Association of Chronic Liver Disease and Mortality in Patients With Aneurysmal Subarachnoid Hemorrhage
Background and Purpose:
Chronic liver disease (CLD) is a risk factor for increased morbidity and mortality in acutely ill patients. For patients with aneurysmal subarachnoid hemorrhage (aSAH), the association between CLD and mortality remains unknown.
In this retrospective cohort study, we analyzed consecutive aSAH patients admitted to the West China Hospital between 2009 and 2019. The primary outcome was in-hospital all-cause mortality.
This study included 6228 cases of aSAH, 489 (7.9%) of whom also had CLD. In a propensity-matched analysis, CLD was associated with increased mortality in patients with aSAH compared with non-CLD (odds ratio, 2.04 [95% CI, 1.43–2.92]). In aSAH patients with CLD, a high Model for End-Stage Liver Disease score was still associated with an increased odds of mortality.
Among aSAH patients, CLD was associated with increased mortality compared with non-CLD. Among aSAH patients with CLD, a higher Model for End-Stage Liver Disease score was associated with an increased odds of mortality.
Chronic liver disease (CLD) is a significant risk factor for increased morbidity and mortality in acutely ill patients.1 For neurosurgeons, CLD and its impact on bleeding risks is a significant clinical concern.1 There is a paucity of studies that investigate the association between CLD and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). Accordingly, we assessed the association between CLD and mortality and investigated whether the Model for End-Stage Liver Disease (MELD) score is an independent predictor of mortality in patients with both CLD and aSAH.
The data that support the findings of this study are available from the corresponding author upon reasonable request. We performed a retrospective review of the electronic medical records of aSAH patients admitted to the West China Hospital, Sichuan University, between January 2009 and June 2019. The ethics committees of this hospital approved the study. The study is reported based on the STROBE statement2 (see Data Supplement for checklist).
Patients were included if they had an intracranial aneurysm identified by imaging in the presence of SAH. Patients were determined to have CLD based on their clinical diagnosis (including chronic hepatitis, steatosis, and cirrhosis). Such patients were identified by both a review of their medical charts and by assessing codes determined by the International Classification of Diseases, Tenth Revision (ICD-10) codes (B18, K70-74).3,4 We used the MELD score for further risk stratification in the CLD cohort.5
The primary outcome was in-hospital all-cause mortality. The secondary outcomes were incidence of hydrocephalus, delayed neurological ischemic deficits, rebleeding, seizures, intracranial infection, pneumonia, acute renal failure, and the length of hospital stay.
We conducted propensity score matching of patients with clinically diagnosed CLD and patients without CLD to balance variables. Variables with P<0.10 in the univariable regression were entered into the multivariable logistic regression. We also conducted a multivariable logistic regression model using all the variables in the Table (regardless of P value), because these risk factors for aSAH are known in the literature. In addition to this sensitivity analysis of multivariable logistic regression results, we assessed unmeasured confounding using E value.6 Details are described in the Data Supplement.
|Characteristics||Before matching (N=489 vs 5739)||After matching (n=319 vs 1276)|
|Unadjusted||Multivariable regression||Propensity score matched|
|OR (95% CI)||P value||OR (95% CI)||P value||OR (95% CI)||P value|
|Mortality||2.66 (2.07–3.41)||<0.001||2.09 (1.56–2.80)||<0.001||2.04 (1.42–2.92)||<0.001|
|Hydrocephalus||1.28 (0.97–1.69)||0.08||0.98 (0.72–1.32)||0.86||0.95 (0.64–1.42)||0.81|
|Rebleeding||2.30(1.61–3.28)||<0.001||2.02(1.40–2.91)||<0.001||2.42 (1.42–4.10)||< 0.001|
|Delayed neurological ischemic deficits||1.27 (1.01–1.59)||0.04||1.25 (0.96–1.58)||0.55||1.24 (0.92–1.68)||0.16|
|Seizures||1.27 (0.81–1.99)||0.30||1.02 (0.64–1.64)||0.92||0.79 (0.41–1.53)||0.49|
|Intracranial infection||1.70 (1.31–2.21)||<0.001||1.47 (1.11–1.95)||0.007||1.09(0.74–1.55)||0.73|
|Pneumonia||3.08 (2.54–3.72)||<0.001||2.73 (2.21–3.36)||<0.001||2.36 (1.82–3.06)||<0.001|
|Acute kidney injury||9.87 (7.70–12.64)||<0.001||7.74 (5.92–10.13)||<0.001||7.17 (4.86–10.58)||<0.001|
In univariable analysis, CLD was associated with increased risk of mortality (odds ratio [OR], 2.66 [95% CI, 2.07–3.41]; Table and Table II in the Data Supplement). In the multivariable logistic regression, CLD was independently associated with mortality (OR, 2.09 [95% CI, 1.56–2.86]). In the sensitivity analysis (which included all known risk factors for mortality), the relationship of CLD with increased mortality was unchanged (OR, 2.13 [95% CI, 1.59–2.87]). Even in the propensity-matched analysis, our findings remained robust: CLD was also associated with increased mortality (OR, 2.04 [95% CI, 1.42–2.92]). The E value obtained for the association between CLD and mortality was 3.5, with a lower limit of 2.19. The Hosmer-Lemeshow test obtained a value of P=0.885 (Table III in the Data Supplement).
Mortality was higher in patients with higher MELD scores (Table IV in the Data Supplement). Compared with patients with a MELD score <10, the odds of in-hospital mortality was significantly higher in patients with a MELD score 20.0 to 29.9 (OR, 2.45 [95% CI, 1.12–5.41]) and 30.0 or higher (OR, 10.37 [95% CI, 2.38–45.16]). Even when the MELD score was analyzed as a continuous variable, every 1-point increase in MELD score was still associated with an increased odd of mortality (OR, 1.05 [95% CI, 1.02–1.09]).
We found no significant modification of CLD associated mortality in this analysis (Figure). We separately analyzed patients with alcohol-related or virus-related CLD. Neither alcohol-related (OR, 1.20 [95% CI, 0.64–3.95]) nor virus-related CLD (OR, 2.21 [95% CI, 0.90–5.45]) was associated with significantly increased mortality (Table V in the Data Supplement). Compared with noncirrhotic CLD, cirrhotic disease was not associated with significantly higher mortality (OR, 1.59 [95% CI, 0.61–4.09]).
CLD was also associated with increased risk of rebleeding (OR, 2.02 [95% CI, 1.40–2.91]), intracranial infection (OR, 1.47 [95% CI, 1.11–1.95]), pneumonia (OR, 2.73 [95% CI, 2.21–3.36]), and acute kidney injury (OR, 7.74 [95% CI, 5.92–10.13]).
We found that CLD was associated with an increased risk of mortality in patients with aSAH. Among aSAH patients with CLD, an increased severity of CLD was associated with a significant increase in the risk of death.
The exact mechanisms explaining such an association between CLD and mortality are unclear. Patients with CLD have higher increased risks for complications, such as bleeding, cerebral edema, epilepsy, ischemic stroke, venous thromboembolism, electrolyte imbalance, and acute kidney injury.1,7 In this study, we also found that CLD was associated with a significantly higher incidence of rebleeding, intracranial infection, pneumonia, and acute kidney injury. Our data thus suggests avenues of future research into potential mechanisms underlying hyponatremia and mortality in aSAH patients.
The association between CLD and outcomes in patients with aSAH has not been studied; we are aware of only 2 retrospective studies that specifically evaluated liver fibrosis8 or cirrhosis9 in patients with intracerebral hemorrhage. In 2008 Huang et al8 identified 36 cirrhotic patients with intracerebral hemorrhage. They concluded that the cause of cirrhosis did not affect patient outcomes. In 2020, Parikh et al9 investigated the association of liver fibrosis indices and outcomes in 432 patients with intracerebral hemorrhage. The study calculated 3 noninvasive liver fibrosis indices, 2 of which were associated with mortality in patients with intracerebral hemorrhage.
Our study has a few limitations. The main limitation of our study is its retrospective design. The nature of the study allows for assessment of only association not causation. This study also lacked information about the duration of cirrhosis in patients with CLD. Ascertainment bias may be present because 16% of aSAH patients with CLD have inadequate MELD data. Recall bias may also be present as the medical history of a few cases with altered mental status were collected from patients’ relatives. Misclassification may arise due to erroneous ICD-10 codes used for CLD.4 To reduce this error, we manually reviewed medical records in all patients with ICD-10 codes indicating CLD. Relatively few patients were included in the analysis of the cause of the CLD (alcohol, virus, and other). This analysis may have been underpowered, resulting in nonsignificant associations. The different prevalence of liver disease causes in China from other countries may limit the generalizability of our findings. For example, the prevalence of hepatitis B virus (6.5%) in China is much higher than the prevalence in the United States (0.7%) and European countries (0.9%).10
This study found that aSAH patients with CLD have a significant increase in inpatient mortality compared with patients without CLD. We also confirmed that a higher MELD score in aSAH patients was associated with an increased risk of mortality.
Ethical approval: The ethics committee of West China Hospital (No. 20191133). The study concept and design were done by Drs Fang and Cheng. The acquisition, analysis, or interpretation of data was done by Drs Zhang, Jia, and Li. The statistical analysis was done by Dr Zhang. The article was drafted by Dr Zhang. The critical revision of the article for important intellectual content was done by all authors.
Sources of Funding
This work is supported by the project of health commission of Sichuan province (19PJ003), and the project of Sichuan Science and Technology Bureau (2017SZ0142 and 2020YFS0490).
Expanded Materials and Methods
Online Tables I–V
Online Figure I
Disclosures Dr Lunsford is a member of the Data Safety Monitoring Board of Insightec and is a stockholder in Elekta. The other authors report no conflicts.
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