Practice Rational Testing

Abnormal liver function tests in pregnancy

BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f6055 (Published 25 October 2013) Cite this as: BMJ 2013;347:f6055
  1. Ian Walker, consultant medical biochemist1,
  2. Lucy C Chappell, clinical senior lecturer in maternal and fetal medicine2,
  3. Catherine Williamson, professor of women’s health2
  1. 1Department of Biochemistry, Wexham Park Hospital, Slough, UK
  2. 2Women’s Health Academic Centre, King’s College London and King’s Health Partners, London SE1 1UL, UK
  1. Correspondence to: C Williamson catherine.williamson{at}kcl.ac.uk
  • Accepted 4 September 2013

Learning points

  • Symptoms and signs associated with the commonest pregnancy-specific liver diseases are pruritus, upper abdominal pain, and jaundice

  • Reference ranges for liver function tests for alanine and aspartate transaminases, bilirubin, and alkaline phosphatase are different in pregnancy

  • Abnormal liver function tests in conjunction with relevant symptoms or signs should result in referral to secondary care, as should raised serum bile acids or coexistent hypertension or proteinuria

  • Palmar erythema, spider naevae, and isolated raised alkaline phosphatase in the third trimester can occur in uncomplicated pregnancy and do not usually require further investigation

A 34 year old South Asian nursery worker presented to her general practitioner at 32 weeks’ gestation in her first pregnancy complaining of increasingly severe itching. There was no relevant medical or family history, and she was not taking regular medication. Physical examination was normal with no evident rash. Her blood pressure was 115/65 mm Hg, and there was no proteinuria. The liver function tests were: total bilirubin 6 μmol/L, alkaline phosphatase 178 IU/L, alanine transaminase 42 IU/L, and albumin 34 g/L.

What is the next investigation?

Alkaline phosphatase normally increases during pregnancy because of production of the placental isoenzyme and, by term, may reach three times the normal adult upper reference value. The value of 178 IU/L is therefore likely to be normal (table 1). Pregnant women with isolated raised alkaline phosphatase in this range do not need any further investigation. Likewise, albumin is often decreased in normal pregnancy (table 1) as a consequence of haemodilution. In contrast, the concentrations of the transaminases (alanine and aspartate) and γ-glutamyltransferase normally decrease during pregnancy, and it is important to compare values to an appropriate reference range (table 1). The alanine transaminase result of 42 IU/L is therefore not normal and, because liver disease in pregnancy can have serious consequences, should be followed up within a week.

Table 1

 Typical reference ranges for liver enzymes by pregnancy and trimester

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Other follow-up tests should include initial investigations directed toward the symptoms, as detailed below and in tables 2 and 3. In the present case these may include:

  • Serum total bile acids (measured in a random blood sample)—Normally present at low concentrations in the peripheral circulation because of efficient hepatic first-pass clearance. The reference range usually quoted (<14 μmol/L) allows for the modest increase seen postprandially, so any increase above this is a sensitive marker of hepatic or post-hepatic cholestasis.

  • γ-glutamyltransferase—Derived principally from the bile ducts, it is a sensitive test of liver dysfunction, and so a normal value helps to reassure that any increase in alkaline phosphatase concentration is physiological and not pathological.

Table 2

 Typical symptoms associated with abnormal liver function tests in pregnancy and likely associated diagnosis

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Table 3

 Typical pattern of liver function tests, and additional investigations, in women with liver diseases specific to pregnancy

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When should liver function testing be considered in pregnancy?

Liver disease may present with non-specific symptoms and signs during pregnancy, as shown in table 2. A careful history will establish whether the woman has any infectious contacts or risk factors for bloodborne infections. Any of these features would justify an initial check of liver function tests. Testing may also be indicated in women known to be at high risk (such as those with previously affected pregnancies, a family history of liver disease in pregnancy, or known pre-existing liver disease). In contrast, palmar erythema and spider naevi may occur in uncomplicated pregnancy and are not a reason for concern (or liver function tests) when present in isolation. Transient mild abnormalities of liver function tests are common whether pregnant or not. Because liver abnormalities presenting for the first time during pregnancy may represent a pregnancy-specific liver disease or may reveal a pre-existing undiagnosed liver condition that has been exacerbated by the physiological and metabolic stresses of the pregnancy, it is important to follow these up promptly. If there is concern about hepatic decompensation, additional tests that should be performed are prothrombin time (a sensitive indicator of hepatic synthetic function) and plasma glucose level (to exclude hypoglycaemia). The normal ranges for these tests do not change in pregnancy.

How are the commonest liver diseases differentiated?

Most liver diseases present with a characteristic constellation of symptoms in pregnant women (table 2). The typical changes in liver function tests for the pregnancy-specific diseases are summarised in table 3. A liver ultrasound scan can be useful if biliary obstruction if suspected.

Generalised pruritus without a rash

Around 25% of pregnant women report pruritus, and it is benign in most cases. However, in combination with abnormal liver function tests, a diagnosis of intrahepatic cholestasis of pregnancy (affecting about 0.7% of pregnant women in the UK) should be considered. It is associated with increased rates of preterm labour, fetal hypoxia, and intrauterine death.5 6 Raised bile acid concentrations, but not alanine transaminase, are predictive of adverse pregnancy outcome.5 6 If intrahepatic cholestasis of pregnancy is diagnosed, referral for hospital review is necessary.

Headache, malaise, epigastric pain, nausea, and vomiting in the second half of pregnancy

For a woman with some of these symptoms (not all need to be present), a disease within the pre-eclampsia spectrum should be excluded. Pre-eclampsia may be complicated by increased transaminase concentrations in 11% of cases,7 but these liver abnormalities are rarely the presenting feature and are not strongly predictive of maternal or fetal outcome.8 Checking for hypertension (≥140/90 mm Hg) and dipstick proteinuria should be a routine part of every antenatal visit. Healthcare professionals should follow the NICE guidelines for management of hypertension in pregnancy9 to determine thresholds for referral and need for further investigations.

At the severe end of the pre-eclampsia spectrum there is overlap with HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome. HELLP syndrome also usually emerges during the third trimester, typically presenting with symptoms of epigastric pain, nausea, vomiting, headache, and visual disturbance. The diagnosis is made on detecting haemolysis (on a peripheral blood film or with elevated serum lactate dehydrogenase levels and unconjugated bilirubin) with elevated liver enzymes (typically increased alanine transaminase) and a low platelet count (<100×109/L) and is not usually made in primary care. It is associated with high maternal and perinatal mortality.10 Haematological and biochemical indices are useful for monitoring ongoing severity of disease but are not independent predictors of adverse outcome.11 However, any woman with hypertension and symptoms, signs, or investigations consistent with liver involvement requires immediate referral to an obstetric centre.

Acute fatty liver of pregnancy is rare, with an estimated incidence between 1:1000 and 1:20 000 pregnancies.12 The presentation is similar to that for HELLP syndrome, but affected women may also complain of polydipsia, polyuria, or jaundice. Women with acute fatty liver of pregnancy may deteriorate rapidly, developing fulminant hepatic failure and encephalopathy. Historical reviews have reported maternal mortality of 12-18%, but in a recent large series from the UK, with modern management, deaths were rare.12 Acute fatty liver of pregnancy is therefore a medical emergency that requires immediate referral if suspected. Typical blood test abnormalities are shown in table 3.

Severe nausea and vomiting in the first trimester

Women with severe nausea and vomiting may have hyperemesis gravidarum (intractable vomiting in pregnancy which prevents a woman from maintaining normal hydration or nutrition). This occurs in less than 1% of pregnancies; abnormal liver tests, likely a consequence of starvation, are found in up to 60% of such cases, more commonly in women who require re-admission to hospital.13 The alanine transaminase concentration will generally improve as the condition resolves. Persistent liver function test abnormalities may reflect a pre-existing underlying liver disease, and referral to a hepatologist is recommended.

Drug induced abnormal liver function tests

There are many drugs that can cause hepatocellular or cholestatic liver injury, but only a few are used during pregnancy (box 1). Affected women are usually asymptomatic, and the abnormal liver function tests are noted when a blood test is performed for another reason (such as a screen for a hypertensive woman treated with methyldopa). First line management should be to stop the drug, switching to an alternative if needed. If the cause is not obvious, it is important to be alert to the possibility of non-prescribed drugs and agents, including some drugs of misuse (such as ecstasy), herbal remedies (which can be hepatotoxic),14 or even mushroom poisoning (such as Amanita and Gyromitra species).

Box 1: Drugs that can cause liver injury and commonly used by women of childbearing age

Hepatocellular damage (typically greatly increased alanine and aspartate transaminase levels, and variably increased total bilirubin)
  • Paracetamol

  • Methyldopa

  • Antibacterial drugs (amoxicillin, co-amoxiclav)

  • Propylthiouracil

  • Nevirapine

  • Highly active antiretroviral therapy

Cholestatic damage (typically increased alanine and aspartate transaminase levels, increased total bile acids, variably increased total bilirubin and γ-glutamyltransferase)
  • Antibacterial drugs (amoxicillin, co-amoxiclav, flucloxacillin)

  • Progestogens and oestrogens

  • First and second generation antipsychotics

  • Proton pump inhibitors

Liver disease not specific to pregnancy

If a pregnancy-specific liver disease is not diagnosed, it is important to consider disorders incidental to pregnancy (box 2), which may require referral to a hepatologist. In the UK probably the commonest cause of abnormal liver function tests (usually an isolated stable raised alanine transaminase concentration) is fatty infiltration with or without chronic low grade inflammation (non-alcoholic steatohepatitis), which does not routinely require referral. Comparison of test results with any previous investigations before pregnancy is important, and the absence of symptoms or other abnormalities on liver function tests may be helpful in distinguishing non-alcoholic steatohepatitis from other liver disease.

Box 2: Incidental liver disease that may present during pregnancy

  • Non-alcoholic steatohepatitis

  • Gallbladder disease; cholangitis

  • Viral hepatitis (hepatitis A, B, C, or E)

  • Primary biliary cirrhosis

  • Primary sclerosing cholangitis

  • Budd-Chiari syndrome

  • Autoimmune hepatitis

  • Note that other multisystem conditions (such as sepsis or cardiac failure) may also present with abnormal liver function tests

Outcome

A repeat blood sample taken from the patient one week later showed total bilirubin concentration 6 μmol/L, alkaline phosphatase 170 IU/L, alanine transaminase 65 IU/L, γ-glutamyltransferase 32 IU/L, and serum total bile acids 30 μmol/L (reference ranges given in table 1). The prothrombin time was normal. A provisional diagnosis of intrahepatic cholestasis of pregnancy was made, and the woman was referred to the obstetric unit for review the next day. Further investigations (table 3) did not show any other cause for this woman’s abnormal liver function tests, and a diagnosis of intrahepatic cholestasis of pregnancy was made.

Liver function tests and total bile acids were monitored weekly, following the Royal College of Obstetricians and Gynaecologists guidelines.15 Monitoring is undertaken with the aim of detecting a rapid rise in total bile acids (to >40 μmol/L), known to be associated with adverse perinatal outcomes in intrahepatic cholestasis of pregnancy.5 6 A marked deterioration in maternal liver function should also alert the clinician to the possibility of other underlying hepatic disorders that might cause maternal decompensation.

By 36 weeks’ gestation, the patient’s alanine transaminase concentration had increased to 160 IU/L and total bile acids to 86 μmol/L. The woman went into spontaneous labour at 36 weeks, delivering a healthy male infant. The woman’s symptoms resolved rapidly postpartum. Her liver function tests and total bile acids were re-checked six weeks postnatally and were normal. This remains an important final check: liver diseases specific to pregnancy should resolve after delivery. Persistence of abnormal liver function tests in the postnatal period should prompt a further search for other liver disease not related to pregnancy.

Notes

Cite this as: BMJ 2013;347:f6055

Footnotes

  • This series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. The series advisers are Steve Atkin, professor, head of department of academic endocrinology, diabetes, and metabolism, Hull York Medical School; and Eric Kilpatrick, honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. To suggest a topic for this series, please email us at practice@bmj.com.

  • Contributors: All authors contributed to planning, drafting, revising, and final approval of the manuscript. CW is guarantor.

  • Funding: No specific funding was received.

  • Competing interests: We have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.

  • Provenance and peer review: Commissioned; peer reviewed.

  • Patient consent not required (patient anonymised, dead, or hypothetical).

References

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