Could this diagnosis save a life? Cardiac amyloidosis and the modern autopsy
Cardiac amyloidosis is one such diagnosis.
During a recent quality improvement project, we reviewed post-mortem cases in which cardiac amyloidosis was recorded on the death certificate. The project was undertaken in part because of the high regional relevance of hereditary transthyretin amyloidosis across the UK.
The West of Scotland has deep historical migration links with County Donegal in Ireland, a global founder region for the T80A (historically T60A) hereditary TTR mutation, while other UK regions see a high prevalence of the V122I variant due to West African and Afro-Caribbean heritage. Because these hereditary variants often present later in life with mixed clinical pictures, they can easily be misattributed as ‘senile’ (wild-type) disease. We therefore sought to determine if it is possible to reliably differentiate between hereditary transthyretin cardiac amyloidosis (hATTR), an inherited condition with major implications for surviving family members and for which treatment options exist, and wild-type transthyretin cardiac amyloidosis (wtATTR, also called senile amyloidosis), an age-related and non-hereditary condition with no implications for immediate family members.
The project ultimately highlighted something unexpected – identifying hereditary disease from information readily available to the pathologist was remarkably difficult.
The clues are often hidden
When residents encounter cardiac amyloidosis at autopsy, it is easy to focus on the pathology itself. The enlarged heart, the thickened ventricular walls and the characteristic amyloid deposits exhibiting apple-green birefringence all provide satisfying pathological explanations for a patient's symptoms and death. The challenge comes, however, when trying to determine whether the diagnosis has implications beyond the deceased patient.
We reviewed clinical records, autopsy reports and available background information in the same way any pathologist would to look for clues that might suggest hereditary ATTR. Features such as younger age of death (75 years or younger) or first presentation to cardiology services (65 years or younger), documented history of peripheral or autonomic neuropathy, and family history of cardiac disease, heart failure or arrhythmia were particularly suspicious for hereditary cardiac amyloidosis. In contrast, a history of bilateral carpal tunnel syndrome, lumbar spinal stenosis or biceps tendon rupture were more revealing of wild-type amyloidosis.
After identifying 22 patients at our West of Scotland unit where cardiac amyloidosis was listed on the death certificate, only 1 had clinical features suggestive of hATTR. Even more interestingly, that patient also displayed features associated with wild-type disease.
Our findings highlighted the challenges of reliably identifying hereditary amyloidosis at post mortem, particularly when key clinical information such as family history is incompletely documented and genetic subtyping – the only true method to confirm the diagnosis – is unavailable.
What does this mean for residents?
At first glance, this may seem like a frustrating conclusion. Should we even bother considering hereditary amyloidosis if we cannot reliably distinguish it? However, we would argue it highlights one of the most important educational opportunities in autopsy practice.
Many pathological diagnoses end with the death certificate. Hereditary disease is an exception to this. A diagnosis of possible hATTR may have implications for children, siblings and other relatives who could carry the same genetic variant. Unlike many inherited conditions encountered in pathology training, transthyretin amyloidosis is now increasingly treatable. Earlier recognition can lead to genetic counselling, family screening and access to therapies that may slow disease progression. In other words, recognising the possibility of hereditary disease at autopsy could potentially alter the future health of an entire family.
Learning to ask the right questions
Pathology findings alone are not enough to distinguish hereditary from wtATTR. Instead, focus on the clinicopathological correlation is essential when certain diagnoses like this are identified in the post-mortem setting. Consider the following:
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was the patient unusually young at time of death?
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was there a history of peripheral or autonomic neuropathy on brief review of their clinical notes?
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was there any mention of family members with unexplained heart failure, arrhythmias or amyloidosis in their clinical notes?
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could this be a diagnosis worth highlighting in the report or discussing with the clinical team?
None of these questions provide certainty. However, they may identify the rare cases where further investigation could benefit surviving relatives and may warrant acknowledgement in the post-mortem report to signpost family members to their general practitioner.
With sufficient evidence that can be associated, even without complete certainty, we can effectively word the clinicopathological correlation to highlight the possibility and, importantly, recommended the next steps for the clinical team that the patient was under. Careful wording is essential, as families can read the post-mortem report and may have anxieties about the issues raised.
The wider value of autopsy training
Autopsy training is sometimes viewed as a way of learning pathology from the past. Our experience with cardiac amyloidosis suggests the opposite. Autopsies encourage residents to utilise the clinical information in a unique and useful way, recognise inherited disease and appreciate that a diagnosis made after death may still create opportunities for prevention, surveillance and treatment in living family members.
For us, that is one of the most rewarding aspects of autopsy pathology. Occasionally, the final diagnosis is not simply an explanation of why someone died. It may also be the first clue that helps protect those they leave behind.
Acknowledgements
We gratefully acknowledge Dr Esther Youd for her supervision of this project and her expertise in interpreting the clinical context of the results.