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USMLE – Jaundice

Jaundice refers to the yellow appearance of the skin, sclera and mucous membranes resulting from an increased bilirubin concentration in the body fluids. It is detectable clinically when the plasma bilirubin exceeds 50 umol/l (3 mg/dl). Internal tissues and body fluids are colored yellow but not the brain, as bilirubin does not cross the blood-brain barrier other than in the immediate neonatal period.

Bilirubin metabolism
Unconjugated bilirubin is produced (425-510 mmol, 250-300 mg daily) from the catabolism of heme after removal of its iron component. Bilirubin in the blood is normally almost all unconjugated and as it is not water-soluble, it is bound to albumin and does not pass into the urine. Unconjugated bilirubin is conjugated by the endoplasmic reticulum enzyme, glucuronyl transferase, into bilirubin mono- and diglucuronide. These bilirubin conjugates are water-soluble and exported into the bile via specific carriers on the hepatocyte membrane. Conjugated bilirubin is metabolized by colonic bacteria forming stercobilinogen, which may be further oxidized to stercobilin. Both stercobilinogen and stercobilin are then excreted in the stool. A small amount of stercobilinogen (4 mg/day) is absorbed from the bowel, passes through the liver and excreted in the urine, where it is known as urobilinogen. or, following further oxidization, urobilin.

HEMOLYTIC JAUNDICE
This results from increased destruction of red blood cells, or their precursors in the marrow, causing increased bilirubin production. Jaundice due to hemolysis is usually mild because a healthy liver can excrete a bilirubin load six times greater than normal before unconjugated bilirubin accumulates in the plasma. Exceptions to this occur in the newborn when the hepatic bilirubin transport mechanism is immature and in patients with liver disease.

Clinical features
There are often no stigmata of chronic liver disease other than jaundice. Increased excretion of bilirubin and hence stercobilinogen leads to normal-colored or dark stools and increased urobilinogen excretion causes the urine to turn dark on standing as urobilin is formed. Pallor due to anemia and splenomegaly due to excessive reticulo-endothelial activity are usually present.

Investigations
The plasma bilirubin is usually less than 100 umol/l (6 mg/dl) and the liver function tests are otherwise normal. There is no bilirubinuria because the hyperbilirubinemia is dominantly unconjugated. The blood count and film may show evidence of hemolytic anemia.

CONGENITAL NON-HEMOLYTIC HVPERBILIRUBINEMIA
Gilbert’s syndrome is the only common form of congenital non-hemolytic hyperbilirubinemia. All other forms are very rare. In adults this condition has an excellent prognosis, needs no treatment and is clinically important only because it may be mistaken for more serious liver disease.

HEPATOCELLULAR JAUNDICE
Hepatocellular jaundice results from an inability of the liver to transport bilirubin into the bile, occurring as a result of parenchymal liver disease. Bilirubin transport across the hepatocytes may be impaired at any point between uptake of unconjugated bilirubin into the cells and transport of conjugated bilirubin into the canaliculi. In addition, swelling of cells and edema resulting from the disease itself may cause obstruction of the biliary canaliculi. In hepatocellular jaundice the concentrations in the blood of both unconjugated and conjugated bilirubin increase, perhaps because of the variable way in which bilirubin transport is disturbed. The severity of jaundice, the other clinical features, and the investigation and treatment vary with the underlying disease and are considered later in this chapter.

CHOLESTATIC JAUNDICE
In unrelieved cholestasis jaundice tends to become progressively severe because conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood and also because there is a failure of clearance of unconjugated bilirubin arriving at the liver cells.

Etiology
Cholestasis may be due to failure of the hepatocytes to generate bile flow to obstruction to bile flow in the bile ducts in the portal tracts, or to obstruction to bile flow in the extrahepatic bile ducts between the porta hepatis and the papilla of Vater. Causes of cholestasis can operate at more than one of these levels, and those confined to the extrahepatic bile ducts may be amenable to surgical correction.

Clinical features
Clinical features in cholestatic jaundice include those due to cholestasis itself and to the development of cholangitis consequent to biliary obstruction. Clinical features in cholestatic jaundice also include those which point to a likely cause for the condition.

Investigations
Investigations in individual patients are determined by the history and clinical findings. Usually, biochemical tests show greater elevation of the alkaline phosphatase and GGTP compared with the aminotransferases and an ultrasound is performed to identify any biliary dilatation.

Management
This depends on the underlying cause of the cholestasis.

UNUSUAL FORMS OF CHOLESTASIS

Cholestasis of pregnancy
This is probably caused by an inherited susceptibility of the patient’s liver cells to estrogens; this condition may also be precipitated by oral contraceptives. Pruritus is the dominant symptom and jaundice occurs in about half of the patients. Itching almost always starts in the third trimester of pregnancy and remits within about 2 weeks of delivery. Pruritus can be relieved with cholestyramine. No harm comes to the fetus, but the condition tends to recur in subsequent pregnancies.

Benign recurrent intrahepatic cholestasis
This is a rare condition in which episodes of cholestasis lasting from 1-6 months occur, starting in adolescence or early adult life. Genetic factors are probably important as more than one family member may be affected. Episodes start with pruritus and painless jaundice develops later. Liver function tests show the pattern of cholestasis; liver biopsy shows cholestasis during an episode but is normal between episodes. Treatment is required to relieve pruritus and the long-term prognosis is good.

Lillian Thompson By Lillian Thompson

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