Serum Perilipin 2 (PLIN2) Predicts Multiple Organ Dysfunction in Critically Ill Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Patient Characteristics
2.2. PLIN2 Measurements
2.3. Assessment of Computed Tomography Scan Body Composition Markers
2.4. Statistical Analysis
3. Results
3.1. PLIN2 Serum Levels Were Significantly Elevated in Critically Ill Patients
3.2. Associations of PLIN2 Serum Concentrations with Clinical Data and Blood-Based Parameters
3.3. PLIN2 Levels Were Associated with Organ Failure and Disease Severity
3.4. PLIN2 Serum Levels and Association with CT Scan Body Composition Markers
3.5. Serum PLIN2 Concentrations May Predict ICU Mortality in Critically Ill Patients Older Than 65 Years
4. Discussion
- (i)
- Because of growing evidence suggesting sex differences in the pathophysiology of critical illness [49,50,51], we investigated whether PLIN2 concentrations show a different distribution based on sex. In contrast to recent data stating that PLIN2 levels were higher in women, especially in patients below 79 years [32], we did not detect any difference of serum PLIN2 in both sexes.
- (ii)
- (iii)
- As BMI and mortality act in a “J-shaped” dependence and, because overweight and moderate obesity appear to be protective factors in critically ill patients, called the “obesity paradox” [36,52,53], we correlated serum PLIN2 with BMI and analyzed PLIN2 in different BMI subgroups (underweight vs. normal vs. overweight vs. obese; data not shown). Serum PLIN2 did not show any significant differences in these analyses, which is in contrast to previously published data [32].
- (iv)
- PLIN2 acts as a regulator in lipid metabolism [5,7,15,16] and previous murine and human studies have shown that PLIN2 dysregulation can be associated with lipid storage malfunction diseases [7,14,17,18,19,20,21,22]. Surprisingly and despite PLIN’s function as a lipid droplet protein, we did not detect an association of serum PLIN2 with classical markers of lipid metabolism such as cholesterol, LDL or triglycerides. These results are not in line with experimental studies, which showed reduction of hepatic steatosis or lower triglycerides in serum and liver after knock-out or downregulation of PLIN2 expression [6,7,9,19,54].
- (v)
- Insulin resistance and diabetes mellitus are important modulators of mortality and morbidity in critically ill patients [36]. Experimental research suggests that PLIN2 is involved in the pathophysiology of insulin resistance [12,13,14]. This encouraged us to analyze the relationship between pre-existent diabetes and PLIN2 serum levels. Of note, serum PLIN2 concentrations were independent of the presence of diabetes. Moreover, we did not observe a correlation between PLIN2 levels and HbA1c levels, but a non-significant trend towards a rather weak correlation with HOMA-IR. Interestingly, a recently published study reports similar results, with no observed association with DM, but a significant correlation between PLIN2 and HOMA-IR [32]. Another group described higher PLIN2 levels in diabetic patients with NAFLD compared to patients without NAFLD, and correlations with age, waist circumference, triglycerides and HOMA-IR. However, these results are difficult to compare to our study because we did not assess our patients for the presence of NAFLD.
- (a)
- There has been evidence of PLIN2 involvement in the development of age-related vascular disease, such as atherosclerosis [6,15,23,24,25,26,27]. Recent studies highlighted the importance of PLIN2 in cardiomyocyte lipid accumulation [28] and were able to connect PLIN2 to coronary microvascular obstruction and infarct size in patients with ST-elevation myocardial infarction and major adverse cardiovascular events during follow-up [55]. Intrigued by these findings, we investigated whether arterial hypertension or coronary artery disease are associated with altered PLIN2 serum levels. However, our results did not prove any obvious association between vascular diseases and PLIN2 levels.
- (b)
- Prompted by experimental research connecting changes in PLIN2 serum levels with hepatic diseases and alcohol consumption [20,21,54,56], we analyzed serum PLIN2 concentrations in ICU patients suffering from liver cirrhosis and patients with a history of alcohol abuse. However, we did not observe any connections between cirrhosis or alcohol abuse and PLIN2 levels. However, this may be due to missing statistical power because only 3.1% of our cohort had cirrhosis. Additionally, the majority of the mentioned studies assessed PLIN2 in NAFLD or non-alcoholic steatohepatitis (NASH) instead of cirrhosis, further reducing the comparability of the results.
- (c)
- PLIN2′s activation state is regulated by pancreatic hormones. While catecholamines permit lipolysis via phosphorylation and dissociation of PLIN2, insulin inhibits lipolysis via dephosphorylation of PLIN2, hindering hormone-sensitive lipases in accessing the lipid droplets [21]. Of note, we observed a strong negative correlation between PLIN2 and lipase. Correspondingly, patients admitted due to acute pancreatitis presented with decreased PLIN2 concentrations. However, serum PLIN2 was not able to discriminate a mortality difference in the small subgroup of patients with acute pancreatitis (n = 13; Figure S4A). To the best of our knowledge, associations with pancreatic markers or disease have not been previously described. Taking physiological mechanisms into consideration, the inverse association of PLIN2 with lipase raises the question of whether this is due to pancreatitis and its associated multiple organ dysfunction or rather an effect of higher PLIN2 metabolization of serum lipases. Importantly, serum PLIN2 levels were not associated with norepinephrine demand. Moreover, the logistic regression analyses of PLIN2 and SOFA score > 9 points remained significant after adjustment for the norepinephrine demand (Table 3).
- (d)
- Previous studies have demonstrated the role of PLIN2 as a tumor marker in different body fluids or in tumor tissue [6,57,58] for several malignant diseases, such as renal cell carcinoma [57,59,60,61], colorectal carcinoma [29] or lung adenocarcinoma [30]. In our ICU cohort, PLIN2 serum concentrations were elevated in patients with preexistent malignant disease. These consistent associations of serum PLIN2 with malignancy even during critical illness underline its potential capacity as a tumor marker for routine diagnostics.
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameters | r | p |
---|---|---|
Demographics | ||
Age | 0.064 | 0.305 |
Body mass index | −0.099 | 0.129 |
FBC and markers of inflammation | ||
MCHC | 0.166 | 0.007 * |
Platelets | −0.135 | 0.030 * |
WBC | −0.109 | 0.080 |
C-reactive protein | 0.025 | 0.688 |
Procalcitonin | −0.023 | 0.751 |
Interleukin 6 | 0.050 | 0.486 |
Interleukin 10 | 0.092 | 0.303 |
TNF-α | −0.165 | 0.157 |
Electrolytes and renal system | ||
Sodium | −0.101 | 0.105 |
Potassium | −0.143 | 0.021 * |
Urea | 0.013 | 0.839 |
Creatinine | −0.042 | 0.499 |
HPB system | ||
Albumin | −0.020 | 0.805 |
INR | 0.004 | 0.955 |
Bilirubin, total | −0.056 | 0.369 |
γGT | −0.099 | 0.115 |
AST | −0.072 | 0.263 |
Lipase | −0.509 | <0.001 * |
Cardiopulmonary system | ||
NTproBNP | 0.024 | 0.785 |
Norepinephrine demand at day 1 (µg/kg/min) | 0.066 | 0.322 |
Horovitz quotient (PaO2/FiO2) | 0.202 | 0.052 |
Ventilatory FiO2 demand | −0.224 | 0.026* |
Metabolism and endocrinology | ||
Glucose | 0.066 | 0.292 |
HbA1c | −0.090 | 0.355 |
Insulin | −0.035 | 0.720 |
C-Peptide | −0.095 | 0.330 |
HOMA IR | −0.173 | 0.077 |
Cholesterol | −0.011 | 0.868 |
HDL-cholesterol | 0.062 | 0.533 |
LDL-cholesterol | 0.101 | 0.309 |
Triglycerides | −0.094 | 0.170 |
ICU parameters | ||
Days on ICU | 0.132 | 0.034 * |
SOFA day 1 | 0.149 | 0.113 |
SOFA day 3 | 0.261 | 0.014 * |
APACHE-II day 1 | −0.102 | 0.151 |
APACHE-II day 3 | 0.240 | 0.020 * |
Parameters | All Patients n = 259 | Non-Sepsis n = 93 | Sepsis n = 166 | p |
---|---|---|---|---|
Female (%) | 40.5% | 39.8% | 41% | n.s. |
Age (years) | 63 (18–89) | 60 (18–85) | 64 (21–89) | n.s. |
Body mass index (kg/m2) | 26 (15.9–86.5) | 25.8 (15.9–53.3) | 26.1 (17.1–86.5) | n.s. |
Comorbidities | ||||
Arterial Hypertension (%) | 23.9 | 26.9 | 22.3 | n.s. |
Diabetes mellitus (%) | 31.3 | 32.3 | 30.7 | n.s. |
Coronary artery disease (%) | 12.7 | 15.1 | 11.5 | n.s. |
COPD (%) | 17.4 | 21.5 | 15.1 | n.s. |
Liver cirrhosis (%) | 3.1 | 5.4 | 1.8 | n.s. |
Malignant disease (%) | 11.2 | 7.5 | 13.3 | n.s. |
Clinical parameters | ||||
Mechanical ventilation demand at day 1 (%) | 72.2 | 64.5 | 76.5 | 0.039 |
Norepinephrine demand at day 1 (%) | 59.1 | 46.2 | 66.3 | <0.001 |
Norepinephrine demand at day 1 (µg/kg/min) | 0 (0–2.4) | 0 (0–2.4) | 0.1 (0–1.5) | 0.001 |
Renal replacement therapy demand at day 1 (%) | 27.4 | 18.3 | 32.5 | 0.010 |
Renal replacement therapy (days) | 0 (0–37) | 0 (0–21) | 0 (0–37) | 0.006 |
APACHE-II score at day 1 | 17 (2–43) | 14 (2–33) | 19 (3–43) | <0.001 |
APACHE-II score at day 3 | 19 (0–36) | 12 (0–28) | 22 (6–36) | <0.001 |
SOFA score at day 1 | 9 (0–19) | 7 (0–17) | 10 (3–19) | <0.001 |
SOFA score at day 3 | 9 (0–18) | 6 (0–15) | 10 (1–18) | <0.001 |
Days on ICU | 8 (2–137) | 6 (2–45) | 10 (2–137) | <0.001 |
Death on ICU (%) | 24.7 | 17.2 | 28.9 | 0.036 |
180-day mortality (%) | 20.8 | 17.2 | 22.9 | n.s. |
Observation period (days) | 137 (1–884) | 195.5 (1–883) | 110 (1–884) | n.s. |
Overall mortality (%) | 47.5 | 34.0 | 54.8 | 0.002 |
Laboratory data at day 1: | ||||
WBC [×103/μL] | 12.7 (0–149) | 11.4 (1.8–29.6) | 13.1 (0–149) | 0.011 |
C-reactive protein [mg/dL] | 97 (5–230) | 17 (5–230) | 161.5 (5–230) | <0.001 |
Procalcitonin [ng/mL] | 0.8 (0–248) | 0.2 (0–100) | 2.7 (0.1–248) | <0.001 |
Creatinine [mg/dL] | 1.4 (0.2–21.6) | 1 (0.2–15) | 1.6 (0.2–21.6) | 0.025 |
Creatinine GFR [mL/min] | 54 (2–60) | 60 (6–60) | 38 (2–60) | 0.004 |
INR [units] | 1.2 (0.9–6.7) | 1.2 (0.9–6.7) | 1.2 (0.9–4.6) | n.s. |
Albumin [mg/dL] | 27 (1.6–61.4) | 30.1 (1.6–48.5) | 25.6 (5–61.4) | 0.005 |
Lactate [mmol/l] | 1.6 (0.4–21.9) | 1.8 (0.6–18.1) | 1.5 (0.4–21.9) | 0.094 |
PLIN2 [µg/dL] | 5.23 (0.48–59.5) | 4.86 (1.4–32.4) | 5.47 (0.48–59.5) | 0.021 |
Sepsis occurrence at ICU admission | OR (95% CI) | p |
Unadjusted | 1.72 (1.03–2.88) | 0.038 |
Adjusted for age and DM | 1.71 (1.02–2.87) | 0.042 |
Adjusted for CRP | 1.75 (0.94–3.28) | 0.079 |
Adjusted for CRP and PCT | 2.07 (0.98–4.38) | 0.058 |
Adjusted for norepinephrine demand | 1.73 (1.01–2.98) | 0.047 |
SOFA > 9 points at ICU admission | OR (95% CI) | p |
Unadjusted | 3.13 (1.36–7.20) | 0.007 |
Adjusted for age and DM | 2.96 (1.27–6.88) | 0.012 |
Adjusted for CRP | 3.07 (1.33–7.09) | 0.009 |
Adjusted for CRP and PCT | 2.62 (0.67–10.24) | 0.166 |
Adjusted for norepinephrine demand | 2.72 (1.08–6.89) | 0.035 |
SOFA > 9 points at day 3 | OR (95% CI) | p |
Unadjusted | 3.08 (1.25–7.60) | 0.015 |
Adjusted for age and DM | 2.91 (1.16–7.29) | 0.023 |
Adjusted for CRP | 2.93 (1.17–7.32) | 0.021 |
Adjusted for CRP and PCT | 15.93 (2.85–88.93) | 0.002 |
Adjusted for norepinephrine demand | 2.79 (1.05–7.42) | 0.040 |
r|p | VAT [mm2] | SAT [mm2] | Skeletal Muscle [mm2] | Skeletal Muscle Mean HU | L3SMI |
---|---|---|---|---|---|
All patients | −0.004|0.983 | −0.160|0.353 | −0.152|0.377 | −0.213|0.213 | −0.095|0.592 |
BMI < 30 kg/m2 | −0.015|0.942 | −0.214|0.305 | −0.002|0.991 | −0.261|0.208 | 0.033|0.875 |
BMI ≥ 30 kg/m2 | −0.750|0.020 * | −0.517|0.154 | −0.567|0.112 | 0.259|0.500 | −0.533|0.139 |
Age < 65 years | −0.030|0.898 | −0.156|0.500 | −0.138|0.552 | −0.152|0.510 | −0.072|0.770 |
Age ≥ 65 years | 0.061|0.830 | −0.036|0.899 | −0.146|0.603 | −0.152|0.589 | −0.079|0.781 |
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Kurt, B.; Buendgens, L.; Wirtz, T.H.; Loosen, S.H.; Schulze-Hagen, M.; Truhn, D.; Brozat, J.F.; Abu Jhaisha, S.; Hohlstein, P.; Koek, G.; et al. Serum Perilipin 2 (PLIN2) Predicts Multiple Organ Dysfunction in Critically Ill Patients. Biomedicines 2021, 9, 1210. https://doi.org/10.3390/biomedicines9091210
Kurt B, Buendgens L, Wirtz TH, Loosen SH, Schulze-Hagen M, Truhn D, Brozat JF, Abu Jhaisha S, Hohlstein P, Koek G, et al. Serum Perilipin 2 (PLIN2) Predicts Multiple Organ Dysfunction in Critically Ill Patients. Biomedicines. 2021; 9(9):1210. https://doi.org/10.3390/biomedicines9091210
Chicago/Turabian StyleKurt, Berkan, Lukas Buendgens, Theresa H. Wirtz, Sven H. Loosen, Maximilian Schulze-Hagen, Daniel Truhn, Jonathan F. Brozat, Samira Abu Jhaisha, Philipp Hohlstein, Ger Koek, and et al. 2021. "Serum Perilipin 2 (PLIN2) Predicts Multiple Organ Dysfunction in Critically Ill Patients" Biomedicines 9, no. 9: 1210. https://doi.org/10.3390/biomedicines9091210