Dilated common bile duct and deranged liver function tests associated with ketamine use in two HIV-positive MSM

Introduction

Ketamine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist that is used as an anaesthetic in emergency medicine. Used recreationally, it has a strong hallucinogenic effect lasting approximately 1 h. There are literature reports of an increase in the recreational use of ketamine in the UK. A recent survey of clubbers ¹ showed that lifetime use of ketamine had increased from 25% (2009) to 68% (2011). ² Ketamine-associated urinary tract pathology is well described.^3,4 Biliary duct dilatation and cholestasis have also been documented in HIV-negative ketamine users.^5–7 CYP2B6 is the main enzyme responsible for ketamine metabolism ⁸ and is inhibited by the protease inhibitor (PI) boosting agent ritonavir. Here we report two cases of hepatobiliary pathology after concomitant use of these two drugs.

Case 1

A 38-year old Caucasian man who has sex with men (MSM) with a nine-year history of well-controlled HIV infection (CD4 788 [27%], VL <40) on abacavir/lamivudine, and ritonavir-boosted darunavir presented with acute-on-chronic epigastric pain, nausea and vomiting. In the preceding year, he had experienced four similar episodes. His medical history included asthma and hypertension for which he was prescribed a salbutamol inhaler and perindopril.

Average alcohol intake was 14 units/week. Previous investigations included endoscopy, duodenal biopsies and barium studies that were normal. He had received triple therapy for positive Helicobacter pylori serology. He reported taking oral ketamine for five months prior to developing epigastric pain but then up-titrated his ketamine dose to 1–2 g a day for a year as (non-prescribed) analgesia for this pain. He did not use other recreational drugs and had never injected. On examination, he had blood pressure of 178/118, but no other significant findings. Liver function tests (LFTs) showed elevated ALT 131 IU/L (3.2 × ULN), ALP 215 IU/L (1.7 × ULN), and normal bilirubin 6 µmol/L. Investigations for viral causes including hepatitis B&C polymerase chain reaction (HBV and HCV PCR), autoimmune and inherited hepatic conditions were negative. MRCP showed CBD, 18 mm (normal adult, 3.1–8 mm), mild cholangiopathy, no gallstones and normal pancreas. No obstructive lesion was found on ERCP (normal ampulla/no cholelithiasis); sphincterotomy was performed. He discontinued ketamine immediately on advice and his symptoms resolved with no further episodes. Repeat MRCP (four weeks after cessation) showed a 28% reduction in CBD diameter (13 mm) and normalisation of LFTs. He has had no recurrence of symptoms or abnormal LFTs 18 months after discontinuation of ketamine.

Case 2

A 25-year-old Asian HIV-positive MSM was admitted for the third time with an eight-week history of intermittent right upper quadrant pain and nausea. He had been HIV-positive for three years with CD4 count of 154 (16%) and VL 6356, despite treatment with tenofovir/emtricitabine (Truvada) and twice daily lopinavir/ritonavir. He was also on cotrimoxazole for PCP prophylaxis. Adherence to all medications was poor. At HIV diagnosis he had reported occasional oral ketamine use; this had increased to 1 g 2–3 times/week in the preceding 12 months, and no other recreational drugs (never injected drugs). Alcohol intake was 70 units/week; initially this was thought to be the underlying cause. His symptoms continued despite reported reduction in alcohol intake to 30 units/week and consequent improvements in his LFTs (ALT = 418 to 91, ALP = 315 to 199 and GGT 1015 to 117). He was also under urological follow up for recurrent E. coli urinary tract infections and haematuria, shown on cystoscopy to be haemorrhagic cystitis. On examination, he had right upper quadrant tenderness (positive Murphy’s sign). LFTs showed elevated ALT 418 IU/L (10.1 × ULN), ALP 315 IU/L (2.5 × ULN), GGT 1015 IU/L (14.5 × ULN) with normal red cell mean corpuscular volume (MCV), bilirubin and clotting screen. Liver screen for viral (HBV and HCV PCR), autoimmune and inherited conditions were all negative. Ketamine was identified in his urine by liquid chromatography. Abdominal USS and MRCP showed CBD dilatation at 14 mm; normal gallbladder, no intra-ductal stones normal liver and pancreas. No cause for the biliary dilatation was found on ERCP; sphincterotomy was performed. Liver biopsy performed a month post-discharge showed a non-cirrhotic liver, no features of HIV cholangitis, opportunistic infections or alcohol toxicity. His ART was changed to once daily Truvada, darunavir and ritonavir, to aid adherence. He continued to have ongoing abdominal pain until one month later when he discontinued ketamine on medical advice. Careful history taking at this time identified the temporal relationship between his symptoms and ketamine use. His pain subsequently resolved and his LFTs normalised within two months of stopping. He continues to take 30 units of alcohol/week. Liver MRI three months after discontinuation of ketamine showed a reduction in CBD by 29% (10 mm).

Discussion

The two individuals reported here presented in a similar fashion with epigastric pain triggered by ketamine use that resolved on discontinuation. While Case 1 had well-controlled HIV, Case 2 had low CD4 counts and persistent viraemia and required further tests to exclude HIV-associated hepatobiliary pathology. No explanation other than regular ketamine use was found for the clinical and radiological findings and a strong temporal relationship was noted. Published case series linking CBD dilation and deranged LFTs to ketamine use have been reported in HIV-negative individuals using ketamine for an average of four years.^6,7 In contrast, our cases had been using regular ketamine for less than a year before developing symptoms, but both were on ritonavir-based ART. This may have increased ketamine hepatotoxicity through inhibition of CYP2B6. The deranged LFTs may be due to direct hepatotoxicity by ketamine. ⁷ The mechanism for the biliary dilation is unknown but may reflect smooth muscle relaxation secondary to inhibition of NMDA receptors by ketamine. This mechanism has been proposed in a recent case series of gall bladder dyskinesia. ⁶ It might also be due to the effect of ketamine on cholecystokinin. HIV physicians should consider ketamine toxicity in the differential diagnoses of hepatobiliary abnormalities in patients misusing this drug.