Authors: S Griffiths MBBS FRCA; C Nicholson MBChB (Otago) FRCA
BJA Education. 2016;16(1):21-25.
Liver disease in pregnancy is not common but can be a significant cause of maternal and fetal morbidity and mortality, frequently appearing in the triennial confidential enquiries ( Table 1 ). Fulminant hepatic failure is very rare and poses major challenges to the anaesthetist, although it is more common to see women with varying degrees of liver dysfunction, classically considered as occurring specific to pregnancy and incidental to pregnancy. The obstetric anaesthetist may be involved with the care of these women either at delivery or during an admission to the obstetric high dependency unit (HDU)
Hepatic Physiological Changes in Pregnancy
Normal pregnancy induces physiological and biochemical changes because of an increase in oestrogen and progesterone. The upper limit of the normal range for transaminases is reduced by about 25% in all three trimesters, while alkaline phosphatase (ALP) tends to increase in the third trimester due to placental production. Changes in liver function are also present in the postnatal period with increases in both transaminases and γ-glutamyltransferase (GGT). These normal changes must be distinguished from abnormalities seen with liver disease. Clinically, it can be difficult to differentiate stigmata of liver disease, such as spider naevi and palmer erythema, as these features may be seen in healthy pregnant women in response to increased oestrogen levels.
The likely diagnosis of a woman presenting with new hepatic dysfunction in pregnancy was reported by Ch’ng and colleagues (Table 2). In advanced liver disease, the liver is unable to synthesis enzymes such that a wide range of abnormal liver function may be seen at diagnosis. A differential diagnosis of liver dysfunction should always be considered as the presenting features may be confusing leading to misdiagnosis
Hepatic Disorders Specific to Pregnancy
Most women will present with disorders specific to pregnancy and of those women requiring intensive care admission, one study showed that 7% were related to the syndrome of haemolysis, elevated liver enzymes, and low platelets (HELLP), while 3% were due to acute fatty liver of pregnancy (AFLP).
Hypertensive Disorders: Pre-eclampsia, Eclampsia, HELLP Syndrome
The high maternal mortality associated with pre-eclampsia (PET) and eclampsia is reducing. HELLP syndrome, a severe form of PET, affects 4–20% of women with PET. The condition usually presents in the late third trimester but can also present post-partum. Maternal mortality is <1%, but the condition makes up a disproportionate number of maternal deaths in the confidential enquiries. Patients should be managed in an HDU setting as the syndrome is unpredictable and can progress slowly or rapidly.
Clinical features include ‘hepatic angina’ (epigastric or right upper quadrant pain) that may precede deranged liver function and it is worth repeating blood tests due to this delay. Patients may present with symptoms suggestive of pulmonary embolus, that is, they may complain of chest pain and have tachypnoea due to an associated metabolic acidosis. Nausea and vomiting is common, while hypertension and proteinuria may only be mild. The low-grade haemolysis is not usually severe enough to cause anaemia. Low or decreasing platelets must be monitored. Disseminated intravascular coagulation occurs in about 20% of cases. Acute renal failure is more common in HELLP syndrome than in other forms of PET. Morbidity is often associated with acute kidney injury but is also higher the lower the platelet count. A platelet transfusion is only required if the patient is actively bleeding, to permit insertion of invasive lines or operative delivery. Other complications include placental abruption, pneumonia, liver haematoma, pulmonary oedema, and intracerebral haemorrhage.
Treatment is that for severe PET, that is, to stabilize the patient and deliver the fetus. Timing of delivery is usually a balance between reducing maternal risk with fetal risk from a premature delivery. Liver function usually recovers before the thrombocytopenia.
Hepatic haematoma or rupture are rare complications that are associated with high mortality (16–60%). Cardiovascular shock is present in half of these patients. Patients with HELLP syndrome complaining of right upper quadrant pain must be scanned (ultrasound, CT, or MRI) to make a rapid diagnosis. Treatment may involve interventional radiology or surgery.
Acute Fatty Liver of Pregnancy
This condition is arguably a variant of pre-eclampsia tending to present in the late third trimester. AFLP is more common in women with multiple pregnancies and lower BMI, and women with the condition are more likely to have children with disorders of β-fatty acid oxidation. AFLP is of particular importance as it is associated with high maternal mortality with recent confidential enquiries reporting on average one death per year. A recent UKOSS study suggests management is improving with 60% of women admitted to an intensive therapy unit (ITU) and a mortality rate of <2% or five cases per 100 000 for their case series of 57 patients. Perinatal mortality is high reported to range between 20% and 50%. As it is a rare but significant cause of maternal mortality, it is worth developing a protocol for the management of these women.
The diagnosis of AFLP is made when at least six of the clinical features described by the Swansea criteria are present in the absence of another explanation (Table 3). Imaging with CT or MRI, a liver biopsy or fat stain may support this. Women will often complain of feeling unwell for a few weeks before presenting usually with non-specific symptoms such as nausea, vomiting, and malaise. There may be associated hypertension and proteinuria. Pruritus should not be confused with obstetric cholestasis. Renal impairment develops in about 90% of patients. Fulminant hepatic failure can occur and patients may develop hepatic encephalopathy, coagulopathy, and profound hypoglycaemia. Metabolic acidosis and elevated lactate are not part of the diagnostic criteria but are also important features. Pancreatitis and adult respiratory distress syndrome are other rare complications.
Delivery must be expedited once the patient is stabilized due to the high fetal mortality. Specific concerns for the anaesthetist are to correct hypoglycaemia and coagulopathy before delivery. Platelet function tends to remain stable unlike in HELLP syndrome. Uneventful regional anaesthesia has been reported and may improve hepatic blood flow, but the technique is often precluded by the presence of coagulopathy.
Symptoms can deteriorate post-partum with worsening liver, renal function, and coagulopathy for 48 h and as such patients require careful management of the complications.
Pregnancy can cause an impairment in the excretion of bile acids causing pruritis typically affecting hands and feet that can be severe but rarely requires admission to an obstetric HDU. Vitamin K malabsorption can occur and patients require an assessment of coagulation before proceeding with regional anaesthesia. Neuraxial opioids may worsen pruritis but this must be balanced against the need for effective pain control. Obstetric cholestasis can be a marker of other liver disease, such as AFLP or hepatitis, and therefore, the collection of symptoms should be considered.
Hepatic Disorders Incidental to Pregnancy
Hepatic disorders that occur incidental to pregnancy are much less common than gestational-related conditions. Nevertheless, when women do present with these problems, they can be a significant cause of maternal morbidity and mortality. Pre-pregnancy counselling should be offered to all women with established severe liver disease.
Viral hepatitis is the most common cause of hepatic dysfunction and jaundice in pregnancy worldwide. A number of viruses can cause hepatitis including hepatitis A, B, C, D, E, and G, along with herpes simplex virus (HSV), cytomegalovirus, and Epstein–Barr virus. Hepatitis B affects about 350 million people globally and nearly 5% of the population are chronic carriers of hepatitis B with one-quarter of these patients at risk of serious liver disease, including cirrhosis and hepatocellular cancer. Vertical transmission to the fetus can be reduced with active and passive immunization. Hepatitis C by comparison is less common.
The clinical features are no different from the non-pregnant population (fever, nausea, jaundice) except for those infections caused by hepatitis E and HSV that have a worse course in pregnant women. Pregnant women are more likely to develop acute viral hepatitis than non-pregnant women, with the majority of women having hepatitis E. Hepatic encephalopathy and hepatorenal syndrome caused by viral hepatitis have a higher incidence during pregnancy. Fulminant hepatic failure in the context of hepatitis E is more common in pregnancy with a mortality rate of about 30%. There is an associated high rate of obstetric complications with premature rupture of membranes, intrauterine growth restriction, and premature delivery and also a high rate of perinatal mortality through vertical transmission. A high viral load is associated with a worse prognosis.
Herpes simplex is a rare cause of viral hepatitis accounting for <1% of acute viral hepatitis in pregnant women. Typically, women will present with a prodromal illness of fever and respiratory or gastrointestinal symptoms. Patients can have very high levels of aminotransferases and develop a coagulopathy. Oral or genital lesions are absent in about 50%of cases. Treatment is with acyclovir and liver transplant has been reported in pregnancy.
As with manyother autoimmune conditions, autoimmune hepatitis (AIH) generally improves during pregnancy. Management is with immunosuppressive therapy and it is important this is continued throughout the pregnancy. Azathioprine, cyclosporine, and tacrolimus are considered safe, whereas mycophenalate is teratogenic and contraindicated. In the absence of cirrhosis, maternal and fetal outcomes are usually favourable.
Drug-induced Liver Injury
If the cause of liver disease is uncertain, drug-induced liver damage should always be considered. The pattern of injury may help to ascertain the causative agent. Paracetamol, methyldopa, and highly active antiretroviral therapy can cause hepatocellular damage with raised transaminases and sometimes elevated bilirubin. Acholestatic picture with raised ALP and GGT can be due to oestrogens, progesterones, amoxicillin, and psychotropic drugs. A mixed picture with both hepatocellular and cholestatic damage may implicate trimethoprim, nitrofurantoin, or carbamazapine.
Cirrhosis, Portal Hypertension, and Oesophageal Varices
Women with cirrhosis rarely become pregnant, but when they do, there is an associated high mortality rate of up to 10%. Portal hypertension worsens during pregnancy and oesophageal varices present a major risk for bleeding. This may be as high as 90% if diagnosed during pregnancy decreasing to 10% if the varices are treated beforehand with banding or sclerotherapy. Concerns over variceal rupture due to the increased venous pressure associated with straining in labour often make Caesarean section the preferred mode of delivery. Other complications of cirrhosis in pregnancy include decompensation, ascites, hepatic encephalopathy, and maternal death. Prognosis can be predicted using a scoring system consisting of the most recent serum bilirubin, creatinine, and international normalized ratio (INR) measurements before pregnancy.
Women who have successfully undergone a liver transplant can be treated as healthy parturients, providing their liver function and coagulation is normal. Outcomes are generally favourable with a 70% live birth rate; however, the incidence of pre-term delivery, low birth weight, PET, and gestational diabetes are increased. Immunosuppression must be continued throughout the pregnancy and the teratogenic risk appears low with commonly used agents. The potential for side-effects complicating anaesthesia such as neuropathy or electrolyte imbalance must also be considered. Pregnancy in the context of graft rejection is uncommon and outcomes are poor.
Budd–Chiari syndrome is characterized by hepatic venous outflow obstruction and presents with ascites and hepatomegaly with or without right upper quadrant pain.
In 75% of cases is due to thrombosis for which pregnancy is a risk factor. The same prothrombotic conditions that predispose to Budd–Chiari make early fetal loss common.
Management of Liver Disease During Pregnancy
Pregnant women with severe hepatic disease will require an individualized care plan with multidisciplinary team (MDT) input and HDU/ITU care. Liaise early with your nearest liver unit before significant complications develop. Patients must be monitored carefully for complications and part of the role of the obstetric anaesthetist is to identify patients at risk of developing fulminant hepatic failure. Low-grade encephalopathy may be subtle with irritability, forgetfulness, and sleep disturbance. In advanced liver disease, pseudonormalization of liver enzymes may occur and will not correlate with a clinical improvement. Worsening synthetic liver function may be indicated by prolonged INR, hypoglycaemia, hypoalbuminaemia, and a lactic acidosis. If a patient develops fulminant hepatic failure or encephalopathy, the nearest liver unit will need to be contacted for consideration of liver transplantation. Consider involving haematologists when treating an associated coagulopathy. N-acetylcysteine improves outcomes in non-pregnant acute liver failure and while its use in pregnancy is unproven, there is no evidence it causes harm. Decisions regarding timing and mode of delivery will require MDT input with a careful evaluation of the risks to the mother of continuing with the pregnancy.
Prediction of Deterioration of Liver Function
A retrospective analysis by Westbrook and colleagues of 54 intensive care admissions with severe liver disease found there were four deaths associated with the 18 admissions due to AFLP and three deaths in the subgroup of 32 patients with hypertensive-related disease. The overall survival rate for the cohort was 87%. The authors found that the best predictor for deterioration necessitating liver transplant or resulting in death were a lactate >2.8 mg dl−1 in combination with encephalopathy.
Specific Anaesthetic Considerations
The anaesthetic considerations for patients with liver disease have been described previously. Advanced liver disease alters the body’s handling of drugs as there are changes to protein binding secondary to reduced synthesis, impaired metabolism, and modified excretion. An associated impaired renal function may also delay excretion of drugs. These all act to prolong drug half-lives, but this has few practical implications for the conduct of general anaesthesia for Caesarean section where multiple dosing or prolonged infusions are rare. Relatively normal doses are thus required for induction of anaesthesia.
The action of thiopental is terminated by redistribution so is a safe choice as an induction agent. Propofol has normal pharmacokinetics in cirrhosis, does not reduce hepatic blood flow, and is an acceptable alternative. Succinylcholine is safe to use and prolonged neuromuscular block due to reduction in plasma cholinesterase is not clinically significant. Atracurium and cisatracurium are the non-depolarizing neuromuscular blocking agents of choice. The duration of action of rocuronium is unpredictable in the presence of liver disease and may be prolonged however can still be reversed with sugammadex. Isoflurane, sevoflurane, desflurane, and nitrous oxide are all safe and the anaesthetist should use what they are familiar with. Non-steroidal anti-inflammatory drugs are best avoided due to the high incidence of concomitant renal dysfunction and gastrointestinal bleeding. Morphine can be given in a standard dose and whilst prolonged metabolism may increase its duration of action, this should not preclude administration for treatment of break-through pain. Oxytocin, ergometrine, and carboprost all undergo hepatic metabolism but should be given in the standard dose for control of uterine haemorrhage. The i.m. route should be used with caution in the presence of coagulopathy. There are no contraindications to intraoperative cell salvage specific to non-oncological liver disease and its use should be encouraged where available. Infusions of propofol and fentanyl are suitable for sedation of intubated patients.
Regional anaesthesia is not contraindicated in the presence of liver disease but needs careful consideration of the risks and benefits to the mother. In rapidly progressive or advanced disease, the presence of coagulopathy in conjunction with the need for resuscitation and organ support often make regional techniques unsuitable. In mild or stable disease, laboratory tests of coagulation maybe minimally affected and mothers may be procoagulant on functional testing as demonstrated by thromboelastography (TEG). While TEG is useful for guiding administration of blood products, its role in assessment of safety for regional anaesthesia is less defined. The presence of gestational hyperfibrinogenaemia is reassuring. The decision to performneuraxial techniques in the presence of borderline values for platelet count and INR should always be undertaken by an experienced anaesthetist who should themselves perform the procedure and may wish to consider administration of replacement blood components immediately before siting.
Epidural analgesia in labour should be reserved for mild, stable disease, so catheter removal can be undertaken without further intervention and to avoid toxicity from local anaesthetics which all undergo hepatic metabolism.
Liver disorders are a relatively rare complication during pregnancy. Patients presenting with new liver dysfunction may have non-specific symptoms and a broad differential diagnosis should be maintained. The most common causes of serious morbidity are pregnancy-specific, namely HELLP syndrome and AFLP. Management for all hepatic disorders that require admission to HDU/ICU should involve an MDT.
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