Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis

Holmgren, Gösta; Steen, Lars; Suhr, Ole B.; Ericzon, Bo‐Göran; Groth, Carl‐Gustav; Andersen, Oluf; Wallin, B. Gunnar; Seymour, Andrew; Richardson, S.; Hawkins, Philip N.; Pepys, Mark B.

doi:10.1016/0140-6736(93)93127-m

Cited by 527 publications

(307 citation statements)

References 14 publications

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“…Several investigators have reported improvement in autonomic and peripheral neuropathies and nutritional status. [6][7][8][9] Although OLT is, at present, the only lifesaving treatment for FAP, recent reports have suggested that cardiomyopathy can progress after OLT for FAP. 10,11 We report the case of a patient who underwent OLT for FAP caused by Tyrosine-77 (Tyr-77) transthyretin variant in whom clinical worsening with progression of cardiomyopathy and neuropathy has been observed after OLT.…”

confidence: 99%

Progression of cardiomyopathy and neuropathy after liver transplantation in a patient with familial amyloidotic polyneuropathy caused by tyrosine-77 transthyretin variant

et al. 1999

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Familial amyloidotic polyneuropathy is an inherited form of amyloidosis associated with a mutant form of a protein called transthyretin. The Methionine-30 variant is the most frequent mutation observed. This disorder is caused by deposition of this protein as amyloid in several organs, such as the heart, kidneys, and peripheral nervous system. The disease is always progressive and fatal, and patients die 7 to 10 years after the onset of symptoms. Liver transplantation is at present the only choice for these patients because it provides improvement of symptoms and/or stops progression of the disease in most patients. We report the case of a patient who showed clear progression of cardiomyopathy and neuropathy after liver transplantation. Copyright 1999 by the American Association for the Study of Liver DiseasesF amilial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited form of amyloidosis associated with a mutant form of a protein called transthyretin or prealbumin. This disorder is caused by the systemic deposition of variant transthyretin molecules as amyloid fibrils in the extracellular matrix of several organs, such as the heart, kidneys, peripheral nervous system, and eyes. 1-3 More than 30 amyloidogenic mutations in the transthyretin gene have been reported, but the Methionine-30 (Met-30) transthyretin variant is the most frequent. 4 Symptoms begin in the middle life with peripheral polyneuropathy, autonomic dysfunction, cardiomyopathy, vitreous opacities, and, occasionally, nephrotic syndrome and renal failure. The disease is always progressive and fatal, and patients usually die 7 to 10 years after the onset of symptoms. 1 The presence of cardiomyopathy is the most important factor that affects patient survival. 5 In 1990, Holmgren et al 6 proposed orthotopic liver transplantation (OLT) as a treatment to remove the major source of variant transthyretin production, thereby arresting the progression of amyloid deposition. Since then, many patients with FAP have received liver transplants in several countries, with a high success rate. Several investigators have reported improvement in autonomic and peripheral neuropathies and nutritional status. 6-9 Although OLT is, at present, the only lifesaving treatment for FAP, recent reports have suggested that cardiomyopathy can progress after OLT for FAP. 10,11 We report the case of a patient who underwent OLT for FAP caused by Tyrosine-77 (Tyr-77) transthyretin variant in whom clinical worsening with progression of cardiomyopathy and neuropathy has been observed after OLT. Case ReportA 61-year-old man had a 2-year history of progressive muscle weakness, sensory impairment (paresthesis and loss of pain and temperature sensations), and deep arreflexia of the limbs, particularly in the legs. In addition, he showed symptoms of autonomic dysfunction with hypotensive episodes, dysuria, impotence, and severe diarrhea accompanied by a weight loss of 12 kg during the last year. The presence of an axonal polyneuropathy was verified by electromyography and n...

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confidence: 99%

Progression of cardiomyopathy and neuropathy after liver transplantation in a patient with familial amyloidotic polyneuropathy caused by tyrosine-77 transthyretin variant

et al. 1999

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“…1 Because the liver predominantly synthesizes TTR, liver transplantation has been thought to be a promising therapy for halting the progression of clinical FAP symptoms. [6][7][8] However, because no other effective therapy is available as of this moment, development of alternative therapeutic strategies based on the mechanism of TTR amyloid fibril formation is urgently needed.…”

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Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy

Kugimiya

Jono

Saito

et al. 2011

Laboratory Investigation

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Transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP) is characterized by systemic accumulation of amyloid fibrils caused by a point mutation in the TTR gene. Despite the urgent need for alternative therapeutic strategies, the pathogenesis of FAP still remains elusive. In our study reported here, we focused on albumin, the most abundant protein in plasma, and described the role of albumin in the TTR amyloid-formation process. Patients with FAP evidenced significantly decreased serum albumin levels as the disease progressed. Biacore analysis showed that albumin had a binding affinity for TTR and exhibited higher affinity for TTR amyloid than native TTR. Albumin functioning as an antioxidant effectively suppressed TTR amyloid formation. In patients with FAP, albumin was significantly oxidized as the disease progressed. Moreover, loss of functional albumin accelerated TTR deposition in analbuminemic rats possessing a human variant TTR gene. Taken together, these results indicate that albumin may have an inhibitory role in the TTR amyloid-formation process.

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“…V30M familial amyloid polyneuropathy is effectively treated by liver transplantation (31,32), which mediates the replacement of the V30M allele by a WT allele in the organ that supplies tissues except the brain and eyes with TTR. However, emerging clinical data suggest that this procedure is substantially less effective against other familial TTR mutations for reasons that are unclear.…”

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Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

Green

Foss

Kelly

2005

Proc. Natl. Acad. Sci. U.S.A.

110

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The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to <10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and V122I, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (K d1 ‫؍‬ 40 nM, Kd2 ‫؍‬ 1.4 M). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavailability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements.amyloidogenesis inhibitor ͉ kinetic stabilization F or many years nutritionists and dieticians have noted the health benefits of a soy-based diet, citing the much lower incidence of cancer, including breast cancer, in Asian countries (1-4). The isoflavone genistein (compound 1 in Fig. 1), found in various soy foods at concentrations of 1.9-229 g͞g, is the component of soy implicated in cancer chemoprevention (5). An additional 71-968 g͞g of genistein is present as its O-glucoside conjugate, genistin (2), which is rapidly deglycosylated by intestinal bacteria in vivo. Genistein is being evaluated in preliminary trials for treatment of breast, prostate, and uterine cancers (6, 7), as well as for osteoporosis (8), cardiovascular disease (9), and treatment of menopausal symptoms (10). Toxicity studies reveal that this isoflavone does not appear to cause adverse health effects, even at the relatively high concentrations used (11-13). The isoflavone daidzein (3), lacking the hydroxyl group at the 5 position of genistein, is also found in soy foods, but no chemoprotective effects have been attributed to it.Transthyretin (TTR) is a tetrameric protein composed of identical 127-aa ␤-sheet sandwich subunits (14, 15). TTR functions to transport holo-retinol-binding protein and thyroxine (T4) in the blood and cerebrospinal fluid (16,17). Under denaturing con...

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Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis

Cited by 527 publications

References 14 publications

Progression of cardiomyopathy and neuropathy after liver transplantation in a patient with familial amyloidotic polyneuropathy caused by tyrosine-77 transthyretin variant

Progression of cardiomyopathy and neuropathy after liver transplantation in a patient with familial amyloidotic polyneuropathy caused by tyrosine-77 transthyretin variant

Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

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