Introduction

Differentiating drug-induced liver injury (DILI) from autoimmune hepatitis (AIH) is a challenge in clinical practice^1-3. Liver biopsy is recommended in unclear cases¹, however available studies comparing histopathological patterns between DILI and AIH have major limitations due to lack of control groups or limited sample sizes^{4, 5}.

Aims & Methods

We aimed to further identify typical histopathological features of DILI in comparison to AIH. Clinical and histopathological data of well-characterized 136 DILI and 43 AIH patients from our prospective cohort on patients with acute liver injury and potential drug-related cause were analysed. Logistic regression was performed to identify models that could differentiate both entities and predict adverse outcome.

Results

We identified high overlaps regarding histological patterns between DILI and AIH, leading to a low overall agreement between clinical and histopathological diagnosis of only 48.9%. Interface hepatitis, plasma cell infiltration and portal-intralobular infiltration was favouring AIH over DILI, however relevant proportions of DILI patients also presented with those features (interface hepatitis: 69.8% vs. 44.1%, p=0.003, plasma cells: 72.1% vs. 46.3%, p=0.003, portal-intralobular infiltration 51.2% vs. 29.2%, p=0.005). Interestingly, lipofuscinosis showed the strongest association with DILI diagnosis on univariate analysis (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.17-1.50). A model comprised of interface hepatitis, cholestasis, lipofuscinosis, portal-intralobular inflammation and steatosis could differentiate DILI from AIH with an accuracy of 77.7% and a sensitivity as high as 94.1% (specificity 25.6%). Multivariate analysis also identified lipofuscinosis as a highly discriminatory feature (OR 8.05, Table 1). Prediction of adverse outcome (defined as death or need for liver transplantation [LT]) in DILI and AIH patients using only histopathological patterns was possible with an accuracy of 88.7% (specificity 97.0%, sensitivity 48.1%). Severe necrosis and ductular proliferation were associated with poor outcome (OR 5.48 and OR 5.00, respectively) while presence of eosinophilic cells and lipofuscinosis (OR 0.36 and OR 0.163, respectively) lowered the risk for death or LT significantly.

Conclusion

We here present the largest prospectively collected cohort of DILI and AIH patients for whom histopathological analysis was performed. Interestingly, DILI and AIH showed highly similar histological patterns, neither interface hepatitis nor plasma cell infiltration could specifically differentiate AIH from DILI patients. However, lipofuscinosis was identified as a novel distinctive feature for DILI with a high discriminatory power. Moreover, a model combining histological features could differentiate both entities with high sensitivity. Histological analysis was especially helpful for predicting severe outcome in DILI and AIH patients showing higher specificity when compared to traditional risk scores predicting acute liver failure in DILI ⁶.

References

1 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015; 63(4): 971-1004. doi:10.1016/j.jhep.2015.06.030.
2 Kullak-Ublick GA, Andrade RJ, Merz M, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017; 66(6): 1154-64. doi:10.1136/gutjnl-2016-313369.
3 Weber S, Benesic A, Rotter I, Gerbes AL. Early ALT response to corticosteroid treatment distinguishes idiosyncratic drug-induced liver injury from autoimmune hepatitis. Liver Int. 2019; 39(10): 1906-17. doi:10.1111/liv.14195.
4 Kleiner DE, Chalasani NP, Lee WM, et al. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology. 2014; 59(2): 661-70. doi:10.1002/hep.26709.
5 Suzuki A, Brunt EM, Kleiner DE, et al. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology. 2011; 54(3): 931-9. doi:10.1002/hep.24481.
6 Andrade RJ, Robles-Diaz M. Diagnostic and prognostic assessment of suspected drug-induced liver injury in clinical practice. Liver Int. 2020; 40(1): 6-17. doi:10.1111/liv.14271.

Disclosure

Sabine Weber, Didem Saka, Nirali Donga and Alexander L. Gerbes received funding from TransBioLine (Translational Safety Biomarker Pipeline (TransBioLine): Enabling development and implementation of novel safety biomarkers in clinical trials and diagnosis of disease; Grant Agreement ID: 821283). The TransBioLine project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821283. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. ​

Introduction

96-98% of patients survive acute pancreatitis (AP), but in the post-AP phase, patients are at high risk of morbidity and mortality. The primary objective of the GOULASH PLUS (ISRCTN63396106) longitudinal, observational multicentre study is to investigate the development of chronic pancreatitis (CP) following AP. The GOULASH PLUS trial reached 50% of the planned patient enrolment. This interim data analysis aims to understand the time course evolution of CP after AP.

Aims & Methods

360 patients were yearly followed after AP. We formed four groups according to the baseline morphology status of the pancreas: 1) AP with one episode, 2) RAP with two episodes, 3) ECP with characteristic signs on imaging or three or more episodes of AP 4) CP: Ultrasound or CT were used in the first and third year, whereas, endoscopic ultrasound or magnetic-resonance-cholangiopancreatography in the second and fourth year of follow-up.

Results

Among the 360 patients followed after AP, 269 (74.7%) had AP, 42 (11.7%) RAP, 27 (7.5%) ECP, and 22 (6.1%) had CP at the time of the baseline AP episode. The following data represent the results at 1, 2, 3, and 4 years after AP. In the AP group, ECP was developed in 3%, 12%, 14%, and 18%, whereas, CP was diagnosed in 1%, 6%, 6%, and 11%, respectively. In the RAP population, ECP was developed in 17%, 19%, 21%, and 42% while CP developed in 0%, 0%, 4%, and 8%. In the ECP patient group, CP was developed in 12%, 25%, 35%, and 36%. 15% of patients had exocrine pancreatic insufficiency (EPI) at the first year visit, while this increased to 21% by the fourth annual visit.

Conclusion

RAP and ECP accelerate CP development. Due to the fast progression, it is important to find risk factors and biomarkers associated with recurrence and early morphology changes and to define possible early interventions to avoid or delay the progression to CP.