Portal hypertension is due to various medical reasons to block the portal static blood flow, blood stasis, then the portal vein pressure is elevated, so that a series of symptoms and signs of increased portal vein pressure responsibility.
1.Etiology of portal hypertension.
(1) intrahepatic type: according to the different pathological forms can be further divided into two kinds of pre-sinusoidal obstruction and post-sinusoidal obstruction, the common cause of pre-sinusoidal obstruction is hopefully schistosomiasis cirrhosis, and the common very poor cause of post-sinusoidal obstruction is post-hepatitis cirrhosis.
(2) extrahepatic: because it is mainly caused by thrombosis of the main trunk of the extrahepatic portal vein and obstruction of the main genus branches of the portal vein.
2, common symptoms of portal hypertension.
Portal hypertension is mostly seen in middle-aged men with slow progression of the disease. The symptoms and signs vary depending on the cause of the disease. The main clinical manifestations are splenomegaly, hypersplenism, and then esophagogastric fundic varices, vomiting blood and black stool and ascites, etc.
(1) Splenomegaly: Most splenomegaly is combined with hypersplenism, which is a symptom of anemia, hematocrit and thrombocytopenia. Generally speaking, the larger the spleen, the more pronounced the hypersplenism.
(2) Upper gastrointestinal bleeding: When the portal vein pressure increases, it causes varices in the fundic vein and lower esophagus vein. Therefore, varices of the lower esophagus are important manifestations of portal hypertension, and often rupture and bleed due to ulcers and trauma.
(3) Ascites: In the advanced stage of intrahepatic portal hypertension, the appearance of ascites is a manifestation of hepatic insufficiency. In patients with ascites, the superficial veins of the abdominal wall tend to be more obviously varicose, sometimes accompanied by jaundice.
3. Screening for portal hypertension.
The diagnosis of portal hypertension is generally not difficult, varices in the lower esophagus can be determined by barium esophageal meal, gastroscopy like examination, and also need to check the past blood routine, biochemical whole.
4.Treatment of portal hypertension.
Portal hypertension is the inevitable result of liver cirrhosis after it has developed to a certain degree. Initially, there may be no symptoms, but the development of portal hypertension to a certain stage can be due to the rupture of esophageal and gastric fundic varices, causing upper gastrointestinal bleeding, promoting hepatic encephalopathy, hepatorenal syndrome, ascites, water-electrolyte and acid-base balance disorders and a series of complications, is an important cause of systemic metabolic and hemodynamic disorders in patients with liver cirrhosis, so effective treatment of portal hypertension and prevention of complications Therefore, effective treatment of portal hypertension and prevention of complications are particularly important. With the continuous development of research on the pathophysiology, hemodynamics and pathogenesis of portal hypertension, as well as the continuous improvement of treatment methods in recent years, the concept of treatment for this case has been completely transformed into a new concept of early, continuous and lifelong treatment for this disease.
(1) General treatment and dietary therapy When a patient with portal hypertension is stable and has no obvious other complications, he or she can be treated in a comprehensive manner according to the following principles, with the main focus on treatment of the cause or related factors
a. Rest: Patients with cirrhotic portal hypertension in the liver function compensation period, generally do not emphasize bed rest, mild disease, can participate in general work, but should be appropriate to reduce the labor time and labor intensity, pay attention to the combination of work and rest, in order not to feel fatigue is appropriate. Those who are more seriously ill or have a recent history of complications such as gastrointestinal hemorrhage should stop working to ensure sufficient bed rest and sleep time to prevent fatigue. Rest can facilitate the improvement of liver microcirculation, promote liver cell regeneration and repair, and reduce liver damage.
b. Diet: Since the whole gastrointestinal function is affected in patients with portal hypertension, high-calorie, easy-to-digest soft food should be given. For patients with chronic liver disease, a proper diet can supplement nutrition, improve liver metabolism, enhance body resistance, promote liver cell regeneration and repair, and prevent the occurrence of various complications. In principle, it is advisable to give food with sufficient calories and rich in various vitamins. In addition to food containing high sugar, high protein (protein intake should be limited in those with hepatic encephalopathy), appropriate fat and vitamins, it should also contain various inorganic salts and trace elements. Daily calories should be guaranteed at 8371-12556 (2000-3000 calories). High sugar is the main source, such as rice, flour and cereals. Protein is given about 100g per day, try to use protein rich in various amino acids or amino acids more complete such as fish, lean meat, poultry, eggs, milk and soy products. Fat is generally not too much, 30-50g per day is enough. Food is mainly soft, hard and rough food should be avoided to cause mechanical damage to the esophagogastric mucosa, try to control spicy and stimulating food, alcohol is strictly prohibited. For those with complications or insufficient food, intravenous supplementation of high nutrition can be given.
c. Etiological treatment: Treatment for the causes of cirrhosis is the basis for reducing portal hypertension, and the causes should be actively eliminated. For example, hepatitis cirrhosis virus replication can be given interferon, immune ribonucleic acid, thymidine and other treatments. In recent years, the application of lamivudine to inhibit the replication of hepatitis B virus has certain efficacy, but long-term medication is required. Alcoholic cirrhosis patients should abstain from alcohol, schistosomiasis cirrhosis can be given praziquantel, nitrothiocyanine treatment.
d. Symptomatic supportive treatment: For those who do not eat enough or cannot eat due to gastrointestinal symptoms such as nausea and vomiting, polarizing solution, energy combination and additional intravenous drip of vitamin C and B can be given, and antiemetic drugs such as domperidone, metoclopramide (Gastrofluan), procaine/bromelain/phenol (Emolol) can be given. For hypoproteinemia, human albumin and fresh plasma can be given as infusion, and testosterone propionate can also be given to promote protein synthesis. Complex amino acids, amino acid infusion for liver (branched chain amino acids), and vitamin K and B12 supplementation as appropriate can also be given according to the condition.
e, liver protection, enzyme lowering, anti-yellowing treatment: a wide variety, in addition to the above-mentioned vitamins, but also can be used to Vipramine, liver music, bifenthrin, silymarin tablets, liver to health, glycyrrhizin (glycyrrhizin), potassium magnesium menthylate, ursodeoxycholic acid, protoporphyrin sodium (liver protection tablets), inosine, coenzyme A, hepatocyte growth promoter, bitter yellow, rhubarb and other preparations for treatment, the efficacy does not vary greatly.
f. Anti-hepatic fibrosis treatment: At present, in the absence of effective methods to cure the original cause of cirrhosis, slowing down or stopping the process of liver fibrosis is quite important, although there has been great progress in recent years in the prevention and treatment of liver fibrosis, but the clinical efficacy is not yet satisfactory. Interferon, prostaglandin, polyunsaturated lecithin, colchicine, penicillamine, monoamine oxidase inhibitors and calcium channel blockers can be given to inhibit the synthesis of collagen fibers and have certain effects. In addition, Chinese medicinal preparations such as Danshen, compound turtle nail tablets, Cordyceps mycelium, and Hanfangjiajia methicin can be given.
g, treatment of ascites: the appearance of ascites is the performance of liver function is impaired to a certain extent, the worse the liver function ascites more difficult to eliminate. Therefore, the treatment of ascites focuses on correcting and restoring liver function. If the liver function is basically normal, the patient can have no ascites. If the patient has only a small amount of ascites, no special treatment is needed. If the patient has more ascites, the necessary treatment is required. Since sodium retention is the main cause of the occurrence and development of ascites, treatment should be carried out in two aspects: controlling sodium intake and promoting sodium discharge. The main methods to promote water-sodium drainage are: administration of diuretics, catheterization, laparotomy for fluid release or treatment with autologous retransfusion of ascites. If there is a decrease in plasma albumin, blood albumin and plasma can be administered, and testosterone propionate can also be given to promote albumin synthesis. If there is secondary abdominal infection, broad-spectrum antibiotic therapy can be given. In case of cancerous ascites, laparotomy chemotherapy is given according to the nature of the cancer.
(2) Pharmacological treatment to reduce portal pressure: Since Lebrec first applied pharmacological treatment to reduce portal pressure in the early 1980s, the importance and necessity of pharmacological treatment to reduce portal pressure has become more and more clearly understood through in-depth and detailed research. Especially in recent years, with the continuous research on the pathophysiology of portal hypertension, its pharmacological treatment can reduce portal vein and its varicose vein pressure, just like the treatment of hypertension, which requires early, continuous and lifelong treatment to reduce its complications and reduce the morbidity and mortality rate.
5.There are three main categories of drugs used to reduce portal vein pressure.
(1) Vasoconstrictor drugs: they can directly or indirectly cause visceral vasoconstriction and reduce portal venous blood flow to lower portal venous pressure and collateral blood flow. Commonly used drugs include: vasopressin and its derivatives, growth hormone inhibitory factor and its analogues, β-adrenergic blocking drugs, etc.
①Vasopressin (vasopressin) and its inhibitors: have a strong visceral vasoconstrictor effect, which reduces portal venous blood flow, lowers portal venous pressure and facilitates control of upper gastrointestinal hemorrhage; at the same time, due to its systemic vasoconstriction, it can cause a series of cardiac and cerebral complications, so it should be used with caution or prohibited in patients of advanced age or with coronary artery disease. Usage and dosage.
a. Pituitarium posterius: a water-soluble component extracted from the pituitary gland of the brain of animals, containing oxytocin and pressin. Most of the intravenous drip, the starting dose is generally 0.2 ~ 0.4U/min, 12 ~ 24h after the maintenance dose of 0.1U/min, 8 ~ 12h after the discontinuation of the drug. If the above treatment is not effective, the dose can be increased to 1.0U/min under close supervision, which is expected to be effective.
b. Terlipressin acetate (terlipressinacetate): It is a synthetic derivative of VP, which can release VP slowly in the body, and its half-life is longer and has less effect on blood supply to the heart. The first dose is 2mg, after that, every 4-6 hours, 1mg is injected, and the total amount can be 10mg. other commonly used drugs include octreotide pressin, bipressin, etc.
②Growth inhibitors and their analogues.
a, growth inhibitor (Somatofalk, also known as Stilamin, Stilamin): a 14-peptide hormone mainly produced by the gastrointestinal tract and pancreatic D cells, metabolized by the liver. It can selectively constrict visceral blood vessels, inhibit the release of hyperglycemic hormone, vasoactive intestinal peptide and gastrin, reduce portal blood flow, alleviate portal vascular resistance and lower portal venous pressure. It is mainly used clinically to control esophagogastric fundic varices and ruptured bleeding. The disadvantage is that it is easy to recur after stopping the drug. Dosage and Administration: After the first dose of 250μg intravenously, then 250µg per hour continuous drip. It is still effective for recurrent bleeding.
b. OCTreotide (OCTreotide, also known as Sandostatin): It is a synthetic long-acting growth inhibitor 8 peptide, its half-life and its action time is longer than that of growth inhibitor. The first dose of 100µg intravenously followed by 20-50µg/h titration for 24-48h, or 100µg every hour subcutaneously or intramuscularly for maintenance. Most scholars believe that octreotide has the potential to replace growth inhibitors as the first-line drug in the clinical treatment of acute ruptured esophagogastric fundic variceal bleeding because of its easy method, precise efficacy and safe use. However, Escorsell A et al. concluded that octreotide significantly and transiently reduced portal venous pressure and odd vein blood flow, but continuous infusion of octreotide did not maintain or prolong its above effects. The possible mechanism is due to the fact that octreotide has bound to all growth inhibitory receptors in the body after the first dose, preventing the binding of octreotide to growth inhibitory receptors and its resulting biological effects after re-dosing.
③ β-adrenergic receptor blocking drugs: including non-selective β-blockers (propranolol, long-acting propranolol, nadolol, carvedilol, etc.), β1-blockers (amiloride, metoprolol, etc.), β2-blockers (ICI-118551), etc.
a. Non-selective β-blockers: propranolol (propranolol, also known as insulin) is the most widely studied and has the most definite efficacy. Propranolol (insulin) can be blocked through the heart β1-receptors, which can slow down the heart rate, reduce cardiac output, reduce visceral arterial perfusion, and reduce portal venous blood flow; block visceral vascular smooth muscle β2-receptors, 1-receptor excitation, visceral vasoconstriction, reduce portal vein and its side branches of the odd vein blood flow, and reduce portal venous pressure. In addition, it also inhibits serum renin-angiotensin activity, also by blocking β2- receptors. Reducing serum hyperglycemia levels and inhibiting hepatic collagen deposition both reduce the adverse effects on portal vein hemodynamics.
Most of the current studies have shown that administration of adequate doses of propranolol (Tipsan) reduces the portal pressure gradient, decreases portal pressure by 15% to 35%, reduces portal blood flow by about 30%, decreases odd vein blood flow by 31% to 35%, and increases visceral arterial resistance by 39%, but does not affect arterial pressure or cerebrorenal blood flow. It affirms the effect of its treatment and prevention of ruptured esophagogastric fundic variceal bleeding. The toxic side effects of this drug are small, such as drowsiness, impotence, dyspnea, dizziness, nausea, headache, etc. Occasionally it can induce hepatic encephalopathy. Allergy to this drug, bronchial asthma, severe bradycardia, II-III degree atrioventricular block, severe heart failure, acute myocardial infarction, shock and other patients are prohibited; severe hepatic and renal insufficiency, especially those with hepatic encephalopathy, bleeding tendency, pregnant women should be used with caution.
Usage and dosage: Generally start with small doses until the heart rate slows down to 25% and then switch to maintenance doses. The dose is 20~30mg, 2~3 times/d orally, or 40mg, 2 times/d; later gradually increase the dose to 80~100mg, 2 times/d maintenance. The drug is completely absorbed orally and metabolized by the liver. However, individual differences should be noted. Other non-selective beta-blockers: nadolol and long-acting propranolol. The doses are 40-160mg/d and 40-320mg/d respectively, with the same mechanism of action and precautions for use as propranolol (Takeaway). Carvedilol is a new non-selective beta-blocker, and its effect of reducing portal pressure is better than propranolol.
b. β1-blocker: represented by atenolol (aminocardium), atenolol, atenolol (Tenormin), selectively blocking cardiac β1-receptors, slowing the heart rate, reducing cardiac output and decreasing the perfusion of the portal venous system, thus reducing portal venous pressure. The drug is rapidly but incompletely absorbed orally (about 50% absorption). It has a low first pass effect, 40% bioavailability, peak effect time of 2-4h, and half-life of 6-7h. It is mainly excreted in its original form by the kidneys. The interval between doses should be extended in cases of renal insufficiency.
Dosage: It is also advisable to start with small doses and gradually increase the dosage until the heart rate slows down to 25% and then switch to maintenance dosage. The dose should be 25-50mg, 1-2 times/d orally, then gradually increase the dose to 100mg, 1-2 times/d for maintenance, and the maintenance amount should be decided by observing the change of heart rate, and individual differences should be noted. Toxic side effects include bradycardia, upright hypotension, dizziness and gastrointestinal discomfort.
Metoprolol (Medocin) can selectively block cardiac β1-receptors, which can reduce cardiac blood output and slow down heart rate. 2mg of sedation can cause a decrease in portal pressure, characterized by oral absorption without hepatic metabolism and excretion from the kidney in its original form.
c. β2-blocker: ICI-118551, specifically blocks β2-receptors in visceral vascular smooth muscle cells, causing visceral vasoconstriction, -receptor excitability is relatively enhanced, visceral vascular resistance increases, portal blood flow decreases, especially hepatic artery constriction, hepatic artery resistance increases, blood flow decreases, intrahepatic sinusoidal pressure decreases, and reduces portal venous pressure. Since this drug does not block β1-receptors, cardiac blood output is not affected. Clinical research data are scarce and further studies are needed.
(2) Vasodilator drugs: The drugs that can reduce portal pressure are: -receptor blockers, 2-receptor excitatory drugs, organic nitrates, calcium channel blockers, angiotensin II receptor blockers, angiotensin converting enzyme inhibitors and sodium nitroprusside. They are described as follows.
① – receptor blocking drugs.
a. Prazosin, also known as Minipress, selectively blocks 1-adrenergic receptors, relaxes vascular smooth muscle, acts directly on 1-receptors in the portal vascular bed, dilates portal vessels, reduces portal venous outflow tract and its side branch resistance in the liver, and reduces portal pressure, or reduces arterial pressure by dilating peripheral vascular resistance, reflexively causing visceral vasoconstriction, decreasing visceral arterial blood flow and thus reducing portal vein pressure. It also blocks norepinephrine to constrict the hepatic vein and post-sinusoidal sphincter, reducing hepatic blood outflow tract resistance and causing a decrease in hepatic venous occlusion pressure. The mechanism has not been fully elucidated.
The drug is well absorbed orally, with a bioavailability of 50%-85%. Peak effect time is 2-4h, half-life is 2-3h, mainly metabolized by the liver (more than 90%). Oral administration for 3 to 8 weeks can reduce portal pressure by 17% to 30%. Dosage and administration: dosage should be started from small dose to avoid first dose reaction. Toxic side effects include dizziness, headache, panic, nausea, diarrhea or constipation, etc. Long-term application may lead to water and sodium retention. Upright hypotension may occur after the first dose, so the blood pressure should be closely monitored and the patient should be advised to rest in bed. Pregnant women, children and those who are allergic to this product are prohibited.
b, phenoxybenzamine (Phenoxybenzamine): also known as oxybenzamine, phenoxyzamine, etc.. Due to the cyclization of the chlorhexidine group in the molecule of the drug into the ethylchloroimine group, the latter is firmly bound to the 1-receptor, which prevents and reverses the effects of catecholamines, dilates the peripheral blood vessels, reflexively constricts the visceral vessels and reduces the portal pressure gradient. Oral absorption is incomplete. Peak time of action after intravenous injection is 1h, half-life is 24h, metabolized by the liver. Dosage and Administration: Oral: 10mg per dose, 1~2 times/d, incremental dose to maintenance dose as appropriate. Intravenous drip: 0.5~1mg/kg, add to 250~500ml of glucose solution in slow drip. Toxic side effects include panic, headache, dry mouth, pupil narrowing and upright hypotension. Use with caution in patients with insufficient blood supply to the heart and brain or hypotension.
c. Phentolamine: non-selective – receptor blocking drug, can reduce hepatic sinusoidal pressure by dilating intrahepatic portal vein, hepatic vein terminal branches and hepatic blood sinusoid, while arterial pressure can also be reduced. Dosage: 5~10mg in 25% glucose 20~40ml by slow sedation, then 10~20mg in 10% glucose solution 250ml by sedation, 1 time/d, 2~3 weeks as a course of treatment.
②2-receptor excitatory drugs: Clonidine: also known as colistin, clonidine. It is a central α2-receptor excitatory drug, acting on the postsynaptic membrane 2-receptors in the delayed brain, causing a decrease in central sympathetic impulse efference and inhibition of peripheral sympathetic activity, reducing plasma norepinephrine concentration, decreasing peripheral vascular resistance, decreasing intrahepatic venous vascular resistance, and decreasing hepatic venous pressure gradient. It also causes a decrease in cardiac output and blood pressure, but has no significant effect on systemic hemodynamics and can be used for a long time. It is rapidly and completely absorbed orally, without first-pass effect, and takes effect 30-60 min after oral administration, with a peak effect time of 4h and a continuous effect of 8h, mainly metabolized by liver and kidney. Usage and dosage: Start with 0.075~0.15mg once orally, 3 times/d. If necessary, increase slowly to a maximum dose of 0.3~0.45mg or 150µg of colistin per day, injected intravenously. Common toxic side effects include dry mouth, weakness, constipation, bradycardia, nausea, vomiting, and upright hypotension. Use with caution if you have cardiovascular disease, hepatic or renal insufficiency.
(3) Organic nitrates.
Nitroglycerin (NTG): acts on the specific nitrate receptors of smooth muscle cells in the vascular wall, has a powerful effect of dilating veins and mildly dilating arteries, causing arterial pressure to fall, stimulating pressure receptors, reflexively causing sympathetic excitation, visceral vasoconstriction, reducing portal blood flow and lowering portal pressure. At the same time, it can directly dilate the portal vein and collateral vessels, and the portal vein resistance decreases. Because NTG is easy to cause blood pressure drop and tissue hypoxia at high dose, coupled with the short duration of action, it is mostly used clinically in combination with vasopressin (VP), which can improve the effect of both in lowering portal pressure (synergistic effect) and reduce the incidence of adverse reactions of both.
The drug has hepatic first-pass effect and low bioavailability after oral administration, so it should not be taken orally. Sublingual administration is rapidly absorbed by oral mucosa and can avoid hepatic first-pass effect, with a bioavailability of 80%. It can be administered sublingually for 1 to 3 min, with a peak effect time of 5 min and a duration of 30 to 60 min. It can also be administered dermally or intravenously. The drug is metabolized by the liver and excreted through the kidney. Dosage and Administration: Sublingual: 0.4~0.6mg/dose every 30~60min; Dermal: 2.6mg/tablet, 1 tablet each time, 2 times/d; Intravenous: Generally, after the VP drip, start from small dose increments. Dilute in glucose solution slowly by IV drip. The initial dose of 10 to 40µg/min, 70%, and the patient’s postoperative quality of life also improved significantly.
China also began the study of liver transplantation from the late 1950s, and is now also increasingly widely valued by the surgical community of hepatology. However, there is a large gap between liver transplantation in China and advanced countries due to many factors such as the lack of domestic donor liver, expensive price, choice of surgical method and timing, uw preservation fluid, immune rejection, and hepatitis virus infection of the donor liver after transplantation.
In summary, we agree with Wang Jiyao on the choice of treatment for portal hypertension in cirrhosis: that is, in acute bleeding from the esophagogastric fundic vein, drugs should be used as the first choice of therapy to control bleeding, and posterior pituitary hormone combined with nitroglycerin or growth inhibitors can be used. If the effect of drug hemostasis is not good, we can perform three lumen two capsule tube compression to stop the bleeding, and emergency endoscopy can be performed 24h after the acute bleeding stops and the patient’s condition is stable, which can clarify the nature, source, site and degree of varices, and endoscopic treatment is also feasible, and those who fail in endoscopic treatment can then choose interventional or surgical emergency decompression treatment according to their condition.
For the prevention of rebleeding treatment is still based on endoscopic treatment and drug treatment, and finally interventional and surgical treatment is considered. For end-stage cirrhotic portal hypertension, liver transplantation is feasible if available.