Unexpected manifestation of cardiac amyloidosis

Abstract

This report discusses an unusual case of cardiac amyloidosis. We report a patient who presented with unexplained ascites on a background of stable hypertension and mild left ventricular systolic dysfunction, cardiovascular complaints commonly associated with age. Due to the unspecific nature of his cardiovascular symptoms, it took 2 years of recurrent, unresolved ascites, numerous investigations, shifting differential diagnoses and significant cardiovascular deterioration before cardiac amyloidosis was recognised, by which the disease was at end stage. This case emphasises the need for more discriminating clinical features in the diagnosis of cardiac amyloidosis and advocates unexplained, recurrent ascites as a possible candidate.

Background

Amyloidosis constitutes a large group of conditions characterised by amyloid deposition, misfolded extracellular protein aggregates deposited in tissues as bundles of β-sheet fibrillar protein.¹ Amyloid deposition can be systemic or localised to a single organ.² The precursor protein that misfolds to form the amyloid fibrils determines the amyloid type and predicts the clinical course.²

Amyloid deposits are the foundation of several conditions that have enormous social and medical impact, underlying Alzheimer’s disease which affects more than 12 million people worldwide.³ It also forms the basis of rare conditions that challenge the physician’s diagnostic capabilities,¹ such as the case we are about to present concerning senile cardiac amyloidosis.

Cardiovascular amyloidosis can be primary, a component of systemic amyloidosis or a consequence of chronic systemic diseases elsewhere in the body.⁴ If left unchecked, cardiac amyloidosis results in progressive diastolic and systolic dysfunction, congestive heart failure and death.² Several types of amyloid can infiltrate the heart and cause abnormalities in the structure and function of myocardium, pericardium, valves and large or small vessels. This frequently leads to restrictive cardiomyopathy, but also direct myocardial toxicity.⁵ Two types of amyloid commonly infiltrate the heart: immunoglobulin light-chain amyloid and transthyretin amyloid.² In conjunction with the severity of involvement, the type determines treatment. Early diagnosis and accurate classification plays a pivotal role in defining the patient’s clinical course.⁶ However, despite advances in treatment options, the prognosis for patients remains poor.⁴

Due to the vast breadth of cardiac involvement, the clinical symptoms vary widely. Clinical manifestations range across cardiomyopathy, congestive heart failure, coronary heart disease, valvular disease, arrhythmia and heart block. Of the literature thus far, the majority of disease manifestations involve classic cardiovascular symptoms, such as exercise intolerance, fatigue, breathlessness, syncope, atrial fibrillation and chest pain, making it difficult to differentiate the condition from more prevalent cardiovascular conditions.² It has been put forward that suspicion of cardiac amyloidosis should be aroused in any patient who presents with restrictive cardiomyopathy or prominent signs of heart failure in the absence of ischaemic disease.⁷ Endomyocardial biopsy remains the gold standard for diagnosis of cardiac amyloidosis with the identification of their apple-green birefringent deposits under a polarised light microscope after Congo red staining.⁸ It is rare for the disease to solely manifest extracardiovascularly.

Yet, in our case, the patient presented unexplained ascites on a relatively unremarkable cardiac background of hypertension and mild left ventricular systolic function, conditions commonly dismissed as being associated with increasing age.⁹ Hence, we believe our case report demonstrates a novel and unusual presentation that could aid future diagnosis of this cryptic cardiac condition.

Case presentation

April 2011

In 3 months, the patient had lost 3 kg since successfully eradicating his Helicobacter pylori-related gastritis. Medical history was remarkable with hypertension, mild left ventricular systolic dysfunction and mild renal impairment. Ultrasound scan revealed moderate ascites; however, the diagnostic tap revealed unremarkable results. Similarly, a CT confirmed ascites but unearthed no other pathology. Repeat cytology and microscopy tests on a further ascitic fluid sample returned negative but a CT scan review revealed some peritoneal haziness. Patient weight loss, anorexia and new CT scan report raised the suspicion of malignancy, particularly peritoneal disease. However, when cytology tumour markers returned negative, it was agreed that the next best step would be to perform a diagnostic laparoscopy.

July 2011

Overarchingly, the patient felt well, but was experiencing recurrent episodes of postprandial abdominal discomfort and bloating. Mild abdominal distension was noted during examination with no organomegaly or tenderness. The laparoscopy confirmed ascites and also revealed a micronodular appearance of the liver. No other visceral abnormality, tumour or lesions were found. A normal-looking peritoneum and a peritoneal biopsy displaying benign, normal-looking mesothelial cells ruled out any other peritoneal disease. In conjunction with these data, when the 2.5 L of ascitic fluid drained and sent for microbiology and cytology analysis did not reveal any malignant cells, intra-abdominal malignancy was excluded.

Paracentesis provided instant symptomatic relief for his abdominal discomfort which was arguably, from William’s perspective, the most troublesome issue. His ascites could be explained by liver cirrhosis, a hypothesis supported by the micronodular appearance of his liver. Conversely, his alcohol intake was a mere one unit per week, and liver screen results, including a hepatitis screen and liver serology, returned unremarkable. Thus the source of his recurrent ascites and resultant abdominal discomfort remained a mystery.

November 2011

As no answers had been elucidated, on re-examination, it was noticed that the patient had an elevated jugular venous pressure (JVP) with possible C-V waves and a pulsatile liver, suggestive of tricuspid regurgitation (TR). Clinical impression was that his liver cirrhosis was linked to his TR, hence referred to cardiology.

January 2012

Patient had been diagnosed in 2009 with hypertension and mild left ventricular dysfunction. An echocardiogram taken at the time revealed concentric left ventricular hypertrophy, mildly impaired left ventricular systolic function, mild mitral and TR, normal valves and mild right ventricular hypertrophy with good right ventricular function (figures 1–4). It was therefore startling when his new echocardiogram showed significant deterioration within the short 2-year span; he still had marked concentric left ventricular hypertrophy, but had since progressed to have moderately impaired left ventricular systolic function, moderate mitral regurgitation and significant right heart failure changes including severe eccentric TR and impaired right ventricular function. His ECG also exhibited novel 2:1 atrio-ventricular (AV) block and left bundle branch block with sinus tachycardia. What could have produced such severe changes to his echocardiogram and ECG? Why were his tricuspid valve and right heart functions so depreciated?

Figure 1.

Pulse wave Doppler of mitral inflow suggesting restrictive diastolic physiology.

Figure 2.

Four-chamber echo image showing severe functional tricuspid valve regurgitation on colour Doppler.

Figure 3.

Four-chamber echo image showing severe concentric left ventricular hypertrophy (LVH) and RVH.

Figure 4.

Parasternal long-axis echo image: showing severe concentric left ventricular hypertrophy (LVH) and mild thickening of the aortic valve.

Investigations were initially directed towards exploring possible causative lung pathologies or constrictive pericarditis, including lung function tests, a review echocardiogram and a repeat chest X-ray to investigate lung fibrosis. However, not long after, it was recognised that the features observed on the latest echocardiogram were suggestive of cardiac amyloidosis.

Interestingly, his clinical picture had continued to stay unchanged during this period. Patient ascites had accumulated once again despite drainage of 2.5 L of ascitic fluid only 2 months prior. He had become increasingly breathless, but denied any chest pain; therefore, his dyspnoea was most likely a symptomatic consequence of his ascites.

May 2012

Diagnosis of severe cardiac amyloidosis was confirmed by MRI (figure 5) and endomyocardial biopsy, which demonstrated myocyte hypertrophy, amyloid deposition on Congo red staining and characteristic apple-green birefringence when visualised under polarised light (figures 6–8). Myeloma and systemic amyloidosis were excluded after thorough, targeted examination and unremarkable full blood blood count, renal function, liver function test and myeloma screen results.

Figure 5.

Four-chamber cardiac MRI showing extensive late enhancement of both ventricles with predominant subendocardial enhancement.

Figure 6.

Endomyocardial biopsy low power view. There is deposition of amyloid as amorphous pink material (arrow 1) in between cardiac muscle fibres (arrow 2).

Figure 7.

Endomyocardial biopsy with Congo red staining. The amyloid deposits are highlighted by Congo red staining (arrowed).

Figure 8.

Endomyocardial biopsy with Congo red staining under polarised light. The amyloid deposits display characteristic ‘apple-green’ birefringence (arrowed).

While waiting for MRI and biopsy results, the heart failure community team arranged education and optimisation of heart failure medications as patient became more breathless and exercise intolerant (New York heart association (NYHA)class II–III). His medications included furosemide 80 mg, spironolactone 25 mg, ramipril 1.25 mg, folic acid 5 mg and later bisoprolol 1.25 mg, which was added after assessment by the heart failure team. When his MRI and endomyocardial biopsy results heralded definitive diagnosis of severe cardiac amyloidosis, it was explained to the patient that he was already on the appropriate medical therapy and that, due to the stage and rarity of his condition, there was no curative treatment option available for patient. Ramipril was suspended due to prominent right-sided heart failure observed during cardiac catheterisation. Patient declined referral to a specialist centre in London and it was agreed that the aim for future management was quality of life and symptom control with diuretic therapy as patient entered the palliative care phase.

Outcome and follow-up

July 2012–present

Patient’s cardiac amyloidosis has led to steadily deteriorating heart function, involving conduction abnormality, severe TR and right-sided heart failure. Yet it was his recurrent reaccumulation of symptomatic ascites that previously and presently causes him most distress. It affects his mobility, exacerbates his increasing dyspnoea and provides significant abdominal discomfort and pain. He has since had to endure multiple elective paracentesis procedures which provide temporary symptomatic relief. Current diuretic therapy fails to control the issue, the dose being struck as a compromise between eliminating his ascites burden and protecting against his worsening stage III chronic kidney disease. Despite all these, the patient and his wife remained resilient, having continued his palliative care at home as he becomes increasingly frail, and passed away 3 months later.

Discussion

It took considerable time for the patient’s cardiac symptoms beginning in 2009 to be recognised as suggestive of cardiac amyloidosis for two main reasons. First, cardiac amyloidosis is an uncommon condition not often considered in the top differential diagnoses of heart failure symptoms. Second, and more importantly, the cardiac features identified were highly unspecific in both clinical and investigative settings. Hypertension and heart failure are common conditions observed with increasing age.⁹ The sensitivity of findings from front-line investigations is low: the sensitivity of echocardiographic features for cardiac amyloidosis does not exceed 60%.¹⁰ Much of the problem lies in that the clinical features and morphological findings are shared with many other diseases, such as hypertrophic cardiomyopathy, ‘athlete’s heart,’ Fabry disease and hypertensive cardiomyopathy.¹¹ It is not surprising that misdiagnosis occurs frequently. Even based on the most recent evidence, when suspicion of amyloid cardiomyopathy should be raised is vague.¹² Also, the current advice is not applicable in all cases: infiltrative cardiomyopathy should be considered in patients with echocardiographic evidence of ventricular thickening without a clear history of hypertension,¹² but our patient possessed both a clear history of hypertension alongside suggestive echocardiographic features.

Therefore, our case illustrates the need for more discriminating symptoms of cardiac amyloidosis outside the cardiovascular system and, in this case, this would have been his unexplained and recurrent ascites. Ascites is a well-established sign of right-sided heart failure, as is the patient’s subsequent elevated JVP.¹³ However, in the majority of cases, these signs are accompanied with lower-extremity oedema, hepatomegaly and splenomegaly which were not observed. Additionally, right-sided heart failure occurs in the later stages of the cardiac amyloid disease progression² and there was a discrepancy between when patient’s ascites began and when his right-sided heart function began deteriorating. Extracardiac features are also generally uncommon unless suffering from systemic amyloidosis,¹⁴ which on examination and investigation, patient was not. Thus, extrapolating from our patient’s clinical picture, unexplained and solitary ascites should be recognised as a potentially unique distinguishing feature of cardiac amyloidosis for patients with a largely unspecific cardiac history.

Our case also emphasises the importance of the multidisciplinary team in the diagnosis and management of cardiac amyloidosis, as the patient could not have achieved either without the integrated work of the gastroenterological and cardiovascular departments.

Cardiac amyloidosis is an uncommon, but increasingly recognised condition. We believe William’s case highlights unexplained ascites as a clinical manifestation of cardiac amyloidosis that should be considered in future practice in order to diagnose cardiac amyloidosis earlier, consequently widen treatment options and, as a result, benefit both longevity and quality of life.

Learning points.

• Cardiac amyloidosis is a rare condition which is often misdiagnosed due to poorly discriminable cardiovascular features. This negatively impacts on patient care and prognosis.

• There is a need for better distinguishing diagnostic features of cardiac amyloidosis in both clinical and investigational settings.

• Our patient’s unusual case proposes the consideration of unexplained, recurrent ascites on a background of unspecific cardiac history, to aid recognition of cardiac amyloidosis.

• Endomyocardial biopsy remains the gold standard for diagnosis with the identification of apple-green birefringent amyloid deposits under a polarised light microscope after Congo red staining.

• Our aim is to suggest that cardiac amyloid can present to gastroenterologist with a restrictive cardiac physiology pattern (similar in physiology to pericardial constriction) with predominant right heart signs such as isolated ascites.