Neuroendocrine Cancer has certain unique features whereby tumours can produce one or more symptoms which are known collectively as a syndrome. Neuroendocrine Tumours secreting excess amounts of serotonin, can be accompanied by Carcinoid Syndrome which if not diagnosed and treated early enough, can lead to an additional complication known as Hedinger Syndrome (often known as Carcinoid Heart Disease (CHD)). However, very late diagnoses can present with CHD already in place.
Excess serotonin, a hormone released by NETs into the bloodstream seems to be the prime and lead suspect for causing thick ‘plaques’ or fibrosis tissue within the heart muscle and damage to (mainly) the tricuspid and pulmonary valves on the right side of the heart which can become ‘tightly narrowed’ or ‘leaky’. It’s very similar to the reasons for mesenteric and peritoneal fibrosis which commonly occurs in midgut and other types of NET, in varying clinical degrees of severity. With Hedinger Syndrome, other substances associated with Carcinoid Syndrome may also be involved (e.g. tackykinins). The presence of liver metastases may allow large quantities of these substances to reach the right side of the heart without being filtered out by the liver but the primary and other secondaries can still contribute to the problem. It’s important to note that the damage is nearly always caused by excess secretions of substances from malignant neuroendocrine cells rather than any direct metastatic involvement of the heart.
Patients with carcinoid heart disease normally present with symptoms such as breathlessness (dyspnea), fatigue, ascites, swollen ankles (edema). However some patients can be asymptomatic. The left side of the heart is relatively protected, with the pulmonary circulation filtering out the majority of the serotonin and other substances produced by the tumours. However, involvement of the left-sided valves can sometimes be seen in patients with very active metastatic disease, bronchial NET or those with an existing heart condition known as Patent Foramen Ovale (hole in the heart).
When I was diagnosed in 2010, I was displaying symptoms of carcinoid syndrome and had to undergo a plethora of tests including something called an Echocardiogram – a sonogram (ultrasound) of the heart. Note – it is NOT abbreviated as ECG, which lay persons often use as an abbreviation for an Electrocardiogram – a totally different test. Carcinoid heart disease is a relatively late manifestation of neuroendocrine tumours; however, it can have an impact on the prognosis of these patients. Thus, early testing is vital for each patient presenting with carcinoid syndrome so that treatment can be considered. Whilst there are certain biomarkers which might indicate the potential for Carcinoid Heart Disease to be present, Echocardiography is the gold standard for detection. Depending on the results of the Echocardiogram, two further investigatory tests may be ordered up – transoesophageal echocardiogram and cardiac catheterisation. Patients without symptoms can undertake a blood test called NT-proBNP which can function as a screening test.
If you ‘google’ Carcinoid Heart Disease, be careful where you look as there are some statistics to be found in terms of incidence and prognosis. I suspect they may be out of date and have yet to catch up with improvements in the latest diagnostic and treatment techniques. Either that or they fail to mention the disease might only be clinically significant in much smaller percentages.
On a positive note, I sense major strides in worldwide awareness campaigns which should lead to earlier diagnosis and therefore earlier treatment for Neuroendocrine Cancer. Combine that with new and innovative treatments in debulking/removing/shrinking tumours and controlling syndromes, particularly the use of somatostatin analogues with the latter, should mean that fewer people will succumb to this additional complication. I don’t see a lot of Carcinoid Heart Disease posts on the various forums which hopefully is a good sign.
I’m fairly stable now so very low risk. I had an Echocardiogram every year from 2010 -2015 and I had one in 2018 as a precaution. The procedure is painless and takes around 20-30 minutes. My results have always been OK. Information on the guidelines for CHD have been a bit sparse but a new paper published has proposed an ‘Algorithm for the Screening and Investigation of CHD – you can see this below.
Who is susceptible to CHD?
Given the name we are clearly talking about serotonin secreting NETs and the statistics would appear to confirm that. I’ve read various figures but many seem to agree it those with small intestine NET and carcinoid syndrome with high levels of 5HIAA (>300 μmol/24 hour – see guidance below) who are most at risk. Some texts put it as high as 50-60% of patients with both NETs and carcinoid syndrome and to put that into even more context, only around one third of serotonin secreting NETs will be functional (i.e. have an active carcinoid syndrome). Some more recent texts put that figure at 20% citing the long term use of somatostatin analogues as a driver for that reduction. The vast majority of patient succumbing to CHD will be those with liver metastases – the tumour products are usually inactivated by the liver. In approximately 30-40% of NET patients, when hepatic spread from a primary gastrointestinal NET results in hormonally active tumour products exceeding the hepatic capacity for degradation, the classical carcinoid syndrome ensues. There are rare exceptions to that when carcinoid syndrome may appear without pre-existing liver metastases in patients with extensive retroperitoneal lymph node metastases and drainage bypassing the liver via the thoracic duct and retroperitoneal venous collaterals; or when the tumour products drain directly into the systemic circulation such as in the rare case of ovarian NETs.
I only found one study which gave some statistical breakdown of where the primary site was. It appears CHD occurs most frequently in patients with NETs originating in the:
– small bowel (72%)
– unknown primary (18%)
– NETs of the lung, large bowel, pancreas, appendix, or ovarian origin (10%).
Spreading those unknown primaries around would potentially put the small bowel figures as closer to 85%.
A slight male preponderance (∼60%) has been reported, with a mean age at diagnosis of 56-63 years.
NEW – 2017 guidance issued
Diagnosing and Managing Hedinger Syndrome (Carcinoid Heart Disease) in Patients With Neuroendocrine Tumors – An Expert Statement published in the Journal of the American College of Cardiology.
The following are key points to remember from this Expert Statement about the diagnosis and management of carcinoid heart disease in patients with neuroendocrine tumors:
- Carcinoid heart disease is a frequent occurrence in patients with carcinoid syndrome and is accountable for substantial morbidity and mortality.
- The pathophysiology of carcinoid heart disease is not well understood; however, chronic exposure to excessive circulating serotonin is considered one of the most important contributing factors.
- N-terminal pro–B-type natriuretic peptide (NT-proBNP) appears to be the best biomarker to date for screening carcinoid syndrome patients for evidence of clinically significant carcinoid heart disease (Evidence Level 2-3, Grade B).
- Measurement of either 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA) or plasma 5-HIAA is mandatory for diagnosis and follow-up of carcinoid syndrome. Furthermore, a 24-hour urinary 5-HIAA level >300 μmol/24 hour is a useful marker for identifying those at risk of developing carcinoid heart disease (Evidence Level 2, Grade B).
- Transthoracic echocardiography remains the gold standard for diagnosis and follow-up of carcinoid heart disease. It should be performed in all patients with carcinoid syndrome and high suspicion of carcinoid heart disease, such as clinical features or raised NT-proBNP and/or 5-HIAA levels. For established carcinoid heart disease, echocardiography should be performed if dictated by a change in clinical status; otherwise/thereafter every 3-6 months, depending on the severity of established carcinoid heart disease and clinical status (Evidence Level 2, Grade B).
- Cardiac magnetic resonance can be used to evaluate the pulmonary valve, identify cardiac metastases, and assess right ventricular size and function (Evidence Level 2, Grade B).
- Long-acting formulations of somatostatin analogs are the standard treatment used to alleviate symptoms related to the carcinoid syndrome, and prevent the development and/or progression of carcinoid heart disease (Evidence Level 2, Grade B).
- In cases of carcinoid syndrome that are refractory to somatostatin analogs, options include escalation of the somatostatin analog dose to above labeled doses, addition of IFN-alfa, or peptide receptor radionuclide therapy (PRRT). The oral serotonin synthesis inhibitor, telotristat, represents a promising agent to improve symptoms of the carcinoid syndrome; however, it is not yet approved, and is currently only available for compassionate use in the United States (author update – now approved). Given the limited data, everolimus cannot currently be recommended for the treatment of carcinoid syndrome (Evidence Level 2-4, Grade B/C). (NOTE: Since publication, PRRT now widely approved).
- The patient with carcinoid heart disease should be managed by a specialized multidisciplinary team, within a setting of a specialized neuroendocrine tumor (NET) center (Evidence Level 5, Grade D).
- An experienced medical (cardiologists and NET specialists with involvement of other specialists as necessary), surgical, and anesthetic team approach to the patient with carcinoid heart disease is critical to provide state-of-the-art management for these patients (Evidence Level 5, Grade D).
- The choice of valve prosthesis should be individually tailored on the basis of the patient’s bleeding risk, and possible future therapeutic interventions. Biological valve prostheses are the preferred option (Evidence Level 4, Grade D).
- To prevent a carcinoid crisis during surgery, the patient should be started on an IV octreotide infusion at a rate of 50-100 mcg/h at least 12 hours preoperatively; this should be continued throughout the procedure and until stable. Patients should be monitored for occurrence of bradycardia if high doses of octreotide are used (Evidence Level 4, Grade C).
- Patients with confirmed carcinoid heart disease should be referred to a NET center with cardiology and cardiac surgery departments having expertise in dealing with this complex pathology (Evidence Level 5, Grade D).
If you have time please check out this excellent video presentation on Carcinoid and Your Heart with cardiologist Dr. Jerome Zacks from Mount Sinai Hospital and the Carcinoid Heart Center, both in New York City.
Please also note that fibrosis due to excess serotonin (and other substances) can also induce fibrosis in the mesentery, retroperitoneum, pleural and pulmonary cavity and the skin. This is fully covered in my article Neuroendocrine Cancer: Fibrosis – an unsolved mystery?
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