Carcinoid Heart Disease

Carcinoid heart disease is a fibrotic valvular disease in which plaque like fibrous tissue coats the endocardium, mainly of the right heart, in patients with carcinoid syndrome. It causes tricuspid regurgitation (often with stenosis), pulmonary valve disease and right heart failure.

Carcinoid syndrome occurs in about 20 to 30% of patients with metastatic midgut neuroendocrine tumours. Cardiac involvement develops in about 20 to 50% of those with the syndrome and is uncommon without liver metastases.

Risk rises with 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) over 300 micromol/24 h, long duration of the syndrome and frequent flushing. Cardiac disease is a major cause of death in this group.

Left sided lesions occur in about 10 to 15% of patients with cardiac involvement, through a patent foramen ovale, a bronchial primary tumour or very high serotonin levels. Drugs that stimulate 5-HT2B receptors (cabergoline, pergolide, ergotamine, methysergide, fenfluramine) cause similar lesions.

Pathophysiology.

Serotonin and other vasoactive substances from hepatic metastases reach the right heart through the hepatic veins. Pulmonary monoamine oxidase inactivates most of them, which is why the left heart is usually spared.

Serotonin acts on 5-HT2B receptors of valve interstitial cells, causing proliferation, matrix deposition and plaque formation. Plaques fix the tricuspid leaflets and subvalvular apparatus in a semi-open position, producing severe regurgitation. Thickened pulmonary leaflets cause stenosis, regurgitation or both.

The right ventricle then faces a large volume load. Congestion causes hepatic and renal dysfunction, and ascites worsens nutritional state.

Prognosis is set by both the tumour and the heart. Untreated severe cardiac disease carries a median survival of only a few years, and valve replacement improves symptoms and survival in selected patients.

Fatigue, exertional dyspnoea, peripheral oedema, ascites and abdominal discomfort. Examination shows a raised jugular venous pressure with prominent v waves, a holosystolic murmur of tricuspid regurgitation at the left lower sternal edge that increases on inspiration (often soft when regurgitation is torrential), an ejection murmur from the pulmonary valve, a right ventricular heave and hepatomegaly.

Syndrome features are flushing, diarrhoea, wheeze, abdominal pain, telangiectasia and pellagra like skin change. Cardiac disease may develop even when flushing is controlled.

• Biochemistry: 24-hour urinary 5-HIAA (avoid serotonin rich foods such as bananas, pineapple, walnuts, avocado and tomatoes for 48 hours, and certain drugs, before collection). Chromogranin A is less specific and is raised by proton pump inhibitors and renal failure.
• NT-proBNP is a useful screen for cardiac involvement (a value over about 260 ng/L warrants echocardiography).
• Echocardiography: thickened, retracted, immobile tricuspid leaflets with failure of coaptation, a dagger shaped late peaking regurgitant jet with early peak velocity, a dilated right atrium and ventricle, thickened pulmonary leaflets with stenosis or regurgitation, and a patent foramen ovale. Quantify tricuspid and pulmonary regurgitation and stenosis, and examine the left sided valves.
• Cardiac MRI or CT for right ventricular volumes and function, and for pulmonary valve assessment when echocardiographic windows are poor.
• Tumour staging: contrast CT or MRI of the liver and abdomen, and somatostatin receptor PET (gallium-68 DOTATATE).
• Right heart catheterisation when pulmonary pressures or intracardiac shunt are uncertain.

Differential diagnosis.

• Rheumatic tricuspid disease and Ebstein anomaly.
• Drug induced valvulopathy.
• Endomyocardial fibrosis and Loeffler endocarditis.
• Functional tricuspid regurgitation from pulmonary hypertension, infective endocarditis and pacemaker lead related regurgitation.

Control the tumour and syndrome (this slows cardiac progression):

• Octreotide long acting release 20 mg intramuscularly every 4 weeks, adjusted to 10 to 30 mg every 4 weeks by symptoms and 5-HIAA (30 mg is the label maximum, and higher doses are used in specialist practice); give short acting octreotide 100 to 200 microgram subcutaneously three times daily for the first 2 weeks. Check glucose, thyroid function, and gallbladder ultrasound yearly. Bradycardia and steatorrhoea occur.
• Lanreotide 120 mg deep subcutaneously every 4 weeks (every 2 to 3 weeks if symptoms break through); start at 60 mg in moderate to severe hepatic impairment.
• Telotristat ethyl 250 mg orally three times daily with food, added to a somatostatin analogue for refractory diarrhoea; monitor for constipation and liver tests; avoid in severe hepatic impairment and reduce in moderate impairment to the product label.
• Lutetium-177 dotatate 7.4 GBq intravenously every 8 weeks for 4 doses, with an amino acid infusion for kidney protection; blood count, creatinine and liver tests before each dose; avoid when creatinine clearance is under 30 mL/min.
• Liver directed treatment (resection, ablation or embolisation) in selected patients, always covered by octreotide.

Heart failure.

• Furosemide 40 to 120 mg orally once or twice daily (intravenous 40 to 80 mg when gut oedema limits absorption), or bumetanide 1 to 5 mg daily; titrate to dry weight; electrolytes and creatinine within 1 week of changes.
• Spironolactone 25 to 100 mg daily (potassium under 5.0 mmol/L and eGFR over 30 mL/min/1.73 m2; check at 1 and 4 weeks).
• Avoid over diuresis (the right ventricle is preload dependent) and avoid catecholamine infusions where possible (they can trigger carcinoid crisis).

Valve surgery or intervention.

• Indicated for symptomatic severe right sided valve disease (or progressive right ventricular dilatation) once the syndrome is controlled and expected survival exceeds 12 months. Earlier referral improves outcome, because severe right ventricular failure raises operative risk.
• Bioprosthetic replacement is usually preferred for the tricuspid and pulmonary valves. Warfarin to an INR of 2.0 to 3.0 for the first 3 to 6 months after a bioprosthesis. A mechanical tricuspid valve needs a target INR of 3.0 (2.5 to 3.5) for life.
• Treat left sided disease surgically when severe. Close a patent foramen ovale at surgery.
• Transcatheter valve-in-valve or replacement is used in selected high risk patients.
• Perioperative octreotide: 100 to 500 microgram intravenous bolus before induction, then 50 to 200 microgram/h until the day after surgery. Avoid histamine releasing drugs (morphine, atracurium, suxamethonium) and catecholamines, which can precipitate carcinoid crisis.

Carcinoid crisis (hypotension or hypertension, bronchospasm, flushing, arrhythmia): octreotide 100 to 500 microgram intravenous bolus, then 50 to 200 microgram/h; fluids; avoid adrenaline, noradrenaline and dopamine unless essential.

Monitoring. Echocardiography every 6 to 12 months (every 3 to 6 months when moderate or worse), NT-proBNP and 5-HIAA every 3 to 6 months, tumour imaging every 6 to 12 months, creatinine and liver tests every 3 months.

Referral and escalation. Refer every patient with carcinoid syndrome for echocardiography, and all with cardiac disease to a neuroendocrine tumour centre with a heart team. Urgent referral for new or worsening right heart failure, syncope, carcinoid crisis or planned procedures.

Special groups.

• Pregnancy: rare; somatostatin analogues are used only after specialist review; avoid lutetium-177 and telotristat.
• Kidney impairment: avoid lutetium-177 at creatinine clearance under 30 mL/min; adjust diuretics by response.
• Liver impairment: octreotide clearance falls; start lanreotide at 60 mg deep subcutaneously every 4 weeks in moderate to severe hepatic impairment.