Drug-drug interactions are a major cause of hospitalization and deaths related to drug use. A large fraction of these is due to inhibition of enzymes involved in drug metabolism and transport, particularly cytochrome P450 (P450) enzymes. Understanding basic mechanisms of enzyme inhibition is important, particularly in terms of reversibility and the use of the appropriate parameters. In addition to drug-drug interactions, issues have involved interactions of drugs with foods and natural products related to P450 enzymes. Predicting drug-drug interactions is a major effort in drug development in the pharmaceutical industry and regulatory agencies. With appropriate in vitro experiments, it is possible to stratify clinical drug-drug interaction studies. A better understanding of drug interactions and training of physicians and pharmacists has developed. Finally, some P450s have been the targets of drugs in some cancers and other disease states.

Acute kidney injury (AKI) is common in advanced cirrhosis. Prerenal azotemia, hepatorenal syndrome, and acute tubular necrosis are the main causes of AKI in patients with cirrhosis. Evaluation of renal function and differentiation between functional and structural kidney injury are important issues in the management of cirrhosis. However, AKI in cirrhosis exists as a complex clinical spectrum rather than concrete clinical entity. Based on current evidence, changes in serum creatinine (Cr) levels remain the most appropriate standard for defining AKI in cirrhosis. However, serum Cr has a limited role in assessing renal function in this population. This review examines previous studies that investigated the ability of recent biomarkers for AKI in cirrhosis from the perspective of earlier and accurate diagnosis, classification of AKI phenotype, and prediction of clinical outcomes. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin have been extensively studied in cirrhosis, and have facilitated improved diagnosis and prognosis prediction in patients with AKI. In addition, urine N-acetyl-β-D-glucosaminidase, interleukin 18, and kidney injury molecule 1 are other promising biomarkers for advanced cirrhosis. However, the clinical significance of these markers remains unclear because there are no cut-off values defining the normal range and differentiating phenotypes of AKI. In addition, AKI has been defined in terms of serum Cr, and renal biopsy―the gold standard―has not been carried out in most studies. Further discovery of innovate biomarkers and incorporation of various markers could improve the diagnosis and prognosis prediction of AKI, and will translate into meaningful improvements in patient outcomes. (Clin Mol Hepatol 2022;28:31-46)

Background/Aims: To develop an early prediction model for gestational diabetes mellitus (GDM) using machine learning and to evaluate whether the inclusion of nonalcoholic fatty liver disease (NAFLD)-associated variables increases the performance of model.
Methods: This prospective cohort study evaluated pregnant women for NAFLD using ultrasound at 10-14 weeks and screened them for GDM at 24-28 weeks of gestation. The clinical variables before 14 weeks were used to develop prediction models for GDM (setting 1, conventional risk factors; setting 2, addition of new risk factors in recent guidelines; setting 3, addition of routine clinical variables; setting 4, addition of NALFD-associated variables, including the presence of NAFLD and laboratory results; and setting 5, top 11 variables identified from a stepwise variable selection method). The predictive models were constructed using machine learning methods, including logistic regression, random forest, support vector machine, and deep neural networks.
Results: Among 1,443 women, 86 (6.0%) were diagnosed with GDM. The highest performing prediction model among settings 1-4 was setting 4, which included both clinical and NAFLD-associated variables (area under the receiver operating characteristic curve [AUC] 0.563-0.697 in settings 1-3 vs. 0.740-0.781 in setting 4). Setting 5, with top 11 variables (which included NAFLD and hepatic steatosis index), showed similar predictive power to setting 4 (AUC 0.719- 0.819 in setting 5, P=not significant between settings 4 and 5).
Conclusions: We developed an early prediction model for GDM using machine learning. The inclusion of NAFLDassociated variables significantly improved the performance of GDM prediction. (ClinicalTrials.gov Identifier: NCT02276144) (Clin Mol Hepatol 2022;28:105-116)

Background/Aims: We aimed to determine the association between blood urea level and incident cirrhosis, hepatic decompensation, and hepatocellular carcinoma in chronic liver disease (CLD) patients.
Methods: The association between blood urea level and liver fibrosis/liver-related events were evaluated on continuous scale with restricted cubic spline curves based on generalized additive model or Cox proportional hazards models. Then, the above associations were evaluated by urea level within intervals.
Results: Among 4,282 patients who had undergone liver stiffness measurement (LSM) by transient elastography, baseline urea level had a U-shaped association with LSM and hepatic decompensation development after a median follow-up of 5.5 years. Compared to patients with urea of 3.6-9.9 mmol/L, those with urea ≤3.5 mmol/L (adjusted hazard ratio [aHR], 4.15; 95% confidence interval [CI], 1.68-10.24) and ≥10 mmol/L (aHR, 5.22; 95% CI, 1.86-14.67) had higher risk of hepatic decompensation. Patients with urea ≤3.5 mmol/L also had higher risk of incident cirrhosis (aHR, 3.24; 95% CI, 1.50-6.98). The association between low urea level and incident cirrhosis and hepatic decompensation was consistently observed in subgroups by age, gender, albumin level, and comorbidities. The U-shaped relationship between urea level and LSM was validated in another population screening study (n=917). Likewise, urea ≤3.5 mmol/L was associated with a higher risk of incident cirrhosis in a territory-wide cohort of 12,476 patients with nonalcoholic fatty liver disease at a median follow-up of 9.9 years (aHR, 1.27; 95% CI, 1.03-1.57).
Conclusions: We identified a U-shaped relationship between the urea level and liver fibrosis/incident cirrhosis/hepatic decompensation in patients with CLD. (Clin Mol Hepatol 2022;28:77-90)

The annual incidence of hepatocellular carcinoma (HCC) continues to rise. Over the last two decades, liver transplantation (LT) has become the preferable treatment of HCC, when feasible and strict selection criteria are met. With the rise in HCC-related LT, compounded by downstaging techniques and expansion of transplant selection criteria, a parallel increase in number of post-transplantation HCC recurrence is expected. Additionally, in the context of an immunosuppressed transplant host, recurrences may behave aggressively and more challenging to manage, resulting in poor prognosis. Despite this, no consensus or best practice guidelines for post-transplantation cancer surveillance and recurrence management for HCC currently exist. Studies with adequate population sizes and high-level evidence are lacking, and the role of systemic and locoregional therapies for graft and extrahepatic recurrences remains under debate. This review seeks to summarize the existing literature on post-transplant HCC surveillance and recurrence management. It highlights the value of early tumour detection, re-evaluating the immunosuppression regimen, and staging to differentiate disseminated recurrence from intrahepatic or extrahepatic oligo-recurrence. This ultimately guides decision-making and maximizes treatment effect. Treatment recommendations specific to recurrence type are provided based on currently available locoregional and systemic therapies. (Clin Mol Hepatol 2022;28:1-16)

Background/Aims: We aimed to investigate the silent atherosclerotic burden of cervicocephalic vessels in cirrhotic patients compared with the general population, as well as the relevant risk factors including coronary parameters.
Methods: This study included 993 stroke-free patients with liver cirrhosis (LC) who underwent magnetic resonance angiography (MRA) of the head and neck as a pre-liver transplant assessment and 6,099 health checkup participants who underwent MRA examination. The two cohorts were matched for cerebrovascular risk factors, and the prevalence of atherosclerosis in major intracranial and extracranial arteries was compared in 755 matched pairs. Moreover, traditional, hepatic, and coronary variables related to cerebral atherosclerosis were assessed in cirrhotic patients.
Results: Overall, intracranial atherosclerosis was significantly less prevalent in the LC group than in the matched control group (2.3% vs. 5.4%, P=0.002), whereas the prevalence of extracranial atherosclerosis was similar (4.4% vs. 5.8%, P=0.242). These results were maintained in multivariate analyses of the pooled samples, with corresponding adjusted odds ratios [ORs] of LC of 0.56 and 0.77 (95% confidence intervals [CIs], 0.36-0.88 and 0.55-1.09). In the LC group, lower platelet count was inversely correlated with intracranial atherosclerosis (adjusted OR, 0.31; 95% CI, 0.13-0.76). Coronary artery calcium (CAC) score ≥100 was the only predictive factor for both intracranial and extracranial atherosclerosis (adjusted ORs, 4.06 and 5.43, respectively).
Conclusions: LC confers protection against intracranial atherosclerosis, and thrombocytopenia may be involved in this protective effect. High CAC score could serve as a potential surrogate for cervicocerebral vascular screening in asymptomatic cirrhotic patients. (Clin Mol Hepatol 2022;28:67-76)

Background/Aims: Maternal and fetal outcomes in pregnant patients with Non-alcoholic fatty liver disease (NAFLD) have been largely unexplored. To determine the level of evidence associated with maternal and fetal outcomes in pregnant women with NAFLD.
Methods: We conducted a comprehensive literature search. The studies included pregnant patients with a previous, current or subsequent diagnosis of NAFLD. We used a random-effects model using odds ratios (OR) with 95% confidence intervals (CI).
Results: Twenty-two studies, with 13,641 female NAFLD patients were reviewed. The results highlight that NAFLD patients had a statistically significant increased likelihood of baseline diabetes mellitus (OR, 6.00; 95% CI, 2.21-16.31; P<0.001; n=7), baseline Hypertension (OR, 3.75; 95% CI, 2.13-6.59; P<0.001; n=4), gestational hypertension (OR, 1.83; 95% CI, 1.03-3.26; P=0.041; n=2), and pre-eclampsia (OR, 2.43; 95% CI, 1.46-4.04; P=0.001; n=3). The odds for a past and current history of gestational diabetes mellitus were OR, 3.78; 95% CI, 2.21-6.44; P<0.001; n=5 and OR, 3.23; 95% CI, 1.97- 5.31; P<0.001; n=6, respectively. As for fetal outcomes, pregnant NAFLD patients were significantly more likely to have a premature birth (OR, 2.02; 95% CI, 1.44-2.85; P<0.001; n=4), large for gestational age birth (OR, 2.01; 95% CI, 1.72-2.37; P< 0.001; n=2) or a history of prior miscarriage or abortion (OR, 1.15; 95% CI, 1.02-1.30; P=0.02; n=2). Egger's regression revealed no evidence of publication bias (P >0.05).
Conclusions: This meta-analysis provides pooled evidence that NAFLD is associated with a substantial increase in maternal diabetic and hypertensive complications and multiple adverse fetal outcomes. This data is important for clinicians managing these patients before, during and after pregnancy. (Clin Mol Hepatol 2022;28:52-66)