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Clinical characteristics of patients with systemic amyloidosis from 2000–2010
Rev Clin Esp. 2013;213(4):186---193
Revista Clínica Española www.elsevier.es/rce
ORIGINAL ARTICLE
Clinical characteristics of patients with systemic amyloidosis from 2000---2010夽 D. Real de Asúa∗ , R. Costa, M.M. Contreras, Á. Gutiérrez, M.T. Filigghedu, M. Armas Servicio de Medicina Interna, Fundación de Investigación Biomédica, Hospital Universitario de La Princesa, Madrid, Spain Received 18 April 2012; accepted 10 September 2012 Available online 21 March 2013
KEYWORDS Amyloidosis; Epidemiology; Spain; Proteinuria; Nephrotic syndrome
Abstract Background: The epidemiology of systemic amyloidosis has been changing in the last decades. We aim to describe the clinical characteristics of the patients seen at our institution with systemic amyloidosis in 2000---2010 and compare them with previous Spanish series. Patients and methods: An observational, retrospective study was performed on all the patients admitted to a tertiary hospital in Madrid, Spain who had been diagnosed of amyloidosis from January 2000 to December 2010. Patients without a proven diagnosis of amyloidosis, with dialysis-associated, senile, or localized forms of amyloidosis were excluded from the study. A systematic review was made of the clinical records, collecting the demographic, clinical and biochemical variables at diagnosis and patients’ outcome. Results: A total of 55 patients were studied, 24 (44%) of whom had AL amyloidosis, 30 (56%) AA amyloidosis, and 1 a familiar form. The most frequent underlying disorders were rheumatoid arthritis (9 patients, 30%) and ankylosing spondylitis (4 cases, 13%). The kidneys were the most frequently involved organ (36 patients, 67%) with nephrotic-range proteinuria during diagnosis (3.4 ± 3.7 g/24 h). Median time to diagnosis was 3 months (interquartile range [IQR]: 1---17). Median follow-up time was 24 months (IQR: 10---91). During follow-up 31 patients died; 18 of those deaths were related to amyloidosis. Conclusions: Renal dysfunction dominates the course of systemic amyloidosis, which does not seem to have changed in the last decades. We have observed an important delay in the diagnosis of these processes. Therefore, it is necessary to maintain a high degree of clinical suspicion regarding these conditions. © 2013 Published by Elsevier España, S.L.
DOI of refers to article: http://dx.doi.org/10.1016/j.rce.2012.09.001 Please cite this article as: Real de Asúa D, et al. Características clínicas de los pacientes con amiloidosis sistémicas en el periodo 2000---2010. Rev Clin Esp. 2012. http://dx.doi.org/10.1016/j.rce.2012.09.001. ∗ Corresponding author. E-mail address: [email protected] (D. Real de Asúa). 夽
2254-8874/$ – see front matter © 2013 Published by Elsevier España, S.L.
Clinical characteristics of the patients with systemic amyloidosis in 2000---2010
PALABRAS CLAVE Amiloidosis; Epidemiología; Espa˜ na; Proteinuria; Síndrome nefrótico
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Características clínicas de los pacientes con amiloidosis sistémicas en el periodo 2000---2010 Resumen Antecedentes: La epidemiología de las amiloidosis sistémicas está cambiando en las últimas décadas. Describimos las características clínicas de los pacientes con amiloidosis sistémicas atendidos en nuestro centro en el periodo 2000-2010 y las comparamos con las anteriores series espa˜ nolas. Pacientes y métodos: Estudio observacional retrospectivo de pacientes con diagnóstico de amiloidosis sistémica en un hospital terciario entre enero de 2000 y diciembre de 2010. Se excluyó a los pacientes sin diagnóstico histológico y a aquellos con formas asociada a diálisis, seniles o localizadas. Mediante revisión sistemática de las historias clínicas se recogieron las variables demográficas, clínicas, de diagnóstico, seguimiento y mortalidad. Resultados: Se estudió a 55 pacientes, 24 (44%) tenían amiloidosis AL, 30 (56%), amiloidosis AA y un paciente, una forma familiar. Las enfermedades inflamatorias subyacentes más frecuentes fueron la artritis reumatoide (9 pacientes, 30%) y la espondilitis anquilosante (4 enfermos, 13%). El órgano más frecuentemente afectado fue el ri˜ nón (36 pacientes, 67%), con una proteinuria al diagnóstico de 3,4 ± 3,7 g/24 h. El tiempo hasta el diagnóstico fue de 3 meses (rango intercuartílico [RIC]: 1-17). La mediana de seguimiento fue de 24 meses (RIC: 10-94). Durante el seguimiento fallecieron 31 pacientes y 18 muertes fueron atribuíbles a la amiloidosis. Conclusiones: La afectación renal es la presentación más prevalente de las amiloidosis sistémicas, sin cambios en las últimas décadas. Observamos un largo tiempo de latencia hasta el diagnóstico, por lo que es preciso mantener un alto grado de sospecha clínica de estos procesos. © 2013 Publicado por Elsevier España, S.L.
Introduction Amyloidosis represents a heterogeneous group of diseases characterized, from the pathogenic standpoint, by an extracellular deposit of proteins in the form of insoluble fibers. These proteins aggregate in a characteristic three-dimensional configuration in beta-sheets, which when stained with Congo red exhibits birefringence under polarized light.1 To date, 25 structurally unrelated proteins capable of causing amyloidosis are known.2 The various forms of amyloidosis are classified according to these precursor proteins and by the distribution of the amyloid deposit in the body.3 The main types of systemic amyloidosis are primary (AL) amyloidosis, secondary (AA) amyloidosis, familial amyloidosis, senile amyloidosis and amyloidosis associated with the deposit of beta-2-microglobulin in patients with end-stage chronic kidney disease.4 Amyloidoses are classified as rare diseases, despite the fact that our knowledge of their epidemiology is based only on small retrospective series and they are probably underdiagnosed conditions.5,6 The last Spanish series of patients with amyloidosis was published more than 20 years ago. These series have reported a predominance of secondary systemic forms combined with a high prevalence of tuberculosis and other chronic infections.7---11 Various authors have indicated that the epidemiology of systemic amyloidosis, particularly secondary forms, has changed in recent decades as a result of earlier diagnoses, more potent and active treatments against the baseline diseases and a reduction in the comorbidity associated with the underlying inflammatory diseases.12,13 At the same time, there is concern that the low diagnosis of these conditions is a reflection of less clinical suspicion due to a change in the type of presentation of systemic amyloidosis and a more indolent course.13
The aim of this study is two-fold. It seeks to describe the clinical characteristics of patients diagnosed with systemic amyloidosis who were treated in a tertiary hospital in Madrid during the period 2000---2010 and compare these with previously published Spanish series.
Patients and methods Study design and patient selection We conducted a retrospective observational study on patients admitted to the University Hospital La Princesa of Madrid in the period between January 2000 and December 2010 who had a diagnosis (primary or secondary) of amyloidosis. The diagnosis of amyloidosis was accepted if it met the clinical, laboratory and histopathological criteria in terms of the personal and family history, the history of inflammatory disease, organ involvement and/or the presence of a monoclonal component in serum or urine, according to the currently accepted diagnostic criteria for amyloidosis.14 Using a computerized review of medical records, we conducted patients follow-up until death, to loss or to the present. We excluded from the final analysis those patients with senile forms of amyloidosis (cerebral amyloid angiopathy and senile cardiac amyloidosis), nodular localized amyloidosis and amyloidosis associated with beta-2-microglobulin. We also excluded from the final analysis those with a presumptive clinical diagnosis (lacking histological confirmation) and those who, with a positive result for amyloids in an abdominal fat biopsy, did not develop symptoms of amyloidosis during the follow-up period. We only analyzed those
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What did we know? The characteristics of systemic amyloidosis in our community have been defined in case study series for more than 20 years. In these series, there is a predominance of systemic forms associated with chronic infectious diseases such as tuberculosis. There have been no studies in Spain that have reviewed these concepts.
What this article provides Starting with the study of patients with a histologically confirmed diagnosis of amyloidosis, the authors have analyzed the characteristics and etiology of systemic amyloidosis over the past decade. Ongoing nephrotic syndrome is a common manifestation of this disease. As expected, there has been a reduction in infections as the cause of secondary amyloidosis, with a greater predominance of inflammatory diseases such as rheumatoid arthritis and ankylosing spondylitis. The delay in time to diagnosis of the disease remains long, despite technological advances. The Editors
admissions in which a diagnosis of amyloidosis was reached. Successive admissions were excluded from the analysis. The study was conducted in accordance with the principles of the Declaration of Helsinki (1996) and the current Good Clinical Practice guidelines. Due to the absence of an intervention and the retrospective nature of the study, the hospital’s ethics committee considered it unnecessary to request the patients’ informed consent. All the data were treated with the upmost confidentiality in accordance with the current legislation.15
Literature search One of the authors of this study performed a systematic search on Medline with the following search terms (amyloidosis [MeSH] AND Spain [MeSH]). This search was crossed with the main Spanish medical journals. We also conducted a selective search by using the bibliographies of the articles of interest. The initial search yielded 216 results, 7 of which were series of patients with systemic amyloidosis. One of the studies was not a Spanish series and another lacked sufficient information to perform a clinical or etiological comparison and were therefore discarded. The rest of the results consisted of 121 case descriptions, 39 specific series and 49 other types of articles.
Variables and measurements Using a systematic review of the medical records, we collected demographic variables (age and gender), clinical variables (type of amyloidosis, baseline disease, evolution time of baseline disease and organ involvement14 ), diagnostic variables (laboratory parameters [hemoglobin,
D. Real de Asúa et al. platelets, activated partial thromboplastin time, glomerular sedimentation rate, C-reactive protein, urea, creatinine, albumin, creatinine clearance (calculated with the MDRD-6 formula16 ), proteinuria, alkaline phosphatase, immunoglobulins and immunoelectrophoresis in serum and urine]; additional tests [especially electromyograms, echocardiograms, computed axial tomography and magnetic resonance imaging] and histological tests: type of biopsy and its result) and follow-up variables (time to diagnosis, time to the end of follow-up and death). The histological diagnosis of amyloidosis was performed on samples obtained through abdominal fat biopsy by fine needle aspiration (FNAC) of rectal fat, bone marrow or tissue from the specific organ. A valid histological diagnosis was considered for those biopsies that were positively stained with Congo red and demonstrated applegreen birefringence under polarized light. The deposited amyloid subtype was characterized by immunohistochemical techniques.14
Statistical analysis The data were analyzed with G-Stat 2.0® software (GlaxoSmithKline SA, Madrid, Spain) and GraphPad Prism® (GraphPad Software, San Diego, CA, USA). The qualitative results are shown as absolute frequencies and percentages, while the quantitative results are shown as mean ± standard deviation (SD). The time-dependent variables are shown as median and interquartile range (IQR). The comparative study of qualitative variables was analyzed according to the chi-squared test or Fisher’s exact test. We used Student’s ttest or the Mann---Whitney U test for quantitative variables. All the statistical tests were analyzed bilaterally. Results with p < 0.05 were considered statistically significant.
Results Clinical and analytical characteristics of the patients at diagnosis We identified 173 admissions of patients with a diagnosis of amyloidosis during the analyzed period. We excluded 118 episodes (68.2%) from the final analysis: 77 episodes (44.5%) corresponded to successive admissions of patients already diagnosed with amyloidosis; 13 patients (7.5%) lacked a histological diagnosis; 8 patients (4.6%) with positive abdominal fat biopsy for amyloid material did not develop symptoms of amyloidosis during their follow-up (median follow-up time: 24 months [IQR: 10---94 months]); 8 patients (4.6%) were diagnosed in other centers or other autonomous communities, 4 patients (2.3%) had nodular localized forms (located in the lungs, lungs and skin, skin and genito-urinary, respectively), and none of the patients developed systemic amyloidosis during the follow-up period; 4 (2.3%) presented senile forms of amyloidosis (2 for cerebral amyloid angiopathy and 2 for senile cardiac amyloidosis); and 2 patients (1.1%) developed amyloidosis associated with dialysis. Insufficient clinical or histological criteria to support a diagnosis of amyloidosis were found in 3 patients (1.7%). Fifty-five patients (31.8%) were included in the final analysis. Only one case of familial amyloidosis was found.
Clinical characteristics of the patients with systemic amyloidosis in 2000---2010 Table 1
189
Clinical characteristics at diagnosis of 54 patients with systemic amyloidosis between 2000 and 2010.
Clinical characteristics
Total n = 54
AL n = 24
AA n = 30
p value
Age (years) Gender (% males)
64 ± 13 26 (48)
66 ± 12 12 (50)
62 ± 14 14 (47)
NS NS
Clinical involvement Renal Required dialysis at diagnosis Cardiac HF at diagnosis Septum thickness IV (mm) Gastrointestinal Hepatic Neurological Polyneuropathy Carpal tunnel syndrome Skin and soft tissue
36 (67%) 11 (20%) 18 (33%) 14 (26%) 15 ± 2 11 (20%) 13 (24%) 16 (30%) 3 (6%) 8 (15%) 6 (11%)
16 (67%) 3 (13%) 12 (50%) 9 (38%) 15 ± 2 5 (21%) 5 (21%) 10 (42%) 3 (13%) 5 (21%) 5 (21%)
20 (67%) 8 (27%) 6 (20%) 5 (17%) 14 ± 1 6 (20%) 8 (27%) 6 (20%) 0 3 (10%) 1 (3%)
NS NS <0.05 NS NS NS NS NS NS NS <0.01
AA: secondary amyloidosis; AL: primary amyloidosis; HF: heart failure; NS: no significant difference; septum IV: interventricular septum.
This case involved a male with familial amyloidosis by mutated transthyretin who began with a clinical picture of mixed polyneuropathy with ‘‘stocking and glove’’ distribution several years before admission to our center. The clinical characteristics during diagnosis of the 54 remaining patients are summarized in Table 1. Cardiac impairment in the form of heart failure was more prevalent in patients with AL amyloidosis. All the patients with heart failure met the current criteria of echocardiography diagnosis of amyloid infiltration.13 Only one endomyocardial biopsy was performed to confirm local involvement, and the result of this biopsy was positive. Furthermore, the impairment of the
Table 2
peripheral nervous system was more common in the primary amyloidosis group, which presented more cases of polyneuropathy and carpal tunnel syndrome (3 [13%] vs. 0 cases and 5 [21%] vs. 3 [10%] cases, respectively; p-value not significant for either comparison). Cutaneous involvement was more common in the AL amyloidosis group. We found no other relevant clinical differences between the groups. The differences in terms of the analytical parameters between the groups are detailed in Table 2. In general, the predominant analytical pattern had mild anemia, moderately increased acute phase reactants, decreased glomerular filtration rate with analytical data showing renal
Analytical characteristics at diagnosis of patients with systemic amyloidosis.
Analytical parameters
Total n = 54
AL n = 24
AAn = 30
p value
Hemoglobin (g/dl) Platelets (1.000/mm3 ) GSR (mm/h) CRP (mg/dl) TTPA (s) Urea (mg/dl) Creatinine (mg/dl) Albumin (g/dl) CRCL (ml/min) Proteinuria (g/24 h) Alkaline P (U/l) IgG (mg/dl) IgM (mg/dl) IgA (mg/dl) Light chains in serum (% pathological) IF serum (% pathological) IF urine (% pathological)
11.6 ± 2.2 229 ± 140 56 ± 36 3.3 ± 4.5 32.8 ± 18.8 73 ± 48 2.2 ± 1.9 3.0 ± 0.8 51 ± 35 3.41 ± 3.76 262 ± 331 647 ± 481 283 ± 400 139 ± 194 10 (19) 13 (24) 13 (24)
12.0 ± 2.0 243 ± 104 47 ± 36 1.1 ± 1.6 32.5 ± 22.0 74 ± 60 2.0 ± 1.9 3.1 ± 0.8 51 ± 32 3.64 ± 4.60 182 ± 286 590 ± 400 327 ± 497 131 ± 213 10 (42) 13 (54) 13 (54)
11.3 ± 275 ± 62 ± 5.2 ± 33.2 ± 72 ± 2.3 ± 2.9 ± 51 ± 3.16 ± 329 ± 753 ± 214 ± 152 ± -------
NS NS NS <0.01 NS NS NS NS NS NS NS NS NS NS -------
2.4 134 36 5.3 14.9 33 2.0 0.8 39 2.73 356 574 165 167
AA: secondary amyloidosis; AL: primary amyloidosis; CRCL: creatinine clearance by the equation MDRD-6; Alkaline P: alkaline phosphatase; IF: immunofluorescence; Ig: immunoglobulin; NS: no significant difference; CRP: C-reactive protein; aPTT: activated partial thromboplastin time; GSR: glomerular sedimentation rate.
190 Table 3
D. Real de Asúa et al. Distribution of baseline diseases causing systemic amyloidosis in 6 Spanish series.
Sample size
Actual n = 54 (%)
García Morán et al.11 n = 69 (%)
González-García et al.10 n = 44 (%)
De la Sierra et al.9 n = 60 (%)
Martínez-Vea et al.8 n = 37 (%)
Castilla et al.7 n = 29 (%)
Amyloidosis AL Multiple myeloma
24 (44) 5 (21)
19 (28) 7 (37)
12 (27) 3 (25)
19 (32) 7 (37)
12 (32) ---
6 (21) 0
Amyloidosis AA Rheumatoid arthritis Ankylosing spondylitis Chronic infections Inflammatory bowel disease Autoinflammatory Psoriasis Other inflammatory processes Tumors N/S
30 9 4 3 2 2 2 2 2 4
49 (71) 10 (20) 1 (2) 29 (59) --5 (10) --3 (7) 1 (2) ---
32 (73) 6 (19) 1 (3) 14 (44) --2 (6) --4 (12) 2 (6) 3 (9)
38 (63) 12 (32) 8 (21) 16 (42) ----4 (11) 1 (3) 1 (3) ---
25 (68) 2 (8) 5 (20) 12 (50) 1 (3) --1 (3) 3 (12) 1 (3) ---
21 (72) 4 (19) --13 (62) --------4 (19) ---
(56) (30) (13) (10) (7) (7) (7) (7) (7) (13)
The results are expressed as n (%). N/S: no underlying inflammatory process was found.
failure and proteinuria in the nephrotic range, hypoalbuminemia and increased alkaline phosphatase. We found no relevant abnormalities in any of the patients’ coagulation times. The activity of factor X was only measured in 4 patients (31%, 54%, 70% and 102%) and was only altered in a single case. When comparing the groups, we observed a significantly greater increase in the serum levels of C-reactive protein in the group of patients with AA amyloidosis (5.2 ± 5.3 vs. 1.1 ± 1.6 mg/dl, difference in means 4.1 mg/dl, 95% confidence interval [CI]: 2.1---6.1; p < 0.01).
Table 4 Biopsies performed to reach the histological diagnosis of amyloidosis. Type of biopsy
Positive
Negative
Not performed
FNAC abdominal fat Rectal fat Bone marrow Target organ
18 6 5 39
15 1 10 2
21 47 39 13
The result is expressed as absolute frequencies. FNAC: fine needle aspiration cytology.
Description of the underlying etiologic processes In 26 of the patients with secondary amyloidosis (26/30, 87%), we identified a baseline chronic inflammatory disease whose distribution is summarized in Table 3. The median time of evolution of the disease to the development of amyloidosis was 101 months (IQR: 51---188 months), with a period from the onset of symptoms to the diagnosis of amyloidosis of 3 months (IQR: 1---17 months). In 4 patients with AA amyloidosis, an etiological diagnosis was not reached despite an intensive study. Five patients with AL amyloidosis (5/24, 21%) had a baseline disease of multiple myeloma diagnosed prior to the development of symptoms suggestive of amyloidosis.
Diagnostic methods for amyloidosis The various methods employed for the histological diagnosis of amyloidosis are detailed in Table 4. Nine patients (17%) were exclusively diagnosed based on their clinical picture and a positive abdominal fat biopsy. In 3 patients (6%), the only positive biopsy was the rectal fat biopsy. Twenty-eight patients (52%) were diagnosed according to their symptoms and a positive target organ biopsy (patients with negative abdominal or rectal fat biopsy). In the remaining patients (14 cases, 25%), the histological confirmation of an amyloid deposit was demonstrated in several locations (target organ, abdominal and/or rectal fat). The most frequently biopsied
organ was the kidney, which was performed on 20 patients (37% of the total, 71% of the cases diagnosed using target organ biopsies).
Follow-up and survival The median follow-up time was 24 months (IQR: 10---94 months); there were no significant differences between the patients with primary and secondary amyloidosis (23 months [IQR: 12---94] vs. 24 months [IQR: 9---103]). Seven patients were lost during follow-up (2 patients with AL amyloidosis and 5 with AA amyloidosis). Ten patients with AL amyloidosis received specific treatment (10/24, 42%). The melphalan---prednisone regimen was used initially in 7 patients. The 3 remaining patients received bortezomib in monotherapy, bortezomib and autologous hematopoietic progenitor cell transplantation, and thalidomide, respectively. There were no significant differences in the median survival between the treated and untreated patients in this group (12 months [IQR: 6---20] vs. 30 months [IQR: 0---75], p value not significant). In 13 of the patients with AA amyloidosis (47%), the regimen was changed prior to treatment: in 2 cases, the treatment with glucocorticoids was intensified, 2 patients received chlorambucil; in 5 cases, infliximab was used; and 4 others received various treatments (surgery, methotrexate and rituximab, melphalan---prednisone and colchicine). These patients had a greater survival than the
Clinical characteristics of the patients with systemic amyloidosis in 2000---2010 Table 5
191
Differences in the presentation symptoms of patients with systemic amyloidosis among 6 Spanish series.
Sample size
Actual n = 54 (%)
García Morán et al.11 n = 69 (%)
GonzálezGarcía et al.10 n = 44 (%)
De la Sierra et al.9 n = 60 (%)
Martínez-Vea et al.8 n = 37 (%)
Castilla et al.7 n = 29 (%)
Age (years) Gender (% males)
64 ± 13 26 (48)
48 ± 15 41 (59)
47 ± 18 23 (52)
57 ± 13 36 (60)
49 ± 16 21 (57)
52 21 (72)
Clinical involvement Renal Required dialysis at diagnosis Cardiac HF at diagnosis Gastrointestinal Hepatic Neurological Polyneuropathy Carpal tunnel syndrome Skin and soft tissue
36 (67) 11 (20) 18 (33) 14 (26) 22 (41) 13 (24) 16 (30) 3 (6) 8 (15) 6 (11)
52 (75) --13 (19) --23 (33) 21 (30) --2 (3) 2 (3) 6 (9)
44 (100) ----12 (27) 20 (45) 21 (47) --12 (27) --3 (7)
47 (78) ----7 (12) 8 (13) 13 (22) --4 (7) 3 (5) 4 (7)
37 (100) 10 (27) 4 (11) 2 (5) 1 (3) 7 (19) --2 (5) --3 (8)
29 (100) ----6 (21) 7 (24) 12 (41) --0 -----
The results are expressed as n (%). HF: heart failure.
untreated group (median survival: 58 months [IQR: 21---96] vs. 8 months [IQR: 2.5---21.2]; p < 0.05). During the follow-up period, 31 patients died (57%). Eighteen of these deaths were attributed to amyloidosis. Ten patients with AL amyloidosis died due to refractory heart failure (42% of this patient group, 18% of the total). Eight patients with AA amyloidosis died due to renal failure progression and associated multiple organ failure (27% of this group, 15% of the sample; the difference in deaths between the groups was not statistically significant).
Clinical and etiological differences compared with previous series Compared with the previously published series, we observed a progressive increase in our sample in the proportion of cases of AL amyloidosis as compared with the AA form (Table 3). We observed a substantial reduction in chronic infections as AA amyloidosis causal processes. Of the 3 cases of amyloidosis secondary to chronic infection in our sample, 2 patients showed chronic osteomyelitis and one showed cystic fibrosis. We did not find any case of AA amyloidosis secondary to tuberculosis in the past decade. When analyzing the clinical presentation of the patients, the primary difference was the greater age of the patients in our series (Table 5).
Discussion The clinical characteristics of the patients diagnosed with systemic amyloidosis over the last decade at our center agree with those described in national and international series.7---11,17,18 Renal impairment, predominantly in the form of nephrotic syndrome, dominates the clinical picture, both in primary and secondary forms. In one of every five patients, the use of renal replacement techniques was necessary during diagnosis. In our series, we also observed a greater cardiac impairment of the peripheral and cutaneous
nervous system in the patients with AL amyloidosis as compared with those with AA amyloidosis. These results contradict the opinion of Hazenberg and Van Rijswijk who indicate a possible change in the current clinical presentation of systemic amyloidosis.13 Although the presentation of these conditions remains classic, the delay time in diagnosis found in our series is, in our opinion, striking. We have not found any other studies in the literature that analyze this issue in detail. However, this fact leads us to insist on the need to maintain a high clinical suspicion of amyloidosis in the study of processes that are associated with renal failure, with heart failure in the absence of classic factors of vascular risk or with polyneuropathies. The greater mean age found in our series as compared with the previous national series agrees with that described by Kyle et al. and Madan et al. in patients with primary amyloidosis.18,19 This result may have numerous bases. The percentage increase in cases of AL amyloidosis is probably associated with an earlier diagnosis of diseases that cause AA amyloidosis and more widespread access to more effective treatments, which achieves better control of the diseases with greater frequency, thus preventing later development of amyloidosis. This would explain not only the gradual reduction of cases of AA amyloidosis but also the proportional reduction in the cases of AL amyloidosis associated with multiple myeloma. We have observed a substantial change in the distribution of diseases that cause secondary amyloidosis, with a highly significant reduction in chronic infections such as etiological agents. These conclusions are also supported by recent international series17,20---22 and appear to be related to more widespread use of more active antibiotics and better control of tuberculosis. Although we have not found any case of amyloidosis due to tuberculosis in the past decade, tuberculosis remains a relevant cause of amyloidosis in other European countries.6 Nevertheless, secondary amyloidoses remain the most common in our community, in contrast to what is observed in the United States, where the AL form is predominant.23,24 A number of authors
192 attribute this greater prevalence of AA amyloidosis in Europe to genetic, dietary and lifestyle factors and to the use of different medical treatments.13 Our study has several strong points. The selection method of cases per episode of admission and the use of the term ‘‘amyloidosis’’ as the only search criterion constitute a sensitive method that identifies all possible cases of interest. This selection method and the retrospective nature of the study also allow us to identify patients whose final diagnosis of amyloidosis was reached after more than one admission. In this manner, we manage to recover those cases in which the histological confirmation was achieved in a subsequent admission. In addition, the diagnoses of amyloidosis encountered were reviewed in light of currently accepted criteria.14 This led to the exclusion of 3 patients due to a lack of clinical or histological data consistent with amyloidosis, as well as 8 more patients with positive abdominal fat biopsies for amyloid material who did not develop symptoms of amyloidosis during follow-up. The treatment of this subgroup of patients with baseline inflammatory disease and with subcutaneous deposits of amyloid material is still controversial (‘‘subclinical amyloidosis’’13 ) and its prognosis is more favorable than that for patients with manifested amyloidosis.25---27 We also excluded from the study those patients with nodular forms of amyloidosis. Previous case series have demonstrated the lack of progression to systemic amyloidosis in this group of patients.28---30 This study, however, also has a number of limitations. It was conducted in a single center. The retrospectively nature of the study may have caused the calculation of the evolution and follow-up times to be inaccurate. We recorded the time in months to minimize the magnitude of this error. The small sample size of the analyzed series helps blur the possible differences between the series in the statistical study. Unfortunately, this limitation is inherent in the low prevalence of amyloidosis in the general population.3,4 In summary, the presentation of systemic amyloidosis in Spain does not seem to have changed in recent decades. Renal impairment remains the most prevalent in the form of nephrotic syndrome, both in primary and secondary forms, followed in the AL form by cardiac and neuropathic impairment. The most commonly found baseline diseases these days are chronic inflammatory processes such as rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease. Although its presentation remains ‘‘classical’’, the delay in time to diagnosis is long. This leads to a greater progression of the disease and limits its subsequent treatment. We must maintain a high clinical suspicion of these conditions when studying processes that are associated with renal failure, with heart failure in the absence of vascular risk factors or with polyneuropathies.
Conflicts of interest The authors have no conflicts of interest to declare.
References 1. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003;349:583---96.
D. Real de Asúa et al. 2. Dember LM. Amyloidosis-associated kidney disease. J Am Soc Nephrol. 2006;17:3458---71. 3. Picken MM. New insights into systemic amyloidosis: the importance of diagnosis of the specific type. Curr Opin Nephrol Hypertens. 2007;16:196---203. 4. Obici L, Perfetti V, Palladini G, Moratti R, Merlini G. Clinical aspects of systemic amyloid diseases. Biochim Biophys Acta. 2005;1753:11---22. 5. Simms RW, Prout MN, Cohen AS. The epidemiology of AL and AA amyloidosis. Baillieres Clin Rheumatol. 1994;8: 627---34. 6. Bergesio F, Ciciani AM, Santostefano M, Brugnano R, Manganaro M, Palladini G, et al. Renal involvement in systemic amyloidosis----an Italian retrospective study on epidemiological and clinical data at diagnosis. Nephrol Dial Transplant. 2007;22:1608---18. 7. Castilla J, Montes R, Quereda C, Marcen R, Rodríguez G, Pereira P, et al. Amiloidosis renal: estudio clínico en 29 pacientes. Rev Clin Esp. 1977;147:349---54. 8. Martínez-Vea A, Torras A, Darnell A, Carrera M, Revert L. Amiloidosis primaria y secundaria renal: manifestaciones clínicas, evolución y supervivencia. Estudio comparativo de 37 pacientes. Med Clin (Barc). 1983;80:191---5. 9. De la Sierra A, Cardellach F, Ingelmo M, Roselló R, Balcells A. Amiloidosis: aspectos clínicos y biológicos de 60 casos. Med Clin (Barc). 1985;84:297---301. 10. González-García JJ, García-Alegría J, Pe˜ na JM, Vicandi B, Picazo ML, Fernández-Capitán MC, et al. Espectro y correlación clinicopatológica en la amiloidosis renal. Estudio de 44 casos. Rev Clin Esp. 1986;178:421---7. 11. García Morán JI, Barat Cascante A, Oliva Aldámiz H. Amiloidosis sistémica: estudio clínico-patológico de 69 casos. Rev Clin Esp. 1992;191:181---6. 12. Laiho K, Tiitinen S, Kaarela K, Helin H, Isomäki H. Secondary amyloidosis has decreased in patients with inflammatory joint diseases in Finland. Clin Rheumatol. 1999;18: 122---3. 13. Hazenberg BP, Van Rijswijk MH. Where has secondary amyoid gone? Ann Rheum Dis. 2000;59:577---9. 14. Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18---22 April 2004. Am J Hematol. 2005;79:319---28. 15. Boletín Oficial del Estado. Ley Orgánica 15/1999, de 13 de diciembre, de protección de datos de carácter personal. Available from: http://www.boe.es/boe/dias/1999/12/14/pdfs/ A43088-43099.pdf [accessed 05.04.12]. 16. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39 Suppl. 1: S1---266. 17. Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361---71. 18. Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, et al. Long-term survival (10 years or more) in 30 patients with primary amyloidosis. Blood. 1999;93:1062---6. 19. Madan S, Dispenzieri A, Lacy MQ, Buadi F, Hayman SR, Zeldenrust SR, et al. Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma. Mayo Clin Proc. 2010;85: 232---8. 20. Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet. 2001;358:24---9.
Clinical characteristics of the patients with systemic amyloidosis in 2000---2010 21. Hazenberg BP, Van Rijswijk MH, Piers A, Lub-de Hooge MN, Vellenga E, Haagsma EB, et al. Diagnostic performance of 123 Ilabeled serum amyloid P component scintigraphy in patients with amyloidosis. Am J Med. 2006;119:355. 22. Palma CL, Grünholz D, Osorio G. Amiloidosis. Comunicación de 11 casos y revisión de la literatura. Rev Med Chile. 2005;133:655---61. 23. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995;32:45---59. 24. Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O’Fallon WM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992;79:1817---22. 25. Gómez-Casanovas E, Sanmartí R, Solé M, Ca˜ nete JD, Mu˜ nozGómez J. The clinical significance of amyloid fat deposits in rheumatoid arthritis. Arthritis Rheum. 2001;44:66---72.
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26. Wakhlu A, Krisnani N, Hissaria P, Aggarwal A, Misra R. Prevalence of secondary amyloidosis in Asian North Indian patients with rheumatoid arthritis. J Rheumatol. 2003;30:948---55. 27. El Mansoury TM, Hazenberg BPC, El Badawy SA, Ahmed AH, Bijzet J, Limburg PC, et al. Screening for amyloid in subcutaneous fat tissue of Egyptian patients with rheumatoid arthritis: clinical and laboratory characteristics. Ann Rheum Dis. 2002;61:42---7. 28. Cordier JF, Loire R, Brune J. Amyloidosis of the lower respiratory tract. Clinical and pathologic features in a series of 21 patients. Chest. 1986;90:827---31. 29. Utz JP, Swensen SJ, Gertz MA. Pulmonary amiloidosis. The Mayo Clinic experience from 1980 to 1993. Ann Intern Med. 1996;124:407---13. 30. Moon AO, Calamia KT, Walsh JS. Nodular amyloidosis. Review and long-term follow-up of 16 cases. Arch Dermatol. 2003;139:1157---9.
Revista Clínica Española www.elsevier.es/rce
ORIGINAL ARTICLE
Clinical characteristics of patients with systemic amyloidosis from 2000---2010夽 D. Real de Asúa∗ , R. Costa, M.M. Contreras, Á. Gutiérrez, M.T. Filigghedu, M. Armas Servicio de Medicina Interna, Fundación de Investigación Biomédica, Hospital Universitario de La Princesa, Madrid, Spain Received 18 April 2012; accepted 10 September 2012 Available online 21 March 2013
KEYWORDS Amyloidosis; Epidemiology; Spain; Proteinuria; Nephrotic syndrome
Abstract Background: The epidemiology of systemic amyloidosis has been changing in the last decades. We aim to describe the clinical characteristics of the patients seen at our institution with systemic amyloidosis in 2000---2010 and compare them with previous Spanish series. Patients and methods: An observational, retrospective study was performed on all the patients admitted to a tertiary hospital in Madrid, Spain who had been diagnosed of amyloidosis from January 2000 to December 2010. Patients without a proven diagnosis of amyloidosis, with dialysis-associated, senile, or localized forms of amyloidosis were excluded from the study. A systematic review was made of the clinical records, collecting the demographic, clinical and biochemical variables at diagnosis and patients’ outcome. Results: A total of 55 patients were studied, 24 (44%) of whom had AL amyloidosis, 30 (56%) AA amyloidosis, and 1 a familiar form. The most frequent underlying disorders were rheumatoid arthritis (9 patients, 30%) and ankylosing spondylitis (4 cases, 13%). The kidneys were the most frequently involved organ (36 patients, 67%) with nephrotic-range proteinuria during diagnosis (3.4 ± 3.7 g/24 h). Median time to diagnosis was 3 months (interquartile range [IQR]: 1---17). Median follow-up time was 24 months (IQR: 10---91). During follow-up 31 patients died; 18 of those deaths were related to amyloidosis. Conclusions: Renal dysfunction dominates the course of systemic amyloidosis, which does not seem to have changed in the last decades. We have observed an important delay in the diagnosis of these processes. Therefore, it is necessary to maintain a high degree of clinical suspicion regarding these conditions. © 2013 Published by Elsevier España, S.L.
DOI of refers to article: http://dx.doi.org/10.1016/j.rce.2012.09.001 Please cite this article as: Real de Asúa D, et al. Características clínicas de los pacientes con amiloidosis sistémicas en el periodo 2000---2010. Rev Clin Esp. 2012. http://dx.doi.org/10.1016/j.rce.2012.09.001. ∗ Corresponding author. E-mail address: [email protected] (D. Real de Asúa). 夽
2254-8874/$ – see front matter © 2013 Published by Elsevier España, S.L.
Clinical characteristics of the patients with systemic amyloidosis in 2000---2010
PALABRAS CLAVE Amiloidosis; Epidemiología; Espa˜ na; Proteinuria; Síndrome nefrótico
187
Características clínicas de los pacientes con amiloidosis sistémicas en el periodo 2000---2010 Resumen Antecedentes: La epidemiología de las amiloidosis sistémicas está cambiando en las últimas décadas. Describimos las características clínicas de los pacientes con amiloidosis sistémicas atendidos en nuestro centro en el periodo 2000-2010 y las comparamos con las anteriores series espa˜ nolas. Pacientes y métodos: Estudio observacional retrospectivo de pacientes con diagnóstico de amiloidosis sistémica en un hospital terciario entre enero de 2000 y diciembre de 2010. Se excluyó a los pacientes sin diagnóstico histológico y a aquellos con formas asociada a diálisis, seniles o localizadas. Mediante revisión sistemática de las historias clínicas se recogieron las variables demográficas, clínicas, de diagnóstico, seguimiento y mortalidad. Resultados: Se estudió a 55 pacientes, 24 (44%) tenían amiloidosis AL, 30 (56%), amiloidosis AA y un paciente, una forma familiar. Las enfermedades inflamatorias subyacentes más frecuentes fueron la artritis reumatoide (9 pacientes, 30%) y la espondilitis anquilosante (4 enfermos, 13%). El órgano más frecuentemente afectado fue el ri˜ nón (36 pacientes, 67%), con una proteinuria al diagnóstico de 3,4 ± 3,7 g/24 h. El tiempo hasta el diagnóstico fue de 3 meses (rango intercuartílico [RIC]: 1-17). La mediana de seguimiento fue de 24 meses (RIC: 10-94). Durante el seguimiento fallecieron 31 pacientes y 18 muertes fueron atribuíbles a la amiloidosis. Conclusiones: La afectación renal es la presentación más prevalente de las amiloidosis sistémicas, sin cambios en las últimas décadas. Observamos un largo tiempo de latencia hasta el diagnóstico, por lo que es preciso mantener un alto grado de sospecha clínica de estos procesos. © 2013 Publicado por Elsevier España, S.L.
Introduction Amyloidosis represents a heterogeneous group of diseases characterized, from the pathogenic standpoint, by an extracellular deposit of proteins in the form of insoluble fibers. These proteins aggregate in a characteristic three-dimensional configuration in beta-sheets, which when stained with Congo red exhibits birefringence under polarized light.1 To date, 25 structurally unrelated proteins capable of causing amyloidosis are known.2 The various forms of amyloidosis are classified according to these precursor proteins and by the distribution of the amyloid deposit in the body.3 The main types of systemic amyloidosis are primary (AL) amyloidosis, secondary (AA) amyloidosis, familial amyloidosis, senile amyloidosis and amyloidosis associated with the deposit of beta-2-microglobulin in patients with end-stage chronic kidney disease.4 Amyloidoses are classified as rare diseases, despite the fact that our knowledge of their epidemiology is based only on small retrospective series and they are probably underdiagnosed conditions.5,6 The last Spanish series of patients with amyloidosis was published more than 20 years ago. These series have reported a predominance of secondary systemic forms combined with a high prevalence of tuberculosis and other chronic infections.7---11 Various authors have indicated that the epidemiology of systemic amyloidosis, particularly secondary forms, has changed in recent decades as a result of earlier diagnoses, more potent and active treatments against the baseline diseases and a reduction in the comorbidity associated with the underlying inflammatory diseases.12,13 At the same time, there is concern that the low diagnosis of these conditions is a reflection of less clinical suspicion due to a change in the type of presentation of systemic amyloidosis and a more indolent course.13
The aim of this study is two-fold. It seeks to describe the clinical characteristics of patients diagnosed with systemic amyloidosis who were treated in a tertiary hospital in Madrid during the period 2000---2010 and compare these with previously published Spanish series.
Patients and methods Study design and patient selection We conducted a retrospective observational study on patients admitted to the University Hospital La Princesa of Madrid in the period between January 2000 and December 2010 who had a diagnosis (primary or secondary) of amyloidosis. The diagnosis of amyloidosis was accepted if it met the clinical, laboratory and histopathological criteria in terms of the personal and family history, the history of inflammatory disease, organ involvement and/or the presence of a monoclonal component in serum or urine, according to the currently accepted diagnostic criteria for amyloidosis.14 Using a computerized review of medical records, we conducted patients follow-up until death, to loss or to the present. We excluded from the final analysis those patients with senile forms of amyloidosis (cerebral amyloid angiopathy and senile cardiac amyloidosis), nodular localized amyloidosis and amyloidosis associated with beta-2-microglobulin. We also excluded from the final analysis those with a presumptive clinical diagnosis (lacking histological confirmation) and those who, with a positive result for amyloids in an abdominal fat biopsy, did not develop symptoms of amyloidosis during the follow-up period. We only analyzed those
188
What did we know? The characteristics of systemic amyloidosis in our community have been defined in case study series for more than 20 years. In these series, there is a predominance of systemic forms associated with chronic infectious diseases such as tuberculosis. There have been no studies in Spain that have reviewed these concepts.
What this article provides Starting with the study of patients with a histologically confirmed diagnosis of amyloidosis, the authors have analyzed the characteristics and etiology of systemic amyloidosis over the past decade. Ongoing nephrotic syndrome is a common manifestation of this disease. As expected, there has been a reduction in infections as the cause of secondary amyloidosis, with a greater predominance of inflammatory diseases such as rheumatoid arthritis and ankylosing spondylitis. The delay in time to diagnosis of the disease remains long, despite technological advances. The Editors
admissions in which a diagnosis of amyloidosis was reached. Successive admissions were excluded from the analysis. The study was conducted in accordance with the principles of the Declaration of Helsinki (1996) and the current Good Clinical Practice guidelines. Due to the absence of an intervention and the retrospective nature of the study, the hospital’s ethics committee considered it unnecessary to request the patients’ informed consent. All the data were treated with the upmost confidentiality in accordance with the current legislation.15
Literature search One of the authors of this study performed a systematic search on Medline with the following search terms (amyloidosis [MeSH] AND Spain [MeSH]). This search was crossed with the main Spanish medical journals. We also conducted a selective search by using the bibliographies of the articles of interest. The initial search yielded 216 results, 7 of which were series of patients with systemic amyloidosis. One of the studies was not a Spanish series and another lacked sufficient information to perform a clinical or etiological comparison and were therefore discarded. The rest of the results consisted of 121 case descriptions, 39 specific series and 49 other types of articles.
Variables and measurements Using a systematic review of the medical records, we collected demographic variables (age and gender), clinical variables (type of amyloidosis, baseline disease, evolution time of baseline disease and organ involvement14 ), diagnostic variables (laboratory parameters [hemoglobin,
D. Real de Asúa et al. platelets, activated partial thromboplastin time, glomerular sedimentation rate, C-reactive protein, urea, creatinine, albumin, creatinine clearance (calculated with the MDRD-6 formula16 ), proteinuria, alkaline phosphatase, immunoglobulins and immunoelectrophoresis in serum and urine]; additional tests [especially electromyograms, echocardiograms, computed axial tomography and magnetic resonance imaging] and histological tests: type of biopsy and its result) and follow-up variables (time to diagnosis, time to the end of follow-up and death). The histological diagnosis of amyloidosis was performed on samples obtained through abdominal fat biopsy by fine needle aspiration (FNAC) of rectal fat, bone marrow or tissue from the specific organ. A valid histological diagnosis was considered for those biopsies that were positively stained with Congo red and demonstrated applegreen birefringence under polarized light. The deposited amyloid subtype was characterized by immunohistochemical techniques.14
Statistical analysis The data were analyzed with G-Stat 2.0® software (GlaxoSmithKline SA, Madrid, Spain) and GraphPad Prism® (GraphPad Software, San Diego, CA, USA). The qualitative results are shown as absolute frequencies and percentages, while the quantitative results are shown as mean ± standard deviation (SD). The time-dependent variables are shown as median and interquartile range (IQR). The comparative study of qualitative variables was analyzed according to the chi-squared test or Fisher’s exact test. We used Student’s ttest or the Mann---Whitney U test for quantitative variables. All the statistical tests were analyzed bilaterally. Results with p < 0.05 were considered statistically significant.
Results Clinical and analytical characteristics of the patients at diagnosis We identified 173 admissions of patients with a diagnosis of amyloidosis during the analyzed period. We excluded 118 episodes (68.2%) from the final analysis: 77 episodes (44.5%) corresponded to successive admissions of patients already diagnosed with amyloidosis; 13 patients (7.5%) lacked a histological diagnosis; 8 patients (4.6%) with positive abdominal fat biopsy for amyloid material did not develop symptoms of amyloidosis during their follow-up (median follow-up time: 24 months [IQR: 10---94 months]); 8 patients (4.6%) were diagnosed in other centers or other autonomous communities, 4 patients (2.3%) had nodular localized forms (located in the lungs, lungs and skin, skin and genito-urinary, respectively), and none of the patients developed systemic amyloidosis during the follow-up period; 4 (2.3%) presented senile forms of amyloidosis (2 for cerebral amyloid angiopathy and 2 for senile cardiac amyloidosis); and 2 patients (1.1%) developed amyloidosis associated with dialysis. Insufficient clinical or histological criteria to support a diagnosis of amyloidosis were found in 3 patients (1.7%). Fifty-five patients (31.8%) were included in the final analysis. Only one case of familial amyloidosis was found.
Clinical characteristics of the patients with systemic amyloidosis in 2000---2010 Table 1
189
Clinical characteristics at diagnosis of 54 patients with systemic amyloidosis between 2000 and 2010.
Clinical characteristics
Total n = 54
AL n = 24
AA n = 30
p value
Age (years) Gender (% males)
64 ± 13 26 (48)
66 ± 12 12 (50)
62 ± 14 14 (47)
NS NS
Clinical involvement Renal Required dialysis at diagnosis Cardiac HF at diagnosis Septum thickness IV (mm) Gastrointestinal Hepatic Neurological Polyneuropathy Carpal tunnel syndrome Skin and soft tissue
36 (67%) 11 (20%) 18 (33%) 14 (26%) 15 ± 2 11 (20%) 13 (24%) 16 (30%) 3 (6%) 8 (15%) 6 (11%)
16 (67%) 3 (13%) 12 (50%) 9 (38%) 15 ± 2 5 (21%) 5 (21%) 10 (42%) 3 (13%) 5 (21%) 5 (21%)
20 (67%) 8 (27%) 6 (20%) 5 (17%) 14 ± 1 6 (20%) 8 (27%) 6 (20%) 0 3 (10%) 1 (3%)
NS NS <0.05 NS NS NS NS NS NS NS <0.01
AA: secondary amyloidosis; AL: primary amyloidosis; HF: heart failure; NS: no significant difference; septum IV: interventricular septum.
This case involved a male with familial amyloidosis by mutated transthyretin who began with a clinical picture of mixed polyneuropathy with ‘‘stocking and glove’’ distribution several years before admission to our center. The clinical characteristics during diagnosis of the 54 remaining patients are summarized in Table 1. Cardiac impairment in the form of heart failure was more prevalent in patients with AL amyloidosis. All the patients with heart failure met the current criteria of echocardiography diagnosis of amyloid infiltration.13 Only one endomyocardial biopsy was performed to confirm local involvement, and the result of this biopsy was positive. Furthermore, the impairment of the
Table 2
peripheral nervous system was more common in the primary amyloidosis group, which presented more cases of polyneuropathy and carpal tunnel syndrome (3 [13%] vs. 0 cases and 5 [21%] vs. 3 [10%] cases, respectively; p-value not significant for either comparison). Cutaneous involvement was more common in the AL amyloidosis group. We found no other relevant clinical differences between the groups. The differences in terms of the analytical parameters between the groups are detailed in Table 2. In general, the predominant analytical pattern had mild anemia, moderately increased acute phase reactants, decreased glomerular filtration rate with analytical data showing renal
Analytical characteristics at diagnosis of patients with systemic amyloidosis.
Analytical parameters
Total n = 54
AL n = 24
AAn = 30
p value
Hemoglobin (g/dl) Platelets (1.000/mm3 ) GSR (mm/h) CRP (mg/dl) TTPA (s) Urea (mg/dl) Creatinine (mg/dl) Albumin (g/dl) CRCL (ml/min) Proteinuria (g/24 h) Alkaline P (U/l) IgG (mg/dl) IgM (mg/dl) IgA (mg/dl) Light chains in serum (% pathological) IF serum (% pathological) IF urine (% pathological)
11.6 ± 2.2 229 ± 140 56 ± 36 3.3 ± 4.5 32.8 ± 18.8 73 ± 48 2.2 ± 1.9 3.0 ± 0.8 51 ± 35 3.41 ± 3.76 262 ± 331 647 ± 481 283 ± 400 139 ± 194 10 (19) 13 (24) 13 (24)
12.0 ± 2.0 243 ± 104 47 ± 36 1.1 ± 1.6 32.5 ± 22.0 74 ± 60 2.0 ± 1.9 3.1 ± 0.8 51 ± 32 3.64 ± 4.60 182 ± 286 590 ± 400 327 ± 497 131 ± 213 10 (42) 13 (54) 13 (54)
11.3 ± 275 ± 62 ± 5.2 ± 33.2 ± 72 ± 2.3 ± 2.9 ± 51 ± 3.16 ± 329 ± 753 ± 214 ± 152 ± -------
NS NS NS <0.01 NS NS NS NS NS NS NS NS NS NS -------
2.4 134 36 5.3 14.9 33 2.0 0.8 39 2.73 356 574 165 167
AA: secondary amyloidosis; AL: primary amyloidosis; CRCL: creatinine clearance by the equation MDRD-6; Alkaline P: alkaline phosphatase; IF: immunofluorescence; Ig: immunoglobulin; NS: no significant difference; CRP: C-reactive protein; aPTT: activated partial thromboplastin time; GSR: glomerular sedimentation rate.
190 Table 3
D. Real de Asúa et al. Distribution of baseline diseases causing systemic amyloidosis in 6 Spanish series.
Sample size
Actual n = 54 (%)
García Morán et al.11 n = 69 (%)
González-García et al.10 n = 44 (%)
De la Sierra et al.9 n = 60 (%)
Martínez-Vea et al.8 n = 37 (%)
Castilla et al.7 n = 29 (%)
Amyloidosis AL Multiple myeloma
24 (44) 5 (21)
19 (28) 7 (37)
12 (27) 3 (25)
19 (32) 7 (37)
12 (32) ---
6 (21) 0
Amyloidosis AA Rheumatoid arthritis Ankylosing spondylitis Chronic infections Inflammatory bowel disease Autoinflammatory Psoriasis Other inflammatory processes Tumors N/S
30 9 4 3 2 2 2 2 2 4
49 (71) 10 (20) 1 (2) 29 (59) --5 (10) --3 (7) 1 (2) ---
32 (73) 6 (19) 1 (3) 14 (44) --2 (6) --4 (12) 2 (6) 3 (9)
38 (63) 12 (32) 8 (21) 16 (42) ----4 (11) 1 (3) 1 (3) ---
25 (68) 2 (8) 5 (20) 12 (50) 1 (3) --1 (3) 3 (12) 1 (3) ---
21 (72) 4 (19) --13 (62) --------4 (19) ---
(56) (30) (13) (10) (7) (7) (7) (7) (7) (13)
The results are expressed as n (%). N/S: no underlying inflammatory process was found.
failure and proteinuria in the nephrotic range, hypoalbuminemia and increased alkaline phosphatase. We found no relevant abnormalities in any of the patients’ coagulation times. The activity of factor X was only measured in 4 patients (31%, 54%, 70% and 102%) and was only altered in a single case. When comparing the groups, we observed a significantly greater increase in the serum levels of C-reactive protein in the group of patients with AA amyloidosis (5.2 ± 5.3 vs. 1.1 ± 1.6 mg/dl, difference in means 4.1 mg/dl, 95% confidence interval [CI]: 2.1---6.1; p < 0.01).
Table 4 Biopsies performed to reach the histological diagnosis of amyloidosis. Type of biopsy
Positive
Negative
Not performed
FNAC abdominal fat Rectal fat Bone marrow Target organ
18 6 5 39
15 1 10 2
21 47 39 13
The result is expressed as absolute frequencies. FNAC: fine needle aspiration cytology.
Description of the underlying etiologic processes In 26 of the patients with secondary amyloidosis (26/30, 87%), we identified a baseline chronic inflammatory disease whose distribution is summarized in Table 3. The median time of evolution of the disease to the development of amyloidosis was 101 months (IQR: 51---188 months), with a period from the onset of symptoms to the diagnosis of amyloidosis of 3 months (IQR: 1---17 months). In 4 patients with AA amyloidosis, an etiological diagnosis was not reached despite an intensive study. Five patients with AL amyloidosis (5/24, 21%) had a baseline disease of multiple myeloma diagnosed prior to the development of symptoms suggestive of amyloidosis.
Diagnostic methods for amyloidosis The various methods employed for the histological diagnosis of amyloidosis are detailed in Table 4. Nine patients (17%) were exclusively diagnosed based on their clinical picture and a positive abdominal fat biopsy. In 3 patients (6%), the only positive biopsy was the rectal fat biopsy. Twenty-eight patients (52%) were diagnosed according to their symptoms and a positive target organ biopsy (patients with negative abdominal or rectal fat biopsy). In the remaining patients (14 cases, 25%), the histological confirmation of an amyloid deposit was demonstrated in several locations (target organ, abdominal and/or rectal fat). The most frequently biopsied
organ was the kidney, which was performed on 20 patients (37% of the total, 71% of the cases diagnosed using target organ biopsies).
Follow-up and survival The median follow-up time was 24 months (IQR: 10---94 months); there were no significant differences between the patients with primary and secondary amyloidosis (23 months [IQR: 12---94] vs. 24 months [IQR: 9---103]). Seven patients were lost during follow-up (2 patients with AL amyloidosis and 5 with AA amyloidosis). Ten patients with AL amyloidosis received specific treatment (10/24, 42%). The melphalan---prednisone regimen was used initially in 7 patients. The 3 remaining patients received bortezomib in monotherapy, bortezomib and autologous hematopoietic progenitor cell transplantation, and thalidomide, respectively. There were no significant differences in the median survival between the treated and untreated patients in this group (12 months [IQR: 6---20] vs. 30 months [IQR: 0---75], p value not significant). In 13 of the patients with AA amyloidosis (47%), the regimen was changed prior to treatment: in 2 cases, the treatment with glucocorticoids was intensified, 2 patients received chlorambucil; in 5 cases, infliximab was used; and 4 others received various treatments (surgery, methotrexate and rituximab, melphalan---prednisone and colchicine). These patients had a greater survival than the
Clinical characteristics of the patients with systemic amyloidosis in 2000---2010 Table 5
191
Differences in the presentation symptoms of patients with systemic amyloidosis among 6 Spanish series.
Sample size
Actual n = 54 (%)
García Morán et al.11 n = 69 (%)
GonzálezGarcía et al.10 n = 44 (%)
De la Sierra et al.9 n = 60 (%)
Martínez-Vea et al.8 n = 37 (%)
Castilla et al.7 n = 29 (%)
Age (years) Gender (% males)
64 ± 13 26 (48)
48 ± 15 41 (59)
47 ± 18 23 (52)
57 ± 13 36 (60)
49 ± 16 21 (57)
52 21 (72)
Clinical involvement Renal Required dialysis at diagnosis Cardiac HF at diagnosis Gastrointestinal Hepatic Neurological Polyneuropathy Carpal tunnel syndrome Skin and soft tissue
36 (67) 11 (20) 18 (33) 14 (26) 22 (41) 13 (24) 16 (30) 3 (6) 8 (15) 6 (11)
52 (75) --13 (19) --23 (33) 21 (30) --2 (3) 2 (3) 6 (9)
44 (100) ----12 (27) 20 (45) 21 (47) --12 (27) --3 (7)
47 (78) ----7 (12) 8 (13) 13 (22) --4 (7) 3 (5) 4 (7)
37 (100) 10 (27) 4 (11) 2 (5) 1 (3) 7 (19) --2 (5) --3 (8)
29 (100) ----6 (21) 7 (24) 12 (41) --0 -----
The results are expressed as n (%). HF: heart failure.
untreated group (median survival: 58 months [IQR: 21---96] vs. 8 months [IQR: 2.5---21.2]; p < 0.05). During the follow-up period, 31 patients died (57%). Eighteen of these deaths were attributed to amyloidosis. Ten patients with AL amyloidosis died due to refractory heart failure (42% of this patient group, 18% of the total). Eight patients with AA amyloidosis died due to renal failure progression and associated multiple organ failure (27% of this group, 15% of the sample; the difference in deaths between the groups was not statistically significant).
Clinical and etiological differences compared with previous series Compared with the previously published series, we observed a progressive increase in our sample in the proportion of cases of AL amyloidosis as compared with the AA form (Table 3). We observed a substantial reduction in chronic infections as AA amyloidosis causal processes. Of the 3 cases of amyloidosis secondary to chronic infection in our sample, 2 patients showed chronic osteomyelitis and one showed cystic fibrosis. We did not find any case of AA amyloidosis secondary to tuberculosis in the past decade. When analyzing the clinical presentation of the patients, the primary difference was the greater age of the patients in our series (Table 5).
Discussion The clinical characteristics of the patients diagnosed with systemic amyloidosis over the last decade at our center agree with those described in national and international series.7---11,17,18 Renal impairment, predominantly in the form of nephrotic syndrome, dominates the clinical picture, both in primary and secondary forms. In one of every five patients, the use of renal replacement techniques was necessary during diagnosis. In our series, we also observed a greater cardiac impairment of the peripheral and cutaneous
nervous system in the patients with AL amyloidosis as compared with those with AA amyloidosis. These results contradict the opinion of Hazenberg and Van Rijswijk who indicate a possible change in the current clinical presentation of systemic amyloidosis.13 Although the presentation of these conditions remains classic, the delay time in diagnosis found in our series is, in our opinion, striking. We have not found any other studies in the literature that analyze this issue in detail. However, this fact leads us to insist on the need to maintain a high clinical suspicion of amyloidosis in the study of processes that are associated with renal failure, with heart failure in the absence of classic factors of vascular risk or with polyneuropathies. The greater mean age found in our series as compared with the previous national series agrees with that described by Kyle et al. and Madan et al. in patients with primary amyloidosis.18,19 This result may have numerous bases. The percentage increase in cases of AL amyloidosis is probably associated with an earlier diagnosis of diseases that cause AA amyloidosis and more widespread access to more effective treatments, which achieves better control of the diseases with greater frequency, thus preventing later development of amyloidosis. This would explain not only the gradual reduction of cases of AA amyloidosis but also the proportional reduction in the cases of AL amyloidosis associated with multiple myeloma. We have observed a substantial change in the distribution of diseases that cause secondary amyloidosis, with a highly significant reduction in chronic infections such as etiological agents. These conclusions are also supported by recent international series17,20---22 and appear to be related to more widespread use of more active antibiotics and better control of tuberculosis. Although we have not found any case of amyloidosis due to tuberculosis in the past decade, tuberculosis remains a relevant cause of amyloidosis in other European countries.6 Nevertheless, secondary amyloidoses remain the most common in our community, in contrast to what is observed in the United States, where the AL form is predominant.23,24 A number of authors
192 attribute this greater prevalence of AA amyloidosis in Europe to genetic, dietary and lifestyle factors and to the use of different medical treatments.13 Our study has several strong points. The selection method of cases per episode of admission and the use of the term ‘‘amyloidosis’’ as the only search criterion constitute a sensitive method that identifies all possible cases of interest. This selection method and the retrospective nature of the study also allow us to identify patients whose final diagnosis of amyloidosis was reached after more than one admission. In this manner, we manage to recover those cases in which the histological confirmation was achieved in a subsequent admission. In addition, the diagnoses of amyloidosis encountered were reviewed in light of currently accepted criteria.14 This led to the exclusion of 3 patients due to a lack of clinical or histological data consistent with amyloidosis, as well as 8 more patients with positive abdominal fat biopsies for amyloid material who did not develop symptoms of amyloidosis during follow-up. The treatment of this subgroup of patients with baseline inflammatory disease and with subcutaneous deposits of amyloid material is still controversial (‘‘subclinical amyloidosis’’13 ) and its prognosis is more favorable than that for patients with manifested amyloidosis.25---27 We also excluded from the study those patients with nodular forms of amyloidosis. Previous case series have demonstrated the lack of progression to systemic amyloidosis in this group of patients.28---30 This study, however, also has a number of limitations. It was conducted in a single center. The retrospectively nature of the study may have caused the calculation of the evolution and follow-up times to be inaccurate. We recorded the time in months to minimize the magnitude of this error. The small sample size of the analyzed series helps blur the possible differences between the series in the statistical study. Unfortunately, this limitation is inherent in the low prevalence of amyloidosis in the general population.3,4 In summary, the presentation of systemic amyloidosis in Spain does not seem to have changed in recent decades. Renal impairment remains the most prevalent in the form of nephrotic syndrome, both in primary and secondary forms, followed in the AL form by cardiac and neuropathic impairment. The most commonly found baseline diseases these days are chronic inflammatory processes such as rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease. Although its presentation remains ‘‘classical’’, the delay in time to diagnosis is long. This leads to a greater progression of the disease and limits its subsequent treatment. We must maintain a high clinical suspicion of these conditions when studying processes that are associated with renal failure, with heart failure in the absence of vascular risk factors or with polyneuropathies.
Conflicts of interest The authors have no conflicts of interest to declare.
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