Pregnancy-Related Liver Disorders

doi:10.1016/j.jceh.2013.03.220

Journal of Clinical and Experimental Hepatology

Volume 4, Issue 2, June 2014, Pages 151-162

https://doi.org/10.1016/j.jceh.2013.03.220 Get rights and content

Pregnancy-related liver disorders accounted for 8% of all maternal deaths at our center from 1999 to 2011. Of the three pregnancy-related liver disorders (acute fatty liver of pregnancy (AFLP), HELLP (Hemolysis, elevated liver enzymes, low platelets) syndrome and pre-eclamptic liver dysfunction, which can lead to adverse maternal and fetal outcome, AFLP is most typically under - diagnosed. Risk of maternal death can be minimised by timely recognition and early/aggressive multi-specialty management of these conditions. Urgent termination of pregnancy remains the cornerstone of therapy for some of these life threatening disorders, but recent advancements in our understanding help us in better overall management of these patients. This review focuses on various aspects of pregnancy-related liver disorders.

Section snippets

Pregnancy-related liver disorders: a preventable cause of maternal death

Maternal mortality, defined as death on account of pregnancy occurring during pregnancy or within 42 days of childbirth/abortion, forms an important part of vital governmental statistics.² In India, maternal mortality ratio has declined from 254 per 100,000 live births in 2004–2006 to 212 per 100,000 live births in 2007–09, however it still falls way short of the United Nation's millennium development goal for 2015 of 109 per 100,000 live births.³ With an estimated birth rate of 22 per 1000

Interpretation of liver function tests during pregnancy

In pregnancy, interpretation of liver function tests remains similar to that in the non-pregnant state. In an uncomplicated pregnancy, serum bilirubin and serum alanine and aspartate aminotransferase remain in the normal range.⁸ A mild increase in serum alkaline phosphatase (attributed to increase in placental isoenzyme) and a mild decrease in serum albumin levels (secondary to hemodilution due to increased plasma volume) are noted during normal pregnancy (Table 1).8, 9

Acute fatty liver of pregnancy (AFLP)

AFLP was first described in 1934 and was termed as ‘acute yellow atrophy of the liver’. AFLP still remains an important obstetric emergency with significant maternal and peri-natal mortality. It is a catastrophic illness, characterised by microvesicular fatty infiltration of the liver cells in late (2nd or 3rd trimester) pregnancy.¹⁰

Pre-eclamptic liver dysfunction

Pre-eclampsia is usually reported as the most common cause of liver dysfunction related to pregnancy.12, 13 It occurs after 20 weeks of pregnancy and is characterised by hypertension (blood pressure >140/90 mm Hg), proteinuria with or without pedal edema.¹²

HELLP syndrome (hemolysis, elevated liver enzymes and low platelets)

Although the association of hemolysis, low platelets and liver dysfunction with hypertensive disorders of pregnancy was known since 1954,⁶¹ the term HELLP syndrome was first coined in 1982 by Weinstein et al⁶² HELLP syndrome is thought to be a severe form of pre-eclamptic liver dysfunction, but it can occur in normotensive patients as well. Table 6 illustrates the overall incidence of HELLP in all pregnancies and also in patients with pre-eclampsia. Abdominal pain, nausea and vomiting with or

Overlap in diagnostic criteria of AFLP, HELLP syndrome and pre-eclamptic liver dysfunction

In a given patient it is often difficult to differentiate AFLP, HELLP syndrome and pre-eclamptic liver dysfunction clinically as the diagnostic criteria for more than one condition is fulfilled in majority of them.³¹ In a study from our center, some of the 20 patients who met the ‘Swansea’ criteria for AFLP also fulfilled the criteria for HELLP syndrome (8 patients), partial HELLP syndrome (5 patients) and pre-eclamptic liver dysfunction (2 patients).³¹ Though liver biopsy may help

Other pregnancy related liver disorders

AFLP, HELLP syndrome and pre-eclamptic liver dysfunction are life threatening obstetric emergencies. Early suspicion, diagnosis and adequate management are essential for maternal and fetal well being. Intrahepatic cholestasis of pregnancy (ICP) and hyperemesis gravidarum (HG) are other pregnancy related disorders associated with liver dysfunction which cause maternal morbidity. These disorders do not increase risk of maternal death, but ICP can increase the risk of fetal death. The detailed

Reducing maternal deaths from pregnancy related liver disorders in India—Lessons from the Vellore experience

While Obstetricians are clear about the management of patient with pre-eclamptic liver dysfunction and HELLP syndrome; there is considerable degree of uncertainty about the management of AFLP.

Our experience spanning 16 years (1996 to date) at Vellore teaches few key learning points. Firstly; there is confusion in making the diagnosis of AFLP. In the early part of our series, we performed post-mortem liver biopsies to document hepatic microvesicular steatosis in patients who died of suspected

Future work

There is an urgent need to increase awareness about this preventable cause of maternal death all over India. Maternal deaths due to liver disease should be included in maternal mortality statistics in India. Though we have made some progress in reducing maternal deaths due to AFLP at our center, fetal outcome remains dismal. Further research is needed to unravel the pathogenesis of this intriguing group of disorders.

Conclusions

Pregnancy-related liver disorders are rare but they are important causes of maternal/fetal morbidity and mortality. The inclusion of jaundice as a cause of maternal mortality in the census of India will help in better documenting the extent of the problem all over India. Better understanding of pathogenetic mechanisms will help us in managing these disorders effectively. Early recognition, timely referral and aggressive management can lead to better maternal and fetal outcome in these patients.

Conflicts of interest

All authors have none to declare.

Acknowledgments

We wish to thank Professor Elwyn Elias, Emeritus Professor, Liver Unit, University Hospital Birmingham, Birmingham, UK for his critical review of this manuscript.

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Liver in Systemic Disease
2023, MacSween's Pathology of the Liver, Eighth Edition
Approach to the patient with cholestasis and jaundice syndrome. Joint AMH, AMG, and AMEG scientific position statement
2022, Revista de Gastroenterologia de Mexico
El término colestasis se refiere a la retención de ácidos biliares ya sea dentro del hepatocito o en los ductos biliares de cualquier calibre. Por laboratorio, se define por la elevación de fosfatasa alcalina arriba de 1.67 veces su valor normal. Las enfermedades colestásicas pueden asociarse a un proceso inflamatorio de la glándula hepática que provoca destrucción de los hepatocitos (hepatitis), a ictericia (coloración amarillenta de piel y mucosas asociada a elevación en niveles séricos de bilirrubinas) o ambas, aunque estos tres conceptos no deben considerarse sinónimos. Los padecimientos colestásicos pueden clasificarse como intra o extrahepáticos dependiendo de su etiología, y esto es importante para elegir los estudios diagnósticos adecuados y la terapéutica indicada en cada uno de los casos. Una historia clínica completa, aunada a exploración física exhaustiva y estudios iniciales básicos como el ultrasonido hepático y las pruebas de funcionamiento del hígado, pueden ayudar al clínico a decidir el camino a seguir al enfrentarse al paciente con colestasis. La Asociación Mexicana de Hepatología, la Asociación Mexicana de Gastroenterología y la Asociación Mexicana de Endoscopia Gastrointestinal decidieron trabajar en el primer posicionamiento científico mexicano sobre este tema.
The term cholestasis refers to bile acid retention, whether within the hepatocyte or in the bile ducts of any caliber. Biochemically, it is defined by a level of alkaline phosphatase that is 1.67-times higher than the upper limit of normal. Cholestatic diseases can be associated with an inflammatory process of the liver that destroys hepatocytes (hepatitis), with jaundice (yellowing of the skin and mucus membranes, associated with elevated serum bilirubin levels), or with both, albeit the three concepts should not be considered synonymous. Cholestatic diseases can be classified as intrahepatic or extrahepatic, depending on their etiology. Knowing the cause of the condition is important for choosing the adequate diagnostic studies and appropriate treatment in each case. A complete medical history, together with a thorough physical examination and basic initial studies, such as liver ultrasound and liver function tests, aid the clinician in deciding which path to follow, when managing the patient with cholestasis. In a joint effort, the Asociación Mexicana de Hepatología (AMH), the Asociación Mexicana de Gastroenterología (AMG) and the Asociación Mexicana de Endoscopia Gastrointestinal (AMEG) developed the first Mexican scientific position statement on said theme.
Maternal and neonatal outcomes and prognostic factors in acute fatty liver of pregnancy
2020, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
However, the pathophysiology of AFLP remains unclear. Different investigations point to severe mitochondrial dysfunction in the liver [12] and the association of fetal fatty acid oxidation defects with maternal liver disease [8], which could be triggered by several genetic and acquired factors [9]. Long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency would play a role in some cases of AFLP [4,13–16].
To report complications of Acute Fatty Liver of pregnancy (AFLP), a rare liver disease of pregnancy, and identify prognostic factors for mothers and children.
We conducted a retrospective descriptive study over 18 years in three French maternities. Demographic, clinical, biological data, and outcomes of patients and their infants were reviewed.
142,450 pregnancies from centers were studied. Eighteen patients with AFLP were identified The prevalence of AFLP was estimated as 1/7,914 pregnancies. Prolonged prothrombin time was identified as a risk factor of maternal complications (OR = 0.86, p = 0.0493). Gestational age at delivery was the only risk factor associated with fetal or neonate complications (OR = 0.37, p = 0.0417). One boy died of previously undiagnosed β-oxidation deficiency at eight months.
In AFLP, prothrombin time must be carefully monitored to anticipate major maternal complications. Infants born to mothers with ALFP should be screened as early as possible for mitochondrial fatty acid oxidation deficiency.
The Liver in Systemic Disease
2018, MacSween's Pathology of the Liver
Liver disease in pregnancy: Medical aspects and their implications for mother and child
2019, Annals of Hepatology
Citation Excerpt :
However, an obstetrical ultrasound is mandatory because HG may be associated with multiple and molar pregnancies. Increased body mass index, pre-existing diabetes, asthma, psychiatric illness, hyperthyroid disorders in a previous pregnancy or a previous pregnancy with HG, have also been shown to be risk factors for this disease [6,7,9,18]. The major etiologies proposed for the development of HG are: (I) High levels of human chorionic gonadotropin (HCG) exert a stimulating effect on the secretory process in the upper gastrointestinal tract; the production of thyroid-binding globulin also increases under estrogen stimulation, leading to a decrease in free thyroxine (T4).
Liver disease during pregnancy is more common than expected and may require specialized intervention. It is important to determine if changes in liver physiology may develop into liver disease, to assure early diagnosis. For adequate surveillance of mother-fetus health outcome, liver disease during pregnancy might require intervention from a hepatologist. Liver diseases have a prevalence of at least 3% of all pregnancies in developed countries, and they are classified into two main categories: related to pregnancy; and those non- related that are present de novo or are preexisting chronic liver diseases. In this review we describe and discuss the main characteristics of those liver diseases associated with pregnancy and only some frequent pre-existing and co-incidental in pregnancy are considered.
In addition to the literature review, we compiled the data of liver disease occurring during pregnancies attended at the National Institute of Perinatology in Mexico City in a three-year period.
In our tertiary referral women hospital, liver disease was present in 11.24 % of all pregnancies. Associated liver disease was found in 10.8% of all pregnancies, mainly those related to pre-eclampsia (9.9% of pregnancies). Only 0.56% was due to liver disease that was co-incidental or preexisting; the acute or chronic hepatitis C virus was the most frequent in this group (0.12%).
When managing pregnancy in referral hospitals in Latin America, it is important to discard liver alterations early for adequate follow up of the disease and to prevent adverse consequences for the mother and child.
Indian National Association for the Study of the Liver—Federation of Obstetric and Gynaecological Societies of India Position Statement on Management of Liver Diseases in Pregnancy
2019, Journal of Clinical and Experimental Hepatology
Liver diseases occurring during pregnancy can be serious and can progress rapidly, affecting outcomes for both the mother and fetus. They are a common cause of concern to an obstetrician and an important reason for referral to a hepatologist, gastroenterologist, or physician. Liver diseases during pregnancy can be divided into disorders unique to pregnancy, those coincidental with pregnancy, and preexisting liver diseases exacerbated by pregnancy. A rapid differential diagnosis between liver diseases related or unrelated to pregnancy is required so that specialist and urgent management of these conditions can be carried out. Specific Indian guidelines for the management of these patients are lacking. The Indian National Association for the Study of the Liver (INASL) in association with the Federation of Obstetric and Gynaecological Societies of India (FOGSI) had set up a taskforce for development of consensus guidelines for management of patients with liver diseases during pregnancy, relevant to India. For development of these guidelines, a two-day roundtable meeting was held on 26–27 May 2018 in New Delhi, to discuss, debate, and finalize the consensus statements. Only those statements that were unanimously approved by most members of the taskforce were accepted. The primary objective of this review is to present the consensus statements approved jointly by the INASL and FOGSI for diagnosing and managing pregnant women with liver diseases. This article provides an overview of liver diseases occurring in pregnancy, an update on the key mechanisms involved in its pathogenesis, and the recommended treatment options.

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SeminarPregnancy-Related Liver Disorders

Section snippets

Pregnancy-related liver disorders: a preventable cause of maternal death

Interpretation of liver function tests during pregnancy

Acute fatty liver of pregnancy (AFLP)

Pre-eclamptic liver dysfunction

HELLP syndrome (hemolysis, elevated liver enzymes and low platelets)

Overlap in diagnostic criteria of AFLP, HELLP syndrome and pre-eclamptic liver dysfunction

Other pregnancy related liver disorders

Reducing maternal deaths from pregnancy related liver disorders in India—Lessons from the Vellore experience

Future work

Conclusions

Conflicts of interest

Acknowledgments

Hepatology

Int J Gynaecol Obstet

J Hepatol

Indian J Med Microbiol

J Clin Exp Hepatol

Lancet

Am J Obstet Gynecol

J Pediatr

Clin Chim Acta

Gastroenterol Clin Biol

J Obstet Gynaecol Can

Am J Obstet Gynecol

J Obstet Gynaecol Can

Lancet

Obstet Gynecol

Am J Obstet Gynecol

Best Pract Res Clin Gastroenterol

Am J Obstet Gynecol

Am J Obstet Gynecol

Dig Liver Dis

Ann Hepatol

Ann Hepatol

Best Pract Res Clin Gastroenterol

Med Hypotheses

Eur J Obstet Gynecol Reprod Biol

BJOG

Best Pract Res Clin Obstet Gynaecol

Liver disease in pregnancy

Hepatology

Maternal Mortality in India: 1997–2003; Trends, Causes and Risk Factors: Registrar General, India in Collaboration with Center for Global Health Research

Special Bulletin on Maternal Mortality in India 2007-09; Sample Registration System: Office of Registrar General, India

Census of India 2011, Provisional Population Totals India Series 1

Trends in Maternal Mortality: 1990 to 2010 WHO, UNICEF, UNFPA and The World Bank Estimates

Contribution of pregnancy related liver diseases to maternal mortality at Vellore

Indian J Gastroenterol

Liver function tests in normal pregnancy: a study from southern India

Indian J Gastroenterol

Liver failure during pregnancy

Gut

A prospective national study of acute fatty liver of pregnancy in the UK

Gut

Prospective study of liver dysfunction in pregnancy in Southwest Wales

Gut

Effect of liver disease on maternal and fetal outcome—a prospective study

Indian J Gastroenterol

Acute fatty liver of pregnancy: a report of two cases

Natl Med J India

A 20-year single-center experience with acute liver failure during pregnancy: is the prognosis really worse?

Hepatology

Liver injury in acute fatty liver of pregnancy: possible link to placental mitochondrial dysfunction and oxidative stress

Hepatology

A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women

N Engl J Med

Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease

Jama

Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy

Pediatr Res

Fetal fatty acid oxidation defects and maternal liver disease in pregnancy

Obstet Gynecol

Absence of the G1528C (E474Q) mutation in the alpha-subunit of the mitochondrial trifunctional protein in women with acute fatty liver of pregnancy

Pediatr Res

No mutation was found in the alpha-subunit of the mitochondrial tri-functional protein in one patient with severe acute fatty liver of pregnancy and her relatives

J Gastroenterol Hepatol

Oxidative stress in experimental liver microvesicular steatosis: role of mitochondria and peroxisomes

J Gastroenterol Hepatol

Seminar
Pregnancy-Related Liver Disorders