Overall Bottom Line

Jaundice occurs when there is an elevation in the plasma total bilirubin level that is visible clinically.
There are several methods of classifying jaundice in the adult patient that provide some indication of the etiology, the simplest being to separate jaundice into unconjugated versus conjugated hyperbilirubinemia.
In the adult patient, the main causes of jaundice are related to intrinsic liver disease or interruption of bile flow due to obstruction of the biliary tree.
The approach to jaundice should include a thorough history and physical examination, appropriate laboratory studies and further directed investigation including imaging and liver biopsy.

Section 1: Background

Definition of disease

Jaundice occurs when there is an elevation in the serum total bilirubin level that can be detected clinically. In adults the normal upper limit for total bilirubin level is 1.2 mg/dL. Jaundice only becomes clinically apparent when the total bilirubin rises to greater than 2 mg/dL, and is first visible in the sclera and sublingual area.
The vast majority of total bilirubin exists in serum in the unconjugated form but acute or chronic liver disease can affect multiple steps in bilirubin processing and can lead to mainly unconjugated, conjugated or mixed hyperbilirubinemia.
Since bilirubin is the end-product of the metabolism of heme and is conjugated in the liver and then excreted into the biliary tree, jaundice can occur from dysfunction at any of these three steps.

Disease classification

There are several methods of classifying jaundice, the simplest being to differentiate into unconjugated (indirect) and conjugated (direct) hyperbilirubinemia. This is an oversimplification as hyperbilirubinemia can be mixed.
Another classification system splits jaundice into pre-hepatic, hepatic and post-hepatic depending on where the pathological process is occurring.

Incidence/prevalence

There is no reliable data on the incidence of jaundice in the general adult population.
In adult patients presenting with jaundice, the incidence of different etiologies depends on several demographic factors, mainly age and geography, and risk factors for underlying liver disease.

Etiology

There are multiple causes of jaundice in adults and the classification into unconjugated and conjugated bilirubin can be useful in determining the etiology.
Causes of predominantly unconjugated hyperbilirubinemia:
- Inherited (e.g. Gilbert’s syndrome) or acquired (e.g. drug-induced) bilirubin conjugation disorders.
- Intravascular and extravascular hemolysis (e.g. autoimmune, toxic, infectious, mechanical).
- Impaired red cell production (dyserythropoiesis) or increased red cell destruction (e.g. sickle cell anemia and other hemoglobinopathies).
Causes of mixed hyperbilirubinemia:
- Acute or chronic liver disease.
Causes of predominantly conjugated hyperbilirubinemia:
- Intrahepatic cholestasis:
  - inherited (e.g. Dubin–Johnson syndrome, Rotor syndrome, PFIC disorders).
  - primary biliary cirrhosis.
  - any cause of chronic liver disease.
  - toxic/drug-related.
  - sepsis.
  - infiltrative (sarcoid, amyloidosis) or sequestrative (sickle cell hepatic crisis) diseases.
  - pregnancy.
  - malignancy (lymphoma).
  - post-operative.
- Extrahepatic cholestasis:
  - intrinsic biliary obstruction:
    - cholelithiasis (choledocholithiasis).
    - malignant (cholangiocarcinoma).
    - primary sclerosing cholangitis.
    - sclerosing cholangitis from other causes (chemotherapy, autoimmune).
  - infectious – parasitic infections.
  - HIV- and AIDS-related cholangiopathy.
  - extrinsic biliary obstruction:
    - malignant:
      - pancreatic cancer.
      - lymphoma.
      - metastatic lymphadenopathy.
    - benign:
      - acute and chronic pancreatitis and its sequelae.
      - post-surgical complications.
      - Mirizzi’s syndrome.
      - developmental anomalies.

Pathology/pathogenesis

Unconjugated hyperbilirubinemia is typically due to increased bilirubin production or impaired uptake or conjugation of bilirubin in the liver.
- Bilirubin is produced by catabolism of heme which is found in several proteins, notably hemoglobin, myoglobin and cytochromes.
- The initial step is the oxidation of heme, catalyzed by heme oxygenase, found in the reticuloendothelial system and in Kupffer cells in the liver.
- This leads to the formation of biliverdin which in turn is converted to bilirubin by biliverdin reductase.
- Bilirubin is poorly soluble in water and is reversibly bound to albumin in plasma which prevents it crossing the blood–brain barrier. It is the unbound unconjugated bilirubin that leads to toxic effects.
- Clinically, any condition leading to increased red cell destruction as in hemolysis or dyserythropoiesis results in increased unconjugated bilirubin production.
- Bilirubin bound to albumin is transported to the liver sinusoids where the bilirubin is actively taken up by the hepatocytes. Inherited disorders can affect several steps in the process, and the formation of portosystemic collaterals in portal hypertension can lead to bypass of the liver, leading to unconjugated hyperbilirubinemia.
- Bilirubin undergoes conjugation inside the endoplasmic reticulum in the hepatocyte. It is catalyzed by the enzyme family termed UGT and leads to the formation of bilirubin glucuronides, mainly the diglucuronide. Inherited deficiency of UGT is seen in Gilbert’s syndrome and in the Crigler–Najjar syndromes. Conjugation can be affected by liver disease and several drugs, notably antibiotics such as gentamicin, chloramphenicol and rifampin, and HIV protease inhibitors such as indinavir.
Conjugated hyperbilirubinemia is caused by impaired excretion of conjugated bilirubin in the liver from inherited causes or acquired liver disease and from obstruction of the biliary tree.
- Conjugated bilirubin is actively transported across the bile canalicular membrane and excreted into bile.
- This process can be affected by several inherited disorders (Dubin–Johnson and Rotor syndromes) and by several drugs (e.g. ethinyl estradiol, chlorpromazine).
- Liver injury secondary to toxins typically leads to conjugated hyperbilirubinemia through a variety of postulated mechanisms. Pyrrolizidine alkaloids such as comfrey and bush teas cause damage to the endothelium of the central vein leading to sinusoidal obstruction syndrome. The resultant hepatic congestion interferes with bilirubin excretion.
- Acute and chronic liver disease can cause conjugated hyperbilirubinemia. Viral hepatitis can acutely lead to jaundice as well as cholestatic variants seen after liver transplantation. The mechanism is multifactorial but involves impaired excretion.
- Parasites are a cause of conjugated hyperbilirubinemia due to intrahepatic cholestasis. In ascariasis, the adult worm migrates into the biliary tree leading to obstruction. Similarly the eggs of Clonorchis sinenis and Fasciola hepatica (liver flukes) can obstruct the biliary tree.
- Obstruction of the extrahepatic biliary tree can be caused by injury to the bile duct at surgery but typically is seen with obstruction of the extrahepatic bile duct by stone disease or malignancy involving the head of the pancreas or cholangiocarcinoma as well as benign disease of the pancreas.

Section 2: Prevention

No interventions have been demonstrated to prevent the development of the disease.

Section 3: Diagnosis

Bottom Line/Clinical Pearls

In the jaundiced patient, a detailed history is critical and can often point to the diagnosis.
On physical examination it is important to look for stigmata of chronic liver disease.
Initial investigations should include a total and fractionated bilirubin, liver enzymes (ALT, AST, AP, GGT), and tests of liver synthetic function.
Imaging should be obtained in the jaundiced patient and a right upper quadrant ultrasound is a reasonable first test.

Typical presentation

The clinical presentation of the jaundiced patient will depend on the etiology. Typically patients have minimal symptoms and it is usually diagnosed when the patient (or family and friends) recognizes scleral icterus but can be preceded by pruritis and dark urine, particularly in patients with conjugated hyperbilirubinemia. If the jaundice is related to intrinsic liver disease, this can be associated with constitutional symptoms such as fatigue, malaise and myalgia. The presence of fever and abdominal pain can point to cholangitis, suggesting biliary obstruction from choledocholithiasis. Malignant causes of jaundice are classically painless but can present with concomitant weight loss.

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