Jaundice (Icterus): Causes

Pathogenesis (development of disease)

Icterus results from a marked elevation of bilirubin levels in the blood (hyperbilirubinemia). Physiological (“natural”) is a daily bilirubin synthesis of circa 300 mg, mainly in the liver and spleen by the breakdown of hemoglobin (80%). Bilirubin is insoluble in water and thus neither excreted in bile nor urinated. In the blood, bilirubin is bound to albumin (unconjugated bilirubin) and transported to the liver. There, the unconjugated bilirubin (indirect bilirubin) is taken up by the hepatocytes (liver cells) after cleavage from albumin and conjugated (coupled) to glucuronic acid by the enzyme UDP-glucuronosyltransferase, which converts it to the water-soluble form (conjugated bilirubin, direct bilirubin). The conjugated bilirubin (bilirubin diglucuronide) is excreted into the intestine with bile. In the terminal ileum (end section of the small intestine) and colon (large intestine), bilirubin is bacterially cleaved to form the bile pigments urobilinogen and stercobilin (brown-red color; main color of stool). The majority is subsequently excreted in the feces (stool). Approximately 20% of urobilinogen is absorbed in the intestine and returns to the liver via the enterohepatic circulation. Thus, it enters the bloodstream and is excreted by the kidneys. There are two types of hyperbilirubinemia:

  • Unconjugated hyperbilirubinemia (= indirect hyperbilirubinemia): increased total bilirubin with a proportion of direct bilirubin of less than 15%.
  • Conjugated hyperbilirubinemia (= direct hyperbilirubinemia; water-soluble form of bilirubin): concentration of conjugated bilirubin > 2 mg/dl or > 20% of total serum bilirubin.

Etiology (causes)

There are three forms/causes of jaundice:

  • Prehepatic icterus – ineffective hematopoiesis (blood formation) → increased Hb (hemoglobin) degradation/hemolysis → increase in bilirubin (especially indirect bilirubin; proportion of indirect bilirubin > 80% of total bilirubin) – e.g., due to hemolytic anemia, large hematomas (bruises), rhabdomyolysis (muscle dissolution), burns, etc.
  • Intrahepatic jaundice – intrahepatic cholestasis (bile stasis in the liver) or disturbed bilirubin metabolism → disturbance of uptake or conjugation, secretion → increase in bilirubin (especially indirect bilirubin).
    • Primary disorders of bilirubin metabolism (e.g., Meulengracht disease; Crigler-Najjar syndrome type 1; Dubin-Johnson syndrome; Rotor syndrome).
    • Secondary disorders of bilirubin metabolism (liver parenchymal damage, e.g., due to intrahepatic cholestasis/cholangitis; viral hepatitis; fatty liver; liver cirrhosis; hepatocellular carcinoma; intoxications (see below); leptospirosis, salmonella).
  • Posthepatic icterus – extrahepatic cholestasis (bile stasis outside the liver) → increase in direct bilirubin (e.g., due to choledocholithiasis; cholangiocellular carcinoma (CCC, cholangiocarcinoma, bile duct carcinoma, bile duct cancer); pancreatic carcinoma; biliary atresia; Ascaris infection).

Biographic causes

  • Genetic load
    • Genetic diseases
      • Alagille syndrome – genetic disorder with autosomal dominant inheritance, conspicuous by hepatic bile duct malformations and other organ malformations; cholestasis (biliary congestion) leading to jaundice already in the newborn; Typical facial abnormalities (broad forehead, deep-set eyes, hypertelorism/excessive interocular distance, narrow chin) and skeletal abnormalities (butterfly vertebrae, short distal phalanges, clinodactyly/lateral bending of one or more finger or toe limbs, shortened ulna/elbow).
      • Familial hyperbilirubinemia (elevation of bilirubin levels in the blood).
        • Meulengracht disease (Gilbert syndrome) – genetic disorder with autosomal recessive inheritance; benign form of hyperbilirubinemia [elevated indirect bilirubin].
        • Crigler-Najjar syndrome type 1 – congenital disorder in the metabolism of bilirubin with autosomal recessive inheritance; neonatal jaundice (neonatal jaundice) caused by wholly absent or minimal activity of bilirubin-UDP-glucuronyltransferase [elevated indirect bilirubin]
        • Dubin-Johnson syndrome (synonym: Dubin-Johnson-Sprinz syndrome) – genetic disorder with autosomal recessive inheritance leading to bilirubin excretion disorders; direct hyperbilirubinemia (severe elevation of bilirubin levels in the blood); typically mild icterus without pruritus (jaundice without itching); macroscopic: Black liver due to bilirubin pigment storage in the lysosomes (cell organelles) [increased direct bilirubin].
        • Rotor syndrome – genetic disease with autosomal recessive inheritance; bilirubin metabolism disorder [increased direct bilirubin].
      • Hemochromatosis (iron storage disease): congenital or hereditary hemochromatosis (HH; primary hemochromatosis) – genetic, autosomal recessive inheritance (4 (5) types are distinguished today, with type 1 (mutation in the HFE gene) being the most common in Europe: 1: 1,000).
      • Byler’s disease (progressive familial intrahepatic cholestasis (PFIC)) – genetic disease with autosomal recessive inheritance; cholestasis (biliary congestion) leading to biliary cirrhosis (gallbladder-related scarring shrinkage of the liver and loss of functional tissue)
      • Wilson’s disease (copper storage disease) – autosomal recessive inherited disease in which copper metabolism in the liver is disturbed by one or more gene mutations.
      • Cystic fibrosis (ZF) – genetic disease with autosomal recessive inheritance, characterized by the production of secretions in various organs to be tamed.
      • Summerskill-Tygstrup syndrome (idiopathic recurrent cholestasis/bile stasis) – genetic disorder with autosomal recessive inheritance; benign form of hyperbilirubinemia (elevated bilirubin in the blood) with intermittent intrahepatic occlusive icterus in children and young adults; Familial hyperbilirubinemia syndromes with elevation of direct bilirubin; jaundice (jaundice) in the sclerae (white part of the eye) and mucous membranes, with more severe occurrence also clear of the skin
      • Zellweger syndrome (cerebral-hepatic-renal syndrome, cerebro-hepato-renal syndrome) – genetic metabolic disease with autosomal recessive inheritance, characterized by the absence of peroxisomes (spherical membrane-limited organelles); Syndrome with malformations of the brain, kidneys (multicystic kidney dysplasia), heart (especially ventricular septal defects), and hepatomegaly (enlargement of the liver); severe cognitive disability.

Behavioral causes

  • Consumption of stimulants
    • Alcohol – (woman: > 20 g/day; man: > 30 g/day).

Disease-related causes

  • AIDS cholangiopathy – changes in the bile ducts caused by AIDS disease.
  • Biliary atresia – congenital malformation describing the absence of bile ducts.
  • Budd-Chiari syndrome – thrombotic occlusion of the hepatic veins.
  • Cholangitis (inflammation of the bile duct)
  • Cholangiocellular carcinoma (bile duct cancer).
  • Choledocholithiasis – gallstones in the ductus choledochus (common bile duct).
  • Cholestasis or fatty liver in pregnancy.
  • Hemolytic anemia (anemia) such as spherocytosis (spherocytic cell anemia) or sickle cell anemia (med: drepanocytosis; also sickle cell anemia, English : sickle cell anemia).
  • Hepatitis (liver inflammation) of any genesis.
  • Heart failure (cardiac insufficiency)
  • Idiopathic ductopenia – an anomaly of the bile ducts, the cause of which is unknown.
  • Idiopathic postoperative jaundice – jaundice of unknown cause occurring after surgery.
  • Liver abscess – formation of an encapsulated collection of pus in the liver.
  • Liver carcinoma (liver cancer)
  • Liver metastases
  • Liver cirrhosis (connective tissue remodeling of the liver with functional impairment; especially alcoholic cirrhosis).
  • Leptospirosis – infectious disease caused by leptospires.
  • Mirizzi syndrome – narrowing of the common bile duct of the liver.
  • Neonatal icterus (Icterus neonatorum) due tolow activity of glucuronyltransferase in the first days of life (physiological).
  • Pancreatic carcinoma (pancreatic cancer).
  • Pancreatic pseudocysts – cystic formation in the area of the pancreas.
  • Pancreatitis (inflammation of the pancreas) – acute and chronic.
  • Papillary stenosis – narrowing of the confluence of the bile duct with the small intestine.
  • Parasitosis – parasites in the area of the bile ducts.
  • Pericholecystitis – inflammation of the gallbladder that also infiltrates the surrounding tissues.
  • Primary biliary cirrhosis – form of liver cirrhosis that occurs as a result of non-purulent bile duct inflammation; most commonly occurs in women
  • Primary sclerosing cholangitis – chronic inflammatory bile duct inflammation.
  • Sarcoidosis (synonyms: Boeck’s disease; Schaumann-Besnier’s disease) – systemic disease of connective tissue with granuloma formation (skin, lungs and lymph nodes).
  • Pregnancy cholestasis – bile stasis that occurs during pregnancy.
  • Sepsis (“blood poisoning”)
  • Congestive liver
  • Erythropoiesis (blood formation) disorders
  • Strictures (narrowing) of the bile ducts
  • Tuberculosis (consumption)
  • Tumors in the area of the bile ducts

Medication

Environmental pollution – intoxications (poisonings).

  • Phenol exposure
  • Mushroom poisoning

Other differential diagnostic considerations

Pseudoicterus

  • Excessive consumption of vegetables such as carrots, leafy vegetables, zucchini.
  • Excessive consumption of fruits such as oranges or peaches.
  • Condition after fluorescein angiography