Amyloidosis

What is Amyloid?

Amyloid is a proteinaceous material that is deposited in tissues. Like a junkyard full of old cars in a community, amyloid in tissue is the junked end product of some functional protein in the body. Just like the different makes and models of the old cars in the junkyard, the amyloid may have different sources. The end result, like the junkyard, is that the amyloid is non-functional debris that displaces normal structures. Amyloidosis is uncommon, but it tends to affect older adults.

Clinical Findings

Immunologic mechanisms may play a role in the deposition of an abnormal proteinaceous substance, known as amyloid, between the cells of a variety of tissues. Amyloid is defined by histopathologic criteria. It is associated with a number of disease states and patterns of distribution. The most common clinical findings are weight loss, fatigue, renal failure, congestive heart failure, carpal tunnel syndrome, and peripheral neuropathy. The most commonly affected organs are heart, liver, and kidney. The gastrointestinal tract and lung are also commonly involved but generally do not lead to clinical manifestations.

Pathologic Findings

Regardless of the disease state with which it is associated, amyloid appears as a homogenous eosinophilic material between the cells of tissues with H and E stains. What distinguishes it from other pink amorphous "hyaline" deposits is the characteristic staining pattern with Congo red. In histologic sections between 2 and 30 microns in thickness, the Congo red dye will line the amyloid fibrils so that they not only appear reddish-orange by light microscopy, but also will have an "apple-green" birefringence under polarized light. By electron microscopy, amyloid appears as a beta-pleated sheet composed of fibrils ranging from 7.5 to 10 nanometers in width that are non-branching and of indefinite length and are associated with a P component which is donut shaped and pentagonal. The P component is very similar to serum C reactive protein. Staining with thioflavin T will demonstrate amyloid by fluorescence microscopy in the blueviolet range.

Diagnosis of amyloidosis is made by biopsy. Sites with a high (75% or greater) yield include: heart, liver, skin, kidney, small intestine, sural nerve, rectum, and tongue. In addition, aspiration of the abdominal fat pad can be performed. Immunohistochemical staining can be performed to subclassify the amyloid proteins present.

Pathogenesis

Amyloidosis can be subclassified based upon the nature of the proteinaceous material forming the amyloid fibrils and the disease states that coexist with it. Amyloidosis can also be classified as systemic or localized. The amyloid is deposited extracellularly and interferes with organ function as it occupies space and displaces normal cellular constituents. Amyloid is often deposited in vascular walls.

Patterns of Amyloidosis

Immunologic Amyloidosis

This is the most common type of amyloidosis seen in the U.S. The kappa and lambda light chains (Bence Jones proteins) secreted by plasma cells with multiple myeloma can contribute to amyloid formation. The fibrils are of the AL (Amyloid Light chain) type. The amyloid can be deposited in any tissue, though liver, spleen, adrenal, and kidney are common sites of deposition.

Reactive Systemic Amyloidosis

Amyloidosis can be secondary to chronic inflammatory conditions such as tuberculosis, osteomyelitis, bronchiectasis, ulcerative colitis, and chronic skin infections. Malignancies such as Hodgkin's disease and renal cell carcinoma may also give rise to this form of amyloidosis. The fibrils are of the AA (Amyloid Associated) type and are composed of a precursor serum protein known as serum amyloid associated (SAA) protein. The amyloid can be deposited in any tissue.

Heredofamilial Amyloidosis

The best characterized form is familial Mediterranean fever, inherited as an autosomal recessive trait, that is associated with recurrent inflammation of joints and serosal surfaces. The amyloid fibrils are composed of AA protein derived from SAA protein in serum. The distribution of amyloid is widespread in tissues. A variety of familial autosomal dominant conditions lead to amyloidosis, and most have as a precursor protein the prealbumin transthyretin (TTR). Some are associated with progressive peripheral neuropathy, while other forms may be seen affecting kidney, eye, and heart.

Hemodialysis-associated Amyloidosis

Persons on long-term hemodialysis can have amyloidosis due to the retention in serum of beta-2-microglobulin, which forms the amyloid fibrils. Amyloid is mainly deposited in joint tissues.

Localized Amyloidosis

Only a single organ is involved. The deposits of amyloid are nodular. The lungs, larynx, skin, urinary bladder, or tongue may be involved. In some of these cases, infiltrates of plasma cells may be found, and the amyloid is of the AL type. In some endocrine neoplasms, particularly medullary carcinomas of the thyroid gland, the amyloid deposited is derived from polypeptide hormones secreted by the neoplasms. Amyloid may also be identified in the islets of persons with type II diabetes mellitus.

Cardiac Amyloidosis

Amyloid deposition in the heart mainly occurs in association with immunologic (AL) amyloid. A "senile cardiac" form of amyloidosis involving the atria and with fibrils derived from atrial natriuretic peptide is quite common in the elderly but usually asymptomatic. Another more significant variant results in atrial and ventricular amyloid deposition in adults and is derived from serum transthyretin (TTR) protein. This form of amyloidosis can produce an infiltrative (restrictive) cardiomyopathy.

Cerebral Amyloidosis

A cerebral amyloid angiopathy (CAA) may be present in brain either as a rare inherited condition or in association with Alzheimer's disease and with Down syndrome. CAA is promoted via the presence of an abnormal apolipoprotein E (apoE) epsilon 4 allele in Alzheimer's disease. In patients without Alzheimer's disease, the apolipoprotein E (apoE) epsilon 2 allele appears to be implicated. Amyloid derived from beta-amyloid (A4) protein can be present in the cores of the senile plaques or in small arteries with Alzheimer's disease and does not appear to contribute to the pathogenesis of the dementia. CAA may account for 10% of cerebral hemorrhages in the elderly. The lesions are typically located in the cortex, so the hemorrhages are often superficial and may rupture into the subarachnoid space. A familial form of cerebral amyloid angiopathy can occur, though rare. Hereditary cerebral haemorrhage with amyloidosis--Dutch type (HCHWA-D) is an autosomal dominant disorder, caused by a single base mutation in the amyloid beta precursor protein (beta PP) gene located on chromosome 21, resulting in recurrent haemorrhagic strokes and dementia.

Images of amyloidosis below have file sizes ranging from 40 to 250k.

1. Spleen, amyloidosis, gross.
2. Kidney, amyloidosis, gross.
3. Kidney, amyloidosis, H&E, microscopic.
4. Adrenal, amyloidosis, Congo red, microscopic.
5. Adrenal, amyloidosis, Congo red, polarized, microscopic.
6. Thyroid, medullary carcinoma, amyloid, H&E microscopic.
7. Thyroid, medullary carcinoma, amyloid with Congo red stain, microscopic.
8. Heart, amyloidosis, H&E, microscopic.
9. Heart, amyloidosis, Congo red, polarized, microscopic.
10. Islet of Langerhans, amyloid deposition with type II diabetes mellitus, H&E microscopic.
11. Cerebrum, Alzheimer's disease with amyloid core in plaque, Congo red stain, microscopic.
12. Cerebrum, amyloid angiopathy, Congo red stain, microscopic.
13. Amyloid, electron micrograph.
14. Amyloid, antibody to lambda light chain, immunofluorescence.

References

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2. Drueke T, Touam M, Zingraff J. Dialysis-associated amyloidosis. Adv Ren Replace Ther. 1995;2:24-39.

3. Hesse A, Altland K, Linke RP, et al. Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant. Br Heart J. 1993;70:111-115.

4. Hoshii Y, Takahashi M, Ishihara T, Uchino F. Immunohistochemical classification of 140 autopsy cases with systemic amyloidosis. Pathol Int. 1994;44:352-358.

5. Itoh Y, Yamada M. Cerebral amyloid angiopathy in the elderly: the clinicopathological features, pathogenesis, and risk factors. J Med Dent Sci 1997;44:11-9.

6. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995;32:45-59.

7. Liepnieks JJ, Kluve-Beckerman B, Benson MD. Characterization of amyloid A protein in human secondary amyloidosis: the predominant deposition of serum amyloid A1. Biochim Biophys Acta. 1995;1270:81-86.

8. Maury CP. Molecular pathogenesis of beta-amyloidosis in Alzheimer's disease and other cerebral amyloidoses. Lab Invest. 1995;72:4-16.

9. Premkumar DR, Cohen DL, Hedera P, Friedland RP, Kalaria RN. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am J Pathol 1996;148:2083-95.

10. Stone MJ. Amyloidosis: a final common pathway for protein deposition in tissues. Blood. 1990;75:531-545.

11. Varga J, Wohlgethan JR. The clinical and biochemical spectrum of hereditary amyloidosis. Semin Arthritis Rheum. 1988;18:14-28.