A 52 year old male with a previous history of hypertension and hypercholesterolaemia, presented to the emergency department of his local hospital with abdominal pain. He had undergone right and left carpal tunnel surgery five and three years previously. He had no family history of cardiac disease or sudden cardiac death. His mother had died from tuberculosis in her fifties and his father was 72 and asymptomatic. He had attended hospital several times during the previous 6 months always complaining of abdominal pain associated with nausea and sweating after meals. He was diagnosed with uncomplicated biliary colic but declined immediate surgical intervention.
Six months later, he represented after a collapse. His electrocardiogram demonstrated complete atrio-ventricular block. An urgent echocardiogram revealed “mild hypertrophy with normal ejection fraction”. A pacemaker was implanted and the patient was discharged on enalapril and simvastatin. Four months after pacemaker insertion he presented with shortness of breath and was still complaining of abdominal pain, asthenia and abdominal distension.
On physical examination his blood pressure was 95/65 mmHg and the jugular vein pressure was slightly raised with hepatic congestion and mild bilateral ankle oedema. The ECG and chest x-ray are presented in Figure 1. The patient was admitted for further investigations. An echocardiogram showed concentric left ventricular hypertrophy (15 mm), granular “sparkling” myocardium, mildly depressed left ventricular ejection fraction (50%) and biatrial enlargement (figure 2).
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Diagnosis, case resolution and treatment
There were several clues that should have prompted consideration of the diagnosis of cardiac amyloidosis. Specifically: the history of bilateral carpal tunnel surgery; abdominal pain; mild cardiac hypertrophy; and AV block. The echocardiographic findings described in the second echocardiogram performed are typical of cardiac amyloidosis.
An endomyocardial biopsy was performed to confirm the clinical suspicion. This demonstrated amorphous acelluar material that separated myocytes (Figure 1) and displayed apple-green birefringence under polarized light after Congo Red stainning.
Figure 1. Cardiac biopsy showing amorphous material (amyloid) between myocytes
Although serum/urine electrophorexis and immunofixation were normal and bone marrow biopsy did not show any dyscrasia, the patient was considered to have primary amyloidosis. He was discharged and followed at the outpatient clinic.
Two years later and after several admissions due to heart failure, the patient was transferred to our institution to consider heart transplantation. At our centre his echocardiogram now showed severely depressed left ventricular function (20%), his 6 minutes walking test was 310 metres, NT-proBNP was 4212 pg/ml and right catheterisation parameters showed a low cardiac index with pulmonary artery systolic hypertension. Renal function was normal and there was no major involvement of other organs/systems by the disease.
In order to determine the type of amyloidosis, another endomyocardial biopsy was performed. Immunohistochemistry was positive for TTR amyloid and genetic analysis of the TTR gene was performed. A mutation leading to the substitution of Glutamic acid by Lysine in position 89 was found. This mutation has been previously described in a Japanese family which had amyloidotic polyneuropathy.
TTR familial amyloidosis is an autosomal dominant disorder with high penetrance due to the production of amyloid from a mutant transthyretin (TTR) protein. The onset occurs most commonly after the age of 40 and depending on the type of mutation, peripheral neuropathy or cardiomyopathy may predominate. Some patients may have autonomic neuropathy with diffuse visceral pains. Renal involvement is usually uncommon. This entity is endemic in some regions of Portugal, Sweden and Japan reaching a prevalence of 1:600. More than 100 different mutations have been described so far with the Val122Ile mutation being found in approximately 4% of the black population in the United States. As transthyretin is almost exclusively produced by the liver, liver transplantation removes the source of amylogenic protein. When advanced cardiac amyloidosis is present combined heart and liver transplantation is the only alternative for these patients.
After an electroneurographic study, which showed mild to moderate polyneuropathy, the patient was considered suitable for heart and subsequent liver transplantation.
Heart transplantation was successfully performed (Figure 2) and during the following year he returned to NYHA functional class I. Endomyocardial biopsies performed to monitor cardiac rejection did not show TTR deposits. One year after heart transplant, liver transplantation was performed and the patient’s liver was used for an alternative recipient (domino transplant). Unfortunately, the patient developed hepatic artery thrombosis and had to be retransplanted urgently 1 month later. Almost 4 years after his heart transplant, the patient is well.
Figure 2. Explanted Heart
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