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Objective: In senile systemic amyloidosis (SSA), a common age-related amyloidosis, wild-type transthyretin accumulates in tissues, with a primary result being cardiac dysfunction. Here, we aimed to clarify the usefulness of B-type natriuretic peptide (BNP) as a prognostic marker of cardiac function in SSA and in familial amyloidotic polyneuropathy (FAP)., Methods and Results: We studied 13 patients with severe SSA and 14 patients with FAP. SSA patients, but not FAP patients, demonstrated a significant correlation of log BNP with the echocardiographic diastolic marker E/e' ratio (r = 0.78, p < 0.01). SSA patients also showed significant correlations between log BNP and log C-reactive protein or log high-sensitive troponin T (r = 0.70, p < 0.01; r = 0.64, p < 0.05). FAP patients, however, had significant correlations between log BNP and left ventricular wall thickness (intraventricular septum thickness diastole and posterior wall thickness diastole) (r = 0.73, p < 0.01; r = 0.77, p < 0.01). The mean log BNP level in the follow-up period was significantly higher than that in the diagnostic period in SSA patients (2.65 ± 0.45 versus 2.36 ± 0.40, p < 0.01) but not in FAP patients (1.91 ± 0.56 versus 1.93 ± 0.45, p = 0.87). An especially notable phenomenon was the high plasma BNP level (≥180 pg/ml) in SSA patients., Conclusion: Plasma BNP levels may be a useful prognostic marker of cardiac function in SSA.

Hepatocyte-derived mutant amyloidogenic transthyretin (ATTR) causes familial amyloidotic polyneuropathy (FAP), for which orthotopic liver transplantation is an established curative treatment. However, some patients with FAP have cardiac amyloidosis after transplantation. Here, we describe a man with an autonomic disorder diagnosed as FAP ATTR Val30Met and marked cardiomegaly after liver transplantation. He underwent orthotopic liver transplantation at 49 years of age and was prescribed prednisolone to prevent graft rejection. Two years later, autonomic dysfunction and severe heart failure gradually developed. He died suddenly at 59. The autopsy revealed marked cardiomegaly (heart weight: 1020 g). Histological and ultrastructural examinations demonstrated massive amyloid deposition and unusual myocardial hypertrophic injury associated with nuclear translocation of the glucocorticoid receptor (GR). No other FAP patients without heart failure showed GR nuclear translocation. GR is a nuclear transcription factor that leads to myocardial hypertrophy, and cumulative prednisolone doses may promote marked cardiomegaly and severe cardiac amyloidosis., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background: Polyneuropathy is associated with several pathological conditions. Amyloidosis is a less common cause of polyneuropathy. Amyloidosis is caused by the accumulation of insoluble protein fibrils (amyloid) in the extracellular matrix. Primary systemic amyloidosis is caused by B-lymphocyte dyscrasia. Polyneuropathy is the first sign of primary systemic amyloidosis in about 20% of the cases, and is characterised by relentless progression, painfulness, and prominent symptoms of autonomic neuropathy., Material and Methods: We describe three cases of primary systemic amyloidosis that started with polyneuropathy., Results: The diagnosis of primary systemic amyloidosis is often delayed more than two years after the onset of polyneuropathy. Biopsy of rectum, fat tissue, bone marrow, or peripheral nerve are diagnostic tools., Interpretation: The survival of non-treated patients is about 18 months after the diagnosis. With chemotherapy the survival is prolonged to approximately 38 months.

To assess the prevalence of chest pain and ischemic electrocardiographic (ECG) changes and relate them to histopathologic findings of coronary arteries in cardiac amyloidosis, 33 patients with AL (primary) amyloidosis and 60 patients with familial amyloid polyneuropathy (FAP) were examined. Five patients (15%) with AL amyloidosis had recurrent anginal pain with exertion and 2 of them also experienced anginal pain after orthostatic hypotension. The chest pain was associated with transient downsloping or horizontal ST-segment depression with or without T-wave inversion in right precordial leads, whereas the remaining patients with AL amyloidosis and all patients with FAP did not show anginal pain or ischemic ST-T changes. Histologic sections of coronary arteries were obtained in 12 patients with AL amyloidosis, including 4 of the 5 patients who had angina pectaris and in 25 patients with FAP. Three patients with anginal pain had variable degrees of stenoses of the intramural coronary arteries by amyloid deposition predominantly in the media with normal or nearly normal epicardial arteries. One patient with AL amyloidosis who had effort angina showed marked stenosis and complete occlusion of the small coronary vessels by transmural amyloid deposition. The remaining 8 patients with AL amyloidosis and 25 with FAP without chest pain did not exhibit any stenosis or occlusion of both the epicardial and intramural vessels. These findings suggest that ischemic ST-T changes with chest pain are not so rare in patients with AL amyloidosis, and that markedly decreased myocardial oxygen supply due to diffuse stenotic or occlusive disease of the small coronary vessels by amyloid deposition contributes to the development of clinically significant ischemic heart disease in these patients.

We report an autopsy case of a pedigree of familial amyloidotic polyneuropathy (FAP) with a mutation of isoleucine-50 transthyretin (ATTR Ser50Ile). A 47-year-old man started developing severe diarrhea and weight loss at age 41 years, followed by urinary incontinence, autonomic-nervous-system abnormalities and serious heart failure; the diagnosis of FAP (ATTR Ser50Ile) was made on the basis of genetic, histochemical and immunohistochemical analysis. Six years after the initial symptoms, he died of septic shock. Autopsy revealed suppurative peritonitis, perforation of the sigmoid colon and marked systemic amyloid deposition. The total amount of amyloid deposited in the heart was greatly increased and was much lower in the thyroid gland and kidneys compared with amyloid deposits in ordinary FAP (ATTR Val30Met). Amyloid deposition in peripheral vessel walls was prominent, particularly in lymphatics and veins. His elder sister, 54 years old, started to develop orthostatic hypotension at age 49 years, followed by dysesthesia, diarrhea and severe congestive heart failure. Endomyocardial biopsy revealed severe TTR-amyloid deposition; ultrastructural examination demonstrated that amyloid fibrils were deposited disproportionately and extended radially around microvessels.

A 65-year-old man with IgG lambda multiple myeloma developed severe polyneuropathy with prominent thermal-pain sensory impairment and autonomic failure. Although the clinical presentation suggested amyloid neuropathy, nerve biopsy showed the immunohistochemical and ultrastructural features typical of light chain deposition disease (LCDD). A precise morphologic and clinical description of LCDD neuropathy is given for the first time in the present report.

Malignant neoplasms may have secondary (reactive, AA), amyloidosis as a sequel. Among carcinomas, this is most frequent with hypernephroma. We report a 60-year-old male patient with progressive polyneuropathy and monoclonal gammopathy of the kappa type. A renal tumor was histologically diagnosed as hypernephroma at nephrectomy. The patient did not improve postoperatively and died three and a half months later from pulmonary embolism. Autopsy revealed a systemic amyloidosis, predominantly with prominent deposits in peripheral nerves. Immunohistochemical staining demonstrated the amyloidosis as of the primary (AL) type, rather than of the expected AA type. A plasmocytoma was not detected, either clinically or at autopsy. We assume here a coincidental rather than causal connection between the hypernephroma and the monoclonal gammopathy with AL amyloid and the neuropathy.

The pathology of primary familia amyloidosis with polyneuropathy is described on the basis of post-mortem examination of six cases from Northern Sweden. Clinically the disease is characterized by progressive sensory and motor disturbances with loss of sensation, muscular wasting and flaccid paralysis. Impotence, urinary bladder dysfunction, motility disturbances of the gastro-intestinal tract and postural hypotension indicate affection of the autonomic nervous system as well. Malabsorption, cardiac insufficiency and vitreous opacites also occur. As regards the distribution of amyloid, the following findings seemed to be characteristic. Usually there were no gross lesions indicating the amyloid disease. Histopathologically, amyloid deposits were observed in great extent in the peripheral nervous system and in various parts of the peripheral autonomic nervous system as well. It occurred extensively in the walls of blood vessels of various calibres, in the perivascular collagenous connective tissue and adjacent to the smooth musculature. Amyloid deposition was also found more or less abundantly in various other organs and tissues. No deposits, however, or only insignificant amounts, were found in the central nervous system, either in the parenchyma of the liver, in the islets of Langerhans, or in the bone marrow. Clinical manifestations seemed to be related to the local deposition of the amyloid substance. Our clinical and pathological findings in this particular type of familial amyloidosis conformed mostly to those previously described.

A family with autosomal dominant transmitted familial amyloid polyneuropathy residing in Texas is described. Clinically, the prominent sensory and severe autonomic nervous system involvement resembles the Andrade (Portuguese) type I familial amyloid polyneuropathy but is unique in that the age of onset is in the seventh decade in all family members affected to date. Using an immunoperoxidase technique, prealbumin was demonstrated in the amyloid deposits. This finding suggests that this family shares biochemical as well as clinical characteristics consistent with similar kinships with type I familial amyloid polyneuropathy of diverse geographic origin.

The association of Adie's syndrome and of neuropathy of chronic evolution is not a frequent occurrence; first made known by Togi in 1967, four cases have been described ever since. The authors report two new observations: one concerns a man showing a unilateral tonic pupil associated to sensory neuropathy, raised C.S.F. protein, rarefaction of myelinated fibres with schwannian proliferation, without amyloid deposit. The other is that of a woman affected with bilateral pupillotonia, motor neuropathy of the four limbs and generalized amylosis. If the first observation is comparable to the five cases reported, the second is more questionable: the absence of amyloid deposit on three nerve biopsies and at the ciliary ganglion level does not absolutely exclude the possibility of amyloid neuropathy.

A 47 year old woman with familial amyloidotic polyneuropathy (FAP) is reported, without familial occurrence of the disease. Her 81 year old mother and 53 year old sister were proved to be asymptomatic carriers for variant transthyretin (TTR) by means of the radioimmunoassay. It is suggested that unknown factor(s) may play a role in preventing or delaying the onset of the disease, producing variations in sex and family incidence. In order to establish the diagnosis of non-hereditary primary amyloidotic polyneuropathy, it must be confirmed that variant TTR is absent in the serum of relatives.

Twenty-seven patients with familial amyloidosis with polyneuropathy were studied with regard to the morphology of the small intestine, and this was correlated to symptoms and malabsorption features. The mucosa was normal in all cases investigated by the dissecting microscope, the light microscope, and the scanning electron microscope. Amyloid was demonstrated in 83% of the cases by the presence of green birefringent material in the biopsy specimens stained with alkaline Congo red and examined in polarized light. Nineteen patients had steatorrhea, and 12 had pathological D-xylose test results. The degree of amyloid infiltration did not correlate with these data, nor did the symptomatic state correlate with the amount of amyloid in the biopsy specimens. The surface ultrastructure was normal when investigated by means of the scanning electron microscope in all patients except five in whom the glycocalyx was altered. As a group, however, those five did not differ in any respect from the rest of the patients. Rod-shaped microorganisms were shown to adhere to the surface in one patient. The results suggest that mechanisms other than bowel-wall deposition of amyloid cause the dysfunction of the gastrointestinal tract in familial amyloid polyneuropathy.

Report of a 35 year old male with hereditary neuropathic amyloidosis of the portuguese type, the second known case in Germany. There are extensive nodular Congo red positive amyloid deposits in the endoneurium of the peripheral nerves which lead to displacement, compression atrophy and interruption of the endoneural fascicles. The amyloid fibril structure is specially noted by interference contrast microscopy. It can also be documented in unstained microscopic sections. Further extensive nodular deposits are present in the mesangium of the glomerula. The remaining organs show preponderantly affected vessel walls and collagen fibres.