2 months old (exception when used with pyrimethamine in treating toxoplasmosis) as they increase unconjugated bilirubin leading to kernicterus. drugs such as protease inhibitors like indinavir can also cause disorders of bilirubin metabolism by competitively inhibiting the ugt1a1 enzyme. hepatitis (levels may be moderate or high) chemotherapy biliary stricture (benign or malignant) very high levels of bilirubin may be caused by: neonatal hyperbilirubinemia, where the newborn's liver is not able to properly process the bilirubin causing jaundice unusually large bile duct obstruction, e.g. stone in common bile duct, tumour obstructing common bile duct etc. severe liver failure with cirrhosis (e.g. primary biliary cirrhosis) crigler–najjar syndrome dubin–johnson syndrome choledocholithiasis (chronic or acute). cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis. to further elucidate the causes of jaundice or increased bilirubin, it is usually simpler to look at other liver function tests (especially the enzymes alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase), blood film examination (hemolysis, etc.) or evidence of infective hepatitis (e.g., hepatitis a, b, c, delta, e, etc.). jaundice main article: jaundice hemoglobin acts to transport oxygen which the body receives to all body tissue via blood vessels. over time, when red blood cells need to be replenished, the hemoglobin is broken down in the spleen; it breaks down into two parts: heme group consisting of iron and bile and protein fraction. while protein and iron are utilized to renew red blood cells, pigments that make up the red color in blood are deposited into the bile to form bilirubin. jaundice leads to raised bilirubin levels that in turn negatively remove elastin-rich tissues. jaundice may be noticeable in the sclera of the eyes at levels of about 2 to 3 mg/dl (34 to 51 μmol/l), and in the skin at higher levels. jaundice is classified, depending upon whether the bilirubin is free or conjugated to glucuronic acid, into conjugated jaundice or unconjugated jaundice.. urine tests urine bilirubin may also be clinically significant. bilirubin is not normally detectable in the urine of healthy people. if the blood level of conjugated bilirubin becomes elevated, e.g. due to liver disease, excess conjugated bilirubin is excreted in the urine, indicating a pathological process. unconjugated bilirubin is not water-soluble and so is not excreted in the urine. testing urine for both bilirubin and urobilinogen can help differentiate obstructive liver disease from other causes of jaundice. history in ancient history, hippocrates discussed bile pigments in two of the four humours in the context of a relationship between yellow and black biles. hippocrates visited democritus in abdera who was regarded as the expert in melancholy "black bile". relevant documentation emerged in 1827 when m. louis jacques thénard examined the biliary tract of an elephant that had died at a paris zoo. he observed dilated bile ducts were full of yellow magma, which he isolated and found to be insoluble in water. treating the yellow pigment with hydrochloric acid produced a strong green color. thenard suspected the green pigment was caused by impurities derived from mucus of bile. leopold gmelin experimented with nitric acid in 1826 to establish the redox behavior in change from bilirubin to biliverdin, although the nomenclature did not exist at the time. the term biliverdin was coined by jöns jacob berzelius in 1840, although he preferred "bilifulvin" (yellow/red) over "bilirubin" (red). the term "bilirubin" was thought to have become mainstream based on the works of staedeler in 1864 who crystallized bilirubin from cattle gallstones. rudolf virchow in 1847 recognized hematoidin to be identical to bilirubin. it is not always distinguished from hematoidin, which one modern dictionary defines as synonymous with it but another defines as "apparently chemically identical with bilirubin but with a different site of origin, formed locally in the tissues from hemoglobin, particularly under conditions of reduced oxygen tension." the synonymous identity of bilirubin and hematoidin was confirmed in 1923 by fischer and steinmetz using analytical crystallography. in the 1930s, significant advances in bilirubin isolation and synthesis were described by hans fischer, plieninger, and others, and pioneering work pertaining to endogenous formation of bilirubin from heme was likewise conducted in the same decade. the suffix ixα is partially based on a system developed fischer, which means the bilin's parent compound was protoporphyrin ix cleaved at the alpha-methine bridge (see protoporphyrin ix nomenclature). origins pertaining to the physiological activity of bilirubin were described by ernst stadelmann in 1891, who may have observed the biotransformation of infused hemoglobin into bilirubin possibly inspired by ivan tarkhanov's 1874 works. georg barkan suggested the source of endogenous bilirubin to be from hemoglobin in 1932. plieninger and fischer demonstrated an enzymatic oxidative loss of the alpha-methine bridge of heme resulting in a bis-lactam structure in 1942. it is widely accepted that irving london was the first to demonstrate endogenous formation of bilirubin from hemoglobin in 1950, and sjostrand demonstrated hemoglobin catabolism produces carbon monoxide between 1949 and 1952. 14c labeled protoporphyrin biotransformation to bilirubin evidence emerged in 1966 by cecil watson. rudi schmid and tenhunen discovered heme oxygenase, the enzyme responsible, in 1968. earlier in 1963, nakajima described a soluble "heme alpha-methnyl oxygeanse" which what later determined to be a non-enzymatic pathway, such as formation of a 1,2-dioxetane intermediate at the methine bridge resulting in carbon monoxide release and biliverdin formation. notable people claudio tiribelli, italian hepatologist, studies on bilirubin