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By: D. Gambal, M.B. B.CH., M.B.B.Ch., Ph.D.
Vice Chair, Rocky Vista University College of Osteopathic Medicine
Bilirubin Metabolism and Icterus Bilirubin is the pigment that gives bile its yellow-brown color antibiotic valinomycin doxycycline 100 mg cheap. Heme resides in red cell hemoglobin and in many enzyme systems treatment for dogs diarrhea cheap 200 mg doxycycline fast delivery, which are preferentially localized in the liver (cytochromes infection in tooth purchase 200 mg doxycycline free shipping, catalase, and peroxidase). Although the pool size of hemoproteins in the liver is small compared with the hemoglobin pool, the production of bilirubin from hepatic heme accounts for 30% of the total production, because the hepatic heme turnover rate is much higher (2 hours to 4 days versus 98 days for hemoglobin). Bilirubin is cleared from the plasma by the liver, and has to be conjugated by the hepatocytes preceding biliary excretion. The unconjugated form is stringently hydrophobic and bound to albumin in the circulation. On conjugation, bilirubin is excreted into bile and the conju gate is not reabsorbed from the intestines. Rarely, in cases of bacterial overgrowth, bilirubin is deconjugated by bacterial enzymes and the unconjugated pigment is reab sorbed in the small intestines into an enterohepatic cycle. Bacterial degradation of bili rubin in the colon produces stercobilins, black and brown pigments that give feces its normal color. Cholestasis causes accumulation of conjugated bilirubin in plasma, which is not only re-excreted by the liver but may also be excreted by the kidneys in the urine. However, the kidney in dogs, particularly males, has all the enzymes to produce bilirubin out of heme and to conjugate it, so that it can be excreted into urine. Therefore, the urine of healthy male dogs may contain detectable concentrations of bilirubin. Urobilinogen is a colorless product, a small fraction of which is absorbed into the portal blood. Most of it is cleared by the liver, but a minor part reaches the systemic circulation and can be excreted by the kidneys. Measurement of urobilinogen in urine has been used to differentiate between different forms of icterus and cholestasis. However, due to many physiologic variations and technical errors, this parameter has no clinical value. Bilirubin is cleared from the blood, conjugated, and excreted into bile by the liver. The clearance is not an efficient process18,19 in contrast to the hepatic clearance of bile acids. Whereas bile acids are nearly completely cleared during the first passage, bilirubin requires many passages to become cleared completely (Fig. As a conse quence, bilirubin is equally distributed over the entire circulation, but bile acids are highly concentrated in the portal blood and have a low concentration in the systemic circulation. This explains the differences in the reaction pattern of bilirubin and bile Clinical Syndromes Associated with Liver Disease 423 Ineffective clearance and recirculation Complete clearance bilirubin in 1 circulation Bile acids gut Fig. Bile acids are reabsorbed and undergo an enterohepatic circulation, which is maintained by an efficient clearance of bile acids from the portal vein. Bilirubin is not absorbed from the small intestines and its hepatic clearance from the blood has low efficiency. Consequently, there is a high gradient between the portal and systemic concentrations of bile acids, but not of bilirubin. Furthermore, systemic bile acids are increased due to portosystemic shunting and cholestasis; bilirubin is only increased due to cholestasis (or increased production in case of severe hemolysis). In diseases with cholestasis, all bile components including bilirubin and bile acids gain entry to the systemic circulation with the hepatic lymph. This process is not related to hepatic clearance or portal perfusion of the liver. Conversely, in diseases characterized by portosystemic shunting (congenital porto systemic shunts, portal hypertension, acquired collateral circulation, and so forth), the high portal bile acid concentration reaches the systemic circulation giving a high plasma bile acid concentration. However, the bilirubin concentration is not influenced by abnormal liver perfusion. The main processes by which plasma bilirubin may increase are increased produc tion and cholestasis. An increased level becomes clinically visible only as icterus (yellow discoloration of sclerae, mucous membranes and skin) when the concentration exceeds 15 mmol/L. Due to the huge liver reserve capacity, most patients remain in the subclinical region and do not become icteric, despite the fact that nearly all nonvascular liver diseases leadto somedegreeofcholestasis.
- Low blood count (anemia)
- Hot flashes
- Abnormally short fingers and toes (brachydactyly)
- Drink 8 to 10 glasses of clear fluids every day. Water is best.
- Age (older patients are at increased risks of complications)
These guidelines recommend that a should be based on unbound blood/plasma concen pharmacokinetic study be carried out during development of trations antibiotics for sinus infection omnicef buy doxycycline 200 mg line, and dosage adjustment may be necessary even a medicinal product that is likely to bacteria questions and answers cheap doxycycline amex be used in patients with though total blood/plasma concentrations are within the impaired hepatic function and when hepatic impairment is normal range virus xp purchase doxycycline without prescription. Drugs with a low hepatic extraction ratio and low substance or its active metabolite(s). The primary objective plasma protein binding (<90%): the oral and intrave of such a study is to identify patients at risk and to assess nous clearance of these drugs is determined by the whether a dosage adjustment is required for patients with intrinsic capacity of the hepatic elimination mecha impaired hepatic function. These guidelines recommend that nisms and the unbound drug fraction in blood or the Child-Pugh classification be used to categorize patients plasma. The intrinsic clearance will be reduced to a according to their degree of hepatic impairment. In addition, degree determined by the functional status of the liver they encourage the use of exogenous markers to assess the and the specific metabolic pathway(s) involved in the elimination capacity of the patients by different mechanisms. Fluctuations in the unbound According to a recent survey, the number of medications drug fraction in blood or plasma are rather small and found to contain specific recommendations for dosage will not significantly affect blood/plasma clearance of adjustment based on hepatic function as determined by the drug. Dosage adjustment may be necessary and the Child-Pugh score is still rather limited . The elimination of drugs that are partly excreted in Child-Pugh classification C, i. It should be problems associated with giving investigational drugs that taken into account that creatinine clearance significant have no potential to confer benefit to patients with severe ly overestimates glomerular filtration rate in these liver disease merit careful consideration. The volume of distribution of hydrophilic drugs may be benefit by being quantified on the basis of an independent increased in patients with chronic liver disease who measure of metabolism of a marker known to be influenced have edema or ascites. As a consequence, the loading by liver disease in addition to clinical assessment by a dose may have to be increased in these patients if a semi-quantitative Child-Pugh score. Since When no recommendations for dosage adjustment in many hydrophilic drugs are eliminated primarily in patients with hepatic dysfunction based on their Child-Pugh unchanged form by the kidneys, renal function should score are available, the following general considerations be taken into consideration. Extreme caution is recommended when using drugs eliminated by hepatic mechanisms (metabolism, biliary with a narrow therapeutic index in patients with liver excretion). Drugs with a relatively high hepatic extraction ratio: with severe liver dysfunction (Child-Pugh class C). The oral bioavailability of these drugs can be drasti cally increased in patients with chronic liver disease, In conclusion, drugs must be given with caution to and the dosage should be reduced accordingly. Follow patients with severe hepatic insufficiency such as is the case 1158 Eur J Clin Pharmacol (2008) 64:1147?1161 in cirrhosis. J Hepatol 31: eliminated by hepatic mechanisms, their potential therapeu 165?178 tic benefits must be carefully counterbalanced with their 10. J Pharmacokinet Biopharm 1:123?136 drugs with a narrow therapeutic index and for sedatives, 11. Pharmacol Rev 39:1?47 central analgesics, and anxiolytics, which may precipitate 12. If these drugs are disease and portal hypertension: gut-liver interactions revisited. Dig Dis Sci 49:621?626 effect of (mostly) cirrhosis on the pharmacokinetic behav 14. It Clin Pharmacokinet 25:300?328 constitutes a valuable information base when selecting a 16. In addition, more recent review articles have pharmacokinetics?principles of therapeutic drug monitoring. Applied Therapeutics, San Francisco, pp 19?41 described the effect of liver disease on the pharmacokinet 17. Neugebauer G, Gabor M, Reiff K (1988) Pharmacokinetics and bioavailability of carvedilol in patients with liver cirrhosis. Drugs use of antineoplastic drugs in patients with liver disease, the 36(Suppl 6):148?154 authors of the review article conclude that not enough data 19. Gastroenterology 77:96?102 by metabolism, to allow quantitative advice for dose 21. Clin Pharmacokinet 29:370?391 pressure and heart rate in patients with liver cirrhosis after 5. Reichen J (1999) the role of the sinusoidal endothelium in liver intravenous and oral administration.