• Carpal tunnel surgery—to relieve symptoms of carpal tunnel syndrome
• Total hip arthroplasty—to correct destruction of femoral head from articular deposits
• Cardiac pacemakers—to treat conducting system disease
• Stabilization of the spine when beta₂-microglobulin amyloidosis causes vertebral collapse

Other Procedures

• Hemodialysis and peritoneal dialysis—to prolong survival with renal failure
• High-flux biocompatible dialysis membranes could be used to delay dialysis-related amyloidosis development.

The idea of an anti-inflammatory dietary regimen, as well as supplements and herbal remedies to help decrease inflammation makes at least theoretical sense for primary and secondary prevention of amyloidosis. Oxidative stress is thought to be related to the pathogenesis of disease processes which develop from hemodialysis for end stage renal disease, including atherosclerosis, anemia, and amyloidosis. Several factors may contribute to reduction of antioxidant defense mechanisms in this clinical situation, including:

• Pro-oxidant state of uremia
• Inflammatory stimulus of hemodialysis leading to increased production of free radicals
• Loss of hydrophilic compounds such as vitamin C and trace elements that may have otherwise conferred some antioxidative protection.

All of these factors may contribute to the particular risk of patients on hemodialysis to develop amyloidosis. There are current investigations to determine whether changes in the dialysis system or addition of antioxidants to the dialysate may slow the development of amyloidosis (Morena et al. 2000).

Also supporting the idea that free radical formation contributes to the development of amyloidosis is the fact that amyloidosis is a disease of aging; age-related susceptibility to disease is typically associated with accumulated free radical damage. Moreover, animal studies support that dietary manipulations to decrease inflammation and provide antioxidants do in fact reduce development of amyloidosis (Harman 1982).

Although it is difficult to draw conclusions for humans, some animal studies suggest that appropriate dietary measures may ultimately prove beneficial for high-risk individuals to prevent development of amyloidosis or to slow progression of known disease. These measures may include:

• Avoiding meat products, particularly if contamination is suspected
• Fish oil supplementation
• Vitamin C supplementation
• Proteolytic enzymes

More detail follows on each of these measures for possible recommendations in the case of amyloidosis.

Some general recommendations for an anti-inflammatory diet include:

• Avoiding meat, processed foods, caffeine, food additives, dairy, and refined sugars.
• Increasing intake of whole grains, and fresh fruits and vegetables, which are good sources of flavonoids, carotenoids and other antioxidants.
• Increasing intake of nuts, seeds, and cold-water fish, which all contain anti-inflammatory oils

Meat Products:

As scientific studies have begun accumulating evidence about the dietary link between bovine spongiform encephalopathy (BSE) and the development of prion protein amyloidosis in humans, the identification of a possible transmissible agent in other amyloid diseases has become increasingly important. Researchers speculate that dietary amyloid enchancing factor (AEF) (derived from a cytokine or other molecule from diseased tissues of ingested animal foods) may enhance the development of amyloid disease in humans, especially when combined with chronic inflammation and up-regulated proteoglycan metabolism. AEF is a poorly defined constituent of mammalian tissues that can induce rapid amyloid deposition in mice following oral ingestion (Elliott-Bryant and Cathcart 1998). Proteoglycan binding to apolipoprotein serum amyloid A (apoSAA) is hypothesized to inhibit the catabolism of apoSAA at its N-terminal region, thus preserving its amyloidogenic potential (see section entitled Pathology/Pathophysiology) (Cathcart and Elliott-Bryant 1999).

Polyunsaturated Fatty Acids:

Fish oil has been shown to modulate inflammation in chronic inflammatory conditions such as rheumatoid arthritis. Fish oil is high in the omega-3 fatty acid eicosapentaenoic acid (EPA), precursor to the 3 series of prostaglandins and 5 series of leukotrienes. In one animal study investigating the effect of intake of oils of differing amounts of polyunsaturated fatty acids (PUFAs), mice receiving fish oil compared to either corn or coconut oil prior to induction of amyloidosis had the following beneficial results:

• The livers of the fish oil group showed decreased incidence and severity of amyloid deposits compared to those of the group fed coconut oil.
• Spleens in the fish oil group revealed significantly less amyloid deposition than spleens in both the corn and coconut oil groups.
• Macrophages of the fish oil group contained EPA and a decreased percentage of linoleic and arachidonic acids relative to the other two groups and they produced significantly less series 1 prostaglandins and thromboxane compared to those from the other groups.

The authors suggest that EPA in fish oil may inhibit amyloidosis by altering membrane fluidity and levels of prostaglandins and leukotrienes. As a consequence of these alterations, fish oil may activate specific proteases involved in serum amyloid A catabolism. Alternatively, the fish oil diet may reduce the severity of amyloidosis by decreasing production of SAA (Cathcart et al. 1987).

Vitamin C:

It is possible that vitamin C may play a role in restoring amyloid-degrading activity and inhibiting the progression of amyloidosis. In one controlled study examining mouse tissue, treatment of the amyloidotic mice with ascorbic acid prior to sacrifice and evaluation of their spleens demonstrated benefits by markedly enhancing amyloid degradation and reducing amyloid deposition (Ravid et al. 1985).

This study refutes an earlier series of mouse experiments in which ascorbic acid did not impact the induction, the extent and distribution, or the progression of amyloidosis (Baltz et al. 1984). More human studies are needed prior to drawing clear conclusions abut the possible benefit of vitamin C for prevention of progression of amyloidosis and even regression; some experts have reported a possible therapeutic value of vitamin C from human in vitro trials (Ravid et al. 1985).

Proteolytic Enzymes:

Proteolytic enzymes, such as bromelain derived from pineapple, have demonstrated promising results in degrading amyloid fibrils. For example, in vitro studies suggest protection from amyloid deposits in kidney tissue from bromelain (Adachi et al. 1988).

Bromelain is thought to have the following actions (Taussig and Batkin 1988):

• Anti-inflammatory; bromelain has been used for this purpose for many years
• Inhibition of the growth of malignant cells
• Inhibition of platelet aggregation
• Promotion of fibrinolysis (Taussig and Batkin 1988).

Glutathione:

Beta₂-microglobulin production in dialysis-related amyloidosis was significantly correlated with decrease in glutathione in the RBCs of a small group of patients on hemodialysis (Lins et al. 1989). Some naturopathic and other practitioners recommend glutathione as a dietary supplement for amyloidosis at a dose of 500 mg bid to tid, although there is no proven benefit of its use for this specific condition.

Vitamin E:

While some animal studies have demonstrated promising nutritional treatments, these results have not always been replicated in human trials. One such paper reports that although vitamin E inhibited the development of amyloidosis in a mouse model, a Phase II clinical trial of 16 patients with established amyloidosis did not show any signs of regression of their disease when supplemented with vitamin E, thus emphasizing that in vitro and animal studies do not necessarily translate to positive benefits for humans and that the approach for primary prevention does not necessarily translate into a treatment modality for amyloidosis or any other condition (Gertz and Kyle 1990).

Flavonoids are a class of plant-derived compounds that have shown antioxidant and anti-inflammatory activities.

Pycnogenol:

Pycnogenol, extracted from the bark of French maritime pine (Pinus maritima), is rich in flavonoids and is composed of approximately 85% procyanidins.

In one study of the effects of pycnogenol, bovine pulmonary artery endothelial cells were incubated with beta-amyloid peptide (betaAP) for 24 hours and later evaluated for lactate dehydrogenase (LDH) release and lipid peroxidation. (BetaAP is a component of senile plaques and vascular amyloid deposits found in Alzheimer's disease – see section entitled Overview.) Endothelial cells preincubated with pycnogenol before being exposed to betaAP had the following benefits compared to cells not preincubated with pycnogenol:

• Protection from betaAP-induced damage
• Inhibition of LDH release in a dose-dependent manner
• Significant reduction of lipid peroxidation

The increased antioxidant activity and protection from free radical damage seen with pycnogenol may be mediated, in part, by a rise in glutathione levels (Liu et al. 2000). (Please see Nutrition section for more information regarding glutathione.)

Ginkgo biloba:

Flavonoids are also present in Gingko biloba extract (GBE), as are terpenoids. GBE has been compared favorably to cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and metrifonate) for the treatment of Alzheimer's disease (Wettstein 2000). Given the connection between Alzheimer's and amyloid deposition (see Overview section) in which accumulation of betaAP contributes to the etiology or progression of Alzheimer's disease, the question has been raised of a possible beneficial impact from GBE on amyloidosis as well. An in vitro trial suggests GBE protection of hippocampal cells against the toxic effects of betaAP by blocking accumulation of reactive oxygen species and cell death (Bastianetto et al. 2000).

After diagnosis, the level of subunit protein precursors (e.g., SAA in patients with reactive amyloidosis) should be monitored and attempts made to keep values near normal. In addition, the development of radiolabeled serum amyloid P component (SAP) scintigraphy has provided insight into the distribution and size of amyloid deposits and yielded information on the natural history and the effects of treatment of amyloid disorders.

Genetic counseling may help families affected by hereditary amyloidosis make responsible reproductive decisions.

Patients with cardiac amyloidosis are extremely sensitive to:

• Digoxin, which may result in fatal arrhythmias
• Calcium channel blockers, which may exacerbate congestive heart failure
• Diuretics and vasodilators, which may cause life-threatening hypotension.

Survival for AL is generally 1 to 2 years following diagnosis; 5-year survival is 20%.

With AA amyloidosis, survival is 5 to 10 years after initial clinical presentation, depending on successful treatment of the underlying inflammatory condition.

In hereditary amyloidosis the prognosis varies with the specific protein mutation and the time of diagnosis. Patients with this disorder may survive as long as 15 years following development of disease. Transthyretin mutations associated with younger age at diagnosis (20-30 years) involve more rapidly progressive disease and shorter survival.

Renal transplantation will arrest beta₂-microglobulin amyloidosis, but most patients are poor candidates for surgery.

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