Bilirubin metabolism disorders

Chowdhury JR et al Hereditary jaundice and disorders of bilirubin metabolism. In The Metabolic and Molecular Bases oflnher itedDisease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001. 

Iyanagi T, Emi Y, Ikushiro S. Biochemical and molecular aspects of genetic disorders of bilirubin metabolism. Biochim Biophys Acta 1998 1407(3) 173-184. 

Know the biochemistry and physiology of bilirubin and urobilinogen, be able to describe their use as diagnostic tools in liver diseases, and recognize the various disorders of bilirubin metabolism. 

Bosma PJ Inherited disorders of bilirubin metabolism./ Hepalol 38 107-117, 2003. 

Gilbert s syndrome - a genetic disorder of bilirubin metabolism which can result in mild jaundice, found in about 5% of the population. 

Three inherited disorders of bilirubin metabolism are associated with defects in bilirubin UGT-1 activity Gilbert s syndrome, and Crigler-Najjar syndrome types I and II. Dubin-Johnson syndrome is due to a defect in the protein pump that extrudes bilirubin from the hepatocyte... 

Table 2.7 Inherited disorders of hepatic bilirubin metabolism and transport [1,4]... 

A wide range of conditions fall into this gronp. They can be roughly categorised further into those causing cholestatic disease, chronic liver disease, acute liver failure/metabolic crisis, storage disorders, disorders of bilirubin metabolism. Table 3.5 snmmarises the types of liver disease that fall into each group. 

Disorders of bilirubin metabolism Gilbert s syndrome Dubin—Johnson syndrome Crigler—Najjar syndrome... 

Tab. 12.2 Different forms of jaundice classified in relation to the metabolic disorder of bilirubin and glucuronidation of bilirubin...

Dysfunction in the metabolism of bile acids (= cholestasis) is often combined with an additional dysfunction in bilirubin metabolism (= jaundice). The rise in bilirubin is the main biochemical and clinical symptom of jaundice it is based on a disorder of bilirubin metabolism. Thus cholestasis is related not directly but indirectly to jaundice. Depending on the constellation of the biochemical and clinical findings, the term jaundice with cholestasis or cholestasis with jaundice can be applied, (s. tabs. 12.1, 12.2, 12.4 13.1) The main clinical sign of advanced cholestasis is pruritus. 

Concurrent jaundice is either due to an additional disorder of bilirubin metabolism or to mechanical biliary... 

Genetically induced disorders of bilirubin metabolism affect (i.) bilirubin conjugation or (2.) bilirubin excretion through the canalicular membrane. This results in functional hyperbilirubinaemia. (s. tabs. 12.1, 12.4) see chapter 12)... 

Defects in bilirubin metabolism resulting in jaundice can occur at each step of the metabolic pathway (see Figure 31-22). The disorders are usually classified as (1) inherited disorders of bilirubin metabolism and (2) jaundice of the newborn. All of these disorders are characterized by predominant elevations in either conjugated or unconjugated bilirubm in the absence of other abnormal liver tests. It is only in these disorders that bilirubin fractionation is clinically useful. 

Serial measurement of bilirubin is helpful in measuring the severity of liver disease. Bhirubiti fractionation is helpfiil only in jaundice of the newborn or in isolated elevations of bilirubin in the absence of other Uver test abnormalities that would indicate an inherited disorder of bilirubin metabolism. 

Jaundice may be a consequence of haemolysis, cholestasis or hepatocellular damage. The causes and features of these arc summarized in Figure. 3 and Table I. In addition there are inherited disorders of bilirubin metabolism. Gilbert s disease is the most common and causes a mild unconJugated hyperbilirubinaemia because of defective conjugation of bilirubin. 

Multiple influences may cause a disorder in the metabolism of bilirubin inside the hepatocyte. This dysfunction may be localized in the premicrosomal, microsomal or postmicrosomal region of the liver cell. (s. tab. 12.2)... 

Hyperbilirubinaemia relates to functional disorders in the hepatocellular metabolism of bilirubin - with and without cholestasis (W. Siede, 1957). This means either dysfunctions regarding bilirubin conjugation (= conjugation jaundice) or bilirubin excretion (= excretion jaundice). 

The frequency of this harmless disorder in the metabolism of bilirubin is quite high it affects 5-12% of the population. The syndrome is 4 times more common in men than in women. Frequency in the affected families lies between 5% and 55%. Genetic transmission occurs in a dominant autosomal way with differing degrees of penetrance, which accounts for the heterogeneous clinical picture. Sporadic occurrences of this syndrome have also been observed. The gene is located on chromosome 2. 

Patients are occasionally seen with isolated elevations in bilirubin concentration. In most cases, this is due to inherited disorders of bilirubm metabolism, famihal hyperbilirubinemia, or hemolysis. It is not difficult to distinguish hemolysis severe enough to cause hyperbilirubinemia, because the patient with hemolysis wiU have many other disease manifestations. An algorithm for differentiating the familial causes of hyperbihrubinemia is presented in Figure 47-19. 

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