Amyloid load in fat tissue reflects disease severity and predicts survival in amyloidosis.

OBJECTIVE: The severity of systemic amyloidosis is thought to be related to the extent of amyloid deposition. We studied whether amyloid load in fat tissue reflects disease severity and predicts survival. METHODS: We studied all consecutive patients with systemic amyloidosis seen between January 1994 and January 2007 in our tertiary referral center. Congo red-stained abdominal fat smears were graded by 2 observers using a validated semiquantitative scoring system. Disease severity was measured by the total number of major organs involved and the extravascular retention of the serum amyloid P component (EVR(24)). The association of amyloid load in fat tissue with disease severity and overall survival was studied using multiple regression analysis. RESULTS: Two hundred twenty patients were included in the study (120 with AL amyloidosis, 66 with AA amyloidosis, and 34 with ATTR amyloidosis). Amyloid grade in fat tissue was associated with the number of major organs involved and EVR(24). Female sex turned out to be associated with a higher grade of amyloid in fat tissue than male sex. Amyloid grade in fat tissue was an independent predictor of decreased survival, as were heart involvement, the number of organs involved, AA or AL type of amyloid, and age. CONCLUSION: The amount of amyloid in subcutaneous fat tissue in systemic amyloidosis reflects disease severity, as measured by the number of organs involved and EVR(24), and predicts decreased survival independent of other well-known factors.

Histological regression of amyloid in AL amyloidosis is exclusively seen after normalization of serum free light chain.

BACKGROUND: Histological regression of amyloid has not been studied systematically but is assessed by clinical parameters. We analyzed the change of amyloid deposition in fat tissue in patients with AL amyloidosis following chemotherapy and studied the relation with type of hematologic response. DESIGN AND METHODS: Between January 1994 and July 2007 all consecutive patients with AL amyloidosis were evaluated in whom fat tissue aspirate was obtained before and following chemotherapy. Patients were divided into three groups depending on response of serum free light chain: complete, partial or non-responders. Fat tissue was assessed using a validated semi-quantitative test (grading 0-4). A change of 2 grades of amyloid deposition in fat tissue was considered significant and used as event to construct Kaplan-Meier curves of the patients who were able to reflect such a change. RESULTS: One hundred and twenty consecutive patients were studied. Fifty-one patients fulfilled inclusion criteria. Thirty patients had a complete response of the amyloidogenic free light chain a median 0.5 year (range 0.3-2.9 years) following chemotherapy. Reduction of 2 grades of amyloid deposition in fat tissue was seen in 50% of these patients after 2.4 years and in 80% after 3.2 years. In contrast to complete responders, none of the patients with partial (n=9) and non-response (n=12) showed reduction of 2 grades (p=0.02) with median follow-up of fat tissue analysis of 1.3 and 0.8 years, respectively. CONCLUSIONS: This study in a selected group of patients with AL amyloidosis shows significant histological regression of amyloid deposition in fat tissue exclusively after normalization of serum free light chain.

Familial amyloidotic polyneuropathy: long-term follow-up of abdominal fat tissue aspirate in patients with and without liver transplantation.

To estimate the evolution of amyloid in tissue, we studied abdominal fat aspirates of cases with familial amyloidotic polyneuropathy (FAP) longitudinally at regular intervals between 1994 and 2006. In 22 cases (13 carriers and nine patients) not yet transplanted median follow-up was 3.3 years (range 0.4-11.3). We found a significant increase in the amyloid grade of fat tissue from 2+ to 4+ and from 0 to 4+ in two of three subjects with follow-ups of >7 years, after 7 and 11 years, respectively. All other subjects remained negative or did not show a significant change. In 11 liver transplant patients, follow-up with fat aspirate was available with a median duration of 3.1 years (range 1.0-10.1). A comparison was made with cardiac amyloid as judged by the cardiac septum diameter and the serum NT-ProBNP (N-terminal pro-B-type natriuretic peptide) level. No stable increase of amyloid in fat was seen in any patient. A stable decrease of amyloid grade was seen in one patient 5 years after transplantation. In contrast, the cardiac septum diameter increased >or=4 mm in six of the 11 transplant patients. Our study shows the diagnostic utility of a regularly repeated fat aspirate in carriers at risk for the development of ATTR amyloidosis. Evolution of amyloid deposition in fat tissue is very gradual. After liver transplantation, amyloid deposition in fat tissue seems to stabilize and may even decrease in the long term, whereas amyloid deposition in cardiac tissue appears to be progressive.

Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice.

OBJECTIVE: Aspiration of subcutaneous abdominal fat is a simple and fast method for detecting systemic amyloidosis; however, the sensitivity of this approach remains undetermined. The aim of this study was to assess the accuracy of fat tissue aspiration for detecting systemic amyloidosis and the utility of this method in clinical practice. METHODS: All consecutive patients with established and suspected systemic amyloidosis who attended our tertiary referral hospital between 1994 and 2004 underwent aspiration of subcutaneous abdominal fat. Congo red-stained tissue was assessed quickly in a single smear in a routine manner by a single observer, and was also assessed thoroughly in 3 smears by 2 independent observers. RESULTS: One hundred twenty patients with established systemic amyloidosis were studied (38 with AA amyloidosis, 70 with AL amyloidosis, and 12 with ATTR amyloidosis). Routine (quick) assessment was associated with a sensitivity of 80% (95% confidence interval [95% CI] 72-87%). Sensitivity increased to 93% (95% CI 87-97%) when 3 smears were thoroughly examined. The specificity of fat aspiration in 45 control subjects was 100% (95% CI 92-100%). One hundred sixty-two patients for whom there was a clinical suspicion of systemic amyloidosis were screened for amyloidosis by fat tissue aspiration and biopsy of at least 1 other tissue. In 69 (43%) of these 162 patients, a diagnosis of amyloidosis was established, and in 66 (96%) of these patients, the results of fat tissue aspiration were positive. The clinical utility of fat tissue aspiration was greater than that of biopsy of the rectum. CONCLUSION: Subcutaneous abdominal fat aspiration is the preferred method for detecting systemic amyloidosis, with sensitivity of 80% associated with use of a routine approach. The use of a thorough assessment (3 fat smears, 2 observers) increased sensitivity to >90%. If the results of fat tissue aspiration are negative, the additional value of a subsequent biopsy of the rectum is negligible.

AL amyloidosis treated with induction chemotherapy with VAD followed by high dose melphalan and autologous stem cell transplantation.

High dose melphalan (HDM) followed by reinfusion of autologous blood stem cells (ASCT) has been applied in AL amyloidosis. Vincristine, doxorubicin, and dexamethasone (VAD) rapidly decrease light chain production in multiple myeloma. In a Phase I/II study of VAD followed by HDM and ASCT in AL amyloidosis, toxicity, feasibility, and response to this regimen were evaluated. Over a 5-year period 38 patients with AL amyloidosis were seen of which 12 out of 18 eligible patients participated in the study. VAD induced a distinct clonal response in 50% (6/12) of the patients, but without clinical improvement. In 11 patients HDM and ASCT was applied. Six months after ASCT 78% (7/9) of the surviving patients showed partial clonal response and none responded completely. Clinical condition evidently improved in 67% (6/9) of survivors, whereby clonal response, clinical response, performance score, and SAP scintigraphs were concordant. Therefore a complete clonal response is not a prerequisite for clinical improvement. With median follow-up after ASCT of 25 months, 75% of the study group patients were alive. Mortality was strongly depending on the number of organs involved Patients treated with HDM and ASCT had better survival than those not eligible (P < 0.0005).