Jaundice- An overview

Bilirubin is the end product of heme degradation. From 70–90% of bilirubin is derived from degradation of the hemoglobin of senescent red blood cells. Bilirubin produced in the periphery is transported to the liver within the plasma, where, due to its insolubility in aqueous solutions, it is tightly bound to albumin.

Under normal circumstances, bilirubin is removed from the circulation rapidly and efficiently by hepatocytes.

Transfer of bilirubin from blood to bile involves four distinct but interrelated steps:

1) Hepatocellular uptake: Uptake of bilirubin by the hepatocyte has carrier-mediated kinetics.

2) Intracellular binding: Within the hepatocyte, bilirubin is kept in solution by binding as a non-substrate ligand to several of the glutathione-S-transferases, formerly called ligandins.

3) Conjugation: Bilirubin is conjugated with one or two glucuronic acid moieties by a specific UDP-glucuronosyl transferase to form bilirubin mono- and diglucuronide, respectively. Conjugation disrupts the internal hydrogen bonding that limits aqueous solubility of bilirubin, and the resulting glucuronide conjugates are highly soluble in water. Conjugation is obligatory for excretion of bilirubin across the bile canalicular membrane into bile. The UDP-glucuronosyl transferases have been classified into gene families based on the degree of homology among the mRNAs for the various isoforms. Those that conjugate bilirubin and certain other substrates have been designated the UGT1 family. These are expressed from a single gene complex by alternative promoter usage.

4) Biliary excretion: Bilirubin mono- and diglucuronides are excreted across the canalicular plasma membrane into the bile canaliculi by an ATP-dependent transport process mediated by a canalicular membrane protein called multidrug resistance-associated protein 2 (MRP2). Mutations of MRP2 result in Dubin-Johnson syndrome.

Extrahepatic Aspects of Bilirubin Disposition

Bilirubin in the Gut

Following secretion into bile, conjugated bilirubin reaches the duodenum and passes down the gastrointestinal tract without reabsorption by the intestinal mucosa. An appreciable fraction is converted by bacterial metabolism in the gut to the water-soluble colorless compound, urobilinogen. About 80–90% of these products are excreted in feces, either unchanged or oxidized to orange derivatives called urobilin. The remaining 10–20% of the urobilinogen is passively absorbed, enters the portal venous blood, and is reexcreted by the liver. A small fraction (usually <3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excreted in the urine. (See figure 1)

Figure-1 – showing the formation and fate of bilirubin

Unconjugated bilirubin ordinarily does not reach the gut except in neonates or, by ill-defined alternative pathways, in the presence of severe Unconjugated hyperbilirubinemia [e.g., Crigler-Najjar syndrome, type I (CN-I)]. Unconjugated bilirubin that reaches the gut is partly reabsorbed, amplifying any underlying hyperbilirubinemia.

Renal Excretion of Bilirubin Conjugates

Unconjugated bilirubin is not excreted in urine as it is too tightly bound to albumin for effective glomerular filtration and there is no tubular mechanism for its renal secretion. In contrast, the bilirubin conjugates are readily filtered at the glomerulus and can appear in the urine in disorders characterized by increased bilirubin conjugates in the circulation.

Jaundice

Jaundice results from the accumulation of bilirubin. Hyperbilirubinemia may be due to abnormalities in the formation, transport, metabolism, and excretion of bilirubin. Total serum bilirubin is normally 0.2–1.2 mg/dL (mean levels are higher in men than women and higher in whites and Hispanics than blacks), and jaundice may not be recognizable until levels are about 3 mg/dL.

In a normal adult, the rate of systemic bilirubin production is equal to the rates of hepatic uptake, conjugation, and biliary excretion. Jaundice occurs (bilirubin levels may reach 30-40 mg/dL in severe disease) when the equilibrium between bilirubin production and clearance is disturbed by one or more of the following mechanisms (1) excessive production of bilirubin, (2) reduced hepatic uptake, (3) impaired conjugation, (4) decreased hepatocellular excretion, and (5) impaired bile flow (both intrahepatic and extrahepatic). The first three mechanisms produce unconjugated hyperbilirubinemia, and the latter two produce predominantly conjugated hyperbilirubinemia. More than one mechanism may operate to produce jaundice, especially in hepatitis, which may produce Unconjugated and conjugated hyperbilirubinemia. In general, however, one mechanism predominates, so that knowledge of the predominant form of plasma bilirubin is of value in evaluating possible causes of hyperbilirubinemia

Classification of jaundice

Jaundice in these cases is caused by the rapid increase in the breakdown and destruction of the red blood cells (hemolysis), overwhelming the liver’s ability to adequately remove the increased levels of bilirubin from the blood.

Examples of conditions with increased breakdown of red blood cells include:

-Malaria,

-Sickle cell crisis,

-Spherocytosis,

-Thalassemia,

-Glucose-6-phosphate dehydrogenase deficiency (G6PD),

-Drugs or other toxins, and

–Autoimmune disorders.

2) Hepatic (the problem arises within the liver)

Jaundice in these cases is caused by the liver’s inability to properly metabolize and excrete bilirubin.

Causes

 –Viral – hepatitis A, B, or C, yellow fever, Bacterial sepsis, tuberculosis,

–Alcohol, Drugs e.g. estrogens, contraceptive pills, and Pregnancy

–Carcinoma: metastases. Lymphoma. Adenocarcinoma of the kidney (non-metastatic)

–Preoperative hypoperfusion/shock

-Chronic active hepatitis

3) Post-hepatic (after bile has been made in the liver)

Jaundice in these cases, also termed obstructive jaundice, is caused by conditions that interrupt the normal drainage of conjugated bilirubin in the form of bile from the liver into the intestines. The obstruction may be intrahepatic or extrahepatic

Causes of obstructive jaundice include:

a) Intrahepatic Obstruction

-Biliary atresia

-Primary Biliary Cirrhosis

-Malignant infiltration of ducts

 b) Extrahepatic obstruction

-Gallstones in the bile ducts,

-cancer (pancreatic and gallbladder/bile duct carcinoma),

-strictures of the bile ducts,

-Pressure on the common bile duct from enlarged lymph nodes,

-cholangitis,

-congenital malformations, 

-pancreatitis,

-parasites,

-pregnancy, and

-Newborn jaundice.

 Congenital conditions that may cause jaundice

1) Crigler-Najjar syndrome: an inherited condition that may lead to severe Unconjugated hyperbilirubinemia (high bilirubin concentrations); a gene mutation leads to a deficiency in an enzyme necessary for bilirubin conjugation.

2) Dubin-Johnson syndrome: an inherited disorder that causes the retention of conjugated bilirubin (and other compounds that turn the liver black) in liver cells; patients may have intermittent jaundice.

3) Rotor’s syndrome: an inherited conjugated hyperbilirubinemia that causes intermittent jaundice; similar to Dubin-Johnson without the retention of other compounds or a black liver.

4) Gilbert syndrome-There is compensatory hemolysis, impaired uptake, and conjugation of bilirubin.

 

 

 

Physiologic Neonatal Jaundice

 

This form of jaundice occurs when there is an incompatibility between the blood types of the mother and the fetus. This leads to increased bilirubin levels from the breakdown of the fetus’ red blood cells (hemolysis).

Breast milk jaundice

This form of jaundice occurs in breastfed newborns and usually appears at the end of the first week of life. Certain chemicals in breast milk are thought to be responsible for inhibition of UDP glucuronyl transferase. It is usually a harmless condition that resolves spontaneously.

Clinical Features

1) Unconjugated Hyperbilirubinemia (Pre hepatic jaundice)Stool and urine color are darker than normal, and there are mild jaundice and indirect (Unconjugated) hyperbilirubinemia with no bilirubin in the urine. Splenomegaly occurs in hemolytic disorders except in sickle cell anemia.

2) Hepatocellular disease (Hepatic jaundice)

Malaise, anorexia, low-grade fever, and right upper quadrant discomfort are frequent. Dark urine, jaundice, and, in women, amenorrhea occur. An enlarged tender liver, depending on the cause, severity, and chronicity of liver dysfunction is observed

There may be right upper quadrant pain, weight loss (suggesting carcinoma), jaundice, dark urine, and light-colored stools. Symptoms and signs may be intermittent if caused by a stone, carcinoma of the ampulla, or cholangiocarcinoma. Pain may be absent early in pancreatic cancer. Occult blood in the stools suggests cancer of the ampulla. Hepatomegaly and a palpable gallbladder (Courvoisier’s sign) are characteristic, but neither specific nor sensitive, of a pancreatic head tumor. Fever and chills are more common in benign obstruction with associated cholangitis.

Diagnosis

The goal of testing is to determine the cause of jaundice and to evaluate the severity of the underlying condition. The initial step is to obtain appropriate blood tests to determine if the patient has an isolated elevation of serum bilirubin. If so, is the bilirubin elevation due to an increased Unconjugated or conjugated fraction? If the hyperbilirubinemia is accompanied by other liver test abnormalities, is the disorder hepatocellular or cholestatic? If cholestatic, is it intra- or extrahepatic? All of these questions can be answered with a thoughtful history, physical examination, and interpretation of laboratory and radiologic tests and procedures.

Laboratory Studies

Measurement of Serum Bilirubin

The terms direct- and indirect-reacting bilirubin are based on the original van den Bergh reaction. This assay, or a variation of it, is still used in most clinical chemistry laboratories to determine the serum bilirubin level. In this assay, bilirubin is exposed to diazotized sulfanilic acid, splitting into two relatively stable dipyrrylmethene azo pigments that absorb maximally at 540 nm, allowing for photometric analysis.

The direct fraction is that which reacts with diazotized sulfanilic acid in the absence of an accelerator substance such as alcohol. The direct fraction provides an approximate determination of the conjugated bilirubin in serum. The total serum bilirubin is the amount that reacts after the addition of alcohol. The indirect fraction is the difference between the total and the direct bilirubin and provides an estimate of the Unconjugated bilirubin in serum.

With the van den Bergh method, the normal serum bilirubin concentration usually is 17 mol/L (<1 mg/dL). Up to 30%, or 5.1 mol/L (0.3 mg/dL), of the total may be direct-reacting (conjugated) bilirubin. Total serum bilirubin concentrations are between 3.4 and 15.4 mol/L (0.2 and 0.9 mg/dL) in 95% of a normal population.

Unconjugated bilirubin is always bound to albumin in the serum, is not filtered by the kidney, and is not found in the urine. Conjugated bilirubin is filtered at the glomerulus and the majority is reabsorbed by the proximal tubules; a small fraction is excreted in the urine. Any bilirubin found in the urine is conjugated bilirubin. The presence of bilirubinuria implies the presence of liver disease. A urine dipstick test (Ictotest) gives the same information as fractionation of the serum bilirubin. This test is very accurate. A false-negative test is possible in patients with prolonged cholestasis due to the predominance of conjugated bilirubin covalently bound to albumin.

Liver biochemical tests: changes in three types of jaundice.

Tests	Pre hepatic jaundice	Hepatocellular Jaundice	Uncomplicated Obstructive Jaundice
Bilirubin
Direct	–	Increased	Increased
Indirect	Increased	Increased	Increased
Urine bilirubinUrine Urobilinogen	NoneIncreased	IncreasedIncreased	IncreasedAbsent
Serum albumin/total protein	Normal	Albumin decreased total protein, 6.5–8.4 g/dL	Unchanged
Alkaline phosphatase	Normal	Increased (+)	Increased (++++)
Prothrombin time	Normal	Prolonged if damage severe and does not respond to parenteral vitamin K	Prolonged if obstruction marked, but responds to parenteral vitamin K
ALT, AST	Normal	Increased in hepatocellular damage, viral hepatitis	Minimally increased

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Serum alanine and aspartate aminotransferase (ALT and AST) levels vary with age and correlate with body mass index. Elevated alkaline phosphatase levels are seen in cholestasis or infiltrative liver disease (such as tumor or granuloma). Alkaline phosphatase elevations of hepatic rather than bone, intestinal, or placental origin are confirmed by concomitant elevation of γ-glutamyl transpeptidase or 5′-nucleotidase levels. The differential diagnosis of any liver test elevation includes toxicity caused by drugs, herbal remedies, and toxins.

Liver Biopsy

Percutaneous liver biopsy is the definitive study for determining the cause and histological severity of hepatocellular dysfunction or infiltrative liver disease.

Imaging

Demonstration of dilated bile ducts by ultrasonography or CT scan indicates biliary obstruction (90–95% sensitivity). Ultrasonography, CT scan, and MRI may also demonstrate hepatomegaly, intrahepatic tumors, and portal hypertension. Magnetic resonance cholangiopancreatography (MRCP) is a sensitive, noninvasive method of detecting bile duct stones, strictures, and dilation; however, it is less reliable than endoscopic retrograde cholangiopancreatography (ERCP) for distinguishing malignant from benign strictures.

Treatment

The treatment is entirely dependent on the cause of jaundice. In some cases, it will be curative e.g. surgical removal of a gallstone blocking the common bile duct. Viral infections e.g. hepatitis A may recover spontaneously. In other cases, treatment will modify the disease process and jaundice will improve or disappear. Treatment may be purely symptomatic e.g., drugs to relieve itching or palliative as in malignant disease. Some types of advanced liver disease-causing jaundice may be treated by liver transplantation.

Phototherapy for Neonatal Jaundice

The goal of therapy is to lower the concentration of circulating bilirubin or keep it from increasing. Phototherapy achieves this by using light energy to change the shape and structure of bilirubin, converting it to molecules that can be excreted even when normal conjugation is deficient

Phototherapy converts bilirubin to yellow photo isomers and colorless oxidation products that are less lipophilic than bilirubin and do not require hepatic conjugation for excretion. Photo isomers are excreted mainly in bile, and oxidation products predominantly in the urine.

Prognosis– is fairly good in the treated cases, except in cases of malignant obstruction of the common bile duct.