Rotor syndrome
Dubin–Johnson syndrome
Intrahepatic cholestasis
Familial and congenital
Progressive familial intrahepatic cholestasis types 1–3
Benign recurrent intrahepatic cholestasis
Cholestasis of pregnancy
Choledochal cysts, Caroli disease
Congenital biliary atresia
Hepatocellular conditions
Alcohol-related disorders
Viral hepatitis
Autoimmune hepatitis
Cirrhosis
Drug-related hepatitis
Wilson disease
Hereditary hemochromatosis
Infiltrative conditions
Granulomatous
Carcinoma
Hematological malignant disease
Amyloidosis
Cholangiopathies
Primary biliary cirrhosis
Idiopathic adult ductopenia
Autoimmune (overlap) cholangiopathies
Infections
Bacterial
Fungal
Parasitic
HIV related
Miscellaneous causes
Postoperative sepsis
Pregnancy
Total parenteral nutrition
Cholestasis after liver transplantation
Drug hepatotoxicity
Extrahepatic cholestasis
Inside bile ducts
Calculi
Parasites
Inside wall
Stricture
Cholangiocarcinoma
Sclerosing cholangitis
Choledochal cysts
Outside duct wall
Tumor in porta hepatis
Tumor in pancreas
Pancreatitis, acute or chronic
Congenital forms
Rotor syndrome is a rare, asymptomatic, autosomal recessive disorder that manifests as mild conjugated hyperbilirubinemia (2–5 mg/dL) in childhood. It is unclear whether the primary defect involves impaired hepatocyte secretion or impaired storage of bilirubin; although oral cholecystograms appear normal, biliary scintigraphy shows absent or delayed secretion. Dubin–Johnson syndrome is an asymptomatic autosomal recessive disorder from the impaired secretion of bilirubin, which produces serum bilirubin levels of 2–5 mg/dL. The results of scintigraphy and oral cholecystography are abnormal, whereas histological examination of the liver reveals darkly pigmented tissue. Patients with progressive familial intrahepatic cholestasis (PFIC) present with watery diarrhea, cholestasis, fat-soluble vitamin deficiency, jaundice, and occasionally pancreatitis caused by defective hepatic secretion of bile acids at the canalicular membrane. PFIC exists in different forms; all are autosomal recessive disorders, which have been mapped to several cloned transporters (FIC1, BSEP, MDR3). Choledochal cysts and Caroli disease are congenital malformations of the bile ducts and can manifest as jaundice or cholangitis, and eventually, cholangiocarcinoma. Choledochal cysts often are resectable, whereas Caroli disease (type IV choledochal cyst) usually requires liver transplantation for cure because of its diffuse intrahepatic nature.
Familial forms
Benign recurrent intrahepatic cholestasis (BRIC) presents with intense pruritus and elevated alkaline phosphatase levels, with mild increases in levels of aminotransferases and serum bilirubin (<10 mg/dL). Attacks, which begin from age 8 to 30, can last weeks to months, only to recur every several months to years. Liver biopsies reveal centrilobular cholestasis, which appears to be related to altered bile acid transport and enterohepatic circulation. BRIC is a milder form of PFIC-1 and, similarly, is caused by mutations in the FIC1 gene. Cholestasis of pregnancy is an autosomal dominant trait that manifests in the third trimester as pruritus. This benign condition must be distinguished from acute fatty liver of pregnancy, toxemia, acute cholecystitis, and acute or chronic hepatitis.
Acquired forms
Acquired disorders constitute the largest group of diseases that manifest conjugated hyperbilirubinemia. Many of these conditions are associated with cholestasis and can exhibit symptoms of pruritus, hypercholesterolemia, and steatorrhea. Intrahepatic cholestasis may result from liver disease (e.g. fulminant hepatitis, chronic hepatitis with significant hepatocellular dysfunction, and the recovery phase of acute hepatitis), infections, and medications. Hyperbilirubinemia occurs in alcoholic patients with acute fatty liver, alcoholic hepatitis, and cirrhosis. Of patients with alcoholic hepatitis, 10–20% present with a predominantly cholestatic condition, which may have a poor prognosis if bilirubin levels exceed 10 mg/dL or if encephalopathy, renal failure, or coagulopathy develop. Primary hepatic malignancy, lymphoma, and metastatic carcinoma cause hyperbilirubinemia late in their courses, whereas cholangiocarcinoma and other biliary obstructing lesions produce early jaundice. Bone marrow transplant patients may develop jaundice because of chemotherapy-induced veno-oclusive disease and acute or chronic graft-versus-host disease. Postoperative jaundice may result from anesthesia, intrahepatic cholestasis, transfusions, hypotension, hypoxia, and hemolysis.
Rheumatological disorders (e.g. rheumatoid arthritis, systemic lupus erythematosus, and scleroderma) elevate alkaline phosphatase levels but rarely produce jaundice. Sjögren syndrome has an increased occurrence of antimitochondrial antibodies and is associated with primary biliary cirrhosis, which produces jaundice late in its course. Congestive heart failure, shock, and trauma may produce hyperbilirubinemia, whereas renal failure can exacerbate hyperbilirubinemia from any cause. Furthermore, obstructive jaundice increases the risk of renal insufficiency, especially in the postoperative period.
Infections can cause jaundice by bile duct obstruction (e.g. ascariasis), cholestasis (e.g. tuberculosis), or by sepsis and endotoxemia. Infections with Legionella, Escherichia coli, Klebsiella, Pseudomonas, Proteus, Bacteroides, and Streptococcus produce conjugated hyperbilirubinemia. Two-thirds of patients with acquired immunodeficiency syndrome have elevated levels of aminotransferases or alkaline phosphatase because of hepatitis, infectious sclerosing cholangitis, papillary stenosis, acalculous cholecystitis, malignancy, or medication effects, and all of these disorders may elevate bilirubin levels.
Hepatotoxicity accounts for 3.5% of adverse drug effects. Oral contraceptives induce intrahepatic cholestasis that leads to jaundice in up to 4 of 10,000 patients. Nonsteroidal anti-inflammatory drugs can cause hepatitis, cholestasis, granulomatous liver disease, and hypersensitivity reactions. Acetaminophen can produce dose-dependent hepatotoxicity, a condition that occurs at lower doses in individuals who consume significant quantities of alcohol. Alcohol induces expression of cytochrome P450 and leads to increased metabolism of acetaminophen to its hepatotoxic metabolite. Alcoholic patients also may have reduced glutathione stores secondary to chronic malnutrition. Isoniazid produces jaundice in 1% of patients. Chemotherapeutic agents delivered into the hepatic arterial circulation may cause a syndrome similar to sclerosing cholangitis. Numerous other medications affect the liver; when identified, the offending medication should be discontinued. Total parenteral nutrition causes hyperbilirubinemia as a result of intrahepatic cholestasis, infection, and the development of gallstones.
The common extrahepatic obstructive causes of jaundice include stones, blood, and malignant and benign strictures. Gallstone disease represents the most common cause of obstructive jaundice in the United States, although biliary parasitic infection is a common problem in certain areas of the world. The most common malignant causes include pancreatic carcinoma, cholangiocarcinoma, and lymphoma. Pancreatitis may produce swelling of the pancreatic head, leading to common bile duct obstruction. Primary sclerosing cholangitis (PSC) is most commonly associated with inflammatory bowel disease. With obstructive jaundice, alkaline phosphatase levels are elevated concurrently. For hyperbilirubinemia to develop, the bile ducts must be largely obstructed. Ductal dilation may not be detectable on radiographs for 72 h or in chronic liver disease, such as PSC.
Unconjugated hyperbilirubinemia
Hemolysis and ineffective erythropoiesis
Hemolysis and ineffective erythropoiesis lead to overproduction of bilirubin that exceeds the conjugative capability of the liver. Hemolysis may result from sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase deficiency, paroxysmal nocturnal hemoglobinuria, ABO blood group incompatibility, or medications. Severe hemolysis rarely elevates serum bilirubin levels above 5 mg/dL, although hepatocyte dysfunction or Gilbert syndrome can magnify the hyperbilirubinemia. Iron deficiency, vitamin B12 deficiency, lead toxicity, sideroblastic anemia, and dyserythropoietic porphyria produce unconjugated hyperbilirubinemia due to ineffective erythropoiesis. Resorption of large hematomas may also increase production of unconjugated bilirubin.
Neonatal jaundice
Physiological neonatal jaundice is noticed in the first 5 days of life in term infants; unconjugated bilirubin levels peak near 6 mg/dL by day 3 and then decrease to normal within 14 days because of the increased activity of uridine diphosphate glucuronosyltransferase (UGT), the hepatic enzyme responsible for bilirubin conjugation. Higher levels of unconjugated bilirubin may persist up to 1 month in preterm infants. Nonphysiological causes in neonates include ABO blood group incompatibility between mother and infant, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and hypothyroidism. Lucey–Driscoll syndrome is transient unconjugated hyperbilirubinemia resulting from a UGT inhibitor in the mother’s blood. Breast milk jaundice, which may produce bilirubin levels up to 20 mg/dL, results from an inhibitor of UGT activity in breast milk. Severe unconjugated hyperbilirubinemia produces kernicterus in infants, which manifests as lethargy, hypotonia, and seizures.
Uridine diphosphate glucuronosyltransferase deficiencies
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