- Email: [email protected]
The interpretation of liver function tests in pregnancy
Journal Pre-proof The interpretation of liver function tests in pregnancy
Maria Guarino, Valentina Cossiga, Filomena Morisco PII:
S1521-6918(20)30002-0
DOI:
https://doi.org/10.1016/j.bpg.2020.101667
Reference:
YBEGA 101667
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date:
06 October 2019
Accepted Date:
17 February 2020
Please cite this article as: Maria Guarino, Valentina Cossiga, Filomena Morisco, The interpretation of liver function tests in pregnancy, Best Practice & Research Clinical Gastroenterology (2020), https://doi.org/10.1016/j.bpg.2020.101667
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Journal Pre-proof Best Practice & Research Clinical Gastroenterology Volume 42C - Pregnancy in GI-disorders The interpretation of liver function tests in pregnancy
Authors: Maria Guarino, Valentina Cossiga, Filomena Morisco Affiliations: Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy;
Tables: 1 Figures: 2 Conflict of interest statement: Morisco Filomena: research grants, lecturing fees, advisory boards, scientific consultancy for Abbvie, BMS, Gilead Science, Janssen, MSD. No personal or financial conflicts of interest for all the other authors. Financial support statement: There is no financial support for this study.
Corresponding author: Filomena Morisco Associate Professor of Gastroenterology Department of Clinical Medicine and Surgery, Gastroenterology Unit University of Naples "Federico II", Via S. Pansini, 5 - 80131 Naples, Italy Tel: +39 081 7464746; Fax: +39 081 7464746. E-mail: [email protected]
Journal Pre-proof ABSTRACT Abnormal liver tests occur in 3-5% of pregnancies and show many different causes. Although alterations of liver enzymes could be a physiological phenomenon, it may also reflect potential severe liver injury, necessitating further assessment and accurate management. The work-up has to consider liver diseases specific of pregnancy and non pregnancy-related liver damage (coincidental and pre-existing to pregnancy). Pre-existing liver diseases during pregnancy are relatively uncommon, as pregnant women are generally young and healthy. Liver diseases unique to pregnancy are intrahepatic cholestasis of pregnancy, the HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and acute fatty liver of pregnancy. These disorders may result in foetal distress, severe liver damage and sometime hepatic failure; for these reasons the diagnostic work-up and treatment must be very fast. This review focuses on the management of pregnant women with altered liver function tests. Furthermore, the main liver diseases specific of pregnancy are described.
ABBREVIATIONS Acute fatty liver of pregnancy (AFLP), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), haemolysis, elevated liver enzyme and low platelets (HELLP), intrahepatic cholestasis of pregnancy (ICP), liver functions tests (LFTs), non alcoholic fatty liver disease (NAFLD),
Key words: Pregnancy, transaminases, cholestasis
Journal Pre-proof Introduction Abnormal liver tests occur in 3-5% of pregnancies, show many different causes and require proper evaluation and diagnosis. The first step is to differentiate between physiological changes and alteration related to the presence of liver disease (1). The physiological changes in liver function tests (LFTs) in pregnancy are commonly mild, transient, rarely permanent. On the other hand, severe liver disease in pregnancy is rare; however, pregnancy-related liver disease is the most frequent cause of liver dysfunction during pregnancy and represents a severe threat to foetal and maternal survival (2). A rapid differential diagnosis between liver disease related or unrelated to pregnancy is required in women who present liver damage during pregnancy. It may be categorized into three major groups: 1- specific liver diseases of pregnancy, such as intrahepatic cholestasis of pregnancy (ICP), haemolysis, elevated liver enzyme and low platelets (HELLP) syndrome, acute fatty liver of pregnancy (AFLP); 2- liver and biliary disease occurring during pregnancy such as viral hepatitis, cholelithiasis, etc; 3- pregnancy in patients with pre-existing chronic liver disease such as chronic hepatitis, cirrhosis, Budd Chiari syndrome etc (3) (4) (5). The present review will focus on the interpretation of LFTs arising in pregnancy and on the subsequent work-up according to the time of onset and the prognostic implications.
Liver tests during pregnancy Typically, we observe physiologically changes in liver biochemical profile during pregnancy. In clinical practice, there are four hepatic enzymes of interest: aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as markers of hepatocellular damage, Alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) suggestive for cholestasis, even if an overlap between the two classes of LFTs is very common.
Journal Pre-proof The LFTs evaluating synthetic function are albumin and International Normalized Ratio (INR). Finally bilirubin is able to evaluate biliary system function (intra and extra hepatic bile ducts and gallbladder) (6). Serum albumin in association to hemoglobin concentration falls (about 25% decrease) in pregnancy and is thought to be related to the increase in total plasma volume as a result of hemodilution (3). Differently any abnormality seen in the 4 enzymes and bilirubin needs further evaluation (1). ALP increases and may reach 2 to 4 times the normal adult upper reference value. This relates to production of the placental isoenzyme. Pregnant women with isolated raised alkaline phosphatase in this range do not need any further investigation. After birth, the ALP level falls, reaching nonpregnant values within 2 weeks. The concentrations of the transaminases, the bilirubin, the bile acids and GGT normally remain in the normal range like non-pregnant women (7).
Markers of hepatocellular injury: Aspartate and alanine transaminases AST or ALT elevations within 1.5 times the upper limits of normal do not necessarily indicate liver disease (1). In case of ALT and AST arise, especially in asymptomatic women, it is necessary to rule out alcohol use/abuse, acute viral hepatitis and acute toxic injury like drug injury or ischemic insult of the liver. Usually a pre-existing liver disease such as non alcoholic fatty liver disease (NAFLD), viral or autoimmune hepatitis etc. is a condition already known, even if in rare cases the onset of these diseases could overlap with pregnancy. If all these possibilities have been ruled out, it is necessary to focus on liver injuries specific of pregnancy (figure 1). Accurate identification of the cause and the potential impact on both maternal and foetal health is mandatory. The pregnancy related diseases carry on a high mortality rate for both mother and baby and require rapid diagnosis and in some cases urgent delivery. A thorough history, including prior pregnancies and behavior of prior pregnancy, high-risk behaviors and medications, and careful physical examination with ultrasound evaluation is necessary (1).
Journal Pre-proof The gestational age of the pregnancy is an important diagnostic indicator and can help tailoring the diagnostic work-up, as these insults typically occur at certain phase of the pregnancy and typically resolve with delivery (Table 1) (8). In particular, during the first trimester the main cause of hypertransaminasemia is the hyperemesis gravidarum which occurs in 0.3% to 2% of pregnancies, and it is characterized by nausea and vomiting. Transaminases can be elevated by up to 20 times the upper limit of normal, rarely with jaundice. LFTs normalize after the resolution of vomiting. Treatment is supportive with thiamine supplements, fluid replacement, and antiemetics (3) (8). During the second and third trimester, the hypertransaminasemia is related to preeclampsia/eclampsia, HELLP syndrome, acute fatty liver disease and also to intrahepatic cholestasis of pregnancy even if this last condition is prevalently characterized by cholestatic damage (8) (figure 2). Dedicated paragraphs on these specific liver diseases of pregnancy are reported later.
Markers of cholestasis: Alkaline phosphatase and gamma-glutamyl transferase The cholestasis represents a clinical picture affecting most of pregnant women. In presence of cholestasis three general concepts are important to consider: 1. Women presenting at any stage of pregnancy cholestatic features should do the same work-up of non-pregnant patient. This includes a familial anamnesis and drugs history, complete physical examination, and serological assessment as indicated by the clinical presentation; 2. The work-up has to consider liver diseases specific of pregnancy and a non-pregnancy related cholestatic diseases (coincidental and pre-existing to pregnancy); 3. Even if the focus is on cholestatic features, the laboratory abnormalities show in almost all cases a contemporary and milder elevation of aminotransferases. A differential diagnosis between liver disease related or unrelated to pregnancy is rapidly required. The key point in the workup of cholestasis is represented by the abdominal ultrasound considered safe and the preferred imaging modality in pregnancy. The abdominal US permit to distinguish
Journal Pre-proof between the extra- and intrahepatic cholestasis and the differential diagnosis between the most frequent cholestatic diseases observed during pregnancy. If ultrasonography is indeterminate and further imaging is necessary, it can be used, in second and third trimester, Magnetic Resonance Imaging (MRI) without gadolinium. Gadolinium is not recommended as it crosses the placenta and it is excreted by the fetal kidneys into the amniotic fluid, where it can remain for long periods, causing potential injury to fetal pulmonary and gastrointestinal systems (9). Computed tomography (CT) scans carry a significant risk of teratogenesis and childhood haematological malignancies, but it can be practiced, judiciously, with minimized radiation protocol (2-5 rads), only in case of acute presentation and after a collegial discussion. Oral and intravascular agents used for CT do not appear teratogenic in animal studies, but they can cause neonatal hypothyroidism (10). Cholelithiasis is common during pregnancy (3.5%), owing to the increased estrogen levels, causing cholesterol saturation and raised gallstone formation. Furthermore, it is the second cause of nonobstetric abdominal surgical pain during pregnancy, after appendicitis and it can result in several complications including symptomatic choledocholithiasis, acute biliary pancreatitis or ascending cholangitis (11). Asymptomatic cholelithiasis treatment is conservative, as it also is for mild pancreatitis. Symptomatic cholelithiasis has been previously managed conservatively, but recent studies showed that pregnant patients with cholelithiasis treated with conservative treatment had more episodes of recurrent biliary symptoms and a higher number of hospitalizations related to biliary complications. Conservative management also resulted in early induction of labor related to biliary symptoms in some patients. So, the endoscopic and surgical management of cholelithiasisrelated complications during pregnancy seems to be safe, effective and superior in comparison to conservative treatment (12) (13). Endoscopic retrograde cholangiopancreatography (ERCP) can be performed safely in pregnant women with biliary disease requiring intervention such as pancreatitis or cholangitis and it remains
Journal Pre-proof the first line modality in case of choledocholithiasis and its complications (14) (15). The main concern of ERCP during pregnancy is the use of fluoroscopy, but there are new techniques that avoid its use or limit fluoroscopy time and overall radiation exposure (16) (17). All the other specific liver diseases of pregnancy have to be considered in the work-up (hyperemesis gravidarum, ICP, eclampsia, preeclampsia, HELLP syndrome and acute fatty liver of pregnancy) even if in these cases, with the exception of ICP, the clinical picture is not prevalently characterized by cholestatic features.
Intrahepatic cholestasis of pregnancy (ICP) The intrahepatic cholestasis of pregnancy (ICP) is one of the most common liver diseases specific of pregnancy. The incidence ranges between 0.5-1.8% of pregnant women, but it varies greatly according to geographic location (18). The etiology of ICP is multifactorial and involves genetic, hormonal and environmental factors. There have been several gene variants in the bile acid pathway, implicated in the development of ICP, which could explain the higher incidence of ICP in some ethnic groups. The principal risk factors for ICP are multiple pregnancies, in vitro fertilization, advanced maternal age, positive family history, prior affected pregnancy and HCV infection (19). The ICP occurs typical in third trimester and has a rapid postnatal resolution. It shows up with pruritus and increasing of both bile salts and liver function tests. Pruritus is generalized but itching worst on the palm of hands and soles and generally precedes biochemical alterations (20). One of the typical features of ICP is elevated serum bile acid levels. The cutoff values, used during pregnancy, range between 10 to 14 µmol/l. Higher bile acid levels (>40 µmol/l) have been found to be associated with higher rates of fetal complications in a large cohort of Swedish women with ICP. This study showed an increased risk of spontaneous preterm delivery and asphyxia events in 17% of pregnancies with bile acid levels >40 µmol/l. This suggests a causal relationship between bile acids levels and fetal complications (21) (22).
Journal Pre-proof The liver transaminases are commonly elevated in ICP and bilirubin levels can increase up 10% of pregnancies. It is important to underline that ICP is a diagnosis of exclusion and differential diagnosis include preeclampsia, HELLP, acute fatty liver of pregnancy (AFLP) and dermatological conditions that induce pruritus. In general, delivery resolves maternal symptoms. Rarely, women have persistence of symptoms and develop a cholestatic disease. These cases may be related to MDR3 deficiency and it should be suspected in young women with cholestasis of unknown origin who develop a severe ICP (23). Ursodeoxycholic acid (UDCA), at dosage of 10-15 mg/Kg/die, is effective in reducing pruritus, improving liver tests in women with ICP and ameliorating fetal outcome (24). The mechanisms of these effects are unknown. UDCA may have a specific effect by improving the transport of bile acids across the placenta. The beneficial effect on pruritus contrasts with the absence of a significant effect in patients with primary biliary cholangitis (PBC), but the mechanisms of pruritus in these two diseases are probably different. The improvement of fetal outcome could be related to a reduction of maternal bile acids induced by UDCA (25). However, the crucial point in the management of ICP is to decide the optimal gestational timing for delivery that would reduce the risk of perinatal mortality. In a large retrospective cohort study, Puljic et al. demonstrated that among women with ICP the induction of delivery at 36 weeks of gestation was associated with lower rates of perinatal mortality than the risk of expectant management (26).
HELLP syndrome Approximately 10% of women with severe preeclampsia have hepatic involvement. Strict control of blood pressure is essential, but hepatic involvement is related to a more severe preeclampsia, and delivery should be undertaken. Three% to twenty% of women with preeclampsia develop HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and it is also noted in 0.1% of all pregnancies. It can be diagnosed antepartum (70% of cases between the 27th and the 30th
Journal Pre-proof gestational week) or postpartum (27). Risk factors are advanced maternal age, multiparity and Caucasian ethnicity (3). The pathophysiology of HELLP syndrome reflects that of pre-eclampsia with microvascular endothelial damage and intravascular platelet activation (28). The diagnosis of HELLP syndrome is based mainly on clinical presentation and laboratory evaluation. Patients typically present with right upper quadrant and epigastric pain, nausea, vomiting, weight gain or oedema, headache and malaise. On the other hand, a significant number of patients are asymptomatic. On examination, hypertension and proteinuria are present in up to 85% of cases. Notable biochemical abnormalities include hemolysis (with high serum unconjugated bilirubin and lactate dehydrogenase (LDH) levels greater than 600 IU/l, a moderate rise in liver enzymes (AST and ALT:
200–700 IU/l) and a platelet count less than 100000 (29). Complications include
pulmonary oedema, placental abruption and disseminated intravascular coagulation (with evidence of elevated fibrin degradation products and d-dimer, a low fibrinogen and a secondary rise in the prothrombin time) (30). Abdominal ultrasound is mandatory in all women with HELLP syndrome, especially those with abdominal pain, shoulder tip pain or hypotension, in order to investigate for the life-threatening complications of hepatic haemorrhage, rupture and infarction, which have been reported to occur in up to 45% of cases (1). No indication in performing liver biopsy, since the diagnosis is clinical and laboratoristic (3). The maternal and foetal complications of HELLP syndrome are relevant. Perinatal mortality rate is 6–70%, while maternal mortality is 1% (30). Once HELLP develops, the only effective treatment is prompt delivery, especially after 34 weeks gestation (1). After delivery, close monitoring of the mother should continue, as some women may have worsening thrombocytopenia and increasing LDH levels up to 2 days postpartum and return to normal within 3–11 days (3). Postpartum corticosteroids have proved efficacious in improving maternal platelet counts, ALT levels and blood pressure. The risk of recurrence of HELLP syndrome in subsequent pregnancies has been reported as 3.4% (31).
Journal Pre-proof Acute fatty liver of pregnancy (AFLP) AFLP is a micro-vescicular fatty infiltration of hepatocytes causing liver failure in pregnancy. AFLP most frequently complicates the third trimester, often occurring at week 28–40. Although rare (with an incidence from 1:7000 to 1:16000 pregnancies), it is a medical and obstetrics emergency and a life-threatening condition, with an 18% maternal and a 23% fetal mortality rate (32) (33). Risk factors are nulliparity, preeclampsia, multiple gestation, pregnancies with a male baby, low BMI (3). An abnormality in mitochondrial b-oxidation (deficiency of the enzyme longchain 3-hydroxyacyl coenzyme A dehydrogenase in the newborn) determining fetal fatty acids accumulation and return to the mother via the placenta, finally depositing in the mother liver, is a recognized cause of AFLP (34) (35). The diagnosis of AFLP is based on clinical presentation and laboratory evaluation. Although the definitive diagnosis of AFLP is histologically, liver biopsy is rarely performed due to the need to stabilize and deliver affected women. Recently clinical diagnostic criteria have been developed and validated for AFLP, aiding rapid diagnosis without the need of a liver biopsy (Swansea criteria) (36). Patients typically present with anorexia, nausea, vomiting, abdominal pain, jaundice, headache, fatigue and central nervous system disturbances, until symptoms of acute liver failure including hypoglycaemia, coagulopathy, jaundice and hepatic encephalopathy. Notable biochemical abnormalities include hyperbilirubinaemia (1–10 mg/dl - 17.1–171.0 mmol/l), moderate elevation of liver enzymes (AST and ALT less than 1000 IU/l), profound hypoglycemia, increase of serum ammonia and lactic acid levels, metabolic acidosis, renal impairment, leucocytosis, anaemia and thrombocytopenia, prolongation of prothrombin time and decreased fibrinogen levels (37). Potential complications include disseminated intravascular coagulation, ascites, pleural effusions, acute pancreatitis, respiratory and renal failure, infections. It is mandatory to differentiate the AFLP from the HELLP syndrome (38) (39). The treatment of AFLP is early recognition and diagnosis (best maternal survival rate when the interval from occurrence of AFLP to delivery is one week) with prompt delivery followed by maternal stabilization in intensive care setting and
Journal Pre-proof supportive therapy (low fat-protein and high- carbohydrates diet, blood components, plasma exchange and haemodialysis, broad-spectrum antibiotics, correction of dehydration, electrolyte and acid-base balance) with improvement of clinical conditions in 1 to 4 weeks postpartum (3).
Overall conclusion The alteration of liver function tests during pregnancy is common and may be physiological. In most cases, the elevation of hepatocellular or cholestatic markers can be caused by liver diseases related or unrelated to pregnancy and it is important to distinguish these two conditions because maternal and foetal outcomes are different. The work-up should include clinical history, physical examination, laboratory and imaging tests. Furthermore, a multidisciplinary team is essential to define the optimal gestational time for delivery, if necessary, in order to avoid maternal or foetal complications.
Practice points
Liver disease in pregnancy can manifest as a benign disease with mild elevation of liver enzyme levels and a good outcome, or it can manifest as a serious entity affecting hepatobiliary function and resulting in liver failure and death to the mother and her foetus. Early recognition can be lifesaving.
A good clinical history, physical examination and abdominal ultrasound are often rewarding.
During pregnancy it is possible to observe a damage mainly hepatocellular or predominantly cholestatic, although an overlap between the two types of damage is usually observed.
A coordinated team approach that involves the primary care physician, obstetrician, hepatologist, and transplant surgeon is often required to promote good maternal and foetal outcomes.
Journal Pre-proof Research Agenda
ICP is characterized by an increase of bile acids during pregnancy. Future studies should evaluate cut-off levels of bile acids to build-up a diagnostic algorithm to apply, especially for deciding between expectant management vs delivery induction.
There is a strong association between AFLP and a deficiency of the enzyme long-chain 3hydroxyacyl-CoA dehydrogenase in the foetus, a disorder of mitochondrial fatty acid betaoxidation. Since AFLP is a serious maternal disorder, the utility of a screening during the second trimester for this enzymatic deficiency should be analyzed.
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Journal Pre-proof 15. Tang SJ et al. Safety and utility of ERCP during pregnancy. Gastrointest Endosc 2009 Mar; 69 (3): 453-61. 16. ASGE Standard of Practice Committee, Shergill AK, Ben-Menachem T, et al. Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc 2012 Jul; 76(1): 18-24. 17. Chan CH, Enns RA. ERCP in the management of choledocholithiasis in pregnancy. Curr Gastroenterol Rep 2012 Dec; 14(6): 504-510. 18. Gabzdyl EM, Schlaeger JM. Intrahepatic cholestasis of pregnancy. A critical clinical review. J Perinat Neonat Nurs 2015;29(1): 41-50. 19. Floreani A, Gervasi MT. New insights on intrahepatic cholestasis of pregnancy. Clin Liver Dis 2016;20: 177-189. 20. Wood AM, Livingston EG, Hughes BL, et al. Intrahepatic cholestasis of pregnancy: a review of diagnosis and management. Obstet Gynecol Survey 2018;73(2): 103-109. * 21. Glantz A, Marschall HU, Matsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004;40(2): 467-74. 22. Herrera CA et al. Perinatal outcomes associated with intrahepatic cholestasis of pregnancy. J Matern Fetal Neonatal Med 2018; 31: 1913-1920. 23. Lucena JF, Herrero JI, Quiroga G, et al. A multidrug resistance 3 gene mutation causing cholelithiasis, intrahepatic cholestasis of pregnancy and adult biliary cirrhosis. Gastroenterology 2003; 124: 1037-42. 24. Grand´Maison S DM, Mahone M. The effects of ursodeoxycholic acid treatment for intrahepatic cholestasis of pregnancy on maternal and fetal outcomes: a meta-analysis including nonrandomized studies. J Obstet Gynaecol Can. 2014;36(7):632-41. 25. Bacq Y, Sentilhes L, Reyes HB, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a metanalysis. Gastroenterology 2012;143: 1492-1501. 26. Puljic A, Kim E, Page J, et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol 2015;212(5): 667e1-e5. 27. Fitzpatrick KE, Hinshaw K, Kurinczuk JJ, et al. Risk factors, management, and outcomes of hemolysis, elevated liver enzymes, and low platelets syndrome and elevated liver enzymes, low platelets syndrome. Obstet Gynecol 2014;123: 618–27 * 28. Abildggard U, Hemidal K. Pathogenesis of the syndrome of hemoly-sis, elevated liver enzymes, and low platelet count (HELLP): a review. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2013;166:117–23. 29. Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management. A review. BMC Pregnancy Childbirth 2009;9:8. * 30. Aydin S, Ersan F, Ark C, et al. Partial HELLP syndrome: maternal, perinatal, sub-sequent pregnancy and long-term maternal outcomes. Journal of Obstetricsand Gynaecology Research 2014;40:932–40. 31. Martin JN Jr, Rose CH, Briery CM. Understanding and managing HELLP syndrome: the integral role of aggressive glucocorticoids for mother and child. Am J Obstet Gynecol 2006; 195: 914. 32. Nelson DB, Yost NP, Cunningham FG. Acute fatty liver of pregnancy: clinical outcomes and expected duration of recovery. American Journal of Obstetrics and Gynecology 2013;209:456.e1. 33. Knight M, Nelson-Piercy C, Kurinczuk JJ, Spark P, Brocklehurst P, Ukoss. A prospective national study of acute fatty liver of pregnancy in the UK. Gut. 2008;57:951-6. 34. Ibdah JA, Bennett MJ, Rinaldo P et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med 1999; 340: 1723. 35. Spiekerkoetter U. Mitochondrial fatty acid oxidation disorders: clinical presentation of longchain fatty acid oxidation defects before and after newborn screening. J Inherit Metab Dis 2010; 33: 527 – 32.
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Tables Specific liver diseases of pregnancy Hyperemesis gravidarum
AFLP
Characteristics
nausea and vomiting, dehydration, ketosis rapid progression to fulminant hepatic failure, ↓ platelets, ↑ INR, hypoglicemia. Liver biopsy: microvescicular steatosis, foamy hepatocytes, hepatic necrosis
ALP
Bilirubin
1-2x in most of the the patients normal normal
Treatment thiamine supplements, fluid replacement, and antiemetics
1-2x
prompt delivery, in some cases liver increased transplantation
1-100x
1-2x
normal
beta-blocker, magnesium sulfate, early delivery
↓ platelets, hemolysis, ↑ LDH, abdominal pain, seizures, proteinuria,↑ creatinin and uric acid, renal failure, pulmonary edema, liver hematoma and rupture; may occur post-partum 1-100x
1-2x
normal
prompt delivery
high blood pressure, Eclampsia/Pre-eclampsia seizures, proteinuria, renal failure, pulmonary edema
HELLP syndrome
ALT and AST
1-10x
Journal Pre-proof
ICP ↑bile acids, pruritus
1-4x
1-2x
normal
Table 1. Differential diagnosis of liver diseases unique to pregnancy.
Figure legends Figure 1. Workup of abnormal liver function test (LFT) in pregnant women. Figure 2. Liver diseases unique to pregnancy accordingly gestational period.
ursodeoxycholic acid, delivery in case of fetal distress
Maria Guarino, Valentina Cossiga, Filomena Morisco PII:
S1521-6918(20)30002-0
DOI:
https://doi.org/10.1016/j.bpg.2020.101667
Reference:
YBEGA 101667
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date:
06 October 2019
Accepted Date:
17 February 2020
Please cite this article as: Maria Guarino, Valentina Cossiga, Filomena Morisco, The interpretation of liver function tests in pregnancy, Best Practice & Research Clinical Gastroenterology (2020), https://doi.org/10.1016/j.bpg.2020.101667
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Journal Pre-proof Best Practice & Research Clinical Gastroenterology Volume 42C - Pregnancy in GI-disorders The interpretation of liver function tests in pregnancy
Authors: Maria Guarino, Valentina Cossiga, Filomena Morisco Affiliations: Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy;
Tables: 1 Figures: 2 Conflict of interest statement: Morisco Filomena: research grants, lecturing fees, advisory boards, scientific consultancy for Abbvie, BMS, Gilead Science, Janssen, MSD. No personal or financial conflicts of interest for all the other authors. Financial support statement: There is no financial support for this study.
Corresponding author: Filomena Morisco Associate Professor of Gastroenterology Department of Clinical Medicine and Surgery, Gastroenterology Unit University of Naples "Federico II", Via S. Pansini, 5 - 80131 Naples, Italy Tel: +39 081 7464746; Fax: +39 081 7464746. E-mail: [email protected]
Journal Pre-proof ABSTRACT Abnormal liver tests occur in 3-5% of pregnancies and show many different causes. Although alterations of liver enzymes could be a physiological phenomenon, it may also reflect potential severe liver injury, necessitating further assessment and accurate management. The work-up has to consider liver diseases specific of pregnancy and non pregnancy-related liver damage (coincidental and pre-existing to pregnancy). Pre-existing liver diseases during pregnancy are relatively uncommon, as pregnant women are generally young and healthy. Liver diseases unique to pregnancy are intrahepatic cholestasis of pregnancy, the HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and acute fatty liver of pregnancy. These disorders may result in foetal distress, severe liver damage and sometime hepatic failure; for these reasons the diagnostic work-up and treatment must be very fast. This review focuses on the management of pregnant women with altered liver function tests. Furthermore, the main liver diseases specific of pregnancy are described.
ABBREVIATIONS Acute fatty liver of pregnancy (AFLP), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), haemolysis, elevated liver enzyme and low platelets (HELLP), intrahepatic cholestasis of pregnancy (ICP), liver functions tests (LFTs), non alcoholic fatty liver disease (NAFLD),
Key words: Pregnancy, transaminases, cholestasis
Journal Pre-proof Introduction Abnormal liver tests occur in 3-5% of pregnancies, show many different causes and require proper evaluation and diagnosis. The first step is to differentiate between physiological changes and alteration related to the presence of liver disease (1). The physiological changes in liver function tests (LFTs) in pregnancy are commonly mild, transient, rarely permanent. On the other hand, severe liver disease in pregnancy is rare; however, pregnancy-related liver disease is the most frequent cause of liver dysfunction during pregnancy and represents a severe threat to foetal and maternal survival (2). A rapid differential diagnosis between liver disease related or unrelated to pregnancy is required in women who present liver damage during pregnancy. It may be categorized into three major groups: 1- specific liver diseases of pregnancy, such as intrahepatic cholestasis of pregnancy (ICP), haemolysis, elevated liver enzyme and low platelets (HELLP) syndrome, acute fatty liver of pregnancy (AFLP); 2- liver and biliary disease occurring during pregnancy such as viral hepatitis, cholelithiasis, etc; 3- pregnancy in patients with pre-existing chronic liver disease such as chronic hepatitis, cirrhosis, Budd Chiari syndrome etc (3) (4) (5). The present review will focus on the interpretation of LFTs arising in pregnancy and on the subsequent work-up according to the time of onset and the prognostic implications.
Liver tests during pregnancy Typically, we observe physiologically changes in liver biochemical profile during pregnancy. In clinical practice, there are four hepatic enzymes of interest: aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as markers of hepatocellular damage, Alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) suggestive for cholestasis, even if an overlap between the two classes of LFTs is very common.
Journal Pre-proof The LFTs evaluating synthetic function are albumin and International Normalized Ratio (INR). Finally bilirubin is able to evaluate biliary system function (intra and extra hepatic bile ducts and gallbladder) (6). Serum albumin in association to hemoglobin concentration falls (about 25% decrease) in pregnancy and is thought to be related to the increase in total plasma volume as a result of hemodilution (3). Differently any abnormality seen in the 4 enzymes and bilirubin needs further evaluation (1). ALP increases and may reach 2 to 4 times the normal adult upper reference value. This relates to production of the placental isoenzyme. Pregnant women with isolated raised alkaline phosphatase in this range do not need any further investigation. After birth, the ALP level falls, reaching nonpregnant values within 2 weeks. The concentrations of the transaminases, the bilirubin, the bile acids and GGT normally remain in the normal range like non-pregnant women (7).
Markers of hepatocellular injury: Aspartate and alanine transaminases AST or ALT elevations within 1.5 times the upper limits of normal do not necessarily indicate liver disease (1). In case of ALT and AST arise, especially in asymptomatic women, it is necessary to rule out alcohol use/abuse, acute viral hepatitis and acute toxic injury like drug injury or ischemic insult of the liver. Usually a pre-existing liver disease such as non alcoholic fatty liver disease (NAFLD), viral or autoimmune hepatitis etc. is a condition already known, even if in rare cases the onset of these diseases could overlap with pregnancy. If all these possibilities have been ruled out, it is necessary to focus on liver injuries specific of pregnancy (figure 1). Accurate identification of the cause and the potential impact on both maternal and foetal health is mandatory. The pregnancy related diseases carry on a high mortality rate for both mother and baby and require rapid diagnosis and in some cases urgent delivery. A thorough history, including prior pregnancies and behavior of prior pregnancy, high-risk behaviors and medications, and careful physical examination with ultrasound evaluation is necessary (1).
Journal Pre-proof The gestational age of the pregnancy is an important diagnostic indicator and can help tailoring the diagnostic work-up, as these insults typically occur at certain phase of the pregnancy and typically resolve with delivery (Table 1) (8). In particular, during the first trimester the main cause of hypertransaminasemia is the hyperemesis gravidarum which occurs in 0.3% to 2% of pregnancies, and it is characterized by nausea and vomiting. Transaminases can be elevated by up to 20 times the upper limit of normal, rarely with jaundice. LFTs normalize after the resolution of vomiting. Treatment is supportive with thiamine supplements, fluid replacement, and antiemetics (3) (8). During the second and third trimester, the hypertransaminasemia is related to preeclampsia/eclampsia, HELLP syndrome, acute fatty liver disease and also to intrahepatic cholestasis of pregnancy even if this last condition is prevalently characterized by cholestatic damage (8) (figure 2). Dedicated paragraphs on these specific liver diseases of pregnancy are reported later.
Markers of cholestasis: Alkaline phosphatase and gamma-glutamyl transferase The cholestasis represents a clinical picture affecting most of pregnant women. In presence of cholestasis three general concepts are important to consider: 1. Women presenting at any stage of pregnancy cholestatic features should do the same work-up of non-pregnant patient. This includes a familial anamnesis and drugs history, complete physical examination, and serological assessment as indicated by the clinical presentation; 2. The work-up has to consider liver diseases specific of pregnancy and a non-pregnancy related cholestatic diseases (coincidental and pre-existing to pregnancy); 3. Even if the focus is on cholestatic features, the laboratory abnormalities show in almost all cases a contemporary and milder elevation of aminotransferases. A differential diagnosis between liver disease related or unrelated to pregnancy is rapidly required. The key point in the workup of cholestasis is represented by the abdominal ultrasound considered safe and the preferred imaging modality in pregnancy. The abdominal US permit to distinguish
Journal Pre-proof between the extra- and intrahepatic cholestasis and the differential diagnosis between the most frequent cholestatic diseases observed during pregnancy. If ultrasonography is indeterminate and further imaging is necessary, it can be used, in second and third trimester, Magnetic Resonance Imaging (MRI) without gadolinium. Gadolinium is not recommended as it crosses the placenta and it is excreted by the fetal kidneys into the amniotic fluid, where it can remain for long periods, causing potential injury to fetal pulmonary and gastrointestinal systems (9). Computed tomography (CT) scans carry a significant risk of teratogenesis and childhood haematological malignancies, but it can be practiced, judiciously, with minimized radiation protocol (2-5 rads), only in case of acute presentation and after a collegial discussion. Oral and intravascular agents used for CT do not appear teratogenic in animal studies, but they can cause neonatal hypothyroidism (10). Cholelithiasis is common during pregnancy (3.5%), owing to the increased estrogen levels, causing cholesterol saturation and raised gallstone formation. Furthermore, it is the second cause of nonobstetric abdominal surgical pain during pregnancy, after appendicitis and it can result in several complications including symptomatic choledocholithiasis, acute biliary pancreatitis or ascending cholangitis (11). Asymptomatic cholelithiasis treatment is conservative, as it also is for mild pancreatitis. Symptomatic cholelithiasis has been previously managed conservatively, but recent studies showed that pregnant patients with cholelithiasis treated with conservative treatment had more episodes of recurrent biliary symptoms and a higher number of hospitalizations related to biliary complications. Conservative management also resulted in early induction of labor related to biliary symptoms in some patients. So, the endoscopic and surgical management of cholelithiasisrelated complications during pregnancy seems to be safe, effective and superior in comparison to conservative treatment (12) (13). Endoscopic retrograde cholangiopancreatography (ERCP) can be performed safely in pregnant women with biliary disease requiring intervention such as pancreatitis or cholangitis and it remains
Journal Pre-proof the first line modality in case of choledocholithiasis and its complications (14) (15). The main concern of ERCP during pregnancy is the use of fluoroscopy, but there are new techniques that avoid its use or limit fluoroscopy time and overall radiation exposure (16) (17). All the other specific liver diseases of pregnancy have to be considered in the work-up (hyperemesis gravidarum, ICP, eclampsia, preeclampsia, HELLP syndrome and acute fatty liver of pregnancy) even if in these cases, with the exception of ICP, the clinical picture is not prevalently characterized by cholestatic features.
Intrahepatic cholestasis of pregnancy (ICP) The intrahepatic cholestasis of pregnancy (ICP) is one of the most common liver diseases specific of pregnancy. The incidence ranges between 0.5-1.8% of pregnant women, but it varies greatly according to geographic location (18). The etiology of ICP is multifactorial and involves genetic, hormonal and environmental factors. There have been several gene variants in the bile acid pathway, implicated in the development of ICP, which could explain the higher incidence of ICP in some ethnic groups. The principal risk factors for ICP are multiple pregnancies, in vitro fertilization, advanced maternal age, positive family history, prior affected pregnancy and HCV infection (19). The ICP occurs typical in third trimester and has a rapid postnatal resolution. It shows up with pruritus and increasing of both bile salts and liver function tests. Pruritus is generalized but itching worst on the palm of hands and soles and generally precedes biochemical alterations (20). One of the typical features of ICP is elevated serum bile acid levels. The cutoff values, used during pregnancy, range between 10 to 14 µmol/l. Higher bile acid levels (>40 µmol/l) have been found to be associated with higher rates of fetal complications in a large cohort of Swedish women with ICP. This study showed an increased risk of spontaneous preterm delivery and asphyxia events in 17% of pregnancies with bile acid levels >40 µmol/l. This suggests a causal relationship between bile acids levels and fetal complications (21) (22).
Journal Pre-proof The liver transaminases are commonly elevated in ICP and bilirubin levels can increase up 10% of pregnancies. It is important to underline that ICP is a diagnosis of exclusion and differential diagnosis include preeclampsia, HELLP, acute fatty liver of pregnancy (AFLP) and dermatological conditions that induce pruritus. In general, delivery resolves maternal symptoms. Rarely, women have persistence of symptoms and develop a cholestatic disease. These cases may be related to MDR3 deficiency and it should be suspected in young women with cholestasis of unknown origin who develop a severe ICP (23). Ursodeoxycholic acid (UDCA), at dosage of 10-15 mg/Kg/die, is effective in reducing pruritus, improving liver tests in women with ICP and ameliorating fetal outcome (24). The mechanisms of these effects are unknown. UDCA may have a specific effect by improving the transport of bile acids across the placenta. The beneficial effect on pruritus contrasts with the absence of a significant effect in patients with primary biliary cholangitis (PBC), but the mechanisms of pruritus in these two diseases are probably different. The improvement of fetal outcome could be related to a reduction of maternal bile acids induced by UDCA (25). However, the crucial point in the management of ICP is to decide the optimal gestational timing for delivery that would reduce the risk of perinatal mortality. In a large retrospective cohort study, Puljic et al. demonstrated that among women with ICP the induction of delivery at 36 weeks of gestation was associated with lower rates of perinatal mortality than the risk of expectant management (26).
HELLP syndrome Approximately 10% of women with severe preeclampsia have hepatic involvement. Strict control of blood pressure is essential, but hepatic involvement is related to a more severe preeclampsia, and delivery should be undertaken. Three% to twenty% of women with preeclampsia develop HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and it is also noted in 0.1% of all pregnancies. It can be diagnosed antepartum (70% of cases between the 27th and the 30th
Journal Pre-proof gestational week) or postpartum (27). Risk factors are advanced maternal age, multiparity and Caucasian ethnicity (3). The pathophysiology of HELLP syndrome reflects that of pre-eclampsia with microvascular endothelial damage and intravascular platelet activation (28). The diagnosis of HELLP syndrome is based mainly on clinical presentation and laboratory evaluation. Patients typically present with right upper quadrant and epigastric pain, nausea, vomiting, weight gain or oedema, headache and malaise. On the other hand, a significant number of patients are asymptomatic. On examination, hypertension and proteinuria are present in up to 85% of cases. Notable biochemical abnormalities include hemolysis (with high serum unconjugated bilirubin and lactate dehydrogenase (LDH) levels greater than 600 IU/l, a moderate rise in liver enzymes (AST and ALT:
200–700 IU/l) and a platelet count less than 100000 (29). Complications include
pulmonary oedema, placental abruption and disseminated intravascular coagulation (with evidence of elevated fibrin degradation products and d-dimer, a low fibrinogen and a secondary rise in the prothrombin time) (30). Abdominal ultrasound is mandatory in all women with HELLP syndrome, especially those with abdominal pain, shoulder tip pain or hypotension, in order to investigate for the life-threatening complications of hepatic haemorrhage, rupture and infarction, which have been reported to occur in up to 45% of cases (1). No indication in performing liver biopsy, since the diagnosis is clinical and laboratoristic (3). The maternal and foetal complications of HELLP syndrome are relevant. Perinatal mortality rate is 6–70%, while maternal mortality is 1% (30). Once HELLP develops, the only effective treatment is prompt delivery, especially after 34 weeks gestation (1). After delivery, close monitoring of the mother should continue, as some women may have worsening thrombocytopenia and increasing LDH levels up to 2 days postpartum and return to normal within 3–11 days (3). Postpartum corticosteroids have proved efficacious in improving maternal platelet counts, ALT levels and blood pressure. The risk of recurrence of HELLP syndrome in subsequent pregnancies has been reported as 3.4% (31).
Journal Pre-proof Acute fatty liver of pregnancy (AFLP) AFLP is a micro-vescicular fatty infiltration of hepatocytes causing liver failure in pregnancy. AFLP most frequently complicates the third trimester, often occurring at week 28–40. Although rare (with an incidence from 1:7000 to 1:16000 pregnancies), it is a medical and obstetrics emergency and a life-threatening condition, with an 18% maternal and a 23% fetal mortality rate (32) (33). Risk factors are nulliparity, preeclampsia, multiple gestation, pregnancies with a male baby, low BMI (3). An abnormality in mitochondrial b-oxidation (deficiency of the enzyme longchain 3-hydroxyacyl coenzyme A dehydrogenase in the newborn) determining fetal fatty acids accumulation and return to the mother via the placenta, finally depositing in the mother liver, is a recognized cause of AFLP (34) (35). The diagnosis of AFLP is based on clinical presentation and laboratory evaluation. Although the definitive diagnosis of AFLP is histologically, liver biopsy is rarely performed due to the need to stabilize and deliver affected women. Recently clinical diagnostic criteria have been developed and validated for AFLP, aiding rapid diagnosis without the need of a liver biopsy (Swansea criteria) (36). Patients typically present with anorexia, nausea, vomiting, abdominal pain, jaundice, headache, fatigue and central nervous system disturbances, until symptoms of acute liver failure including hypoglycaemia, coagulopathy, jaundice and hepatic encephalopathy. Notable biochemical abnormalities include hyperbilirubinaemia (1–10 mg/dl - 17.1–171.0 mmol/l), moderate elevation of liver enzymes (AST and ALT less than 1000 IU/l), profound hypoglycemia, increase of serum ammonia and lactic acid levels, metabolic acidosis, renal impairment, leucocytosis, anaemia and thrombocytopenia, prolongation of prothrombin time and decreased fibrinogen levels (37). Potential complications include disseminated intravascular coagulation, ascites, pleural effusions, acute pancreatitis, respiratory and renal failure, infections. It is mandatory to differentiate the AFLP from the HELLP syndrome (38) (39). The treatment of AFLP is early recognition and diagnosis (best maternal survival rate when the interval from occurrence of AFLP to delivery is one week) with prompt delivery followed by maternal stabilization in intensive care setting and
Journal Pre-proof supportive therapy (low fat-protein and high- carbohydrates diet, blood components, plasma exchange and haemodialysis, broad-spectrum antibiotics, correction of dehydration, electrolyte and acid-base balance) with improvement of clinical conditions in 1 to 4 weeks postpartum (3).
Overall conclusion The alteration of liver function tests during pregnancy is common and may be physiological. In most cases, the elevation of hepatocellular or cholestatic markers can be caused by liver diseases related or unrelated to pregnancy and it is important to distinguish these two conditions because maternal and foetal outcomes are different. The work-up should include clinical history, physical examination, laboratory and imaging tests. Furthermore, a multidisciplinary team is essential to define the optimal gestational time for delivery, if necessary, in order to avoid maternal or foetal complications.
Practice points
Liver disease in pregnancy can manifest as a benign disease with mild elevation of liver enzyme levels and a good outcome, or it can manifest as a serious entity affecting hepatobiliary function and resulting in liver failure and death to the mother and her foetus. Early recognition can be lifesaving.
A good clinical history, physical examination and abdominal ultrasound are often rewarding.
During pregnancy it is possible to observe a damage mainly hepatocellular or predominantly cholestatic, although an overlap between the two types of damage is usually observed.
A coordinated team approach that involves the primary care physician, obstetrician, hepatologist, and transplant surgeon is often required to promote good maternal and foetal outcomes.
Journal Pre-proof Research Agenda
ICP is characterized by an increase of bile acids during pregnancy. Future studies should evaluate cut-off levels of bile acids to build-up a diagnostic algorithm to apply, especially for deciding between expectant management vs delivery induction.
There is a strong association between AFLP and a deficiency of the enzyme long-chain 3hydroxyacyl-CoA dehydrogenase in the foetus, a disorder of mitochondrial fatty acid betaoxidation. Since AFLP is a serious maternal disorder, the utility of a screening during the second trimester for this enzymatic deficiency should be analyzed.
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Tables Specific liver diseases of pregnancy Hyperemesis gravidarum
AFLP
Characteristics
nausea and vomiting, dehydration, ketosis rapid progression to fulminant hepatic failure, ↓ platelets, ↑ INR, hypoglicemia. Liver biopsy: microvescicular steatosis, foamy hepatocytes, hepatic necrosis
ALP
Bilirubin
1-2x in most of the the patients normal normal
Treatment thiamine supplements, fluid replacement, and antiemetics
1-2x
prompt delivery, in some cases liver increased transplantation
1-100x
1-2x
normal
beta-blocker, magnesium sulfate, early delivery
↓ platelets, hemolysis, ↑ LDH, abdominal pain, seizures, proteinuria,↑ creatinin and uric acid, renal failure, pulmonary edema, liver hematoma and rupture; may occur post-partum 1-100x
1-2x
normal
prompt delivery
high blood pressure, Eclampsia/Pre-eclampsia seizures, proteinuria, renal failure, pulmonary edema
HELLP syndrome
ALT and AST
1-10x
Journal Pre-proof
ICP ↑bile acids, pruritus
1-4x
1-2x
normal
Table 1. Differential diagnosis of liver diseases unique to pregnancy.
Figure legends Figure 1. Workup of abnormal liver function test (LFT) in pregnant women. Figure 2. Liver diseases unique to pregnancy accordingly gestational period.
ursodeoxycholic acid, delivery in case of fetal distress