Normal bilirubin metabolism process
1. The average life span of normal red blood cells derived from bilirubin is 120 days. Hemoglobin released by aging red blood cells is the main source of bilirubin, accounting for 80% ~ 85%. About 10% ~ 15% of bilirubin comes from hemoglobin of immature red blood cells in bone marrow, and the other 1% ~ 5% comes from free heme and liver containing heme. Heme is converted into biliverdin by microsomal heme oxygenase, and biliverdin is reduced to bilirubin by biliverdin reductase.
Second, the transfer of bilirubin The above bilirubin is free bilirubin, which is called free bilirubin because it has not been absorbed by liver cells and has not been combined with glucuronic acid. Free bilirubin adheres to albumin in blood circulation, forming bilirubin-albumin complex, which is taken to the liver.
Third, bilirubin is ingested in the hepatic sinuses, and bilirubin is ingested by the microtubules of liver cells, and albumin is separated from bilirubin. After bilirubin enters hepatocytes, it is carried by cytoplasmic carrier proteins Y and Z and transported to microsomes in smooth endoplasmic reticulum.
Fourthly, bound bilirubin free bilirubin is catalyzed by glucuronosyltransferase in microsomes and combines with glucuronosyl to form bound bilirubin. Mainly bilirubin glucuronic acid, accounting for about 75% of the total bound bilirubin, and the rest bound glucose, xylose, disaccharide and glycine.
5. The mechanism of bilirubin excretion combined with bilirubin excretion from hepatocytes is not clear. It may be transported to the capillary bile duct, bile duct, bile duct and discharged into the intestine through Golgi apparatus, but it is undoubtedly an active transport, speed-limiting and energy-consuming process, in which bile salts and sodium ions participate. After bound bilirubin enters the intestinal cavity, it is dehydrogenated by intestinal bacteria and reduced to urine urobilinogen. Most of it (about 68 ~ 473 μ mol per day) is excreted with feces, which is called fecal bile. A small part (65,438+00% ~ 20%) is reabsorbed through the lower ileum or colon, returned to the liver through portal vein blood, converted into bilirubin, or discharged into the intestine with bile without conversion. This process is called "enterohepatic circulation" of bilirubin, and a small part (less than 6.8μmol per day) of urine urobilinogen reabsorbed from the intestine enters the systemic circulation and is excreted by the kidney.
Classification of hyperbilirubinemia (jaundice)
1. Etiological classification (1) Hemolytic jaundice; (2) Hepatocellular jaundice; (3) cholestatic jaundice; (4) Congenital non-hemolytic jaundice.
Second, according to the nature of bilirubin classification
(1) Jaundice with increased unconjugated bilirubin 1. Excessive bilirubin production 2. Bilirubin uptake disorder 3. Bilirubin binding disorder.
(2) Jaundice, mainly the increase of bound bilirubin, can be caused by the transport and excretion of bilirubin by hepatocytes or the simultaneous intake, binding and excretion of bilirubin.
No matter which classification method, the occurrence of jaundice comes from one or more metabolic disorders of bilirubin in the final analysis.
Pathogenesis and clinical characteristics of various jaundice
First, hemolytic jaundice
When a large number of red blood cells are destroyed (hemolyzed), excessive unconjugated bilirubin is produced, which exceeds the absorption, binding and excretion ability of liver cells, resulting in unconjugated bilirubin remaining in the blood and jaundice.
Features: (1) mild scleral jaundice, acute attack (hemolytic crisis) fever, backache and obvious pale skin and mucosa; (2) The skin has no itching sensation; (3) splenomegaly; (3) There are exuberant manifestations of bone marrow hyperplasia, such as the increase of reticulocytes in peripheral blood, the appearance of nucleated red cells and the active proliferation of bone marrow red cell system; (5) The serum total bilirubin is increased, generally not exceeding 85μmol/L, mainly unconjugated bilirubin; (6) When bilirubin is absent, urinary biological protein increases, hemoglobinuria occurs in acute attack, and hemosiderin increases in urine in chronic hemolysis;
Second, hepatocellular jaundice.
Due to the pathological changes of liver cells, the functions of bilirubin intake, binding and excretion are disturbed, so that a considerable amount of unbound bilirubin remains in the blood. At the same time, due to the damage of liver cells and/or hepatic lobule structure, conjugated bilirubin can not be discharged from small bile duct normally, but flows back to liver lymph and blood, resulting in jaundice.
Features: (1) The skin and sclera are light yellow to deep golden yellow, and the skin sometimes itches; (2) Both unconjugated bilirubin and conjugated bilirubin in blood increased; (3) Urine bilirubin is positive, and urine urobilinogen is often increased, but at the peak of the disease, due to intrahepatic cholestasis, urine urobilinogen is reduced or missing; (4) Serum transaminase increased significantly; (5) Hepatitis virus markers in blood are often positive; (6) Liver biopsy is of great significance in the diagnosis of diffuse liver disease.
Third, cholestatic jaundice
Intrahepatic cholestasis refers to the decrease of bile production and secretion, as well as the stagnation and concentration of bile flow in molecular cytology. Intrahepatic cholestasis occurs alone or coexists with liver parenchyma damage, and its mechanism is quite complicated, involving many factors: (1) Changes in the structure and function of hepatocyte plasma membrane: The hepatocyte plasma membrane is composed of liquid bilayer lipids embedded with protein (carrier, receptor, structural protein and enzyme), and the contents of phospholipids and cholesterol in the plasma membrane are in a certain proportion to maintain normal membrane micro-viscosity and membrane fluidity. The production and secretion of bile, and the transport of bile solutes into and out of hepatocytes depend on the complete membrane structure and function of hepatocytes. When chlorpromazine, estradiol, lithocholic acid, endotoxin and hypoxia cause liver cell injury, it can increase the plasma membrane cholesterol content, decrease membrane fluidity and sodium pump activity, and decrease bile secretion and bile flow. (2) Microfilament and microtubule dysfunction: bile flow and forward fluidity are reduced due to the transport of cholic acid, the movement of sodium water to the capillary bile duct cavity and the weakening of coordinated peristalsis and contraction around the capillary bile duct; (3) The permeability of capillary bile duct membrane and tight junction increases, and solute molecules in bile diffuse around or reflux, resulting in the decrease of water content in bile; (4) Abnormal bile acid metabolism: insufficient hydroxylation, formation of toxic monohydroxy carboxylic acid or lithocholic acid, necrosis of liver cells and small bile duct epithelium.
Features: (1) dark yellow, yellow-green or green-brown; (2) Skin itching is obvious, which often occurs before jaundice appears; (3) The increase of bilirubin in the blood is mainly bound with bilirubin, and the qualitative test of bilirubin shows a direct reaction; (4) Urinary bilirubin is positive, but urinary urobilinogen is reduced or absent; (5) The urine urobilinogen in feces is reduced or lacking, and the feces are light gray or clay color; (6) Serum total cholesterol, alkaline phosphatase, γ -glutamyltranspeptidase increased, and lipoprotein -X was positive.
Fourth, congenital non-hemolytic jaundice
(1) Gilbert syndrome is caused by the obstacle of free bilirubin uptake by hepatocytes and the lack of glucuronosyltransferase in microparticles. Serum unconjugated bilirubin increased, liver function test was normal, erythrocyte fragility was normal, gallbladder developed well and liver biopsy was normal.
(2) Dobbin-Johnson syndrome is due to the dysfunction of liver cells secreting bound bilirubin and other organic anions (indocyanine green, X-ray contrast agent) to the capillary bile duct, which leads to the increase of serum bound bilirubin, but the intake and binding of bilirubin are normal. Oral gallbladder contrast agent often can't develop gallbladder. The appearance of liver is green and black (black liver), and liver biopsy shows that there are scattered brown pigment particles (melanin or adrenaline metabolite polymer) in liver cells.
(3) Rotor syndrome is due to the congenital defects of free bilirubin uptake and bound bilirubin excretion by hepatocytes, which mainly leads to the increase of bound bilirubin in blood and the decrease of indocyanine green (ICG) excretion test. Cholecystography showed that most cases were well developed and a few cases were not developed. Liver biopsy was normal, and there were no pigment particles in liver cells.
(4) Kriging-Naggar syndrome is due to the lack of glucuronosyltransferase in liver cells, which can not form conjugated bilirubin, so the concentration of unconjugated bilirubin in blood is high, which may be complicated with nuclear jaundice; The prognosis is very poor.
Differential diagnosis of hyperbilirubinemia (jaundice)
According to the medical history, signs, laboratory results, comprehensive analysis and judgment, in order to get the correct diagnosis.
First, medical history
(1) Age and sex Physiological jaundice and neonatal hepatitis are more common in infancy, and viral hepatitis is more common in adolescents. Middle-aged and elderly people should always consider gallstones, liver cirrhosis and malignant tumors.
(2) The contact history includes the contact history of hepatitis patients, blood transfusion history, medication history and unclean food consumption history.
(3) Family history is mainly the family history of hepatitis and various hereditary diseases.
(4) Past medical history, such as the history of stones and the history of hepatobiliary system surgery.
(5) Pregnancy history Pregnancy is often complicated with abnormal liver function, and pregnancy-related jaundice may occur, such as acute fatty liver during pregnancy.
(6) Drinking and traveling history are helpful for the diagnosis of alcoholic liver disease and viral hepatitis.
(7) The course of disease, such as cholelithiasis and jaundice, occurs slowly and progressively due to liver cirrhosis and malignant tumor.
Second, symptoms
(1) Febrile cholangitis often presents moderate to high fever, and patients with liver cancer often have fever due to necrosis of cancer tissue or secondary infection.
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(2) Abdominal pain and liver swelling are more common in patients with viral hepatitis and liver cancer. Right epigastric colic is common in cholelithiasis, and pancreatic diseases often occur in upper abdomen and low back pain.
(3) Patients with dyspeptic viral hepatitis, liver cirrhosis and cancer are often accompanied by dyspeptic symptoms.
(4) cholestatic jaundice can be seen with itchy skin.
(5) Weight changes Patients with malignant tumors often lose weight significantly.
(6) Changes of urine and feces color
Third, signs.
(1) Skin changes such as liver palm, spider nevus and abdominal varicose veins are common in patients with liver cirrhosis, and anemia is common in patients with hemolytic jaundice.
(2) Spleen enlargement is more common in patients with cirrhosis and portal hypertension.
(3) Gallbladder enlargement In the case of extrahepatic obstructive cholestasis, the gallbladder is often swollen with smooth surface and no tenderness, which is called Courvoisier sign.
(4) Others such as ascites and male breast development.
Four. Laboratory and other inspections
(1) alkaline phosphatase (ALP): ALP increased significantly in extrahepatic and intrahepatic obstructive jaundice and intrahepatic cholestasis.
(2) Determination of serum total cholesterol, cholesterol ester and lipoprotein -X(LP-X) In cholestatic jaundice, the total cholesterol content increases; Hepatocellular jaundice, especially when extensive necrosis occurs, reduces cholesterol ester.
(3) Prothrombin time: In hepatocellular jaundice and cholestatic jaundice, the production of prothrombin is reduced, so the prothrombin time is prolonged. If the 24-hour prothrombin time is obviously shortened after injection of vitamin K2 ~ 4 mg, the liver function is normal, and jaundice may be cholestasis. If there is no change, it means that the function of liver to produce prothrombin is impaired, and jaundice may be hepatocyte-like.
(4) Ultrasonic imaging: If intrahepatic bile duct dilatation is found, it must be jaundice caused by extrahepatic bile duct obstruction.
(5) X-ray examination
1. If esophageal or gastric varices are found in barium swallowing and gastrointestinal barium meal examination, liver cirrhosis can be diagnosed.
2. ERCP is very helpful for the diagnosis of chronic pancreatitis and pancreatic cancer and for understanding the biliary system.
3.CT is of great diagnostic value in the diagnosis of hepatobiliary and pancreatic diseases and the location, scope and nature of extrahepatic obstruction.
(6) Liver biopsy and laparoscopy are helpful to diagnose hepatocellular jaundice, intrahepatic cholestasis and Dobbin-Johnson syndrome.
To sum up, jaundice is an important symptom and sign of many diseases. The cause of jaundice stems from the abnormality of bilirubin metabolism. Through the analysis of bilirubin, urine urobilinogen and fecal cholin, the nature of jaundice can be preliminarily classified, but the accurate determination of the cause still depends on the comprehensive analysis of clinical history, signs, various laboratories and auxiliary examinations.