Cholestasis

Another sinusoidal transporter catalyzes Na+-independent uptake of organic anions and is instrumental for biliary clearance of glucuronidated and sulfated steroids, the diagnostic chemical bromosulfophthalein (BSP) and possibly bilirubin. Canalicular transport of glucuronidate and GSH conjugates is coupled to ATP 

Toxicity to bile duct epithelial cells also causes cholestasis. Necrosis of these cells can result in sloughing of an obstructive cast into the duct lumen. The experimental chemical a-naphthylisothiocyanate (ANIT) is known to target bile duct epithelial cells in addition to hepatocytes. Bile duct epithelial toxicity is GSFI-dependent and is thought to depend upon concentrative accumulation within bile ducts subsequent to hepatocanalicular transport of the ANIT-GSH conjugate. 

---

Yellow phosphorus was the first identified liver toxin. It causes accumulation of lipids in the liver. Several liver toxins such as chloroform, carbon tetrachloride, and bromobenzene have since been identified. I he forms of acute liver toxicity are accumulation of lipids in the liver, hepartxiellular necrosis, iii-trahepatic cholestasis, and a disease state that resembles viral hepatitis. The types of chrome hepatotoxicity are cirrhosis and liver cancer. 

TABLE 5.13 Examples of Drugs that Induce Intrahepatic Cholestasis or Liver Damage Resembling That Induced by Viral Hepatitis... 

Antithyroid drags have several side effects. The most frequent side effects are maculopapular rashes, pruritus, urticaria, fever, arthralgia and swelling of the joints. They occur in 1-5% of patients [1, 2]. Loss of scalp hair, gastrointestinal problems, elevations of bone isoenzyme of alkaline phosphatase and abnormalities of taste and smell are less common. The incidence of all these untoward reactions is similar with MMI and PTU. Side effects of MMI are dose-related, whereas those of PTU are less clearly related to dose [1]. PTU may cause slight transient increases of serum aminotransferase and y-glutamyl transpeptidase concentrations but also severe hq atotoxicity whereas methimazole or carbimazole can be associated with cholestasis. The side... 

Pauli-Magnus C, Meier PJ (2006) Hepatobiliary transporters and drag-induced cholestasis. Hepatology 44 778-787... 

Familial lecithimcholesterol acyltransferase (LCAT) deficiency Absence of LCAT leads to block in reverse cholesterol transport. HDL remains as nascent disks incapable of taking up and esterifying cholesterol. Plasma concentrations of cholesteryl esters and lysolecithin are low. Present is an abnormal LDL fraction, lipoprotein X, found also in patients with cholestasis. VLDL is abnormal ( 3-VLDL). 

There is very little evidence relating to the role of ROMs in cholestatic liver disease. Serum selenium and glutathione peroxidase activity are decreased in humans with intrahepatic cholestasis of pregnancy (Kauppila et al., 1987). Low levels of vitamin E have been reported in patients with primary biliary cirrhosis, and in children with Alagille s syndrome or biliary atresia (Knight et al., 1986 Jeffrey etal., 1987 Lemonnier etal., 1987 Babin etal., 1988 Kaplan et al., 1988 Sokol etal., 1989). Serum levels of Mn-SOD are increased in patients with all stages of primary biliary cirrhosis compared with patients with other forms of chronic liver disease, although whether this causes or results from the disease process is unclear (Ono etal., 1991). 

Kauppila, A., Korpela, H., Makila, U-M. and Yrjanheikki, E. (1987). Low serum selenium concentration and glutathione peroxidase activity in intrahepatic cholestasis of pregnancy. Br. Med. J. 294, 150-152. 

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

Hepatobiliary disease occurs due to bile duct obstruction from abnormal bile composition and flow. Hepatomegaly, splenomegaly, and cholecystitis may be present. Hepatic steatosis may also be present due to effects of malnutrition. The progression from cholestasis (impaired bile flow) to portal fibrosis and to focal and multilobar cirrhosis, esophageal varices, and portal hypertension takes several years. Many patients are compensated and asymptomatic but maybe susceptible to acute decompensation in the event of extrinsic hepatic insult from viruses, medications, or other factors.7... 

Acid-base imbalance Acute liver failure Amphetamines Anaphylaxis Autoimmune diseases Cholestasis Chronic inflammatory diseases... 

Cholelithiasis, biliary sludge, acute and chronic cholecystitis, and cholestasis (can be progressive and life-threatening)... 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Trace elements are essential cofactors for numerous biochemical processes. Trace elements that are added routinely to PN include zinc, selenium, copper, manganese, and chromium. There are various commercial parenteral trace element formulations that can be added to PN admixtures (e.g., MTE-5 ). Zinc is important for wound healing, and patients with high-output fistulas, diarrhea, burns, and large open wounds may require additional zinc supplementation. Patients may lose as much as 12 to 17 mg zinc per liter of gastrointestinal (GI) output (e.g., from diarrhea or enterocutaneous fistula losses) however, others have demonstrated that 12 mg/day may be adequate to maintain these patients in positive zinc balance.18 Patients with chronic diarrhea, malabsorption, and short-gut syndrome may have increased selenium losses and may require additional selenium supplementation. Patients with severe cholestasis should have copper and manganese... 

It helps to limit PN-associated liver cholestasis by avoiding continuous compulsive nutrient overload on the liver.25... 

Trace elements Provide standard parenteral trace element preparation (containing zinc, copper, manganese, chromium, and selenium) daily in PN Assess patient for any possible adjustments needed (e.g., delete copper and manganese from PN if the patient has evidence of severe cholestasis, supplemental zinc and selenium for any Gl or fistula losses) or potential deficiencies... 

Total calories Hepatic steatosis, cholestasis, hypercapnia... 

The incidence of liver complications associated with PN ranges from approximately 7% to 84%, and end-stage liver disease develops in as many as 15% to 40% of adult patients on long-term PN.35 Patients often develop a mild increase in liver enzymes within 1 to 2 weeks of initiating PN, but this generally resolves when PN is discontinued. Severe liver complications include hepatic steatosis (fat deposition in liver), steatohepatitis (a severe form of liver disease characterized by hepatic inflammation that may progress rapidly to liver fibrosis and cirrhosis), cholestasis, and cholelithiasis.35... 

Pregnant or lactating women should not take orlistat because no data exist to establish safety. Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis.31... 

Cholestasis Reduced or lack of flow of bile, or obstruction of bile flow. 

Herbal remedies that have been reported to be he-patotoxic include chaparral (Larrea tridentata), germander (Teucrium chamaedrys), and life root (Senecio aureus) [18]. Cases reported patients developing jaundice, fatigue, pruritus, markedly elevated serum liver enzyme levels, severe cholestasis, hepatitis, and hepatocellular injury or necrosis documented by serial liver biopsies [19-21]. Signs and symptoms may occur as early as 3 weeks to as late as 7 months following ingestion [20,21]. 

MDR3, a homologue of MDR1, is responsible for the biliary excretion of phospholipids, and a hereditary defect in this gene results in the acquisition of progressive familial intrahepatic cholestasis Type 3 [80-82]. 

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. 

S. J., Helgason, C. D., Ackerley, C., Phillips, M. J., Ling, V., Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis, Proc. Natl. Acad. Sci. USA 2001, 98, 2011-2016. 

J., Kuliak-Ublick, G. A., Meier, P. J., Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver, Gastroenterology 2000, 118, 422-430. 

Huang, L., Smit, J. W., Meijer, D. K., Vore, M., Mrp2 is essential for estradiol-17beta( beta-D-glucuronide)-induced cholestasis in rats, Hepatology 2000, 32, 66-72. 

Soroka CJ, Lee JM, Azzaroli F, Boyer JL. Cellular localization and up-regula-tion of multidrug resistance-associated protein 3 in hepatocytes and cholangio-cytes during obstructive cholestasis in rat liver. Hepatology 2001 33(4) 783 791. 

De Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. 

---