Jaundice is the clinical sign of hyperbilirubinemia. Normal values of total bilirubinemia are < 1mg/dL, of which the conjugated form accounts for less than 5% (Table 1). 

Table1. Reference range of bilirubin

Total bilirubinemia values between 2 and 3 mg/dL result in sub-jaundice, characterized by a yellowish discoloration of the sclerae; values >3 mg/dL result in a clinically manifest jaundice condition characterized by a yellowish discoloration of the sclerae, skin, and mucous membranes. Jaundice and asymptomatic hyperbilirubinemia represent common clinical conditions that may be caused by a variety of disorders, which include increased bilirubin synthesis, impaired bilirubin conjugation, and biliary obstruction, and hepatic inflammation. Jaundice may represent the first and only sign of liver disease; therefore, its evaluation is of critical importance.

Various classifications of jaundice have been proposed. The following are the main ones.

According to traditional classification, jaundice can be distinguished based on the site of the cause into:

• Prehepatic: it results from the hyperproduction of bilirubin and it is characterized by an increase in the indirect bilirubin form

 • Hepatocellular: it results from parenchymal lesions of the liver that impair the hepatic metabolism of bilirubin, leading to an increase in total bilirubinemia

 • Posthepatic: it results from intra- and/or extra-hepatic biliary obstruction, with an increase in the direct form

According to a clinical biochemistry classification based on the form of altered bilirubin, jaundice is divided into three main categories:

• Jaundice characterized by a predominant increase in unconjugated bilirubin, which may be due to three pathophysiological mechanisms: increased production of bilirubin; altered uptake; or altered conjugation of bilirubin in the liver. The physiological jaundice of the newborn is a classic example in which all three pathophysiological mechanisms are present.

• Jaundice characterized by increased circulating levels of conjugated bilirubin, mainly due to biliary obstruction.

• Jaundice characterized by increased circulating levels of both conjugated and unconjugated bilirubin due to hepatocellular disease.

Finally, according to a pathophysiological classification, jaundice is distinguished as:

• Increased production of bilirubin

• Bilirubin uptake defect • Bilirubin conjugation defect

• Defective bilirubin excretion

• Mechanical obstruction of the intra- and/or extra-hepatic biliary tract

Jaundice due to increased Bilirubin production

Overproduction of bilirubin is the result of excessive catabolism of heme derived from hemoglobin that may be due to hemolytic anemia, extravasation of blood into tissues, or dyserythropoiesis (characterized by altered incorporation of hemoglobin in erythrocytes resulting in the degradation of a large fraction of unincorporated hemoglobin).

These forms of jaundice are characterized by an increase in indirect bilirubinemia due to the inability of the liver to metabolize excess bilirubin.

Jaundice due to Bilirubin Uptake and Conjugation Defect

These forms of jaundice are characterized by a normal pro duction of bilirubin, but the liver is unable to fully metabolize, leading to an increase in indirect bilirubinemia. Alterations in the release of bilirubin to the liver and in bilirubin internalization in hepatocytes result in reduced hepatic uptake. Congestive heart failure or portosystemic shunt (spontaneous collaterals in subjects with cirrhosis or surgical shunts) reduce hepatic blood flow and bilirubin release to hepatocytes, resulting in mainly indirect hyperbilirubinemia. In some patients with cirrhosis, direct plasma contact with hepatocytes may be impaired by capillarization of sinusoidal endothelial cells (loss of fenestrae), resulting in further reduced bilirubin uptake. Other causes of altered bilirubin uptake include Gilbert’s syndrome and administration of various drugs, such as rifamycin, flavaspidic acid, and chole cystogram agents; drug-induced defects usually resolve within 48 hours of discontinuation of therapy.

Congenital Defects

 Reduced or absent UGT1A1 enzyme activity is a major cause of jaundice due to bilirubin conjugation defects and can be detected in several acquired or inherited disorders, such as Gilbert’s syndrome and Crigler–Najjar’s syndrome types I and II. UGT1A1 activity is, moreover, modulated by various hormones; for example, thyroid hormones and ethinylestradiol inhibit bilirubin glucuronidation. Conversely, the combination of progestin and estrogenic steroids results in an increase in enzyme activity. Bilirubin glucuronidation may also be inhibited by some antibiotics (e.g., novobiocin or gentamicin at serum concentrations above therapeutic levels) and in chronic persistent hepatitis, advanced cirrhosis, and Wilson’s disease.

Gilbert’s syndrome is a benign hereditary disorder trans mitted in an autosomal dominant trait, characterized by a defect in bilirubin uptake associated with a glucuronidation deficit due to alterations in the gene encoding for the enzyme UGT1A1. From an epidemiological point of view, Gilbert’s syndrome is quite common, with a prevalence that varies between 4% and 16% in various populations. Patients with Gilbert’s syndrome have moderately elevated levels of unconjugated bilirubin, with total bilirubin levels generally <3 mg/dL. Some associated diseases or physiological or paraphysiological events, such as stress, fasting, menstrual cycle, or asthenia, may determine an increase in total bilirubinemia, generally not exceeding 6 mg/dL. Other than jaundice, patients are typically asymptomatic, and no treatment is required.

Crigler-Najjar syndrome, also known as “congenital non- hemolytic jaundice with glucuronyltransferase deficiency” is a rare autosomal recessive disorder of bilirubin metabolism. Depending on the severity of the disease, two forms can be distinguished.

• Type I: It results from mutations (deletions, insertions, missense mutations, etc.) in one of the five exons of the gene encoding for the enzyme UGT1A1, which are associated with an altered protein characterized by a complete loss or a strong reduction in catalytic activity. Affected patients have severe jaundice and neurological impairment due to bilirubin encephalopathy, which can result in permanent neurological sequelae. Frequently, subjects affected by type I die in the neonatal period due to kernicterus (bilirubin encephalopathy). The hallmark of type I syndrome is the presence of pure unconjugated hyperbilirubinemia, with levels ranging from 20 to 25 mg/dL up to 50 mg/dL.

• Type II: It is known as “Arias syndrome” and it is phenotypically similar to type I. However, the unconjugated hyperbilirubinemia is usually lower than type I, with a con centration ranging from 8 to 18 mg/dL. Patients commonly survive to adulthood without neurological alterations. The disease is due to mutations in any of the five exons of the gene encoding for UGT1A1 but compared with the type I syndrome, which can be caused by a wide variety of alterations, the type II syndrome is due only to point mutations resulting in the substitution of single amino acid, with con sequent reduction, but not abrogation, of the catalytic activity of the enzyme. The residual catalytic activity is responsible for the partial conjugation of bilirubin and the reduced severity of hyperbilirubinemia.

The differential diagnosis between Crigler–Najjar syn drome type I and type II is based on hyperbilirubinemia levels (lower in type II) and age of onset (late for type II). In addition, administration of phenobarbital may support the differential diagnosis because in most type II patients, but not type I, phenobarbital (60–120 mg for 14 days) can reduce bilirubinemia levels by 25%. Table 2 summarizes the main features of Gilbert’s syndrome and Crigler–Najjar’s syndrome types I and II.

Table2. Characteristics of Gilbert syndrome and Crigler–Najjar syndrome type I and II

Jaundice due to Defective Excretion of Bilirubin or Mechanical Obstruction of the Intra- and/or Extra-hepatic Biliary Tracts

These forms of jaundice are characterized by a normal pro duction of bilirubin, which is taken up and conjugated in the liver but is not regularly excreted, leading to an accumulation of circulating direct bilirubin. Since direct bilirubin is water- soluble, it is filtered through glomerulus and eliminated in urine. In these forms of jaundice, therefore, there is direct hyperbilirubinemia and bilirubinuria. The altered excretion may be due to intra- and/or extra-hepatic cholestasis, the causes of which are summarized in Tables 3 and 4.

Table3. Causes of jaundice from intra-hepatic cholestasis

Table4. Causes of jaundice from extra-hepatic cholestasis

Neonatal Jaundice

 In newborns, jaundice is a relatively frequent condition due to several mechanisms. Almost all newborns have total bilirubinemia values >1 mg/dL. As bilirubinemia increases, neonatal jaundice is observed. First, it affects the face and then progresses cranio-caudally to the trunk and extremities. Approximately 60% of term infants and 80% of preterm infants have physiologic jaundice, which is the result of the different neonatal metabolism of bilirubin, characterized by:

• Increased production of bilirubin: hemocateretic (shorter erythrocyte half-life) and hepatic share.

• Insufficient metabolic capacity of the liver: reduced levels of ligandin, glucuronic acid and UGT1A1. Specifically, UGT1A1 activity in term infants, at 7 days after birth, is approximately 1% of that of adults and does not reach adult levels until 14 weeks of age.

 • Insufficient development of intestinal bacterial flora, resulting in insufficient production of bilinogens.

All these conditions result in an increase in unconjugated bilirubinemia. In Caucasian and African-American term infants, the mean peak total plasma bilirubinemia is 7–9 mg/ dL and is reached between 48 and 96 hours of life. East- Asian infants may have total bilirubinemia values up to 10–14 mg/dL between 72 and 120 hours of life.

Generally, neonatal jaundice resolves within the first 2 weeks after birth, depending on the maturation of the bilirubin clearance system. Infants with severe hyperbilirubinemia, defined as total bilirubinemia >25 mg/dL, are at high risk of developing bilirubin-induced neurologic dysfunction due to the passage of indirect bilirubin across the blood–brain barrier.

Infants with clinically relevant hyperbilirubinemia should undergo phototherapy, which exploits the ability of radiation in the visible spectrum to convert bilirubin into isomers that can be rapidly eliminated hepatically and renally.