Recently, many patients have been troubled by unexplained bilirubin elevation (jaundice), especially for those with no history of chronic liver disease and no obvious symptoms, and “jaundice” has become a “heart attack” that affects work and life. So what exactly can cause bilirubin to rise? Is jaundice a sign of liver disease? Do all cases of bilirubin elevation require treatment? The following is a brief description of the common clinical causes of bilirubin elevation. Jaundice is a symptom and sign of yellowing of the skin, mucous membranes and sclera due to elevated bilirubin in the serum (the source, uptake, binding, conversion and transport, excretion and reabsorption of bilirubin are omitted). The maximum normal bilirubin is 17.1 μmol/l, of which 3.42 μmol/l is conjugated bilirubin (direct bilirubin, CB) and 13.68 μmol/l is unconjugated bilirubin (indirect bilirubin, UCB), which is not easily detectable clinically and is called occult jaundice, while more than 34.2 μmol/l can be recognized by the naked eye and is called dominant jaundice. Clinically, it can be divided into four categories according to the etiology: 1, hemolytic jaundice Any disease that can cause massive destruction of red blood cells and produce hemolysis can cause hemolytic jaundice. There are two major categories of common diseases as follows. (1) congenital hemolytic anemia: such as thalassemia (hemoglobinopathy), hereditary spherocytosis. (2) Acquired acquired hemolytic anemia: such as autoimmune hemolytic anemia, hereditary glucose-6-phosphate dehydrogenase deficiency (serpentine disease), hemolysis after allogeneic blood transfusion, neonatal hemolysis, falciparum malaria, drugs such as primaquine, snake venom, mushroom poisoning, and paroxysmal sleep hemoglobinuria. Hemolytic jaundice is characterized by elevated indirect bilirubin, and jaundice is usually mild, without skin pruritus, but with manifestations of the primary disease. For example, in acute hemolysis, there may be fever, chills, lumbago, headache, vomiting, and varying degrees of anemia and hemoglobinuria (soy sauce-colored urine), and even renal failure in severe cases; in chronic hemolysis, there may be anemia and splenomegaly. Treatment is mainly based on the primary cause. 2, hepatocellular jaundice Various liver diseases, such as viral hepatitis, toxic hepatitis, drug-related liver disease, hereditary metabolic liver disease, autoimmune hepatitis, various types of cirrhosis, primary and secondary liver cancer, sepsis and leptospirosis, can cause jaundice due to diffuse damage to liver cells. This type of jaundice is characterized by an increase in both direct and indirect bilirubin, as well as other manifestations of liver damage such as an increase in various liver enzymes, a decrease in albumin (inversion of the white/bulb ratio), and impaired coagulation mechanisms. The level of bilirubin directly reflects the degree of liver inflammation and necrosis, and progressive bilirubin elevation may be a manifestation of liver failure, and this type of jaundice is treated mainly for etiology and liver preservation. 3, obstructive jaundice (bile depression jaundice) according to the site of obstruction can be divided into two types of extrahepatic bile duct and intrahepatic bile duct obstruction. (1) Common diseases causing extrahepatic bile duct obstruction include common bile duct stones, stenosis, inflammatory edema, roundworms, tumors and congenital biliary atresia, etc.; common diseases or causes of bile duct obstruction due to extra-biliary compression include cancer of the head of the pancreas, chronic pancreatitis with enlarged head of the pancreas, lack of special potbelly cancer, cancer of the common bile duct, hepatocellular carcinoma and enlarged lymph nodes around the hilar region or common bile duct (cancer metastasis), etc. (2) Intrahepatic bile duct obstruction can be further divided into intrahepatic obstructive biliary depression and intrahepatic biliary depression. The former is common in intrahepatic bile duct sediment-like stones, cancerous emboli (mostly hepatocellular carcinoma), and schistosomiasis; the latter is common in capillary bile duct viral hepatitis, drug biliary depression (such as chlorpromazine, methyltestosterone, oral contraceptives, etc.), bacterial sepsis, recurrent jaundice during pregnancy, primary biliary cirrhosis, and a few after heart or abdominal surgery. Obstructive jaundice (bile depression jaundice) is characterized by a predominantly elevated direct bilirubin accompanied by pruritus, significantly elevated alkaline phosphatase and glutamyl transpeptidase in liver function indicators, and lighter stool color or white clay color in severe obstruction. Indirect bilirubin may also be significantly elevated in later stages as the liver function becomes more impaired. The treatment of this type of jaundice is based on relieving obstruction, biliary, anti-inflammatory and liver protection. 4, congenital non-hemolytic jaundice refers to a congenital defect in the metabolism of bilirubin, the onset of which is usually seen in infants, young children and young adults, often with a family history. It is often induced after a cold or exercise, infection, or fatigue, but the patient is generally in good health. This type of jaundice is clinically rare and is sometimes easily misdiagnosed as hepatobiliary disease. The common diseases that belong to this type of jaundice are the following. (1) Gilbert syndrome: The mechanism of jaundice is due to impaired uptake of unconjugated bilirubin by hepatocytes (mild, the most common form of familial jaundice in clinical practice) and insufficient glucuronosyltransferase in hepatocyte microsomes. The disease is characterized by normal liver function tests other than jaundice and increased concentrations of unconjugated bilirubin in the serum, which generally does not require treatment, and is one of the most common clinical causes of elevated simple indirect bilirubin. (2) Dubin-Johnson syndrome: The cause of jaundice is the dysfunction of the transport and secretion of unconjugated bilirubin to the capillary bile ducts after the conversion of unconjugated bilirubin into conjugated bilirubin in the hepatocytes. The disease is characterized by an increase in serum conjugated bilirubin and has a good prognosis. (3) Rotor syndrome: Jaundice occurs due to partial impairment of hepatocyte uptake of unconjugated bilirubin and conjugated bilirubin secretion to the capillary bile ducts. The disease is characterized by increased serum unconjugated and conjugated bilirubin, and normal liver biopsies. The prognosis is generally good. (4) Crigler-Najjar syndrome: jaundice occurs due to the lack of glucuronosyltransferase in the hepatocyte particles, which prevents the conversion of unconjugated bilirubin into conjugated bilirubin. The former is prone to bilirubin encephalopathy (nuclear jaundice) because of the high concentration of unconjugated bilirubin in the blood and the strong affinity for adipose tissue in the brain tissue, mostly in neonates, with a very poor prognosis and death within 1 year after birth; the latter is due to a partial lack of glucuronosyltransferase in the hepatocyte particles, so the symptoms are milder and the prognosis is slightly better than that of the heavy. From the above introduction, we can see that the causes of jaundice are sometimes very complex and can have multiple factors overlapping at the same time, while sometimes the causes are very simple and can be easily identified with careful observation. We can also learn that jaundice is not always caused by liver disease, and that elevated bilirubin does not always require treatment. If you find jaundice in your daily life or during a physical examination, you should be vigilant and seek medical attention in a timely manner; you should also analyze it calmly and not panic and do nothing.