Ketamine abuse, biliary tract disease, and secondary sclerosing cholangitis

Authors

  • Aaron Turkish,

    1. Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, New York Hospital Queens, Weill-Cornell Medical College, Flushing, NY
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  • Jean J. Luo,

    1. Department of Pathology, New York Hospital Queens, Flushing, NY
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  • Jay H. Lefkowitch

    Corresponding author
    1. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY
    • Address reprint requests to: Jay H. Lefkowitch, M.D., Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, PH 15 West, Room 1574, New York, NY 10032. E-mail: JHL3@columbia.edu; fax: 212-305-5498.

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  • Potential conflict of interest: Nothing to report.

Abbreviations
ALP

alkaline phosphatase

ARF

acute renal failure

CBD

common bile duct

GGT

gamma-glutamyl transpeptidase

MRCP

magnetic resonance cholangiopancreatography

A 21-year-old obese male with a history of acute renal failure (ARF) and bilateral hydronephrosis presented with fever, marked abdominal pain, and abnormal liver function studies in the setting of acute pyelonephritis. There was no diarrhea or blood in the stool. He admitted to occasional alcohol binging and daily inhalation of ketamine for at least 9 months. His body mass index was 29.5 kg/m2. Physical exam showed no jaundice, but there was moderate diffuse abdominal pain without ascites or hepatosplenomegaly. His serum liver function tests were abnormal 5 months earlier when admitted with ARF and now showed worsened transaminitis (Table 1). Other serum test results included albumin of 3.6 g/dL, creatinine of 1.6, and international normalized ratio of 1.01. Abdominal ultrasound revealed a diffusely echogenic liver with normal portal vein blood flow, and a non-contrast-enhanced abdominal computed tomography scan showed no hepatic or bile duct abnormalities. After antibiotic therapy, his liver function tests slowly improved, albeit without a return to baseline. During a repeat hospitalization 2 months later for recurrent pyelonephritis, a liver biopsy was obtained to determine the cause of his persistent serum liver test abnormalities, this time with peak alkaline phosphatase (ALP) of 537 U/L and gamma-glutamyl transpeptidase (GGT) of 1,544 U/L, without normalization at discharge. His creatinine was normal during uroseptic free periods, and his electrolytes, amylase, lipase, lipid profile, insulin, and thyroid studies were normal. Hepatitis A, B, and C and other viral infections, such as Epstein-Barr virus, cytomegalovirus, and human immunodeficiency virus, were ruled out. There was no evidence of autoimmune hepatitis, alpha-1-antitrypsin deficiency, Wilson's disease, or hemochromatosis.

Table 1. Liver Function Test Abnormalities Over Time
DateAST (Normal 5-40 U/L)ALT (Normal 5-41 U/L)ALP (Normal 40-130 U/L)GGT (Normal 4-59 U/L)TB (Normal 0.0-1.2 mg/dL)Comment
  1. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; D/C, discharge; N/A, not available; TB, total bilirubin.

July 201151116590N/A1.2Acute renal failure
 5569291N/A0.4D/C
January 20125618362929940.5Pyelonephritis
 123404321N/A0.5D/C
February 2012661754838230.52 weeks after D/C, outpatient visit
March 20122762573849850.7Readmit for pyleonephritis
 2172605371,5440.21 week after admission
April 2012128300438N/A0.2Liver biopsy
January 20133644214N/A0.52 months “ketamine free”

Percutaneous liver biopsy (Fig. 1A-C) showed striking concentric periductal fibrosis surrounding bile ducts of varying sizes, consistent with primary or secondary sclerosing cholangitis (Fig. 1). Small portal tracts showed interlobular bile ducts with thickened basement membranes, mild lymphocytic infiltrates, and a mild ductular reaction (Fig. 1C). Cholestasis was not identified.

Figure 1.

(A) Needle liver biopsy showing concentric fibrosis surrounding an intrahepatic bile duct (upper left), consistent with sclerosing cholangitis (Mallory trichrome stain: ×100). (B) Bile duct shown in (A) is surrounded by concentric fibrosis with mild inflammation, and there is mild proliferation of bile ductular structures (ductular reaction) at the edge of the portal tract (arrows). Note the hepatic arteriole (a) with a similar caliber to the bile duct. (C) Thick yellow arrows show cross-sections of an interlobular bile duct with thickened basement membrane. A mild ductular reaction is present at the edge of the portal tract (thin black arrows). (B and C: hematoxylin and eosin stain: ×200). (D) MRCP with normal CBD (arrow).

After participation in a drug rehabilitation program and several months of being drug free, his liver function studies improved greatly, although with residual mild elevation of ALP. Follow-up magnetic resonance cholangiopancreatography (MRCP) revealed normal intrahepatic and extrahepatic bile ducts without common bile duct (CBD) dilation or obstruction (Fig. 1D).

Ketamine is a general anesthetic used in human and veterinary medicine and is metabolized in the liver by microsomal cytochrome enzymes to metabolites that are excreted in urine and bile. Recreational ketamine abuse is well known in Hong Kong, Taiwan, and elsewhere[1-3] because of its hallucinogenic effects and its use in clubs (“raves”). The major side effects reported with ketamine abuse have been related to urinary bladder dysfunction (recurrent episodes of nocturia, dysuria, increased urinary frequency, and hematuria[4, 5]) with inflammation, cystitis, and morphologic changes in the bladder wall.[4, 5] Recent attention has been drawn to biliary tract disease in ketamine abusers, where recurrent epigastric pain and elevated serum ALP and GGT[1-3] are noted at clinical presentation. MRCP and endoscopic retrograde cholangiopancreatography at presentation have shown dilatation of the CBD and/or fusiform dilatation of the common hepatic bile duct and CBD, sometimes with short segment strictures. Cholangiographic abnormalities have been shown to resolve after cessation of ketamine abuse.[2, 3] In our case, the normal-appearing MRCP after ketamine cessation is nonetheless compatible with a “small-duct sclerosing cholangitis”–like condition (where cholangiography is typically negative, despite chronic biliary obstruction[6]). The pathogenesis of bile duct dilatation resulting from ketamine is unknown, although animal studies have demonstrated increased flow resistance across the sphincter of Oddi with ketamine administration.[7] This case highlights the need to consider recreational or alternative agents such as ketamine in the differential diagnosis of a sclerosing cholangitis-like hepatobiliary disease in a young individual.

Acknowledgment

The authors thank Constance H. Halporn at Columbia University Medical Center (New York, NY) for her photographic assistance.

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