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Effective Opiate-Receptor Antagonist Therapy of Cholestatic Pruritus Induced by an Oral Contraceptive

2005; Lippincott Williams & Wilkins; Volume: 40; Issue: 5 Linguagem: Inglês

10.1097/01.mpg.0000148775.64966.96

1536-4801

Steffen Kunzmann, Gerd A. Kullak‐Ublick, Andreas Greiner, Reinhart Jeschke, Helge Hebestreit,

Cholesterol and Lipid Metabolism

INTRODUCTION Cholestatic jaundice can result from conditions such as infectious and metabolic diseases. Infrequent causes of intrahepatic cholestasis are pregnancy and oral contraceptive use (1). The risk of developing cholestasis during pregnancy ranges from 1-500 per 1,000,000. The risk with oral contraceptives is 100-250 per 1,000,000 (1,2). Both conditions seem to have the same pathophysiological basis (1). Women who experience pruritus and jaundice during pregnancy often develop the same symptoms during medication with oral contraceptives and vice versa (3). Both cholestasis of pregnancy and cholestasis during contraceptive therapy appear to be caused by elevated estrogen concentrations. In susceptible individuals, estrogen can induce cholestasis by impairing the capacity of the liver to excrete bile acids and other substances. Cholestasis is reversible within weeks after delivery or after estrogen therapy is stopped. Recurrent familial cases indicate a genetic predisposition for this form of intrahepatic cholestasis (4,5). Severe pruritus can be an early and frequent symptom of intrahepatic cholestasis. Pruritus can lead to severe psychologic and physical problems in affected patients. Treating physicians often treat pruritis as being less important than pain. Pruritus may limit normal activities and cause sleep deprivation, and can even be the cause of suicidal inclination (6). The relief of pruritus often presents a therapeutic challenge. Conventional anti-pruritic therapies such as anion binding resins (colestipol, cholestyramine), antihistamines and ursodeoxycholic acid are often unsatisfactory against cholestatic pruritus. Many other substances (phenobarbital, rifampicin, flumecinol, S-adenosylmethionine) or therapeutic approaches (phototherapy, plasmapheresis, charcoal hemoperfusion) have been found to be without proven efficacy (7). Unrelieved pruritus can be an indication for liver transplantation (8). It is well recognized that endogenous opiate agonists accumulate in cholestasis and that endogenous opiates can modify the peripheral and enteral sensations of pruritus. Furthermore, pruritus is a recognized side effect of opiate agonist drugs such as morphine. Accumulating evidence suggests that opiate-receptor antagonists such as naloxone can diminish pruritus (9). There is little experience with the use of these drugs in children and adolescents. We present a 16-year-old-girl with a familial form of intrahepatic cholestasis, induced by estrogens, who presented with severe pruritus. Sequence analysis of the bile salt export pump (BSEP, ABCB11) and multidrug resistance gene product (MDR3, ABCB4) genes, mutations of which have been shown to cause progressive familial intrahepatic cholestasis types 2 and 3, respectively, and intrahepatic cholestasis of pregnancy (10) indicated the presence of a heterozygous G855R (glycine to arginine) amino acid substitution in exon 21 of the BSEP gene and a R590Q (arginine to glutamine) amino acid substitution in exon 15 of the MDR3 gene. The role of these mutations in causing the patient's phenotype remains elusive at present. We describe an effective and well-tolerated anti-pruritic therapy with opiate-receptor antagonists. CASE REPORT A 16-year-old female patient presented to our hospital with jaundice and a severe persistent pruritus. She had hardly slept for several days preceding admission. Seven days before the onset of symptoms, she had started a two-phase contraceptive, a combination of an estrogen and a progesten (Leios; 100 μg levonorgestrel, 20 μg ethinylestradiol). The medical history of the patient was unremarkable, except for several urinary tract infections during childhood. In the family history, it was noted that the grandmother developed jaundice with pruritus after taking an estrogen hormone medication to relieve menopausal symptoms and the mother had developed cholestatic jaundice during pregnancy. Physical examination of the girl revealed multiple excoriations over the whole body, scleral icterus, yellow discoloration of the skin, and dark urine. No other physical abnormalities were noted. The stools were acholic. Laboratory evaluations showed an elevation of the liver enzymes (aspartate transaminase, 85 U/L; alanine transaminase, 26 U/L), serum bilirubin (total bilirubin, 18 mg/dL; conjugated bilirubin, 7 mg/dL) and bile acids (fasting, 430 μmol/L; 2 hours postprandial, 428 μmol/L). The alkaline phosphatase, cholinesterase and γ-glutamyltranspeptidase (GGT) activity, albumin and prothrombin time were normal. Abdominal ultrasound and magnetic resonance imaging cholangiography were normal. Severe intrahepatic cholestasis was seen on the liver biopsy (Fig. 1). Infectious (hepatitis viruses A-D, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1,2,6, adenovirus, rotavirus, Toxoplasma gondii), metabolic (α1-antitrypsin deficiency, cystic fibrosis, Wilson disease, hypothyroidism, hemochromatosis, porphyrias, disorder of amino acid metabolism, lipid metabolism and carbohydrate metabolism) and autoimmunologic (autoimmune hepatitis) causes were excluded.FIG. 1: Diffuse and centrilobular hepatocanalicular cholestasis with prominent dark bile plug (arrows) between hepatocytes without lobular or portal hepatis (hematoxylin & eosin stain, 400×).To investigate whether mutations of hepatocellular transport proteins associated with progressive familial intrahepatic cholestasis types 2 and 3 or with intrahepatic cholestasis of pregnancy were present in the patient, the genes coding for the bile salt export pump (BSEP, gene symbol ABCB11) and the multidrug resistance gene product 3 (MDR3, gene symbol ABCB4) were sequenced through all exons including exon-intron boundaries and two kilobases of the promoter region as described previously (11). The patient was heterozygous for a G855R (glycine to arginine) amino acid substitution in exon 21 of the BSEP gene. This mutation has not been reported in a previous study of healthy Caucasians and women with normal pregnancies (10), suggesting a possible pathogenetic role in this patient's phenotype. In addition to the BSEP mutation, the patient was also heterozygous for a R590Q (arginine to glutamine) amino acid substitution in exon 15 of the MDR3 gene. This mutation has been found in rare instances in normal Caucasians, although little is known about the phenotype of these supposedly healthy controls. Thus, although no known disease-causing mutations could be detected in either the BSEP or the MDR3 gene, heterozygous mutations were found in both genes. Whether these mutations are the causes of the patient's phenotype will need to be determined in future studies analyzing the functional consequences of the amino acid substitutions in appropriate in vitro assays. As estrogen therapy was assumed to be the cause of cholestasis, the contraceptive medication was stopped. Complete resolution of jaundice and normalization of the laboratory values occurred within 2 months. Because of the severe itching despite the use of conventional anti-pruritic therapies (antihistaminic drug, cholestyramine, ursodeoxycholic acid, topical application of local anesthetic and betamethasone) the patient had to interrupt her training and suffered severe sleep deprivation with marked psychologic problems. Therefore, intravenous therapy with the opiate-receptor antagonist naloxone was started (starting dose, 0.02 μg·kg−1·min−1; final dose, 0.1 μg·kg−1·min−1). This therapy resulted in a marked subjective improvement in pruritus within 24 hours and normalization of sleep. Pruritis recurred a few hours after stopping the naloxone infusion. Therefore, therapy with the oral opiate-receptor antagonist naltrexone (25 mg/day) was initiated. This treatment was highly effective. The patient was able to re-start her training and no longer suffered from insomnia. After 2 months, medication with naltrexone was be discontinued without recurrence of symptoms. Neither opiate receptor antagonist caused any adverse drug effects. DISCUSSION Intrahepatic Cholestasis Induced by Contraceptive Drugs We present a 16-year old girl with histologically confirmed intrahepatic cholestasis. Cholestasis was most likely induced by an estrogen-containing contraceptive agent. This hypothesis is supported by the positive family history and the clinical course, as jaundice disappeared after cessation of the estrogen therapy. Other causes of intrahepatic cholestasis such as infectious, autoimmunologic or metabolic causes were excluded. The mechanism underlying cholestasis in the treatment with synthetic sex steroids appears to be identical with that responsible for idiopathic jaundice of late pregnancy (1,3,12-14). Stieger et al. (15) proposed a possible molecular basis for drug-induced cholestasis. They identified BSEP as an important target for inhibition by drugs and estrogens in mammalian liver. BSEP has been shown to mediate canalicular adenosine triphosphate-dependent bile salt excretion (16). Drugs and drug metabolites can either directly (cyclosporin A, rifamycin, rifampicin, glibenclamide) or indirectly (the estrogen metabolite estradiol-17β-glucuronide) inhibit BSEP function at the canalicular membrane of hepatocytes. Both mechanisms lead to an intracellular accumulation of toxic bile salts that may be associated with structural disintegration of hepatocytes. This defect in bile formation results in cholestasis, with accumulation of bile salts and other toxic bile constituents within hepatocytes and blood plasma (17). Neither in the patient nor in her grandmother could any of the known mutations associated with progressive familial intrahepatic cholestasis type 2, progressive familial intrahepatic cholestasis type 3 or intrahepatic cholestasis of pregnancy be detected in the BSEP and MDR3 genes (18). However, heterozygous mutations were found in exon 21 of the BSEP gene and exon 15 of the MDR3 gene. Although the exact pathogenetic role of these mutations remains elusive at present, the changes in the BSEP transport function that they potentially confer could be studied in future functional assay (19). Treatment of Pruritus by Opiate-Receptor Antagonists The main therapeutic challenge in our patient was the severe pruritus, which did not improve with the use of conventional medication. In 1979, Bernstein et al. (20) reported the first case of intractable pruritus relieved by opiate antagonist therapy. Since then several controlled trials have shown that opiate-receptor antagonists (intravenously administered naloxone or orally administered nalmefene and naltrexone) are effective in reducing scratching in adults with pruritus of cholestasis (21-26). The importance of this therapeutic principle in the treatment of pruritus is highlighted by the fact that liver transplantation for intractable pruritus is only indicated when an adequate trial of opiate-receptor antagonist therapy has failed (27). In contrast to naloxone, nalmefene and naltrexone can be given orally. Both have a more potent action on opioid receptors and a longer plasma half-life than naloxone. Although naloxone infusions may have a place in the emergency treatment of severe exacerbations of the pruritus of cholestasis, the oral opiate antagonists may have a place in long-term management (9). Contraindications are limited to severe liver insufficiency, acute hepatitis, pregnancy, breast-feeding, and opiate use. One of the main adverse effects can be an opiate withdrawal syndrome, which is characterized by anorexia, abdominal pain, constipation, tremor, hallucinations, changes of mood, perspiration, pallor and cool skin (9). It is attributed to increased levels of endogenous opiates in liver diseases. Opioid withdrawal-like reactions in cholestatic patients can probably be avoided by starting opiate antagonist therapy with an intravenous infusion of naloxone. The infusion rate of naloxone should initially be very low (in our case, 0.02 μg·kg−1·min−1) and should then be gradually increased to a rate known to be associated with opioid antagonist effects (in our case, 0.1 μg·kg−1·min−1). The infusion can then be stopped and small oral doses of an orally bioavailable opiate antagonist can be given. The oral dosage should be gradually increased until an optimal therapeutic response is obtained (in our case, 25 mg naltrexone per day). Other reversible adverse effects such as idiopathic thrombocytopenic purpura, transient elevation of liver enzymes, paresthesia, disturbed body image, nausea, fatigue, dizziness, heartburn, diarrhea and headache have been described. No such adverse reaction occurred during the treatment of our patient. Although opiate receptor antagonists are used as antipruritic drugs in adult patients with cholestatic jaundice, only a few reports have been published in children or adolescents (23). Our case shows that this approach can be highly effective and without notable side effects in adolescents. CONCLUSIONS Before the first estrogen-progesterone combination is initiated as a contraceptive agent, a detailed family history to identify cases of familial intrahepatic cholestasis of pregnancy (jaundice, pruritus, hepatitis or cholelithiasis) should be performed. Furthermore, index patients should be informed about their risk of intrahepatic cholestasis of pregnancy. Treatment with opiate-receptor antagonists is a feasible and-under close monitoring-safe option for severe pruritus in cholestatic diseases and can lead to fast symptomatic improvement. Future studies are necessary to define the functional consequences of the described amino acid substitutions in the BSEP (G855R) and the MDR3 (R590Q) genes before a pathogenetic role in causing this patient's phenotype can be conclusively assigned. Acknowledgements The authors thank Dr. Reinhold Kerb and Dr. Thomas Lang from Epidauros Biotechnology, Bernried, Germany, for sequence analysis of the ABCB11 and ABCB4 genes, and Dr. Christiane Pauli-Magnus, Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland, for mutation analysis and interpretation.