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PubMed1983

alpha 1-Antitrypsin and reactive systemic amyloidosis.

1. Serum contains amyloid A-degrading activity. This activity is markedly reduced in patients with rheumatoid arthritis (RA) complicated by amyloidosis. alpha 1-Antitrypsin inhibits the degradative activity. To test the hypothesis that the activity of this enzyme is regulated by alpha 1-antitrypsin, we determined the concentrations, elastase-inhibitory activity and phenotypes of alpha 1-antitrypsin in 24 RA patients with and in 26 RA patients without amyloidosis. 2. alpha 1-Antitrypsin concentrations and biological activity were significantly increased in both patient groups compared with control subjects, but there was no difference between the two patient groups. 3. All patients who had developed amyloidosis were of the normal protease inhibitor (Pi) MM-phenotype. 4. We conclude that the difference in the amyloid A-degrading activity between RA patients with or without amyloidosis cannot be accounted for by differences in concentration, activity or Pi type of alpha 1-antitrypsin.

Adult↗
PubMed2004

Successful treatment of systemic amyloidosis with hepatic involvement and factor X deficiency by high dose melphalan chemotherapy and autologous stem cell reinfusion.

Systemic amyloidosis with hepatic involvement is a rare disorder, which is characterized by the deposits of amyloid fibrils in the liver. The prognosis is poor and the median survival is 13 months. Bleeding problems resulting from coagulopathy frequently complicates systemic amyloidosis. We present two patients with a severe factor X deficiency and hepatomegaly as the presenting abnormalities of systemic amyloidosis. One of the patients was treated with high dose melphalan chemotherapy and autologous stem cell reinfusion, resulting in a normalization of the liver enzyme tests and the factor X level. The diagnosis and treatment of systemic amyloidosis with hepatic involvement and the management of the multifactorial coagulopathy in these cases is discussed.

Alkaline Phosphatase↗
PubMed2000

Anosacral cutaneous amyloidosis: a study of 10 Chinese cases.

BACKGROUND: Primary cutaneous amyloidoses are rare in Western countries, but are relatively common in Taiwan. Anosacral cutaneous amyloidosis is a rare type of primary cutaneous amyloidoses, first reported in Japanese patients. PATIENTS/METHODS: In the present study, we investigated the age of onset, sites of involvement, associated systemic diseases, and histopathological findings in 10 cases of anosacral cutaneous amyloidosis seen during the past 27 years. RESULTS: In previous reports the aetiology of anosacral cutaneous amyloidosis was thought to be a senile change, but half of our patients developed the disease before the age of 60 years. Based on our histopathological findings, apoptosis may be the initial event causing amyloid deposition, although the precise mechanism causing apoptosis needs further investigation. Three patients were found to have diabetes mellitus, but any relationship to anosacral cutaneous amyloidosis is unclear. CONCLUSIONS: No cases of this cutaneous disorder have been reported in the Western literature; there seems to be a racial difference accounting for the disease, although the precise factor is not clarified yet. The disease could easily be misdiagnosed as lichen simplex chronicus, postinflammatory hyperpigmentation or tinea cruris; therefore, a thorough history, a careful physical examination and a skin biopsy is needed to establish a firm diagnosis.

Adult↗
PubMed2002

Cutaneous lymphatic amyloid deposits in "Hungarian-type" familial transthyretin amyloidosis: a case report.

Multiple transthyretin (TTR) mutations have recently been identified and implicated in the development of familial systemic amyloidoses, but early diagnosis of these disorders is still largely unresolved. We investigated the presence and tissue distribution of TTR-derived amyloid in skin biopsies of a 59-year-old woman carrying the "Hungarian-type" mutation of TTR (Asp18Gly). Clinical symptoms involved severe central nervous system dysfunction without signs of polyneuropathy, also referred to as the "central form" of TTR-related systemic amyloidosis. Skin biopsy was also evaluated as a tool in order to diagnose this type of TTR amyloidosis. Biopsy samples were collected from the infra-axillary region. Light microscopy using Congo red and polarized light was used to diagnose amyloid deposits. Subsequently, electron microscopic analysis was performed to correlate the amyloid deposits with vicinal dermal structures. The amyloid class was determined by means of immunocytochemistry. TTR amyloid was primarily localized to lymphatic microvessels in the present case, whereas arterioles were devoid of TTR amyloid deposits. In addition, the well-known association of TTR amyloid with neural structures along the erector pilorum and around the sebaceous and serosal (sweat) glands was also evident. Electron microscopic analysis of amyloid deposits revealed characteristic amyloid fibrils that were irregular in shape, and exhibited a heterogeneous density and a random deposition pattern. Immunocytochemistry confirmed the cutaneous accumulation of TTR amyloid. In conclusion, amyloid deposits were abundantly present in the skin of a patient with "Hungarian-type" TTR amyloidosis; skin biopsy seems to be appropriate for the diagnosis of this disorder. We showed that besides the erector pilorum, sweat glands and nerve terminals, lymphatic microvessels are also severely infiltrated by TTR amyloid. Whether these pathological alterations can exclusively be found in "Hungarian-type" TTR amyloidosis should still be investigated. If such changes are not specific for the Asp18Gly mutation, they may be considered as diagnostic markers for "central" TTR amyloid disorders.

Amyloidosis↗
PubMed2003

Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy.

Monoclonal immunoglobulin light chains are deposited as amyloid fibrils in systemic AL (primary) amyloidosis, but the underlying plasma cell dyscrasias are often difficult to detect or unquantifiable. The relationships between circulating monoclonal light chains, amyloid load and clinical outcome, and the relative efficacies of chemotherapy regimens aimed at suppressing monoclonal immunoglobulin production, have not been determined. Circulating free immunoglobulin light chain (FLC) concentration was measured with a sensitive nephelometric immunoassay in 262 patients with AL amyloidosis, and followed serially in 137 patients who received either high-dose chemotherapy or one of two intermediate-dose cytotoxic regimens. Amyloid load was quantified by serum amyloid P component scintigraphy. A monoclonal excess of FLC was identified at diagnosis in 98% of patients. Among 86 patients whose abnormal FLC concentration fell by more than 50% following chemotherapy, 5-year survival was 88% compared with only 39% among those whose FLC did not fall by half (P < 0.0001). Amyloid deposits regressed in 58 patients. The magnitude and duration of the FLC responses to intermediate- and high-dose chemotherapy regimens were similar. The FLC assay enabled the circulating fibril precursor protein in AL amyloidosis to be quantified and monitored in most patients. Reduction of the amyloidogenic FLC by more than 50% was associated with substantial survival benefit, regardless of the type of chemotherapy used. Clinical improvement following chemotherapy in AL amyloidosis is delayed, but treatment strategies can be guided by their early effect on serum FLC concentration.

Adult↗
PubMed2002

AL amyloidosis is not present as an incidental finding in cutaneous biopsies of patients with multiple myeloma.

Multiple myeloma (MM) is a monoclonal B-cell neoplasm characterized by autonomous proliferation of immunoglobulin-secreting plasma cells that are capable of synthesizing amyloidogenic light chains resulting in AL amyloidosis. Clinically occult AL amyloid deposition may occur in up to 31% of patients with MM. The prognosis of combined amyloidosis and MM is improving with new therapeutic options. Thus it is imperative that patients with MM be screened for amyloidosis. Sixty-six consecutive skin biopsies from patients with MM and the diagnosis of graft vs. host disease (GVHD) were stained with Congo red and assessed for the presence of amyloid deposition. Twelve cases that had amyloid deposition in other tissue and had a cutaneous biopsy were also stained with Congo red and assessed for the presence of amyloid deposition. None of the 66 biopsies of GVHD, and none of the 12 cases that had documented amyloid deposition in other tissue showed evidence of amyloid deposition in the cutaneous biopsies. In the absence of specific cutaneous manifestations of amyloidosis, it is unlikely that amyloidogenic light chain deposition in the skin would be found. Type I collagen may appear similar to amyloid, both by light microscopy and fluorescence, after staining with Congo red. Thus care must be taken not to confuse type I collagen autofluorescence with positivity for amyloid when assessing skin biopsies stained with Congo red.

Amyloidosis↗
PubMed1997

Primary localized cutaneous amyloidosis: a clinicopathologic study from Saudi Arabia.

BACKGROUND: Primary localized cutaneous amyloidosis (PLCA) refers to deposition of amyloid in apparently previously normal skin with no evidence of deposits in internal organs. Certain ethnic groups are particularly predisposed. The objective of this study was to investigate the occurrence of PLCA in a hospital-based set-up and to review the clinico-pathologic findings of histologically confirmed cases. METHODS: Methods included a retrospective evaluation of the records and paraffin sections of skin biopsies of all patients, diagnosed clinically as cutaneous amyloidosis in a tertiary care teaching hospital during the period 1987-95. RESULTS: Twenty-one out of 42 suspected cases were histologically confirmed as PLCA; the total number of biopsied patients during the whole period was 920. Eleven were cases of lichen amyloidosis (LA) and 10 were of macular amyloidosis (MA). All were adults, and women dominated in MA. The mean duration of symptoms was shorter for the latter subtype. Histologically epidermal changes were the main differentiating feature between LA and MA. CONCLUSIONS: PLCA is a rare chronic progressive skin disorder affecting adults, with a prevalence of 0.15 among patients attending the dermatology clinic in a tertiary care teaching hospital in Saudi Arabia. There were few differences in demographic profile or histochemical characteristics between LA and MA. Meticulous histologic examination of sections and even sequential biopsies may be needed to confirm the diagnosis in clinically suspected cases.

Adolescent↗
PubMed2001

Frictional amyloidosis: a study of 10 cases.

Ten patients with macular amyloidosis were studied with particular reference to the role of friction. All 10 patients had a history of prolonged rubbing over a period of 2-5 years with various objects, such as bath sponges, brushes, towels, plant sticks and leaves. The presence of amyloid was confirmed by histochemical stains in six cases and by electron microscopy in four cases. The study confirms the role of friction in the causation of macular amyloidosis and hence, the term 'frictional amyloidosis' aptly describes the condition. The study also emphasizes the need for electron microscopy in the diagnosis of frictional amyloidosis.

Adult↗
PubMed2001

Pathogenesis of beta2-microglobulin amyloidosis.

Hemodialysis-related amyloidosis is a relatively new form of systemic amyloidosis, with beta2-microglobulin (B2M) being identified as the major constituent protein. Most of the clinical findings are related to amyloid deposition in osseo-articular tissues. B2M amyloid deposits first appear in the cervical intervertebral discs, which are well known to be susceptible to mechanical stress. A close relationship between changes of microenvironment caused by such stress and amyloid deposition is highly suggested. In advanced cases, an inflammatory reaction composed of macrophages, multinucleated giant cells, and granulation tissue, is observed around the amyloid deposits. Purified amyloid protein is native B2M, and mutations and proteolysis are not believed to be important for its deposition. Plasma levels of B2M are elevated as much as 5-10 times because of the inability of hemodialysis equipment removal of B2M from blood plasma, the duration being very important for B2M amyloid fibrillogenesis. Heparan sulfate proteoglycans, perlecan, is increased at the same sites of amyloid deposits from the early stages. In B2M amyloidosis, an increase of heparan sulfate proteoglycans is observed in the vascular wall and synovium, but in the discs, ligaments and cartilage, there is an increase of chondroitin sulfate proteoglycans predominantly. B2M has an affinity for heparan sulfate proteoglycans, although it is weaker than that for laminin and type IV collagen. This is related to the interactions between negative charges of sulfate groups of proteoglycans and positive charges of basic amino acids in N-terminal side of B2M. Increased cytokines production in the synovium, induced by advanced glycation end products as well as elevated plasma levels, is also linked to inflammatory reactions. Increased expression of matrix metalloproteinases (MMP), especially MMP-1 and -9, is related to the destructive changes of the bone and cartilage. The decrease of plasma levels by high flux membrane and control of inflammatory reactions are very important for prevention of B2M amyloidosis.

Amyloid↗
PubMed2000

Pleural amyloidosis in a patient with intractable pleural effusion and multiple myeloma.

Pleural involvement of systemic amyloidosis has been rarely reported. We report a case with multiple myeloma presenting an intractable right pleural effusion, in which pleural amyloidosis was diagnosed through pleural biopsy using a Cope needle. The diagnosis of pleural amyloidosis is important, because its refractory pleural effusion should be treated with pleurodesis. Since closed pleural biopsy using a Cope needle is much less invasive than thoracoscopy, the former should be attempted first whenever pleural amyloidosis is suspected.

Aged↗
PubMed2001

Holter monitoring in AL amyloidosis: prognostic implications.

The heart is involved in more than one third of patients with primary (AL) amyloidosis at diagnosis and it is by far the most common cause of death. Rhythm and conduction abnormalities generally represent the terminal event. The aims of this study were to determine the spectrum of Holter abnormalities found in AL amyloidosis and to assess their prognostic significance, particularly in relation to sudden death. Fifty-one patients with AL amyloidosis were included, and all of them had a complete history, physical examination, two-dimensional echocardiography, and 24-hour Holter monitoring. Fifty-five percent of these patients had echographic signs of heart involvement and 23% had heart failure. Complex ventricular arrhythmias were found in 57% of patients, couplets in 29%, and nonsustained ventricular tachycardia in 18%. Overall median survival was 23.4 months. Congestive heart failure, echocardiographic abnormalities, and Holter abnormalities adversely affected survival. The multivariate analysis demonstrated that interventricular septum thickness and couplets were independent predictors of survival. The presence of couplets correlated with sudden death. Holter monitoring may contribute to assessing the prognosis of patients with AL amyloidosis.

Adult↗
PubMed2003

Incidence and outcome of acute renal failure complicating autologous stem cell transplantation for AL amyloidosis.

BACKGROUND: High-dose intravenous melphalan and autologous peripheral blood stem cell transplantation (HDM/SCT) is an effective treatment for AL amyloidosis but is associated with significant toxicity, including the development of acute renal failure (ARF). The incidence and outcome of ARF as a complication of such treatment is not known. METHODS: All AL amyloidosis patients treated with HDM/SCT at a single institution between July 1, 1994 and May 31, 2000 were included in the analysis unless they were dialysis-dependent prior to treatment. Baseline data were collected prospectively. Treatment-related data were obtained from a prospectively maintained database and medical record review. ARF was defined as either a >/=1 mg/dL increase in serum creatinine or a doubling of serum creatinine to >/=1.5 mg/dL for at least 2 days. Recovery of renal function was defined as a return of serum creatinine to less than or within 0.5 mg/dL of the pretreatment value or the ability to discontinue dialysis initiated as a result of ARF. RESULTS: ARF occurred in 37 of 173 patients (21%). Initiation of dialysis was required in nine patients (5%). Forty-six percent of patients with ARF, including four of nine who required dialysis, had recovery of renal function. Baseline clinical variables that were independent predictors of transplant-associated ARF included creatinine clearance, proteinuria, and cardiac amyloidosis. Treatment-related variables associated with ARF included melphalan dose and bacteremia. ARF was associated with reduced survival at 90 days but did not have an impact on overall survival at a median follow-up of 2.9 years. CONCLUSION: ARF is a frequent but often reversible complication of HDM/SCT for AL amyloidosis. Specific clinical and treatment-related factors are associated with the development of this complication.

Acute Kidney Injury↗
PubMedDate not supplied

[Amyloidosis: a model of misfolded protein disorder].

Amyloidosis bears many characteristics of orphan diseases. Its diagnosis is difficult and often delayed. The main reasons thereof are its quite various clinical presentation: amyloidosis behaves as a new great masquerader, and the need to get a tissue sample to submit to specific dyes. Although we have been able for a long time to recognize amyloid, its intimate nature has remained quite completely enigmatic until recently. In fact, major advances in this way have appeared only in the last decade and it is now possible to consider the mechanisms of amyloidosis as a multistep phenomenon. Amyloidosis is no more thought only as a << storage disease >> of the extracellular space. This archaic viewpoint has shifted to the emerging paradigm of misfolded protein disorders. Amyloid proteins thus appear as a subgroup of misfolded proteins, where misfolding leads to subsequent aggregation. This aggregation may be a generic property of polypeptide chains possibly linked to their common peptide backbone that does not depend on specific amino acid sequences. And, in fact, many proteins can in vitro form amyloid-like aggregates, while in vivo, only 20 amyloid proteins have been so far identified. Although misfolding and aggregation are quite well studied in vitro, the last step of amyloid deposition, i.e. anchorage to the extracellular matrix, can not be so easily approached. Proteoglycans and serum amyloid P component have nevertheless been identified as key elements involved in extracellular deposition of amyloid proteins. These advances have opened new avenues in the therapeutic of amyloid disorders. Current treatment consists of support or replacement of impaired organ function and measures to reduce the production of amyloidogenic precursor proteins. Potential novel therapeutic strategies include stabilisation of the native fold of precursor proteins with targeted small molecules, reversion of misfolded proteins to their native state with << beta-sheet breakers >>, inhibition of amyloid fibril propagation and enhancement of amyloid clearance either through immunotherapy or by reducing the stability of deposits through depletion of serum amyloid P component, and breaking the anchorage to the extracellular matrix with glycosaminoglycan analogs.

Amyloid↗
PubMed2000

AL-amyloidosis of the kidney initially presenting as minimal change glomerulonephritis.

Small amounts of amyloid in kidney biopsy specimens may be missed on routine examination unless specifically targeted. Occasionally, this oversight results in a diagnosis of minimal change glomerulonephritis (MCGN). This misdiagnosis may be facilitated by the fact that typical "minimal changes" with flattening and effacement of the epithelial foot processes can be found in capillary loops directly affected by amyloid deposition as well as in capillary loops of glomeruli with only mild amyloid deposition in the mesangium. Repeatedly, the diagnosis of MCGN had to be corrected to renal amyloidosis when re-examination by special techniques succeeded in detecting even small amounts of amyloid fibrils. We present the case of a previously healthy 49-year-old man who suddenly developed nephrotic syndrome. A first renal biopsy showed MCGN. Proteinuria remained refractory to immunosuppressive treatments, and creatinine clearance deteriorated rapidly. Two years later, a repeat renal biopsy showed AL-amyloidosis. In this case, re-examination of the first biopsy in the light of the final diagnosis again did not show any deposition of amyloid fibrils. We suspect that proteinuria and epithelial podocyte changes in amyloidosis are caused by factors other than deposition of amyloid fibrils itself. Possibly a cytokine release during the early fibril formation leads to abnormalities even before the typical structural changes of renal amyloidosis can be detected. This is analogous to the hypothesis of a circulating factor that leads to proteinuria in focal segmental glomerulosclerosis or the speculation of altered lymphokine expression associated with the development of MCGN in Hodgkin's disease.

Amyloidosis↗
PubMed2000

[Therapy options in systemic AL-amyloidosis with renal involvement].

BACKGROUND AND OBJECTIVE: Despite significant efficacy of melphalan and prednisone in the therapy of systemic AL(light chain amyloid)amyloidosis the prognosis of the disease is poor. In patients with severe renal manifestation the reported results of low-dose melphalan therapy are inconclusive with respect to relief of clinical symptoms and overall prognosis. PATIENTS AND METHODS: We report our results of therapy in a group of 22 patients (8 women, 14 men, mean age 60 years) with renal involvement as the main manifestation of systemic AL-amyloidosis without overt myeloma. RESULTS: Ten patients were treated with low doses of melphalan and prednisone. No significant clinical improvement was observed in any case: the patients died an average of 12 months after diagnosis of the disease. Three patients were treated with high doses of melphalan followed by autologous stem cell transplantation. One patient died due to septicaemia after high-dose chemotherapy. Two of the patients experienced significant remission and live virtually free of clinical symptoms 12 and 18 months after therapy. Nine patients were treated only symptomatically: four of them were alive an average of 30 months after diagnosis of systemic AL-amyloidosis. CONCLUSIONS: Only high-dose melphalan therapy offered a realistic chance of amelioration of clinical symptoms in our group of patients, although therapy-associated risks seem to be high. In patients with severe renal amyloidosis, who are not considered for high-dose therapy, particularly careful consideration of potential benefits and possible risks of conventional melphalan therapy is necessary, because the results of this approach are in doubt.

Adult↗
PubMed2001

[Augmentation of left ventricular outflow tract gradient by digitalis glycosides in a case of cardiac (AL-) amyloidosis].

HISTORY AND CLINICAL FINDINGS: A 61-year-old man suffering from histologically confirmed amyloidosis associated with coagulation disturbances presented with exercise induced shortness of breath and symptoms of cardiac asthma after four cycles of chemotherapy with melphalan and prednisolone. As a result, treatment with digitoxin was initiated. In addition furosemide and an oral nitrate were administered. INVESTIGATIONS: Disparity between electrocardiogram and echocardiographic findings was observed in that, while the electrocardiogram showed loss of 'R wave in precordial leads V(2 - 4), excessive thickening of both left and right ventricular wall was shown in the echocardiogram. Doppler-echocardiography revealed a left ventricular outflow tract obstruction at rest with a peak pressure gradient of 64 mm Hg which rose to 145 mm Hg during Valsalva manoeuvre. Colour Doppler presented a moderate mitral insufficiency and the transmitral Doppler flow studies detected a restrictive left ventricular filling pattern. DIAGNOSIS, TREATMENT AND COURSE: Digitalis therapy was stopped because of the outflow tract obstruction complicating cardiac amyloidosis. Cardiac symptoms abated over the following weeks. This improvement was reflected in a significant reduction of the outflow tract gradient, the gradients now being 16 mm Hg under resting conditions and a maximum of 36 mm Hg during the Valsalva manoeuvre. The transmitral Doppler flow pattern showed a pseudonormalisation and the mitral regurgitation regressed nearly completely. The patient was free from cardiac complaints until his sudden death 21 months after the diagnosis of cardiac amyloidosis. CONCLUSION: Cardiac amyloidosis can present with left ventricular outflow tract obstruction mimicking hypertrophic obstructive cardiomyopathy. This fact must be borne in mind to avoid therapy with preload-reducing or positive inotropic drugs and especially glycosides.

Amyloidosis↗
PubMed2003

Chronic hyposphagma revealing primary ocular amyloidosis.

BACKGROUND: Amyloidosis is an extracellular accumulation of a clear substance called amyloid in different organs. Fragments of identical proteinic chains are the components of this substance. Amyloidosis can be primary, secondary (chronic inflammation, multiple myeloma, tumour), senile or hereditary. HISTORY AND SIGNS: A 59-year-old healthy patient was referred with recurrent subconjunctival haemorrhages in his right eye since one year. The clinical examination disclosed the presence of yellowish subconjunctival deposits associated with haemorrhages. THERAPY AND OUTCOME: Histopathologic examination of these deposits revealed the presence of amyloid. A complete work-up to exclude a systemic disease gave negative results. CONCLUSIONS: Primary conjunctival amyloidosis is a rare clinical entity that is mainly diagnosed histopathologically. In the presence of a recurrent hyposphagma of unknown aetiology the diagnosis of amyloidosis should be excluded.

Amyloidosis↗
PubMed2006

[Haemorrhagic diathesis as an early symptom of systemic amyloidosis].

HISTORY: A 63-year-old man, known to have Bechterev's disease was admitted because of weight gain and nocturnal sweating. He also had signs of heart failure with progressive exertional dyspnoea. Many months previously numerous bleedings had occurred in the skin, predominantly the face (periorbital and perioral), the inguinal region and the penis. INVESTIGATIONS: Extensive diagnostic test failed to find any evidence of tumor. The Rumpel-Leede tourniquet test was positive, while platelet functions was normal, suggesting vascular disease. The skin biopsy showed many perivascular amyloid deposits (AL). Immunochemical differentiation also demonstrated the same amyloid in rectal and hepatic biopsies. But there was AA amyloid in a hepatic artery. Immunophoresis indicated a biclonal gammopahty of unknown significance. DIAGNOSIS, TREATMENT AND COURSE: These findings indicated the diagnosis of primary AL amyloidosis associated with a gammopathy of unknown significance and a secondary AA amyloidosis in the presence of chronic Bechterev s disease. The clinical picture also showed cardiac complications, predominantly heart failure and numerous previous myocardial infarctions without S-T elevations. Echocardiography, which revealed marked thickening of the left ventricle with a restrictive filling pattern, suggested cardiac co-morbidity. The patient underwent chemotherapy with melphalan and prednisone but had a sudden cardiac death. CONCLUSION: In a case of bleeding of unknown cause systemic amyloidosis should be considered in the differential diagnosis. A tendency towards bleeding, as in this patient, may be the first sign of amyloidosis, which ist often diagnosed quite late in the course of the disease.

Amyloidosis↗