Heart Transplantation for Homozygous Familial Transthyretin (TTR) V122I Cardiac Amyloidosis

Heart failure is the usual cause of death in patients with amyloid cardiomyopathy. The commonest form of hereditary cardiac amyloidosis is associated with the Val122Ile variant of transthyretin (TTR), which is carried by 3–4% of the African American population. Here, we report the outcome of the first cardiac transplantation in a patient with TTR V122I. A 59-year-old Caribbean man presented with biventricular failure. Other than previous bilateral carpel tunnel syndrome, he had been well and had no evidence of extracardiac amyloidosis. An endomyocardial biopsy demonstrated amyloid of TTR type. Sequencing of TTR gene indicated homozygosity for V122I. He underwent cardiac transplantation and 3 years later, remains well with no evidence of allograft or systemic amyloid deposition.     

Visceral involvement of dialysis amyloidosis

Carpal tunnel syndrome, peripheral arthropathy, erosive spondyloarthropathy and lytic bone lesions have all been associated with dialysis amyloidosis. Recent studies indicate that beta 2-microglobulin is the major constituent protein in this new form of amyloidosis. Dialysis amyloidosis was reported to have a local rather than a systemic involvement, although its full extent is yet to be determined. We investigated 3 patients on maintenance hemodialysis with bilateral carpal tunnel syndrome and amyloid arthropathy and found amyloid depositions in several organs. These findings suggest that, in contrast to what had been thought previously, dialysis amyloidosis could have systemic as well as visceral distribution. The amyloid deposits found were resistant against potassium permanganate treatment and reacted with anti-human beta 2-microglobulin antibody.     

Unsuitable value of abdominal fat tissue aspirate examination for the diagnosis of amyloidosis in long-term hemodialysis patients

Abdominal fat tissue aspiration was used in 22 long-term hemodialysis patients (5-17 years). Fourteen of these patients had carpal tunnel syndrome and amyloid deposits of beta 2-microglobulin in the synovium. One patient had a spontaneous rupture of the spleen with amyloid deposits in spleen vessels. Seven other patients presented carpal tunnel syndrome and/or articular pains, and radiological lytic lesions in bone, strongly suggesting an amyloid origin. As a control group, in 22 patients with biopsy-proven amyloidosis, abdominal fat tissue aspirates were performed and were studied under the same conditions: by light microscopy these tissues were stained with Congo red and examined with a polarizing microscope; these specimens were also studied by electron microscopy. In all hemodialyzed patients, no amyloid deposit was present in fat tissue with Congo red staining and by electron microscopy. On the contrary, amyloid was observed in 17 of 22 cases in other types of amyloidosis. It seems that this method which has been proved to be simple and sensitive for the diagnosis of systemic amyloidosis is not a good marker for the presence of amyloid in long-term hemodialysis patients.     

Transthyretin amyloidosis with cardiomyopathy after domino liver transplantation: Results of a cross-sectional study

Domino liver transplantation (DLT) has been used widely in patients with hereditary amyloid transthyretin (ATTR) amyloidosis. New-onset polyneuropathy in recipients of DLT has been reported, but there are few cases of cardiac involvement reported. We aimed to perform a cross-sectional study for ATTR amyloidosis with cardiomyopathy (ATTR-CM) in DLT recipients. We evaluated 23 living DLT recipients a median of 9 years since DLT at 2 referral centers with a systematic cardiac evaluation, including bone scintigraphy. Median age was 72 years, 91% had hypertension, 35% had diabetes mellitus, 67% had chronic renal failure, and 8 patients (35%) developed new-onset polyneuropathy. Only 13% had a normal electrocardiogram and a normal echocardiography, and most of them showed some conduction disturbance or increase in left ventricular wall thickness, but only 1 patient with a Glu89Lys mutation developed ATTR-CM diagnosed by bone scintigraphy and endomyocardial biopsy. None of the recipients of a DLT with Val30Met mutation showed cardiac involvement by bone scintigraphy. In conclusion, DLT from Val30Met donors seems to be safe regarding the development of ATTR-CM. Evaluation of cardiomyopathy in DLT recipients is challenging due to concomitant comorbidities and in this context, bone scintigraphy can be helpful to evaluate ATTR-CM.     

Effect of synovial transthyretin amyloid deposition on preoperative symptoms and postoperative recovery of median nerve function among patients with idiopathic carpal tunnel syndrome

Background The clinical characteristics of wild-type transthyretin amyloid deposition among patients with carpal tunnel syndrome (CTS) have not been well investigated.Methods One-hundred and seven patients with idiopathic CTS who underwent carpal tunnel release were enrolled. They underwent physical examination of the hand, nerve-conduction study, and magnetic resonance imaging (MRI) study of the wrist, and completed a patient-oriented questionnaire. The tests, except for MRI, were repeated 1, 3, and 6 months postoperatively. Synovial tissue was obtained during surgery and analyzed by Congo red and immunohistochemical staining. Ordinal logistic regression analysis was used to evaluate the significance of different clinical and subjective findings between patients with and without amyloid deposition. Postoperative improvements were also compared.Results Wild-type transthyretin amyloid deposition was observed for 38 patients. Greater symptom severity and 2-point discrimination scores, and larger cross-sectional areas of the carpal tunnel, were significantly correlated with a larger amount of preoperative amyloid deposition. However, the presence and amount of preoperative amyloid deposition did not affect postoperative improvements in physical findings and nerve-conduction studies.Conclusions Although transthyretin amyloid deposition can worsen CTS symptoms, postoperative improvements were similar for patients with and without this deposition.     

Clinical and biochemical outcome of hepatorenal transplantation for hereditary systemic amyloidosis associated with apolipoprotein AI Gly26Arg

BACKGROUND: Treatment of systemic amyloidosis comprises measures to support failing organ function coupled with attempts to reduce the supply of the respective amyloid fibril precursor protein. Orthotopic hepatic transplantation is effective in familial amyloid polyneuropathy associated with variant transthyretin, because this protein is produced almost exclusively in the liver. Hepatic transplantation has not been performed in hereditary apolipoprotein AI (apoAI) amyloidosis, and the liver's contribution to plasma apoAI levels has not been determined in vivo. METHODS: A 57-year-old Irish man with hereditary systemic amyloidosis associated with apoAI Gly26Arg, which had led to end-stage renal failure and progressive liver dysfunction, underwent hepatorenal transplantation. His outcome was followed clinically and his amyloid deposits were monitored with serum amyloid P component scintigraphy. The proportion of variant apoAI in the plasma was estimated by quantitative isoelectric focusing before and after liver transplantation. RESULTS: Plasma levels of variant apoAI decreased by 50% after liver transplantation, and the patient was asymptomatic 2 years after surgery. Subclinical amyloid deposits that were present in his spleen and heart preoperatively have regressed and stabilized respectively. CONCLUSIONS: Orthotopic liver transplantation substantially reduces the supply of the amyloid fibril precursor protein in hereditary apoAI amyloidosis, and the excellent outcome in this patient probably reflects the balance between deposition and turnover of amyloid having been altered in favor of the latter. These findings support the use of liver transplantation in patients with hereditary apoAI amyloidosis who develop hepatic dysfunction.     

Systemic involvement of dialysis-amyloidosis

A new type of amyloidosis, predominantly osteoarticular, has recently been recognized in uremic patients on hemodialysis, beta 2-microglobulin being the major constituent protein. Nowadays, it is not clear whether the amyloid deposition is limited to osteoarticular structures or whether it has a systemic character. In order to investigate the extension of dialysis amyloidosis, we studied 26 patients receiving hemodialysis treatment (mean time 12.2 years) for chronic renal failure due to nonamyloid nephropathy and who were affected by symptomatic dialysis amyloidosis. Twenty-two patients developed a carpal tunnel syndrome, and amyloid arthropathy was present in 21. Subcutaneous abdominal fat aspiration, rectal and skin biopsy, and two-dimensional echocardiography were performed in most of the patients, searching for the visceral involvement. Surgical pieces (one stomach and two colon) and three necropsies of symptomatic patients were included in the systemic investigation. Also, we studied five necropsies of patients without articular symptoms. Histological confirmation of amyloid visceral involvement was demonstrated in 15 (58%) of the 26 patients studied. When positive two-dimensional echocardiograms were included, the percentage increased to 81%. No differences in the rate of visceral involvement could be found between the two clinical groups (with and without carpal tunnel syndrome). Two-dimensional echocardiography represents the most useful tool to search for the visceral involvement of beta 2-microglobulin amyloidosis, followed by abdominal fat aspiration and rectal biopsy. Amyloid deposits were resistant to potassium permanganate treatment and reacted with antihuman beta 2-microglobulin (avidin-biotin-peroxidase method).     

Amyloid deposition in systemic organs in long-term hemodialysis patients

It has not been yet elucidated whether, in long-term hemodialysis patients, amyloid deposition in the transverse carpal ligament (TCL) is a symptom of systemic amyloidosis or a localized one. In 2 patients amyloid deposition was noted in the TCL which had been resected at operation, and we observed amyloid deposits also in other organs at autopsy after their deaths. In the two patients, no diseases resulting in secondary amyloidosis were observed. The unlabeled antibody peroxidase-antiperoxidase method (PAP method) served to reveal the deposits of beta 2-microglobulin (beta 2M) in the TCL and other organs comparable to the Congo red positive area. And the Congo red staining for the amyloid protein after potassium permanganate treatment was preserved. According to these results, the carpal tunnel syndrome (CTS) in long-term hemodialysis was considered as a symptom of systemic amyloidosis. Amyloid was deposited mainly in the vessel walls and the deposition was not circumferential but segmental.     

Effect of dialysis membrane and patient's age on signs of dialysis-related amyloidosis. The Working Party on Dialysis Amyloidosis

This 12 center study was designed to assess factors affecting the development and progression of beta 2-microglobulin amyloidosis in long-term dialysis. A total of 221 patients who were on hemodialysis for more than five years, and who were treated the entire time only with AN69, a biocompatible, highly permeable membrane, or cuprophane, a less permeable, poorly biocompatible membrane (Cell) were evaluated for time on dialysis, development of carpal tunnel syndrome, and cystic bone lesions. X-ray documentation was taken in a minimum of four of the six following joints: both hips, wrists and shoulders. The data demonstrate that patients treated solely by AN69 membranes display signs of bone amyloidosis less frequently than do those treated by Cell membranes. Age at onset of dialysis was found to have a striking correlation with the development of carpal tunnel syndrome and bone amyloidosis, while no significant influence was found for hyperparathyroidism, sex or year of first dialysis.     

Beta 2-microglobulin: a new form of amyloid protein associated with chronic hemodialysis

Carpal tunnel syndrome (CTS) has been associated with amyloid deposits and is now regarded as a major complication in chronic hemodialysis patients. While this new syndrome has been receiving increasing attention, its etiology has not been clarified. We have isolated amyloid fibrils from amyloid laden tissues inside the carpal tunnel in four different hemodialysis patients with CTS. After solubilization in guanidine HCl, a significant amount of the protein was located in a homogeneous, low molecular weight fraction. Each protein was found to be identical to beta 2-microglobulin with regard to its molecular weight of 11,000 on SDS-PAGE, amino acid composition and N-terminal amino acids: Ile-Gln-Arg-Thr-Pro-Lys-Ile-Gln-Val-Tyr-Ser-Arg-His-Pro-Ala-Glu. In direct immunofluorescent study, anti-beta 2-microglobulin did react positively with amyloid deposits. These results demonstrate that the amyloid associated with chronic hemodialysis contains as major component a new form of amyloid fibril protein that is homologous to beta 2-microglobulin. It is postulated that beta 2-microglobulin cannot be removed from the blood by conventional hemodialysis, and accumulates in tissues causing the formation of amyloid fibrils, which, having a relatively high affinity to the carpal tunnel area, thus causes CTS.     

Hereditary Apolipoprotein A-1 Amyloidosis With Glu34Lys Mutation Treated by Liver Transplantation: A Case Report

Hereditary apolipoprotein A-1 (ApoA-1) amyloidosis is a rare disease characterized by progressive deposition of amyloid fibrils in the kidney, heart, and liver. We observed a 45-year-old male patient with liver failure. Liver dysfunction was detected at 30 years of age during an annual health check-up. At 35 years of age, renal dysfunction was also found. At 40 years of age, the pathologic findings of the liver revealed amyloid deposition. A testis biopsy specimen taken at 42 years of age to identify the cause of male infertility showed amyloid accumulation. At 43 years of age, the amyloid results and genetic profile led to a definitive diagnosis of hereditary ApoA-1 amyloidosis caused by Glu34Lys mutation. A family history was absent. Liver failure showed Budd-Chiari–like formation, including enlargement of the caudate lobe and liver congestion. Although the patient showed end-stage liver cirrhosis and renal failure, only liver transplant was performed considering the burden for a living donor. The enlarged liver (4.9 kg) showed amyloid deposition in parenchyma and the space of Disse. Amyloid also accumulated in the giant spleen. The APOA1 mutation Glu34Lys is extremely rare, and in this case hepatic failure was successfully treated by liver transplant to both replace organ function and reduce production of the amyloidogenic ApoA-1–variant protein. Careful observation for reaccumulation of amyloidosis in the organ is required.     

Macroglossia and amyloidoma of the buttock: evidence of systemic involvement in dialysis amyloid

A 48-year-old male on cuprophane haemodialysis for 18 years, with a history of dialysis arthropathy and recurrent carpal tunnel syndrome developed macroglossia and bilateral buttock tumoral masses. The tongue and buttock masses were biopsied. Histology of both biopsies showed amyloid deposits of the beta 2-microglobulin (B2M) variety. Amyloidomas in the gluteal region and macroglossia have not been previously described in amyloid derived from B2M. These findings suggest that systemic B2M amyloidosis can have a similar tissue distribution to AL amyloidosis. This case also stresses the importance of inspection of the tongue, and palpation of the gluteal region for masses, in the assessment of patients with dialysis arthropathy.     

Orthotopic liver transplantation for hereditary fibrinogen amyloidosis

Systemic amyloidosis results from the deposition of insoluble protein fibrils in various organs and tissues. To date, several different proteins have been associated with amyloid fibril formation, including immunoglobulin light chain, serum amyloid A protein, and transthyretin. Recent reports have shown that variant fibrinogen chains can form amyloid in certain kindreds. Hepatic transplantation has previously been reported in the treatment of hereditary amyloidosis associated with variant transthyretin proteins, which are mainly synthesized in the liver. This article reports the first use and long-term follow-up of combined hepatic and renal transplantation in the successful treatment of two patients with hereditary fibrinogen amyloidosis. Both patients experienced sustained improvement in renal function and nutritional status at 61/2 years and 28 months of follow-up, respectively. Orthotopic liver transplantation is effective and potentially curative treatment of hereditary fibrinogen amyloidosis.     

Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with ATTR amyloid

Transthyretin-derived amyloidosis (ATTR) amyloidosis is the third most prevalent amyloid type in surgical pathology and may occur as a hereditary disease with germline mutations in the TTR gene or as senile systemic amyloidosis (SSA) without mutations. Distinction between hereditary ATTR amyloidosis and SSA is of central importance, as the former necessitates genetic counseling and can be treated by liver transplantation. However, little is known about the prevalence of hereditary ATTR amyloidosis in surgical pathology specimens. We have examined the distribution of hereditary ATTR amyloidosis and SSA in a consecutive series of surgical pathology specimens with histologically and immunohistochemically confirmed ATTR amyloid. Thirty-three consecutive patients were retrieved from the Amyloid Registry of the Charité University Hospital. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue or patient blood and examined by DNA sequencing. ATTR amyloid was found in the gastrointestinal tract, endomyocardium, peripheral nerve, carpal tunnel ligament, synovia, breast, and testicle. Amyloid fibrils were present as interstitial and vascular deposits, as evidenced by Congo red staining. TTR gene mutations were detected in 12 of 30 patients, with p.Val30Met being the most prevalent (5 patients). Furthermore, 2 novel mutations (p.Asp39Val and p.Glu54Asp) were found. In patients carrying a mutation, ATTR amyloid was found in the gastrointestinal tract, myocardium, nerve, and testicles. To conclude, the hereditary form of ATTR amyloid seems to be more common in elderly patients than previously thought. It is, therefore, important to genetically test every patient when diagnosing ATTR amyloidosis.     

Intestinal pseudo-obstruction due to dialysis amyloidosis

Marked gastric dilatation and the carpal tunnel syndrome developed concurrently in a 58-year-old man treated with hemodialysis for 14 years. Despite extensive examinations, no attributable organic lesion was demonstrated in the gastrointestinal tract. However, amyloid deposition, which was immunohistochemically identified as beta-2 microglobulin, was demonstrated in the stomach and the synovia excised from the right carpal tunnel. Intestinal pseudo-obstruction due to dialysis amyloidosis was considered to be the cause of the gastric dilatation. There have been a few recently reported cases with dialysis amyloidosis in which extra-articular amyloid deposition resulted in overt clinical problems. The present case provides additional evidence that dialysis amyloidosis can develop serious extra-articular complications; intestinal pseudo-obstruction is a very rare gastrointestinal manifestation.     

Cystic radiolucencies of carpal bones, distal radius and ulna as a marker for dialysis-associated amyloid osteoarthropathy.

Patients on long-term hemodialysis (HD) are known to develop amyloid osteoarthropathy, evidenced as cystic radiolucencies on X-rays of the affected joints. To study the relationship between cystic radiolucencies and amyloid osteoarthropathy in 394 patients, we classified the severity of the cystic radiolucencies seen in the wrist joint on a 4-point scale and evaluated the association between lesion severity (grade) and several parameters. Biopsy was performed in 8 patients with 11 bone cysts of the wrist joint who had been operated for carpal tunnel syndrome. HD for 10 years or longer, age 50 or older and the presence of carpal tunnel syndrome were associated with severe cyst rating. There was no association between lesion grade and serum level of PTH-C, aluminum or beta 2-microglobulin (B2M). Ten of the 11 biopsied bone cysts in 8 patients with carpal tunnel syndrome demonstrated amyloid deposits which reacted with B2M. We conclude that a cystic radiolucency observed in the wrist joint of a patient undergoing HD indicates the deposition of amyloid. The cyst grade provides a useful marker for the severity of amyloid osteoarthropathy in HD patients.     

Monomeric and dimeric {beta}2-microglobulin may be extracted from amyloid deposits in vitro

Background. There is a controversy as to whether {beta}2-microglobulin ({beta}2M amyloid deposits may be degraded resulting in regression and cure of amyloidosis. We have recently reported a long-term clinical study involving transplanted patients suggesting that there is no resorption of amyloid deposits in vivo, even after correction of the primary cause of amyloidosis. To progress in the study of the solubility of amyloid fibrils we performed an in vitro study with the intent to remove protein constituents from amyloid fibrils and amyloid deposits. Methods. Amyloid fibrils were prepurified from four amyloid deposits surgically obtained from carpal tunnel. They were incubated for 2 h with a phosphate-buffered saline (PBS) solution containing trypsin, collagenase, kallikrein, the three of them, or PBS alone. The experiments were repeated in the presence of the antiprotease &agr;2M). Results. Several bands were observed when the supernatants were run through SDS-PAGE. Western blotting identified in these bands the presence of &agr;2M, light chains of immunoglobulins and {beta}2M in mono- and dimeric form. The same proteins were solubilized with PBS alone. Equivalent results were obtained with crude amyloid deposits; however, {beta}2M presented almost exclusively in monomeric form. Conclusions. These results show that the protein constituents may be recovered from the amyloid fibrils in vitro. They also show that even the more insoluble {beta}2M dimers are resuspended by the action of PBS, with no need for proteases to cleave their attachment to the amyloid deposits.     

Renal Transplantation in Systemic Amyloidosis—Importance of Amyloid Fibril Type and Precursor Protein Abundance

Renal transplantation remains contentious in patients with systemic amyloidosis due to the risk of graft loss from recurrent amyloid and progressive disease. Outcomes were sought among all patients attending the UK National Amyloidosis Centre who received a renal transplant (RTx) between January 1978 and May 2011. A total of 111 RTx were performed in 104 patients. Eighty‐nine percent of patients with end‐stage renal disease (ESRD) due to hereditary lysozyme and apolipoprotein A‐I amyloidosis received a RTx. Outcomes following RTx were generally excellent in these diseases, reflecting their slow natural history; median graft survival was 13.1 years. Only 20% of patients with ESRD due to AA, AL and fibrinogen amyloidosis received a RTx. Median graft survival was 10.3, 5.8 and 7.3 years in these diseases respectively, and outcomes were influenced by fibril precursor protein supply. Patient survival in AL amyloidosis was 8.9 years among those who had achieved at least a partial clonal response compared to 5.2 years among those who had no response (p = 0.02). Post‐RTx chemotherapy was administered successfully to four AL patients. RTx outcome is influenced by amyloid type. Suppression of the fibril precursor protein is desirable in the amyloidoses that have a rapid natural history.     

Organ Transplantation in Hereditary Apolipoprotein AI Amyloidosis

Patients with hereditary apolipoprotein AI (apoAI) amyloidosis often have extensive visceral amyloid deposits, and many develop end-stage renal failure as young adults. Solid organ transplantation to replace failing organ function in systemic amyloidosis is controversial due to the multisystem and progressive nature of the disease and the risk of recurrence of amyloid in the graft. We report the outcome of solid organ transplantation, including dual transplants in 4 cases, among 10 patients with apoAI amyloidosis who were followed for a median (range) of 16 (4–28) and 9 (0.2–27) years from diagnosis of amyloidosis and transplantation, respectively. Eight of 10 patients were alive, seven with a functioning graft at censor. Two patients died, one of disseminated cytomegalovirus infection 2 months after renal transplantation and the other of multisystem failure following severe trauma more than 13 years after renal transplantation. The renal transplant of one patient failed due to recurrence of amyloid after 25 years. Amyloid disease progression was very slow and the natural history of the condition was favorably altered in both cases in which the liver was transplanted. Failing organs in hereditary apoAI amyloidosis should be replaced since graft survival is excellent and confers substantial survival benefit.     

Amyloidosis AA

Amyloidosis remains one of the three major types of multisystemic amyloidosis, with immunoglobulinic (AL) and hereditary varieties. Recently, however, its incidence has been decreasing in Western countries. Inflammatory disorders are currently the major causes of amyloid-associated (AA) amyloidosis; first of all it is rheumatoid arthritis, then ankylosing spondylarthropathy and auto-inflammatory syndromes. Some tumours may lead to amyloidosis, including Castleman's disease. Complete surgery can result in regression of amyloid. It is not exactly known why some patients develop a progressive amyloidosis, whereas others do not. A permanent acute phase response, ideally evaluated with serial measurement of serum protein SAA, the precursor of the AA protein deposited in tissues, seems to be a prerequisite to the development of inflammatory (AA) amyloidosis. Genetic factors have however been recently emphasized. Nephropathy is the main clinical manifestation of amyloidosis. Serial search for proteinuria and serum creatinine measurement remain quite useful for detecting the first sign of renal impairment during chronic inflammatory disorders. A thorough diagnosis of AA amyloidosis deserves to gather whole clinical and pathological data, including immunohistochemistry. Some pitfalls exist and another type of amyloidosis should not be misdiagnosed as the AA variety. Ultimate renal failure and gut involvement with denutrition account for the persistent poor prognosis of AA amyloidosis. Current treatment aim at decreasing the inflammatory response; drugs targeting other steps of amyloid deposition are currently developed.