Treatments in Chronic Cholestasis in Children

Few specific treatments for children with chronic cholestasis are available. Most therapy strategies relieve bile component retention or palliate some of the consequences of chronic cholestasis. Ursodeoxycholic acid is the most frequently used pharmacological agent in children with chronic cholestasis. This bile acid is administered at dosages between 10 and 30 mg/kg/day to patients with cystic fibrosis, inborn errors of bile acid metabolism, progressive familial intrahepatic cholestasis, sclerosing cholangitis, biliary atresia, Alagille syndrome, or those receiving total parenteral nutrition. Ursodeoxycholic acid mainly increases bile flow and has a membrane-stabilizing effect, reducing the toxicity of more hydrophobic bile acids. Rifampicin, an antibiotic, at dosages between 10 and 20 mg/kg/day is very efficient in relieving pruritus. Similar effects are obtained using nonabsorbable ion exchange resins. In addition, these molecules decrease the serum cholesterol levels contributing to reduce xanthomas. Replacement of some deficiencies created by total parenteral nutrition by administration of essential fatty acids or cysteine can prevent or contribute to improve the associated liver disorders. In some cholestatic diseases, surgical procedures can help to relieve the obstacle to the bile flow, as it is the case for portoenterostomy in patients with Prof. Fernando Alvarez, MD Division of Gastroenterology, Hepatology and Nutrition CHU Sainte-Justine, University of Montreal 3175, Cote Sainte-Catherine road, Montreal, Qué. H3T 1C5 (Canada) E-Mail [email protected] © 2008 Nestec Ltd., Vevey/S. Karger AG, Basel 0517–8606/08/0663–0127$24.50/0 Accessible online at: www.karger.com/ane D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /7 /2 01 7 4: 56 :0 8 A M Alvarez Ann Nestlé [Engl] 2008;66:127–135 128 described below, aiming to avoid the enterohepatic recirculation of bile acids, can aggravate this situation. Pharmacological agents such as ursodeoxycholic acid (UDCA) and rifampicin improve choleresis by enhancing hepatocyte excretion of bile acids. Nonabsorbable ion exchange resins bind bile acids in the lumen of the intestine, decreasing its enterohepatic circulation. All these drugs increase choleresis and diminish pruritus and levels of cholesterol. Opioid antagonists have been proposed to treat pruritus; however, their limited availability, as well as their side effects, restricted their use in pediatrics ( table 1 ). Surgical interventions can be curative, as the Kasai intervention in some patients with biliary atresia, or palliative as the partial biliary diversion and the ilial exclusion in patients with Alagille syndrome or progressive familial intrahepatic cholestasis (PFIC). The latter could improve pruritus, decrease cholesterol retention and prevent evolution to cirrhosis. Ursodeoxycholic Acid UDCA (3 ,7 -dihydroxy-5  -cholan-24-oic acid) is present in small quantities in human bile, up to 3%, and is the result of the 7 epimerization of chenodeoxycholic acid by colonic bacteria [1] . The rather than the  hydroxy group at the 7th position gives UDCA a higher hydrophilicity when compared with chenodeoxycholic acid, its precursor. Thus, because of less hydrophobicity, UDCA is poor at micelle formation. In addition, it is poorly absorbed in the proximal intestine [1] . Mechanisms of Action – Replacement of more hydrophobic bile acids at the circulating pool and at cell membranes. After 6 months of treatment at 10–12 mg/kg/day, UDCA represents 40–50% of the bile acid pool [2] . Because of their detergent capabilities, more hydrophobic bile acids are toxic for cell membranes, causing hepatocellular damage and an increase in cholestasis. UDCA has a membrane-stabilizing effect, reducing disruption of cholesterol-rich membranes [3] . – UDCA, but not its conjugated form taurodeoxycholate, decreases the toxicity of lipophilic bile acids on the function of the electron transport chain in a concentration-dependent form (up to 100 mol/l), but increases bile acid-induced mitochondrial toxicity at higher concentrations [4] . – Interference in the ileum with the absorption of more toxic bile acids [2] . – UDCA is reabsorbed by the biliary epithelium in a protonated form and it is secreted again into bile (cholehepatic shunt) producing a hypercholeretic effect. Table 1. Available treatments for chronic cholestasis in children Treatment Indication Contraindication Side effects Dosage UDCA influence on the pathogenesis of PFIC, CF, TPN; ‘pruritus’ obstruction of bile ducts (e.g., failure of portoenterostomy in BA) diarrhea 20–30 mg/kg/day Rifampicin ‘pruritus’ mycobacterium infection1 10–20 mg/kg/day Nonabsorbable ion exchange resins ‘pruritus’ hypercholesterolemia intestinal stenosis or subocclusion constipation hyperchloremic acidosis 8–16 g orally daily divided in 2–3 times (increased progressively from 2 g orally daily) Opioid antagonists ‘pruritus’ 4 withdrawal reactions ? -3 fatty acids TPN-induced liver disease 4 4 1 g/kg/day (increased progressively from 0.2 mg/kg/day) NAC TPN-induced liver disease 4 4 70–135 mg/kg/day (increased progressively from 20 mg/kg/day) Associations of some of these drugs are usually required. BA = Biliary atresia. D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /7 /2 01 7 4: 56 :0 8 A M Treatments in Cholestasis Ann Nestlé [Engl] 2008;66:127–135 129 The protons absorbed lead to the formation of bicarbonate that is secreted and enrich the bile in this component [2] . – UDCA increases the bile salt-independent flow [1, 2] . – UDCA may stimulate transporter expression at the canalicular hepatocyte surface [5] . – A reduction in human leukocyte antigen class I expression at the hepatocyte surface has been reported [6] . – UDCA also suppresses interferon-mediated induction of human leukocyte antigen class II expression via the glucocorticoid receptor-mediated pathway [7] . UDCA is responsible for very few and transitory side effects, such as diarrhea and skin reactions more probably due to drug adjuvants than to the active substance. However, it should be avoided or carefully administered to patients with an obstructive bile duct disease. In experimental animals with a ligation of the main bile duct, UDCA can aggravate bile infarcts [8] . In children with biliary atresia and unsuccessful Kasai intervention, UDCA can precipitate a liver failure. UDCA is the most frequent drug used in children with chronic cholestasis. In several diseases, the benefit of the long-term administration of UDCA has not been proven beyond any doubt, as is the case for cystic fibrosis (CF). In other cases, the administration of the drug improves liver tests, but not the final outcome, as in patients with sclerosing cholangitis. In PFIC, it appears to stop the progression of the disease in some children and, associated with cholic acid, it is the treatment of choice in patients with inborn errors of the bile acid metabolism. In children with Alagille syndrome or biliary atresia, UDCA is mainly used to reduce symptoms such as pruritus. Cystic Fibrosis After 2 months of UDCA therapy, the presence of this bile acid represents between 25 and 42% of the pool, at the expense of cholic and chenodeoxycholic acids; these differences are dose dependent [9] . From these studies, it was concluded that the recommended dosage of UDCA is 20 mg/kg/day or greater [9] . UDCA stimulates the biliary secretory capacity in livers of CF patients, as determined by hepatobiliary scintigraphy [10] . Several pilot studies have shown that UDCA is responsible for an improvement in biochemical tests, mainly a decrease in serum levels of aminotransferases (ALT and AST) and -glutamyl transferase (GGT) [11] . In addition, liver inflammation and/or bile duct proliferation were improved after 2 years of UDCA therapy in control biopsies. UDCA administration also improves the nutritional state of young adults with CF and, in children, ameliorates essential fatty acids and retinol status [12–14] . However, because of poor UDCA activity in micelle formation it did not affect steatorrhea [13] . If UDCA modifies the natural history of liver diseases in CF patients, it still remains to be studied in a large randomized prospective study. Encouraging results were recently reported on UDCA-induced arrest or even reversion of liver ultrasound lesions observed in patients with CF, in a long-term study [15] . Total Parenteral Nutrition Fasting associated with total parenteral nutrition (TPN) leads to bile stasis related to lack of stimulation of the bile acid-dependent and -independent bile flow. In a model of TPN-induced cholestasis, the intravenous administration of UDCA improved bile flow and reduced bilirubin levels [16] . Similar encouraging results were recorded in a pilot study of children with intractable diarrhea depending on TPN, but tolerating UDCA at the dosage of 30 mg/kg/day in 3 daily doses [17] . In very low birth weight infants with TPN-associated cholestasis, UDCA at doses of 10–30 mg/kg/day reduces the duration and intensity of cholestasis [18] . In most of these patients, intestinal complications, including partial resections of the bowel, preclude the standard use of UDCA. Eventually, a very fractionated daily dosage of the medication can be well tolerated, avoiding diarrhea. Unfortunately, the UDCA intravenous form is not commercially available. Inborn Errors of Bile Acid Metabolism Two main forms of bile acid synthesis defect are responsible for chronic cholestasis in children: the 3-oxo4-steroid 5 -reductase deficiency and the 3 -hydrosteroid5-oxireductase/isomerase deficiency. Hepatotoxicity is probably due to the accumulation of bile acid precursors and the lack of primary bile acids. To reduce the synthesis of toxic molecules, the activity of cholesterol 7 hydroxylase, the rate-limiting enzyme in endogenous bile acid synthesis, must be inhibited. Most patients respond only partially to UDCA treatment alone; association of cholic acid (250 mg/day) is therefore indicated. The administration of chenodeoxycholic and cholic acids has also been proposed in these patients. The latter treatment can lead to a faster improvement in the liver injury [19] . Progressive Familial Intrahepatic Cholestasis UDCA is a valuable initial treatment for patients with PFIC when administered orally at doses between 20 and D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /7 /2 01 7 4: 56 :0 8 A M Alvarez Ann Nestlé [Engl] 2008;66:127–135 130 30 mg/kg/day. Similar improvement was observed no matter the PFIC type, meaning patients with normal (PFIC types 1 and 2) or increased levels (PFIC type 3) of serum GGT. In patients with normal GGT, an improvement in parameters of cholestasis was observed in 61% of cases and in 71% of those with type 3 PFIC [20] . The duration of the disease prior to the beginning of the UDCA treatment could influence these results; early diagnosis and initiation of UDCA therapy could further improve the final outcome. In some patients, the improvement, even if complete, is only transitory, and the cholestasis reappears some years after the beginning of UDCA. In patients with less deleterious mutations in genes responsible for types 1 or 2 of PFIC, a benign recurrent intrahepatic cholestasis is observed. In benign recurrent intrahepatic cholestasis patients, UDCA treatment fails in preventing a cholestatic episode, but could improve some of the symptoms (e.g., pruritus) [21] . Sclerosing Cholangitis An initial pilot study of UDCA in patients with welldeveloped sclerosing cholangitis showed an improvement in liver tests. Later, a statistically significant difference in the serum levels of ALT/AST/GGT was observed between UDCA and placebo-treated patients with sclerosing cholangitis during a study of 3 years of follow-up [22] . An improvement in pruritus and fatigue was also observed, but the difference was not significant. Unfortunately, more recent results in a randomized, doubleblind study comparing UDCA (13–15 mg/kg/day) with placebo showed no differences in treatment failure (progression of the disease, death or liver transplantation). This study confirmed an improvement in liver tests, but concluded that UDCA did not offer clinical benefits to patients with sclerosing cholangitis [23] . Thus, low dosages of UDCA apparently do not modify the progression of this disease. A very recently published study showed that, on the contrary, high doses of UDCA were associated with an improvement in survival and a trend toward stability/improvement in the histological stage in a relatively small group of patients with sclerosing cholangitis [24] . Despite these results, new trials could be proposed using high dosages of UDCA very early in the evolution of sclerosing cholangitis, and particularly in patients with small duct disease. When the disease affects the main bile ducts (as in most cases), probably, the disturbance in the bile flow can contribute irreversibly to the aggravation of the liver disease. The larger experience in the use of UDCA in chronic cholestatic diseases was obtained in adult patients with primary biliary cirrhosis, a severe form of intrahepatic cholangiopathy [25] . Different groups showed controversial results with UDCA therapy, partially explained by the different time in the evolution of the disease at the starting of treatment. The dose of UDCA administered also appears to play a role in the influence of this medication on the final outcome. This vast experience should be considered in planning new trials in patients with sclerosing cholangitis. Biliary Atresia An early preliminary study using UDCA after hepatic portoenterostomy showed that this drug was effective in patients with a good postoperative bile drainage, resulting in lower total bile acid levels and better weight gain [26] . Long-term administration of UDCA significantly improves the final outcome after Kasai portoenterostomy, more patients cleared jaundice and survived with their native liver. In children without recovery of a good bile flow after portoenterostomy, UDCA administration can lead to faster development of liver injury, and eventually, precipitates a liver failure [27] . Alagille Syndrome Few reports are available on the use of UDCA in patients with Alagille syndrome. Improvement in the jaundice and pruritus was found, as well as a decrease in circulating lipid levels and a decrease in xanthomas [28] . No controlled study is available; however, UDCA is widely prescribed to these patients. The influence of this bile acid in the natural history of the disease is still unknown.