Transthyretin-Related Amyloidosis Clinical Presentation

Updated: Jul 19, 2022
  • Author: Jefferson R Roberts, MD; Chief Editor: Emmanuel C Besa, MD  more...
  • Print


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. Patient presentation, including history and symptoms, can help identify organ system involvement. Specific organ system involvement will determine the complications the patient will face.  

Cardiovascular involvement

Patients with cardiac deposition often present with signs and symptoms suggesting chronic heart failure (ie, dyspnea on exertion, peripheral edema) and/or arrhythmias (ie, palpitations, lightheadedness, syncope). [20]

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, including normal-sequence TTR. Carpal tunnel syndrome may precede other clinical manifestations, sometimes by as much as 20 years.

Ophthalmological involvement may present as follows:

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

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

Severe postural hypotension may reflect amyloid deposition in the subendothelium of the peripheral vasculature. [20] However, postural hypotension may also be due to neuropathic involvement. 

Cardiac involvement typically results in the following [20] :

  • Diastolic dysfunction
  • Chronic heart failure (in particular, heart failure with preserved ejection fraction [HFpEF]) [23] ; findings may include peripheral edema, elevated jugular venous pressure, hepatojuglular reflux
  • 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. [24] 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.