Transthyretin Cardiac Amyloidosis: A Case Report

Amyloidosis is a constellation of diseases caused by protein misfolding resulting in extracellular deposition of autologous protein laid out in beta-pleated sheets which are described as amyloid fibrils [1]. Multiple different kinds of fibril proteins have been identified in humans, and these diseases are now classified according to the nature of the amyloid precursor protein. Extracellular deposition of amyloid fibrils in organs and tissues results in tissue infiltration and swelling, leading to progressive loss of function of the affected organ.

We describe a case of systemic amyloidosis, focusing on the cardiac imaging findings. This is the first case reported in Singapore with genetically proven transthyretin amyloidosis (ATTR) demonstrated on MRI.

A 63-year-old Chinese female presented with chronic dry cough, unintentional weight loss over a few years, long-standing bilateral upper and lower limb weakness, and long-standing constipation with abdominal bloating. Her clinical examination was unremarkable, and she had no significant past medical history. Her initial chest radiograph revealed a moderate left pleural effusion and her initial electrocardiogram (Fig. 1A) showed borderline low-voltage and intraventricular conduction delay.

Fig. 1
Case of a 63-year-old female diagnosed with transthyretin amyloidosis, gastric biopsy histology images and initial ECG. A: The patient's initial ECG dated 26 Jan 2021 demonstrating poor R-wave progression, widening of the QRS complexes, borderline low QRS voltage complexes and known atrial fibrillation. B: The amyloid deposits are seen as light-pink acellular hyaline extracellular deposits (black arrowheads) (haematoxylin & eosin stain, ×100). C: The amyloid deposits show rose-pink staining on Congo Red stain (black arrow) (Congo red stain without polarisation, ×400). D: Polarised light on the same sections reveal the classically described apple-green birefringence (Congo red stain with polarisation, ×400). ECG: electrocardiogram.

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A CT scan of her thorax, abdomen, and pelvis was performed, which showed cardiomegaly, diffuse myocardial enhancement of both the right and left ventricles, a small pericardial effusion, and bilateral pleural effusions, larger on the right. No suspicious primary lung mass was identified. This raised suspicion of an infiltrative disease of the heart and an MRI of the heart was performed.

The MRI demonstrated a normal sized left ventricle with increased wall thickness, suggestive of concentric left ventricular (LV) hypertrophy. No segmental wall motion abnormality was detected. On the late phase, there was diffuse myocardial enhancement of both ventricles that did not conform to any particular coronary territory, with associated abnormal gadolinium kinetics (Fig. 2). The overall findings were suggestive of cardiac amyloidosis (CA) with ATTR subtype. Histological correlation was suggested.

Fig. 2
Case of a 63-year-old female diagnosed with transthyretin amyloidosis, radiological images. A: Axial CT showing cardiomegaly and diffuse hyper-enhancement of the myocardium of the left and right ventricles (white arrow). There is also an incidental left pleural effusion. B: Short axis steady-state free precession image of the mid-ventricle at end-diastole showing left ventricular hypertrophy. C: Short axis T1 image of the mid-ventricle at end-diastole showing global transmural/subendocardial late gadolinium enhancement (yellow arrow). D: Sequential short axis inversion scout sequence images of the mid-ventricle showing nulling of the myocardium (white arrowhead) before the blood pool (yellow arrowhead) and spleen (blue arrowhead). The inversion times are as shown on the respective figures.

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The initial transthoracic echocardiogram showed bi-ventricular hypertrophy, a granular appearance of the LV wall, together with apical sparing “cherry on top” pattern seen on global longitudinal peak systolic strain, suggestive of amyloidosis.

The patient was referred to neurology for work-up of her chronic bilateral upper and lower limb weakness. An electromyography nerve conduction study was performed, demonstrating electro-physiological evidence of a severe, symmetrical, mixed axonal and demyelinating sensorimotor polyneuropathy. Clinically, there was autonomic involvement with poorly reactive pupils, and the patient describes a history of anhidrosis in the past few years.

The patient also underwent abdominal fat-pad, bone marrow, and sural biopsies, which were unremarkable.

Over the subsequent few months, the patient presented with epigastric discomfort, associated with post-prandial intractable vomiting. A gastric emptying study was performed to investigate for possible gastroparesis; however, this came back normal. Subsequent gastric and duodenal biopsies performed during oesophago-gastro-duodenoscopy showed positive apple-green birefringence in polarised light with Congo red staining, confirming amyloidosis (Fig. 1B, C, and D).

A transthyretin (TTR) mutation test also came back positive, confirming the ATTR subtype.

Over the next few years, the patient had multiple admissions for intractable vomiting and gastrointestinal symptoms, requiring periods of parenteral feeding. Subsequently, she required longterm feeding through a gastrostomy tube. Her neuropathy also progressed and functionally she deteriorated until she was unable to perform her activities of daily living and required institutionalisation. The patient eventually had an out-of-hospital collapse and demised approximately four years after her initial presentation.

Amyloidosis is a diverse group of disorders which ultimately leads to organ dysfunction.

TTR is a 127-amino acid, 56-kDa transport protein primarily expressed by the liver. Variant TTR deposition causes autosomal dominant hereditary ATTR amyloidosis, the third most common subtype of amyloidosis, after light chain and autoimmune amyloidosis. Its 3 main phenotypes are: familial amyloid polyneuropathy, familial amyloid cardiomyopathy (FAC), and familial lepto-meningeal amyloidosis. In FAC, cardiac structures are infiltrated by beta-amyloid protein, leading to a constellation of findings on history, physical examination, and cardiac imaging [2].

The amyloid fibrils are typically deposited in the interstitial space. Biopsy remains the gold standard of diagnosis, demonstrating apple-green birefringence secondary to the binding of Congo red stain by amyloid fibrils. Due to the associated risks of performing an endomyocardial biopsy, the role of non-invasive cardiovascular imaging, such as cardiovascular MRI and technetium-99m pyrophosphate scintigraphy are increasingly being recognised [3]. Echocardiography is easily accessible and is frequently the initial investigative modality. However, the gross morphological changes seen in amyloidosis, such as the echogenic appearance of the myocardium, ventricular wall thickening, and the presence of functional dysfunction are not specific, usually seen in late disease. Although CT findings such as cardiomegaly, concentric wall thickening and abnormal wall enhancement can suggest myocardial fibrosis or inflammation, such as in this case, it remains nonspecific in isolation. The value of cardiovascular MRI in the diagnosis of amyloidosis is demonstrated in this case as it displayed the hallmark features of amyloidosis on a background of nonspecific clinical symptoms and allowed the clinical team to narrow the list of differential diagnoses before graduating on to more invasive techniques to confirm the diagnosis [4].

The MRI features of CA are well described. Late gadolinium enhancement (LGE) is very common in CA and represents interstitial expansion from amyloid deposition. Global transmural or subendocardial LGE patterns are most common. It is strongly associated with clinical markers of prognosis of CA and precedes a morphologic increase in LV thickness in a significant proportion of patients, which may allow for early detection of cardiac infiltration [5]. The different temporal order of nulling of myocardium and blood pool is highly sensitive for patients with myocardial amyloidosis and is easily appreciated on the inversion scout (TI scout) sequence, as demonstrated in this case (Fig. 2). This phenomenon is not well understood, but it has been attributed to faster clearance of gadolinium-based contrast from the blood, due to a higher volume of distribution of gadolinium-based contrast in the setting of amyloid deposition throughout the body. Another MRI technique useful in the diagnosis of CA is the determination of the extracellular volume using gadolinium enhanced T1 mapping, which is expands more significantly in CA. An important caveat with regards to the use of contrast-enhanced MRI in this population is that many may have renal dysfunction related to amyloid deposition in the kidneys in addition the myocardium, which may preclude the use of gadolinium given the risk of nephrogenic systemic fibrosis. In such cases, non-enhanced (native) T1 mapping is a tool for the diagnosis of CA through assessment of the degree of fibrosis [6]. Unfortunately, at the time of the patient's cardiac MR, T1 quantification techniques were not yet available at our centre. The diagnosis of CA is often challenging, but there is a large body of emerging evidence supporting the role of cardiac MR techniques, being able to differentiate between CA and other cardiomyopathies, and even the identification of the different subtypes of CA.

At present, apart from transplantation to replace failed organs and liver transplantation to remove the source of amyloidogenic proteins of hepatic origin; only symptomatic treatment is available in hereditary systemic amyloidosis. However, with the advent of novel therapies such as TTR tetramer stabilisers, gene therapy and immunotherapy which would be able to halt the amyloid fibril formation cascade, early diagnosis and therapy will become increasingly important in ATTR amyloidosis, as none of the therapies available can recover the organ damage already established [7].

In conclusion, this rare case of systemic ATTR amyloidosis demonstrates the utility of cardiac MRI in providing a sensitive and low-risk tool to demonstrate cardiac involvement.