Jaundice

Jaundice is a yellow discoloration of the skin and mucous membranes associated with the accumulation of bilirubin in them due to hyperbilirubinemia. The occurrence of jaundice is always associated with a disturbance in bilirubin metabolism.

Since the liver plays a primary role in bilirubin metabolism, jaundice is traditionally classified as a typical major liver syndrome, although in some cases it can occur without liver disease (for example, with massive hemolysis). The jaundice syndrome is caused by an increase in the bilirubin content in the blood (hyperbilirubinemia) over 34.2 μmol/l (2 mg/dl), when it accumulates in the skin, mucous membranes and sclera. Yellowing of the skin, the main external manifestation of hyperbilirubinemia, can also be caused by other factors - carotene (intake of appropriate food, such as carrots, tomatoes), quinacrine, picric acid salts, but in these cases there is no staining of the sclera.

From a clinical point of view, it is important to keep in mind that the coloration of different areas depends on the degree of hyperbilirubinemia: the first to appear is yellowing of the sclera, the mucous membrane of the lower surface of the tongue and palate, then the face, palms, soles, and the entire skin turn yellow. Sometimes there may be a discrepancy between the bilirubin level and the degree of jaundice: for example, jaundice is less noticeable in the simultaneous presence of hypooncotic edema, anemia, obesity; on the contrary, thin and muscular faces are more yellowish. It is interesting that with congestive liver, if hyperbilirubinemia occurs, the upper half of the body predominantly turns yellow.

With more prolonged hyperbilirubinemia, the icteric staining becomes greenish (oxidation of bilirubin in the skin and formation of biliverdin) and even bronze-black (melanojaundice).

Hyperbilirubinemia is a consequence of disturbances in one or more links of bilirubin metabolism. The following fractions of bilirubin are distinguished: free (indirect), or unbound (unconjugated), and bound (direct), or conjugated, which is divided into the little-studied bilirubin I (monoglucuronide) and bilirubin II (diglucuronide-bilirubin). Usually, the indicators of unconjugated bilirubin and conjugated bilirubin II (diglucuronide) are used to characterize bilirubin metabolism.

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Causes of Jaundice

Jaundice may be a consequence of increased bilirubin production or diseases of the hepatobiliary system (hepatobiliary jaundice). Hepatobiliary jaundice may be a result of hepatobiliary dysfunction or cholestasis. Cholestasis is divided into intrahepatic and extrahepatic.

Increased bilirubin formation and hepatocellular diseases result in impaired or decreased conjugation of bilirubin in the liver and cause hyperbilirubinemia due to unconjugated bilirubin. Impaired bile excretion results in hyperbilirubinemia due to conjugated bilirubin. Although these mechanisms appear to be different, in clinical practice jaundice, especially that caused by hepatobiliary diseases, almost always results from hyperbilirubinemia due to unconjugated and conjugated bilirubin (mixed hyperbilirubinemia).

In some disorders, a predominance of one or another fraction of bilirubin is observed. Unconjugated hyperbilirubinemia due to increased bilirubin formation may be a consequence of hemolytic disorders; decreased conjugation of bilirubin is observed in Gilbert's syndrome (mild bilirubinemia) and Crigler-Najjar syndrome (severe bilirubinemia).

Hyperbilirubinemia due to conjugated bilirubin due to impaired excretion may be seen in Dubin–Johnson syndrome. Conjugated hyperbilirubinemia due to intrahepatic cholestasis may result from hepatitis, drug toxicity, and alcoholic liver disease. Less common causes include cirrhosis, namely primary biliary cirrhosis, cholestasis of pregnancy, and metastatic cancer. Conjugated hyperbilirubinemia due to extrahepatic cholestasis may result from choledocholithiasis or pancreatic cancer. Rarer causes include common bile duct strictures (usually related to previous surgery), ductal carcinoma, pancreatitis, pancreatic pseudocyst, and sclerosing cholangitis.

Liver diseases and biliary obstruction usually cause various disturbances, accompanied by an increase in conjugated and unconjugated bilirubin.

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Brief overview of bilirubin metabolism

The destruction of heme leads to the formation of bilirubin (an insoluble metabolic product) and other bile pigments. Before bilirubin can be excreted in bile, it must be transformed into a water-soluble form. This transformation occurs in five stages: formation, transport in blood plasma, uptake by the liver, conjugation, and excretion in bile.

Formation. Approximately 250-350 mg of unconjugated (unbound) bilirubin is formed daily; 70-80% is formed during the destruction of red blood cells and 20-30% in the bone marrow and liver from other heme proteins. Hemoglobin is broken down into iron and biliverdin, which is converted to bilirubin.

Transport. Unconjugated (indirect) bilirubin is not soluble in water and is transported bound to albumin. It cannot pass through the glomerular membrane of the kidney and enter the urine. Under certain conditions (e.g. acidosis), the bond with albumin weakens, and some substances (e.g. salicylates, some antibiotics) compete for bond sites.

Liver uptake: The liver quickly takes up bilirubin.

Conjugation. In the liver, unconjugated bilirubin is conjugated, forming mainly bilirubin diglucuronide or conjugated (direct) bilirubin. This reaction, catalyzed by the microsomal enzyme glucuronyl transferase, results in the formation of water-soluble bilirubin.

Excretion of bile. Small canals located between the hepatocytes gradually merge into ducts, interlobular biliary tracts and large hepatic ducts. Outside the portal vein, the hepatic duct itself merges with the gallbladder duct to form the common bile duct, which flows into the duodenum through the ampulla of Vater.

Conjugated bilirubin is excreted into the biliary tract along with other components of bile. In the intestine, bacteria metabolize bilirubin into urobilinogen, most of which is then converted into stercobilin, which gives the stool its brown color. In complete biliary obstruction, the stool loses its normal color and becomes light gray (clay-like stool). Urobilinogen itself is reabsorbed, captured by hepatocytes and re-entered into bile (enterohepatic circulation). A small amount of bilirubin is excreted in the urine.

Because conjugated bilirubin is excreted in the urine but unconjugated bilirubin is not, bilirubinuria is caused only by the conjugated fraction of bilirubin (eg, hepatocellular or cholestatic jaundice).

Diagnosis of jaundice

In the presence of jaundice, the examination should begin with the diagnosis of hepatobiliary diseases. Hepatobiliary jaundice may be a consequence of cholestasis or hepatocellular dysfunction. Cholestasis may be intrahepatic or extrahepatic. The diagnosis is decisive for establishing the cause of jaundice (for example, hemolysis or Gilbert's syndrome, if there is no other hepatobiliary pathology; viruses, toxins, liver manifestations of systemic diseases or primary liver damage with hepatocellular dysfunction; gallstones in extrahepatic cholestasis). Although laboratory and instrumental studies are of great importance in diagnostics, most errors are the result of underestimation of clinical data and incorrect assessment of the results obtained.

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Anamnesis

Nausea or vomiting preceding jaundice often indicates acute hepatitis or obstruction of the common bile duct by a calculus; abdominal pain or chills occur later. Gradual development of anorexia and malaise is usually characteristic of alcoholic liver disease, chronic hepatitis, and cancer.

Since hyperbilirubinemia causes the urine to darken before visible jaundice appears, this indicates hyperbilirubinemia more reliably than the appearance of jaundice.

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Physical examination

Mild jaundice is best visualized by examining the sclera in natural light; it is usually visible when the serum bilirubin reaches 2 to 2.5 mg/dL (34 to 43 mmol/L). Mild jaundice in the absence of dark urine suggests unconjugated hyperbilirubinemia (most often caused by hemolysis or Gilbert's syndrome); more severe jaundice or jaundice accompanied by dark urine suggests hepatobiliary disease. Symptoms of portal hypertension or portosystemic encephalopathy or skin or endocrine changes suggest chronic liver disease.

In patients with hepatomegaly and ascites, distended jugular veins suggest the possibility of cardiac involvement or constrictive pericarditis. Cachexia and an unusually firm or nodular liver are more likely to indicate liver cancer than cirrhosis. Diffuse lymphadenopathy suggests infectious mononucleosis with acute jaundice, lymphoma, or leukemia in chronic jaundice. Hepatosplenomegaly in the absence of other symptoms of chronic liver disease may be caused by infiltrative lesions (eg, lymphoma, amyloidosis, or, in endemic areas, schistosomiasis or malaria ), although jaundice is usually subtle or absent in such disorders.

Laboratory research

Aminotransferase and alkaline phosphatase levels should be measured. Mild hyperbilirubinemia [eg, bilirubin < 3 mg/dL (< 51 μmol/L)] with normal aminotransferase and alkaline phosphatase levels is often consistent with unconjugated bilirubin (eg, hemolysis or Gilbert's syndrome rather than hepatobiliary disease). Moderate or severe hyperbilirubinemia, bilirubinuria, or high alkaline phosphatase or aminotransferase levels suggest hepatobiliary disease. Hyperbilirubinemia due to unconjugated bilirubin is usually confirmed by bilirubin fractionation.

Other blood tests should be performed as indicated. For example, serologic tests should be performed if acute or chronic hepatitis is suspected, PT or INR if liver failure is suspected, albumin and globulin levels should be measured if chronic liver disease is suspected, and antimitochondrial antibodies should be measured if primary biliary cirrhosis is suspected. In cases of isolated alkaline phosphatase elevation, gamma-glutamyl transpeptidase (GGT) levels should be measured; these enzymes are elevated in hepatobiliary disease, but high alkaline phosphatase levels may also be due to bone disease.

In hepatobiliary pathology, neither the determination of bilirubin fractions nor the degree of bilirubin elevation are helpful in the differential diagnosis of hepatocellular pathology and cholestatic jaundice. An increase in aminotransferase levels of more than 500 units suggests hepatocellular pathology (hepatitis or acute liver hypoxia), and a disproportionate increase in alkaline phosphatase (e.g., alkaline phosphatase greater than 3 ULN and aminotransferase less than 200 units) suggests cholestasis. Liver infiltration may also lead to a disproportionate increase in alkaline phosphatase levels relative to aminotransferases, but bilirubin levels usually do not increase or increase only slightly.

Because isolated hepatobiliary disease rarely causes bilirubin levels greater than 30 mg/dL (>513 μmol/L), higher bilirubin levels usually reflect the combination of severe hepatobiliary disease and hemolysis or renal dysfunction. Low albumin and high globulin levels suggest chronic rather than acute liver disease. An elevated PT or INR, which decreases with vitamin K (5-10 mg intramuscularly for 2-3 days), suggests cholestasis rather than hepatocellular disease but is not definitive.

Instrumental examination allows better diagnosis of infiltrative changes in the liver and causes of cholestatic jaundice. Abdominal ultrasonography, CT or MRI are usually performed immediately. These studies can detect changes in the biliary tree and focal liver lesions, but they are less informative in the diagnosis of diffuse hepatocellular changes (eg, hepatitis, cirrhosis). In extrahepatic cholestasis, endoscopic or magnetic resonance cholangiopancreatography (ERCP, MRCP) provide a more accurate assessment of the biliary tract; ERCP also provides treatment of obstruction (eg, removal of a calculus, stenting of a stricture).

Liver biopsy is rarely used to diagnose jaundice directly, but may be useful in intrahepatic cholestasis and some types of hepatitis. Laparoscopy (peritoneoscopy) allows examination of the liver and gallbladder without the need for traumatic laparotomy. Unexplained cholestatic jaundice justifies laparoscopy and sometimes diagnostic laparotomy.