Peripheral Nerve Amyloidosis

Peripheral nerve amyloidosis is the cardinal feature of familial amyloid polyneuropathy (FAP) but can also be seen in primary light chain (AL) amyloidosis and dialysis (β₂-microglobulin) related amyloidosis. The generalized neuropathy seen in all forms of peripheral nerve amyloidosis is similar, characterized by a severe progressive mixed neuropathy with autonomic dysfunction. Pathologically, amyloid is found in the peripheral nervous system as amorphous, eosinophilic, extracellular deposits. FAP is most commonly associated with variant plasma transthyretin (TTR), although it has also been described in association with mutant apolipoprotein A-1 and gelsolin. There are now at least 36 point mutations in the TTR gene associated with FAP and these continue to be described. Recent studies on the possible role individual point mutations in the TTR gene may play in amyloidosis have helped give us an insight into the mechanisms behind peripheral nerve amyloidosis. This article reviews the clinical and pathological features of the peripheral nerve amyloidosis and discusses theories of amyloidogenesis based on studies of FAP.     

PERIPHERAL AND AUTONOMIC NERVE LESIONS IN SYSTEMIC AMYLOIDOSIS Three Pathological Types of Amyloid Polyneuropathy

Twenty autopsy cases of systemic amyloidosis, consisting of 10 cases of primary systemic amyloidosis, 6 cases of myeloma-associated amyloidosis, 2 cases of secondary amyloidosis, and 2 cases of hereditary amyloidosis, were studied clinically and pathologically with special reference to peripheral and autonomic neuropathy. The peripheral nerves of 8 cases with clinical manifestations of polyneuropathy showed deposition of amyloid in the endoneurium, capillaries within the nerve fascicles, perineurium, and epineurium with a loss and degeneration of the nerve fibers. In the peripheral nerve lesions of these cases, there appeared to be three types: I. Endoneurial deposition of amyloid— loss of unmyelinated and small myelinated fibers, 11. vessel wall deposition of amyloid in the vasa nervorum — loss of large myelinated fibers; and III. aixed type of I and II. While the peripheral nerves of 12 cases without neuropathy mainly showed deposition of amyloid in the epineurium and perineurium with well preserved nerve fibers. The possibility was considered that the pathogenesis and variety of peripheral and autonomic nerve lesions might be related to the various molecular features of amyloid proteins or their precursors in systemic amyloidosis. ACTA PATHOL. JPN. 34 : 1251–1266, 1984.     

Familial Amyloidosis A Histopathological Study

Four autopsy cases of familial amyloidosis were reported. The ages of the patients ranged from 37 to 51 years consisting of 3 males and 1 female. They all complained of neurological symptoms. Histologically, amyloid deposition in familial amyloidosis was different in site and grade from that of other types of amyloidosis, showing heavy deposition in nervous and endocrine system but no differences were found referring to deposition in other tissues. Electronmicroscopically, the peripheral nervous tissue was examined and amyloid fibrils were found to be deposited massively in interstices of nerve fiber.     

Familial amyloidosis. A histopathological study

Four autopsy cases of familial amyloidosis were reported. The ages of the patients ranged from 37 to 51 years consisting of 3 males and 1 female. They all complained of neurological symptoms. Histologically, amyloid deposition in familial amyloidosis was different in site and grade from that of other types of amyloidosis, showing heavy deposition in nervous and endocrine system but no differences were found referring to deposition in other tissues. Electronmicroscopically, the peripheral nervous tissue was examined and amyloid fibrils were found to be deposited massively in interstices of nerve fiber.     

Transthyretin Amyloid Goiter in a Renal Allograft Recipient

Amyloid deposition in the follicular, perifollicular blood vessels, and thyroid stroma can occur in systemic forms of amyloidosis, although diffuse enlargement of the thyroid is generally not present. Marked, widespread enlargement of the thyroid gland with amyloid deposits or amyloid goiter is a rare condition reported in association with primary and secondary amyloidosis but has not been described in association with transthyretin amyloid deposition. Senile transthyretin amyloidosis is primarily associated with amyloid deposits in the heart, while the familial forms of amyloidosis due to transthyretin gene mutations are associated with deposits of amyloid in multiple tissues, classically giving rise to polyneuropathy. In this report, we describe the findings of parathyroid and lymph node amyloid deposits and amyloid goiter with transthyretin reactivity in a recipient of a kidney allograft, reportedly for renal amyloidosis, initially assumed clinically to be due to inflammatory bowel disease-related secondary amyloid deposition. This case underscores the importance of routine immunohistochemical classification of amyloid deposits for accurate diagnosis and to guide clinical management decisions.     

Relationship between amyloid deposition and intracellular structural changes in familial amyloidotic polyneuropathy

Transthyretin-related familial amyloidotic polyneuropathy is a systemic amyloidosis caused by mutations in the transthyretin gene. Extracellular deposition of amyloid is the common pathologic hallmark of amyloidoses including Alzheimer disease, AL amyloidosis, AA amyloidosis, and familial amyloidotic polyneuropathy. However, the exact relationship between amyloid deposition and cell death has not yet been clarified. To elucidate this relationship, we studied the effect of transthyretin amyloid fibrils and prefibrillar aggregates on cells by using autopsy tissues obtained from 8 patients with familial amyloidotic polyneuropathy, as well as cultured cell lines. Ultrastructural studies of amyloid-laden cardiomyocytes showed that intracellular structural changes correlated with the degree of amyloid deposition and may reflect metabolic disturbances caused by physical limitations imposed by the amyloid deposits. Amyloid-laden vascular endothelial cells, mesangial cells, smooth muscle cells, Schwann cells, and cardiomyocytes, however, had well-preserved cell nuclei and showed no apoptotic changes, even when cells were completely surrounded by prefibrillar transthyretin aggregates and amyloid fibrils. Synthesized prefibrillar transthyretin aggregates, transthyretin fibrils, and amyloid fibrils obtained from patients with familial amyloidotic polyneuropathy evidenced no cytotoxicity in cell culture experiments. Our data thus indicate that neither transthyretin amyloid fibrils nor prefibrillar transthyretin aggregates directly induced apoptosis. However, cellular metabolic disturbances caused by cells' being physically confined by amyloid deposits may induce cell degeneration.     

Clinicopathological importance of deposits of amyloid in the femoral head.

The pattern of amyloid deposits in the femoral head is described in four cases, two of which had deposits of amyloid related to age and two of which had generalised systemic amyloidosis (one of primary amyloidosis, one of multiple myeloma). The deposition of amyloid in the articular cartilage of the femoral head was similar in all four cases. Heavy deposits of synovial amyloid were identified in the case with primary amyloidosis and in one of the cases with amyloidosis related to age. Both cases of generalised systemic amyloidosis showed abundant deposits of amyloid in the bone marrow. Amyloid was not present in the bone marrow of either case with amyloidosis related to age. The importance of these findings is discussed in relation to the pathogenesis of the arthropathy syndrome of a rheumatoid type described in cases of primary amyloidosis and multiple myeloma.     

Late onset type I familial amyloidotic polyneuropathy: Presentation of three autopsy cases in comparison with 19 autopsy cases of the ordinary type

Clinicopathological features of three autopsy cases of extremely rare late onset type I familial amyloldotic polyneuropathy were presented and compared with 19 autopsy cases of the ordinary type. In the late onset cases, the ages at onset and at death were 27.5 and 24.5 years older, respectively, compared with the ordinary type. Also, duration of the total clinical course form onset to death was 3.7 years less than in the late onset cases. The degree of amyloid deposition was more marked in the heart of the late onset cases, causing prominent cardiac hypertrophy. It was also marked In the kidneys or thyroid of two cases, but slight to moderate in the peripheral or autonomic nervous tissues in all cases. Immunohistochemical Investigation demonstrated the presence of transthyretin (TTR) as an amyloid precursor protein and of serum amyloid P-component in amyloid deposits in various organs and tissues of the late onset type. These findings, as well as serum levels of variant TTR, were similar to those of the ordinary type. These results suggest that there are some factors other than the amyloid precursor protein that effect the degree of amyloid deposition.     

Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene. Pathologic similarity to human familial amyloidotic polyneuropathy, type I.

To analyze the pathologic processes of amyloid deposition in type I familial amyloidotic polyneuropathy (FAP), mice were made transgenic by introducing the human mutant transthyretin (TTR) gene. In these transgenic mice, amyloid deposition started in the gastrointestinal tract, cardiovascular system, and kidneys 6 months after birth and extended to various other organs and tissues with advancing age. At age 24 months, the pattern of amyloid deposition was similar to that observed in human autopsy cases of FAP, except for its absence in the choroid plexus and in the peripheral and autonomic nervous systems. Amyloid deposition was shown to be composed of human mutant TTR and, in addition, mouse serum amyloid P component. These results clearly indicate that human variant TTR produced in transgenic mice deposits is a major component of amyloid fibrils in various organs and tissues. Thus this animal model is useful for analyzing how amyloid deposition initiates and proceeds in FAP.     

Tissue distribution of amyloid deposits in Abyssinian cats with familial amyloidosis

The tissue distribution of amyloid deposits was studied in 15 related Abyssinian cats with familial amyloidosis. There was interstitial medullary amyloidosis in the kidneys of all 15 cats but only 11 had detectable glomerular involvement. The thyroid glands, stomach and colon were affected in all cats examined. Most of the cats also had amyloid deposits in the small intestine, spleen, heart, adrenals, pancreas, liver, lymph nodes and bladder. In 50 per cent or fewer of the cats examined, there was involvement of the parathyroids, lung and gonads. The central nervous system was not involved in any of the 3 cats evaluated. In 8 of the cats, no concurrent inflammatory disease could be detected. The tissue distribution of amyloid deposits resembled that found in other breeds of domestic cats with systemic amyloidosis. Despite the wide tissue distribution of amyloid deposits, clinical signs were related to renal amyloidosis. Familial amyloidosis in the Abyssinian cat may represent a valuable spontaneous animal model for the study of Familial Mediterranean Fever in man and the pathogenesis of reactive amyloidosis in general.     

Beta-protein amyloid is widely distributed in the central nervous system of patients with Alzheimer''s disease.

To clarify the distribution, morphology, and density of amyloid deposits in patients with Alzheimer's disease (AD), tissue sections from various areas of the central nervous system of 14 patients with AD and from 20 nondemented aged controls were investigated immunohistochemically using anti-beta protein antiserum. beta-protein amyloid deposits were present not only in the cores of the senile plaques and in the vascular wall (amyloid angiopathy), but also in various sized plaque-shaped fibrillary, perivascular, subpial, and subependymal deposits. Amyloid deposits were found mainly in the cerebral cortex in nondemented controls, while in AD they were distributed widely in the regions that were not affected in nondemented controls. The positivity of amyloid deposits in AD was 100% in the cerebral cortex, hippocampus, amygdala, thalamus, caudate nucleus, claustrum, hypothalamus, nucleus basalis of Meynert, and cerebellar cortex. Putamen and brain-stem nuclei were affected frequently, and the spinal cord, dentate nucleus, and globus pallidus were sometimes (less than 50%) affected. This result provides an evidence that Alzheimer's disease is a beta-protein amyloidosis of the central nervous system. An assessment of the distribution of amyloid deposits should prove to be useful for the histopathologic diagnosis of AD.     

Induction in mice of human light-chain-associated amyloidosis.

Primary (idiopathic) or multiple myeloma-associated amyloidosis is characterized by the deposition in tissue of monoclonal light chains or light-chain fragments (AL amyloidosis). In contrast to other types of amyloidosis, information regarding the pathogenesis of light-chain-related amyloid has heretofore been limited due to the lack of a suitable in vivo model. The authors report the successful experimental induction of human AL amyloid deposits. The repeated injection into mice of Bence Jones proteins obtained from two patients with AL amyloidosis produced the histopathologic lesions characteristic of this disease. Partial dehydration of animals before protein injection resulted in the acceleration of amyloid formation. The human proteins were deposited as amyloid within the mouse renal blood vessel walls and parenchymal tissue, as well as in other organs. The deposits were Congo red-positive, exhibited green birefringence, and had a fibrillar ultrastructure. As evidenced immunohistochemically, the experimentally induced amyloid deposits consisted of the injected human light chains, and in addition, contained mouse amyloid P component (AP); mouse immunoglobulin (Ig) or inflammatory-associated amyloid A protein was not detected. Extraction and characterization of the amyloid deposits found within the mouse kidney revealed the presence of a predominantly intact human light polypeptide chain. Mice injected in identical manner with a non-amyloid-associated Bence Jones protein had no or only rare amyloid deposits. The experimental mouse model provides a means to ascertain the amyloidogenic potential of human monoclonal light chains and to study further the pathogenesis of AL amyloidosis.     

Alpha 1-antichymotrypsin is associated solely with amyloid deposits containing the beta-protein. Amyloid and cell localization of alpha 1-antichymotrypsin

Our recent studies demonstrated that alpha 1-antichymotrypsin (ACT), a serine protease inhibitor, was associated with the beta-protein in the brain amyloid deposits of Alzheimer's disease, aged human controls and aged monkeys, suggesting a role for the inhibitor in the amyloid deposition. In the present study we used immunohistochemistry to test for the presence of ACT in the amyloid deposits which contain, as their major component, a protein different from the beta-protein. ACT was not found in the amyloid deposits in primary or secondary amyloidosis, familial and amyloidotic polyneuropathy or Creutzfeldt-Jakob disease (non-beta-protein amyloidoses), but was found (together with beta-protein) in Alzheimer's disease, Down's syndrome, normal aging, and hereditary cerebral hemorrhage with amyloidosis of Dutch origin. These results suggest a specific association of ACT with beta-protein amyloid. We next examined the distribution of the inhibitor in normal human brain and in various human neuropathological states in order to identify cells that express this protein during brain degeneration. In addition to its association with amyloid, ACT immunoreactivity was also located in astrocytes near areas of neuronal or tissue loss, in a few neurons and pericytes and in the epithelium of the choroid plexus.     

Diagnosis and treatment in systemic amyloidosis

Systemic amyloidosis is characterized by the involvement of multiple organs and the presence of an amyloid precursor protein in serum. This disorder is classified into four major forms: immunoglobulin light chain-derived (AL), reactive AA, dialysis-related (beta2M) and hereditary transthyretin (ATTR) type. Heart, kidney, gastrointestinal tract and peripheral nerves are commonly affected by amyloid deposition in systemic amyloidosis and histopathological demonstration of amyloid deposits on any of affected organs is the first step leading to the diagnosis of this disease. Immunohistochemical analysis of amyloid protein on tissue amyloid deposits is necessary to make classification of the disease and DNA testing is also useful in a hereditary form. Amyloidosis had been considered to be an incurable disease but during the past one decade several therapeutic approaches have been employed for the amyloidosis patients with diverse pathogenetic backgrounds: intravenous large dose of melphalan accompanied by autologous peripheral blood stem cell transplantation for AL amyloidosis and liver transplantation for hereditary ATTR type amyloidosis. As a result some amyloidosis patients have been rescued and are now enjoying their own social lives. It is likely that recent advance on the research of amyloidosis has changed the concept of this disease.     

Immunohistochemical and immunochemical study of amyloid in liver affected by systemic Alambda amyloidosis with antibodies against three different regions of immunoglobulin lambda light chain

The purpose of the present paper was to investigate the heterogeneous nature of amyloid deposits in the liver, by immunohistochemical and immunochemical examination of liver samples from cases of immunoglobulin lambda light chain amyloidosis (Alambda amyloidosis) with antibodies generated against the peptides corresponding to the three different regions of the lambda light chain. Amyloid deposits in the hepatic artery tended to react better with anti-lambda(118-134) than with anti-lambda(159-175). Amyloid deposits in the space of Disse tended to react weakly or partially with anti-lambda(118-134) but well with anti-lambda(159-175). Amyloid deposits in the portal vein reacted relatively well with both antibodies. By western blotting of water-extracted amyloid in which amyloid deposits were not stained with anti-lambda(118-134) immunohistochemically, the three antibodies detected 27 kDa bands consistent with the full-length Ig lambda chain and some smaller bands. These findings indicate that amyloid deposits may not be homogeneous in the liver of AL amyloidosis, and that molecular heterogeneity of amyloid fibril protein or a difference in the mode of deposition results in the histopathological heterogeneity of AL amyloid deposits even within a single patient.     

Microscopical atrial amyloidosis in chronic heart disease

Nineteen out of 121 consecutive cardiac biopsies from 107 patients were found to contain amyloid deposits on routine Congo red screening. Seventeen were left atrial appendages removed during mitral valvotomy for chronic rheumatic mitral valve disease while the remaining two were right atrial appendages excised during surgical repair of atrial septal defects. The distribution of amyloid deposits within the atria and their tinctorial characteristics are described. The high prevalence of atrial amyloidosis observed could not be attributed to generalized or senile amyloidosis. The possibility that this is a distinctive localized form of amyloidosis secondary to chronic heart disease is discussed.     

Hepatic amyloidosis: morphologic differences between systemic AL and AA types

The liver is almost universally involved in systemic amyloidosis. Patterns of topographic distribution of amyloid within the liver lobule have been recognized, but the reliability of using these for classification of amyloid type is in question. We examined 286 livers from cases of systemic amyloidosis obtained from autopsies at Los Angeles County-University of Southern California Medical Center, classifying them as AL or AA type by means of the potassium permanganate Congo red-staining method along with a specific anti-AA antiserum. Prior publications have asserted that deposition of secondary (AA) amyloidosis is limited to the vessels in the portal tract, constituting a "vascular" pattern, and that in primary (AL) amyloidosis the deposits exhibit a "sinusoidal" pattern in that they are seen along hepatic sinusoids as well as in portal vessels. We confirmed that AL amyloid involves the portal vessels as frequently as AA amyloid and that deposition occurred significantly more frequently in the portal stroma, the central vein, and the "sinusoidal" areas. However, we also found a "sinusoidal" pattern in 29 of 78 cases of secondary (AA) amyloidosis; in 14 of these, more than half of the sinusoidal spaces were replaced by amyloid deposits. We also noted that in 23 of the 29 AA amyloidosis cases with "sinusoidal" involvement, a "sago" pattern of distribution of amyloid in the spleen was present. No consistent association of a specific chronic inflammatory disease with "sago" spleen and "sinusoidal" deposits could be documented. We conclude that topographic distribution of amyloid within the liver lobule is not a reliable method of distinguishing AA from AL amyloidosis and that specific staining methods must be used if the physician is to be able to attempt modern therapeutic modalities.     

Familial amyloidotic polyneuropathy type 1 in Kumamoto, Japan: a clinicopathologic, histochemical, immunohistochemical, and ultrastructural study

Seventeen autopsy and five biopsy cases of familial amyloidotic polyneuropathy were examined clinicopathologically, histochemically, immunohistochemically, and ultrastructurally. In the autopsy cases, amyloid deposits were predominant in the peripheral nerve tissues, autonomic nervous system, choroid plexus, cardiovascular system, and kidneys. Amyloid involvements in the anterior and posterior roots of the spinal cord, spinal ganglia, thyroid, and gastrointestinal tract were also frequent. In the cardiac conduction system, amyloid deposition was prominent in the sinoatrial node and in limbs of the intraventricular bundle. In the sural nerve biopsy, besides amyloid deposits, degenerative changes of nerve fibers and Schwann cells were detected ultrastructurally, and the morphometric analysis showed a marked reduction in the number of myelinated fibers which correlated with the clinical stage. Amyloid deposits were resistant to pretreatment with potassium permanganate in Congo red staining, and transthyretin was confirmed immunohistochemically as a major component of amyloid deposits, along with the presence of serum amyloid P-component. Besides the amyloid deposits, transthyretin was proven in the liver cells, epithelial cells of the choroid plexus, and pancreatic islet A cells, suggesting that the transthyretin produced by these cells is secreted, transferred into tissues, and deposited in situ as the major component of amyloid in this disorder.     

Wild-type transthyretin-derived amyloidosis in various ligaments and tendons

Transthyretin-derived amyloid deposition is commonly found in intercarpal ligaments of patients with senile systemic amyloidosis. However, the frequency of transthyretin-derived amyloid deposits in ligaments of other tissues remains to be elucidated. This study aimed to determine the frequency of amyloid deposition and the precursor proteins of amyloid found in orthopedic disorders. We studied 111 specimens from patients with carpal tunnel syndrome (flexor tenosynovium specimens), rotator cuff tears (rotator cuff tendon specimens), and lumbar canal stenosis (yellow ligament specimens). To identify amyloid precursor proteins, we used immunohistochemical staining with antibodies that react with transthyretin, immunoglobulin light chain, amyloid A protein, and β(2)-microglobulin. By means of Congo red staining, we identified 47 (42.3%) amyloid-positive samples, 39 of which contained transthyretin-derived amyloid (18 flexor tenosynovium specimens, 5 rotator cuff tendon specimens, and 16 yellow ligament specimens). Genetic testing and/or clinical findings suggested that all patients with transthyretin amyloid deposits did not have familial amyloidotic polyneuropathy. The occurrence of amyloid deposition in those tissues depended on age. These results suggest that transthyretin-derived amyloid deposits may occur more frequently in various ligaments and tendons than originally expected. In the future, such amyloid deposits may aid determination of the pathogenesis of ligament and tendon disorders in older patients.     

Catecholamine metabolism in familial amyloid polyneuropathy

In order to evaluate the involvement of the peripheral autonomic nervous system in the pathogenesis of type 1 familial amyloid polyneuropathy, the urinary excretion rates of catecholamines and serum dopamine-beta-hydroxylase (DB/) activity were examined in 22 patients at various clinical stages. Changes in both indices were closely linked to the progression of the illness; urinary excretion rates of catecholamines were first decreased in patients suffering from moderate autonomic dysfunction, while serum DBH activity was significantly reduced only in patients with far advanced disease. These findings suggested that patients with advanced disease might be suffering from a chronic deficiency of catecholamines in the peripheral sympathetic nerves. Administration of L-dopa, however, failed to improve the clinical manifestations.