metabolized and inactivated by the liver in a process known as first pass metabolism. This is why carcinoid syndrome most often occurs in patients whom the neuroendocrine tumor has metastasized to the liver, which allows the substances to bypass the first pass metabolism. Neuroendocrine tumors arising in the bronchi may be associated with manifestations of carcinoid syndrome without liver metastases because their biologically active products reach the systemic circulation before passing through the liver and being metabolized. Tryptophan metabolism is altered in the carcinoid syndrome. With neuroendocrine tumors, there is a shift in conversion of tryptophan to serotonin from the normal 1% to as high as 70%. Increased amounts of serotonin lead to increased gut motility causing the diarrhea seen in carcinoid syndrome. Increased amounts of serotonin can also cause the flushing seen as the main symptom of carcinoid syndrome. Tryptophan is also needed for niacin synthesis which can be a cause for pellagra associated with carcinoid syndrome. In the pulmonary neuroendocrine tumors or metastases, histamine release and kallikrein metabolism are the vasoactive mediators of flushing and the other symptoms of carcinoid syndrome. Carcinoid crisis Carcinoid crisis is an extreme exacerbation of the carcinoid syndrome. This results from excessive release of amines by the neuroendocrine tumors. It is largely a result of stressful procedures such as anesthesia, surgery, or radiation treatment. Symptoms of carcinoid crisis include flushing, hypotension, arrhythmia and bronchospasm. Carcinoid heart disease Carcinoid heart disease is the result of valvular damage related to the vasoactive substances released by the neuroendocrine tumor reaching the right side of the heart. This mainly affects the right side of the heart unless there is anomalous circulation (i.e. patent foramen ovale) because the lungs will metabolize the substances released by the tumor similar to how the liver will. After initial tissue injury around the valves, plaque will develop and fibrosis will occur, possibly mediated by excess serotonin. Diagnosis With a certain degree of clinical suspicion, the most useful initial test is the 24-hour urine levels of 5-HIAA (5-hydroxyindoleacetic acid), the end product of serotonin metabolism. Chromogramin A, a glycoprotein released by neuroendocrine tumors, can be used to detect non-secreting tumors. Imaging Imaging studies should be largely focused on the abdomen and pelvis because the neuroendocrine tumors causing the carcinoid syndrome largely arise in the gut. CT and MRI that utilize radioactive somatostatin analogues such as indium-111 penoctreotide are used to localize the tumor.