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The case of a patient with confirmed amyloid, initially believed to be light chain (AL) type, whose diagnosis was clouded by an atypical gastrointestinal tract system presentation and a concomitant haematological condition, is presented. Duodenal biopsy samples subsequently stained positive for transthyretin and the diagnosis was revised to senile systemic amyloidosis. The patient was managed medically and remains alive more than 2 years after the diagnosis was formally established. Differentiating the systemic amyloidoses from one another can be challenging as the features often overlap and the most sensitive tests usually require a tertiary referral. Ultimately, cases usually require histological verification from tissue biopsies. Helpful pointers can be obtained with a careful history and examination in combination with some routinely available diagnostic tests.
A total of 25% of postmortem cardiac tissue samples in patients over 80 years of age contain amyloid protein. Most patients remain asymptomatic or mildly symptomatic during life, but senile amyloid is an important and under-recognised cause of morbidity in older patients. It runs an indolent course and can be partially attenuated with medical treatment. This case highlights the difficulty in obtaining the correct diagnosis in such patients, especially where frailty and comorbidity prohibit invasive investigations. We demonstrate that simple tests, knowledge of the condition and its presentation can be vital in making the correct diagnosis.
An 82-year-old man had experienced several years of bilateral leg oedema, impotence and occasional dizziness on standing. His exercise tolerance was limited to just under 10 m, mainly by leg oedema. There was no history of chest pain, dyspnoea or orthopnoea. Echocardiography in 2007 had revealed moderate impairment of right and left ventricular function with a mildly enlarged left atrium. The left ventricular cavity size was normal with mild concentric thickening.
A referral was made to the gastroenterologists for persistent diarrhoea and weight loss, which was investigated with an oesophagogastroduodenoscopy and computed pneumocolon tomography. Duodenal biopsies were highly suggestive of amyloid (figure 1).
Medical history included bilateral carpal tunnel releases 2 years previously. He was taking ramipril, furosemide, digoxin, aspirin, amiloride, tamsulosin and simvastatin.
On examination, he was frail with severe peripheral oedema to both knees. The chest was clear and heart sounds normal. The pulse was 82 beats per min and irregular, oxygen saturations 95% on air and blood pressure 116/53 mm Hg, dropping to 98/46 mm Hg on standing. New York Heart Association heart failure class was 3.
Urinalysis showed mild proteinuria with preserved renal function (estimated glomerular filtration rate 100 ml/min). Liver function was normal and haemoglobin 10.0 mg/dl. NT-pro brain naturetic peptide was elevated at 522 pMol/litre. Protein electrophoresis demonstrated an IgG lambda paraprotein of 3 g/litre. Electrocardiography revealed atrial fibrillation, right bundle branch block and normal limb lead voltage amplitude. A repeat echocardiogram remained largely unchanged although interventricular septal width was now 25 mm (NR 7–12 mm).
Subsequently, sequencing of the transthyretin (TTR) gene was undertaken and demonstrated that wild type (unmutated) transthyretin was present. This finding effectively excluded hereditary amyloid as a cause and the diagnosis was then believed to be AL (primary) amyloidosis.
The duodenal biopsy samples were passed to the National Amyloidosis Centre for immunostaining, which proved positive for transthyretin. The diagnosis was revised to one of senile systemic amyloidosis (SSA) with an incidental finding of monoclonal gammopathy of unknown significance (MGUS).
AL amyloidosis, SSA, hereditary amyloidosis.
Treatment was aimed at symptom attenuation with medical treatment. Ramipril, amiloride and tamsulosin were stopped and furosemide increased. Salt and fluid restrictions were imposed. Heart transplantation for cardiac involvement was considered inappropriate due to the patient’s age and general frailty.
The pedal oedema improved markedly on this regimen, although recent echocardiography has shown progression of amyloid deposition with severe diastolic left ventricular dysfunction and worsening systolic dysfunction. He remains stable at present.
In SSA, the amyloidogenic protein is transthyretin. This tetramer is produced by the liver and is normally responsible for transportation of thyroid hormones. Under certain circumstances, transthyretin dissociates into monomers that are then deposited in various tissues of the body.
Autopsy reports show that 25% of patients over 80 years have evidence of transthyretin cardiac amyloid deposition.1 In the majority of patients, the deposits are small and asymptomatic. A few patients develop more extensive infiltration, leading to a restrictive cardiomyopathy. This typically presents as biventricular heart failure, although it may be picked up incidentally on echocardiography.
SSA almost exclusively affects men; the reasons for which remain unclear.
SSA is typically a diagnosis of exclusion, where underlying malignancy or hereditary and AL amyloidosis have been ruled out. Table 1 summarises features that may tend towards a diagnosis of SSA. As the name suggests, this form of amyloid does have systemic distribution. Outside the heart, lung involvement predominates but SSA is also found in the gastrointestinal tract, liver, spleen, bone marrow, kidneys and endocrine glands.
The characteristic signs seen in light chain amyloidosis (AL), such as macroglossia, nephrotic syndrome and bruising around the eyes (panda eyes), are usually absent in SSA. However, there is a strong association with carpal tunnel syndrome. The electrocardiogram (ECG) voltage in AL and hereditary amyloidosis is typically low, whereas in SSA this tends to be normal.
However, the myocardium may be thicker in SSA than AL. One study found a mean intraventricular septum thickness of 17.8 mm in patients with SSA, compared to 14.3 mm in an AL group.2 Several studies have noted that AL patients develop symptomatic heart failure with much thinner ventricular walls than SSA patients. The evidence would suggest that light chains in AL amyloidosis have an intrinsic toxic effect on myocytes.3
Patients with AL typically deteriorate rapidly with a median survival of 5–11 months, whereas SSA patients have a median survival of 60–75 months.4
While the ‘gold standard’ for the diagnosis of amyloidosis is biopsy of affected tissue, in SSA the heart may frequently be the only site involved. Endomyocardial biopsy is a procedure with significant risk and other sites for biopsy should be rigorously sought if possible. Serum amyloid-P (SAP) scanning, a radiolabelling technique for quantifying amyloid load, is unsuitable for visualising hollow organs such as the heart.5
Medical treatment using diuretics and antiarrhythmics may render the patient asymptomatic. Anticoagulation should be used in atrial arrhythmias as the risk of thromboembolism is particularly high. A permanent pacemaker may be required if atrioventricular conduction block occurs. The definitive treatment for SSA is cardiac transplantation and, while the majority of patients are older and will not meet the selection criteria, at least three patients have been successfully transplanted for SSA. All were men, but unusually two were under 60 years of age6 and the third was 68 years of age.7
We acknowledge the support of the National Amyloidosis Centre based at the Royal Free Hospital, London, UK.
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.