Overall Bottom Line

Pregnancy-specific liver diseases are the most common cause of abnormal liver tests in pregnancy.
It is imperative to evaluate for pre-existing or newly acquired liver disease (viral hepatitis) in pregnant patients with liver dysfunction.
Hypertension-related liver diseases in pregnancy (pre-eclampsia, eclampsia, HELLP syndrome and hepatic rupture) have overlapping symptoms and similar management.
Acute fatty liver of pregnancy is a rare catastrophic disorder presenting late in pregnancy, and usually improves with prompt delivery.
Most pregnancy-related liver diseases tend to recur in subsequent pregnancies.

Section 1: Background

Definition of disease

Liver dysfunction during pregnancy is encountered in 3–5% of patients. It can be caused by conditions that are specific to pregnancy or by liver diseases that coexist in pregnancy.
Normal physiological changes in pregnancy include a low serum albumin (plasma volume expansion), increased alkaline phosphatase (placental secretion).
The hyperestrogenic state of pregnancy can lead to spider angiomas and palmar erythema.

Disease classification

Pregnancy-related liver diseases:
- Hyperemesis gravidarum (HG).
- Intrahepatic cholestasis of pregnancy (ICP).
- Pre-eclampsia and eclampsia.
- HELLP syndrome.
- Acute fatty liver of pregnancy (AFLP).
Pregnancy-unrelated liver diseases: all liver diseases that may affect non-pregnant women may also occur during pregnancy. They may be pre-existing or be acquired during pregnancy.

Incidence/prevalence

HG occurs in 0.3–2.0% of all pregnancies in the first trimester.
ICP affects in 0.1–1.5% of pregnancies, with a much higher incidence in Scandinavia and South Africa.
Pre-eclampsia affects 5–7% of all pregnancies, complicated by HELLP syndrome in 4–12% of these women.
AFLP occurs in the third trimester in 1 : 10 000–15 000 pregnancies.

Etiology

ICP is related to abnormal biliary transport across the canalicular membrane due to mutations in the bile salt export pump – specifically the multidrug resistance protein 3 (MDR3).
Pre-eclampsia is caused by placental ischemia leading to endothelial dysfunction and coagulation activation. An imbalance of prostacyclin and thromboxane has also been implicated.
AFLP results from an abnormality in mitochondrial beta oxidation of fatty acids due to a deficiency in the LCHAD in the fetus.

Pathology/pathogenesis

The pathogenesis of AFLP has been well elucidated. The LCHAD deficiency in the fetus leads to long-chain fatty acid accumulation which return to the maternal circulation, depositing in the liver causing microvesicular steatosis, diffuse cytoplasmic ballooning sparing the periportal hepatocytes and resultant AFLP.
In pre-eclampsia/HELLP syndrome, liver injury is precipitated by intravascular fibrin deposition, hypovolemia, and increased sinusoidal pressure leading to sinusoidal fibrin thrombi, hemorrhage and hepatocellular necrosis in the periportal areas.

Predictive/risk factors

HG: increased BMI, psychiatric illness, molar pregnancy, diabetes mellitus, multiple pregnancies, hyperthyroidism.
Intrahepatic cholestasis: history of cholestasis on oral contraceptive pill, family history, ICP in previous pregnancy.
Pre-eclampsia: extremes of maternal age, primiparity, pre-existing hypertension, family history and occurrence in previous pregnancy.
HELLP: advanced maternal age, multiparity and white ethnicity.
AFLP: low BMI, nulliparity, twin pregnancy.

Section 2: Prevention

Regular pre-natal visits and screening for pre-eclampsia/ICH lead to early diagnosis and treatment especially in high risk patients and those with a family history

Section 3: Diagnosis (Algorithm 25.1)

Clinical Pearls

Patients with HG present in the first trimester with intractable vomiting resulting in dehydration, ketosis and weight loss of 5% or more. Symptoms typically resolve by week 18. Liver enzymes can be 20 times the ULN, along with renal failure.
ICP occurs in the second half of pregnancy usually after 25 weeks and resolves with delivery. The onset of disease is marked by pruritus of palms and soles followed rarely by jaundice in 2–4 weeks. Liver enzymes may be markedly increased and a fasting serum bile acid concentration >10 µmol/L is diagnostic.
Pre-eclampsia is characterized by hypertension and proteinuria (>300 mg in 24 hours) after 20 weeks of gestation and/or within 48 hours of delivery. Liver enzymes may be elevated to 10 times ULN; jaundice is uncommon.
HELLP syndrome is a combination of hemolysis with a micro-angiopathic blood smear, increased liver enzymes and low platelets; it develops in the second or third trimester or after delivery.
AFLP occurs in the third trimester and remains a medical and obstetric emergency due to liver failure and high fetal mortality. Hypertension, vomiting, hypoglycemia, lactic acidosis and hyperammonemia are the hallmarks of this condition.

Differential diagnosis

Differential diagnosis	Features
Cirrhosis with portal hypertension	History of pre-existing liver disease, ascites, abnormal liver synthetic function
Hepatitis A/Hepatitis E	History of travel to endemic areas, positive serology, marked elevation of liver enzymes, 16% mortality in acute HEV infection
AIH	Flares likely post-partum, azathioprine is safe
Wilson disease	Undiagnosed Wilson, presenting with liver failure and hemolytic anemia can be misinterpreted as HELLP. Check ceruloplasmin level
PBC	May present for first time with protracted pruritus post-delivery and misinterpreted as ICP. AMA positive in PBC
Biliary disease (gallstones)	More common in pregnancy due to lithogenic bile
Budd–Chiari syndrome	Prothrombotic state of pregnancy predisposes to syndrome presenting with RUQ pain, jaundice and ascites. Doppler US is diagnostic
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome	Renal failure, neurological symptoms, skin rash