Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Hereditary transthyretin amyloidosis (hATTR) is a gradual and progressive disorder that can cause peripheral sensorimotor and/or autonomic neuropathies along with non-neuropathic abnormalities such as cardiomyopathy, nephropathy, vitreous opacities, and central nervous system amyloidosis. The disorder typically presents in the third to fifth decades in people from endemic areas in Japan and Portugal; however, for those from other regions, it often manifests later.1
Hereditary transthyretin amyloidosis is a rare disease that causes the abnormal accumulation of amyloid deposits made of misfolded transthyretin (TTR) protein in the organs and tissues of the body. Since many of the signs and symptoms of hATTR resemble those of other disorders, it can be challenging to accurately identify and diagnose the condition. Early detection, diagnosis, and treatment are crucial since hATTR is lethal if left untreated, having a life expectancy of 3 to 15 years from the time of symptom onset.2 The diagnosis can be confirmed by identifying amyloid deposits on tissue biopsy and/or demonstrating an amyloidogenic mutation using TTR gene sequencing.3
To confirm amyloidosis, the demonstration of amyloid deposits via tissue biopsy is essential. Deposition of amyloid in the tissue can be demonstrated by performing Congo red staining on biopsy specimens. With Congo red staining, amyloid deposits show a characteristic green birefringence when viewed under polarized light.4 Characteristic deposition of amyloid can be seen in various tissues of the body, including the fat, skin, nerves, myocardium, kidneys, labial salivary glands, and gastrointestinal mucosa.3
Serum Variant TTR Protein
TTR protein is a soluble protein with a tetrameric structure that generally circulates in the serum or plasma. The normal TTR concentration in plasma is 20 to 40 mg/dL (0.20 to 0.40 mg/mL). After anti-TTR antibody immunoprecipitation, serum variant TTR protein can be found using mass spectrometry. The mass shift described by the single amino acid substitution of the variant TTR is present in about 90% of the identified TTR variants.4
TTR is the only gene known to be linked to hATTR. Although mass spectrometry can show a mass difference between wild-type and TTR protein variants in serum, it cannot distinguish the site and type of amino acid substitution in a variety of disease-related TTR gene mutations, so DNA sequencing is necessary. The majority of disease-causing mutations can be found using current methods for sequence analysis of TTR.4
Testing for hATTR-Associated Peripheral Neuropathy
Standard nerve conduction investigations can determine the presence and severity of peripheral neuropathy. Although skin biopsy is still the gold standard for the diagnosis of small fiber neuropathy, autonomic neuropathy can be explored using electrochemical skin conductance for sudomotor function assessment, heart rate variability analysis, and tests for orthostatic hypotension.3
Testing for hATTR-Associated Cardiomyopathy
Endomyocardial biopsy is the gold standard for establishing the diagnosis of cardiac amyloidosis. However, there is a non-negligible risk of complications, especially in elderly patients. Thus, myocardial biopsies are not frequently performed on a routine basis in clinical settings.5 Scintigraphy is a noninvasive study that may help with early diagnosis and the identification of hypertrophic cardiomyopathy of amyloid origin. It can be used to discern cardiac uptake of bone tracers like 99mTc-2,3-dicarboxypropane-1,1-diphosphonate (DPD), 99mTc-hydroxymethylene diphosphonate (HMDP), or 99mTc-pyrophosphate (PYP).
Cardiac serum biomarkers, particularly cardiac troponins (T or I), brain natriuretic peptide (BNP), or its N-terminal prohormone (NT-proBNP), are helpful and have prognostic significance in amyloid cardiomyopathy.3
Testing for hATTR-Associated Nephropathy
It is important to perform a renal assessment, which is often done by measuring serum creatinine, proteinuria, microalbuminuria, and estimated glomerular filtration rate (GFR). Because serum cystatin C concentration appears to be unrelated to sex, age, and muscle mass, it has been proposed that it is a more sensitive indicator of kidney dysfunction than serum creatinine levels. This suggests that serum cystatin C determination may represent another reliable marker for noninvasive GFR estimation.3
- Sekijima Y. Hereditary transthyretin amyloidosis. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2022. November 5, 2001. Updated June 17, 2021. Accessed July 5, 2022.
- Transthyretin amyloidosis (ATTR). Pfizer Inc. Accessed July 5, 2022.
- Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979
- Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31. doi:10.1186/1750-1172-8-31
- Carroll A, Dyck PJ, de Carvalho M, et al. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. J Neurol Neurosurg Psychiatry. 2022;93(6):668-678. doi:10.1136/jnnp-2021-327909
Reviewed by Kyle Habet, MD, on 7/25/2022.