Bilirubin Physiology
- Bilirubin: tetrapyrrole formed by the breakdown of hemoglobin and other hemoproteins
- Bilirubin is highly insoluble in water
- Bilirubin Metabolism: due to water insolubility of bilirubin, it needs to be converted into a soluble conjugate before it can be excreted
- Hepatic uridine disphosphate (UDP)-gluconyl transferase (UGT) converts bilirubin (via an esterification reaction) to conjugated bilirubin (a mixture of bilirubin monoglucuronide and bilirubin diglucuronide)
- Conjugated bilirubin is excreted into the bile by an ATP-dependent transporter
- Bilirubin diglucuronide accounts for 80% of the pigment in normal human bile (this percentage decreases in patients with decreased UGT activity)
- As the conjugation and excretion process is normally very efficient, plasma concentrations of unconjugated bilirubin are normally low
- Renal Filtration of Bilirubin: the kidneys do not filter unconjugated bilirubin (as it is avidly bound to albumin)
- Therefore, the presence of bilirubinuria indicates the presence of conjugated bilirubinemia
Laboratory Assay of Bilirubin
- Assay: assay of bilirubin involves its cleavage in the presence of diazotized sulfanilic acid to generate a colored azodipyrrole, which is assayed spectrophtometrically
- Due to limited water solubility, unconjugated bilirubin reacts slowly in absence of an accelerator (such as ethanol), while conjugated bilirubin reacts rapidly
- Total Bilirubin: measured in presence of accelerator
- Direct Bilirubin: measured in absence of accelerator
- Approximates the conjugated bilirubin concentration in most cases, but is not necessarily the same thing
- Indirect Bilirubin: calculated by subtracting total-direct bilirubin
- Approximates the unconjugated bilirubin concentration in most cases, but is not necessarily the same thing
- Clinical Patterns
- Predominantly unconjugated bilirubinemia -> indicates the presence of a disease with either increased bilirubin production, impaired bilirubin conjugation, or impaired hepatic bilirubin uptake
- Predominantly conjugated bilirubinemia -> indicates presence of hepatobiliary diesase
- Mixed unconjugated and conjugated bilirubinemia -> indicates presence of disease which impairs the secretion of conjugated bilirubin into bile or disease which impairs the flow of bile into intestine
Etiology of Hyperbilirubinemia (see also Elevated Liver Function Tests)
Unconjugated (Indirect) Hyperbilirubinemia
Increased Bilirubin Production
- Dyserthropoiesis
- Primary Shunt Hyperbilirubinemia (Idiopathic Dyserythropoietic Jaundice)
- Hematoma
- Hemolytic Anemia (Extravascular/Intravascular) (see Hemolytic Anemia)
- Paroxysmal Nocturnal Hemoglobinuria (PNH) (see Paroxysmal Nocturnal Hemoglobinuria)
- Sickle Cell Disease (see Sickle Cell Disease)
- Thalassemias (see Thalassemias)
- Physiology
- Severe Hemolytic Anemia
- Types
- Hemoglobin H Disease (Alpha Thalassemia Intermedia)
- Beta Thalassemia Major (Cooley’s Anemia)
- Physiology
- Wilson Disease (see Wilson Disease)
- Physiology
- Coombs-Negative Hemolytic Anemia (see Hemolytic Anemia): may occur in some cases
- Decreased Hepatic Bilirubin Uptake and Conjugation
- Physiology
Impaired Hepatic Bilirubin Uptake
- Congestive Hepatopathy (Passive Hepatic Congestion) (see Congestive Hepatopathy): due to congestive heart failure (CHF)
- Drugs
- Bunamiodyl Cholecystographic Contrast Agent
- Flavaspidic Acid
- Probenecid (see Probenecid)
- Rifamycins (see Rifamycins)
- Rifabutin (see Rifabutin)
- Rifampin (Rifampicin, Rifadin) (see Rifampin)
- Rifapentine (Priftin) (see Rifapentine)
- Gilbert Syndrome (see Gilbert Syndrome)
- Physiology: impaired hepatic bilirubin uptake occurs in some cases
- Portosystemic Shunt
- Naturally-Occurring Portosystemic Shunt
- Transjugular Intrahepatic Portosystemic Shunt (TIPS) (see Transjugular Intrahepatic Portosystemic Shunt)
- Wilson Disease (see Wilson Disease)
- Physiology
- Coombs-Negative Hemolytic Anemia (see Hemolytic Anemia): may occur in some cases
- Decreased Hepatic Bilirubin Uptake and Conjugation
- Physiology
Impaired Bilirubin Conjugation
- Breast Milk Jaundice
- Crigler-Najjar Syndrome (Type I and II) (see Crigler-Najjar Syndrome)
- Ethinyl Estradiol (see Estrogen): found in almost all oral contraceptives (see Oral Contraceptives)
- Gilbert Syndrome (see Gilbert Syndrome): decreased hepatic bilirubin uptake and/or decreased conjugation
- Hyperthyroidism (see Hyperthyroidism)
- Hypothyroidism (see Hypothyroidism)
- Liver Disease
- Chronic Hepatitis
- Hepatitis B Virus (HBV) (see Hepatitis B Virus)
- Hepatitis C Virus (HCV) (see Hepatitis C Virus)
- Cirrhosis (see Cirrhosis)
- Wilson Disease (see Wilson Disease)
- Physiology
- Coombs-Negative Hemolytic Anemia (see Hemolytic Anemia): may occur in some cases
- Decreased Hepatic Bilirubin Uptake and Conjugation
- Physiology
- Chronic Hepatitis
- Maternal Serum Jaundice
- Neonatal Physiologic Jaundice
Conjugated (Direct) Hyperbilirubinemia
Inherited Disorders
- Rotor Syndrome (see Rotor Syndrome)
- Physiology: defective sinusoidal reuptake of conjugated bilirubin
- Dubin-Johnson Syndrome (see Dubin-Johnson Syndrome)
- Physiology: defective canalicular organic anion transport
Intrahepatic Cholestasis
- Acute Fatty Liver of Pregnancy (see Acute Fatty Liver of Pregnancy)
- Acute Viral Hepatitis
- Cytomegalovirus (CMV) (see Cytomegalovirus)
- Epstein-Barr Virus (EBV) (see Epstein-Barr Virus)
- Hepatitis A Virus (see Hepatitis A Virus)
- Hepatitis B Virus (HBV) (see Hepatitis B Virus)
- Hepatitis C Virus (HCV) (see Hepatitis C Virus)
- Alcoholic Hepatitis (see Alcoholic Hepatitis)
- Alpha-1 Antitrypsin Deficiency (see Alpha-1 Antitrypsin Deficiency)
- Autoimmune Hepatitis (see Autoimmune Hepatitis)
- Benign Postoperative Cholestasis
- Caroli Disease (see Caroli Disease)
- Chronic Viral Hepatitis
- Hepatitis B Virus (HBV) (see Hepatitis B Virus)
- Hepatitis C Virus (HCV) (see Hepatitis C Virus)
- Cirrhosis (see Cirrhosis)
- Congestive Hepatopathy (Passive Hepatic Congestion) (see Congestive Hepatopathy
- Epidemiology: due to congestive heart failure (CHF) (see Congestive Heart Failure)
Drugs/Toxins
- Acetaminophen (Tylenol) (see Acetaminophen)
- Alkylated Steroids
- Arsenic (see Arsenic)
- Chlorpromazine (Largactil, Thorazine) (see Chlorpromazine)
- Erythromycin (see Erythromycin)
- Jamaican Bush Tea (see Jamaican Bush Tea)
- Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition)
Graft vs Host Disease (GVHD) (see Graft vs Host Disease)
- Epidemiology: following hematopoietic stem cell transplant (HSCT) (see Hematopoietic Stem Cell Transplant)
Hemochromatosis (see Hemochromatosis) Hepatic Infiltration
- Amyloidosis (see Amyloidosis)
- Hepatocellular Carcinoma (see Hepatocellular Carcinoma)
- Liver Abscess (see Pyogenic Liver Abscess)
- Liver Metastases
- Lymphoma (see Lymphoma)
- Sarcoidosis (see Sarcoidosis)
- Tuberculosis (see Tuberculosis)
- Wegener’s Granulomatosis (see Wegener’s Granulomatosis)
Hepatic Veno-Occlusive Disease (VOD) (see Hepatic Veno-Occlusive Disease) Intrahepatic Cholestasis of Pregnancy (see Pregnancy) Ischemic Hepatitis (Hypoxic Hepatitis, Shock Liver) (see Ischemic Hepatitis)
- Physiology: hepatic hypoperfusion
Non-Alcoholic Fatty Liver Disease (NAFLD) (see Non-Alcoholic Fatty Liver Disease) Post-Liver Transplant (see Liver Transplant) Pre-Eclampsia (see Pre-Eclampsia, Eclampsia) Primary Biliary Cirrhosis (PBC) (see Primary Biliary Cirrhosis) Reye Syndrome (see Reye Syndrome) Sepsis (see Sepsis)
- Physiology
- Hepatic Hypoperfusion
Sickle Cell Disease (Hepatic Crisis) (see Sickle Cell Disease)
Extrahepatic Cholestasis (Biliary Obstruction)
- Acute Pancreatitis (see Acute Pancreatitis)
- Biliary Infection
- AIDS Cholangiopathy (see Human Immunodeficiency Virus)
- Ascaris Lumbricoides (see Ascariasis)
- Liver Flukes (Trematodes)
- Clonorchis (see Clonorchiasis)
- Fasciola (see Fascioliasis)
- Metorchis (see Metorchiasis)
- Opisthorchis (see Opisthorchiasis)
- Biliary Stricture
- Chronic Pancreatitis with Stricture of Distal Bile Duct (see Chronic Pancreatitis)
- Post-Liver Transplant Biliary Anastomotic Stricture (see Liver Transplant)
- Post-Procedure
- Primary Sclerosing Cholangitis (PSC) with Extrahepatic Bile Duct Stricture (see Primary Sclerosing Cholangitis)
- Secondary Sclerosing Cholangitis (see Secondary Sclerosing Cholangitis)
- Choledocholithiasis (see Cholelithiasis)
- Epidemiology: most common etiology of extrahepatic biliary obstruction
- Malignant Biliary Obstruction
- Ampullary Carcinoma (see Ampullary Carcinoma)
- Cholangiocarcinoma (see Cholangiocarcinoma)
- Gallbladder Cancer (see Gallbladder Cancer)
- Pancreatic Cancer (see Pancreatic Cancer)
Clinical Manifestations
Gastrointestinal/Hepatic Manifestations
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References
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