1 Third Department of Internal Medicine, Akita University School of Medicine, 2 Department of Internal Medicine, Honjo Daiichi Hospital, Akita, 3 Department of Internal Medicine, Kichijoji Asahi Hospital, Tokyo and 4 Department of Nephrology and Rheumatology, Aichi Medical University, Aichi, Japan
Correspondence and offprint requests to: Atsushi Komatsuda, MD, Third Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543, Japan. Email: komatsud{at}med.akita-u.ac.jp
Keywords: AL amyloidosis; CH1-deleted -heavy; heavy chain deposition disease;
-light chain
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Introduction |
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We previously have described clinical and immunopathological features of a patient with HCDD [9]. Subsequent immunochemical analysis of the patient's serum showed that the CH1-deleted 1-heavy chain circulated free and unassembled. A monoclonal IgG1-
with a non-deleted heavy chain component was also found [10]. During long-term follow-up, this patient developed systemic light chain (AL) amyloidosis, in addition to HCDD, and died of heart failure and cerebral infarction. To our knowledge, this is the first report of the metachronous development of AL amyloidosis in a patient with HCDD.
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Case |
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In February 1989, she had had proteinuria, microhaematuria, hypoproteinaemia and hypocomplementaemia. On the basis of the findings of her first renal biopsy, showing nodular glomerulosclerosis (Figure 1A), she was diagnosed as having HCDD [9]. A bone marrow aspirate revealed normocellular marrow with 5.8% plasma cells. After a low-dose steroid therapy was started, urinary protein and her oedema disappeared. Subsequent immunochemical studies of her serum demonstrated that a low titre of CH1-deleted 1-heavy chain was circulating free and unassembled. A circulating monoclonal IgG1-
with a non-deleted heavy chain component was also found [10].
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The second renal biopsy was performed in October 1999. Light microscopy showed a remarkable diminution of the nodular glomerular lesions (Figure 1B). In the arterial walls, however, Congo red-positive deposits were found (Figure 2A). The application of potassium permanganate to the Congo red-stained sections did not abolish the positive staining. For immunohistochemistry, frozen sections of the specimen were stained by a direct method using fluorescein isothiocyanate (FITC)-conjugated rabbit antisera to human IgG (-heavy chain), IgA, IgM
and
light chains, C3, C1q and fibrinogen (DakoCytomation, Glostrup, Denmark). On immunofluorescence microscopy, a positive staining for
-heavy chain was observed in the mesangial area, and along the glomerular basement membranes, Bowman's capsule and tubular basement membranes, but not in the arterial walls (Figure 2B). A positive staining for
-light chain was observed in the arterial walls, but not in the glomeruli (Figure 2C). On electron microscopy, fine amyloid fibrils were found in the arterial walls (Figure 3A and B), while granular material was present in the mesangial area.
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On admission, her temperature was 36.5°C, pulse rate 95 beats/min, respiratory rate 36 and blood pressure 118/90 mmHg. She had marked pitting oedema in both legs, diminished respiratory sounds in the lower lungs bilaterally, an increased area of cardiac dullness, a distended abdomen, non-palpable liver and spleen, and normal neurological examination.
Her erythrocyte sedimentation rate was 30 mm/h and C-reactive protein was 2.0 mg/dl. The erythrocyte count was 379 x 104/µl, haemoglobin 11.5 g/dl, haematocrit 33.1%, leukocyte count 6000/µl (neutrophils 64%, monocytes 14%, eosinophils 1%, lymphocytes 21%), and platelet count 25.9 x 104/µl. Her urine was 1+ for protein, with the sediment containing 59 red blood cells per high power field. Total 24 h urinary protein was 0.7 g. Her serum total protein was 6.2 g/dl, albumin 3.8 g/dl, blood urea nitrogen 25 mg/dl, creatinine 1.4 mg/dl and creatinine clearance 44.6 ml/min. Serum immunoglobulins were normal. Anti-nuclear antibodies and cryoglobulins tested negative. Serum complement C3 was 90 mg/dl, C4 26 mg/dl and CH50 54 U/ml. Circulating immune complexes were not detected by the C1q binding assay. Serum electrophoresis showed IgG- monoclonal protein. Urine electrophoresis revealed
-Bence-Jones protein. On blood gas analysis, pH was 7.492, pO2 70 mmHg, pCO2 41.5 mmHg,
31.5 mEq/l, and base excess 8.7 mEq/l.
She was treated with intravenous diuretics, but her congestive heart failure worsened. She had a cerebral infarction on March 1, 2001, and died 3 days later. A renal necropsy revealed the same findings as her second renal biopsy. There were no depositions of IgG1 in the heart or liver. Depositions of -light chain were observed within the myocardium, and in the arterial walls in the heart and liver. These deposits stained with Congo red, and the application of potassium permanganate did not abolish the positive stainings. On electron microscopy, fine amyloid fibrils were observed in the heart (Figure 3C) and liver. From these findings, we concluded that the main cause of her death was congestive heart failure due to systemic AL amyloidosis.
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Discussion |
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There is a wide spectrum of renal diseases associated with monoclonal immunoglobulin deposition. The two main categories are amyloidogenic and non-amyloidogenic. The non-amyloidogenic monoclonal immunoglobulin-related renal diseases include HCDD and light chain deposition disease (LCDD) [1]. Ultrastructually, HCDD and LCDD are characterized by non-organized electron-dense granular deposits, while amyloidosis is characterized by fibrillar deposits.
In 1985, Jacquot et al. [11] were the first to describe three cases of LCDD associated with amyloidosis. A review by Gallo et al. [12] indicated that amyloid was found focally in one or more sites, such as tongue, myocardium, skin and vessels of various organs, in 7% of the 135 cases of LCDD reported. They also suggested that the true incidence may be greater, because the amyloid, which is usually focal, may not be detected in limited biopsy samples, and complete examination of organs at necropsy takes place in only a few cases.
Our patient had two kinds of circulating monoclonal immunoglobulins: CH1-deleted 1-heavy chain without assembled light chain, and IgG1-
with a non-deleted heavy chain component. In her urine she had
-Bence-Jones protein. The development of glomerular HCDD was due to the deposition of CH1-deleted
-heavy chain, while systemic AL amyloidosis was due to the deposition of
-light chain. This indicates that the monoclonal CH1-deleted
1-heavy chain was non-amyloidogenic, and that the monoclonal
-light chain was amyloidogenic in our patient. Since idiotypic specificity studies or sequence analysis were not performed, it is impossible to determine if the same plasma cell clone or other clones produced the different monoclonal immunoglobulins in our patient. Considering the length of time between the developments of HCDD and AL amyloidosis, it seems reasonable to assume that the different monoclonal immunoglobulins were produced by different clones, and that the clone producing monoclonal CH1-deleted
1-heavy chain seemed more sensitive to steroid therapy than another clone producing monoclonal
-light chain.
The prognosis of patients with HCDD is usually poor; the majority of reported patients had progressive renal failure. In some patients treated with steroids or steroids plus cytotoxic agents, favourable clinical outcomes have been reported [7,9,10]. Our patient was treated initially with low-dose steroid alone, and had a favourable outcome of HCDD. Follow-up renal biopsy and necropsy findings showed the remarkable diminution of the nodular lesions of HCDD. Therefore, the histological resolution of HCDD could be achieved by treatment with steroids or with steroids plus cytotoxic agents, as seen in patients with LCDD [13]. On the other hand, the median duration of survival in patients with AL amyloidosis is still <18 months, despite the use of melphalan and prednisolone [14]. Congestive heart failure is one of the unfavourable prognostic features. Treatment with melphalan and prednisolone was not effective in our patient, and she died 18 months after the development of congestive heart failure. In eligible patients with AL amyloidosis, treatment with high-dose melphalan and stem cell transplantation may result in haematological remission and improved survival [15].
In summary, we have presented an unusual case of a patient who developed HCDD and later systemic AL amyloidosis during long-term follow-up. This case reveals a previously unreported association between AL amyloidosis and HCDD.
Conflict of interest statement. None declared.
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References |
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