Article, Gynecology

Aspartate-aminotransferase to platelet ratio index score for predicting HELLP syndrome

a b s t r a c t

Introduction: HELLP (hemolysis, elevated liver enzyme levels, low platelet counts)-syndrome is a rare but dra- matic pregnancy-related illness. The difficult part of this syndrome is the lack of standardised diagnostic criterias and tests to be used to predict it. The aim of this study is determining the role of APRI score in the diagnosis of HELLP syndrome.

Material and methods: In this cross sectional, retrospective study, patients with HELLP syndrome as case group and age-matched healthy pregnants at the similar pregnancy trimester as control group were included between January 12,017 and May 31, 2018. Data including sex, age, laboratory values, prognosis were recorded from the computerized system of the hospital. The p-value b0.05 was considered statistically significant.

Results: 40 patients with HELLP syndrome and 124 age-matched healthy pregnants included in the study. There was a statistically significant difference between control group and HELLP patients in terms of the mean urinary protein, platelet count, ALT, AST, creatinin, D dimer levels and also the mean APRI score. In the multivariate re- gression analysis, APRI score was found a better predictor than AST and both were in a good significant in predicting HELLP. On the ROC curve in order to distinguish the patients with HELLP from the control group for AST and APRI score, the sensitivity was found to be 71.7% and 82.6%, specificity to be 91.2% and 87.6% respectively. Maternal mortality rate of HELLP syndrome was 10%.

Conclusion: We concluded that the APRI score was robustly predicted HELLP syndrome than AST alone in this study. Further studies are needed to support our data with prospective, multicentre, larger patient groups.

(C) 2019

Introduction

HELLP (hemolysis, elevated liver enzyme levels, low platelet counts)-syndrome is a rare but dramatic pregnancy-related illness fre- quently complicated by cerebral edema and multiorgan failure which can be established with the examination of blood and urine. It is seen 0.17% to 0.85% during pregnancy and the mortality rates of gravidas and fetuses reach up to 23.1% – 56.9% [1]. It is characterized by the pres- ence of microangiopathic hemolytic anemia, elevated Liver enzymes, low platelet counts and associated with severe clinical complications lead to maternal end-organ failure or death [2]. It can worsen within hours and concerned patients complain about abdominal pains, nausea and vomiting. Further, patients have an increased blood pressure and proteinuria. The most important feared complication is the rupture of

* Corresponding author.

E-mail address: eylemkuday@hotmail.com (E.K. Kuday Kaykisiz).

the liver. There are some risk factors for the occurrence of HELLP- syndrome as Arterial hypertension, overweight or multipl pregnancies. The goal of therapy in patients with HELLP-syndrome consists of treat- ment of arterial hypertension and proteinuria and to postpone the de- livery of the baby until the 32nd week. The risk of recurrent HELLP- syndromes in following pregnancies is existent [3].

Since it’s first described in 1982, there has been controversy regard- ing it’s diagnosis and management. The difficult part of this syndrome is the lack of standardised diagnostic criterias and tests to be used to pre- dict it. Also, discriminating HELLP from other pregnancy related disor- ders is often hard and may result in increased mortality [3]. Although presence of elevated liver enzymes and low platelet counts is familiar, finding efforts for predictive tests with high sensitivity and specificity is still continues.

Aspartate-aminotransferase (AST)-to-platelet ratio index (APRI) score, traditionally, has been used for diagnosing liver cirrhosis. A score higher than 3 points is strongly suggestive non-invasive

https://doi.org/10.1016/j.ajem.2019.02.014

0735-6757/(C) 2019

460 M.I. Sasmaz et al. / American Journal of Emergency Medicine 38 (2020) 459462

Table 1

Descriptive statistics and comparison results of the groups

Control group Study group (patients with HELLP) p.

Mean

St. Dev.

Min.

Max.

Mean

St. Dev.

Min.

Max.

Age

30,40

7,00

18,00

47,00

30,60

7,41

18,00

52,00

,869

Proteinuria

180,32

211,88

10,00

1000,00

418,44

347,35

30,00

1000,00

,001

Hemoglobin

10,33

1,63

6,60

15,00

9,75

4,24

5,70

35,00

,184

PLT

201,52

74,21

22,00

567,00

85,73

46,85

11,00

200,00

,001

ALT

22,54

24,08

3,00

158,00

160,38

258,74

7,00

1300,00

,001

AST

33,82

49,72

8,00

550,00

295,73

564,37

12,00

2880,00

,001

Creatinine

,60

,21

,30

2,00

,90

,83

,20

5,00

,001

LDH

553,54

275,95

252,00

2100

2106,39

2292,46

450,00

10,000

,001

APTT

28,52

6,08

12,00

67,00

33,71

14,79

20,00

115,00

,001

INR

1,17

1,36

,60

10,00

1,03

,29

,73

2,30

,515

PT

11,85

2,71

,70

32,00

12,70

2,83

10,00

23,30

,073

D-DiMER

4,50

4,70

,20

20,00

12,88

10,58

1,30

30,00

,001

FiBRiNOJEN

492,59

141,71

254,00

732,00

347,47

187,81

71,00

684,00

,009

Abbreviations: ALT: alanine-aminotransferase, AST:aspartate-aminotransferase, LDH: Lactate dehydrogenase, INR: International normalized ratio, APTT: Activated Partial Thromboplastin Time PT: Prothrombine Time.

marker for cirrhosis [4-6]. The question of whether the APRI score, which is a strong indicator for cirrhosis, is a strong predictor in deter- mining patients with HELLP syndrome is an unexplored field in the literature.

The aim of this study is determining the role of APRI score in the di- agnosis of HELLP syndrome.

Material and methods

This cross sectional, retrospective, single centre study was con- ducted at Van Yuzuncu Yil University Hospital, Turkey. In this study, pa- tients with HELLP syndrome as case group and age and sex matched healthy pregnants at the similar pregnancy trimester as control group were included between January 12,017 and May 31, 2018. After ap- proval from Van Yuzuncu Yil University Hospital, data pertaining to pa- tients aged at least 18 years who had presented to the Obstetric and Gynecology Clinic with various symptoms and had diagnosis of HELLP syndrome suggested by American collage of obstetricians and Gynecol- ogist [7] was studied. Data including sex, age, laboratory values (com- plete blood count, hepatitis markers and liver enzymes, Biochemical parameters), prognosis as exitus or discharged were recorded from the computerized system of the hospital. The exclusion criteria were as follows: age of b18 years, patients with additional liver pathology, pregnants with intrahepatic cholestasis of pregnancy (IHCP) (Diagnosis of IHCP was done by elevated levels of fasting serum bile acids with any level above than 45 U/L), patients had prior hypertension from preg- nancy and patients whose data cannot be accessed from the system.

Statistical analysis

Data were evaluated using SPSS 22 (Statistical Package for the Social Sciences), IBM, USA. Descriptive statistics for the continuous variables

(characteristics) were presented as mean, standard deviation (SD), while count and percent for the categorical variables. The Mann- Whitney U test was used for the analytical statistics when independent two groups were compared, while the parametric test assumptions were not met.

Chi-square test was used to determine the relationship between cat- egorical variables. The Spearman Correlation coefficients were calcu- lated for determination of the linear relationship between the variables. Multivariate logistic regression analysis was used to evaluate the independent associates of the risk of HELLP. Parameters with a p– value of b0.1 in univariate analysis were included in the model. The odds ratios (OR) and 95% confidence intervals (CI) were calculated [8]. The sensitivity and specificity were determined by calculating the area below the ROC curve to determine whether the APRI values were effec- tive to distinguish the patients with HELLP from the control group. The p-value b0.05 was considered statistically significant.

Results

In this study, 40 pregnant patients with HELLP syndrome formed the study group and 124 age-matched pregnant women without HELLP syndrome formed the control group. No patients with HELLP syndrome had prior hypertension. The mean age of the patients with HELLP syn- drome was 30.6 +- 7.4 years, while the mean age of control group was

30.4 +- 7 years. There was no statistical difference between groups in terms of the mean age (P = 0.869).

At further analysis; there was a significant and robust difference be- tween control group and HELLP patients in terms of the mean urinary protein level (183 +- 21.1 versus 418 +- 34.7 mg/dl); the mean platelet level (201 +- 74 versus 85 +- 46 percubicmilliliter); the mean ALT level (22 +- 2.4 versus 160 +- 25.8 U/L); the mean AST level (33 +- 4.9 versus 295 +- 56.4 U/L); the mean creatinine level (0.6 +- 0.21versus 0.91 +-

Table 2

Predictors of HELLP, univariate and multivariate analysis.

Variable

Univariate

Model APRI

Model AST

Multivariate

Multivariate

OR (95% CI)

P value

Adjusted OR(95% CI)

P value

Adjusted OR(95% CI)

P value

Age

1.008 (0.962-1.057)

0.729

Hemoglobin (g/dL)

0.848 (0.699-1.031)

0.098

0.810 (0.585-1.122)

0.205

1.003(0.858-1.172)

0.973

ALT (IU/L)

1.034 (1.020-1.048)

b0.0001

0.993 (0.968-1.019)

0.586

1.001(0.979-1.024)

0.898

Creatinine (ml/dk)

5.323 (1.737-16.307)

0.003

1.243 (0.232-6.669)

0.799

2.019(0.603-6.760)

0.254

INR

0.886 (0.608-1.292)

0.531

APRI

50.378 (8.809-288.113)

b0.0001

56.679 (4.747-676.693)

0.001

AST

1.032(1.020-1.046)

b0.0001

1.031(1.009-1.052)

0.005

HELLP: hemolysis, elevated liver enzyme levels, low platelet counts; APRI: AST-to-platelet ratio index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase INR: International normalized ratio.

M.I. Sasmaz et al. / American Journal of Emergency Medicine 38 (2020) 459462

461

Fig. 1. ROC curve of AST to the diagnosis of HELLP (HELLP: hemolysis, elevated liver enzyme levels, low platelet counts; AST: Aspartate aminotransferase.

0.62 mg/dl); the mean D dimer level (4.5 +- 2.3 versus 12.8 +- 6.7 U/L) and also the mean APRI score (0.16 +- 0.05 versus 3.47 +- 1.7) (Table 1). All patients with HELLP syndrome had actual evidence of hemolysis.

In the multivariate regression analysis, two models were created, the first with APRI and the other with AST. Upper limit of AST to be taken in pregnancy for calculation of APRI score was considered as 52 U/L which was characterized by prior Turkish studies involving pregnant women. Both of models were performed with hemoglobin, ALT, creatinine and APRI score, which were evaluated as a result of univariate regression analysis with age, hemoglobin, ALT, creatinine, INR and APRI score to evaluate the independent predictors of HELLP diagnosis. APRI was found a better predictor than AST score both were in a good significant in predicting HELLP (OR:56.679 (4.747-676.693), p = 0.001; OR:1.031

Fig. 2. ROC curve of APRI to the diagnosis of HELLP (HELLP: hemolysis, elevated liver enzyme levels, low platelet counts; APRI: AST-to-platelet ratio index).

(1.009-1.052), p = 0.005, respectively) (Table 2). When the cut-off value for the AST levels were taken as 52 U/L on the ROC curve in order to distinguish the patients with HELLP from the control group, the sensitivity was found to be 71.7%, specificity to be 91.2% (AUC:0.855, %95 CI: 0.796-0.903) (Fig. 1). When the cut-off value for the APRI levels were taken as 0.339 on the ROC curve in order to distin- guish the patients with HELLP from the control group, the sensitivity was found to be 82.6%, specificity to be 87.6% (AUC:0.927, %95 CI: 0.879-0.960) (Fig. 2).

There were 4 deaths on the intensive care unit among HELLP cases, and mortality rate of patients with HELLP syndrome was 10%.

Discussion

As a result of the present study, the APRI score was found to be more predictive in the diagnosis of HELLP syndrome than AST alone. As known, HELLP syndrome is a serious complication in pregnancy charac- terized by hemolysis, elevated liver enzymes and low platelet count. This syndrome may be misdiagnosed as viral hepatitis, cholangitis and other cute diseases such as acute fatty liver of pregnancy, benign throm- bocytopenia of pregnancy, gastritis, acute pancreatitis or haemolytic uremic syndrome [9-12]. Besides this, these conditions may be mis- taken for HELLP syndrome and a careful diagnostic evaluation is re- quired as their treatments are quite different.

APRI score, is a scoring method found by dividing AST to platelet count, has been traditionally used for diagnosing liver cirrhosis. It was described in 2003 as an accurate predictor of degree of liver fibrosis in patients with HCV [13]. The score was first described in a training cohort of 192 patients with HCV who underwent liver biopsy. A score higher than 3 points is strongly suggestive non-invasive marker for cirrhosis [5,6]. In literature review about APRI score, Sarkar et al. found that, pa- tients with small Hepatocellular carcinoma who underwent hepatic re- section and radiofrequency ablation, and with an APRI score <=0.5 have stronger survival than others [14]. Similarly, Peleg et al. found in their study that, although the APRI score is a good predictor for advanced fi- brosis in non-alcoholic fatty liver disease patients, it was modestly infe- rior as compared to the well-validated fibrosis 4 calculator (FIB-4) [15]. We found out that a cut-off value for the APRI levels as 0.339 has high sensitivity and specificity (82.6% and 87.6% respectively) to detect HELLP syndrome and APRI score is an effective and useful method for predicting HELLP syndrome as well.

Recently, authors revealed that D-dimer levels increased progres-

sively and significantly during pregnancy and peaked in the third tri- mester, in which D-dimer levels were above the conventional cut-off point (500 ug/L) in 99% of pregnant women. The following reference in- tervals were also defined: first trimester: 169-1202 ug/L, second trimes- ter: 393-3258 ug/L and Third trimester: 551-3333 ug/L [16]. Activation of vascular endothelium and hemolysis and liver damage are the basic pathophysiological features for the HELLP syndrome, each predisposing to disseminated intravascular coagulation [17]. So that d-dimer levels have been increased. Paternoster et al. reported that patients with HELLP syndrome had a higher concentration of d-dimer levels than in a normal pregnancy [18].

In the current study we firstly demonstrated that, a D-dimer level above than 10.000 ug/L was an additional key diagnostic factor of the HELLP syndrome. On the other hand, the AST to ALT ratio index higher than 3 points was also key for diagnosing HELLP connection with ele- vated D-dimer levels. Both of increased D-dimer levels plus APRI scores can estimate HELLP syndrome as new diagnostic tools. Furthermore, HELLP syndrome appears to predispose to renal failure independent of other diagnostic factors for HELLP.

In the literature, maternal mortality of HELLP syndrome varies from 1% to 25% [19,20]. Cavkaytar et al. reported the overall maternal compli- cation rate as 73% and maternal mortality rate as %5 in 61 patients with HELLP syndrome in their study [21]. In another large retrospective co- hort study, it is reported the maternal mortality rate as 1,1% [22].

462 M.I. Sasmaz et al. / American Journal of Emergency Medicine 38 (2020) 459462

However Ellison et al. have reported up to %25 mortality in their studies [23]. In our study, maternal mortality rate has been detected as 10%. Varying rates of maternal mortality inpatients with HELLP syndrome may be originated from the differences of treatment. Generally, there are three major options for the management of patients with HELLP syndrome [9,11,24]. These are immediate delivery as 34 gestation weeks or later; delivery within 48 h after evaluation and stabilization of the maternal clinical condition and kortikoSteroid treatment and con- servative management for N48-72 h may be considered in patients be- fore 27 gestation weeks. The treatments of patients are not included in our data due to retrospective nature of our study. This issue may be sub- ject of another study.

Limitations

The most important limitation of our study is limited number of pa- tients. Also, the complications other than death, symptoms in admis- sion, vital signs such as blood pressure and pulse rate reflecting clinical status of patients and treatment strategies are not included in our data due to retrospective nature of our study.

Conclusion

As a striking finding, APRI score was robustly predicted HELLP syn- drome than AST alone in this study. Further prospective and multicenter studies with larger patient groups comparing two groups of HELLP syn- drome are needed to support our data will belter assess the applicability of APRI score.

Acknowledgements

Funding sources

No funding was received.

Authors’ contribution

MIS performed the study design, data collection and analysis, MAA and ACD study design and data collection; EKK study design, analysis and article’s drafting and RG article’s drafting and all authors seen and approved the final version of the study.

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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