The Impact of Cirrhosis on Outcomes of Patients Admitted With Diabetic Ketoacidosis: A Nationwide Study

Introduction Diabetic ketoacidosis (DKA) is the most common acute hyperglycemic emergency in people with diabetes mellitus (DM). Cirrhosis is a consequence of chronic inflammation that is followed by hepatic fibrosis. It has been noted that cirrhosis is associated with an increased risk of developing type II DM due to altered glucose homeostasis. The prognostic value of DM in cirrhotic patients has been studied before and was found to be associated with lower survival. However, the risk of mortality and adverse events in cirrhotic patients admitted with DKA needs further evaluation. The aim of this study is to compare outcomes in patients with cirrhosis admitted to the hospital with DKA compared to non-cirrhotic patients. Methods The data for this study were extracted from the National Inpatient Sample (NIS) 2016-2019. The NIS was queried for all patients who had a discharge diagnosis of DKA. Patients with cirrhosis were identified and subclassified into compensated and decompensated cirrhosis using the International Classification of Diseases 10th revision, Clinical Modification (ICD-10-CM) codes. Patients without cirrhosis were the control group. ICD-10-CM codes that have been validated for cirrhosis were utilized. The primary outcome was in-hospital mortality. Secondary outcomes were hospital charges, length of stay (LOS), and in-hospital complications, including shock, mechanical ventilation, and acute kidney injury (AKI) requiring dialysis. Results We included 1,098,875 hospitalizations with a discharge diagnosis of DKA. Overall, 9,190 patients had compensated cirrhosis and 4,355 had decompensated cirrhosis. Cirrhotic patients had overall worse outcomes compared to non-cirrhotics. Decompensated cirrhotics had the highest mortality (11.26%; 95% confidence interval [CI]: 9.36% to 13.49%) compared to compensated cirrhotics (3.54%; 95% CI: 2.79% to 4.48%) and non-cirrhotics (2.15%; 95% CI: 1.89% to 2.43%). Similarly, decompensated cirrhotics also had the highest LOS, total charges, and in-hospital complications among the groups. On multivariate analysis, decompensated cirrhosis, rather than compensated cirrhosis, was an independent predictor of higher mortality (adjusted odds ratio [AOR]: 2.30; 95% CI: 1.81 to 2.92), LOS (regression coefficient: +1.82 days; 95% CI: +1.19 to +2.44 days), hospital charges (regression coefficient: +$28,497; 95% CI: +$18,107 to +$38,887), shock (AOR: 2.31; 95% CI: 1.68 to 3.18), mechanical ventilation (AOR: 1.91; 95% CI: 1.58 to 2.29), and AKI requiring dialysis (AOR: 2.31; 95% CI: 1.68 to 3.18). Conclusion This study showed that patients with decompensated liver cirrhosis who were admitted with DKA had the worst in-hospital outcomes. Additionally, only decompensated cirrhosis was an independent predictor of worse outcomes. Decompensated cirrhotics who develop DKA should be approached with more caution with a probable lower threshold for intensive care unit admission for a higher level management.


Introduction
Diabetic ketoacidosis (DKA) is the most common acute hyperglycemic emergency in people with diabetes mellitus (DM) [1]. This potentially life-threatening complication can occur in both type 1 and type 2 DM, and it can be associated with significant morbidity and increased length of hospital stay [2,3]. Mortality rates in DKA patients have fallen significantly in the past 20 years to <1% [3,4].
Liver cirrhosis is a consequence of chronic liver inflammation followed by diffuse hepatic fibrosis, which can eventually lead to liver failure [5]. Cirrhosis is the leading cause of liver-related death globally. Deaths due to cirrhosis constituted 2.4% of total deaths globally in 2017 compared with 1.9% in 1990 [6]. Agestandardized deaths due to cirrhosis are highest in Egypt due to the high prevalence of hepatitis C and hepatitis B and lowest in Singapore [6]. The natural history of cirrhosis starts with an asymptomatic phase known as compensated cirrhosis, followed by the development of complications from portal hypertension and/or liver dysfunction, termed as decompensated cirrhosis [1]. Most deaths in patients with decompensated cirrhosis result from hepatic and extrahepatic organ failure. Deaths during the compensated stage are largely due to cardiovascular disease, malignancy, and renal disease [5].
Cirrhosis is associated with an increased risk of developing type II DM due to altered glucose homeostasis [7]. The prognostic value of DM in cirrhotic patients has been studied before and was found to be associated with lower survival [7][8][9][10][11]. However, to the best of our knowledge, no studies have been conducted before to evaluate the risk of mortality and adverse events in cirrhotic patients admitted with DKA compared to noncirrhotic patients. This national inpatient-based study will compare potential outcomes in patients with liver cirrhosis admitted to the hospital with DKA with outcomes in non-cirrhotic DKA patients.

Data source
The data for this study were extracted from the National Inpatient Sample (NIS) 2016-2019. NIS is the largest publicly available all-payer inpatient healthcare database [12]. The NIS is drawn from all states participating in the Healthcare Cost and Utilization Project (HCUP), covering more than 97% of the United States population. The database contains data on more than seven million hospital stays with a weighted estimate of 35 million hospital stays each year. It includes information on patients' demographics, hospital characteristics, hospital outcomes, and up to 40 diagnostic and 25 procedure codes based on the International Classification of Diseases 10th revision, Clinical Modification (ICD-10-CM), and Procedure Coding System (ICD-10-PCS).
The University of Missouri School of Medicine Institutional Review Board has deemed research using the NIS and similar deidentified datasets exempt from institutional approval.

Study design and inclusion criteria
The NIS was queried for all patients who had a discharge diagnosis of DKA between 2016 and 2019. Patients younger than 18 years, elective admissions, and patients with missing demographic variables such as age, gender, and age were excluded from the study. Patients with cirrhosis were identified and subclassified into compensated and decompensated cirrhosis. Compensated cirrhotics were identified using ICD-10 codes for cirrhosis without the presence of decompensation variables: portal hypertension, hepatic encephalopathy, ascites, variceal bleeding, hepatocellular carcinoma, or hepatorenal syndrome. Decompensated cirrhosis was defined using both cirrhosis diagnosis and one or more decompensation variables. Combination codes for defining compensated and decompensated cirrhosis have been validated and shown to have a good positive and negative predictive value [13]. Patients without cirrhosis were considered the control group. Table 1 contains the list of ICD-10-CM and ICD-10-PCS codes used in the study.  Patients' demographics included in the NIS database were age, sex, race, median household income, and insurance status. Hospital characteristics included hospital size, region, and teaching status. The comorbidity burden was assessed using the Charlson comorbidity index. The primary outcome was inhospital mortality. Secondary outcomes were hospital charges, length of stay (LOS), and the following inhospital complications: mechanical ventilation, vasopressor use, and acute kidney injury (AKI) requiring dialysis.

Statistical analysis
Data analysis was performed using Stata version 17 (StataCorp, College Station, TX). This software implements weighing of patient-level observations, which facilitates producing nationally representative unbiased results, variance estimates, and p-values. Statistical hypotheses were tested using p < 0.05 as the level of statistical significance. Categorical variables were compared using the chi-square test, and continuous variables were compared using Student's t-test. Outcomes were evaluated using a multivariate logistic regression model to adjust for confounders. Confounders included in the multivariate regression test were the Charlson comorbidity index along with patients' demographics and hospital characteristics. Covariates with p ≥ 0.1 on univariate analysis, except for age and sex, were excluded from the multivariate analysis.

Patient and hospital characteristics
We included 1,098,875 weighted discharges of DKA between January 1, 2016, and December 30, 2019. Of those, 9,190 patients had compensated cirrhosis and 4,355 had decompensated cirrhosis.   Table 3 summarizes the outcomes in the study groups. Figure 1 shows a forest plot of AOR of the studied categorical outcomes.

Mechanical ventilation
Of the patients with DKA, 6.15% (CI, 6.03% to 6.27%) were mechanically ventilated in the non-cirrhotics group. Decompensated cirrhotics had a much higher rate of intubation (

Discussion
This study showed that patients with liver cirrhosis admitted with DKA had overall worse outcomes than non-cirrhotics, with decompensated cirrhotics having the worst outcomes of all groups. Decompensated liver cirrhosis in patients admitted with DKA was associated with significantly increased mortality, length of hospital stay, and higher hospital charges. Moreover, decompensated cirrhotics had increased in-hospital complications such as an increased risk of respiratory failure requiring mechanical ventilation, AKI requiring dialysis, and shock requiring vasopressors. On the other hand, although patients with compensated liver cirrhosis had worse mortality, increased rates of respiratory failure requiring mechanical ventilation, and shock requiring vasopressors, this association was not significant on multivariate analysis. These findings indicate that decompensated cirrhosis, rather than compensated cirrhosis, is an independent predictor of worse outcomes in patients admitted with DKA. Interestingly, after controlling for other factors, patients with compensated liver cirrhosis had lower odds of developing an AKI requiring dialysis compared to noncirrhotics.
There is no well-established explanation for the worse mortality outcomes in patients with decompensated liver cirrhosis admitted with DKA compared to non-cirrhotics. However, this can be potentially attributed to the poor liver function in decompensated cirrhotic patients, which, in turn, will affect glucose metabolism and homeostasis. Several structural changes in liver cirrhosis can decrease the extraction of insulin by the liver, leading to increased systemic insulin levels by a reduction in liver cell mass and/or the formation of portosystemic venous collaterals [14,15]. This resultant hyperinsulinemia can lead to resistance to insulin through insulin receptor downregulation [16]. Other described mechanisms of liver cirrhosis effect on glucose homeostasis include increased advanced glycations products, increased formation of hypoxiainducible factors, and reduced pancreatic beta-cell function, which will lead to decreased insulin secretion [17][18][19]. All of these mechanisms will lead to increased insulin resistance in cirrhotic patients and thus may contribute to worse outcomes of patients who develop DKA. Such changes are expected to be more pronounced in patients with decompensated liver cirrhosis compared to patients with compensated cirrhosis due to advanced stages of liver fibrosis and functional impairment.
Our study has also shown that patients with decompensated liver cirrhosis admitted with DKA are at a very high risk of developing respiratory failure requiring mechanical ventilation. Patients with liver cirrhosis are at an increased risk of respiratory complications such as hepatopulmonary syndrome (HPS), portopulmonary hypertension, and hepatic hydrothorax, which, in turn, can increase the risk of respiratory failure and mechanical ventilation [20]. A prospective study conducted by Schenk et al. on 111 patients with liver cirrhosis, including 27 patients with HPS, showed that patients with HPS had a higher mean Child-Pugh score and MELD (Model for End-Stage Liver Disease) score [21]. Moreover, they found that arterial deoxygenation was more severe in patients with a higher Child-Pugh class [21]. This can explain our finding that patients admitted with DKA who also have decompensated cirrhosis have a higher chance of respiratory failure and mechanical ventilation compared to non-cirrhotics.
Our study has some limitations. Due to the nature of the NIS database, our observations reflect admissions and not individual patients. Therefore, the unit of analysis is the admission. Given the inability to account for multiple admissions for a given patient in the NIS, our conclusions may be confounded by the risk of repeat hospitalization. Thus, our reported rates may be viewed as overestimates of a per-patient admission rate. Mortality rates, however, are unlikely to be affected. Under-or over-coding can lead to misclassification, although the large number of patients in the database strongly mitigates against substantial misclassification bias. NIS undergoes data quality assessment annually to ensure the internal validity of the data. Moreover, patients in the decompensated group were not classified based on the etiology of decompensation, as this can potentially affect the outcome. Additionally, observational studies may not be able to fully adjust for unmeasured confounding factors that might affect our estimates for the reported associations between in-hospital mortality and included covariates. Therefore, conclusions based on these observational data should be viewed as associational and not causal in nature. Finally, these observations pertain to the DKA population in the United States and may not be generalizable to other cirrhosis populations in other countries.

Conclusions
This study showed that patients admitted with DKA who also have decompensated cirrhosis had the worst outcomes compared to those with compensated cirrhosis and without cirrhosis. Furthermore, decompensated cirrhosis was an independent predictor of worse outcomes in DKA patients. DKA should be approached with more caution in decompensated cirrhotics with probable lower threshold for intensive care unit admission for a higher level management.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.