Bardet-Biedl syndrome

　　The incidence of carcinoid syndrome in carcinoid tumors is relatively high, and there are often widespread liver metastases. The most characteristic biochemical abnormality of carcinoid tumors is the excessive production of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA). Normally, 99% of tryptophan in the diet is used for the synthesis of niacin and protein, while more than half of the tryptophan intake in carcinoid patients is converted into 5-hydroxytryptophan (5-HTP) by tryptophan decarboxylase, and then into 5-HT, which is then metabolized into 5-HIAA. Recent studies have confirmed that carcinoid tumors not only produce amines but also produce peptides, PP substances, motilin, and prostaglandins, etc. Carcinoid tumors are small, and generally do not cause symptoms and signs when the diameter does not exceed 3.5 cm. When the carcinoid tumor is large, it produces a large amount of secretions, converting all tryptophan in food into 5-HT, etc. Due to the liver metastasis of the tumor, the liver cannot effectively metabolize and inactivate the products of the primary tumor, and the secretory products of the carcinoid tumor then enter the systemic circulation through the hepatic vein. The liver metastases are larger than the primary carcinoid tumor, also produce a large amount of secretory products entering the systemic circulation and causing a series of changes. After the formation of 5-HT, it enters the blood and is taken up and carried by platelets, distributed in tissues, and acts on target cells.

　　6. The lung manifests as asthma and dyspnea, occurring in 20% to 30% of patients, similar to bronchial asthma.

　　5. Abdominal pain, bloating, and tenesmus are common in the gastrointestinal tract, and diarrhea is like urine, up to 10-20 times a day, and can be accompanied by abdominal pain or colic before defecation.

　　4. The heart may show symptoms such as rapid heartbeat, decreased blood pressure, or shock. In the late stage, there may be congestive right heart failure, manifested as sitting breathing and lower limb edema.

　　1. Intermittent erythema mainly occurs on exposed areas such as the face, neck, and anterior chest, and can also spread throughout the body. It is intermittent, can occur suddenly, and appear in bright red or purple, with a duration of several minutes to 1-2 days. If the skin erythema occurs in a fit for several years, fixed skin changes will appear in the frequently发作部位, presenting multiple dilated capillaries and slight purplish redness. During the attack, other symptoms may accompany, such as tachycardia, low blood pressure, and symptoms of the gastrointestinal, pulmonary system. Factors that can trigger the attack include alcohol consumption, certain foods, pain, emotional fluctuations, and physical activity. Drugs such as adrenaline, norepinephrine, and catecholamines can cause attacks, and α-adrenergic blockers can stop the erythema.

　　2. Pulmonary symptoms The main manifestations are asthma and dyspnea, occurring in 20% to 30% of patients, similar to bronchial asthma, and asthma may occur simultaneously with skin flushing. Anesthesia or adrenaline can induce asthma or exacerbate asthma. The cause of asthma is due to smooth muscle spasm caused by substances such as 5-HT.

　　3. Gastrointestinal symptoms Abdominal pain, bloating, and tenesmus are relatively common, with varying degrees of severity. Diarrhea is like urine, up to 10-20 times a day, and may be accompanied by abdominal pain or colic before defecation. Diarrhea does not necessarily occur simultaneously with skin flushing and is caused by 5-HT. The use of 5-HT antagonists such as methysergide can stop diarrhea, and may also cause nausea, vomiting, and malabsorption. When there is a large liver metastasis of carcinoid, there may be persistent or intermittent upper right abdominal pain, radiating to the right shoulder and back, and fever, which is related to the large tumor volume, involvement of the liver capsule, relative ischemia, necrosis, or hemorrhage.

　　4. Cardiac symptoms Concurrent with the appearance of skin flushing, patients may experience rapid heartbeat, decreased blood pressure, or shock. In the late stage, there may be congestive right heart failure, manifested as orthopnea, lower limb edema, and auscultation of pulmonary valve stenosis murmur and tricuspid valve stenosis and insufficiency murmur.

　　5. Carcinoid crisis Carcinoid crisis is a serious complication of carcinoid syndrome, usually occurring in foregut carcinoids, with a sudden increase in 5-HIAA in urine. Clinically, it is characterized by severe and widespread flushing of the skin, marked worsening of diarrhea with abdominal pain, and symptoms of central nervous system dysfunction such as dizziness, somnolence, and coma, as well as cardiovascular abnormalities such as tachycardia, arrhythmia, hypertension, and severe hypotension.

　　6. Other manifestations due to the catabolic action of the tumor, and severe diarrhea can lead to weight loss, even cachexia, and hypoproteinemia. There may be some hyperfunction of hormone functions, such as insulin, growth hormone, parathyroid hormone, gonadotropin, and adrenocorticotropic hormone, with corresponding symptoms. The level of 5-hydroxyindoleacetic acid (5-HIAA) in the urine of patients with carcinoid syndrome is increased, exceeding 50mg/24h urine (normal range is 2-9mg/24h urine).

　　1. Regular check-ups, timely detection, and surgery.

　　2. Follow up after treatment.

This disease seriously affects the patient's daily life, so it should be actively prevented. The patient's diet should be light and easy to digest, with an emphasis on eating more vegetables and fruits, and a reasonable diet should be balanced, with attention to adequate nutrition. In addition, patients need to pay attention to avoiding spicy, greasy, and cold foods.

　　Mainly used for the diagnosis of carcinoid syndrome:

　　1. Determination of 5-HIAA in urine The value of this test is increased in patients with carcinoid syndrome, as 99% of 5-HT is converted into 5-HIAA in the body and excreted through urine. Therefore, the increase in 5-HIAA in 24 hours of urine has diagnostic value. The blood concentration of most patients is greater than 120μg/L, and the 5-HIAA in urine exceeds 30mg/24h urine. A level exceeding 50mg/24h urine has diagnostic value.

　　2. Determination of 5-HT or 5-HTP (5-hydroxytryptophan) in urine If the excretion of 5-HIAA in urine is low, further use of paper chromatography to determine whether there is an increase in 5-HT or 5-HTP should be considered.

　　3. 5-HT measurement in tumor tissue The level of 5-HT in tumor tissue is significantly elevated. This method is more sensitive than the determination of 5-HIAA in urine.

　　4. Pentagastrin stimulation test The pentagastrin stimulation test is helpful for the diagnosis of carcinoid syndrome. After intravenous injection of pentagastrin at a dose of 0.6μg/kg, blood is drawn at 1, 3, 5, 10, and 15 minutes to measure 5-HT. The increase in blood 5-HT in all cases is greater than 40% or greater than 50μg/L.

　　5. Screening test Drip a drop of the patient's urine onto filter paper and spray azo P-dinitrobenzidine. If red is observed, it is positive, indicating an increase in 5-HIAA in the urine. If purple is observed, it indicates a pheochromocytoma, and this test helps to differentiate between the two.

　　6. Determining the level of 5-HT in whole blood, plasma, or platelets can help with diagnosis, but the method is cumbersome and difficult to popularize.

　　7. Chromogranin Currently known neuroendocrine cell markers include neuron-specific enolase, chromogranin, synaptophysin, etc. These markers are mostly used for immunohistochemical identification of tumors, and chromogranin is mainly used as a circulating marker. Chromogranin is a secretory protein that is widely distributed in the neuroendocrine granules of normal neuroendocrine cells or tumor cells. Three types of chromogranin proteins have been identified, namely chromogranin A, B, and C, which have different amino acid structures but share many common biochemical characteristics. Immunohistochemistry or radioimmunoassay shows that the level of carcinoid chromogranin in patients can reach 90% to 100%. A group of reports indicate that in 44 cases of carcinoid, 17 cases of sporadic pancreatic endocrine tumors, and 11 cases of familial multiple endocrine tumors associated with the pancreas, the level of chromogranin A in plasma is elevated in 99% of cases, and the levels of chromogranin B and C are elevated in 88% and 6% of cases, respectively. This indicates that chromogranin A or B is a very valuable indicator for the diagnosis of pancreatic endocrine tumors.

　　8. Inducing tests During the non-attack phase of flushing, an induction stimulation test can be used to trigger an attack. Common methods include:

　　(1) The patient is asked to drink 10ml of alcohol, about 1/3 of the patients develop flushing on the skin 3-5 minutes later.

　　(2) After 1-2 minutes of injection of 5-10μg of adrenaline or 15-20μg of norepinephrine, patients with carcinoid syndrome may experience flushing of the skin on the face and neck, accompanied by conjunctival hemorrhage, lacrimation, and increased respiratory rate. This method may cause a decrease in blood pressure and shock symptoms, so it should be used with caution.

　　1. Fruits

　　There are many ways to eat apples to promote gastrointestinal motility, such as washing, peeling, and eating them. Add water and eat them as fruit soup. Drink them as juice. Cook them with fish. Make apple tea.

　　2. Winter melon

　　Fresh vegetables and fruits with little fiber, such as cucumbers and melons, are ideal daily foods for diaphoresis and diuresis. Boiling them with the skin on has a more obvious effect.

　　1. The basic goals of pancreatic carcinoid surgical treatment

　　Surgery is the only curative means for this type of tumor, and early diagnosis and early surgical resection of the tumor are the best treatment methods. Even if metastasis occurs, the resection of the functional primary carcinoid can alleviate and eliminate symptoms. However, pancreatic carcinoids are often multifocal and metastatic at the time of diagnosis, and cannot be treated with radical surgery. Paliative lobectomy or resection of metastatic tumors can be performed. The basic goals of surgical treatment are two: first, to cure the tumor or control the development of malignant tumors; second, to eliminate or alleviate the endocrine symptoms caused by the tumor. For this purpose, it is required that internists and surgeons:

　　1. Understand the clinical characteristics, pathological characteristics, natural history, and prognosis of various pancreatic endocrine tumors.

　　2. Understand whether the patient is sporadic or part of MENⅠ, and understand the differences in surgical outcomes between the two types of tumors.

　　3. Understand the potential effects of surgical treatment and conservative medical treatment for various membrane gland endocrine tumors. Only on the basis of fully mastering the above knowledge and conditions can a correct treatment plan be formulated.

　　2. The principles of extensive radical surgery for pancreatic endocrine tumor surgery

　　Extensive radical surgery refers to the complete or at least 90% above complete resection of the primary and metastatic tumors, including the removal of intrapulmonary metastatic tumors, including hemihepatectomy or lobectomy, and resection of metastatic lymph nodes. The main reasons for adopting the extensive radical surgery approach are:

　　1. Such tumors have a relatively good prognosis, and the long-term survival rate after surgical resection is high.

　　2. Extensive radical surgery can effectively alleviate the endocrine symptoms caused by tumors and improve the quality of life.

　　3. Extensive radical surgery is very beneficial for improving the effectiveness of future treatments.

　　4. The National Institutes of Health in the United States reported 42 consecutive cases of metastatic pancreatic endocrine tumors, of which 17 were considered resectable and a total of 20 surgeries were performed (including hemihepatectomy). The 5-year survival rate of the extensive radical surgery group reached 79%, with a 5-year survival rate of 100% for patients with localized metastases who underwent complete resection, while the 5-year survival rate of the remaining patients who did not undergo extensive radical surgery was only 28%.

　　Three, the purpose of non-surgical treatment

　　Symptomatic treatment aims to reduce the production or counteract the effects of 5-HT and kallikrein; antitumor treatment controls the development of tumors; supportive therapy improves the general condition of the patient.

　　1. Many drugs can increase the release of 5-HT and should be avoided or used sparingly. Examples include morphine, halothane, dextran, polymyxin, tyramine, and guanithidine.

　　2. 5-HT Combination: P-chlorophenylalanine, 1g each time, 3-4 times/d, can effectively alleviate or reduce nausea and vomiting and diarrhea, and can also reduce the severity of facial and neck skin flushing, but cannot reduce the frequency of attacks; mainly by inhibiting tryptophan hydroxylase; thereby reducing the production of 5-HTP and 5-HT. Its side effects can cause central nervous system dysfunction, occasionally causing hypothermia. Methyldopa, also known as levomethyldopa, is taken orally at 0.25-0.5g each time, 4 times/d, intravenous injection, 0.25-0.5g each time, can be repeated every 6 hours, and can be changed to oral administration when symptoms improve. This drug can also inhibit tryptophan hydroxylase; thereby reducing the production of 5-HT. Side effects include mild dizziness, dry mouth, bloating, and occasionally granulocytopenia, but it can recover after discontinuation of the drug.

　　3. 5-HT Antagonists: Butylmethylecgonine: During an acute attack, 1-4mg can be administered intravenously once; or 10-20mg can be added to 100-200ml of normal saline and infused intravenously within 1-2 hours, which can control flushing, asthma, and diarrhea. Seganidine 4-8mg, once every 6 hours, and nozinam 2.5g intravenous injection can alleviate symptoms, and have a role in controlling diarrhea and urgency.

　　4. Other drugs: Corticosteroids such as prednisone 15-40mg/d can achieve varying degrees of efficacy. Codeine and tincture of camphor can also be used to control diarrhea.

　　5. Chemotherapy and radiotherapy: Patients with metastases that cannot be surgically removed should receive chemotherapy. Commonly used chemotherapy drugs include 5-FU, cyclophosphamide, levorotatory solubile botulinum toxin, doxorubicin, streptozotocin, VP-16, nitrogen mustard, etc., which can alleviate symptoms but have poor efficacy, with an average effective rate of 30% to 50%. Combination chemotherapy is better than single drug use, and common combination chemotherapy regimens include STZ + ADM or 5-FU, VP-16 + cisplatin, etc. Radiotherapy can alleviate pain caused by bone metastases.

　　6. Hepatic artery embolization for liver metastases: The application of hepatic artery embolization and/or chemotherapy for liver metastases of carcinoid tumors can alleviate symptoms in 80% to 90% of patients. If hepatic artery embolization and chemotherapy are used sequentially, more than half of the patients' symptoms can be completely relieved, and some patients may have varying degrees of symptom relief.