Observational Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 14, 2018; 24(38): 4393-4402
Published online Oct 14, 2018. doi: 10.3748/wjg.v24.i38.4393
Liver stiffness reversibly increases during pregnancy and independently predicts preeclampsia
Franziska J Ammon, Anna Kohlhaas, Omar Elshaarawy, Johannes Mueller, Thomas Bruckner, Christof Sohn, Gabriele Fluhr, Herbert Fluhr, Sebastian Mueller
Franziska J Ammon, Christof Sohn, Herbert Fluhr, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany
Anna Kohlhaas, Omar Elshaarawy, Johannes Mueller, Gabriele Fluhr, Sebastian Mueller, Department of Medicine and Center for Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
Thomas Bruckner, Institute of Medical Biometry und Informatics, University of Heidelberg, Heidelberg 69121, Germany
Author contributions: Fluhr H and Mueller S designed research; Ammon FJ, Kohlhaas A and Fluhr G performed measurements; Ammon FJ, Mueller J and Mueller S analyzed the data and wrote the paper; Elshaarawy O revised the paper; Bruckner T reviewed statistics; Elshaarawy O, Sohn C and Fluhr H reviewed the paper.
Supported by the Dietmar Hopp Foundation (in part, DFG), No. MU 1373/9-1.
Institutional review board statement: The study was approved by the Ethical Committee of the University of Heidelberg.
Informed consent statement: All participants of the study, or their legal guardians, provided written informed consent prior to study enrollment.
Conflict-of-interest statement: The authors have declared no conflicts of interest.
Data sharing statement: Dataset and other information are available from the corresponding author at sebastian.mueller@urz.uni-heidelberg.de. Patients gave informed consent before inclusion in the study; the presented data are anonymized and the risk of identification is very low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sebastian Mueller, MD, PhD, Professor, Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research and Liver Disease, University of Heidelberg, Zeppelinstraße 11-33, Heidelberg 69121, Germany. sebastian.mueller@urz.uni-heidelberg.de
Telephone: +49-6221-483210 Fax: +49-6221-484494
Received: August 1, 2018
Peer-review started: August 1, 2018
First decision: August 24, 2018
Revised: September 20, 2018
Accepted: October 5, 2018
Article in press: October 5, 2018
Published online: October 14, 2018
Research background

Hypertension and preeclampsia remain the leading causes of maternal morbidity and mortality. Moreover, up to 3 % of all pregnancies are accompanied by liver complications which can have a high maternal and perinatal mortality. So far, no detailed studies existed on pregnancy and liver stiffness, a novel parameter and gold standard to early screen for liver fibrosis and other pathologies. We here present the first large cohort to study liver stiffness during pregnancy and its association with complications during pregnancy. Our data show that liver stiffness significantly and reversibly increases in the final trimester in pregnant women without complications. In women with preeclampsia, liver stiffness is significantly elevated and an independent non-invasive predictor. In conclusion, we think that liver stiffness could be an easy to use and fast non-invasive tool for the prediction and diagnosis of pregnancy complications.

Research motivation

Many liver-related complications during pregnancy are still poorly understood, life threatening and difficult to diagnose. The main motivation for this study, therefore, was to investigate the novel parameter liver stiffness for the first time in a large cohort of pregnant women and its relation to pregnancy complications. Based on first preliminary observations, it was our further goal to provide the normal range of liver stiffness values during pregnancy and its response to delivery.

Research objectives

The first aim was to test the performance and validity of liver stiffness measurements using FibroScan in pregnant women with and without pregnancy complications. The second aim was to investigate liver stiffness in women with normal pregnancies at different gestational ages and its response to delivery. We eventually demonstrate that liver stiffness can be measured in pregnant women with sufficient accuracy using the XL probe. We further demonstrate an elevated liver stiffness in the final trimester of pregnant women without complications. Interestingly, liver stiffness can reach levels that could suggest the presence of advanced liver fibrosis. Finally, we show that liver stiffness is higher in patients with pregnancy complications such as preeclampsia or intrahepatic cholestasis of pregnancy and can even predict these complications. Our data pave the way for more detailed studies of liver stiffness in pregnant women in the future e.g. with the aim to investigate associations with more rare complications such as the hemolysis, elevated liver enzymes and low platelets (HELLP)-syndrome or acute fatty liver of pregnancy.

Research methods

We prospectively recruited 537 pregnant women including 22 with preeclampsia and 40 with intrahepatic cholestasis. Liver stiffness was measured by transient elastography (FibroScan, Paris) with the M and XL-probe. Additionally, transabdominal ultrasound and standard laboratory tests were performed. In some patients, liver stiffness was also measured 24 h after delivery. This study design allowed us to demonstrate elevated liver stiffness in the third trimester during uncomplicated pregnancy and its normalization after delivery. In addition, however, elevated liver stiffness was identified as sensitive and early prognostic parameter of pregnancy complications such as preeclampsia and intrahepatic cholestasis of pregnancy.

Research results

We first demonstrate that valid liver stiffness measurements can be obtained in most women (> 95%) using the XL-probe. Second, liver stiffness increases from ca. 4.5 kPa to 6 kPa (P < 0.001) in the third trimester of women with normal pregnancy. Importantly, 41% of women in the third trimester showed a liver stiffness above 6 kPa; in rare cases even higher than 20 kPa. Of note, elevated liver stiffness here was significantly correlated with alkaline phosphatase, leukocytes, gestational age and an increase in body weight and body mass index (BMI). Women with pregnancy complications such as preeclampsia or intrahepatic cholestasis had significantly higher liver stiffness measurements than women with uncomplicated pregnancy (P < 0.0001). Results even stayed significant when compared only to women in the third trimester (P < 0.01). Moreover, in multivariate analysis, liver stiffness could be identified as an independent predictor for preeclampsia with an odds ratio of 2.05 (1.27-3.31). Finally, liver stiffness rapidly decreased in all women within 24 h after delivery from 7.2 ± 3.3 kPa down to 4.9 ± 2.2 kPa (P < 0.001).

Research conclusions

For the first time, this study investigates liver stiffness in a large prospective cohort of pregnant women prior and after delivery. It shows that liver stiffness can be accurately measured in pregnant women. Surprisingly, liver stiffness significantly increased in the final trimester but normalized after delivery. Thus, an elevated liver stiffness during pregnancy should not be mistaken for a liver disease and e.g. prompt to further invasive diagnostic measures. Furthermore, liver stiffness is significantly higher in women with pregnancy complications and it can independently predict complications such as preeclampsia. Although an exact molecular cause of the liver stiffness elevation could not be identified, its rapid normalization after delivery in the absence of inflammation highly suggests mechanical factors e.g. hemodynamic changes as underlying cause. The findings are also in line with our recently introduced sinusoidal pressure hypothesis that highlights the role of pressure in modulating liver stiffness and eventually causing liver complications. Based on our findings we also suggest to routinely assess liver stiffness during pregnancy in order to early identify women at risk of preeclampsia.

Research perspectives

Transient elastography is a promising non-invasive, easy to use method to study liver stiffness during pregnancy. In future research, broader and more detailed studies are needed to investigate the cause for liver stiffness elevation in the third trimester and in complicated pregnancies and to investigate other aspects such as HELLP-syndrome or acute fatty liver of pregnancy.