Bilirubin cholestasis

E Bilirubin. Cholestasis may dramatically impair clearance of anthracyclines (including doxorubicin), and dose reductions are recommended for elevated bilirubin levels. Diabetes and asthma are unlikely to affect doxorubicin clearance or toxicity. Although the baseline platelet count is somewhat low in this patient, the myelosuppression from anthracyclines is primarily seen as leukopenia, and thrombocytopenia is rarely severe. Because anthracyclines are primarily eliminated in the bile, renal impairment (often present in patients with multiple myeloma) does not affect routine dosing. 

Boyce W, Witzleben CL. 1973. Bilirubin as a cholestatic agent, n. Effect of variable doses of bilirubin on the severity of manganese-bilirubin cholestasis. Am J Pathol 72 427-432. 

De Lamirande E, Plaa GL. 1978. Role of manganese, bilirubin and sulfobromophthalein in manganese-bilirubin cholestasis in rats (40189). Proc Soc Exp Biol Med 158 283-287. 

Witzleben CL, Boyer JL, Ng OC. 1987. Manganese-bilirubin cholestasis. Further studies in pathogenesis. Lab Invest 56 151-154. 

Cholestasis (increased total bilirubin, direct bilirubin, alkaline phosphatase, and y-glutamyl transferase)... 

Carbamazepine therapy is occasionally associated with hepatic toxicity, usually a hypersensitivity hepatitis that appears after a latency period of several weeks and involves increases in ALT, AST, and lactate dehydrogenase levels. Cholestasis is also possible, with increases in bilirubin and alkaline phosphatase concentrations. Mild, transient increases in transaminase levels generally do not necessitate discontinuation of carbamazepine. If ALT or AST levels increase more than three times the upper limit of normal, carbamazepine should be discontinued. 

In some studies, women taking estradiol or conjugated estrogens for hormone replacement therapy had no cholestasis or hepatotoxicity, as assessed by rises in serum alkaline phosphatase, bilirubin, or transaminases, whereas these effects did occur with ethinylestradiol. 

A 73-year-old woman who had taken acarbose 450 mg/ day for 3 months became very tired and icteric (61). Her total bilirubin was 427 pmol/l (direct bilirubin 335 pmol/1) and her liver enzymes were very high. Liver biopsy showed cholestasis and cytolysis without eosinophils. Acarbose was continued for 3 days and her condition did not change. When the acarbose was withdrawn she improved rapidly. 

Bilirubin. An increase in the bilirubin level and an accompanying increase in aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities most often result from obstmctive jaundice developed as a consequence of pancreas head edema and pressure exerted on the papilla of Vater (cholestasis). 

Viral hepatitises Cholestasis, cytolysis of hepatocytes, intoxication Sorption of viruses, bile acids, and bilirubin Monotherapy combination with hepatoprotectors... 

Bilirubin is carried within the plasma by albumin to the liver, where it is conjugated by glucuronidation. Subsequently, low circulating albumin levels and/or damage to the liver cells result in reduced conjugation of the bilirubin. Blockage of the biliary tract (e.g. cholestasis) will result in increased levels of... 

Alkaline phosphatase (ALP) is present in high concentrations in the cells lining the biliary tract and an ALP level exceeding 300 IU/L, together with a raised bilirubin as in the case of Mrs MW, is indicative of cholestasis. Jaundice becomes progressively more severe in unrelieved cholestasis. 

Possible increase in serum conjugated bilirubin Obstruction of bile flow commonly due to common bile duct stone or pancreatic carcinoma Failure of bile secretion Extrahepatic cholestasis Intrahepatic cholestasis... 

Liver enzymes and serum bilirubin should be measured before treatment is commenced to indicate the degree of cholestasis. These parameters should then be closely monitored, with treatment being stopped if a significant increase is seen. The optimum duration of treatment has yet to be defined, but it is recommended that the minimum effective dose should be used for the shortest period. 

The findings of this study suggest that women who are already jaundiced at the initiation of HRT are most at risk of increased bilirubin levels and cholestasis. In view of this it would seem sensible that, as well as assessing bilirubin levels prior to treatment, women who want to take HRT should also be assessed for any history (including family history) of jaundice. This will include specific defects in bilirubin excretion, such as intrahepatic cholestasis of pregnancy or familial conjugated hyper-bilirubinaemia, which may worsen cholestasis. 

As this patient has cholestasis they may be at a higher risk of HRT causing a further increase in bilirubin levels and worsening cholestasis. Liver function tests should be measured before treatment is started, and be monitored closely during treatment. Treatment should be stopped if a significant change occurs. 

Differentiation between obstructive and parenchymatous cholestasis is possible in > 90% of cases. A serum bilirubin level of up to 30 mg/dl is not seen as a methodological impediment to sequential scintigraphy. In incomplete obstruction with nondilated bile ducts, this technique provides more information than can be obtained using ultrasound. (17, 18)... 

Additional cholestasis Isolated defects in the transport mechanisms of bilirubin not only display jaundice, but also an impairment in the secretion of bile. The outcome is additional intrahepatic, nonobstructive cholestasis. 

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). 

As a result of impaired bilirubin conjugation, unconjugated lipophilic bilirubin IXa increases (80-85% of the total bilirubin gives rise to an indirect diazo reaction). This free bilirubin can pass unhindered through biological membranes and hence have a toxic impact on cells. Many factors may affect the various stages of the metabolic process, which is still incomplete up to this point. Cholestasis is absent in these diseases. (59) (s. tab. 12.4)... 

The clinical picture is characterized by chronic or intermittent jaundice with values between 2 and 6 mg/dl, and in rare cases between 6 and 12 mg/dl. With acute icteric episodes, values can be in excess of 20 mg/dl. The proportion of conjugated bilirubin in the serum is about 60%, almost exclusively in the form of diglucuronidated bilirubin. The liver or spleen are only occasionally enlarged (50-60% or 10-15% of cases, respectively). Both the laboratory values and the bile acids in the serum are normal cholestasis is absent. Coagulation factor VII is frequently reduced (approx. 60% of cases). In more pronounced jaundice, bilirubinuria and urobilinogenuria are in evidence. Excretion of coproporphyrin I in the... 

Determination of total bilirubin with differentiation between direct (conjugated) and indirect (unconjugated) bilirubin Determination of cholestasis-indicating enzymes (AP, LAP, y-GT) bile acids and bile pigments in the urine (s. tab. 12.6) Test for signs of haemolysis (s. tab. 12.3)... 

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. 

In classifying cholestasis, the cause, localization and duration of the disease as well as the involvement of bilirubin metabolism must be considered. Laboratory parameters of liver cell damage (increased activity of GPT, GOT and GDH) may be attributed to the underlying liver disease, but can also appear subsequently during the course of cholestasis-related hepatocellular damage, (s. tab. 13.1)... 

Jaundice does not necessarily accompany cholestasis. In severe and prolonged cholestasis, particularly if obstructive, jaundice is generally always in evidence. In cholestasis, the third fraction, known as delta bilirubin, can largely be detected by means of the diazo method. This fraction is firmly bound to albumin and can therefore only be dissociated and excreted slowly. For this reason, jaundice occurring together with cholestasis tends to subside at a significantly slower rate than the increased bile acid level in the serum. In this case, jaundice is due to a reflux of bilirubin from the canaliculus into the blood or a bidirectional transport of bilirubin via the sinusoidal membrane. Sometimes jaundice is caused by metabolic dysfunction of the liver cells. Bilirubin also acts as an antioxidant. 

Feathery degeneration is the term used to describe the delicate honeycomb-like, brownish streaky change of liver cells, which is due to bilirubin impregnation of the visible cytoplasmic structures. It can occur following long-term cholestasis. Cellular hydrops is evident with dilation of the endoplasmic cisternas, caused by the toxic impact of biliary acids, (s. fig. 13.4)... 

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