[1665] Drug-Induced Ductopenia: Natural History and p16^INK4 Expression

M Westerhoff, L Hovan, G Yoshiba, R Pierce, J Hart. University of Chicago, Chicago

Background: Many medications have been documented in case reports to cause cholestasis due to bile duct damage and loss, but the histological features have not been reported for a large case series. Recently, biliary p16 expression has been noted to be a marker of cellular senescence and to be important in the pathogenesis of bile duct loss in primary biliary cirrhosis (PBC). The role of p16 expression in drug-induced ductopenia has not been reported to date.
Design: The pathology database was searched for all liver biopsies with duct loss attributable to drugs; chart reviews were then performed. Biopsies (18) were stained immunohistochemically with p16. For comparison, PBC (15) and normal liver (5) were also stained. Combined nuclear and cytoplasmic staining of bile duct epithelium was scored as positive or negative.
Results: All drug-induced ductopenia patients had elevated total bilirubin (TB) (mean 22.6 mg/dL) and alkaline phosphatase (AP) levels (mean 600 U/L) at time of biopsy. Follow-up ranged from 3 - 84 months. Table 1 displays their clinical outcomes.

Table 1

		Following cessation of drug
Drug Class	n	Re-biopsy showed resolution of duct loss (n)	Labs and symptoms improved (n)	TB or AP remained elevated; symptoms continued (n)	Expired or transplant (n)	p16 positivity (n=6)
Antibiotic	2		2
Anti-depressant	3	2		1		1
Anti-psychotic	1			1
Anti-seizure	3		2	1
ACE-inhibitor	1				1	1
Weight loss	1			1
NSAID	1	1
Multiple drugs, no established agent	6		1	2	3	4

On average, biopsies sampled 14 portal tracts with 58% bile duct loss. 8 patients improved clinically, 1 underwent transplantation, and 3 expired. Degree of duct loss and ductular proliferation did not correlate with liver function tests (LFTs) or outcome. 3 of 4 patients improved with ursodiol treatment in addition to stopping the offending drug. All normal livers were p16 negative. 13 of 15 PBC cases had positive bile duct staining. In 6 of 18 drug-induced ductopenia cases, damaged ducts exhibited p16 reactivity. All 6 of these patients did poorly (2 deaths, 2 developed biliary cirrhosis, 2 with persistent elevated LFTs). In contrast, 8 of 12 patients with negative p16 staining improved their LFTs or showed resolution of duct loss on re-biopsy.
Conclusions: This is the largest series reporting histological features and clinical follow-up on drug-induced ductopenia. Degree of bile duct loss did not correlate with clinical severity or outcome. 44% had histological or clinical resolution by discontinuing the offending drug. However, p16 reactivity, which occurred in 33% of ductopenia cases, was associated with poor prognosis (p<0.01).
Category: Liver & Pancreas

Monday, March 22, 2010 1:00 PM

Poster Session II # 180, Monday Afternoon