losartan-potassium and Amyloid-Neuropathies--Familial

Familial amyloidotic polyneuropathy, ATTRV30M (p. TTRV50M) amyloidosis, is a neurodegenerative disease characterized by systemic extracellular amyloid deposition of a mutant transthyretin, TTR V30M. Anemia, with low erythropoietin (EPO) levels and spared kidney function, affects about 25% of symptomatic patients, suggesting a blockage of EPO-producing cells. Early non-fibrillar TTR aggregates are highly cytotoxic, inducing oxidative stress, the expression of apoptosis-related molecules and secretion of pro-inflammatory cytokines, factors capable of inhibiting EPO production. Low EPO levels in these patients are not related to renal amyloid deposition or the presence of circulating TTR V30M. However, the role of early non-fibrillar TTR aggregates remains unexplored. We used the EPO producing Hep3B human hepatoma cell line to study the effect of TTR oligomeric aggregates on EPO expression. Hep3B cells were incubated with soluble and oligomeric TTR V30M, and cell proliferation as well as caspase 3/7 activation was evaluated. Relative quantification of EPO mRNA transcripts was performed by real-time PCR. Significant reductions in cell viability (13 ± 7.3%) and activation of caspases 3/7 were seen after 24 h in the presence of oligomeric TTR V30M. Also, EPO expression was significantly reduced (50 ± 2.8%), in normoxic conditions. A reporter assay was constructed with a PCR fragment of the EPO promoter linked to the luciferase gene to evaluate the role of transcription factors targeting the promoter. A significant reduction of EPO promoter activity (53 ± 6.5%) was observed in transfected cells exposed to TTR oligomers. Our results show that oligomeric TTR V30M reduces EPO expression, at least in part through inhibition of promoter activity.

Topics: Amyloid Neuropathies, Familial; Carcinoma, Hepatocellular; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Dynamic Light Scattering; Erythropoietin; Humans; Liver Neoplasms; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; RNA, Messenger

Glaucoma is the leading cause of irreversible blindness in familial amyloidotic polyneuropathy (FAP) patients. Erythropoietin (EPO) is a cytokine that has been shown to play a role in neuroprotection and is endogenously produced in the eye. EPO levels in the aqueous humor are increased in eyes with glaucoma. In this study, we evaluated the EPO concentration in the aqueous humor of FAP and non-FAP patients, with and without glaucoma.. Undiluted aqueous humor samples were obtained from 42 eyes that underwent glaucoma surgery, phacoemulsification, or vitrectomy. EPO concentration in the aqueous humor and blood were measured using the Immulite 2000 Xpi using an automatic analyzer (Siemens Healthcare Diagnostics).. The mean EPO concentration in the aqueous humor of non-FAP glaucoma eyes group 2 (75.73±13.25 mU/ml) was significantly higher than non-FAP cataract eyes (17.22±5.33 mU/ml; p<0.001), FAP glaucoma eyes (18.82±10.16 mU/ml; p<0.001), and FAP nonglaucoma eyes (20.62±6.22 mU/ml; p<0.001). There was no statistically significant difference between FAP nonglaucoma eyes versus non-FAP cataract eyes (p = 0.23) and FAP glaucoma eyes versus FAP nonglaucoma eyes (p = 0.29). In the glaucoma groups, there was no correlation between the aqueous humor EPO concentration and the ocular pressure (p = 0.95) and mean deviation (p = 0.41). There was no correlation between the EPO serum concentration and EPO aqueous humor concentration in our patients (p = 0.77).. Unlike other glaucomatous patients, FAP patients with glaucoma do not show increased and potentially neuroprotective endocular EPO production in the aqueous humor and may need more aggressive glaucoma management.

Topics: Amyloid Neuropathies, Familial; Aqueous Humor; Demography; Erythropoietin; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Mutant Proteins

Anemia with low serum erythropoietin (EPO) is common in Portuguese transthyretin V30M amyloid polyneuropathy (FAP). Low EPO production can be observed before clinical disease. Renal amyloidosis is observed in FAP, mainly in the medulla. Renal manifestations correlate with glomerular and vascular involvement, but not with tubulointerstitial deposition. To evaluate the potential role of renal amyloid deposits in the genesis of the EPO defect in FAP, we analyzed the renal biopsies of 12 patients (5 males, 7 females, aged from 29 to 54 years) with a clinical evolution varying from 3 to 12 (mean 5.4 +/- 2.8) years.. Formalin-fixed, paraffin-embedded sections of renal biopsies were stained by Congo red. Amyloid deposits were assessed by a semiquantitative method based on the percentage of amyloid deposition in each renal structure. Hemoglobin, creatinine, urea, EPO and proteinuria were concomitantly evaluated and correlated with the pathological findings.. Renal amyloid deposits were observed in all biopsies analyzed, independently of the neuropathy score. Low serum EPO levels were not related with either the amount of amyloid deposition or the renal clinical manifestations.. Impairment of EPO production in FAP is not directly related to renal amyloid deposits and more studies are needed to clarify this question.

Topics: Adult; Amyloid; Amyloid Neuropathies, Familial; Cerebral Amyloid Angiopathy; Erythropoietin; Female; Humans; Kidney; Male; Middle Aged

Familial amyloid polyneuropathy type I (FAP-I) is caused by a mutant transthyretin (TTR V30M) produced by liver, and orthotopic liver transplantation (OLT) is a widely accepted treatment for stopping the major production of TTR V30M. Anemia affects 24.8% of symptomatic FAP-I patients with low erythropoietin (Epo) levels, suggesting a blockage of Epo-producing cells by local or circulating factors. To evaluate the putative toxicity effect of the mutant protein on Epo-producing cells and consequent Epo production, clinical and laboratory parameters of 20 FAP patients were collected before and after liver transplantation, analyzed and compared. Following OLT, the prevalence of anemia increased, with a significant decrease in transferrin saturation, but without significant change in ferritin. Serum Epo levels remained low after OLT and the observed to expected (O/E) Epo level ratio decreased even further after OLT (O/E < 0.8 rose to 70%). Despite the decrease in creatinine clearance (95.1 to 66.9 ml/min, p < 0.001), a similar median O/E Epo level was observed, independently of the presence of renal failure, excluding an important impact of renal failure on Epo production. The increase of anemia after OLT and the maintenance of a defective endogenous Epo production after liver transplantation excluded an inhibitory effect of the circulating TTR V30M on the Epo-producing cells.

Topics: Adult; Amyloid Neuropathies, Familial; Amyloidosis, Familial; Anemia; Cross-Sectional Studies; Erythropoietin; Female; Humans; Liver Transplantation; Male; Middle Aged; Prealbumin; Retrospective Studies; Treatment Outcome

Familial amyloid polyneuropathy (FAP) type I is caused by a mutated transthyretin (TTR V30M) and characterized by a sensorimotor and autonomic neuropathy. Renal, cardiac, and ocular abnormalities can also occur. Anemia has been described in previous reports, but its prevalence in Portuguese FAP patients is not precisely known. The aim of this study was to estimate the prevalence of anemia in FAP type I Portuguese patients and to evaluate the contribution of erythropoietin (Epo) to its genesis.. A retrospective cross-sectional study was undertaken to determinate the prevalence and characteristics of anemia in 165 FAP patients. For comparison analysis, 3 control groups were also evaluated, 1 group of 46 apparently healthy subjects, 1 group of 17 asymptomatic carriers of FAP-trait, and a group of 14 non-FAP patients with chronic renal insufficiency. Serum Epo levels were analyzed in all groups.. Anemia was present in 24.8% of symptomatic FAP patients. Iron stores, B12 vitamin, and serum folate levels were normal. FAP patients presented significantly lower serum Epo levels than healthy controls (P= 0.003). Epo levels were found lower than expected for the degree of anemia and in 17.5% were undetectable. Low Epo values were observed independently of the presence of renal failure or anemia, and sometimes preceded clinical disease.. Anemia in FAP type I is a common manifestation. The results clearly suggest a defective endogenous Epo production in the genesis of the anemia.

Topics: Adult; Aged; Amyloid Neuropathies, Familial; Anemia; Autonomic Nervous System Diseases; Case-Control Studies; Cross-Sectional Studies; Erythropoietin; Female; Heterozygote; Humans; Kidney Failure, Chronic; Male; Methionine; Middle Aged; Mutation; Portugal; Prealbumin; Prevalence; Retrospective Studies; Valine

A 71-year-old man, who was diagnosed with familial amyloidosis type I, was admitted for treatment of severe orthostatic hypotension associated with recurrent syncopal attacks. Head-up tilt testing demonstrated severe orthostatic hypotension (114/72 mmHg in the supine position and 62/34 mmHg in the upright position) with syncope or presyncope. Oral midodorine and fludrocortisone therapies failed to prevent his symptoms. After administration of subcutaneous erythropoietin, his blood pressure drop in the upright position was decreased and symptoms disappeared unassociated with improvement of anemia. Although previous reports have shown that the mechanism by which erythropoietin improves orthostatic hypotension is related to improvement in anemia, other mechanisms may also play a role.

Topics: Aged; Amyloid Neuropathies, Familial; Blood Pressure; Erythropoietin; Humans; Hypotension, Orthostatic; Male; Recombinant Proteins; Syncope; Tilt-Table Test