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Transthyretin amyloidosis

Transthyretin (TTR) amyloidosis (ATTR) is a progressive, multiorgan, multigenotypic disease caused by TTR amyloid fibril deposition in various tissues.

ATTR is caused by a single-point mutation, that promotes destabilization of the native quarternary structure into beta-pleated sheet predominant, insoluble and inactive form. 

 

The natural history of the disease has a 10-15 year prognosis.

 

ATTR amyloidosis is progressive, culminating in death with a median of 2-6 years after diagnosis with patients with amyloid  cardiomyopathy and 4-17;years after symptom onset in patients with amyloid polyneuropathy in the absence of cardiomyopathy.

 

ATR Is a progressive fatal disease characterized by the accumulation in tissues of amyloid fibrils composed of misfolded transthyretin (TTR) proteins.

 

Transthyretin tetramer made up of monomers that contain 127 amino acids and have a marked beta-pleated secondary structure.

 

AATR may be acquired and is referred to as wild type ATTR amyloidosis and is an increasingly recognized cause of cardiomyopathy and heart failure.

ATTR amyloidosis due to a genetic variant is more common in people who are older.

Genetic variants are inherited as an autosomal dominant manner.

TTR  is a four-exon gene residing on chromosome 18.

Most of the 130 gene variant in TTR promote transthyretin protein folding and result in ATTR amyloidosis.

Most patients with wild type ATTR amyloidosis are older men with cardiomyopathy.

Wild type ATTR cardiomyopathy has been diagnosed by myocardial biopsy in 6.5% and variant ATTR cardiomyopathy in 3.7% of patients with heart failure and preserved ejection fraction.

Symptomatic polyneuropathy, affects approximately 1/3 of patients with wild type ATTR amyloidosis.

ATTR deposition and nerves causes a small fiber peripheral and/or autonomicpolyneuropathy.

ATTR deposition in ligaments manifest as carpal tunnel syndrome, and cervical or lumbar spinal stenosis.

Bilateral carpal tunnel syndrome and spinal canal stenosis occur frequently in transthyretin cardiac amyloidosis, both in the variant and the wild type form.

Caused by misfolded transthyretin protein that accumulates as amyloid fibrils in multiple organs, including: the heart, nerves, G.I. tract, and muscular skeletal tissues.

Germline pathogenic variants of the TTR gene result in unstable mutant transthyretin and cause autosomal dominant hereditary ATTR amyloidosis.

Aging adults who do not carry a pathogenic TTR variant, meaning they have wild type ATTR amyloidosis, the failure of homeostatic mechanisms reduces  protein stability.

The reduced protein  stability causes tetramer dissociation selective, proteolysid, and the formation of amyloid fibrils.

TTRs dissociation, misfolding and aggregation which leads to the degeneration of post-mitotic tissue.

Progressive organ dysfunction, derives from cytotoxicity generated by aberrant interactions between pre-fibrillar oligomers and fibrils with cellular components, especially in systemic amyloidosis and physical disruption caused by amyloid deposits, especially in wildtype ATTR amyloidosis.

In variant ATTR amyloidosis the specific genetic variant largely determines the phenotype: polyneuropathy, cardiomyopathy, or as in most patients,  both.

A large percentage of the rapidly expanding older  population have wild type ATTR cardiomyopathy which is not associated with a mutation in  TTR, the gene encoding transthyretin.

Rarer cases of ATTR amyloidosis is hereditary cases of ATTR amyloidosis and is triggered by more than 100 different pathogenic mutations in TTR.

Patients with inherited TTR gene variant have hereditary ATTR amyloidosis, which can manifest as cardiomyopathy, polyneuropathy, or a mixture of the two phenotypes.

Patient with wild type ATTR amyloidosis predominantly have cardiomyopathy, although polyneuropathy may coexist.

The hereditary form of ATTR amyloidosis is thought to be present in approximately 50,000 persons worldwide and has an autosomal dominant pattern of inheritance in the clinical phenotype dominated by amyloid polyneuropathy or cardiomyopathy, with most patients have a combination of the two.

Biopsy free method of diagnosis by bone scan, together with effective therapies is transformed ATT or cardiomyopathy from under diagnosed, untreated disease, to a manageable condition that is diagnose more frequently

It is inherited in an autosomal dominant fashion and has age dependent, incomplete penetrance.

 

The misfolded monomers deposit predominantly in to organs-the myocardium and the nerves resulting in poly neuropathy, cardiomyopathy or most common a combination of the two.

 

Transthyretin amyloid  is found in as many as 25% of all older adults 85 years or older on autopsy.

Wild-type ATTR is estimated to have a prevalence of 155-191 cases per million persons.

The incidence of variant ATTR amyloidosis is estimated is 0.3 cases per year per million persons, with a prevalence estimate of 5.2 cases per million persons.

There are more than 120 points variations in the TTRG gene most of which are rare. 

The substitution of isoleucine with valine  ar position ATTR 1221 is an amylodogenic variation that exists in 3.5% of black individuals. 

This variation can produce cardiac amyloidosis later in life.

 

Tetramer dissociation is a required step in amyloid fibril formation.

Transthyretin (TTR) functions as a  protein transporter of thyroxine and retinol.

In amyloidosis, a secondary protein structure, which is normally soluble forms insoluble extracellular fibril deposits, causing organ dysfunction. 

 

All types of amyloid contain a major fibril protein that defines the type of amyloid, plus minor components. 

There are over 20 different fibril proteins described in human amyloidosis, each with a different clinical picture.

Radiolabeled P-component scanning is used to evaluate the total body burden of amyloid and is a sensitive noninvasive means of diagnosing amyloid in most organs. 

 

Radiolabeled P-component scanning is not useful for diagnosing or monitoring cardiac amyloid, because the concentration of label in the intracardiac blood pool obscures the weaker signal from the molecule bound to myocardial amyloid.

Radiotracer myocardial uptake on bone scintigraphy is more than 99% sensitive and 86% specific for the diagnosis of cardiac ATTR amyloidosis.

TTR acts as a transport protein for thyroxine in plasma, and also transports retinol (vitamin A) through its association with the retinol-binding protein. 

 

It circulates as a tetramer of four identical subunits of 127 amino acids each. 

The TTR monomer contains eight antiparallel beta pleated sheet domains.

In this setting, wtATTR the deposited TTR is usually of normal sequence.

Familial ATTR was traditionally thought of as a group of autosomal dominant diseases.

Clinically sporadic cases in kindreds with unaffected allele carriers also have been observed with other TTR variants. 

Morbidity and mortality from ATTR depends on whether a TTR variant is present.

Widely underdiagnosed and misdiagnosed, thereby prolonging the time to appropriate treatment. 

Suspicions for diagnosis include a history of orthopedic problems such as bilateral carpal tunnel syndrome, biceps tendon rupture, or lumbar spinal stenosis, unexplained peripheral neuropathy, heart failure with elevated biomarkers and poor tolerance to conventional heart failure therapy, 

Some variants cause clinical disease by age 40 years in all gene carriers and may  be fatal within a few years of symptom onset. 

Other variants are much milder with later onset disease, and some carriers of the variant genes remain asymptomatic until late in life. 

Normal-sequence cardiac ATTR presents after age 60 years and usually after age 70 years.

Variant-sequence ATTR presents in teenagers and people in their early 20s for the most aggressive variants.

The average age of onset for ATTR V30M is 32 years in Japan and Portugal and 56 years in Sweden.

TTR variants occur in all races.

The most common variant worldwide is TTR V122I.

The most common ATTR mutation in the United States Val122Ile, can be found in 3.43% of individuals of Afro Caribbean dissent, which translates into 1.4 million carriers.

Hereditary ATTR’s have been found in greater than 10% of African-Americans older than 65 years of age with severe congestive heart failure.

The most common TTR variants are: 

TTR V30M is found throughout Europe, in North and South America, and Japan. L

TTR V30M is most common in some areas of northern Sweden, being carried by more than 1% of the population, and northern Portugal, and certain areas in Japan. 

TTR V122I originated in West Africa, and is carried by 3.9% of African Americans and 5% or more of the population in some areas of West Africa. 

TTR V122I variant increases the risk of late-onset, after age 60 years, cardiac amyloidosis. 

The most widely recognized TTR variants are as follows:

TTR V30M: This was the first TTR variant discovered.

It carries a substitution of methionine for valine at position 30, arising from a point mutation. 

TTR V30M variant is found worldwide.

TTR V30M kindreds was termed FAP because early symptoms arose from peripheral neuropathy, but patients usually do not have peripheral neuropathy. 

However, TTR V30M patients have systemic amyloidosis, with widespread deposits often involving the heart, gastrointestinal tract, eye, and other organs. 

Dry eye, red eye, painful eye, conjunctivitis, floaters and decreased visual acuity may occur.

Ocular manifestations of TTR-FAP, which may include: 

Keratoconjunctivitis sicca

Secondary glaucoma

Vitreous opacities

Pupillary abnormalities.

Gastrointestinal TTR involvement manifests as diarrhea alternating with constipation, along with nausea and vomiting.

TTR V30M appears to be the most common amyloid-associated TTR variant worldwide. 

Neuropathy in patients with ATTR V30M often presents as lower extremity weakness, pain, and/or impaired sensation. 

It may be accompanied by painless ulcers.

The  peripheral neuropathy is progressive, and motor nerve conduction velocity slowly decreases. 

Neurologic examination may demonstrate:

Cranial neuropathy, autonomic neuropathy may cause severe orthostatic hypotension, diarrhea, and/or impotence,  and deep tendon reflexes often are diminished or absent.

Objective CNS findings may include nystagmus and pyramidal signs, with spastic paraparesis.

Patients with leptomeningeal and cerebrovascular deposits can have seizures, subarachnoid hemorrhages, hearing loss, cerebeller ataxia, and dementia. 

Amyloid deposits may be found in the corpus vitreum. 

TTR T60A variant causes late-onset systemic amyloidosis with cardiac, and sometimes neuropathic, involvement. 

TTR T60A variant originated in northwest Ireland and is found in Irish and Irish American patients. 

TTR L58H affects the carpal ligament and nerves of the upper extremities.

The  variant TTR L58H often presents with weakness and paresthesias of one or both hands, suggesting carpal ligament involvement.

Carpal tunnel syndrome sometimes precedes other clinical manifestations by as much as 20 years in TTR variants.

TTR L58H variant originated in Germany, and has spread throughout the United States but is most common in the mid-Atlantic region. 

TTR G6S is the most common TTR variant, but it appears to be a neutral polymorphism and Ibs not associated with amyloidosis. 

TTR G6S is carried by about 10% of people of white European descent. 

There are about 100 TTR variants known, with varying geographic distributions, degrees of amyloidogenicity, and organ predisposition. 

TTR V30M has variation in age of onset: 

TTR V122I originated in West Africa, has spread throughout that area and the Americas, and is carried by 3.9% of African Americans. 

As a result cardiac amyloidosis is more prevalent among African Americans than among people of other races in the United States. 

The usual age of disease onset among gene carriers in Portugal, Brazil, and Japan is in the third to fourth decade of life. 

Late-onset cases,as seen in Sweden, in which disease onset is in the fifth to sixth decade of life.

There is variance in penetrance:  

In Portugal and Japan, more than 90% of TTR V30M gene carriers develop symptoms by middle age. 

In Sweden, disease penetrance is only 2%, and some V30M homozygous individuals remain asymptomatic. 

Some atypical Portuguese and Japanese  families follow the late-onset, low-penetrance Swedish pattern. 

Disease onset is earlier in males than in females, and the age of symptom onset is progressively earlier in successive generations. 

Morbidity and mortality from ATTR depends on whether a TTR variant is present.

Some variants cause clinical disease by age 40 years in all gene carriers and may  be fatal within a few years of symptom onset. 

Other variants are much milder with later onset disease, and some carriers of the variant genes remain asymptomatic until late in life. 

Amyloidogenic mutations destabilize the native quaternary and tertiary structures of TTR, thereby inducing conformational changes that lead to dissociation of the tetramers into partially unfolded species, which can subsequently self-assemble into amyloid fibrils. 

When the peripheral nerves are prominently affected, the  disease is termed familial amyloidotic polyneuropathy (FAP).

TTR-FAP usually proves fatal within 7-12 years from the onset of symptoms, most often due to cardiac dysfunction, infection, or cachexia. 

Clinical onset of TTR-FAP often occurs before age 40 years with progressive sensory-motor and autonomic neuropathy, leading to cachexia and eventually death. 

Small-fiber sensory and motor polyneuropathy with life-threatening autonomic dysfunction is a distinguishing feature of TTR-FAP in these endemic areas. 

Autonomic dysfunction, can manifest as sexual or urinary dysfunction.

In addition, cardiac, renal, and ocular involvement are also common. 

Neuropathy tends to affect all nerve fibers and resembles chronic inflammatory demyelinating polyneuropathy.

Sensory and motor neuropathy symptoms of upper and lower extremities occur primarily, associated with mild autonomic symptoms. 

Transthyretin deposition in the subendothelium of the peripheral vasculature can lead to severe postural hypotension. 

The majority present with bilateral, lower-to-upper extremity symptoms.

Some variants present as lower-limb neuropathy, while other variants present as primarily upper-limb neuropathy.

When the heart is involved primarily but the nerves are not, the disease is called familial amyloid cardiomyopathy (FAC).

In contrast to variant ATTR, normal-sequence cardiac ATTR is associated with aging.

Senile cardiac ATTR associated with aging, usually developing in the seventh and eighth decades of life. 

Senile cardiac ATTR is commonly of little or no clinical significance and only noted on autopsies.

In one autopsy study revealed that in people >85 years of age, ATTR was present in 25%. 

Normal-sequence ATTR forms cardiac amyloidosis predominantly in men above 60 years of age, a disorder termed senile cardiac amyloidosis.

Senile cardiac amyloidosis is often associated with microscopic deposits in many other organs.

The clinical manifestations of severe senile cardiac amyloidosis  are similar to those observed in familial ATTR and in cardiac amyloidosis of the immunoglobulin light chain type (AL).

 

 

It is produced primarily by the liver (> 95%), with additional production within the choroid plexus of the brain and the retinal pigment epithelium. 

 

 

TTR can be found in plasma and in cerebrospinal fluid.

Common clinical manifestations include peripheral and autonomic neuropathy and cardiomyopathy.

It is associated with substantial morbidity and a poor prognosis.

For ATTR-FAP  nephrologic follow-up involves monitoring for microalbuminuria and possibly nephrotic-range proteinuria, as patients may progress to end-stage renal disease .

Its gene is located on the long arm of chromosome 18 and contains 4 exons and 3 introns. 

TTR variants have probably originated in all races. 

All TTR variants are encoded on chromosome 18.

All TTR variants are inherited with equal frequency in males and females. 

Disease penetrance is greater and age of onset earlier in males than in females. 

Some series suggest that normal-sequence cardiac ATTR is significantly more common in males than in females, although the sex ratio is unknown. 

 

 

It is associated with the formation of amyloid fibrils, leading to TTR-related amyloidosis (ATTR), in which these fibril proteins are deposited into various organs and tissues.

 

 

Deposition of these fibrils is preferentially into the nervous system and cardiac tissue, resulting in their dysfunction.

Cutaneous findings may include purpura, which results from the vascular fragility produced by amyloid deposition in the subendothelium of the small blood vessels.

Therapies have not prevented disease progression.

Amyloid precursor proteins are typically circulating proteins that undergo conformational changes resulting in the formation of beta-pleated sheets.

Amyloid deposits over time can cause cellular death, disruption of normal tissue architecture, function, and death.

The most common kinds of acquired amyloidosis are light-chain amyloidosis and amyloid A amyloidosis. involving acute-phase reactant protein.

TTR is intrinsically amyloidogenic.

ATTR can develop through hereditary TTR mutation (hATTR) or secondary to age-related protein misfolding, the wild-type ATTR.

Wild type ATTR is estimated to have a prevalence of 155-191 cases per million persons.

Clinical manifestations include peripheral and autonomic neuropathy and cardiomyopathy, with substantial morbidity and poor prognosis.

TTR is a plasma protein responsible for the transport of retinol (vitamin A) and a small fraction (15%) of thyroxine.

The liver is a major producer of TTR, but small amounts are synthesized by the retinal pigment epithelium and choroid plexus.

Vitrectomy is useful in patients with vitreous involvement. 

TTR is a homotetrameric protein; however, because of aging or in the presence of mutation, tetramers can dissociate into dimers and monomers that misfold and form amyloid fibril aggregates.

ATTR may be fully derived from wtTTR in nonhereditary disease or from a mixture of mutated and wtTTR in hereditary disease.

The deposition of TTR-derived amyloid in various tissues leads to multisystemic disease.

Mainly the peripheral and autonomic nervous systems and the heart are involved.

wtATTR primarily affects the heart, manifests after an individual�s sixth decade, and is predominant in men.

Up to 10% of heart-failure (HF) cases in the elderly population are due to wtATTR.

hATTR is an autosomal-dominant disorder, with variation in penetrance, prevalence, organ-system involvement, and patient outcome depending on the TTR mutation.

There are more than 130 mutations in the TTR gene that can cause an increase in TTR instability or amyloidogenicity, leading to hATTR.

The most common ATTR mutations are: 

Thr60Ala (24%)

Val30Met (15%)

Val122Ile (10%)

Ser77Tyr (5%)

ATTR is caused by a single-point mutation, that promotes destabilization of the native quarternary structure into beta-pleated sheet predominant, insoluble and inactive form. 

Tetramer dissociation is a required step in amyloid fibril formation.

Amyloidogenic mutations destabilize the native quaternary and tertiary structures of TTR, thereby inducing conformational changes that lead to dissociation of the tetramers into partially unfolded species, which can subsequently self-assemble into amyloid fibrils. 

Val30Met, is the most prevalent TTR mutation worldwide, and is typically associated with early-onset neuropathy.

The Val122Ile mutation is found primarily in African American individuals, and cardiomyopathy is the predominant feature.

Many hATTR patients present with a mixed clinical findings involving neurologic, cardiac, and other system impairment.

CNS variant disease is rare but may have the following manifestations: 

 

 

Nystagmus and pyramidal signs, with spastic paraparesis.

 

 

Leptomeningeal/cerebrovascular deposits with seizures, subarachnoid hemorrhages, dementia.

 

 

Isolated leptomeningeal disease with hearing loss, cerebellar ataxia.

hATTR is reported to affect 50,000 individuals worldwide.

ATTR amyloidosis can have a heterogeneous clinical presentation manifesting as sensorimotor or autonomic neuropathy, nonspecific cardiac symptoms, or more rarely renal or ocular impairment.

Sensory neuropathy is progressive.

Sensory neuropathy initially affects the lower limbs and eventually reaches the upper limbs.

Symptoms include: neuropathic pain, numbness, and impaired thermal sensitivity.

Motor impairment typically occurs in the lower limbs initially, with difficulty walking and loss of balance and eventually rendering the patient wheelchair- or bed-bound.

Autonomic neuropathies may develop and include: sweating abnormalities, erectile dysfunction, urinary retention, orthostatic hypotension, and disturbed G.I. motility.

Cardiac amyloid deposits in the heart cause ventricular-wall thickening and diastolic dysfunction, arrhythmias, and subsequently heart failure.

With cardiac deposition typical symptoms of chronic heart failure (CHF) are seen with dyspnea on exertion, peripheral edema, hepatomegaly, ascites, and elevated jugular venous pressure, diastolic dysfunction, and/or arrhythmias.

Atrial arrhythmias or conduction system disease may occur due to to amyloid fibril deposition within areas responsible for electrical impulse conduction.

 

 

Heart failure with preserved ejection fraction (HFpEF) predominates.

Early cardiac disease is usually minimally symptomatic, with edema, dyspnea, progressive fatigue, elevated jugular venous distention, and other HF symptoms developing with disease progression.

Carpal tunnel syndrome may be an early but nonspecific manifestation of hATTR.

Carpal ligament amyloid deposition with weakness and paresthesias of one or both hands may occur.

 

 

Symptomatic carpal ligament deposition sometimes precedes other clinical manifestations by as long as 20 years.

Because of its nonspecific and variable presentation, it is often misdiagnosed as a chronic inflammatory demyelinating polyneuropathy or hypertrophic cardiomyopathy.

Management for ATTR patients with polyneuropathy include: medications for neuropathic pain and control of autonomic dysfunction.

Polyneuropathy in patients affected by ATTR familial amyloid manifests as a symmetric, ascending length?dependent, sensorimotor, axonal polyneuropathy subtype

 

 

It may include PNS sensimotor impairment affecting all functional classes of nerve fibers: motor, sensory and autonomic.

 

 

Manifestations include: 

 

 

Lower-limb neuropathy 

 

 

Upper-limb neuropathy 

 

 

Lower extremity weakness, pain, and/or impaired sensation

 

 

Autonomic dysfunction, often manifesting as sexual or urinary dysfunction.

Physical examination findings depend on the organ involved.

All variants of amyloidosis are diagnosed definitively on the basis of demonstration of Congo red binding material in a biopsy.

After Congo red staining establishes a diagnosis of amyloidosis, the specific type of amyloidosis must be determined with immunostaining of a biopsy specimen using antiserum against TTR. 

Biopsy affected organs  reveals homogeneous interstitial eosinophilic material. 

Amyloid material stained with Congo red under polarized light appears bright green. 

Specific staining with antibodies against TTR proves the diagnosis of ATTR, as all types of amyloidosis have similar appearance after hematoxylin and eosin or Congo red staining.

Distinguishing between ATTR and AL cardiac amyloidosis on clinical grounds is difficult.

Mass spectroscopy can also be used to determine the protein subunit and classify the disease as immunoglobulin light-chain amyloidosis or ATTR. 

The most common amyloidosis-associated TTR variants: 

TTR V30M – Also the most widespread variant worldwide and most common cause of FAP

TTR T60A – Most common in an area centered in West Virginia

TTR L58H – Most commonly seen in Maryland but also throughout the United States

TTR S77Y – Also found in Europe

TTR I84S – Found in an area centered in Indiana

Because ATTR deposition in the peripheral nerves leads to axonal degeneration of the small nerve fibers, causing polyneuropathy a diagnosis can often be made with sural nerve biopsy.

Additional diagnostic biopsy sites include:

Myocardium

Stomach

Rectum

Subcutaneous fat aspiration, biopsy  of an organ with impaired function can identify amyloid deposition.

 

Differential Diagnoses: 

 

 

Amyloidosis

 

 

Alcoholic Neuropathy

 

 

Charcot-Marie-Tooth and Other Hereditary Motor and Sensory Neuropathies

 

 

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

 

 

Diabetic Neuropathy

 

 

Familial Renal Amyloidosis

 

 

Idiopathic Axonal Polyneuropathy

 

 

Immunoglobulin-Related Amyloidosis

 

 

Nephrotic Syndrome

 

 

Restrictive Cardiomyopathy

 

 

Spinal Stenosis

Normochromic normocytic anemia

Electrolyte abnormalities secondary to heart failure or malabsorption

Varying degrees of proteinuria, albuminuria, azotemias, and diminished glomerular filtration rate in patients with renal deposition 

Elevated N-terminal pro-B-type natriuretic peptide levels in patients with cardiac involvement 

Protein electrophoresis and serum free light chain measurement can be used to assess for coexisting monoclonal gammopathy of undetermined significance (MGUS). 

Amyloidosis of all types) is diagnosed definitively based on demonstration of Congo red binding material in a biopsy specimen. 

Management of ATTR cardiomyopathy includes fluid balance and reduction of filling pressure

Low-dose loop diuretics with or without aldosterone antagonists are the mainstay of fluid management therapy.

Diuretics are the mainstay of therapy for amyloid-related CHF.

Heart failure in amyloidosis treated with some agents may be poorly tolerated or not beneficial: calcium channel blockers and digoxin may lead to symptom exacerbation because they bind to amyloid fibrils.

Patients with cardiac amyloidosis may be particularly sensitive to beta-blockers, ACE inhibitors, and angiotensin receptor blockers,with the development of profound hypotension, fatigue, or worsening heart failure.

Amiodarone or a permanent pacemaker may be used to manage arrhythmias, but studies have not demonstrated a survival benefit with implanted cardiodefibrillators for primary or secondary prevention.

Orthotopic liver transplantation (OLT), significantly reduces the production of mutant TTR, replacing it with the donor’s wt protein.

Orthotopic liver transplantation reduces variant TTR concentrations by up to 98% and significantly increases patient survival.

Orthotopic liver transplantation is particularly beneficial for patients with Val30Met mutations and early-stage disease.

Despite recent drug approvals, liver transplantation remains the gold standard for treating transthyretin-related amyloidosis (ATTR). 

 

 

Multi-organ transplantation of heart, liver and kidney has been successful in slowing the natural course of the disease. 

Orthotopic liver transplantation is Val30Met prevents progressive neuropathy and results in excellent survival rates.

Orthotopic liver transplantation outcomes in patients with other mutations, however, seem to be markedly worse: cardiomyopathy and neuropathy can progress owing to wtTTR complexing with already-existing amyloid deposits.

Liver transplant transplantation replaces the main source of variant TTR with a source of normal-sequence TTR, sometimes leading to gradual fibril reabsorption and disease stabilization, especially of neurologic complications. 

 

 

Liver transplantation may halt progression of sensory, motor, and autonomic neuropathy. 

Complications of liver transplant:Central nervous system (CNS) complications,  Atrial fibrillation.

 

 

Transplantation should be performed as early in the disease course as possible, before significant neurologic disability has been incurred. 

 

 

Despite transplantation cardiac, leptomeningeal, gastrointestinal, or ocular involvement often progresses.

 

 

Overall 20-year survival after transplantation is 55.3%. 

 

 

The expected mortality rate decreased on average by approximately 4% per year.

 

 

Improved survival in TTR Val30Met patients was most pronounced during the first 5-year period.

 

 

Mon-TTR Val30Met patients survival improves throughout the 20-year period. 

Combined liver and heart transplantation are considered for patients with preexisting ATTR cardiomyopathy.

Some patients do not report an improvement in quality of life despite slower disease progression after transplantation.

After liver transplants central nervous system (CNS) complications are increasingly noted ,  as is atrial fibrillation (AF).

 

 

While meuropathy and cardiomyopathy are most common after transplantation, the  most common immediate cause of death is cardiac failure or fatal arrhythmia. 


The two available therapies that aim to stabilize TTR are diflunisal and tafamidis.

Dissociation of TTR into two dimers is the rate limiting step in the formation of amyloid fibrils, a therapeutic approach is to stabilize the circulating tea tea or protein to prevent its  dissociation.

Therapeutic approaches include the use of transthyretin stabilizers diflunisal and tafamidis, that prevent dissociation of the transthyretin and tetramer into monomers, as well as all the oligonucleotide-based or a small interfering RNA based silencers that knock  down transthyretin  messenger RNA and prevent hepatic production of the protein.

The two available therapies that aim to stabilize TTR are diflunisal and tafamidis.
Diflunisal is a nonsteroidal anti-inflammatory drug (NSAID) that stabilizes TTR by binding to its thyroxine-binding sites.

Diflunisal successfully complexes to the thyroxine binding site and kinetically stabilizes circulating TTR tetramers, inhibiting release of the TTR monomer required for amyloidogenesis. 

 

In patients with stage I-II ATTR-FAP, diflunisal improved quality of life scores and reduced progression of neurological impairment compared with placebo. 

Diflunisal may be given off-label, as it decreased progression of neuropathy and improved QoL compared with placebo in a controlled trial.

In patients with cardiac involvement, diflunisal treatment did not significantly decrease left ventricular (LV) wall thickness or LV longitudinal strain versus placebo.

Diflunisal administered at a dosage of 250 mg orally twice daily is well tolerated, but cases of renal dysfunction and thrombocytopenia have been reported.

Tafamidis is a small-molecule TTR stabilizer, to treat cardiomyopathy of wtATTR or hATTR in adults.

Diflunisal and tafamidis act by stabilization of the tetrameric form of TTR or through the in addition TTR protein synthesis by inotersen  or patisiran by means of degradation of TTR messenger RNA.

It delays peripheral neurologic impairment in adults with hATTR and stage 1 symptomatic polyneuropathy.

The drug’s efficacy for hATTR with polyneuropathy: more patients achieved treatment response and better preservation of quality of life with tafamidis compared with placebo (60% vs. 38.1%, respectively.

Tafamidis’s effect on decrease in disease progression is less pronounced in patients with more advanced, late-onset disease or mutations other than Val30Met.

In the phase III ATTR-ACT trial in wtATTR and hATTR patients with predominantly cardiac manifestations tafamidis significantly reduced all-cause mortality and cardiovascular-related hospitalizations at 30 months compared with placebo (29.5 vs 42.9%; hazard ratio, 0.70).

Greater benefit is seen in patients with less severe HF, suggesting that initiation of tafamidis for early disease stage may be most beneficial.

Tafamidis a safety profile similar to that of placebo.

As circulating TTR is not required for life: two gene-silencing treatments have been FDA-approved to treat hATTR polyneuropathy: inotersen and patisiran.

RNA interference results in the knockdown of target messenger RNA (mRNA) by siRNA bound to the silencing complex.

Patisiran and inotersen have been approved for treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults. 

 

Patisiran siRNA targets the untranslated region of TTR mRNA, which is devoid of any known TTR mutations, thus preventing production of wt and mutated protein.

Anti-transthyretin small interfering ribonucleic acid (siRNA) agents causes degradation of mutant and wild-type TTR mRNA through RNA interference-

 

Patisiran.

 

Patisiran is an siRNA agent that reduces serum transthyretin (TTR) protein and TTR protein deposits in tissues. 

 

It is indicated for treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults.

Its encapsulation with lipid nanoparticles enables siRNA delivery to the site of hepatocytes.

Patisiran Reduces the level of circulating transthyretin by 80 to 90% of most patients.

Patisiran Trial over a period of 12 months preserve, cardiac functional capacity.

Inotersen, binds at the 3 untranslated region of TRR mRNA, resulting in mRNA degradation.

 

Inotersen, an antisense oligonucleotide, has improved neurological scores compared with placebo. 

 

Inotersen is an antisense oligonucleotide that causes degradation of mutant and wild-type transthyretin mRNA by binding TTR mRNA. 

 

Its use results in reduced TTR protein in serum and tissue.

 

It is indicated for polyneuropathy of hATTR in adults.

The safety profile of patisiran is similar to that of placebo.

In the inotersen trial there was increased risks of thrombocytopenia and glomerulonephritis.

Tolcapone approved for treatment of Parkinson disease and has Orphan Drug designation for treatment of ATTR. 

 

It occupies the T4-binding sites located at the TTR dimer-dimer interface and prevents amyloidogenesid by stabilizing the teramer in humans, and also inhibits TTR cytotoxicity.

 

CRISPR-Cas9 based gene therapy is associated with mild adverse  events, and decreases in serum TTR protein concentrations.

ATTR amyloidosis as a life expectancy untreated of 2 to 10 years after in symptom onset. N-terminal pro-B- type natriuretic peptide (NT-pro BNP) is a validated marker of cardiac response at three and six months and predicts survival.

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