Primary Localized Cutaneous Amyloidosis of Keratinocyte Origin: An Update with Emphasis on Atypical Clinical Variants.

Amyloid is a protein derived from at least 20 different substances. Once misfolded, it results in a group of cutaneous and systemic conditions. Primary localized cutaneous amyloidosis of keratinocyte origin is a very common subtype that can manifest either as lichen or macular amyloidosis, lacking systemic involvement. Lichen amyloidosis often presents as multiple hyperpigmented papules on the lower extremities whereas macular amyloidosis is classically characterized by dark brown rippled macules on the interscapular area. Review of the literature reveals that in addition to the classical presentation of primary localized cutaneous amyloidosis there exists a plethora of various manifestations that can be grouped into either geographic or morphologic categories. This review provides clinicians with the intimate knowledge of these presentations and summarizes the available treatment modalities.

Novel clinical manifestations and treatment of hereditary apoA-I amyloidosis: when a good protein turns bad.

Amyloidoses are life-threatening diseases caused by the deposition of various proteins including apolipoprotein A-I, the major protein of plasma high-density lipoprotein. Timely diagnostics of amyloidoses are crucial for their treatment. Colombat et al. reported novel aspects of the hereditary apolipoprotein A-I amyloidosis, including its unexpected clinical presentation and genetic origins, as well as life- and vision-saving hepatorenal transplantation. This study improves the diagnostics of apolipoprotein A-I amyloidosis, optimizes its treatment, and expands our understanding of the molecular basis of this multipronged disease.

Efficacy of therapeutic soft contact lens in the management of gelatinous drop-like corneal dystrophy.

BACKGROUND/AIMS: To investigate the efficacy of therapeutic soft contact lenses (SCLs) in gelatinous drop-like corneal dystrophy (GDLD) management. METHODS: This was a retrospective, consecutive, observational case series, including 20 patients (40 eyes) with GDLD treated in Osaka University Hospital within the last 15 years. We tested the effects of therapeutic SCL on clinical features, visual acuity and surgical interventions. Examinations for clinical features and visual acuity were done on patients who had no surgical intervention for 3 years. Scoring and evaluation of changes in three main clinical GDLD features and visual acuity (logMAR units) were performed using Fisher's exact test and Mann-Whitney U test. Surgery-free survival time was compared by Kaplan-Meier analyses in all patients. RESULTS: We found a significantly lower rate of progression in GDLD nodular lesions in patients wearing SCLs compared with those who did not (p=0.0179). No suppressant effects were observed regarding opacity and neovascularisation, and no significant improvements were found in visual acuity (in logMAR values, SCL-on: mean=- 0.036, median=0; SCL-off: mean=0.149, median=+ 0.088; p=0.14). The surgery-free survival time for all 16 SCL-on eyes was 2770 ± 1918 days, significantly longer than that for 22 SCL-off eyes, 1342 ± 1323 days (Kaplan-Meier analysis, p=0.0007), suggesting that therapeutic SCL extends the period until surgical intervention and reduces their necessity in patients with GDLD. CONCLUSION: Wearing therapeutic SCLs in GDLD slows the progression of nodular lesions and decreases the need for surgical interventions.

Primary Localized Cutaneous Nodular Amyloidosis in the Absence of Systemic Disease.

A 41-year-old man presented with an asymptomatic, slowly enlarging plaque on the lower aspect of his left cheek, present for approximately 4 months. His past medical history was remarkable for allergic rhinitis. Three years before, he had had a nearly identical lesion surgically excised by Mohs method at the same site. On examination, there was a waxy, yellowish plaque, measuring 2.1 cm × 1.0 cm on the left cheek in proximity to the oral commissure (Figure 1). A shave biopsy revealed an atrophic epidermis with nodular aggregates of eosinophilic material in the dermis (Figure 2). Higher magnification showed an inflammatory infiltrate composed largely of plasma cells, which stained positively for CD20 and κ light chains (Figure 3). Congo red staining confirmed the diagnosis of nodular amyloidosis (Figure 4).

Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease characterized by deposition of amyloid fibrils in various organs and tissues of the body. There are a wide variety of clinical presentations for this multisystemic disorder, so it is often misdiagnosed or subject to delayed diagnosis. Although the exact prevalence is difficult to determine, existing estimates suggest a worldwide prevalence of 50,000 individuals, with varying phenotypic presentations of disease. Due to the heterogeneous nature of its presentation, incorrect or delayed diagnosis can severely impact quality of life for these patients. hATTR amyloidosis can lead to significant disability and mortality. After an accurate diagnosis of hATTR amyloidosis is established, new patients should undergo appropriate therapy as soon as possible. Current treatment options for hATTR amyloidosis are limited, but orthotopic liver transplant serves as an established option for patients with early-stage disease. Consequently, there is a need for new, effective, and safe therapies.

Primary Localized Cutaneous Amyloidosis: A Systematic Treatment Review.

BACKGROUND: Primary localized cutaneous amyloidosis (PLCA) is characterized by extracellular deposition of heterogenic amyloid proteins in the skin without systemic involvement. Lichen amyloidosis, macular amyloidosis, and (primary localized cutaneous) nodular amyloidosis are different subtypes of PLCA. OBJECTIVE: The aim of this study was to review the current reported treatment options for PLCA. METHODS: This systematic review was based on a search in the PubMed database for English and German articles from 1985 to 2016. RESULTS: Reports on the treatment of PLCA were limited predominantly to case reports or small case series. There were a few clinical trials but these lacked control groups. A variety of treatment options for PLCA were reported including retinoids, corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, cepharanthin, tacrolimus, dimethyl sulfoxide, vitamin D3 analogs, capsaicin, menthol, hydrocolloid dressings, surgical modalities, laser treatment, and phototherapy. CONCLUSION: No definitive recommendation of preferable treatment procedures can be made based on the analyzed literature. Randomized controlled trials are needed to offer patients an evidence-based therapy with high-quality standardized treatment regimens for PLCA.

Fiebre mediterránea familiar. Dificultades diagnósticas en un caso atípico / Familial mediterranean fever: diagnostic difficulties in an atypical case

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Marked biochemical difference in amyloid proportion between intra- and extraocular tissues in a liver-transplanted patient with hereditary ATTR amyloidosis.

In order to elucidate the pathomechanism of ocular amyloid formation in a liver-transplanted patient with hereditary ATTR amyloidosis, we investigated detailed biochemical features of ocular amyloid. The patient was a 49-year-old woman with V30M transthyretin (TTR) variant (p.TTRV50M), who underwent ophthalmectomy due to corneal rupture 10 years after liver transplantation (LT). The amyloid was selectively isolated from several portions in intra- and extraocular tissues using a laser microdissection (LMD) system and analyzed by liquid chromatography-tandem mass spectrometry to determine the composition percentage of wild-type and variant TTR in the isolated amyloid. Biochemical analysis revealed that the amyloid consisted mainly of variant TTR in intraocular tissues with a percentage > 80%. On the contrary in the extraocular muscles, wild-type TTR was the main component of the amyloid with a percentage of ∼70%. Our data indicate that intraocular amyloid formation strongly depends on locally synthesized variant TTR and the contribution of wild-type TTR to amyloid formation is quite limited.

Gelatinous drop-like corneal dystrophy: a review.

Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive form of corneal dystrophy characterised by subepithelial and stromal amyloid deposits. It is relatively common in Japan. It usually presents in the first two decades of life with subepithelial nodular lesions that later coalesce to form mulberry-like opacities. Although various surgical modalities have been attempted, recurrence remains a major challenge.

Amiloidosis renal hereditaria por depósito de apolipoproteína AI: un reto diagnóstico / Hereditary apolipoprotein AI-associated renal amyloidosis: A diagnostic challenge

La amiloidoisis renal hereditaria es un trastorno autosómico dominante cuya clínica se solapa con la de otros tipos de amiloidoisis. Hacer un adecuado diagnóstico diferencial puede ser difícil, pero tiene una gran relevancia respecto al pronóstico y tratamiento, que difiere según sea el origen de la enfermedad. Presentamos el caso clínico de un paciente con síndrome nefrótico e insuficiencia renal progresiva, con antecedente familiar de madre con amiloidosis renal. En la biopsia renal se observó depósito de amiloide a nivel glomerular, con negatividad para cadenas ligeras y proteína AA. La sospecha clínica inicial fue la de amiloidosis por depósito de cadena A alfa de fibrinógeno, que es la causa más frecuente de amiloidosis hereditaria en Europa, con afectación preferentemente glomerular. Sin embargo, el estudio genético determinó una nueva mutación previamente no descrita de la Apolipoproteina AI (APO AI). En la biopsia de la madre se detectó depósito glomerular, pero también depósito masivo en médula, lo que caracteriza a la amiloidosis por depósito de APO AI. El diagnóstico se confirmó mediante inmunohistoquímica. La amiloidosis por depósito de Apo AI progresa a enfermedad renal crónica terminal en el plazo de de 3 a 15 años. Se diferencia clínicamente de la amiloidosis AL por su menor afectación extrarrenal y su mejor pronóstico. El trasplante renal ofrece una supervivencia del injerto aceptable y el trasplante hepato-renal se podría tener en cuenta en pacientes con disfunción significativa de ambos órganos (AU)

Hereditary renal amyloidosis is an autosomal dominant condition with considerable overlap with other amyloidosis types. Differential diagnosis is complicated, but is relevant for prognosis and treatment. We describe a patient with nephrotic syndrome and progressive renal failure, who had a mother with renal amiloidosis. Renal biopsy revealed amyloid deposits in glomerular space, with absence of light chains and protein AA. We suspected amyloidosis with fibrinogen A alpha chain deposits, which is the most frequent cause of hereditary amyloidosis in Europe, with a glomerular preferential affectation. However, the genetic study showed a novel mutation in apolipoprotein AI. On reviewing the biopsy of the patient's mother similar glomerular deposits were found, but there were significant deposits in the renal medulla as well, which is typical in APO AI amyloidosis. The diagnosis was confirmed by immunohistochemistry. Apo AI amyloidosis is characterized by slowly progressive renal disease and end-stage renal disease occurs aproximately 3 to 15 years from initial diagnosis. Renal transplantation offers an acceptable graft survival and in these patients with hepatorenal involvement simultaneous liver and kidney transplantation could be considered (AU)

Primary localized cutaneous nodular amyloidosis of the feet: a case report and review of the literature.

Primary localized cutaneous nodular amyloidosis (PLCNA) is a rare disorder that manifests as the cutaneous formation of nodules composed of light-chain amyloid. Although the type of amyloid deposit is similar to primary systemic amyloidosis, there seems to be little, if any, crossover between the 2 diseases. Because reports of PLCNA are sparse, there is no established protocol for treating this disease. This case report presents a 42-year-old man with a visually striking presentation of PLCNA on both feet with some of the lesions possibly being secondary to trauma, a rare phenomenon. The lesions had been present for more than 4 years, and there were no signs or symptoms of systemic amyloidosis. The lesions responded well to a combination of complete curettage followed by CO2; laser ablation. Primary localized cutaneous nodular amyloidosis is rare and difficult to treat, with high rates of recurrence and a concern for progression to systemic amyloidosis. The diagnosis, workup, treatment, and monitoring of PLCNA also are discussed.

Current trends in diagnosis and management of cardiac amyloidosis.

Amyloidosis is a rare disease in which insoluble extracellular protein fibrils in ß-pleated sheets infiltrate multiple organs, causing organ dysfunction and failure. Amyloidoses are generally classified into light chain or primary systemic amyloidosis, hereditary amyloidosis (most commonly, transthyretin amyloidosis), senile systemic amyloidosis, secondary amyloidosis, and isolated atrial amyloidosis. At least 100 different amyloidogenic proteins have been identified in humans and can be differentiated by mass spectroscopy after laser capture microdissection and genetic testing. Organ involvement can include kidneys, skin, blood vessels, central and peripheral nervous systems, lungs, liver, intestines, and heart. Developments in noninvasive techniques are facilitating earlier and more accurate diagnosis. Management depends on the specific disease type, thus early and accurate diagnosis is imperative. Prognosis generally correlates with degree of cardiac involvement but varies widely with specific amyloid protein type. New treatment strategies involving chemotherapy and organ transplantation are improving survival, but prognosis is guarded.

Amyloid heart disease: a brief review of treatment options.

Heart involvement by amyloid deposition remains the most challenging of all organ sytems that may become involved, in what is generally a systemic disease. The correct diagnosis of amyloid type is critical to selection of the appropriate and wide range of therapies. The treatment of amyloid heart disease comprises two strategies: conventional management of a restrictive cardiomyopathy, and varied therapies aimed at the underlying amyloidogenic process. In light chain (AL) amyloidosis, many of the most efficacious therapies involve chemotherapeutic agents with their own inherent toxicities to the heart and bone marrow. In the case of the hereditary amyloidosis, major surgery in the form of liver transplantation is usually required. Moreover, consideration should be given to screening of family members for a potentially hereditary disease. Several types of amyloidosis may require one or more, of heart, liver and/or kidney transplantation, sometimes in addition to high-dose chemotherapy. The objective is to provide a schematic overview of available therapies in the management of AL, hereditary, senile systemic, isolated atrial and secondary forms of amyloidosis.

Direct tissue evaluation via immunofluorescence: in the diagnosis of hereditary transthyretin cardiac amyloidosis.

Multiple precursor proteins have been shown to cause cardiac amyloidosis. The most common forms are due either to immunoglobulin light chains or to transthyretin proteins (either wild-type or mutant forms). Correct subclassification of the amyloid is paramount because treatment differs in accordance with the type of amyloidosis. Indirect diagnostic methods, including serologic analysis, can lead to misdiagnosis. Definitive diagnosis often requires analysis of amyloid in the tissue. We present a case of a woman who was diagnosed with hereditary transthyretin cardiac amyloidosis by means of immunofluorescence and genetic analysis. This case highlights the importance-in the diagnostic algorithm of cardiac amyloidosis-of direct evaluation of the tissue with immunofluorescence and of genetic testing.

Cardiac amyloidosis: a practical approach to diagnosis and management.

Cardiac amyloidosis, the primary determinant of prognosis in systemic amyloidoses, is characterized by infiltration of myocardium by amyloid protein resulting in cardiomyopathy and conduction disturbances. Cardiac involvement is primarily encountered in immunoglobulin (AL) and transthyretin-associated (hereditary/familial and senile) amyloidoses. Although the latter variants could be indolent, untreated AL amyloidosis with clinical cardiac involvement is a rapidly fatal disease. The management decisions of cardiac amyloidosis are based on the underlying cause. Although treatment of senile systemic amyloidosis is largely supportive, the therapeutic approaches for AL amyloidosis include chemotherapy, autologous stem cell transplantation, and, rarely, cardiac transplantation. The familial variant is potentially curable with a liver ± cardiac transplantation. This narrative review outlines a practical approach to these challenging diagnoses in the face of rapidly evolving management strategies.

Amiloidose familiar por transtirretina TTR Val30Met e os primórdios do Centro de Estudos de Paramiloidose Antonio Rodrigues de Mello / Principles of the Familial transthyretin amyloidosis TTR Val30Met and the beginning of the Paramyloidosis Center of Antonio Rodrigues de Mello

Objetivos: considerar as etapas de desenvolvimento do conhecimento sobre a Polineuropatia amiloidótica familiar de Corino Andrade, atualmente conhecida como Amiloidose familiar por transtirretina (TTR) TTR Val30Met - AFTTTRVal30Met; registrar os primórdios e os princípios fundamentais do Centro de Estudos de Paramiloidose Antonio Rodrigues de Mello (CEPARM) de atendimento aos sofredores de doença de herança autossômica dominante sistêmica e com polineuropatia de predomínio sensitivo-motora-autonômica; rever aspectos atuais sobre a doença, etiológicos, epidemiológicos, clínicos, diagnósticos e terapêuticos. Método: Revisão narrativa sobre a AFTTTRVal30Met baseada em: documentos da época da fundação do CEPARM e de seis casos iniciais (além de outros 23 arrolados pelo Centro Português); artigos recentes. Resultados: Três momentos básicos são registrados no desenvolvimento do conhecimento sobre os doentes: 1-o inicial, clínico-patológico (1939-52); 2-da abordagem multiprofissional (1952-80); 3-de melhor conhecimento da sua fisiopatogenia e tentativa de debelá-la ou abrandá-la, aí mencionadas as revelações genômicas e o papel da TTR mutante (TTRm) (1980-91); 4-a partir do transplante hepático e evolução do conhecimento sobre a TTRm (1991-). A criação do CEPARM surgiu na confluência dos momentos dois e três: necessidade de contemplar o atendimento integral aos sofredores da doença ultrapassando a etapa diagnóstica, e início da definição da pré-albumina anômala (TTRm). Conclusão: a abordagem multidisciplinar continua a ser a meta de atendimento aos pacientes com PAF, além das iniciativas ao aprimoramento terapêutico, diagnóstico e profilático da doença, dependentes da aliança com áreas de pesquisa das ciências biológicas.

Objective: to consider the development stages of the knowledge about the Familial amyloid neuropathy of Corino Andrade, currently known as Familial transthyretin (TTR) amyloidosis TTR Val30Met - FTATTR Val30Met; to register the beginnings and the basic principles of the Center of Studies of Paramyloidosis Antonio Rodrigues de Mello (CEPARM) of the disease sufferers consultations: systemic disease, autosomal dominant inheritance, sensorial-motor and autonomic polyneuropathy; to review the current state of knowledge on the illness, etiologic, clinical, epidemiologic, diagnostic and therapeutic. Method: Narrative review about FTAVal30Met based on: documents at the time of CEPARM foundation and the initial cases (beyond 24 others enrolled by the Portuguese Center); recent articles. Results: in the development of the knowledge on the mentioned patients: 1-initial, medical-pathological one (1939-52); 2-of multiprofessional approach (1952-80); 3 of better knowledge of its physiopathogeny and attempt to reduce or eradicate it, the genomics revelations and the paper of the mutant TTR (TTRm) (1980-91); 4-from the first liver transplant and the increasing knowledge about the TTRm (1991-). The creation of the CEPARM appeared in the confluence of moments two and three: necessity to contemplate the integrated management of the patients exceeding the diagnostic stage, and the beginning of the definition of the anomalous pre-albumin (TTRm). Conclusion: the patients' multidisciplinary approach continues to be the main goal of their management, besides the initiatives to improve therapeutic, diagnostic and prophylactics goals, based on the alliance between basic and clinical sciences.