Jaundice pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2], Ahmed Elsaiey, MBBCH [3]

Overview

Bilirubin is the catabolic product of the heme which is the main component of the red blood cells. Bilirubin is formed in the liver and spleen then it passes through several process in order to be metabolized. Metabolism processes include hepatic uptake, conjugation, clearance and excretion of the bilirubin in the bile. Jaundice develops due to increase the level of bilirubin and deposition under the skin and cause the yellow discoloration of the skin. Pathogenesis of neonatal jaundice includes physiologic process of bilirubin accumulation or pathological mechanism. The pathological jaundice may be acquired or inherited. Acquired neonatal jaundice include Rh hemolytic disease, ABO incompatibility disease, and hemolytic disease due to G6PD enzyme deficiency. Inherited neonatal jaundice is due to defect of one of the processes of bilirubin metabolism and it concludes some inherited syndromes. Inherited neonatal jaundice include Gilbert's syndrome, Crigler-Najjar syndrome type I and II, Lucey-Driscoll syndrome, Dubin-Johnson syndrome, and Rotor syndrome.

Pathophysiology

 Bilirubin formation and metabolism

• Bilirubin is the final catabolic product of the heme. The heme is a component of various biological molecules and enzymes but, it is mainly incorporated in the hemoglobin which is the primary component of the red blood cells.
• Bilirubin is formed mainly in the liver and spleen through two steps which include:
  • Heme oxygenase enzyme degrades the porphyrin ring of the heme and breaks it down. A green compound called biliverdin is then formed as a result of the previous reaction. Carbon monoxide is released as a result of the reaction.
  • Biliverdin reductase enzyme catalyzes the formation of bilirubin from biliverdin.
• Bilirubin is a toxic metabolite so, the body has physiologic processes to eliminate the bilirubin. Bilirubin elimination process includes:
  • Hepatic uptake
    • After the formation of the bilirubin and its secretion into the bloodstream, bilirubin becomes bound to the albumin to facilitate its transportation to the liver.
    • The hepatocytes then reuptake the bilirubin and prepare it for excretion.
  • Conjugation
    • Bilirubin is then conjugated with glucuronic acid producing bilirubin diglucuronide which is water soluble.
    • Being water soluble, hence, the conjugated bilirubin can be excreted into bile.
    • The conjugation process occurs by the glucuronosyltransferase enzyme in the liver cells.
  • Clearance and excretion
    • After conjugation of the bilirubin in the liver, it is secreted into the bile then into the gastrointestinal tract.
    • In the GIT, the conjugated bilirubin is metabolized by the gut enzymes into urobilinogen which is oxidized into urobilin.
    • Metabolism of the conjugated bilirubin occurs properly in the adults. However, the newborns have sterile gastrointestinal canal which impedes the catalyzation of the conjugated bilirubin.
    • The sterile tract ends up with a small amount of excreted bile.
    • The remaining conjugated bilirubin is unconjugated by the beta-glucuronidase enzyme in the neonatal intestine.
    • The unconjugated bilirubin is reabsorbed back into the blood and to the liver through the enterohepatic circulation of bilirubin.
    • A small amount of bilirubin is cleared into the urine as urobilinogen.

Pathogenesis of Adult jaundice

• Jaundice in adult patients classified into two major types:
  • Unconjugated hyperbilirubinemia
  • Conjugated hyperbilirubinemia

Unconjugated hyperbilirubinemia

The primary pathophysiology of unconjugated hyperbilirubinemia include:

• Overproduction of bilirubin
• Reduced bilirubin uptake
• Impaired bilirubin conjugation
  • The combination of progestational and estrogenic steroids may result in increased UDP-glucuronyl transferase activity

Conjugated hyperbilirubinemia

Biliary tract obstruction

• Biliary tract obstruction leads to both conjugated and unconjugated bilirubinemia.
• Bilirubin is transported back to the plasma by ATP-consuming pumps.
• The markers are serum concentrations of bilirubin and alkaline phosphatase.
• Biliary retention secondary to obstruction may reverse the glucuronidation.
• Produced unconjugated bilirubin will diffuse or be transported back into the plasma.
• Mirizzi syndrome
  • Extrahepatic bile ducts compression by a distended gallbladder due to cholelithiasis.
• Primary sclerosing cholangitis and cholangiocarcinoma
  • Intrahepatic and extrahepatic portions of the bile ducts are affected.
• Parasites
  • Adult Ascaris lumbricoides
  • Eggs of certain liver flukes (e.g., Clonorchis sinensis, Fasciola hepatica)
• AIDS cholangiopathy
  • Cryptosporidium species
  • Cytomegalovirus
  • HIV
    • Viral hepatitis (hepatitis viruses, herpes simplex virus, Epstein-Barr virus)
    • Mycobacterium tuberculosis and atypical mycobacteria (especially Mycobacterium avium intracellulare)
    • Fungal infections (Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Coccidioides immitis)
    • Parasites (Pneumocystis carinii)
    • Tumor infiltration (lymphoma, Kaposi sarcoma)
    • Drug-induced liver disease

Liver infrastructure damage

• Viral hepatitis: For more information about viral hepatitis click here
• Alcoholic hepatitis: For more information about viral hepatitis click here
• Nonalcoholic steatohepatitis: For more information about viral hepatitis click here
• Primary biliary cholangitis: For more information about viral hepatitis click here
• Toxicity
  • Dose-related fashion (e.g., alkylated steroids such as methyltestosterone and ethinyl estradiol)
  • Idiosyncratic or allergic reaction (e.g., chlorpromazine, halothane).
  • Pyrrolizidine alkaloids which may cause veno-occlusive disease of the liver (e.g., Jamaican bush tea)
• Sepsis and low perfusion states
  • Hypotension
  • Drugs
  • Bacterial endotoxins
• Paraneoplastic syndromes
  • Renal cell carcinoma
  • Malignant lymphoproliferative diseases
  • Gynecologic malignancies
  • Prostate cancer
• Infiltrative diseases of the liver
  • Amyloidosis
  • Lymphoma
  • Sarcoidosis
  • Tuberculosis
• Total parenteral nutrition (TPN)
  • At least two to three weeks of TPN may lead to development of cholestasis.
    • Intestinal endotoxins transfer into the portal system
    • Bacterial sepsis
    • Formation of secondary bile acids (e.g., lithocholic acid)
    • Biliary sludge after six weeks of TPN
    • Hepatotoxic factors, such as tryptophan degradation metabolites and aluminum contaminants
    • Bacterial overgrowth in the small intestine
• Sickle cell disease
  • Hemolysis
  • Mild hepatic dysfunction
  • Both unconjugated and conjugated bilirubin accumulate in the plasma
• Intrahepatic cholestasis of pregnancy
  • Usually in the third trimester but sometimes earlier
  • Heralds cholestasis and then frank jaundice
  • May be associated with increased stillbirths and prematurity
  • All the pathologic changes would disappear after delivery

Hepatocellular injury

• Different presentations simulate cholestatic syndromes.
• Intracellular proteins and small molecules are released into the plasma.
• Increased transaminases, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

Sepsis

Paraneoplastic syndrome

Infiltrative hepatic diseases

Total parenteral nutrition

Sickle cell disease

Pregnancy

Extravascular hemolysis

Intravascular hemolysis

Extravasation

Dyserythropoiesis

• Cholelithiasis • Tumor • Primary biliary cholangitis • Parasites • Pancreatitis • Stricture

• Choledochal cyst • Cholelithiasis • Tumor

• Biliary atresia • Choledochal cyst

• Decreased hepatic blood flow • Decreased delivery of bilirubin

• Capillarization of the sinusoidal endothelial cells (loss of fenestrae)

• Impaired bilirubin uptake at the sinusoidal surface of hepatocytes

• Rifamycin antibiotics • Probenecid • Flavaspidic acid • Bunamiodyl (a cholecystographic agent)

• Type I and II Crigler Najjar syndrome

• Hyperthyroidism • Ethinyl estradiol

• Novobiocin • Gentamicin

• Chronic persistent hepatitis • Advanced cirrhosis • Wilson's disease

Adult

Children

Neonates and infants

Heart failure Portosystemic shunt

Cirrhosis

Gilbert's Syndrome

Drug-induced defect

↓ or NoUGT activity

Inhibit UGT

Hepatocellular Disease

Biliary obstruction

Intrahepatic cholestasis

Reduced bilirubin uptake

Overproduction of bilirubin

Impaired bilirubin conjugation

Conjugated hyperbilirubinemia

Unconjugated hyperbilirubinemia

Jaundice