Transthyretin-Related Amyloidosis Clinical Presentation

Patients often present with nonspecific symptoms such as weakness and weight loss. The presenting symptoms depend on the TTR variant present and the organ(s) involved. Amyloid deposition in a particular organ leads to similar clinical consequences and therefore similar complaints, regardless of the type of amyloid deposited. For example, cardiac ATTR and cardiac AL cause similar symptoms. The most common sites of deposition are the following:

• Cardiovascular involvement

  • Patients with cardiac deposition often present with symptoms suggesting congestive heart failure (ie, dyspnea on exertion, peripheral edema) and/or arrhythmias (ie, palpitations, lightheadedness, syncope).^[8]
  • Deposition in the subendothelium of the peripheral vasculature can lead to severe postural hypotension.^[8]
• Neuropathic involvement

  • Peripheral nerve problems are the presenting symptomatology in most cases.
  • Patients with peripheral nerve deposits note sensorimotor impairment. Some TTR variants present with lower-limb neuropathy (eg, TTR V30M), while other variants present with primarily upper-limb neuropathy (eg, TTR I84S, TTR L58H).^[9]
  • Patients also experience hyperalgesia and altered temperature sensation.
  • 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.^[10]
• Gastrointestinal involvement

  • Patients with gastrointestinal deposits present with diarrhea and/or constipation.
  • Nausea and vomiting also occur.
• Carpal tunnel syndrome

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

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 include cachexia, peripheral edema, hepatomegaly, purpura, orthostatic hypotension, impaired sensation and/or strength in the upper and/or lower extremities, and carpal tunnel syndrome.

• Cardiac involvement

  • Cardiac amyloidosis typically causes diastolic dysfunction; congestive heart failure; and arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias.^[8]
  • The physical findings observed are not specific for cardiac amyloidosis. Generally speaking, in patients with amyloidosis, the findings are not specific for ATTR; they are very similar to findings in patients with cardiac amyloidosis of the AL (immunoglobulin-related) type (see Amyloidosis, Overview and Amyloidosis, Immunoglobulin-Related). A recent study supports TTR-related cardiac disease as presenting with higher voltage-to-mass (LV wall thickness) ratios, but with less frequent hemodynamic alterations. Thus, their clinical course appears to be less aggressive than that of AL patients.^[11]
• Neuropathy

  • Deposition in the peripheral nerves causes sensorimotor peripheral neuropathy, which is a prominent finding in many patients with TTR V30M and other variants but not normal-sequence ATTR.^[12]
  • 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.^[13]
  • Cranial neuropathy is occasionally observed.
  • Autonomic neuropathy may cause severe orthostatic hypotension, diarrhea, and/or impotence.^[10]
  • Deep tendon reflexes often are diminished or absent, particularly late in disease.^[12]
• Central nervous system findings

  • Patients with rare TTR variants that cause CNS disease develop a wide range of abnormalities observed upon mental status and neurologic examination.^[12]
  • Objective findings may include nystagmus and pyramidal signs, with spastic paraparesis.^[12]
  • Patients with leptomeningeal and cerebrovascular deposits can have seizures, subarachnoid hemorrhages, and dementia.^[12] Patients with isolated leptomeningeal TTR disease, a rare presentation, can have hearing loss and cerebellar ataxia.^[14]
• Eye findings

  • Amyloid deposits can 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: Purpura results from the vascular fragility produced by amyloid deposition in the subendothelium of the small blood vessels.

The most important risk factor for ATTR is the presence of an amyloid-associated TTR variant. Among people carrying the same TTR variant, the clinical picture varies widely. Apparently, other unknown environmental and/or genetic factors also play a major role in influencing the course of disease.