Intrahepatic cholestasis of pregnancy and acute fatty liver

• Intrahepatic cholestasis of pregnancy (ICP), sometimes called obstetric cholestasis, is the commonest pregnancy-specific liver disease: bile acids accumulate in the blood, usually in the third trimester, and the hallmark is generalised itching without a rash, often worst on the palms and soles at night. ^[3]
• Severity is graded by the peak bile acid level: mild 19 to 39 micromol/L, moderate 40 to 99 micromol/L, severe 100 micromol/L or more. Only severe disease carries an increased risk of stillbirth, and the timing of planned birth follows these bands.
• Ursodeoxycholic acid is the only drug with a real evidence base in ICP. Guidelines differ on exactly how much to use (10 to 15, 10 to 20 or up to 25 mg per kg per day), but agree it helps pruritus a little and reduces spontaneous preterm birth when bile acids are 40 micromol/L or more.
• Acute fatty liver of pregnancy (AFLP) is a rare, third-trimester emergency in which the mother develops acute liver failure: nausea, vomiting, jaundice, encephalopathy and coagulopathy. The only cure is delivery. ^[3]
• AFLP and HELLP syndrome look alike and must be told apart; both sit in the pre-eclampsia spectrum, and the Swansea criteria are the standard checklist for AFLP.

By the end of this page you should be able to:

1. Recognise ICP from its symptoms, grade it by peak bile acids, and explain why bile acids rather than liver enzymes predict harm to the baby.
2. Plan investigations, monitoring and the exact timing of birth for a woman with ICP, and choose and dose ursodeoxycholic acid while stating the honest limits of the evidence.
3. Describe the presentation, Swansea criteria and emergency management of acute fatty liver of pregnancy.
4. Put AFLP, HELLP syndrome and pre-eclampsia side by side in a table and pick out the features that separate them.
5. Apply all of this in a low-resource setting and know when to transfer.

These two conditions sit at opposite ends of severity and urgency. ICP is common, uncomfortable and mostly a fetal-risk problem managed out of hospital; AFLP is rare, dangerous to the mother and cured only by delivery. Both belong to the family of pregnancy-specific liver diseases, together with hyperemesis gravidarum and the hypertensive liver disorders (pre-eclampsia and HELLP syndrome), and the liver numbers overlap between them, which is why the differential diagnosis matters so much.

ICP is reported to affect between 0.3% and 5% of pregnancies worldwide, and about 7 in 1000 in the United Kingdom. It is more common in women of Indian-Asian or Pakistani-Asian origin, up to 15 in 1000. ^[1][3] Pruritus itself is extremely common in pregnancy, affecting about 25 in 100 women, so most itching in pregnancy is not ICP. ^[1]

Risk factors for ICP include a previous episode of cholestasis with the combined oral contraceptive pill, chronic hepatitis C infection, advanced maternal age, multiple pregnancy, a previous ICP and a family history. ^[3] There is a strong genetic component: mutations in the bile salt export pump (ABCB11) and the phospholipid floppase (ABCB4) are recognised contributors, so a woman whose mother or sister had ICP should be watched closely. ^[3][2]

AFLP is far rarer, with an incidence of about 1 in 7000 to 1 in 20000 pregnancies. It occurs in the third trimester, or occasionally the late second trimester or postpartum. Risk factors include a fetal homozygous mutation for long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), multiple pregnancy and a male fetus. ^[3] The mother is typically heterozygous: impaired beta-oxidation in the fetus with a partially impaired mother is the accepted explanation. ^[3]

HELLP syndrome, the third member of this group, occurs in up to 0.9% of all pregnancies and in 10% to 20% of women with severe pre-eclampsia. It usually presents between 28 and 36 weeks but can appear in the first week after delivery. ^{[3] [1]}

For ICP the starting point is reduced bile flow. A combination of rising oestrogen and progesterone metabolites in the third trimester, genetically determined transporter function and environmental factors lowers the capacity of the canalicular membrane to excrete bile acids. ^[3] The result is cholestasis inside the liver, spillover of bile acids into the blood, and deposition of those acids in the maternal skin (itch) and in the placenta and fetal compartment (risk). UDCA does not fix the transporter; it makes the bile acid pool less toxic and more water-soluble, which is why it can only modify, not abolish, the process.

For AFLP the defect is in the mitochondria. LCHAD catalyses the third step of long-chain fatty acid beta-oxidation. When the fetus lacks the enzyme, toxic intermediates cross the placenta into the maternal circulation, where a heterozygous mother metabolises them slowly and deposits microvesicular fat in her own liver. ^[3] This is why every child of an AFLP pregnancy should be screened for LCHAD deficiency after birth. ^[3][2]

HELLP is best understood as severe pre-eclampsia with endothelial injury: activated platelets and endothelial dysfunction produce haemolysis, hepatic sinusoidal obstruction and thrombocytopenia, with LFTs rising because of ischaemia rather than true necrosis. ^[3]

ICP bile acids rise in the maternal blood and cross the placenta. Fetal bile acid concentrations track maternal ones with a lag, and it is the high fetal and placental bile acid load, not the maternal liver numbers, that is thought to drive stillbirth, preterm labour and meconium passage. That is the reason the RCOG severe band is defined by a bile acid level of 100 micromol/L or more, and the reason fetal monitoring tests such as cardiotocography do not predict or prevent stillbirth in ICP. ^[1][3]

AFLP is different in kind. Hepatocellular fat accumulation impairs synthetic function first: clotting factors fall, glucose falls, ammonia rises, and only then do transaminases climb. The coagulopathy of AFLP is therefore severe and early, whereas in ICP the prothrombin time stays normal unless vitamin K is malabsorbed. ^[3] This synthetic-failure pattern is the single most useful bedside distinction between AFLP and HELLP, which usually shows a predominantly haemolytic and hypertensive picture.

The predominant symptom is pruritus, especially on the palms and soles, usually worst at night, starting after 28 weeks though it can begin earlier, even at 7 weeks. ^[1][3] There is no rash; scratch marks only. Generalised itching, fatigue, anorexia and nausea follow, and jaundice occurs in under a quarter of cases, with bilirubin often under 100 micromol/L. ^[3] Rarely a woman presents with jaundice rather than itch, and that should prompt a search for another diagnosis. ^[3]

Liver tests are not the story in ICP: aminotransferases can climb to up to 8 to 10 times the upper limit of normal, GGT is usually normal, and the bile acid level is the sensitive test because it can be raised when everything else is normal. ^[3] That is the reason every woman with persistent itch needs bile acid and LFT measurement repeated if the first set is normal. ^[1][3]

Associated problems deserve attention: ICP is more common alongside pre-eclampsia and gestational diabetes, so blood pressure and glucose handling should be assessed. ^[1]

The presentation is deliberately non-specific and that is the trap. Nausea and vomiting, anorexia, headache and abdominal pain lead to liver failure over days: jaundice, confusion from encephalopathy, hypoglycaemia and coagulopathy. There may be an overlap with pre-eclampsia. ^[3] Almost all cases begin in the third trimester. ^[3]

Laboratory features point towards synthetic failure: AST and ALT in the 300 to 500 international units per litre range (5 to 15 times normal), bilirubin 6 to 8 times normal, raised creatinine, ammonia, uric acid and lactate, low glucose, leukocytosis, reduced or normal platelets, hypofibrinogenaemia, prolonged prothrombin time and a raised D-dimer. ^[3] Disseminated intravascular coagulation occurs in roughly 70% of cases. ^[3] Liver ultrasound is insensitive, showing the classic bright liver in only 25%; CT is better but still only about 50%. ^[3] Biopsy is not required but helps in indeterminate cases. ^[3]

Right upper quadrant or epigastric pain, nausea and malaise, often without dramatic hypertension; 85% have hypertension and proteinuria. HELLP usually presents 28 to 36 weeks and can postdate delivery. ^[3]

The three pregnancy-specific liver disorders and acute viral hepatitis can look identical on a first pass. Use the clinical picture plus the pattern below.

Two extra points prevent errors. First, itch plus raised bile acids is ICP until every other cause of pruritus has been excluded, including dermatological and cholestatic disease. ^[3][2] Second, raised transaminases in severe pre-eclampsia can be the warning that HELLP is evolving, and worsening coagulopathy, hypoglycaemia or encephalopathy in that setting is AFLP until proven otherwise. ^[3]

Bile acids and LFTs (ALT, AST, bilirubin, GGT, PT) plus a full blood count and a urinary protein check. ^[3] Bile acids are the best single test because they can be abnormal when LFTs are normal; PT is normal unless vitamin K has been malabsorbed, in which case a vitamin K supplement is reasonable. ^{[3] [1]} Hepatitis C serology is recommended for all women with ICP if not already screened. ^[2]

Liver ultrasound is advised by ACG in all cases to exclude stones, but AASLD and RCOG recommend it only in selected cases such as atypical presentation, pruritus that does not fit, early onset, jaundice or persistently abnormal tests after delivery. ^[3] Screening for viral hepatitis and autoimmune liver disease should follow individual risk factors. ^[3]

Both are diagnosed clinically and by the pattern above. The non-invasive work-up includes LFTs, PT, fibrinogen, D-dimer, platelets, creatinine, ammonia, glucose, uric acid, lactate and an abdominal ultrasound to look for haematoma. ^[3] Liver biopsy is hazardous and unnecessary in classic disease, but can be useful in indeterminate cases to guide whether urgent delivery is needed. ^[3]

HELLP is defined by the Tennessee or Mississippi criteria.

AFLP is diagnosed with the Swansea criteria: six or more features in the absence of another explanation. ^[3]

• Vomiting, abdominal pain, polydipsia or polyuria, encephalopathy
• Bilirubin above 14 micromol/L, blood glucose under 4 mmol/L ^[3]
• Urea above 340 micromol/L, leukocytosis above 11 x 10^9 cells per L ^[3]
• AST or ALT above 42 units/L, ammonia above 47 micromol/L ^[3]
• Creatinine above 150 micromol/L ^[3]
• Coagulopathy: prothrombin time above 14 seconds or APTT above 34 seconds ^[3]
• Ascites or a bright liver on ultrasound
• Microvesicular steatosis on liver biopsy ^[3]

ICP is graded by peak bile acid concentration, and since bile acids fluctuate, the highest value ever recorded in that pregnancy is what counts.

• Mild ICP: peak bile acids 19 to 39 micromol/L ^[1]
• Moderate ICP: peak bile acids 40 to 99 micromol/L ^[1]
• Severe ICP: peak bile acids 100 micromol/L or more ^[1]

AASLD (as summarised) defines ICP as pruritus in the second or third trimester with total bile acids above 10 micromol/L and no other cause of pruritus. ^[2]

For monitoring, EASL advises measuring serum bile acids at least weekly from 32 weeks, and post-prandial sampling from 32 weeks identifies women at risk: concentrations of 40 micromol/L or more mark increased risk of adverse outcomes, and 100 micromol/L or more after 35 weeks is the point at which stillbirth risk rises and elective early delivery should be planned. ^[4] AASLD and EASL agree that bile acids, not liver enzymes and not cardiotocography, are the quantity that predicts fetal harm. ^[2][4]

^[1] Continuous electronic fetal monitoring in labour is advised when bile acids are above 100 micromol/L or other risk factors exist. ^[1]

Monitoring. Once diagnosed, the woman needs obstetric care, a plan individualised to her bile acid level and repeat blood tests. RCOG patient guidance notes that blood tests are repeated after a week. In practice most units repeat bile acids and LFTs at least weekly, and the EASL position is explicit about weekly bile acids from 32 weeks. ^[1][4] She should watch fetal movements closely and attend immediately for reduced movements.

First-line drug: ursodeoxycholic acid. UDCA is the only drug that every major body recommends. It works by replacing the endogenous hydrophobic bile acid pool with a more hydrophilic one and reduces maternal bile acid levels. ^[2][3] It is safe in pregnancy and breastfeeding. ^[2] Doses genuinely differ by guideline, so quote them as such rather than averaging. ^[3]

What UDCA actually does deserves an honest paragraph. RCOG says it may slightly reduce itching in a small number of women and that there is no treatment that helps the baby or makes bile acid levels better; RCOG also says it may reduce the chance of premature birth but does not prevent stillbirth. ^[1] EASL, by contrast, recommends offering UDCA when bile acids are 40 micromol/L or more because it reduces spontaneous preterm birth and may be protective against stillbirth, while acknowledging only a relatively small effect on symptoms. ^[4] The largest trial of UDCA found no benefit for maternal symptoms. ^[3] The fair reading is that guidelines differ: UDCA is safe and reasonable, helps a little with itch, lowers bile acids a little, probably reduces preterm birth, and may but does not clearly reduce stillbirth. ^[1][3][4]

Second-line and symptomatic measures. For pruritus that does not settle, rifampin, cholestyramine, S-adenosyl-L-methionine (SAMe), antihistamines and guar gum or activated charcoal are all mentioned somewhere; evidence for them is scant. ^[2][3][4] AASLD cites ursodeoxycholic acid as first-line and lists cholestyramine 4 to 16 g daily, rifampin 300 to 600 mg daily and SAMe 1000 to 1200 mg daily in its cholestatic disease section. ^[2] Cholestyramine should be separated from other drugs by at least 2 hours and patients on it need more frequent PT monitoring. ^[2] Antihistamines work best as night-time sedation and do not relieve the itch itself. ^[3] Topical emollients, cool baths and cotton clothing are safe comfort measures. ^[1][3]

Vitamin K 5 to 10 mg daily is recommended when the prothrombin time is prolonged, with more frequent PT monitoring in women on cholestyramine. ^[3][2]

Delivery plan. The timing table above is the core of modern ICP management. For a single uncomplicated pregnancy the threshold is 40 micromol/L, and for women at 100 micromol/L or more the recommendation is birth at 35 to 36 weeks. ^[1][4] RCOG frames individualised choice: induction of labour, planned caesarean or waiting for spontaneous labour, with informed consent. ^[1] ICP alone does not mandate caesarean section. ^[1] If bile acids are above 100 micromol/L or other risk factors exist, continuous fetal heart rate monitoring in labour is advised. ^[1]

What not to do. Antenatal cardiotocography and ultrasound do not predict or prevent stillbirth in ICP, so extra scans are not needed. ^[1]

AFLP is a liver-failure emergency. The management sequence is: maternal stabilisation first, then delivery, then intensive support.

• Correct hypoglycaemia, coagulopathy and hypertension before delivery, and replace factors and platelets as needed. ^[3]
• Expedite delivery once those are corrected; delivery is the only cure because the process continues until the fetus is delivered. ^[3][4]
• Mode of delivery is an obstetric decision made jointly by obstetricians, hepatologists and the multidisciplinary team. ^[4]
• Post-delivery, monitor LFTs, renal function and haematology every 6 hours for 24 to 48 hours. ^[3]
• Six or more Swansea criteria or MELD 30 or more, or a lactate above 2.8 mg per dl, or encephalopathy moves her to level 2 or 3 (intensive) care. ^[4]
• Plasma exchange after delivery may be considered in severe hepatic impairment; N-acetylcysteine can be considered for women needing intensive care. ^{[4] [3]}
• Refer early to a transplant centre for ongoing deterioration after delivery, severe hepatic impairment or hepatic rupture. ^[3][4]
• Screen all babies of AFLP mothers for LCHAD deficiency at birth and follow them up. ^[3][2]

Delivery is the only cure; once coagulopathy and severe hypertension are corrected, delivery should be expedited. ^[3][4] Antenatal corticosteroids should be given for fetal lung maturity if delivery will be before 35 weeks, but corticosteroids do not improve maternal outcomes and are not recommended for that purpose. ^[4] Platelet transfusion maintains counts above 40000 to 50000 cells per microlitre when bleeding or when caesarean section is needed. ^[3] Labetalol, nifedipine or methyldopa control hypertension; magnesium sulphate prevents seizures and neuroprotects under 32 weeks. ^[4] Transfer to a transplant centre if there are signs of hepatic rupture or acute liver failure. ^[4]

ICP. Preterm birth, meconium passage, fetal anoxia and stillbirth in the severe band; an association with pre-eclampsia and gestational diabetes; steatorrhoea and malabsorption of vitamin K; and maternal pruritus severe enough to disturb sleep. ^[1][3] CTG does not predict or prevent stillbirth. ^[1]

AFLP. Acute liver failure, DIC, postpartum haemorrhage, acute renal failure, gastrointestinal bleeding, hepatic rupture and hepatic infarction. Maternal mortality is under 10% now; fetal mortality up to 20%. ^[3]

HELLP. Hepatic haematoma and rupture, liver infarction, stroke, acute kidney injury, DIC, placental abruption and pulmonary oedema. Maternal mortality 1 to 3%; perinatal mortality 8 to 34%. ^[3]

ICP generally resolves within 4 to 6 weeks of delivery; LFTs and bile acids are rechecked at 6 weeks and persistent abnormalities need specialist investigation for primary biliary cholangitis, primary sclerosing cholangitis or genetic cholestasis. ^[3][1] Recurrence in a later pregnancy is common, up to 90%, and ICP is associated with cholestasis on the combined pill, gallstones and a small increase in hepatobiliary cancer risk. ^[3]

AFLP LFTs start falling within 1 to 2 days after delivery and normalise over 4 to 6 weeks; the course is usually self-limiting and uncomplicated. ^[3] Recurrence occurs in a minority of future pregnancies and may be milder; all children need LCHAD screening. ^[3]

HELLP laboratory values should start improving within 48 hours of delivery and recurrence in a future pregnancy is probably 2 to 6%. ^[3]

Pregnancy with twins or triplets, gestational diabetes and pre-eclampsia each raise stillbirth risk independently of ICP and should lower the threshold for earlier birth planning. ^[1] Women whose previous cholestasis was triggered by the combined pill should use progestogen-only or non-hormonal contraception until bile acids and LFTs are normal. ^[3] Mothers with AFLP pass on a recessive condition, so counselling includes testing the partner and prenatal or newborn screening.

A hand-held diagnosis is possible. Any pregnant woman with late-pregnancy itch and no rash needs at minimum a bile acid level or, if that is impossible, LFTs repeated if normal. ^[1][3] UDCA at 10 to 15 mg per kg per day is a simple tablet and is safe; if it is unavailable, antihistamines for sleep, emollients and timed delivery still apply. ^[2][3] If the only available laboratory is in a referral hospital, transfer before the bile acid result rather than waiting. For AFLP and HELLP, the essentials are early recognition, correction of glucose and clotting, magnesium for hypertension and transfer to intensive care and a transplant-capable centre, since delivery without supportive care is not enough. ^[3][4]

• ICP is the commonest pregnancy-specific liver disease: pruritus without a rash, usually from the third trimester, with rising bile acids; prevalence 0.3% to 5% worldwide and about 0.7% in the UK.
• Severity is set by peak bile acids: mild 19 to 39, moderate 40 to 99, severe 100 micromol/L or more. Only severe ICP increases stillbirth risk.
• Bile acids are the diagnostic and prognostic test in ICP; LFTs can be normal and cardiotocography does not predict stillbirth.
• UDCA is first-line at roughly 10 to 15 mg per kg per day by ACG and AASLD, 10 to 20 by EASL and up to 25 by EASL titration; it is safe, gives a small symptomatic benefit and lowers bile acids, with probable reduction in preterm birth and a possible but uncertain effect on stillbirth. ^[2][3]
• Other anti-pruritics (rifampin, cholestyramine, SAMe, antihistamines) have limited evidence; vitamin K 5 to 10 mg daily if PT is prolonged.
• Delivery timing by bile acid band: 40 weeks for mild, 38 to 39 weeks for moderate, 35 to 36 weeks for severe; individualise for multiples, diabetes and pre-eclampsia.
• HELLP syndrome occurs in up to 0.9% of pregnancies, usually at 28 to 36 weeks, and is defined by haemolysis, elevated LFTs and platelets under 100 x 10^9 per L; incomplete forms exist.
• AFLP is a third-trimester acute liver failure emergency, incidence about 1 in 7000 to 1 in 20000, linked to fetal LCHAD deficiency, diagnosed by the Swansea criteria (six or more), and cured only by delivery with intensive support.
• AFLP and HELLP differ most by synthetic liver failure in AFLP (coagulopathy, hypoglycaemia, hypofibrinogenaemia) versus haemolysis and hypertension in HELLP.
• Postnatal resolution is the rule in ICP (4 to 6 weeks) and in AFLP; recheck LFTs and bile acids at 6 weeks and screen AFLP babies for LCHAD deficiency. ^[1]

Pruritus and pregnancy, liver disease in pregnancy, pre-eclampsia, eclampsia, HELLP syndrome, hyperemesis gravidarum, gestational diabetes, multiple pregnancy. Plain-text references are given because this topic is published before its companion topics.