Study design and cohort selection
Patients with primary ICH who were admitted to West China Hospital within 24 h of ICH symptom onset between January 2015 and June 2018 were retrospectively selected from among patients prospectively registered in our ICH database [23]. The study was approved with waived consent by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University (2019 362).
Patients were included if they received a baseline brain computed tomography (CT) scan immediately upon arrival in the Department of Emergency Medicine, as well as a follow-up brain CT scan within 72 h after symptom onset. Patients were excluded if they met any of the following criteria: (1) were < 18 years old; (2) had a secondary cause of ICH (i.e., underlying aneurysm, vascular malformation, brain neoplasm or metastasis, head trauma, dural sinus thrombosis, hemorrhagic transformation of ischemic infarction, infection), or primary intraventricular hemorrhage (IVH), or primary subarachnoid hemorrhage (SAH); (3) were on anticoagulant therapy before admission; (4) had severe liver disease (i.e., an ICD-code for liver failure, cirrhosis, hepatocellular carcinoma or decompensated liver disease) or clinical syndrome associated with liver disease; (5) had undergone surgical evacuation; or (6) were lacking laboratory data of hepatic assays or coagulation parameters, which were tested routinely in most of patients.
Data collection
The following data were collected for all patients: demographic information including age, sex, Glasgow Coma Scale (GCS) score, National Institutes of Health Stroke Scale (NIHSS) score, as well as systolic and diastolic blood pressure on admission; comorbidities diagnosed either before admission or at discharge (hypertension, diabetes mellitus, hyperlipidemia, heart disease (includes any history of atrial fibrillation, coronary heart disease, or valvular heart disease); previous smoking (defined as smoking more than 10 cigarettes a day prior to onset, for at least 1 year) and alcohol consumption (defined as drinking almost every day, the average amount of daily drinking being more than 50 g, for more than 1 year); and the use of antiplatelets before admission. In addition, data were collected on the previous history of stroke (ischemic or hemorrhagic stroke).
Laboratory findings on admission included platelet count, international normalized ratio (INR), prothrombin time (PT), activated plasma thromboplastin time (APTT), ALT, AST and albumin (ALB). Data were also collected about onset of ICH symptoms, how long the patient was symptom-free, and when baseline and follow-up brain CT scans were performed.
The initial CT scan taken at presentation was reviewed to determine the ICH location (lobar, deep, and infratentorial), the presence of IVH, and baseline hematoma volumes. Hematoma volumes were estimated from CT scans using the formula A*B*C/2, where A was the largest diameter on the largest hemorrhage slice; B, the maximal diameter perpendicular to A; and C, the vertical hematoma depth [24]. Intraventricular hemorrhage were not considered for volumetric calculations.
Estimation of liver fibrosis indices
We selected six liver fibrosis indices: APRI, AARPRI, FIB-4, mFIB-4, FibroQ, and Forns index. Fibrosis indices were calculated according to the following formulas [16, 17, 21]:
$$\mathrm{APRI}=\frac{\mathrm{AST}\ \left(/\mathrm{ULN}\right)}{\mathrm{Platelet}\ \mathrm{count}\ \left({10}^9/\mathrm{L}\right)}\times 100.$$
$$\mathrm{AAR}=\frac{\mathrm{AST}}{\mathrm{ALT}}\mathrm{ratio},\mathrm{AARPRI}=\frac{\mathrm{AAR}}{\mathrm{Platelet}\ \mathrm{count}\ \left({10}^9/\mathrm{L}\right)/150}$$
$$\mathrm{FIB}-4=\frac{\mathrm{Age}\ \left(\mathrm{years}\right)\times \mathrm{AST}\left(\mathrm{U}/\mathrm{L}\right)}{\mathrm{Platelet}\ \mathrm{count}\ \left({10}^9/\mathrm{L}\right)\times \sqrt{\mathrm{ALT}\left(\mathrm{U}/\mathrm{L}\right)}}$$
$$\mathrm{mFIB}-4=\frac{10\times \mathrm{Age}\ \left(\mathrm{years}\right)\times \mathrm{AST}\ \left(\mathrm{U}/\mathrm{L}\right)}{\mathrm{Platelet}\ \mathrm{count}\ \left({10}^9/\mathrm{L}\right)\times \mathrm{ALT}\ \left(\mathrm{U}/\mathrm{L}\right)}$$
$$\mathrm{FibroQ}=10\times \frac{\mathrm{Age}\ \left(\mathrm{years}\right)\times \mathrm{AST}\left(\mathrm{U}/\mathrm{L}\right)\times \mathrm{INR}}{\mathrm{ALT}\left(\mathrm{U}/\mathrm{L}\right)\times \mathrm{Platelet}\ \mathrm{count}\ \left({10}^9/\mathrm{L}\right)}$$
$$\mathrm{Forns}\ \mathrm{index}=7.811-3.131\times \mathrm{In}\ \left(\mathrm{Platelet}\ \mathrm{count}\left[{10}^9/\mathrm{L}\right]\right)+0.781\times \mathrm{In}\ \left(\upgamma \mathrm{GT}\ \left[\mathrm{IU}/\mathrm{L}\right]\right)+3.467\times \mathrm{In}\ \left(\mathrm{age}\right)-0.014\times \mathrm{cholesterol}\ \left(\mathrm{mg}/\mathrm{dl}\right)$$
Outcome
The outcome of interest was substantial HE within 72 h of symptom onset. Substantial HE was defined as a proportional increase of hematoma volume>33% or an absolute growth of hematoma volume>6 mL from baseline CT scan to follow-up CT scan [25].
Statistical analysis
Categorical variables were presented as n (%), whereas continuous variables were presented as mean ± standard deviation (SD) or median and interquartile range (IQR). Differences between groups with or without substantial HE were assessed for significance using the chi-squared test or Fisher exact test in the case of categorical variables, or using Student’s t test or Mann-Whitney U test in the case of continuous variables.
Potential associations between liver fibrosis indices and substantial HE were estimated using binary logistic regression. All variables associated with p ≤ 0.10 were considered in the regression. Laboratory data were not included as variables in the regression, since the liver fibrosis indices were estimated from such data. To avoid effects of interactions between liver fibrosis indices, each index was included separately in the binary logistic regression. Since hematoma volume on admission may affect the association between liver fibrosis indices and substantial HE, we considered two models: Model 1 and Model 2, which contained the same variables as Model 1 in addition to baseline hematoma volume. Analysis was planned both in all patients and an early admission group within 6 h of ICH onset.
Statistical analyses were conducted using SPSS 24.0 (IBM, New York, USA). Differences and statistical results associated with a 2-tailed p<0.05 were defined as significant.