2011/01/31 by Nagaaki Katoh, Masayuki Matsuda, Ayako Tsuchiya‐Suzuki +1 · 5 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Amyloidosis: Diagnosis, Treatment, Outcomes #Neuroendocrine Tumor Research Advances #Drug Transport and Resistance Mechanisms
paper · pdf · doi:10.1111/j.1365-2141.2010.08503.x
Intensive chemotherapies, such as high-dose melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT), have recently been shown to produce improvement of organ dysfunction with prolonged survival of the patients in primary systemic AL amyloidosis. Nevertheless, it remains controversial whether or not histopathological regression of AL amyloid deposits occurs after treatment (Lachmann et al, 2003; Zeier et al, 2003). To approach this clinical issue, we retrospectively evaluated the amyloid burden in the gastroduodenal mucosa before and after intensive chemotherapies. The chemotherapeutic regimens performed were VAD (vincristine, doxorubicin, dexamethasone) and subsequent HDM/SCT in eight patients, HDM/SCT alone in two and VAD alone in two. After these intensive chemotherapies eight patients achieved complete haematological remission (CR), while the remainder had a positive M-protein in either serum or urine. None of the CR patients showed reappearance of M-protein in either serum or urine at post-treatment examinations performed at an approximate 1-year interval. The CR group included six patients with nephrotic syndrome, all of whom showed marked decreases in daily protein excretion in urine after treatment. Painful paresthesia in the legs markedly ameliorated after CR in one patient with polyneuropathy. All CR patients remain alive, and their observation periods after treatment range from 1 year 5 months to 8 years 3 months (mean, 57·8 ± 29·8 months). In the non-CR group clinical symptoms were almost stable or worsened with persistently positive M-protein. Microscopic examinations after treatment revealed obvious decreases in amyloid deposition in both the gastric and duodenal mucosa of the CR patients (Fig 1). All eight CR patients showed obvious decreases in the amyloid deposition score of the gastric mucosa after treatment (Fig 2A). There were significant differences in the amyloid deposition score between before and 1–2 or 3–4 years after treatment. The amyloid deposition score also decreased in the duodenal mucosa of five of the seven CR patients 1–2 or 3–4 years after treatment compared with before, but this difference was not significant (Fig 2C). The magnitude of decreases in the amyloid deposition score after treatment in the gastric mucosa showed a significantly positive correlation with the reduction rate of amyloidogenic FLCs in serum (Fig 2E). The duodenal mucosa also showed the same correlation between the magnitude of decreases in the amyloid deposition score and the reduction rate of amyloidogenic FLCs, but was not statistically significant. In the non-CR patients the amyloid deposition score in both the gastric and duodenal mucosa slightly decreased or did not change after treatment (Fig 2B, D). A representative case (Patient 3) showing marked reduction of amyloid deposition in the gastric mucosa. A and B are before treatment, and C and D are 2 years after treatment. Heavy deposition of amyloid is visible mainly in muscularis mucosae before treatment, while these deposits show an obvious decrease after treatment: in the latter slight deposition of amyloid is present also in submucosal vascular walls (Congo red staining, original magnification ×18). The amyloid deposition score before and after treatment was 2.89 and 1.87 respectively. The insert in A is immunohistochemistry of the framed area, which shows a positive reaction for the anti-ALκ antibody (original magnification ×23). The amyloid deposition score in the gastric mucosa significantly decreased at 1–2 and 3–4 years after treatment (P = 0·04) compared with before treatment in the patients with complete haematological remission (CR) (A). The duodenal mucosa also showed such a tendency, but was not statistically different (B). In the non-CR patients no significant change was present in either the gastric (C) or duodenal mucosa (D). The CR patients showed a significant correlation between the magnitude of decreases in the amyloid deposition score in the gastric mucosa and the reduction rate of the amyloidogenic free light chains (FLCs) in serum (P = 0·03, r = 0·75) (E). The present study found a clear decrease in AL amyloid deposits in almost all CR patients. Two CR patients showed no obvious decrease in the duodenal mucosa, but their amyloid deposition scores had already been low before treatment. Considering that the severity of amyloid deposition in the gastric mucosa significantly decreased within 1–2 years after CR in our patients, regression of AL amyloid deposits seemed to occur more rapidly than previously recognized (Glenner, 1980). Several reports have demonstrated similar prompt changes in gastroduodenal amyloid deposition in a few successfully treated patients with rheumatoid arthritis -related systemic AA amyloidosis (Kuroda et al, 2009). It was long thought that amyloid deposits formed by the accumulation of insoluble fibrillar proteins were stable in vivo (Glenner, 1980). However, it has recently been proposed that amyloid deposits turn over continuously in vivo (Gillmore & Hawkins, 1999) and that the balance between deposition and removal of amyloid fibrils determines whether the amyloid load will progress or regress (Lachmann et al, 2007). Gastrointestinal mucosal cells are continually replaced with new ones and, especially in humans, turnover of the gastric surface epithelium occurs every 4–5 days (Padykula, 1977). This physiological property of the gastrointestinal mucosa might affect the rapid regression of amyloid deposits on gastroduodenal mucosa after radical treatments. Another notable finding in the present study is that there was a close relationship between regression of AL amyloid and the reduction rate of amyloidogenic FLCs in serum. Several reports have demonstrated that serum levels of FLCs are useful as a clinical marker not only for diagnosis (Abraham et al, 2003) but also for evaluating the therapeutic efficacy of chemotherapy in primary systemic AL amyloidosis (Lachmann et al, 2003). In addition, serum levels of FLCs can contribute to predicting the prognosis of the disease. A >50% reduction of amyloidogenic FLCs or normalization of the κ/λ ratio after treatment have been reported to indicate a substantial survival benefit, irrespective of the chemotherapeutic regimens in primary systemic AL amyloidosis (Lachmann et al, 2003). The present study revealed that the magnitude of decreases in the gastric amyloid deposition score in CR patients was positively correlated with the reduction rate of amyloidogenic FLCs in serum. Although the mechanisms by which amyloid is mobilized and cleared from the affected tissues are incompletely understood, cessation of the supply of amyloidogenic monoclonal light chains by intensive chemotherapies can lead to regression of amyloid deposits in primary systemic AL amyloidosis, accompanied by restored organ function. This is the first clear histopathological evidence supporting the hypothesis mentioned above. This work was supported by a grant from the Intractable Disease Division, the Ministry of Health and Welfare, Amyloidosis Research Committee in Japan.