1. Persistent histological inflammation in autoimmune hepatitis despite
biochemical remission: assessment of factors influencing outcome
B. Hoeroldt3, C. Salmon1, A. Dube2, E. McFarlane1, D. Gleeson1.
. 1Liver Unit and 2 Department of Pathology, Royal Hallamshire Hospital, Sheffield, UK, and 3Gastroenterology Department, Rotherham General Hospital, Rotherham, UK .
Background:
We have previously reported (Hoeroldt, J Hepatol 2009 Abst) that 40% of patients with AIH, who attain biochemical remission on immunosuppressive therapy, still have necro-inflammation (Ishak NI-Score >3) on follow-up liver biopsy, and that this is associated with progression of fibrosis and increased mortality.
Results 3:
On further follow-up biopsy “Bx3” , 40 (5-164) months later whilst in biochemical remission (n=33), NIS remained low if low on initial follow up biopsy “Bx2” (figure 3). However, higher NIS values on Bx2 tended to persist on Bx3, and higher values remained significantly associated with fibrosis progression (not shown).
At remission biopsy
(Median (Range))
NIS ≤ 3
(n=75)
NIS >3
(n=54) p
On Prednisolone 62 43 NS
Med. Pred dose (mg)
8.7 (2.5 –15)
10 (2.5-10)
On Azathioprine. 56 48
.Aza dose (mg)
75 (25-150)
75 (50-150)
Interval to biopsy (yr)
2.3 ( )
2.5 (1.5-12)
No with serum ALT >ULN
Serum ALT (U/L) 2
19.5 (7-102) 8
27 (9-84)
0.017
0.082
Time ALT normal (months)
Serum AST (U/l)
18 (0-66)
22 (0-84)
0.030
Serum Globulin (mg/dL)
29 (22-60)
31(20-40)
Overlap 3
0.051
Aim:
To assess further the outcome in this group of patients and to identify factors associated with death or need for liver transplantation.
Patients and methods:
176 patients presenting ( ), with AIH by International Group criteria had >1 follow-up biopsy. 53 patients were excluded, because follow up biopsy was performed before commencing treatment or whilst not in remission, or was unavailable.
The remaining 129 patients were in biochemical remission (ALT<2 ULN). In 119 patients, ALT was normal (<55 U/L) for (median (range)) 1.8 (0.5 to 8) years. Follow up biopsies were obtained 2.2 (0.7 – 12) years after index biopsy; in 2 patients the interval was <1 year.
Biopsies were reviewed by a liver pathologist (AKD) without access to clinical details. Necroinflammatory score (NIS) and Fibrosis stage were assessed using Ishak system.
Figure 1
Figure 3
23 (12-75)
28 (10-164)
0.015
Results 1:
54 of the 129 patients (42%) had NIS>3 on follow up biopsy. As shown in the table, compared to those with NIS<3, more of those with NIS>3 had overlap syndrome and they had higher serum ALT and AST; but the groups were similar as regards serum globulins and as regards treatment dose or duration. As we previously reported, patients with NIS>3 had higher rate of (all-cause) death or liver transplantation (figure 1).
Results 2:
Patients with NIS>3 subsequently had either (a) Standard immunosuppression (IS) (n=32): withdrawal of Prednisolone, plus increased dose of Azathioprine or (b) Enhanced IS (n=22): reintroduction or increased dose of Prednisolone plus increased dose of Azathioprine or change to another IS agent. Outcome was not associated with whichever strategy was adopted (figure 2) nor with whether or not Prednisolone was continued (not shown). On Cox regression analysis, only age was associated with mortality (p=0.009).
Conclusions:
Patients with AIH and persisting histological inflammation represent a “poor outcome” group.
Conventional immunosuppression may not be adequate for these patients.
Follow-up liver biopsy may be a good surrogate marker for trials of more potent treatment regimes.
Figure 1
Figure 1
Figure 2