In the Journal of Medical Case Reports, Lee and colleagues presented the case of a patient diagnosed with hereditary transthyretin-mediated amyloidosis (hATTR), illustrating in vivid detail the difficulties in diagnosing the disease due to its often nonspecific presentation.
A 64-year-old man presented with symptoms of weight loss and diarrhea. His diarrhea was described as gradual in onset over the past year; there was no blood or change in stool caliber. One year prior to the onset of his diarrhea, he experienced mild numbness and a burning sensation in the hands; these sensations then spread to his feet a few months later.
Due to his past history of neurological disease, a thorough neurological assessment was performed, which was normal. As for his gastrointestinal abnormalities, a fecal immunochemical test was conducted, which was also normal. A computed tomography (CT) scan of his abdomen and pelvis did not show signs of a neoplasm.
The patient was subsequently referred to gastroenterology for further assessments. An esophagogastroduodenoscopy and colonoscopy were carried out, which were both unremarkable. Random biopsies of the gut were also normal. Blood investigations revealed mild normocytic anemia (hemoglobin levels were between 127 and 132 g/L). His physicians suspected that he had choleraic diarrhea and he was prescribed colestipol, which partially alleviated his symptoms.
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Neurological Symptoms Worsening
Upon follow-up 1 year later, the patient described progressive numbness and significant deterioration in hand strength; he was now unable to perform simple tasks such as buttoning his shirt or opening jars. In addition, the numbness and burning in his feet returned with greater severity. He also complained of new symptoms, such as erectile dysfunction, bladder urgency, and orthostatic lightheadedness (without syncope). Blood investigations revealed anemia and mild leukopenia (3.1 × 109/L).
“Given his hematologic abnormalities, a referral to a hematologist was made for consideration of a bone marrow biopsy and evaluation of cytopenia,” the authors wrote.
Upon hematological evaluation, his clinicians suspected a diagnosis of amyloidosis due to his unique combination of symptoms. His previous duodenal biopsies were re-examined using Congo red staining, revealing amyloid deposition; this was consistent with a newly taken bone marrow biopsy. Mass spectrometry was performed on areas that were positive for Congo red, demonstrating a peptide profile consistent with transthyretin-type amyloid deposition.
A genetic test revealed a Val30Met mutation of the transthyretin gene, and a diagnosis of hATTR was made. Further neurological assessments demonstrated significant atrophy and weakness of the hand muscles. He also suffered from sensory loss extending to his elbows and knees; his gait revealed bilateral foot drop. A cardiological assessment revealed cardiac ATTR deposition, despite good cardiac health.
The patient was started on patisiran, which reduces the production of mutant TTR. He began to experience improvements in the motor strength of his distal hands and legs; a nerve conduction study conducted 9 months after treatment initiation was stable. Eventually, his symptoms stabilized, neither improving nor worsening.
Assessing Diagnostic Decision Making
Let us return to the primary symptoms in the patient that prompted an encounter with a clinician: weight loss and diarrhea. In a man of his age with these symptoms, the first possible cause to be urgently ruled out is colorectal cancer. This was done when tests did not reveal evidence of a neoplasm, despite his mild anemic status.
The initial decision to have a working diagnosis of choleric diarrhea is understandable, even if it later proved to be incorrect. Most cases of diarrhea of unknown etiology are self-resolving (with the exception of irritable bowel syndrome). However, his physicians notably did not reinvestigate his neurological symptoms until they worsened upon further follow-ups.
“Challenges to early diagnosis include nonspecificity of symptoms, with many possible and more common etiologies responsible for the patient’s presenting symptoms,” Lee et al wrote.
With the addition of new symptoms suggesting multisystemic disease, clinicians had further basis for suspecting a more global diagnosis, which in this case turned out to be hATTR. The careful re-examination of the patient’s gut biopsies was an excellent step, as it confirmed the presence of amyloid deposition, proving to his physicians that they were on the right track. When a diagnosis of hATTR was made, 20 months had passed from the time of presentation.
“For people in nonendemic areas, diagnosis is likely to be missed,” Adams and colleagues wrote in the Journal of Neurology. “52–77% of cases occur with no family history of the disease. Multiple misdiagnoses before the correct diagnosis of amyloid neuropathy have been reported in 20–40% of cases.”
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The most important symptom for the suspicion of hATTR in an elderly individual is progressive and disabling polyneuropathy, which became obvious in the patient described years after his initial presentation. However, upon follow-up, the patient’s polyneuropathy was severe enough for his neurological symptoms to be revisited and reassessed, eventually leading to a diagnosis of hATTR.
The 2 main diagnostic tools for hATTR are TTR gene sequencing and the detection of amyloid deposits in classical biopsies. Both of these tools were used with this patient. In addition, they used Congo red staining, which can indicate the presence of amyloid fibrils.
In summary, the diagnosis of hATTR is complicated by the sheer clinical heterogeneity among patients with regard to the initial presentation/main complaint. However, sustained investigations into the cause of polyneuropathy when it appears can lead to a swift diagnosis and the initiation of appropriate treatment.
Lee A, Fine NM, Bril V, Delgado D, Hahn C. Hereditary transthyretin amyloidosis: a case report. J Med Case Rep. 2022;16(1):248. doi:10.1186/s13256-022-03437-0
Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122. doi:10.1007/s00415-019-09688-0