Value of HbA1c in stratifying the risk for SBP in patients eligible for antibiotic prophylaxis
In order to simulate a setting in which primary antibiotic prophylaxis could be considered, all patients with a history of SBP or current norfloxacin treatment were withdrawn from the analysis. A number of 309 no-DM patients and 84 DM patients (n = 21 with an HbA1c ≥6.4% and n = 63 with an HbA1c <6.4%) remained eligible for the final analysis (Supplementary Table 3). SBP incidence within 90 days was significantly higher in individuals with HbA1c levels ≥6.4% compared to those with levels <6.4% or without DM (HR: 3.22: p = 0.01 and HR: 4.58; p = 0.002, respectively) (Fig. 3). For the DM patients HbA1c ≥6.4%, platelet count, CHE, and AP were associated with an increased risk for SBP within 90 days in the univariate Cox regression but only HbA1c ≥6.4%, CHE values and AP remained statistically significant in the multivariate approach (Table 3). Of note, in this cohort serumbilirubin and ascites protein levels were both not signi ficantly associated with the risk for SBP even in the univariate analysis.
An additional analysis was conducted including all patients that had a SBP in their first paracentesis and with all patients with a documented history of SBP (patients eligible for secondary prophylaxis). DM and HbA1c values ≥6.4% were significantly associated with a higher incidence of recurrent SBP episodes (p = 0.04 and p = 0.02, respectively) (Supplementary Figures 4a, b).
Impact of DM on mortality in patients with decompensated liver cirrhosis
Overall mortality was numerically higher among DM patients. However, this closely failed to reach statistical significance (HR: 1.43; p = 0.07) (Fig. 4a). Similarly, the overall 90-day mortality rate was similar in DM patients with HbA1c levels ≥6.4% and those with values <6.4% (HR: 0.85; p = 0.70) (Fig. 4b). Furthermore, neither DM nor HbA1c was identified as significant risk factor for mortality in the uni- and multivariate Cox regression analysis (Supplementary Table 5,6).
Impact of DM on mortality in patients with SBP
There was no difference in the detected microorganisms in the ascites cultures between no-DM and DM patients with HbA1c levels < and ≥6.4% (Supplementary Table 7a, b). Estimated mortality within 90-days after SBP diagnosis was neither significantly associated to the presence of DM nor HbA1c values (HR: 1.53; p=0.51 and HR: 0.96; p=0.91, respectively) (Fig. 5).
Development of SBP is a severe complication in patients with liver cirrhosis and often indicates a significant acceleration of the natural history of the disease19. Over the recent years several studies tried to identify risk factors for either a higher likelihood of SBP development or a more severe course of SBP. However, the role of comorbidities has rarely been investigated in this context. In this study, we show that the presence of DM leads to signi ficant increase of SBP incidence. Importantly, we were able to demonstrate for the first time that the HbA1c level, an established marker for the severity of blood glucose dysregulation, may serve as a valuable tool to further stratify the risk for SBP in patients with decompensated liver cirrhosis.
Presence of DM is associated with a more complicated course of cirrhosis and a higher likelihood for hepatic decompensation15,20. Kwon et al. reported that an insufficient glycemic control is associated with a higher mortality among cirrhotic patients with HCV infection21. DM increases the incidence of HCC22 and quite a few studies could show that DM is also a relevant risk factor for the development of HE14,15,20,23,24. Therefore, it is quite surprising that the impact of DM on the risk for SBP has rarely been studied in the past. In line with our data, Liu et al. documented an increased incidence of SBP in a large US cohort in an analysis based on ICD-9 coded diagnoses15.
Similar results have been observed in a smaller cohort from the Netherlands11. In a large cohort from France DM increased the overall risk for bacterial infections in patients with cirrhosis, while SBP was not specifically analyzed20. There are a couple of possible explanations for the increased SBP incidence among the DM patients. DM leads to significant alterations of the human immune system, including an impaired leukocyte function13,25, which adds to the altered immune functions that are caused by liver cirrhosis2. Furthermore, DM-induced polyneuropathia may lead to dyskinesia of the gastral and bowels muscles resulting in a prolonged intestinal transit time26,27. This may result in an increased risk for bacterial translocation from the gut, which is a key part in SBP pathogenesis28.
One of the major findings of our study is that we were able to demonstrate for the first time that the risk for SBP in DM patients is depended on the degree of blood glucose disturbance as indicated by the HbA1c level. While the value of HbA1c as a marker for infections in patients with cirrhosis has not been investigated so far, there are quite some data available demonstrating the link between HbA1c values and DM specific complications like retinopathy and nephropathy29–31. Moreover, HbA1c is one of the central markers to adjust antidiabetic treatment16. One might argue that the identified HbA1c threshold of 6.4% in our study might be quite low given the fact that values around 6.5–7.5% are currently suggested as target levels to indicate a sufficient treatment16. However, it has to be considered that HbA1c target values have not been validated for patients with liver cirrhosis, in particular not for those with decompensated disease and portal hypertension. Portal hypertension may lead to an increased hemolysis and splenomegaly, which both results in a decreased survival time of erythrocytes32. This may help to explain why HbA1c values are in general lower in DM patients with compared to those without liver cirrhosis, often even within normal ranges (<6.5%), despite a signi ficant degree blood glucose dysregulation33–35.
Given the fact that DM was linked to SBP development in our study and has previously been associated with HE14,15,20,22–24 as well as other severe complications of cirrhosis, it seems to be quite likely that it also impairs the overall survival in patients with liver cirrhosis. Indeed, a higher mortality in cirrhotic patients with DM compared to those without DM has been reported from some centers20,36. In our study we documented only a numerical higher mortality rate in the DM group. Of note, no difference in the 90-day mortality rate was found between those with HbA1c levels < and ≥ 6.4% despite the signi ficant differences in SBP incidence. However, it has to be considered that patients with lower HbA1c levels in our cohort had a higher MELD score and lower platelets, which may indicate more severe liver disease in this group. Furthermore, it has been shown in non-cirrhotic cohorts that very low HbA1c levels are even associated with a higher overall mortality in DM patients most likely due to a higher risk for hypoglycemic episodes37. Therefore, an intensified antidiabetic treatment should not be generally recommended. Interestingly, AP seems to have a predictive value for mortality in our cohort, which might be further investigated in future studies.
Presence of DM leads to significant changes of the gut microbiota38. Therefore, it would have been quite convincing if there had been a relevant change in the pathogens that are involved in SBP episodes in DM patients. However, this was not the case in our cohort.
Our study has some important limitations which need to be considered while interpreting the results. Although all patients were included consecutively, the analysis has been performed retrospectively. Therefore, the identified HbA1c threshold needs to be further validated prospectively in a larger setting before specific recommendation can be made for patient management. Furthermore, we unfortunately did not have access to multiple HbA1c values over a longer follow-up period, which would have allowed a more detailed analysis.
However, we are convinced that our results have still some important implications for clinical practice and future studies. Even if an adequate treatment is timely initiated many patients with cirrhosis and SBP will experience severe complications like AKI or a fatal outcome3. In the past, prophylactic treatment with antibiotics has been shown to be effective in preventing SBP episodes in selected patients and to improve survival in individuals with a high risk for a severe course of SBP5,28,39. However, to achieve a reasonable risk/benefit ratio a wise and specific selection of patients for prophylactic treatments is essential. Currently suggested risk factors for the selection of patients for prophylaxis include an impaired liver function, a decreased ascites protein level, elevated creatinine level and a history of a previous SBP episode5,28,39. According to our data, presence of DM and more specifically in case of higher HbA1c levels should be further evaluated as possible indication for antibiotic prophylaxis in patients with cirrhosis to prevent SBP development.
In summary, we demonstrated that DM is an important, independent risk factor for SBP development in cirrhotic patients with ascites. Importantly, we could show for the first time that the risk for SBP in DM patients can be further stratified using HbA1c values as long-time marker for the severity of dysregulation of glucose metabolism.
What is current knowledge
- Spontaneous bacterial peritonitis (SBP) is the most frequent type of infection in individuals with decompensated liver cirrhosis.
- Type 2 diabetes mellitus (DM) is one of the most common comorbidities in patients with liver cirrhosis affecting 20–40% of cirrhotic patients.
What is new here
- DM is associated with a significantly increased risk for the development of a SBP.
- The risk for SBP in DM patients is linked to levels of glycosylated hemoglobin A1c (HbA1c).
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