Carcinoid Syndrome

Carcinoid syndrome is a paraneoplastic syndrome caused by neuroendocrine tumours, most commonly located in the gastrointestinal tract. These tumours release biologically active substances into the bloodstream, leading to a variety of symptoms. Though it primarily affects the gut, it can also involve other organs like the lungs, pancreas, and kidneys.

Signs and Symptoms

Carcinoid syndrome occurs in about 10% of all neuroendocrine tumours and 30–40% of more advanced cases. The biologically active substances released by these tumours act on blood vessels, producing characteristic symptoms:

• Flushing: The most common symptom, occurring in approximately 85% of patients. Flushing typically affects the face and upper thorax and can be triggered by factors like diet, activity, and stress.
• Diarrhoea: The second most common symptom, affecting about 80% of patients. It is often accompanied by abdominal cramping and pain.
• Bronchoconstriction: A less common symptom, affecting about 15% of patients. It is often associated with sneezing, shortness of breath, and flushing.
• Heart Disease: Cardiac complications affect 60–70% of patients, primarily involving the right side of the heart. This can lead to fibrosis of the tricuspid and pulmonic valves, detectable as a murmur and contributing to fatigue.

Less frequent symptoms include malabsorption, leading to pellagra, fatigue, muscle loss, cognitive impairment, and late complications such as mesenteric and retroperitoneal fibrosis.

Pathophysiology

Neuroendocrine tumours produce several biologically active substances, including serotonin, histamine, tachykinins, kallikrein, and prostaglandins. These substances primarily affect blood vessels, leading to the symptoms of carcinoid syndrome. Normally, the liver metabolises these substances (first-pass metabolism), but if the tumour metastasises to the liver, this process is bypassed. Pulmonary neuroendocrine tumours can also cause symptoms without liver metastases, as their products reach systemic circulation directly.

In these tumours, there is a shift in tryptophan metabolism towards serotonin production, increasing gut motility and causing diarrhoea. Excess serotonin also leads to flushing, while tryptophan deficiency can result in pellagra. In pulmonary neuroendocrine tumours, histamine and kallikrein are the main contributors to symptoms.

Carcinoid Crisis

Carcinoid crisis is a severe exacerbation of carcinoid syndrome due to excessive amine release, often triggered by stress, anaesthesia, surgery, or radiation. Symptoms include flushing, hypotension, arrhythmia, and bronchospasm.

Carcinoid Heart Disease

Carcinoid heart disease results from valvular damage due to vasoactive substances. It mainly affects the right side of the heart, causing fibrosis and plaque development. Detection is primarily done via echocardiography.

Diagnosis

A high degree of clinical suspicion is required for diagnosis. The most useful initial test is the 24-hour urine levels of 5-HIAA (5-hydroxyindoleacetic acid). Chromogranin A, a glycoprotein released by neuroendocrine tumours, can help detect non-secreting tumours.

Imaging

Imaging studies should focus on the abdomen and pelvis. CT and MRI using radioactive somatostatin analogues like indium-111 pentetreotide can localise the tumour. PET scans and bronchoscopy with biopsy are also useful. Echocardiography is recommended for patients with significantly elevated serotonin levels to evaluate carcinoid heart disease.

Differential Diagnosis

Conditions to consider include irritable bowel syndrome, celiac disease, and Ogilvie syndrome.

Treatment

Treatment focuses on controlling tumour proliferation and symptom management using somatostatin analogues like octreotide or lanreotide. In refractory cases, increasing the dose, switching to pasireotide, or using mTOR inhibitors like everolimus may be effective. Telotristat ethyl can help control diarrhoea.

Peptide receptor radionuclide therapy (PRRT) with radioactive somatostatin analogues like 177Lu-Dotatate or 90Y-Edotreotide is another option for metastatic disease. Cytoreductive surgery with 131I-MIBG, radiofrequency ablation, and radioembolisation are also employed, especially for liver metastases.

Carcinoid Heart Disease

Detection with echocardiography is very important. Treatment aligns with standard heart failure management, with surgical valve repair or replacement as a definitive option.

Uncertainties

Disease progression is challenging to predict due to the potential for small, undetectable metastases. Current markers like chromogranin-A are not perfect indicators of disease progression.

Epidemiology

The US incidence of neuroendocrine tumours ranges from 2.7 to 4.3 per 100,000 people, with carcinoid syndrome affecting about 0.27 per 100,000. There is no gender variance, but African Americans are more frequently affected.

Nonhuman Animals

Carcinoid syndrome can affect animals similarly to humans, with signs like vomiting, diarrhoea, and weight loss. The cause is the release of bioactive substances such as serotonin and histamine, as in humans.

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Self-assessment MCQs (single best answer)

What is the most common symptom of carcinoid syndrome?

Which substance is primarily responsible for the increased gut motility seen in carcinoid syndrome?

What percentage of advanced neuroendocrine tumour cases present with carcinoid syndrome?

Which diagnostic test is most useful initially for detecting carcinoid syndrome?

What is the main cause of carcinoid heart disease?

Which therapeutic option is used specifically for controlling diarrhoea in carcinoid syndrome?

Which imaging modality is recommended for evaluating carcinoid heart disease?

What substance is shifted towards serotonin production in neuroendocrine tumours, leading to symptoms of carcinoid syndrome?

Which of the following is NOT a typical symptom of carcinoid syndrome?

What is the estimated incidence of neuroendocrine tumours in the United States?