Primary systemic amyloidosis.
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Amyloidosis↗
Biomedical subjects
R A Kyle
Publications and source records attributed to R A Kyle.
Current concepts on monoclonal gammopathies.
This is a review of the monoclonal gammopathies, including a discussion of cause. The role of T lymphocytes and B lymphocytes is presented. The recognition of a monoclonal protein in the serum and urine is presented in detail. The frequency of benign and malignant monoclonal gammopathies is provided. A long-term follow-up of 241 patients with apparently benign monoclonal gammopathy is examined closely. In this series, multiple myeloma, macroglobulinaemia, amyloidosis, or related disorders developed in 22% of the 241 patients with long-term disease. The median duration from the recognition of the monoclonal protein until the development of serious disease was approximately eight to ten years. The differentiation of benign from malignant monoclonal gammopathies is examined in detail. The point is made that patients must be followed indefinitely because malignancy may develop more than 20 years later. The association of monoclonal gammopathies with other apparently unrelated diseases is discussed.
Amyloidosis↗
Laryngeal amyloidosis: a clinicopathologic and immunohistochemical review.
The clinical nature of laryngeal amyloidosis has not been well established, and the natural history of the disease remains a controversial matter. To address these issues, we reviewed the clinicopathologic and immunohistochemical features of 22 cases (11 men and 11 women; mean age, 56 years) of laryngeal amyloidosis. Hoarseness was the most common symptom, and the most frequent site affected was the false vocal cords. Six patients had concomitant tracheal amyloidosis. Paraffin blocks were available for immunostaining in 20 cases. Nineteen cases were positive for amyloid P component. lambda-Light chains were detected in 12 cases and kappa-light chains in 5; three cases did not show definite light-chain staining. Ten patients underwent repeated operations for persistent or recurrent respiratory tract disease. One patient died of progressive tracheobronchial amyloidosis, but systemic amyloidosis did not develop in any of the patients. Laryngeal amyloidosis is a form of localized amyloidosis characterized by monoclonal light-chain deposition. Recurrent respiratory tract disease is not uncommon, but the usual clinical course is relatively benign.
Adult↗
Immunohistochemical characterization of amyloid proteins in sural nerves and clinical associations in amyloid neuropathy.
To test whether immunohistochemical characterization of proteins in amyloid deposits in biopsied sural nerves gives reliable and useful diagnostic information using commercially available reagents, biopsy specimens of sural nerves from 38 patients with amyloid neuropathy were studied. Transthyretin (TTR) was detected in the amyloid deposits of 11 nerves, lambda light chains (LC) in 8 nerves, kappa LC in 7 nerves, and both lambda and kappa LC in 3 nerves. In 9 nerves, the amyloid deposits were too small to allow adequate immunohistochemical characterization of amyloid proteins in serial sections. Evidence that immunohistochemical characterization was correct came from: 1) evaluation of kin, 2) search for monoclonal proteins in the plasma, and 3) sequencing of the gene abnormalities in TTR+ cases. In 9 of 11 TTR+ cases, in which DNA could be obtained, sequencing of the gene showed that each of the 9 cases was heterozygous for a gene mutation; 7 had previously described mutations and 2 undescribed mutations. Therefore, in the nine sporadic cases without plasma monoclonal light chains, the immunohistochemical characterization correctly identified the protein in amyloid as transthyretin. Likewise, there was a high concordance between immunoglobulin light chains in plasma and light chains in amyloid in primary amyloidosis. Evaluation of the type, distribution, and severity of the neurologic symptoms and deficits showed: 1) the sensorimotor and autonomic neuropathy of amyloidosis characteristically affects proximal as well as distal limbs, and 2) the type of amyloidosis probably cannot be determined from the characteristics or severity of the neuropathy alone or from the location or size of amyloid deposits in nerve.
Aged↗
Monoclonal proteins in neuropathy.
The presence of a monoclonal protein in the serum of a patient with peripheral neuropathy raises the suspicion of systemic amyloidosis, POEMS syndrome, macroglobulinemia, multiple myeloma, or lymphoma. If these conditions are excluded, the patient is classified as having a monoclonal gammopathy of undetermined significance (MGUS) with an associated neuropathy. Approximately one half of patients with peripheral neuropathy and IgM monoclonal gammopathy have IgM antibodies that bind to a myelin-associated glycoprotein (MAG). In addition to MAG, other antigens such as glycolipids or gangliosides represent other target antigens. Monoclonal gammopathies and motor neuron diseases have also been reported. Sensorimotor peripheral neuropathy occurs in about 15% of patients with primary amyloidosis but is uncommon in multiple myeloma.
Autoantibodies↗
Dialysis support of patients with primary systemic amyloidosis. A study of 211 patients.
BACKGROUND: The study assessed dialysis support in patients with primary systemic amyloidosis without associated multiple myeloma in whom renal insufficiency developed. METHODS: The study group consisted of 211 patients with biopsy-proved primary systemic amyloidosis examined at the Mayo Clinic, Rochester, Minn. No patient was lost to follow-up. RESULTS: Thirty-seven (18%) of the patients received dialysis therapy. Of those presenting with renal amyloid, one third received dialysis. The median time from diagnosis to initiation of dialysis was 13.8 months. The median survival for patients from the start of dialysis was 8.2 months. There was no survival difference between hemodialysis (n = 27) and peritoneal dialysis (n = 10). The most important predictors of which patients would ultimately require dialysis were the 24-hour urinary protein loss and serum creatinine values at the time amyloidosis was diagnosed. None of the patients seen at diagnosis with a normal serum creatinine value and proteinuria of less than 2 g/d required dialysis during follow-up. Of the 37 patients who received dialysis, 31 died, and 21 of the 31 died as a result of extrarenal progression of their systemic amyloidosis. Fifteen of the 31 deaths were a result of cardiac amyloidosis. All long-term survivors had normal echocardiograms without evidence of amyloid. CONCLUSION: Eighteen percent of patients with primary amyloidosis undergo dialysis. The 24-hour urinary protein loss and creatinine values are helpful in predicting which patients eventually will require dialysis. The median survival for patients starting dialysis is less than 1 year. Patients whose two-dimensional echocardiograms are normal are most likely to derive long-term benefit from dialysis.
Aged↗
Diagnostic criteria of multiple myeloma.
Immunoelectrophoresis or immunofixation is necessary for the identification of a monoclonal protein. During 1990 at the Mayo Clinic, 787 patients were found to have a monoclonal gammopathy. IgG accounted for 61% of the cases, followed by IgM (18%), IgA (11%), Bence Jones proteinemia (6%), biclonal gammopathy (3.5%), and IgD (0.5%). Monoclonal gammopathy of undetermined significance accounted for approximately two thirds of patients. This denotes the presence of a monoclonal protein in persons without evidence of multiple myeloma, macroglobulinemia, amyloidosis, or other related diseases. During long-term follow-up of patients with monoclonal gammopathy of undetermined significance, we found that one fourth developed multiple myeloma or related disorders. The interval from recognition of the monoclonal gammopathy to the diagnosis of multiple myeloma ranged from 2 to 29 years (median, 10 years). Waldenström's macroglobulinemia developed in seven patients 4 to 20 years (median, 8.5 years) after recognition of the monoclonal protein. Systemic amyloidosis (AL) was found in eight patients 6 to 19 years (median, 9 years) after the diagnosis of a serum monoclonal protein. Five patients developed a malignant lymphoproliferative process 6 to 22 years (median, 10.5 years) after recognition of a monoclonal protein. Minimal criteria for the diagnosis of multiple myeloma include the presence of at least 10% abnormal plasma cells in the bone marrow or histologic proof of a plasmacytoma, the usual clinical features of multiple myeloma, and at least one of the following abnormalities: monoclonal serum protein (usually greater than 3 g/dL), monoclonal protein in the urine, or osteolytic lesions. No single technique differentiates benign from malignant plasma cell proliferation. The most dependable means is serial measurement of the monoclonal protein in the serum and urine and periodic reevaluation of pertinent clinical and laboratory features to determine whether multiple myeloma, systemic amyloidosis, macroglobulinemia, or other lymphoplasma cell proliferative disease has developed.
Antibodies, Monoclonal↗
Analysis of B-lymphoid malignancies using allele-specific polymerase chain reaction: a technique for sequential quantitation of residual disease.
The junctional sequences corresponding to the complementarity determining region 3 (CDR3) of rearranged heavy chain Ig genes can provide allele-specific markers in the detection of B-lymphoid malignancies. Consensus oligonucleotide primers were used to amplify CDR3 regions of rearranged heavy chain alleles in clinical samples from myeloma, acute lymphocytic leukemia, and chronic lymphocytic leukemia patients. From the sequence of the amplified products, allele-specific primers were synthesized and used directly in polymerase chain reaction (PCR) amplification to detect the malignant clone. This method was both highly specific and sensitive to 1 malignant B-cell in a background of 10(5) normal cells. In addition, parameters that affect the linearity of PCR detection were determined and, by using titrations of malignant target cells to generate standard curves, quantitations of residual malignancies were determined. The application of this method is shown in an analysis of myeloma patients whose marrows were analyzed sequentially during therapy. Allele-specific oligonucleotide-PCR provided a rapid, highly specific and quantitative measure of residual disease, even in patients with clinical parameters indicating complete remission.
Alleles↗
Genetic variants of serum albumin in Americans and Japanese.
A collaborative search for albumin genetic variants (alloalbumins) was undertaken by cellulose acetate and agarose electrophoresis at pH 8.6 of the sera of patients at two major medical centers in the United States and of nearly 20,000 blood donors in Japan. Seventeen instances of alloalbuminemia were ascertained, and seven different alloalbumin types were characterized by structural study. Two previously unreported alloalbumin types were identified. In one type, which was present in a Caucasian family and designated Iowa City-1, aspartic acid at position 365 was replaced by valine (365 Asp----Val); this is the second reported mutation at this position. The other type present in a Japanese blood donor had the mutation 128 His----Arg. An unexpected finding was the presence in a single Japanese of a Naskapi-type alloalbumin (372 Lys----Glu), a variant that had previously been described only for certain Amerindian tribes in whom it occurs with a polymorphic frequency (greater than 1%) and in Eti Turks. An arginyl-albumin (-1 Arg, 1 Asp----Val) occurred in an American family. The other alloalbumin types identified were proalbumins Lille and Christchurch and albumin B that have a cumulative frequency of about 1:3500 in Caucasians probably because of the hypermutability of CpG dinucleotides at the mutated sites. All of the variants characterized in this study are point mutants, and the sites are spread throughout the albumin gene. However, about one-fourth of all known albumin mutations are clustered in the sequence segment from position 354 through 382.
Amino Acid Sequence↗
Inhibitor of the thrombin time in systemic amyloidosis: a common coagulation abnormality.
Patients with primary systemic amyloidosis (AL) often experience bleeding, and we report a newly recognized coagulation abnormality in AL. Of 103 patients with primary systemic AL studied over 2 years, 41 had prolongation of the thrombin time (range, 25 to 46 seconds; normal, less than 22 seconds) and reptilase time (range, 17 to 39 seconds; normal, 14 to 16 seconds). The fibrinogen from the plasma of 36 patients was precipitated by beta-alanine and diluted to a concentration of approximately 200 mg/dL. The thrombin times of the precipitated fibrinogens were normal in 34 patients, implying that an inhibitor was responsible for the abnormal tests. The addition of patient fibrinogen-free plasma to normal plasma prolonged the thrombin times, and this result confirmed the presence of an inhibitor. The inhibitor is more likely to be present in patients with nephrotic syndrome (20 of our patients) and congestive heart failure (six). A circulating monoclonal protein (24 patients), the presence of amyloid liver involvement (eight), and the presence of amyloid neuropathy (nine) were not predisposing factors. Only one patient had deficiency of factor X. We conclude that inhibition of fibrinogen conversion to a fibrin clot rather than dysfibrinogenemia is the cause of the prolonged thrombin time in primary systemic AL.
Amyloidosis↗
Response rates and survival in primary systemic amyloidosis.
Patients (153) with biopsy-proven primary systemic amyloidosis (AL) were evaluated for their response rate to alkylating agent-based chemotherapy. Twenty-seven of the patients (18%) responded. The serum creatinine concentration had an adverse effect on response rate (P = .05). In patients with nephrotic syndrome, a normal serum creatinine value, and no echocardiographic evidence of cardiac amyloidosis, the response rate was 39% (12 of 31). Five of 34 patients with amyloid cardiomyopathy responded. Two of these five are alive 10 years after diagnosis. None of the 18 patients with amyloid peripheral neuropathy showed regression of their disease. The median time to achieve response was 11.7 months. The median survival of the 27 patients was 89.4 months and 21 of 27 survived 5 years (78%). Eight patients remain alive with a minimum follow-up of 90 months. Seven died of acute leukemia or dysmyelopoietic syndrome, a presumed complication of melphalan therapy. In the group of 126 patients who showed no response to alkylating agent-based therapy, the median survival was 14.7 months and 9 (7%) survived over 5 years. All 126 patients have died. Alkylating agent-based chemotherapy for AL is beneficial in a subset of patients and a trial of chemotherapy is strongly recommended. Those patients who do respond demonstrate survival benefit.
Amyloidosis↗
High-dose dexamethasone for refractory or relapsing multiple myeloma.
In order to assess the efficacy and toxicity of dexamethasone as a single agent without the concomitant infusion of Adriamycin and vincristine (VAD), an ECOG pilot study was initiated using 40 mg by mouth daily for 4 days every week for 8 weeks. Patients who responded were then maintained on the same treatment, but at 2 week intervals. Of the 32 patients evaluable for response, three were completely refractory to all prior therapy. All patients had advanced disease and 26 had received multiple prior treatments. There were 13/32 (40%) objective responses by ECOG criteria. Of the 28 patients evaluable for subjective response, i.e., significant decrease in performance status and/or bone pain, eight (28.5%) responded. Of the 34 patients evaluable for toxicity, 19 patients (55%) had moderate to severe side effects, including nine who had central nervous system effects, three who had gastrointestinal bleeding, two who had pulmonary emboli, one with psychosis, and four who had serious infections with one death. Median survival for the entire group was 19 weeks, with 31 weeks in the responders and 9 weeks in the non-responders. Although high-dose dexamethasone is capable of producing a significant number of partial responses (40%), it is associated with excessive toxicity. Less frequent administration of the dexamethasone at 2 week intervals was well tolerated in the maintenance of partial response, but has not been studied for efficacy in induction of remission.
Adolescent↗
Computed tomography for diagnosis of hepatic rupture in primary systemic amyloidosis.
Hepatic rupture in primary systemic amyloidosis is extremely ominous; death occurs in hours to days. We present two cases of hepatic rupture diagnosed ante mortem with computed tomography (CT). Surgical repair was possible in one instance and successfully controlled the bleeding. In the setting of primary amyloidosis, the early use of CT scanning for undiagnosed ascites, hypotension, or rapid organ enlargement may lead to early diagnosis and potential surgical correction.
Adult↗
Cranial neuropathy associated with primary amyloidosis.
We report 6 patients for whom cranial neuropathy was a major manifestation of primary amyloidosis. In 3 of the 6, multiple cranial nerves were involved. All had tissue biopsy documentation of amyloidosis. In 2, nerve biopsy also confirmed amyloidosis. All had renal involvement manifested by proteinuria. Primary systemic amyloidosis must be considered in the differential diagnosis of cranial neuropathy, especially when proteinuria is present.
Amyloidosis↗
Neuropathy associated with monoclonal gammopathies of undetermined significance.
Monoclonal proteins (IgM, IgG, and IgA) in the serum or urine of patients with neuropathy may provide a marker for amyloidosis, myeloma, lymphoma, leukemia, Waldenström's macroglobulinemia, or monoclonal gammopathy of undetermined significance (MGUS). The clinical characteristics, course, and electromyographic features among neuropathies associated with monoclonal IgM (IgM-MGUS, 31 patients), monoclonal IgG (IgG-MGUS, 24 patients), and monoclonal IgA (IgA-MGUS, 10 patients) evaluated between 1980 and 1986 were compared. Four statistically significant differences set IgM-MGUS neuropathies apart from IgG-MGUS and IgA-MGUS neuropathies: (1) higher frequency of sensory loss and ataxia, (2) higher frequency of nerve conduction abnormality--10 attributes were significantly worse (none were significantly better), (3) higher frequency of dispersion of the compound muscle action potential, and (4) higher frequency of IgM-MGUS in the MGUS neuropathy cohort than is characteristic of MGUS without neuropathy seen at our institution or than is encountered in epidemiological surveys. These differences were not thought to be due to selection or severity biases. Neither the amount of IgM nor the estimated size of the monoclonal peak was associated with severity of neuropathy. The type and severity of IgM-MGUS neuropathies with anti-myelin-associated glycoprotein antibodies were not significantly different from those without anti-myelin-associated glycoprotein antibodies. A simple relationship between the presence and amount of IgM-MGUS or anti-myelin-associated glycoprotein antibodies and neuropathy cannot be assumed.
Action Potentials↗
Sebastian Petrycy--famous Polish physician.
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History, 16th Century↗
Czerwiakowski--father of Polish surgery.
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General Surgery↗
Antoine-César Becquerel--head of a family of French physicists.
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France↗