Vanishing Bile Duct Syndrome: Amoxicillin‐Clavulanic Acid Associated Intra‐Hepatic Cholestasis Responsive to Ursodeoxycholic Acid

Abstract

INTRODUCTION Vanishing bile duct syndrome (VBDS) is a rare cause of cholestatic liver disease characterized by destruction of segments in the intrahepatic biliary tree (1,2). Ductopenia, on liver biopsy, a 50% reduction of the interlobular bile ducts, confirms the diagnosis of VBDS (2,3). The causes of VBDS include developmental, immune-mediated, infectious, drug-induced, neoplastic and ischemic disorders (3). The pathogenesis of bile duct destruction is not well understood (3). VBDS presents clinically with symptoms of jaundice, scleral icterus and pruritus. Prognosis varies from hepatic failure and death or liver transplantation to resolution of cholestasis and normal liver function. Although multiple cases of drug-induced VBDS have been reported in adults, cases of VBDS are uncommon in children (4). The current literature documents five pediatric cases of acute drug-related VBDS: two cases related to amoxicillin-clavulanate, two cases related to ibuprofen, and one case related to carbamazepine (4-8). We present a child who developed pancreatitis, hepatitis and cholestasis after amoxicillin-clavulanate administration whose symptoms resolved after treatment with high-dose ursodeoxycholic acid. CASE REPORT A 10-year-old boy with depression, attention deficit hyperactivity disorder and mild-intermittent asthma presented to the pediatric emergency room with new-onset jaundice. Seven days before admission he developed bilateral facial and neck swelling and was treated with an oral antihistamine and prednisone (20 mg) for a presumed allergic reaction. He also received oral mebendazole (100 mg twice daily for 3 days) for cutaneous larva migrans. The next day, he developed cough, rhinitis, dyspnea and fever of 100.6° Fahrenheit. The chest radiograph was normal and a 5-day course of azithromycin was prescribed. Two days later, he continued to experience dyspnea, fever and upper respiratory symptoms. He was started on albuterol and amoxicillin-clavulanate (600 mg twice daily for 5 days). He then developed fatigue, anorexia, nausea, vomiting, jaundice and dark colored urine, which prompted his evaluation in the emergency room. His medical history included a 5-kilogram weight loss, headache, productive cough, rhinitis, nausea, emesis, mild abdominal pain, dark urine, pale stools and pruritus. There was no previous history of hepatitis and no family history of jaundice, hepatitis, liver disease or inflammatory bowel disease. Medications were daily clonidine (0.1 mg) for attention deficit hyperactivity disorder, risperidone (0.5 mg) and citalopram (20 mg) for depression. On physical examination he had scleral icterus and jaundice without xanthomas. He had mild right upper quadrant tenderness without ascites or hepatosplenomegaly. He had no rash, pedal edema, adenopathy or fever. Initial laboratory studies showed a total bilirubin of 3.7 mg/dL (0.2-1.2 mg/dL) and a direct bilirubin of 2.4 mg/dL (0-0.4 mg/dL). He had mildly elevated serum transaminase levels; alanine aminotransferase: 210 IU/L (0-40 IU/L), aspartate aminotransferase: 66 U/L (0-40 IU/L), gamma glutamyl transpeptidase: 210 IU/L (0-65 IU/L) and a normal alkaline phosphatase level of 424 IU/L (150-530 IU/L). The amylase was 683 U/L (0-120 U/L) and lipase was 1975 U/L (0-190 U/L). His fasting triglyceride level was 329 mg/dL (<160 mg/dL) and total cholesterol was 260 mg/dL (<200 mg/dL). The white blood cell count was 9.9 × 10 3 cells/μL with 8.1% eosinophiles (normal range, 0% to 5%). The chest radiograph was normal and ultrasound of the abdomen showed a contracted gall-bladder without stones or bile duct dilatation. Computed tomography scan of the abdomen showed a prominent pancreas without calcifications or other complications of pancreatitis. The initial diagnoses included pancreatitis, hepatitis and cholestasis with concurrent upper respiratory infection. On admission his psychiatric medications were withheld; however, amoxicillin-clavulanate was continued. His pancreatitis resolved with supportive measures but jaundice, scleral icterus and serum bilirubin level continued to increase (Fig. 1). Pediatric gastroenterology was consulted. Amoxicillin-clavulanate was discontinued after 7 days of therapy and ursodeoxycholic acid was started at a dose of 15 mg/kg/d.FIG. 1: Total bilirubin levels over time.Serological tests for hepatitis A, B and C, human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus, enterovirus, leptospira and Bartonella henselae were negative. Mycoplasma immunoglobulin M was positive. Anti-nuclear antibody, anti-double stranded DNA, anti-smooth muscle antibody and liver/kidney microsomal antibodies were negative. Thyroid function, serum ceruloplasmin, alpha-1-antitrypsin and sweat chloride tests were normal. He had progressive cholestasis with severe pruritus. His total bilirubin peaked at 26.5 mg/dL with direct bilirubin of 14.8 mg/dL. Alkaline phosphatase (381 U/L) and gamma glutamyl transpeptidase levels (28 U/L) returned to normal within 2 weeks. Two weeks after onset of illness, biliary scintigraphy showed uniform hepatic uptake without visualization of the gallbladder or excretion into the gut. An obstructive process was suspected. Magnetic resonance cholangiopancreatograph of the biliary tree showed uniform narrowing of the extrahepatic and intrahepatic biliary tract with a contracted gallbladder suggesting diffuse biliary hypoplasia. However, endoscopic retrograde cholangiopancreatography demonstrated a normal extrahepatic and intrahepatic biliary tree without beading or stenosis. Liver biopsy 1 month after presentation showed canalicular cholestasis with ductopenia (Fig. 2). Periportal chronic inflammation was apparent with lymphocytes and scattered eosinophils and mild fibrosis. Diastase-digested sections stained with periodic acid Schiff were negative and liver tissue copper level was normal.FIG. 2: 1-month liver biopsy. Portal tract devoid of interlobular bile duct. Note the presence of a mononuclear inflammatory infiltrate extending partly into the lobule (hematoxylin & eosin stain, ×100).Diphenhydramine, hydroxyzine, naltrexone and lorazepam were used to treat pruritus and supplemental vitamins A, D, E and K were provided to prevent fat-soluble vitamin deficiencies. After 1 month of pruritic symptoms, ursodeoxycholic acid was increased to 30 mg/kg per day and cholestyramine (2 g orally with meals) was given for 6 weeks. Ursodeoxycholic acid was then increased to 45 mg/kg per day for intractable debilitating pruritus and rifampin (150 mg twice daily) was started. Cholestyramine was subsequently discontinued. Within 2 weeks the total bilirubin significantly decreased (Fig. 1). Five weeks later (4 months after initial presentation) pruritus, jaundice and scleral icterus completely resolved. A repeat liver biopsy showed minimal cholestasis with proliferating bile ductules surrounding the portal areas. Chronic lobular inflammation was associated with focal hepatocyte necrosis and portal fibrosis (Fig. 3). Electron microscopy showed normal bile canaliculi with normal-appearing hepatocytes and no abnormal inclusion bodies. Two years later the patient continues to be symptom-free with normal laboratory values. A follow-up liver biopsy reveals residual portal fibrosis with mild bridging fibrosis (Fig. 4).FIG. 3: 4-month liver biopsy. Portal tract with proliferating bile ductules, recruited from the periportal hepatocytes and expressing keratin filaments (anti-AE1,3 ×250).FIG. 4: 17-month liver biopsy. Hepatic bridging fibrosis (hematoxylin & eosin stain, ×250).DISCUSSION VBDS in children is rare. Initial symptoms include nausea, vomiting, jaundice, pruritus and abdominal pain. Developmental, immunologic, neoplastic and infectious causes were excluded in this case. Although mycoplasma pneumonia could explain the respiratory symptoms in our case, mycoplasma infection does not typically cause cholestasis. A liver biopsy in one patient with mycoplasma associated chronic active hepatitis showed significant hepatocellular destruction and inflammatory infiltration without evidence of ductopenia, which was not the case in our patient (9). In our case, VBDS appears to be a drug-induced injury. Psychotropic medications, ibuprofen, prednisone and azithromycin were excluded in this case, as the patient has been re-exposed to these medications without development of recurrent VBDS symptoms. Mebendazole has not been associated with VBDS in the literature; however the drug cannot entirely be excluded in this case. Given the presentation and clinical course of this patient, VBDS associated with amoxicillin-clavulanate seems most likely. In adults, acute cholestasis accounts for 17% of all hepatic adverse drug reactions and VBDS comprises 0.5% of all cases of small-duct biliary disease (10). Augmentin (GlaxoSmithKline, Philadelphia, PA), a combination of amoxicillin and clavulanate potassium, is one of many compounds that has been associated with VBDS (Table 1) (2,10,11,12). The incidence of amoxicillin-clavulanate induced cholestatic injury in the pediatric population is unknown. The incidence of liver injury from amoxicillin-clavulanate in adults is estimated to be 1.7/10,000 prescriptions, with approximately 75% of cases being cholestatic liver injury (13).TABLE 1: Compounds reported to cause cholestatic hepatitisIn a retrospective review of 208 adult patients with amoxicillin-clavulanic induced hepatitis, liver injury was hepatocellular, cholestatic or, more commonly, mixed (14). Clinical features of drug-induced small bile duct injury include an acute phase of hepatocholangiolitis of highly variable severity followed by cholestasis resulting from lesions of the interlobular ducts between the cholangioles (11). Ductopenia in VBDS affects the 0.03-mm diameter interlobular ducts within the intrahepatic biliary tree (2,3). The larger ductal components are spared and thus VBDS cannot be detected by cholangiography. An international consensus report states that drug-induced cholestasis is suggested if reaction time from drug exposure to the onset of elevated bilirubin is within 5 to 90 days and there is a reduction in cholestasis by 50% within 180 days (15). In adults, reported cases of cholestatic liver injury occurred within 2 to 3 weeks of exposure to amoxicillin-clavulanate (14). In two pediatric case reports, jaundice developed within 3 to 7 days of ingesting amoxicillin-clavulanate (5,7). In our patient, the temporal relationship between amoxicillin-clavulanate administration and the onset of symptoms (5 days) together with the pathologic findings of scattered eosinophils and lymphocytes on liver biopsy support amoxicillin-clavulanate associated liver injury. Hepatic dysfunction and cholestasis may be severe in amoxicillin-clavulanate induced hepatic injury but are usually reversible. Chronic liver disease and mortality have been rarely reported (16). The outcome of amoxicillin-clavulanate-induced VBDS treated with ursodeoxycholic acid in two adult case reports was excellent (17). Normalization of liver transaminases, alkaline phosphatase, and serum bilirubin with relief of pruritus was reported within 10 days of ursodeoxycholic acid (750 mg/day) (17). In two pediatric case reports, one child made a full recovery in 2 months without treatment, whereas one child needed liver transplantation as a result of progressive liver failure despite 30 mg/kg per day of ursodeoxycholic acid (5,7). Our patient had complete resolution of pruritus and cholestasis shortly after initiation a 45 mg/kg per day dose of ursodeoxycholic acid and discontinuation of cholestyramine. Residual hepatic fibrosis remains evident on liver biopsy 17 months after exposure to amoxicillin-clavulanate. The pathophysiology of bile duct injury from amoxicillin-clavulanate remains unknown. Hepatic dysfunction with hypersensitivity manifestations (skin rash, hypereosinophilia) and shortening of the latent period with repeated drug exposure and lymphocyte sensitization suggests an immunoallergic mechanism (2,10,11,12). Proposed mechanisms include an immunoallergic hepatitis involving presentation of human leukocyte antigen class II molecules on macrophages producing cytotoxic T cells and/or antibody-producing B cells (11). Other mechanisms include cytokines secreted by the portal tract inflammatory cells that contribute to the increased human leukocyte antigen expression (11). A human leukocyte antigen-dependent predisposition to amoxicillin-clavulanate induced liver toxicity has been documented in adults (11,18). The primary treatment of drug-induced cholestasis is withdrawal of the precipitating agent and prevention of re-exposure. Symptomatic treatment of cholestasis and pruritus includes cholestyramine, ursodeoxycholic acid, rifampicin and opiate antagonists (12). Corticosteroids have not proven effective (11). Rifampin provides relief of pruritus but its mode of action is unclear. There is evidence that ursodeoxycholic acid exerts its therapeutic effect through multiple mechanisms, including choleresis, protection of the hepatocellular lipid membranes against hydrophobic cytotoxic bile acids and suppression of bile acid-induced apoptosis of the liver (19,20). Ursodeoxycholic acid improves canalicular transport restoring bile flow, promotes excretion of toxic hydrophobic bile salts from the hepatocyte, preventing hepatocyte necrosis and apoptosis (20). Ursodeoxycholic acid decreases biliary expression of MHC class II molecules, suggesting that it might reduce T-cell medicated hepatocellular damage (20). Concurrent use of cholestyramine and ursodeoxycholic acid reduces the bioavailability of ursodeoxycholic acid as a result of intraluminal binding and diminishes the intestinal uptake of ursodeoxycholic acid (21). Our patient experienced normalization of laboratory tests and resolution of pruritus within 12 days of high-dose ursodeoxycholic acid therapy (45 mg/kg per day) and discontinuation of cholestyramine. Although it is difficult to determine whether ursodeoxycholic acid influenced the overall prognosis of our patient, we believe high-dose ursodeoxycholic acid therapy contributed to the improvement of our patient's extreme hyperbilirubinemia and debilitating pruritus symptoms. To our knowledge, this is the third pediatric case of amoxicillin-clavulanate induced cholestatic liver injury with associated hepatitis and pancreatitis and the first pediatric VBDS case responsive to ursodeoxycholic acid therapy. Severe drug-induced hepatic injury including VBDS should be considered in patients taking amoxicillin-clavulanate who have elevations of serum transaminases, alkaline phosphatase or bilirubin levels. Further studies are needed to determine to what degree ursodeoxycholic acid therapy influences overall morbidity and mortality in patients with drug-induced VBDS.