Ursodeoxycholic acid in the treatment of cholestasis and hyperbilirubinemia in pediatric intensive care unit patients.

ABSTRACT

Background. The purpose of this study was to evaluate the efficacy of ursodeoxycholic acid (UDCA) in the treatment of cholestasis and hyperbilirubinemia in a pediatric intensive care unit population.

Methods. Medical records were retrospectively reviewed to identify children and adolescents in the pediatric intensive care unit (PICU) who received UDCA for the treatment of hyperbilirubinemia and cholestasis.

Results. Ursodeoxycholic acid was administered at a dose of 20 mg/kg per day to 5 PICU patients with cholestasis and hyperbilirubinemia of various etiologies. In 4 of 5 patients, there was a decrease in serum bilirubin levels following the start of UDCA therapy. There was no response to therapy in 1 patient, who developed disseminated fungal disease and died. No adverse effects related to therapy were noted.

Conclusions. These preliminary data suggest that UDCA is effective in the treatment of cholestasis and hyperbilirubinemia of various etiologies in the PICU patient. Prospective, randomized trials are warranted to further assess the efficacy of this therapy in this patient population.

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CHILDREN IN THE PEDIATRIC INTENSIVE CARE UNIT (PICU) may suffer secondary complications related either to the disease process itself, treatment regimens and drug therapy, or opportunistic infections. Several factors may be responsible for the development of cholestasis and subsequent hepatic dysfunction, including hypoxia from hypoxemia or hypoperfusion, direct or metastatic infiltration of the liver, pharmacologic agents (including chemotherapeutic agents), and opportunistic infections that directly invade the liver or induce inflammatory changes resulting in hepatitis and/or cholestasis. Additionally, various factors may interfere with the ability to provide adequate enteral nutrition in the PICU patient, requiring the use of parenteral nutrition for varying periods of time until adequate enteral intake is tolerated. Parenteral nutrition and the lack of enteral feeding may cause or further aggravate cholestasis. The effects of one or a combination of these conditions can result in either intrahepatic or ext rahepatic cholestasis.

Patients with cholestatic liver disease may develop hepatotoxic injury from endogenous bile acids, resulting in progressive hepatic damage, hepatic failure, and, ultimately, death. (1,2) Treatment of these patients with orally administered exogenous bile acids, such as ursodeoxycholic acid (UDCA), can decrease intrahepatic cholestasis and potentially decrease the hepatotoxic effects of endogenous bile acids and prevent hepatic failure. (3-5) The initial experiences using this form of therapy for various etiologies of cholestatic liver disease have been promising. (6-8) We present our experience with UDCA in the treatment of the multifactorial cholestatic liver disease in 5 PICU patients.

METHODS

This retrospective chart review was approved by the hospital's Institutional Review Board. The pharmacy database was searched to identify patients aged [greater than or equal to] 18 years who had been admitted to the PICU and received UDCA for the treatment of cholestatic liver disease. Demographic data gathered included patient age, sex, primary underlying disease process, and potential etiologies for the cholestasis. The maximum bilirubin (direct and indirect) values and the change in bilirubin levels following the administration of UDCA were recorded. Data collected regarding UDCA included the dose, duration of therapy, and potential adverse effects.

RESULTS

Ursodeoxycholic acid was administered to 5 PICU patients over a 12-month period. The demographic data, primary disease process, potential etiologic factors for cholestasis and hyperbilirubinemia, as well as. the maximum direct and indirect bilirubin levels prior to the start of treatment with UDCA are listed in Table 1. The starting dose of UDCA was 20 mg/kg, divided every 12 hours, by mouth or nasogastric tube. This dose was continued as maintenance therapy in 4 of the 5 patients. The dose, duration of therapy, and response to therapy (as measured by the serum bilirubin levels) are listed in Table 2. In the fifth patient, the dose was increased to 30 mg/kg per day because there was a progressive increase in the serum bilirubin levels, despite the start of UDCA.

DISCUSSION

We report our preliminary experience with UDCA to treat cholestasis and hyperbilirubinemia in 5 PICU patients. Previous experience has demonstrated the efficacy of UDCA in the treatment of cholestatic liver disease in both adults and children; however, the data from previous studies have involved patients with a uniform etiology for their cholestatic process, with long-term evaluations in the outpatient setting. In critically ill patients in the PICU setting, several factors may be responsible for cholestasis, including the primary disease process (sepsis, shock, leukemic infiltrate), lack of enteral feedings, use of total parenteral nutrition (TPN), secondary infectious agents, various pharmacologic agents (eg, amphotericin B, chemotherapeutic agents), and multisystem organ failure.

Regardless of the etiology, of prime importance is the elimination of potentially treatable causes of cholestasis and hyperbilirubinemia. The initial evaluation should include a search for treatable infectious etiologies (especially in patients with associated hepatitis), elimination of hepatotoxic drugs, treatment and reversal of inciting events (eg, hypoperfusion or hypoxemia), and an evaluation of the biliary system to rule out conditions requiring surgery (eg, cholelithiasis). In the PICU setting, removal of all potential etiologic factors may not be possible, since TPN may be essential to provide adequate calories, essential amino acids, and fats. In our 5 patients, imaging of the biliary tree did not reveal cholelithiasis or other abnormalities of the biliary system. Likewise, the work-up for potential infectious etiologies, including hepatitis screens and urine cultures for cytomegalovirus, was negative. It was impossible to identify a single etiologic factor that was responsible for cholestasis and h yperbilirubinemia in any of our patients. It is most likely that cholestasis, like many PICU problems, is multifactorial. In all 5 patients, we noted a decrease in both the total and direct bilirubin levels with the start of UDCA therapy. In 1 patient (patient 5), the initial response was short-lived and was followed by progressive hyperbilirubinemia, despite increasing the UDCA dose to 30 mg/kg per day.

Untreated cholestasis and hyperbilirubinemia can have significant consequences, aside from the issues of pruritus and jaundice. Patients with cholestatic liver disease can develop secondary hepatocellular injury from one of several possible mechanisms. Endogenous bile acids are hydrophobic. Retention of bile acids leads to solubilization of cholesterol and phospholipids in the cellular membranes of hepatocytes and the biliary canaliculi. (9) Endogenous bile acids increase intracellular calcium concentration, leading to intracellular organelle dysfunction and accelerated apoptosis. Oxidative phosphorylation is uncoupled in the mitochondrial membrane, leading to cellular adenosine triphosphate (ATP) depletion. (10) In the presence of increased concentration of endogenous bile acids, there is increased cellular influx of magnesium, which stimulates magnesium-dependent endonucleases and results in cell death. (11) Retained bile acids also have a cholestatic effect, reducing bile flow by altering vesicular transpo rt and sodium/potassium ATPase activity, thereby further increasing the cholestatic process and the above-mentioned pathologic processes. As hepatocytes are damaged, cytokines are released and human leukocyte antigen (HLA) class I antigens are expressed on hepatocytes, which may lead to autoimmune-related injury. (12) Therefore, regardless of the primary etiology of cholestatic liver disease, the retention of endogenous bile acids leads to the development of severe secondary hepatocellular injury and further aggravates the primary problem of cholestasis. If cholestasis goes untreated, the secondary effects can compound the initial disease process and potentially progress to hepatocellular dysfunction and even hepatic failure.

Ursodeoxycholic acid was initially identified as a major constituent of dried bile from the Chinese black bear. Prior to modern use, it was used as a treatment for various liver diseases in ancient Chinese medicine. In Japan in the 1950s, UDCA was combined with vitamins in pill form and used for the treatment of various liver ailments. Initial clinical trials with UDCA demonstrated its efficacy in the nonsurgical management of cholelithiasis. (13) In humans, UDCA accounts for only 3% of total bile salts. With oral administration, 30% to 60% is absorbed through the small intestine. (14) If UDCA is solubilized in a mixture of micelles from endogenous bile acids, the absorption in the small intestine is more efficient. Once absorbed, UDCA is secreted into the bile, undergoes enterohepatic circulation, and is reabsorbed in the distal ileum.

The current clinical and laboratory evidence suggests 2 potential mechanisms for UDCA: an effect at the level of the biliary tree, resulting in increased bile flow; and a direct effect on hepatocytes, preventing the potential hepatotoxic effects of hydrophobic bile acids. (15,16) When present in secreted bile, UDCA decreases the absorption of endogenous bile acids and decreases the level of toxic hydrophobic bile acids. Ursodeoxycholic acid reduces disruption of cholesterol membranes and mitochondrial injury by endogenous bile acids. A full discussion of the potential mechanisms of action, as well as the reported applications of UDCA therapy in the pediatric population, can be found in articles by Beuers et al (15) and Balistreri. (16)

The current cohort of patients provides preliminary evidence to support the efficacy of UDCA in the treatment of cholestatic liver disease in the PICU population. Previous reports (15,16) have demonstrated the potential role of UDCA in the treatment of infants and children with cholestatic liver disease of various etiologies, including cystic fibrosis, inborn errors of bile-acid synthesis, Alagille syndrome, Byler disease, biliary atresia, and cholestasis associated with TPN. Unlike previous reports, in which the cholestatic process was generally related to a single etiology, we found UDCA effective in the treatment of the multifactorial cholestatic liver disease that may occur in the PICU patient. Although we cannot conclusively prove a cause-and-effect relationship between the declining bilirubin levels and the use of UDCA, there was definitely a temporal relationship between the administration of UDCA and the decreasing bilirubin levels. The decrease occurred despite ongoing problems that were at least par tially responsible for the cholestasis.

Current UDCA dosage regimens are limited to enteral administration, with dosage recommendations of 10 to 20 mg/kg, and reports of escalations up to 30 to 45 mg/kg per day in refractory cases. (15,16) As there is no pediatric suspension available, the doses must be prepared from the commercially available 300 mg capsule. (17) Despite this minor limitation, and given its limited adverse-effect profile, we suggest that UDCA may be a useful adjunct in the treatment of cholestasis in the PICU patient. Prospective, randomized trials are needed to definitely prove its efficacy in this setting.

TABLE 1

Demographic Data, Underlying Disease Process, and Maximum Billrubin
Levels Before Administration of Therapy

                                       Primary
Patient No.  Age (Years)   Sex     Disease Process

     1           11        Male         ALL





     2          1.1        Male     Neuroblastoma






     3          1.5       Female   NEC, short gut
     4           10       Female   Septic shock
     5           14       Female   Hodgkin's disease





             Possible Etiology      Maximum Bilirubin:
Patient No.   for Cholestasis      Total/Direct (mg/dL)

     1       Leukemia, TPN,              3.7/18.4
             Bacteremia, Sepsis
             Chemotherapy:
               L-asparaginase,
               Prednisone,
               Vincristine
     2       Neuroblastoma:              16.8/3.3
               Hepatic metastasis
             Chemotherapy:
               Vincristine,
               Cyclophosphamide,
               Doxorubicin
             Sepsis, TPN
     3       Chronic TPN, Sepsis         7.6/6.8
     4       Shock, MSOF, TPN            6.2/4.8
     5       Leukemia, TPN               12.1/8.0
             Sepsis
             Chemotherapy:
               Bleomycin,
               Doxorubicin,
               Vinblastine

ALL=Acute lymphocytic leukemia; TPN=total parenteral nutrition;
NEC=necrotizing enterocolitis; MSOF=multisystem organ failure.

TABLE 2

Duration of and Response to Theapy

Patient No.  Duration   Response: Total/Direct Bilirubin (mg/dL)

     1       6 days     Day 6: 10.6/8.8 -- Patient developed
                        disseminated Aspergillus and care was
                        withdrawn at this point.

     2       14 days    Day 14: 4.5/3.9 -- Bilirubin normalized
                        at 2 weeks after discharge.

     3       12 months  Day 8: 3.2/2.6
                        Day 14: 0.9/0.4 -- Compared with baseline
                        values of 2.1/1.7 before acute event and
                        hospitalization.

     4       16 days    Day 8: 3.8/1.4
                        Day 16: 0.9/0.5

     5       7 days     Initial decline of total bilirubin by
                        3-4 mg/dL; then rapid increase to > 30
                        mg/dL, despite increasing does of UDCA
                        to 30 mg/kg per day. Patient developed
                        disseminated Aspergillus and died.

References

(1.) Schmucker DL, Ohta M, Kanai S, et al: Hepatic injury induced by bile salts: correlation between biochemical and morphological events. Hepatology 1990; 12:1216-1221

(2.) Attili AF, Angelico M, Canagora A, et al: Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses 1986; 19:57-69

(3.) Lim AG, Ahmed HA, Jazrawi RP, et al: The effect of ursodeoxycholic acid and chenodeoxycholic acid on human hepatocyte and erythrocyte membranes. Gut 1998; 34:45-49

(4.) Kitani K, Ohta M, Kanai S: Tauroursodeoxycholate prevents biliary protein excretion induced by other bile salts in the rat. Am J Physiol 1985; 248:G407-G417

(5.) Heuman DM, Bajaj R: Ursodeoxycholate conjugates protects against disruption of cholesterol-rich membranes by bile salts. Gastroenterology 1994; 106:1333-1341

(6.) Bellentani S, Podda M, Tiribelli C, et al: Ursodiol in the long-term treatment of chronic hepatitis C: a randomized clinical trial with long-term follow-up. Am J Gastroenterol 1995; 90:263-269

(7.) Poupon RE, Balkau B, Eschwege E, et al: A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med 1991; 324:1548-1554

(8.) Lindor KD: Ursodiol for primary sclerosing cholangitis. N Engl J Med 1997; 336:691-695

(9.) Javitt JB: Cholestasis in rats induced by taurolithocholate. Nature 1966; 210:599-604

(10.) Krahenbuhl S, Talos C, Fischer S, et al: Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology 1995; 22:607-612

(11.) Patel T, Bronk SF, Gores GJ: Increases of intracellular magnesium promotes glycodeoxycholate-induced apoptosis in rat hepatocytes. J Clin Invest 1994; 94:2183-2192

(12.) Calmus Y, Gane P, Rouger P, et al: Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology 1990; 11:12-15

(13.) Bachrach WH, Hofmann AF: Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Dig Dis Sci 1982; 24:737-762,833-858

(14.) Parquet M, Metman EH, Raizman A, et al: Bioavailability, gastrointestinal transit, solubilization and faecal excretion of ursodeoxycholic acid in man. Eur J Clin Invest 1985; 15:171-178

(15.) Beuers U, Boyer JL, Paumgartner G: Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology 1998; 28:1449-1453

(16.) Balistreri WF: Bile acid therapy in pediatric hepatobiliary disease: the role of ursodeoxycholic acid. J Pediatr Gastro Nutrit 1997; 24:573-589

(17.) Johnson CE, Nesbitt J: Stability of ursodiol in an extemporaneously compounded oral liquid. Am J Health Syst Pharm 1995; 52:1798-1800

RELATED ARTICLE: KEY POINTS

* Several factors, including parenteral nutrition, medications, malignant infiltration, sepsis, lack of enteral feedings, and multisystem organ failure, may be responsible for the development of hyperbilirubinemia and cholestasis in patients who are critically ill.

* Patients with cholestasis may develop hepatotoxic injury from endogenous bile acids, resulting in progressive hepatic damage, hepatic failure, and, eventually, death.

* Studies have shown ursodeoxycholic acid to be effective in the treatment of chronic cholestasis of various uniform etiologies in the outpatient setting.

* Ursodeoxycholic acid may be effective in the treatment of the multifactorial cholestasis and hyperbilirubinemia of patients in the pediatric intensive care unit.

From the Departments of Child Health and Anesthesiology, Division of Pediatric Critical Care/Pediatric Anesthesiology, University of Missouri, Columbia.

Reprint requests to Joseph D. Tobias, MD, Vice-Chairman, Department of Anesthesiology, Director, Pediatric Critical Care/Pediatric Anesthesiology, Professor of Anesthesiology and Child Health, University of Missouri, Department of Anesthesiology, 3W40H, One Hospital Drive, Columbia, MO 65212.