Continuing Education Activity

Acute fatty liver in pregnancy (AFLP) is an obstetric emergency and carries high morbidity and mortality, including death in the mother and her fetus. It is characterized by maternal liver failure. Maternal mortality has decreased to 4% in recent years due to quicker diagnosis and immediate delivery. AFLP is not a predictable or preventable condition. Liver failure, coagulopathy, hemorrhage, renal failure, and severe infection can be lethal for both the mother and fetus. This activity outlines the pathogenesis, evaluation, and management of this disease.

Objectives:

• Describe the pathophysiology of fatty liver in pregnancy.
• Review the typical presentation of acute fatty liver in pregnancy and the laboratory findings associated with it.
• Explain the evaluation and management of patients presenting with signs and symptoms of fatty liver in pregnancy.
• Outline the importance of a team-based approach and the collaboration and coordination among the interprofessional team for the management of patients with acute fatty liver of pregnancy.

Introduction

Pregnancy-related liver disease includes several distinct liver disorders that affect different stages of pregnancy; these include acute fatty liver of pregnancy, pre-eclamptic liver dysfunction, and hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP). 

Acute fatty liver of pregnancy is a relatively rare complication of pregnancy, with an incidence of approximately 5 cases per 100000 pregnancies.[1] It usually presents in late pregnancy and can result in maternal or fetal complications. It is characterized by acute liver dysfunction due to fatty infiltration of liver parenchyma, which can precipitate coagulopathy, electrolyte imbalance, and multi-organ failure. Early recognition and treatment of this disease entity are essential as it carries high morbidity and mortality. Along with supportive care for the mother, delivery of the fetus is the only definitive treatment of this condition.

Etiology

Defects in fatty acid metabolism during late pregnancy are thought to play a role in the pathogenesis of acute fatty liver of pregnancy, although the pathogenesis of this disease remains poorly understood. During late pregnancy, free fatty acids increase, to support fetoplacental growth. The thinking is that in the presence of defects related to the metabolism of these fatty acids, they accumulate in hepatocytes, and cause cellular damage.[2] Long-chain 3 hydroxy acyl CoA dehydrogenase (LCHAD) deficiency is the most important of these metabolic defects, and 20 percent of all cases of acute fatty liver in pregnancy is associated with a deficiency of this enzyme.[3] Homozygous G1528C mutation appears to be most commonly associated with AFLP, although other mutations in this enzyme, as well as mutations in other enzymes that metabolize free fatty acids, can lead to AFLP as well.[2][4]

Epidemiology

Acute fatty liver of pregnancy is a rare complication of pregnancy, and various studies have estimated that it affects 1 in 7,000 to 20,000 pregnancies.[5][6]  A host of conditions have been shown to be associated with a potentially increased risk of developing AFLP. Feta long-chain 3 hydroxy acyl CoA dehydrogenase deficiency, as mentioned above, is the most important of these predisposing conditions. Other proposed risk factors include[7][3][8][1][8][3][7]:

• History of AFLP in a previous pregnancy
• HELLP syndrome and preeclampsia
• Multiple gestations
• Male fetus

Histopathology

Histological appearance of the liver is consistent with micro-vesicular fatty infiltration of hepatocytes in patients with AFLP. A foamy appearance of cytoplasm is observable, as the fat surrounds the nuclei intracellularly. Around the portal tracts, sparing of a rim of cells can be observed; the central and mid zonal parts of the liver demonstrate characteristic infiltration.[9]

History and Physical

Pregnant women with acute fatty liver of pregnancy present in the third trimester, usually between 30 and 38 weeks of gestation.[10] Symptoms include nausea, vomiting, anorexia, and abdominal pain — some patients present with hypertension and proteinuria, usually as a consequence of concurrent HELLP syndrome or pre-eclampsia. Acute liver failure; characterized by jaundice, ascites, coagulation disorders, and confusion, develops rapidly and can result in multi-organ failure.

A physical examination can reveal jaundice, abdominal tenderness, and confusion, and is otherwise generally unrevealing.

Evaluation

In patients presenting with the above clinical findings in pregnancy, suspected of having acute fatty liver of pregnancy, require a thorough workup, including a complete blood count, liver function tests, aspartate and alanine aminotransferase levels, creatinine, and urine protein assessment.

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT), are always elevated in patients with AFLP. Other laboratory abnormalities can include elevated serum bilirubin, hypoglycemia, and low platelets. Elevated ammonia and white blood cell count may be present. Coagulopathy may be present, which manifests as prolonged prothrombin time and international normalized ratio, and low fibrinogen.

Radiological examinations are usually non-diagnostic. Imaging may support the diagnosis but is not required to diagnose AFLP. Ultrasound examination of the liver may be non-specific or may reveal fatty infiltration in some cases.[11] Computed tomography (CT) scan and magnetic resonance imaging may also reveal fatty infiltration in the liver. CT scan is inappropriate in pregnancy due to teratogenicity linked with radiation exposure.

Liver biopsy is generally not necessary or indicated. In patients with clinical and laboratory findings consistent with AFLP, prompt resuscitation, and management, as discussed below, should be initiated without confirming the diagnosis with a biopsy. It may rarely be necessary in cases where the liver function does not normalize post-partum, or rarely in very early stages of AFLP in cases of a questionable diagnosis to make a definitive diagnosis which would justify prompt delivery.

In patients who are found to have liver dysfunction, other causes of liver dysfunction, including viral hepatitis, drug-induced liver dysfunction, and acetaminophen poisoning should be ruled out. A presumptive diagnosis of AFLP is possible in a pregnant female with characteristic symptoms who found to have significant liver dysfunction after ruling out other etiologies. It may be challenging to differentiate AFLP from HELLP syndrome or severe preeclampsia in some cases, but the clinical management is largely the same for these disorders, so the management should not be delayed to form a definitive diagnosis.

The “Swansea criteria” have been proposed and validated in a large cohort in the United Kingdom for the diagnosis of ACLF.[1] These criteria comprise symptoms and laboratory findings. When applied to a group of women who subsequently underwent liver biopsies, they had a positive and negative predictive value of 85% and 100% respectively.[12] 6 or more of the following criteria are needed in the absence of another known cause of liver dysfunction to establish a diagnosis by the Swansea criteria.[13]

1. Vomiting
2. Encephalopathy
3. Polydipsia/polyuria
4. Abdominal pain
5. Elevated bilirubin (over 0.8 mg/dL or 14 micromol/L)
6. Hypoglycemia (less than 72 mg/dL or 4 mmol/L)
7. Leukocytosis (over 11000 cells/microL)
8. Elevated transaminases (AST or ALT) (greater than 42 international unit/L)
9. Elevated ammonia (over 47 micromol/L)
10. Elevated uric acid (above 5.7 mg/dL or 340 micromol/L)
11. Acute kidney injury, or creatinine over 1.7 mg/dL or 150 micromol/L
12. Coagulopathy or prothrombin time greater than 14 seconds
13. Ascites or bright liver on ultrasound scan
14. Microvesicular steatosis on liver biopsy

Treatment / Management

Supportive resuscitation and prompt fetal delivery remain the cornerstone of therapy. American College of Gastroenterology clinical guideline recommends prompt delivery for AFLP.[3] Expectant management is not appropriate (strong recommendation, very low level of evidence).[3]

Maternal supportive care and stabilization should be initiated first, with correction of electrolyte disturbance, and therapy for hypoglycemia, coagulopathy, and hypoglycemia. Frequent maternal and fetal evaluation is necessary; including continuous monitoring of fetal heart rate. Fluid replacement should take place if needed.

The delivery route depends on the presence of fetal or maternal decompensation and/ or the presence of other contraindications to vaginal birth. Vaginal delivery and labor induction can be done if no contraindications exist. However, cesarean delivery has to be performed in many cases due to maternal or fetal distress and deterioration. If a cesarean delivery is necessary, platelet transfusions may be necessary as current guidelines recommend transfusions to a level of 40000 to 50000.[3] Magnesium sulfate is administered in pregnancies less than 32 weeks to prevent neonatal cerebral palsy.

After delivery, the patient will require monitoring for bleeding, hypoglycemia, or renal dysfunction. If hepatic dysfunction does not abate rapidly after pregnancy, liver transplantation should be a considered approach, as it may prove life-saving.[14][15] The child of AFLD affected mother should undergo molecular testing for LCHAD deficiency, as well as close monitoring for its manifestations, including hypoglycemia and fatty liver.

Differential Diagnosis

Acute fatty liver of pregnancy sometimes presents as a diagnostic challenge, as it may be challenging to differentiate from HELLP syndrome and preeclampsia with severe features. There is a significant overlap between these disease entities, and in fact, they may co-exist in the same patient. 

Signs of liver failure such as coagulopathy and disseminated intravascular coagulation and hypoglycemia are more consistent with AFLP as compared to HELLP or preeclampsia. Transaminase levels and hyperbilirubinemia is also more severe in AFLP. 

Prognosis

In most cases of acute fatty liver of pregnancy, complete resolution, and liver function normalization occur within one week to 10 days after delivery.[6] Maternal mortality rates have now decreased to less than 5 percent from more than 75% in the past.[16][17]

Complications

Acute fatty liver of pregnancy can precipitate pulmonary edema, due to the decrease in plasma oncotic pressure. Its prevalence has been estimated at 14% of patients with AFLP.[6] Liver failure can also be associated with pancreatitis, disseminated intravascular coagulation and metabolic acidosis leading to maternal or fetal deterioration that can prove fatal. Hence, prompt diagnosis and delivery after maternal stabilization are necessary. 

Deterrence and Patient Education

Patients with acute fatty liver of pregnancy and their infant should undergo testing for LCHAD deficiency. Patients should receive counseling that AFLP can still occur in subsequent pregnancies even if testing for LCHAD is negative, and therefore, patients planning another pregnancy can potentially benefit from a specialist referral. 

Pearls and Other Issues

• Acute fatty liver of pregnancy (AFLP) is a moderately rare complication of pregnancy that affects women in the third trimester of pregnancy and characteristically presents with microvesicular fatty infiltration of the liver.
• Predisposing factors include LCHAD deficiency, male fetus, history of AFLP, and multiple gestations. 
• Acute fatty liver of pregnancy is a clinical diagnosis, in the presence of liver dysfunction after 20 weeks of pregnancy with supporting clinical and laboratory findings. 
• AFLP can lead to rapid liver failure with coagulopathy, encephalopathy, and hypoglycemia.
• Supportive management and prompt delivery are the cornerstones of therapy.
• Most patients recover completely after delivery, and the liver function returns to normal in 7 to 10 days.
• The affected mother and infant should undergo molecular testing for LCHAD deficiency. 

Enhancing Healthcare Team Outcomes

Diagnosis and management of AFLP are complex and should involve an interprofessional team; this is a true obstetric emergency which if not treated promptly can lead to the loss of two lives. The interprofessional team comprising an obstetrician, hepatology service, and critical care trained physicians should be involved.

Because there may be a need for an emergent cesarean section, the anesthesiology staff require notification. The operating room personnel and the NICU nurses should be informed of the emergency and the nurses should monitor the patient, reporting to the clinical team changes. Labor and delivery nurses, including clinicians, must ensure that the patient is hemodynamically stable, hydrated, and ready for delivery. Nurses and clinicians should educate the family members of the seriousness of this disorder and not give unrealistic expectations.

The blood bank should be notified, and the neonatology team must be on standby. There is no room for expectant management of these patients; if the mother is stable vaginal delivery may be undertaken; otherwise, a cesarean section is recommended.  Following delivery, the mother has to be managed in an ICU setting to ensure that there is no coagulopathy. The infant should receive care in the NICU.

Pharmacy staff needs to also remain on standby, conducting medication reconciliation and providing the required medications for surgery and post-surgical care, verifying dosing, and informing the team of any interactions or discrepancies.

In this manner, the entire interprofessional healthcare team functioning as a collaborative unit can provide optimal care for acute fatty liver of pregnancy and drive patient outcomes for both mother and child. [Level 5]

Outcomes

As the outcome of AFLP is time-sensitive in many cases, a multispecialty team-based approach with effective communication is key to the efficient management of these patients.