• Yellowish discoloration of tissue, also called icterus, resulting from the deposition of bilirubin, which occurs only in the presence of serum hyperbilirubinemia.
  • Jaundice is not usually detected until the serum bilirubin level exceeds 3.0 mg/dL.
  • Although usually a sign of significant disease, many persons have a congenital predisposition to mild jaundice (e.g., Gilbert’s syndrome) that is not pathologic.
  • Inherited Unconjugted hyperbilirubinemia : Gilbert’s syndrome and Crigler-Najjar syndrome
  • Inherited Conjugated hyperbilirubinemia : ​​Dubin-Johnson syndrome and Rotor’s syndrome
Mechanism of jaundice: 
  • Bilirubin is an end product of hemoglobin catabolism. Its serum level reflects a balance between input from production of bilirubin, Hepatic/biliary removal of pigment. 
  • Bilirubin is conjugated within the liver to glucuronic acid. Only conjugated bilirubin can be excreted into bile. It then passes into the intestines where it turns the stool dark. Intestinal flora also degrades bilirubin into urobilinogen, which is reabsorbed and excreted in the urine, turning it dark as well.
  • Unconjugated bilirubin binds to serum proteins and does not follow the above pathways. Thus, in cases of unconjugated bilirubinemia, neither dark stools nor the presence of urobilinogen occur.
  • Hyperbilirubinemia may result from
    • Overproduction of bilirubin, which results in an increase in unconjugated bilirubin (e.g., from massive hemolysis)
    • Impaired uptake, conjugation, or excretion of bilirubin: In physiologic neonatal jaundice, hepatic physiologic processes are incompletely developed at birth.
    • Regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts
    • Obstruction of bile ducts as in cancer or stones results in an increase primarily in conjugated bilirubin.
Symptoms & Signs
  • Stigmata of chronic liver disease
    • Commonly seen in advanced alcoholic cirrhosis and occasionally in other types of cirrhosis
      • Spider nevi
      • Palmar erythema
      • Gynecomastia
      • Caput medusae
      • Dupuytren’s contractures
      • Parotid gland enlargement
      • Testicular atrophy
      • Enlarged left supraclavicular node (Virchow’s node) or periumbilical nodule (Sister Mary Joseph’s nodule) Suggests abdominal malignancy
  • Jugular venous distention
    • Sign of right-sided heart failure
    • Suggests hepatic congestion
    • Right pleural effusion in absence of clinically apparent ascites, may be seen in advanced cirrhosis
  • Abdominal examination may reveal hepatomegaly, splenomegaly, tender liver and ascites.
Isolated indirect (unconjugated) hyperbilirubinemia
  • Physiologic neonatal jaundice
  • Hemolytic disorders: Spherocytosis, Sickle cell anemia, G6PD deficiency, Microangiopathic hemolytic anemia, hemolytic uremic syndrome,  Paroxysmal nocturnal hemoglobinuria , Auto immune hemolysis
  • Resorption of large hematoma 
  • Ineffective erythropoiesis : Cobalamin, folate, thalassemia, and severe iron deficiencies
  • Drugs : Rifampicin,probenecid, ribavirin
  • Inherited conditions
    • Crigler-Najjar syndrome
    • Gilbert’s syndrome: Marked by impaired conjugation of bilirubin due to reduced bilirubin uridine diphosphate glucuronosyltransferase activity
Isolated direct (conjugated) hyperbilirubinemia
  • Found in 2 rare inherited conditions
    • Dubin-Johnson syndrome
    • Rotor’s syndrome
Causes of elevation of both conjugated and unconjugated bilirubin (percent of conjugated bilirubin usually >50%)
  1. Hepatocellular diseases
    • Viral hepatitis :  Hepatitis A,B, C, D, and E, EBV , CMV, Herpes simplex
    • Drug toxicity like acetaminophen
    • Wilson disease
    • Autoimmune hepatitis
    • Alcoholic hepatitis
  2. Hepatic cirrhosis from any cause : Alcohol is the leading cause of cirrhosis
  3. Cholestatic conditions
    • When the pattern of the liver tests suggests a cholestatic disorder, the next step is to determine whether it is intra- or extrahepatic, which can be difficult.
    • Absence of biliary dilatation suggests intrahepatic cholestasis.
    • Biliary dilatation suggests extra hepatic cholestasis.
    • False-negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis or primary sclerosing cholangitis.
Intrahepatic cholestasis
  • Diagnosis often is made by serologic testing in combination with percutaneous liver biopsy.
  • A number of conditions that typically cause a hepatocellular pattern of injury can also present as cholestatic variants. Hepatitis B and C can cause cholestatic hepatitis (fibrosing cholestatic hepatitis) .
  • Drug-induced cholestasis
  • Primary biliary cirrhosis : Progressive destruction of interlobular bile ducts
  • PSC : Characterized by destruction and fibrosis of larger bile ducts. In 95% of patients, both intra- and extra hepatic ducts are involved. May involve only intrahepatic ducts and present as intrahepatic cholestasis. 
  • Cholestasis of pregnancy:  Occurs in second and third trimesters. Resolves after delivery. 
  • Other causes include:
    • Total parenteral nutrition (TPN) Jaundice
    • Nonhepatobiliary sepsis
    • Benign postoperative cholestasis
    • Congestive hepatopathy 
    • Infiltrative diseases like amyloid, lymphoma and TB
    • Paraneoplastic syndrome is associated with a number of different malignancies
    • HLH syndrome
    • Patients may develop cholestasis in intensive care unit. Major considerations should be sepsis, shock liver, and TPN jaundice.
    • Jaundice occurring after bone marrow transplantation most likely is due to venoocclusive disease or graft-versus-host disease.
Malignant causes of extrahepatic cholestasis
  • Pancreatic and gallbladder tumors
  • Ampullary carcinoma
  • Cholangiocarcinoma : Most commonly associated with PSC. Exceptionally difficult to diagnose because appearance often identical to PSC
Non-neoplastic (benign) causes of extra hepatic cholestasis
  • Choledocholithiasis Most common cause of extra hepatic cholestasis
  • Chronic pancreatitis rarely causes strictures of distal common bile duct, where it passes through head of pancreas.
  • AIDS cholangiopathy: Usually due to infection of bile duct epithelium with CMV or cryptosporidia
  • Parasitic disease (ascariasis)
Diagnostic Approach
  • History (focus on medication/drug exposure)
  • Physical examination
  • Lab tests: bilirubin with fractionation, alanine aminotransferase (ALT), aspartate (AST), alkaline phosphatase, prothrombin time, and albumin
  • If bilirubin and other liver tests are elevated, look at the pattern of abnormalities.
    • Hepatocellularpattern: ALT/AST elevated out of proportion to alkaline phosphatase
      • Viral serologies: hepatitis A IgM, hepatitis B surface antigen and core antibody, hepatitis C RNA
      • Toxicology screen:acetaminophen level
      • Ceruloplasmin (if patient < 40 years of age)
      • Antinuclear antibody, smooth muscle antibody( found in chronic auto immune hepatitis), liver–kidney microsomal antibody, serum protein electrophoresis
      • Additional virologic testing [e.g., CMV , EBV , hepatitis D antibody, hepatitis E IgM
      • Liver biopsy
    • Cholestatic pattern: alkaline phosphatase out of proportion to ALT/AST
      • Obtain an abdominal ultrasound.
      • If ultrasound shows dilated ducts, extrahepatic cholestasis: CT/endoscopic retrograde cholangiopancreatography (ERCP)
      • If ultrasound shows ducts not dilated, intrahepatic cholestasis: serologic testing for antimitochondrial antibody( primary biliary cirrhosis), hepatitis serologies, hepatitis A, CMV, EBV and review of drugs
      • Liver biopsy
Laboratory Tests
  • Serum bilirubin : Normal serum bilirubin concentration usually < 1 mg/dL
  • Urine bilirubin : Bilirubinuria implies presence of liver disease
  • Conjugated bilirubin: Filtered by glomerulus and most of it is reabsorbed by proximal tubules. A small fraction is excreted in urine.
  • Unconjugated bilirubin: Always bound to albumin in serum and not filtered by kidney
  • Enzyme tests : ALT, AST, Alkaline phosphatase
  • Albumin and prothrombin time
    • Low albumin suggests chronic process such as cirrhosis or cancer
    • Normal albumin suggests more acute process such as viral hepatitis or choledocholithiasis 
    • Elevated prothrombin time indicates either Vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or Significant hepatocellular dysfunction
    • Failure of prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.
Further testing in hepatocellular disease
  • Appropriate testing for acute viral hepatitis, including:
    • Hepatitis A IgM antibody
    • Hepatitis B surface antigen and core IgM antibody
    • Hepatitis C viral RNA : Can take many weeks for hepatitis C antibody to become detectable; unreliable if acute hepatitis C suspected
    • Depending on circumstances, the following studies may be indicated:
      • Hepatitis D
      • Hepatitis E
      • EBV
      • CMV
      • Drug levels (acetaminophen)
    • Wilson disease: Initial screening test is Ceruloplasmin
    • Hemochromatosis : check Iron, transferrin, and ferritin
    • Autoimmune hepatitis : ANA, Anti-smooth muscle and liver-kidney microsomal antibodies
    • Antimitochondrial antibody is found in 95% of patients with primary biliary cirrhosis
    • Alpha-1-antitrypsin activity
  • Ultrasound
  • CT
  • ERCP
    • "Gold standard" for identifying choledocholithiasis
    • Used to make diagnosis of primary sclerosing cholangitis : Multiple strictures of bile ducts with dilatations proximal to strictures.
  • Magnetic resonance cholangiopancreatography ( MRCP )
    • noninvasive technique for imaging the bile and pancreatic ducts. Particularly useful in the diagnosis of primary sclerosing cholangitis. 
    • It has replaced ERCP as the initial diagnostic test in cases where the need for intervention is felt to be small.

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