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PubMed2002

Toxic megacolon: a life-threatening complication of high-dose therapy and autologous stem cell transplantation among patients with AL amyloidosis.

AL amyloidosis is a plasma cell disorder in which tissue deposition of immunoglobulin light chains leads to organ dysfunction. Recent reports of high-dose therapy with autologous stem cell transplantation for amyloidosis suggest higher response rates and extended survival compared to those seen with conventional chemotherapy. However, substantial treatment-related toxicity has been observed. This case series describes our institutional experience with autologous transplantation in four patients with amyloidosis with an emphasis on unique gastrointestinal toxicities, including toxic megacolon.

Amyloidosis↗
PubMed1990

Gelsolin variant (Asn-187) in familial amyloidosis, Finnish type.

Familial amyloidosis, Finnish type (FAF), is an inherited form of systemic amyloidosis clinically characterized by cranial neuropathy and lattice corneal dystrophy. We have demonstrated that the protein subunit isolated from amyloid fibrils shows considerable sequence identity with gelsolin, an actin-binding protein. We have purified the amyloid subunit from a second case and further analysed different fractions from the previous one. Sequence analysis shows that, in both cases, the amyloid subunit starts at position 173 of the mature molecule; it has a heterogeneous N-terminus and contains one amino acid substitution, namely asparagine for aspartic acid, at position 15 (gelsolin residue 187), that is due to a guanine-to-adenine transversion corresponding to nucleotide-654 of human plasma gelsolin cDNA. The substitution maps in a fragment with actin-binding activity and is located in a repetitive motif highly conserved among species. Thus FAF is the first human disease known to be caused by an internal abnormal degradation of a gelsolin variant. We designate this variant of gelsolin-associated amyloidosis 'Agel Asn-187'.

Aged↗
PubMed2002

Coexistence of beta2 microglobulin and lambda light chain in amyloid fibrils of dialysis-unrelated plasma cell dyscrasia-associated systemic amyloidosis.

BACKGROUND: Systemic amyloidosis occurs as a result of amyloid deposition in various tissues. The amyloid fibrils in systemic amyloidosis have been reported to originate from immunoglobulin light chains. OBJECTIVE: We studied the composition of amyloid fibrils from two patients with plasma cell-associated systemic amyloidosis (PASA). METHODS: A double immunofluorescence study of the lesional skin of PASA was undertaken. Amyloid proteins were extracted with distilled water from one case of PASA. RESULTS: The double immunofluorescence study showed that anti-lambda light chain and anti-beta2 microglobulin antibodies mostly reacted with the same area of amyloid deposit. Amyloid deposits from two patients with PASA who had never undergone haemodialysis showed a positive reaction with the antibodies for beta2 microglobulin as well as immunoglobulin lambda light chain. By the use of immunoblot assay of amyloid fibril proteins, polypeptides immunoreactive with antigamma light chain antibody (29 kDa) and with anti-beta2 microglobulin antibody (12 kDa) were detected. CONCLUSIONS: These results indicate that beta2 microglobulin is a component of amyloid fibrils in PASA.

Aged↗
PubMed1997

Amyloidosis: a review of recent diagnostic and therapeutic developments.

Amyloid deposition is associated with a diverse range of disorders that includes Alzheimer's disease, type II diabetes mellitus and dialysis arthropathy. Although less common, systemic AA and AL amyloidosis remain important because effective treatments have increasingly become available. The pathology in all forms of amyloidosis involves the extracellular deposition of protein as characteristic fibrillar aggregates which interfere with tissue structure and function. Amyloid fibrils are derived from different unrelated proteins in the different forms of the disease but share many common properties, including the capacity to bind the normal plasma protein serum amyloid P component (SAP). This is the basis for our development of radiolabelled SAP as a nuclear medicine tracer for the diagnosis and quantitative monitoring of amyloid. Serial studies have shown that the deposits are far from inert but are actually turned over quite rapidly in many patients. The treatment of amyloidosis involves supportive measures whilst every effort is made to reduce the supply of the respective fibril precursor protein. Under favourable circumstances further amyloid deposition will be prevented. existing deposits will regress and improvement of organ function will occur. Since this strategy is not always possible or may fail, new approaches to inhibit fibril formation and promote regression of amyloid are being pursued.

Amyloid↗
PubMed1998

Allogeneic bone marrow transplantation for systemic AL amyloidosis.

Low-intensity chemotherapy is ineffective in most patients with AL amyloidosis, probably because clinical benefit requires regression of the amyloid deposits, and this occurs only very gradually after the underlying plasma cell dyscrasia has been suppressed. We report the first successful allogeneic bone marrow transplant (allo-BMT) for AL amyloidosis, which after 3 years was associated with complete clinical recovery. This supports the idea that there may be a brief window of opportunity in patients with AL amyloidosis during which dose-intensive chemotherapy is feasible and most likely to produce clinical benefit.

Amyloidosis↗
PubMed1999

Acute tumour lysis syndrome: a case in AL amyloidosis.

Tumour lysis syndrome (TLS) in plasma cell dyscrasias is extremely rare. TLS has been described in eight cases of multiple myeloma undergoing high-dose therapy with autologous stem cell transplant (ASCT). Recently, clinical trials of intensive chemotherapy followed by autologous or allogeneic stem cell support has been shown to offer potential benefit in AL (amyloid light-chain) amyloidosis. TLS in primary AL amyloidosis in this setting has not been previously reported. We report a case of TLS in a patient with AL amyloidosis which developed after high-dose melphalan chemotherapy supported by ASCT.

Acute Disease↗
PubMed2000

Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis.

Haemorrhage is a frequent manifestation of amyloidosis. We performed a retrospective clinical analysis of 337 patients with systemic immunoglobulin light-chain (AL)-amyloidosis, in whom whole-body serum amyloid P component (SAP) scintigraphy and a clotting screen had been performed. Abnormal bleeding was noted in 94 cases (28%), and the coagulation screen was abnormal in 172 cases (51%). The most common abnormalities were prolongation of the thrombin time (TT; 108 cases, 32%) and the prothrombin time (PT; 82 cases, 24%). In multivariate analysis, a prolonged PT was the only coagulation abnormality associated with abnormal bleeding (P = 0.0012), but this was independent of the whole-body amyloid load. Prolongation of the TT was associated with hepatic amyloid infiltration (P < 0.00001), with proteinuria (P < 0.001) and low serum albumin (P < 0.00001). In 154 patients who were studied further, subnormal factor X activity (FX:C) was found in 22 cases (14%). In cases with subnormal FX:C, the corresponding factor X antigen (FX:Ag) measurements were consistently higher (median FX:Ag/FX:C 2.5, range 0.81-9.25, n = 16) than cases with normal FX:C (median FX:Ag/FX:C 0.96, range 0.65-1.29, n = 28, P < 0.0001). No evidence was found of an FX inhibitor. Of the 48/154 (31%) cases with a prolonged TT, the reptilase time was also prolonged in 38/48 cases (79%). These data show that haemorrhage and abnormal coagulation are common in AL-amyloidosis and are multifactorial in origin. We provide evidence suggesting that hepatic amyloid infiltration and nephrotic syndrome are determinants of the TT. In most patients, prolongation of the PT was explained by reduction in FX:C, but this was not wholly explained by a reduction in FX:Ag.

Adult↗
PubMed2003

Dystrophic epidermolysis bullosa complicated by cutaneous squamous cell carcinoma and pulmonary and renal amyloidosis.

A 25-year-old woman with Hallopeau-Siemens recessive dystrophic epidermolysis bullosa had generalized blistering, scarring and milia since birth. In the course of the disease, acral pseudosyndactyly developed, and the patient suffered from corneal erosions, oesophageal strictures, malabsorption, recurrent severe pneumonias and nephrotic syndrome. In addition, she had severe anaemia, sideropaenia, hypocalcaemia, heavy proteinuria and hypoalbuminaemia. A rapidly growing skin squamous cell carcinoma developed on the neck that spread to axillary and cervical lymph nodes. Recurrent hypocalcaemic tetanic convulsions and dyspnoea and a pneumonia refractory to antibiotics led to the premature demise of the patient. Autopsy revealed extensive amyloidosis of the renal, hepatic and splenic tissues. AA type amyloid deposits were detected in the renal glomeruli and in the lung, explaining the patient's unusually severe pulmonary infections. In essence, the patient had severe recessive dystrophic epidermolysis bullosa, complicated by squamous cell carcinoma, recurrent pneumonias and nephrotic syndrome due to secondary amyloidosis of the kidney and lung. The possibility of secondary pulmonary amyloidosis should be considered in severe dystrophic epidermolysis bullosa patients with recurrent pulmonary infections.

Adult↗
PubMed1996

Primary localized amyloidosis of the eyelid: two cases of immunoglobulin light chain-derived proteins, subtype lambda V respectively lambda VI.

Primary localized amyloidosis has been described in many different organs in the body. Studies by immunohistochemical techniques have suggested an immunoglobulin light chain origin of the amyloid material. Only in a limited number of cases has the amyloid protein been characterized by amino acid sequence analysis as subtypes of immunoglobulin light chain or heavy chain. In this report, two cases of primary localized amyloidosis of the eyelid are presented. The amyloid substance has been extracted and a major fibril protein subjected to amino acid sequence analysis. Both amyloid proteins were part of the variable region of immunoglobulin light chains, subtype lambda V and subtype lambda VI, respectively. While lambda VI has been shown to be a common subtype in systemic immunoglobulin light chain-amyloidosis, it has never been demonstrated in localized amyloid. Very few lambda V immunoglobulin light chains have been characterized and the subgroup has never been found in amyloid before.

Aged↗
PubMed1996

Systemic amyloidosis in a patient with hypogammaglobulinaemia.

A 49-year-old patient with an 18-year history of hypogammaglobulinaemia presented with nephrotic syndrome due to systemic amyloidosis. Recurrent infections as a consequence of an inadequate gammaglobulin substitution therapy were regarded as the main reason for the development of amyloidosis. When a high-dose intravenous immunoglobulin therapy was started, the clinical symptoms declined and the patient felt moderately well. Later the patient developed symmetrical polyarthritis clinically suggestive of rheumatoid arthritis. Although the incidence of arthritis is increased in hypogammaglobulinaemia, arthritis has not been reported in any of the few previously described patients with hypogammaglobulinaemia-associated amyloidosis. Moreover, this case provides further evidence that, in these patients, the amyloid fibrils may be of the AA type.

Agammaglobulinemia↗
PubMed1997

Familial amyloidosis in one Chinese family: clinical, immunological, and molecular genetic analysis.

Three members of a Taiwanese kindred developed severe, systemic, early onset (< age 25 years), biopsy-proven amyloidosis. Clinical features included upper and lower extremity sensorimotor neuropathy, abdominal pain, vomiting, corneal ulcerations, cardiomyopathy, and syncope. Immunohistochemical analysis indicated that the deposits consisted of transthyretin. Molecular genetic studies revealed a heterozygous codon 55 point mutation, resulting in a proline for leucine-substitution, a mutation previously associated with aggressive familial amyloidosis in a US kindred of Dutch and German descent. The clinical courses and echocardiographic findings are typical for many types of amyloidosis; the pathologic data and genetic studies were necessary to establish a precise diagnosis.

Adult↗
PubMed1999

Obstructive sleep apnoea syndrome in hereditary gelsolin-related amyloidosis.

Gelsolin-related amyloidosis (AGel amyloidosis) is a rare autosomal dominant disorder, reported worldwide in kindreds carrying a G654A or G654T gelsolin gene mutation. The main clinical signs are cutis laxa, cranial and peripheral neuropathy, and corneal lattice dystrophy but heavy intermittent snoring also occurs. To evaluate whether sleep apnoea is present we performed nocturnal sleep recordings, cephalometric and spirometric analyses and multiple sleep latency tests (MSLT) in five snoring patients with a G654A gelsolin gene mutation. Four patients had obstructive sleep apnoea syndrome (OSAS) with redundant oropharyngeal and hypopharyngeal soft tissues, macroglossia and cranial neuromuscular dysfunction. The fifth patient had hypersomnia without obstructive sleep apnoea. Nasal continuous positive airway pressure (CPAP) was an effective treatment. This study presents the first evidence in favour of an association between AGel amyloidosis and OSAS, but further studies are needed to define the prevalence of OSAS and the pathogenetic roles of amyloid and variant gelsolin in its evolution.

Aged↗
PubMed1996

Experimental AA-amyloidosis in mice is inhibited by treatment with the anti-rheumatic drug tenidap.

In a mouse model for induction of experimental AA-amyloidosis, treatment with tenidap was shown to inhibit the development of amyloidosis. Studies have shown that the drug inhibits the cytokines interleukin (IL)-6, IL-1 and tumour necrosis factor alpha (TNF-alpha) which are known to stimulate hepatocytes to synthesize acute phase proteins (APPs). The APP serum amyloid protein (SAA) is the precursor for amyloid protein AA and tenidap treatment reduces the serum levels of SAA in mouse and humans. It is suggested that reduction of SAA levels reduces the risk of AA fibril formation and thus the development of amyloidosis.

Amyloidosis↗
PubMed1999

Changes in plasma apolipoprotein AI and AII concentrations in murine reactive amyloidosis.

Based on the recent findings that patients with systemic amyloidosis have reduced plasma apolipoprotein AII (apoAII) concentrations, this study assessed the behaviour of apolipoprotein AI (apoAI) and apoAII in a murine model of reactive amyloidosis. ICR mice were subjected to a single inflammatory stimulus and then sacrificed at the end of week 1 (group I), week 2 (group II) or week 8 (group III). Amyloid deposits were found in approximately one-half of the animals. Plasma apoAI and apoAII concentrations were reduced in all stimulated animals compared with control animals. In groups II and III, apoAII and apoAII/apoAI ratios were lower in the amyloidotic animals than in nonamyloidotic animals, similar to findings in the human amyloidosis patients. Both apoAI and apoAII mRNA in the liver were reduced in group I, but not in group II or III. Both apoAI and apoAII were detected immunohistochemically in the amyloid deposits in groups I and II, but not in group III. Thus, the reduction of plasma apoAs in the amyloid-forming phase may be due, in part, to the involvement of high-density lipoproteins in the deposits. However, that in the chronic phase may be affected by other mechanisms.

Amyloidosis↗
PubMed2003

Current clinical and pathogenetic understanding of beta2-m amyloidosis in long-term haemodialysis patients.

As the number of patients undergoing long-term haemodialysis continues to grow, beta2-microglubulin (beta2-m) amyloidosis is emerging as an increasingly common complication. The frequency of beta2-m amyloid-related osteoarthropathy in haemodialysis patients rises steadily with length of survival. We confirmed that the prevalence of carpal tunnel syndrome increases with years of dialysis. Up to 50% of patients had developed this complication after 20 years were affected and the percentage was even higher after 25 years. Although retention of beta2-m is a necessary requirement for onset of amyloidosis, it is probably not sufficient. Using an in vitro model of beta2-m-related amyloid fibril (fAbeta2-m) extension, we demonstrated that various amyloid-associated molecules, such as apolipoprotein (apo) E and proteoglycans, accelerate beta2-m amyloid fibril formation. General categories of therapeutic approaches for amyloidosis include prevention of onset or progression, symptomatic therapy (conservative treatment, orthopedic procedures, and physiotherapy), and renal transplantation. In association of haemodialysis, beta2-m has been removed by high-flux membranes or a beta2-m adsorption column. However, proof is lacking that amyloid deposits are decreased by long-term use of dialysis techniques to eliminate beta2-m. More effective treatment procedures are needed.

Amyloidosis↗
PubMed2001

Pulmonary presentations of amyloidosis.

Respiratory tract involvement with amyloid is rare. We report eight cases of lower respiratory tract amyloidosis including a case of isolated pulmonary interstitial amyloidosis treated with chemotherapy, two cases of recurrent endobronchial amyloid with airway obstruction successfully treated with laser therapy and three cases of localized nodular pulmonary amyloidosis. The subjects with endobronchial and nodular amyloid demonstrated good long-term survival, while those with systemic or interstitial pulmonary amyloid had progressive disease and poor survival. Circulating monoclonal immunoglobulins were identified in five of the eight cases as the likely cause of the amyloid.

Adult↗
PubMed2000

Lichen amyloidosis, ankylosing spondylitis and autoimmune thyroiditis: coincidence or association?

Primary localized cutaneous amyloidosis (PLCA) is characterized by the deposition of amyloid in a previously apparently normal skin with the absence of other systemic or cutaneous disorder. Although ankylosing spondylitis may be associated with secondary systemic amyloidosis, no reports have been found showing the association of this disease with PLCA. In addition, the association of PLCA with autoimmune thyroiditis has not been previously reported. We report a concomitant occurrence of lichen amyloidosis, ankylosing spondylitis and autoimmune thyroiditis in a caucasian woman.

Adult↗
PubMed1998

N epsilon-(carboxymethyl)lysine in blood from maintenance hemodialysis patients may contribute to dialysis-related amyloidosis.

BACKGROUND: Recent studies demonstrated not only that advanced glycation end product could be found in amyloid tissue from patient with dialysis related amyloidosis, but also that amyloid beta2-microglobulin was modified with N(epsilon)-(carboxymethyl)lysine (CML). We wanted to determine if CML could be a biomarker in these patients. METHODS: To raise polyclonal anti-carboxymethyllysine antibody, human serum albumin was carboxymethylated by glyoxylic acid and was immunized to rabbits as antigen. Carboxymethyllysine-hemoglobin (CML-Hb) levels were measured by the dot blotting method using this antibody. RESULTS: The levels of CML-Hb were 6.68 +/- 3.10 nmol CML/mg Hb in nondiabetic hemodialysis patients (N = 70), 6.39 +/- 3.43 nmol CML/mg Hb in diabetic hemodialysis patient (N = 21), and 3.13 +/- 0.88 nmol CML/mg Hb in 47 healthy volunteers. For clinical signs of dialysis-related amyloidosis, 70 nondiabetic hemodialysis patients were scored according Gejyo's criteria. The CML-Hb levels in patients with a high amyloid score as well as a low amyloid score were significantly higher than in patients with negative amyloid score (8.89 +/- 3.53 nmol CMLmg Hb, 7.28 +/- 2.32 nmol CML/mg Hb vs. 5.11 +/- 2.09 nmol CML/mg Hb, P < 0.001, P < 0.05). Furthermore, the CML-Hb levels correlated significantly with serum values of the methylguanidine over creatinine ratio and hyaluronate. CONCLUSIONS: We suggest that CML-Hb is increased in blood from patients on maintenance hemodialysis and is thus a potential biomarker of oxidative damage in these patients. Moreover, CML-modification of protein may play a pathogenic role in the development of dialysis related amyloidosis.

Adult↗