Transthyretin-Related Amyloidosis

Practice Essentials

Transthyretin (TTR) is a protein that functions as a transporter of thyroxine and retinol and is produced chiefly by the liver (> 95%), with additional production within the choroid plexus of the brain and the retinal pigment epithelium. However, it is also 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, preferentially the nervous system and cardiac tissue, resulting in their inherent dysfunction.

Signs and symptoms

The presenting signs and symptoms in patients with ATTR are fairly nonspecific and often attributed to more common diseases affecting both the heart and the peripheral and autonomic nervous sytems.

Patients with cardiac deposition typically present with the following typical symptoms of chronic heart failure (CHF):

• Symptoms suggestive of right-sided CHF (ie, dyspnea on exertion, peripheral edema, hepatomegaly, ascites, and elevated jugular venous pressure), diastolic dysfunction, and/or arrhythmias (ie, palpitations, lightheadedness, syncope); heart failure with preserved ejection fraction (HFpEF) predominates in ATTR
• Patients may also present with atrial arrhythmias or conduction system disease due to amyloid fibril deposition within areas responsible for electrical impulse conduction

Neuropathic involvement in patients affected by ATTR–familial amyloid polyneuropathy (FAP) is classically a symmetric, ascending length−dependent, sensorimotor, axonal polyneuropathy subtype and may include the following:

• PNS sensimotor impairment affecting all functional classes of nerve fibers: motor, sensory and autonomic fibers
• Lower-limb neuropathy (eg, TTR V30M)
• Upper-limb neuropathy (eg, TTR I84S, TTR L58H)^[1]
• ATTR V30M variant: Lower extremity weakness, pain, and/or impaired sensation; autonomic dysfunction, often manifesting as sexual or urinary dysfunction^[2]

Carpal ligament deposits: Weakness and paresthesias of one or both hands (eg, variant TTR L58H, normal-sequence TTR); localized symptomatic carpal ligament deposition sometimes precedes other clinical manifestations by as long as 20 years

Patients with rare TTR variants that cause CNS disease may present with the following features:

• Nystagmus and pyramidal signs, with spastic paraparesis^[3]
• Leptomeningeal/cerebrovascular deposits: Seizures, subarachnoid hemorrhages, dementia^[3]
• Isolated leptomeningeal disease (rare): Hearing loss, cerebellar ataxia^[4]

See Clinical Presentation for more detail.

Diagnosis

Physical examination findings in patients with ATTR depend on the organ involved, which is affected by the presence and genetic identity of a TTR variant. Symptoms consistent with HFpEF, along with concurrent peripheral/autonomic neuropathy, warrant consideration of ATTR as a diagnosis. A complete family history is of great value.

Biopsy

All types of amyloidosis are diagnosed definitively on the basis of demonstration of Congo red binding material in a biopsy or autopsy specimen. Subcutaneous fat aspiration often provides sufficient tissue for diagnosing amyloid, as well as for further studies (eg, immunostaining). Biopsy of an organ with impaired function (eg, heart, GI tract) can definitively establish a cause-and-effect relationship between organ dysfunction and amyloid deposition. See the image below.

View Image

Congo Red staining of a cardiac biopsy specimen containing amyloid, viewed under polarized light.

Laboratory results for different types of amyloidosis are generally nonspecific, including the following:

• Complete blood count: Normochromic normocytic anemia
• Chemistry panel: Electrolyte abnormalities (due to heart failure or malabsorption)
• Renal function tests: Evidence of varying degrees of proteinuria and diminished glomerular filtration rate in patients with renal deposition

Other tests include electrocardiography, nerve conduction studies, and genetic studies (eg, polymerase chain reaction, electrospray ionization mass spectrometry, single-strand conformation polymorphism analysis and/or direct sequencing).

Imaging studies

• Radiolabeled P-component scanning
• Cardiac imaging (eg, 2-dimensional echocardiography, electrocardiography, or both; CT scanning; nuclear scintigraphy, cardiac MRI)

See Workup for more detail.

Management

Patisiran and inotersen have been approved by the FDA for treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults. Several other medications are under investigation, but liver transplant remains the gold standard.

Diuretics are the mainstay of therapy for amyloid-related CHF, but must be used with caution due to the restrictive physiology involved.

Surgery

Depending on the organ and/or tissue involvement, surgical intervention for patients with ATTR may involve the following:

• Liver transplantation: The only effective therapy for familial amyloid polyneuropathy, as it removes the source of mutant TTR
• Combination heart/liver or liver/kidney transplantation in select patients
• Carpal tunnel release
• Vitrectromy

See Treatment for more detail.

• References

Background

The amyloidoses are a wide range of diseases of secondary protein structure, in which a normally soluble protein 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. Over 20 different fibril proteins have been described in human amyloidosis, each with a different clinical picture (see Amyloidosis, Overview). One such protein that forms human amyloid fibrils is transthyretin (TTR).

TTR acts as a transport protein for thyroxine in plasma. TRR 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. TTR was once called prealbumin because it migrates anodally to albumin on serum protein electrophoresis, but this name was misleading, as TTR is not a precursor of albumin. The TTR monomer contains eight antiparallel beta pleated sheet domains.

TTR can be found in plasma and in cerebrospinal fluid and is synthesized primarily by the liver and the choroid plexus of the brain and, to a lesser degree, by the retina. Its gene is located on the long arm of chromosome 18 and contains 4 exons and 3 introns.^[5]

The systemic amyloidoses are designated by a capital A (for amyloid) followed by the abbreviation for the chemical identity of the fibril protein. Thus, TTR amyloidosis is abbreviated ATTR.

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Pathophysiology

Normal-sequence transthyretin-related amyloidosis

In contrast to variant ATTR, normal-sequence cardiac ATTR is associated with aging, usually developing in the seventh and eighth decades of life. This disorder is commonly of little or no clinical significance and only noted on autopsies in studies aiming at estimating its prevalance in an otherwise asymptomatic, aging population. In one autopsy study of people >85 years of age, ATTR was present in 25%.^[6] The fraction of autopsied patients with clinically significant symptoms is not known.

The stimuli that lead to normal-sequence ATTR are not understood. Normal-sequence TTR forms cardiac amyloidosis predominantly in men above 60 years of age, a disorder termed senile cardiac amyloidosis (SCA). When it was recognized that SCA is often accompanied by microscopic deposits in many other organs, the alternative name senile systemic amyloidosis (SSA) was proposed. Both terms are now used.^[5]  The clinical manifestations of severe SCA are similar to those observed in familial ATTR and in cardiac amyloidosis of the immunoglobulin light chain type (AL).

Mutant transthyretin-related amyloidosis

TTR mutations accelerate the process of TTR amyloid formation and are the most important risk factor for the development of clinically significant ATTR. More than 100 amyloidogenic TTR variants cause systemic familial amyloidosis. The age at symptom onset, pattern of organ involvement, and disease course vary, but most mutations are associated with cardiac and/or nerve involvement. The gastrointestinal tract, vitreous, lungs, and carpal ligament are also frequently affected.^[5]

In a retrospective cross-sectional study of 284 ATTR and non-ATTR patients, the most common ATTR mutations were as follows^[7] :

• Thr60Ala (24%)
• Val30Met (15%)
• Val122Ile (10%)
• Ser77Tyr (5%)

ATTR is caused by a single-point mutation, of which more than 100 have been described, that promotes destabilazation of the native quarternary structure into beta-pleated sheet predominant, insoluble and inactive form. This conformational change hypothesis has been researched in vitro with a key finding that tetramer dissociation is a required and generally rate-limiting step in amyloid fibril formation.

Energetic studies have suggested that 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. However, the wild-type (wt) TTR form can also result in amyloid deposits found in peripheral nerves and cardiac tissue in patients affected by the disease, usually in older patients. It is expected that the process of amyloid aggregation will be further elucidated in the future to address this and other concerns.^[8]

When the peripheral nerves are prominently affected, the disease is termed familial amyloidotic polyneuropathy (FAP). When the heart is involved heavily but the nerves are not, the disease is called familial amyloid cardiomyopathy (FAC).

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Epidemiology

United States

The most common amyloidosis-associated TTR variants in the United States are as follows:

• 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

Cardiac ATTR amyloidosis has a progressive increase in prevalence in people older than 80 years and is seen in about 15% of autopsies, with one study finding a prevalence of about 25%. In this setting, the deposited TTR is usually of normal sequence (wt-ATTR).

International

A few amyloidosis-associated TTR variants are common in certain populations, although few data indicate population frequencies. The most common TTR variants include the following:

• TTR V30M is found throughout Europe, in North and South America, and Japan. It is most common in some areas of northern Sweden (where it is carried by more than 1% of the population), northern Portugal, and certain areas in Japan.^[9]
• TTR V122I originated in West Africa. It is carried by 3.9% of African Americans and 5% or more of the population in some areas of West Africa.^[10]

Familial TTR variants

Most variants that cause familial ATTR are rare, but a few are common in certain populations. TTR variants are written, according to convention, by the normal amino acid found at a position in the mature protein, followed by the number of the amino acid from the amino terminal end, and the variant amino acid found, using either the three-letter or single-letter amino acid code. The most widely recognized TTR variants are as follows:

• TTR V30M: This was the first TTR variant discovered. The role of TTR in amyloidosis was first established when TTR was found in the fibrils in several kindreds with autosomal dominant amyloidosis affecting the peripheral nerves, heart, and other organs. This syndrome was first described in Portugal in the 1950s and later in Japan and Sweden.^[11] The fibrils in patients in all 3 endemic areas were found to contain TTR that carried a substitution of methionine for valine at position 30, arising from a point mutation. This variant has now been found worldwide, it is the most widely studied TTR variant, and has served as a prototype for variant-sequence ATTR. The disease in the TTR V30M kindreds was termed FAP because early symptoms arose from peripheral neuropathy, but these patients actually have systemic amyloidosis, with widespread deposits often involving the heart, gastrointestinal tract, eye, and other organs.^[9]
• TTR V122I: This variant, carried by 3.9% of African Americans and over 5% of the population in some areas of West Africa, increases the risk of late-onset (after age 60 years) cardiac amyloidosis. It appears to be the most common amyloid-associated TTR variant worldwide. Affected patients usually do not have peripheral neuropathy.^[10]
• TTR T60A: This variant causes late-onset systemic amyloidosis with cardiac, and sometimes neuropathic, involvement. This variant originated in northwest Ireland and is found in Irish and Irish American patients.^[12]
• TTR L58H: Typically affecting the carpal ligament and nerves of the upper extremities, this variant originated in Germany. It has spread throughout the United States but is most common in the mid-Atlantic region.^[12]
• TTR G6S: This is the most common TTR variant, but it appears to be a neutral polymorphism not associated with amyloidosis. It is carried by about 10% of people of white European descent.^[12]

Currently, about 100 TTR variants are known, with varying geographic distributions, degrees of amyloidogenicity, and organ predisposition. Currently known TTR variants are listed in the table below.^[5] For organ involvement, the following abbreviations are used: PN = peripheral nerves, AN = autonomic nervous system, H = heart, L = liver, LM = leptomeninges, K = kidney, S = skin, E = eye, GI = gastrointestinal tract, CL = carpal ligament, and CNS = central nervous system.

Known TTR Variants (adapted from Benson^[13] and Connors et al^[5] )

View Table

See Table

Expression of transthyretin-related amyloidosis

Familial ATTR was traditionally thought of as a group of autosomal dominant diseases, but it is now known that disease expression is more complicated. The most abundant data pertain to TTR V30M; the following observations have been made:

• Variation in age of onset: The usual age of disease onset among TTR V30M gene carriers in Portugal, Brazil, and Japan is in the third to fourth decade of life. However, there are late-onset cases (as seen in Sweden) in which disease onset is in the fifth to sixth decade of life.
• Disease penetrance: In Portugal and Japan, more than 90% of TTR V30M gene carriers develop symptoms by middle age. However, in Sweden, disease penetrance is only 2%, and some V30M homozygous individuals remain asymptomatic.^[9]
• Some atypical Portuguese and Japanese kindred follow the late-onset, low-penetrance Swedish pattern.^[11]
• Some patients with no family history of amyloidosis and asymptomatic relatives with the variant gene carry the V30M variant.
• Disease onset is earlier in males than in females.^[14]
• Age of symptom onset is progressively earlier in successive generations. This feature is referred to as anticipation. Anticipation in some neurologic disorders is caused by expansion of trinucleotide repeats. However, in ATTR, this mechanism seems not to apply.

The explanation for the above observations is not well understood. Other genetic and/or environmental variables are thought to be at play. Anticipation, incomplete penetrance, and clinically sporadic cases in kindreds with unaffected allele carriers also have been observed with other TTR variants.^[12]

Race

TTR variants occur in all races.

• The most common variant worldwide, TTR V122I, apparently originated in West Africa, has spread throughout that area and the Americas, and is carried by 3.9% of African Americans. Therefore, cardiac amyloidosis is more prevalent among African Americans than among people of other races in the United States.^[10]
• Other variants are documented to have originated in people of European, Japanese, and Chinese ancestry. TTR variants have probably originated in all races.^[12]

Sex

All TTR variants encoded on chromosome 18 are inherited with equal frequency in males and females. For unknown reasons, disease penetrance is greater and age of onset earlier in males than in females. Individual case reports and several small series suggest that normal-sequence cardiac ATTR is significantly more common in males than in females, although the sex ratio is unknown.^[14]

Age

The age of onset varies widely, depending on the presence and identity of the TTR variant.

• 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 and in people older than 50 years for many others.
• The average age of onset for ATTR V30M is 32 years in Japan and Portugal and 56 years in Sweden. The reason for this difference is not known.

• References

Mortality/Morbidity

Morbidity and mortality from ATTR depends on whether a TTR variant is present and, if so, which variant. Some variants cause clinical disease by age 40 years in all gene carriers and are always fatal within a few years of symptom onset. Other variants typically cause much milder, later onset disease, and some carriers of the variant genes remain asymptomatic until late in life.^[15]

Central nervous system (CNS) complications are increasingly noted in liver-transplanted ATTR patients. Atrial fibrillation (AF), is a risk factor for ischemic CNS complications observed after liver transplantation.^[16]

Morbidity depends on the organ(s) involved. Neuropathy and cardiomyopathy are most common. The most common immediate cause of death is cardiac failure or fatal arrhythmia.^[17]

• References

Prognosis

TTR-FAP usually proves fatal within 7–12 years from the onset of symptoms, most often due to cardiac dysfunction, infection, or cachexia.^[18]  

Within most of the regions in which it is endemic, clinical onset of TTR-FAP often occurs before age 40 years with progressive sensory-motor and autonomic neuropathy, leading to cachexia and eventually death. Length-dependent small-fiber sensory and motor polyneuropathy with life-threatening autonomic dysfunction is a distinguishing feature of TTR-FAP in these areas. In addition, cardiac, renal, and ocular involvement are also common.^[19]

In nonendemic areas, and in endemic regions of Sweden, the onset of disease-related symptoms tends to be later in life, from age 50 years onward and with a male predominance for the late-onset TTR-FAP. Neuropathy tends to affect all fibers and may closely resemble chronic inflammatory demyelinating polyneuropathy (CIDP). Typically, sensory and motor neuropathy symptoms of upper and lower extremities occur, associated with mild autonomic symptoms.^[19]

• References

Patient Education

N/A

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History

The subtype of transthyretin (TTR) protein mutation, its tissue distribution, and the amount of amyloid deposition largely determine the clinical manifestations of TTR-related amyloidosis (ATTR). The key characteristic of ATTR that should raise clinical suspicion for this disorder remains the reliable coexistence of both cardiac and peripheral nervous system (PNS) involvement. This association will require the clinician to adequately interview the patient, who is likely to be presenting with a chief complaint related to one but not both organ systems.

Cardiovascular involvement

Patients with cardiac deposition often present with symptoms suggesting chronic heart failure (ie, dyspnea on exertion, peripheral edema, elevated jugular venous pressure, hepatojuglular reflux) and/or arrhythmias (ie, palpitations, lightheadedness, syncope).^[17]

Deposition in the subendothelium of the peripheral vasculature can lead to severe postural hypotension.^[17]

Neuropathic involvement

Peripheral nerve problems are the presenting complaints in most cases of ATTR, and can be reliably differentiated from other types of PNS disease by the fact that they are most often symmetric, distal polyneuropathies that typically begin in the lower limbs, progress to the upper limbs, and then affect more proximal aspects of the limbs and the trunk. A family history of a similar polyneuropathy is usually present and hence warrants a rigorous family history discussion as part of the history.

Patients with peripheral nerve deposits note sensorimotor impairment. While the majority present with bilateral, lower-to-upper extremity symptoms, as described above, some TTR variants present as lower-limb neuropathy (eg, TTR V30M), while other variants present as primarily upper-limb neuropathy (eg, TTR I84S, TTR L58H).^[1]

Neuropathy in patients with ATTR V30M often presents as lower extremity weakness, pain, and/or impaired sensation. Autonomic dysfunction, often manifested as sexual or urinary dysfunction, is common.^[2]

Other manifestations

Patients with gastrointestinal deposits present with alternating diarrhea and constipation. Nausea and vomiting also occur.

Weakness and paresthesias of one or both hands, suggesting carpal ligament involvement, is often the presenting symptom in patients with the variant TTR L58H. It can also be observed in patients with other variants. Carpal tunnel syndrome sometimes precedes other clinical manifestations by as much as 20 years. Patients with normal-sequence TTR also may develop localized symptomatic carpal ligament deposition.

Ophthalmological involvement may present as follows:

• Dry eye, red eye, painful eye, conjunctivitis
• Floaters in eyes, decreased visual acuity

A study by Phull et al showed a high prevalence of coexistent monoclonal gammopathy of undetermined significance (MGUS) in patients with ATTR, with a rate higher than the general population.^[20]

• References

Physical Examination

As with the history, the physical findings depend on the organ involved, which is affected by the presence and identity of a TTR variant.

Common physical findings in advanced disease include the following:

• Cachexia
• Peripheral edema
• Hepatomegaly
• Purpura
• Orthostatic hypotension
• Impaired sensation and/or strength in the upper and/or lower extremities
• Carpal tunnel syndrome

Cardiac involvement typically results in the following^[17] :

• Diastolic dysfunction
• Chronic heart failure
• Arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias

Neurologic findings

Typical findings include symmetric sensory impairment and weakness, sometimes accompanied by painless ulcers, similar to the picture in diabetic neuropathy. In the absence of treatment, the peripheral neuropathy is progressive, and motor nerve conduction velocity slowly decreases.^[21] Other findings on neurologic examination may include the following:

• Cranial neuropathy is occasionally observed
• Autonomic neuropathy may cause severe orthostatic hypotension, diarrhea, and/or impotence^[2]
• Deep tendon reflexes often are diminished or absent, particularly late in disease^[3]

Central nervous system findings may include the following:

• Patients with rare TTR variants that cause CNS disease develop a wide range of abnormalities observed upon mental status and neurologic examination.^[3]
• Objective findings may include nystagmus and pyramidal signs, with spastic paraparesis.^[3]
• Patients with leptomeningeal and cerebrovascular deposits can have seizures, subarachnoid hemorrhages, and dementia.^[3] Patients with isolated leptomeningeal TTR disease, a rare presentation, can have hearing loss and cerebellar ataxia.^[4]

Other systems

On ophthalmologic examination, amyloid deposits may be found in the corpus vitreum. This finding may be the most specific for hereditary transthyretin amyloidosis (as opposed to other systemic amyloidoses).

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

• References

Approach Considerations

Diagnostic tests for transthyretin (TTR) amyloidosis are listed in the table below (adapted from Ando et al^[23] ).

Table. Diagnostic tests for transythyretin (TTR) amyloidosis

View Table

See Table

BSB = 1-Bromo-2,5-bis(3-carboxy-4-hydroxystyryl)benzene; ESI = electrospray ionization; FSB = 1-Fluoro-2,5-bis(3-carboxy-4hydroxystyryl)benzene; FT-ICR = Fourier transform ion cyclotron resonance; LC-MS/MS = liquid chromatography–tandem mass spectrometry; MALDI-TOF = matrix-assisted laser desorption/ionization time-of-flight; PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism; SELDI-TOF = surface enhanced laser desorption/ionization–TOF; SSCP = single-strand conformation polymorphism 

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Laboratory Studies

Nonspecific findings found in different types of amyloidosis include the following:

• 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^[23]
• Elevated N-terminal pro–B-type natriuretic peptide levels in patients with cardiac involvement^[24]

Protein electrophoresis and serum free light chain measurement can be used to assess for coexisting monoclonal gammopathy of undetermined significance (MGUS).^[20]

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Biopsy

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

View Image

Congo Red staining of a cardiac biopsy specimen containing amyloid, viewed under polarized light.

For many years, rectal biopsy was the favored procedure when systemic amyloidosis was suspected. Currently, the capillaries in subcutaneous fat are known to be involved often in TTR-related amyloidosis (ATTR) and in some other types of systemic amyloidosis; therefore, subcutaneous fat aspiration often provides sufficient tissue for diagnosing amyloid, as well as for further studies such as immunostaining. On the other hand, biopsy of an organ with impaired function, such as the heart or gastrointestinal tract, has the advantage of definitively establishing a cause-and-effect relationship between organ dysfunction and amyloid deposition.

The sensitivity of detecting ATTR varies by site, as follows^[18] :

1. Labial salivary gland biopsy: 91%
2. Sural nerve biopsy: 80%
3. Abdominal fat pad biopsy: 14-83%

ATTR deposition in the peripheral nerves leads to axonal degeneration of the small nerve fibers, causing polyneuropathy. Diagnosis can often be made with sural nerve biopsy, although the deposits may be proximal to the sural nerve and therefore not found in biopsy samples.

Other potential biopsy sites include the following:

• Myocardium
• Stomach
• Rectum
• Other organ suspected of heavy involvement

Amyloid should not be assumed to be of the TTR type based solely on the Congo red staining and clinical picture. After Congo red staining establishes a diagnosis of amyloidosis, the specific type of amyloidosis must be determined with immunostaining of a biopsy specimen using commercially available antiserum against TTR. Control antisera against other types of amyloid precursors, including immunoglobulin light chains and amyloid A protein, should also be performed to confirm staining specificity. Even patients known to carry a TTR variant should ideally have the diagnosis confirmed with immunostaining to rule out the possibility of a different type of amyloidosis.

Distinguishing between ATTR and AL cardiac amyloidosis on clinical grounds alone is particularly difficult. Without immunologic identification of the deposited protein, an incorrect diagnosis of ATTR in a patient with AL, or the reverse, could lead to ineffective or harmful treatment. Mass spectroscopy can also be used to determine the protein subunit and classify the disease as immunoglobulin light-chain amyloidosis or ATTR.^[25]

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Cardiac Imaging

Cardiac deposition is, in many patients, the most serious complication of ATTR. For that reason, cardiac involvement usually should be assessed and monitored by imaging studies. Echocardiograms, cardiac magnetic resonance imaging (MRI), and scintigraphy with bone tracers can all help to diagnose infiltrative cardiomyopathy.^{[18, 26]}

Echocardiography enables visualization of increased ventricular wall thickness, increased septal thickness, and an appearance of granular "sparkling." This finding is neither sensitive nor specific enough to be diagnostic but is highly suggestive when present.

Amyloid deposits in the heart occur in the ventricular interstitium, leading to thickening of the ventricular walls and interventricular septum without an increase in the intracardiac volume. Evaluation of diastolic function by Doppler echocardiography reveals impaired ventricular relaxation early in the course of disease, which progresses to short deceleration. The ejection fraction is preserved until late in disease.^[25]

Other echocardiographic findings include the following:

• Valvular thickening
• Valvular insufficiency
• Atrial enlargement

Bone scintigraphy using technetium-labelled radiotracers provides very high diagnostic accuracy in the noninvasive assessment of cardiac ATTR.^[27] 99mTc-DPD–based single-photon emission computed tomography (SPECT) imaging enables noninvasive diagnosis of cardiac ATTR amyloidosis, particularly in patients rejecting biopsy.

• References

Other Tests

Other cardiac testing

The classic finding on electrocardiography is a low-voltage QRS complex in the limb leads, resulting from replacement of normal cardiac tissue by nonconducting amyloid material. In some cases, loss of anterior forces suggests anteroseptal infarction that is not confirmed at autopsy. Various arrhythmias are observed and can be life threatening.^[17]

The prevalence of low QRS voltages at the time of diagnosis has been found to be lower than in light chain amyloidosis (AL), despite the finding, in some studies, of greater myocardial infiltration in TTR-related forms.^[28]

Holter monitoring and intracardiac electrophysiology study are helpful to detect conduction disorders.^[18]

Nerve conduction studies

In patients with amyloid neuropathy, serial nerve conduction studies can be useful for objectively monitoring the course of disease and for assessing response to treatment such as liver transplantation.^[29]

Genetic studies

In patients with progressive, length-dependent axonal neuropathy predominantly involving small nerve fibers, genetic testing for TTR gene mutations should be performed during the initial diagnostic workup, to prevent serious consequences from delayed diagnosis.^[30] Genetic studies to look for a TTR variant can be helpful in many patients with ATTR, particularly in younger patients not known to belong to a kindred carrying a defined TTR variant. These studies generally are not available through routine clinical laboratories.

One approach is to perform polymerase chain reaction (PCR) testing to look for known, common TTR variants. This approach is most useful if the likely TTR variant can be surmised on the basis of the clinical history and genetic background of the patient. These studies are performed by PCR amplification of regions of the TTR gene followed by digestion with restriction enzymes.

If a TTR variant is suspected but initial screening results for a few common known variants are negative, more comprehensive analysis for a TTR variant can be performed. Either the protein can be isolated from the serum and studied using methods such as electrospray ionization mass spectrometry (ESIMS) or the gene can be studied by PCR and such methods as single-strand conformation polymorphism analysis and/or direct sequencing.

Determination of whether a TTR variant is present is important because the treatment options for variant-sequence ATTR differ from those for normal-sequence ATTR. Information about a TTR variant also can be of use to other family members at risk. 

Ophthalmological assessment

Ophthalmological assessment is warranted to identify any ocular manifestations of TTR-FAP, which may include the following:

• Keratoconjunctivitis sicca
• Secondary glaucoma
• Vitreous opacities
• Pupillary abnormalities

Radiolabeled P-component scanning

Radiolabeled P-component scanning is available in a few European centers. Where it is available, radiolabeled P-component scanning is a very useful means of evaluating the total body burden of amyloid and is a sensitive noninvasive means of diagnosing amyloid in most organs. Serial studies are useful for monitoring the response to therapy in many settings.

One drawback of P-component scanning is that it 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 labeled molecule bound to myocardial amyloid.

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Histologic Findings

Biopsy of an affected organ followed by routine hematoxylin and eosin staining reveals homogeneous interstitial eosinophilic material. Amyloid material stained with Congo red and viewed under polarized light appears bright green. Specific staining with antibodies against TTR proves the diagnosis of ATTR, as opposed to other types of amyloidosis that have similar appearance after hematoxylin and eosin or Congo red staining.

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Staging

Once the diagnosis has been made, the neuropathy stage and systemic extension of the disease should be determined to direct the course of management. The three stages of ATTR-FAP severity are graded according to the patient’s walking disability and degree of assistance required, as follows^{[18, 19]} :

Stage 0: Asymptomatic carrier of a known ATTR mutation

Stage I: Sensory polyneuropathy; preserved walking capacity without the need for a walking stick

Stage II: Progressive walking disability; ambulatory, but requires assistance, one to two walking sticks or crutches required

Stage III: Wheelchair bound or bedridden

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Approach Considerations

Transthyretin-related amyloidosis (ATTR) involves many organs and systems, so an interdisciplinary approach is essential for the management of comorbidities. Patisiran and inotersen are approved by the US Food and Drug Administration (FDA) for treatment of polyneuropathy caused by hereditary transthyretin-related amyloidosis (hATTR) in adults. Several other medications are under investigation, but liver transplantation remains the gold standard for therapy. Ideally, patients should be referred while early in stage I for liver transplantation—or possibly multi-organ transplantation, depending on heart or kidney involvement.  

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Medical Care

The US Food and Drug Administration (FDA) has approved patisiran (Onpattro) and inotersen (Tegsedi) for treatment of polyneuropathy caused by hATTR in adults. Tafamidis, diflunisal, revusiran, and tolcapone remain under investigation.

Patisiran

Patisiran utilizes RNA interference, a cellular process in which small interfering RNAs (siRNAs) control gene expression by mediating the cleavage of specific messenger RNAs (mRNAs).^[31]  Patisiran comprises siRNAs that are specific for TTR mRNA, formulated in lipid nanoparticles. Administration is via intravenous infusion every 3 weeks.

Approval was based on the APOLLO clinical trial, in which patients taking patisiran (n=148) showed significantly improved scores on the Neuropathy Impairment Score+7 and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (QOL-DN) at 18 months, compared with those taking placebo (n=77) (P <  0.001).^[32]

Inotersen

Inotersen was approved by the FDA in October 2018. Like patisiran, it is indicated for polyneuropathy of hATTR in adults; unlike patisiran, inotersen is given as a once-weekly subcutaneous injection that the patient or caregiver can administer. It is an antisense oligonucleotide that causes degradation of mutant and wild-type transthyretin mRNA by binding TTR mRNA. This action results in reduced TTR protein levels in serum and tissue.

Approval was based on an international, randomized, double-blind, placebo-controlled phase III trial (NEURO-TTR) in which patients with stage 1 or 2 hATTR with polyneuropathy (n=172) were randomly assigned in a 2:1 ratio to receive weekly inotersen or placebo. Scores on the mNIS+7 and the QOL-DN showed improvement in those receiving inotersen (P <  0.001).^[33]

Tafamidis

Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively binds to TTR with negative cooperativity and kinetically stabilizes wild-type native TTR and mutant TTR. Therefore, tafamidis has the potential to halt the amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding, and aggregation.^[34]  Early intervention with tafamidis led to minimal disease progression over 5.5 years in patients with mild ATTR-FAP.^[35]

A tafamidis trial in patients with stage I neuropathic ATTR (mobilization without need for support) failed to achieve statistical significance for its primary endpoints of neurological deterioration and quality of life. However, because all measured endpoints indicated that the drug decreased the rate of disease progression, tafamidis was approved by the European Medical Agency in 2011 for patients in stage I of neuropathic ATTR.^[36] Since 2011, tafamidis has been approved for use in Japan, Mexico, and Argentina, where it is used as a first-line treatment option for patients with early-stage ATTR–familial amyloid polyneuropathy (FAP).

Diflunisal

Diflunisal is a nonsteroidal anti-inflammatory drug that is FDA approved for treatment of arthritis. At a dosage of 250 mg twice daily, diflunisal successfully complexes to the thyroxine binding site and kinetically stabilizes circulating TTR tetramers, inhibiting release of the TTR monomer required for amyloidogenesis. In a randomized, placebo-controlled trial in patients with stage I-II ATTR-FAP, diflunisal improved quality of life scores and reduced progression of neurological impairment compared with placebo. Its use for this indication remains off-label.^{[37, 38]}

Tolcapone

Tolcapone is FDA approved for treatment of Parkinson disease and has Orphan Drug designation for treatment of ATTR. Tolcapone occupies the T₄-binding sites located at the TTR dimer-dimer interface and prevents amyloidoenesis by stabilizing the teramer in vivo in mice and humans.^[39]  In addition, an added benefit is it also inhibits TTR cytotoxicity. It has been shown that tolcapone docks better than tafamidis in wt-TTR.

Treatment of cardiac involvement

Diuretic agents must be used with caution. Although diuretics are commonly prescribed for patients with heart failure, their use in amyloidosis is complicated. Due to the restrictive effect of the disease, ventricular compliance is poor and end-diastolic volumes are low. Patients often require a higher filling pressure to distend the stiffened heart, and diuretic therapy reduces preload, which can further reduce stroke volume and systolic blood pressure.^[22]

Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) are poorly tolerated in cardiac amyloidosis and should be avoided. Digoxin binds to amyloid fibrils and can lead to locally high levels; it also must be used with caution.^[22]

Given the high incidence of sudden death in patients with TTR cardiac amyloidosis, it is prudent to consider prophylactic placement of an implantable cardioverter defibrillator (ICD).^[22]

• References

Surgical Care

Liver transplantation

Prior to 1990, no therapy for TTR-FAP was available. Liver transplantation was first performed for FAP in 1990 and to date more than 2100 liver transplants have been reported to the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR).^[40] 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 seems to halt progression of sensory, motor, and autonomic neuropathy. Ideally, the transplantation should be performed as early in the disease course as possible, before significant neurologic disability has been incurred.^[41]

Cardiac, leptomeningeal, gastrointestinal, or ocular involvement often progresses despite transplantation.

Overall 20-year survival after transplantation, all mutations included, was 55.3%. The expected mortality rate decreased on average by approximately 4% per year between 1990 and 2010. Improved survival in TTR Val30Met patients was most pronounced during the first 5-year period, whereas non-TTR Val30Met patient survival improved throughout the 20-year period. The natural history of the disease has a 10-15 year prognosis.^[41]

Combination heart and liver or liver and kidney transplantation has been performed in select patients, with variable success, and an 18.1% rate of postoperative cardiac complications has been shown with heart transplantations. Patients undergoing combined transplantation were generally older than those only being treated with liver transplant for TTR amyloidosis and more likely carrying a non-TTRVal30Met mutation.^[41]

Carpal tunnel release

Involvement of the carpal ligament is observed not only in ATTR but also, most commonly, in patients undergoing dialysis and in patients with light chain amyloidosis (AL). Treatment is surgical release.

At the time of carpal tunnel release, a biopsy should be performed if a definitive diagnosis has not been established previously so that both Congo red staining and immunostaining can be performed. Why the carpal ligament, or indeed any organ, is a favored location for amyloid deposition is not known.

Vitrectomy

Vitrectomy is useful in patients with vitreous involvement. TTR is known to be produced locally by retinal pigment epithelial and ciliary pigment epithelium cells. The progression of ocular disease after liver transplantation suggests that continued intra-ocular TTR production is relevant in this context. In a review of 513 cases, no differences were found in ocular tests between patients who received liver transplants and nontransplanted patients.^[42]

• References

Diet

There is no specific diet for ATTR. A small observational study of 24 men with wt-ATTR cardiomyopathy demonstrated that consumption of green tea extract for 1 year may potentially inhibit amyloid fibril formation in the heart.^[43] Patients with associated heart disease can also benefit from a low-sodium diet, and may wish to review American Heart Association recommendations on reducing dietary sodium.

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Complications

Central nervous system (CNS) complications are increasingly noted in liver-transplanted ATTR patients. Atrial fibrillation (AF) is a risk factor for ischemic CNS complications observed after liver transplantation.^[16]

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Consultations

Once the diagnosis of ATTR has been made, a multi-disciplinary approach with the following consultations is advised:

• Rheumatology
• Cardiology
• Neurology
• Nephrology
• Ophthalmology
• Gastroenterology
• General Surgery
• Genetic Counseling
• Physical therapy
• Nutrition

• References

Activity

Since polyneuropathy (FAP) is a major constellation of symptoms in ATTR, a loss of function is a trigger for liver transplantation. Early involvement of physical therapy to detect subtle changes in function would be helpful.

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Prevention

There are no known primary preventive measures. Once the diagnosis has been made, medical and surgical treatments serve as secondary prevention, and supportive care for complications serve as tertiary prevention.

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Long-Term Monitoring

For cardiac follow-up, monitor New York Heart Association (NYHA) class and electrocardiographic (ECG) changes in order to mitigate symptoms and determine the need for ICD placement and possibly accompanying heart transplantation in select cases if liver transplant is indicated. Early detection of cardiac abnormalities is important; the prophylactic implantation of pacemakers was found to prevent 25% of major cardiac events in TTR-FAP patients followed up over an average of 4 years.^[44]

For ATTR-FAP, liver transplantation should be considered while the patient is still in stage I FAP.

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

Ophthalmological monitoring recommendations, which are the same for liver transplant recipients and non-transplanted patients, set out the following schedule for eye examinations^[42] :

• Starting at the time of genetic diagnosis and, thereafter, repeated every 2 years in asymptomatic carriers and annually in symptomatic patients
• Annually after discovery of abnormal conjunctival vessels
• Every 6 months for lacrimal dysfunction, amyloid deposition of the iris, and amyloid deposition of the anterior capsule of the lens
• Every 3 months for scalloped iris, glaucoma, vitreous amyloidosis, retinal angiopathy

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Medication Summary

Despite recent drug approvals, liver transplantation remains the gold standard for treating transthyretin-related amyloidosis (ATTR). Multi-organ transplantation (heart, liver and kidney) has been successful in slowing the natural course of the disease. In 2018, the US Food and Drug Administration (FDA) approved patisiran and inotersen for treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults.^{[32, 33]} In Europe, tafamidis is approved for stage I FAP. Research continues to identify and refine effective medical treatments for preventing the deposition of amyloid fibrils.

Cautious, closely monitored medical treatment for ATTR cardiomyopathy and consideration of implantable cardioverter-defibrillator (ICD) placement are required, as the restrictive pathophysiology of the heart failure differs from the more common hypertrophic or dilated varieties and standard treatments such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or diuretics could worsen symptoms. Digoxin can increase local amyloid fibril levels in the heart^[22]

• References

Patisiran (Onpattro)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Class Summary

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

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Inotersen (Tegsedi)

• Dosing, Interactions, etc.

Clinical Context:  Inotersen is an antisense oligonucleotide that causes degradation of mutant and wild-type transthyretin mRNA by binding TTR mRNA. This action results in reduced TTR protein in serum and tissue. It is indicated for polyneuropathy of hATTR in adults.

• References

Class Summary

In a clinical trial, inotersen, an antisense oligonucleotide, has improved neurological scores compared with placebo.^[33]

• References

Complications

Complications of transthyretin-related amyloidosis (ATTR) include the following:

• Familial amyloid polyneuropathy (FAP): Sensory, motor and autonomic neuropathy; cachexia; leptomeningeal involvement
• Cardiac: Restrictive cardiomyopathy, arrhythmias
• Renal: End-stage renal disease, nephrotic syndrome
• Ophthalmologic: Keratoconjunctivitis sicca, glaucoma, vitreous opacities, pupillary abnormalities

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Prognosis

The natural course of TTR-FAP can be classified into the following three stages:

• Stage I – Sensory polyneuropathy
• Stage II – Progressive walking disability
• Stage III – Wheelchair bound or bedridden

Life expectancy ranges from 7.3 to 11 years from onset.^[19] The prognosis depends on the presence and identity of a TTR variant and organ(s) involved. Patients with early-onset of variant-sequence TTR may die within a few years of diagnosis. Older patients with slowly progressive disease can live for decades after the onset of symptoms and may never develop life-threatening disease.^[15]

Penetrance of the individual ATTR mutations vary. The penetrance of the same mutation in different geographic areas can also vary, for example, the Portuguese population showing much higher penetrance of the Val30Met mutation during middle age (80% at 50 years) compared with the French population (18% at 50 years).^[19]

In contrast to light chain amyloidosis (AL), symptomatic cardiac involvement in ATTR does not necessarily portend a poor prognosis. Median survival in cardiac AL is about 6 months, but is several years in older patients with cardiac ATTR, even in those with a TTR variant.

• References