Acute Fatty Liver of Pregnancy (AFLP)

1. What every clinician should know

Clinical features and incidence

Acute fatty liver of pregnancy (AFLP) is a rare complication (1 in 7,000-20,000 pregnancies) of the third trimester of pregnancy. The hallmark of this disorder is evidence of acute liver failure leading to coagulopathy and renal insufficiency. The liver failure is due to mitochondrial fatty acid beta-oxidation, leading to fatty infiltration of hepatocytes. The most common presenting symptoms include nausea, vomiting, epigastric abdominal pain, anorexia and jaundice. Preeclampsia commonly accompanies AFLP (in approximately half of patients), but is not necessary for the diagnosis of AFLP.

Risk factors

The disorder is more likely to develop in underweight patients, nulliparas and with multiple gestations. An association between maternal AFLP and abnormal fatty oxidation is well described. Fetuses who are homozygous for long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency will lead to additional fetal long-chain fatty acids entering maternal circulation. This load may overwhelm maternal hepatic capacity (she by definition is heterozygous for the same LCHAD deficiency) and result in fat deposition and hepatic failure. In patients diagnosed with AFLP, up to 19% of their fetuses will have LCHAD deficiency.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

Patients with AFLP commonly offer a several-week history of malaise, nausea, vomiting, headache and abdominal pain. Other signs and symptoms include evidence of coagulopathy with gastrointestinal, surgical site, pelvic or IV site bleeding, edema, hypertension, oliguria and mental status changes. Jaundice is clinically evident once the bilirubin exceeds 2-3 mg/dL. When suspected clinically in a patient presenting with these symptoms, laboratory testing is indicated to confirm the diagnosis.

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The diagnosis is confirmed by laboratory tests that confirm liver failure: hyperbilirubinemia, elevated transaminases, elevated serum ammonia, severe hypoglycemia, prolonged PT/PTT, hypofibrinogenemia, antithrombin III deficiency and renal insufficiency. Coagulopathy develops as the liver fails to produce adequate amounts of vitamin K-dependent clotting factors and fibrinogen. The PT will become abnormal before PTT prolongation. Hypoglycemia results from impaired glycogenolysis in the liver. Initial lab tests should consist of a CBC, creatinine and electrolytes, AST, ALT and bilirubin. If these are abnormal, additional testing should include PT/PTT, fibrinogen, antithrombin III, ammonia, serum lactate, amylase and lipase.

Initial laboratory tests to be drawn should include the following:

Complete blood count: exclude HELLP(hemolysis, elevated liver enzymes, and low platelets) syndrome; white count may be elevated.

Transaminases: usually less than 500U/mL; AST levels typically higher than ALT levels.

Alkaline phosphatase:elevated up to 10-fold.

Electrolytes: abnormalities vary based on renal function and volume depletion.

Bilirubin: direct hyperbilirubinemia, elevated 3-15 mg/dL.

Blood sugar: Moderate to severe hypoglycemia.

Creatinine: elevated usually greater than 2 mg/dL

Ammonia: elevated

Viral hepatitis serology: negative for hepatitis A, B and C.

Diabetes insipidus is reported in up to 10% of cases. If present, hypernatremia and polyuria will be noted.

Computed tomography, MRI and ultrasound imaging of the liver are nonspecific for confirming the diagnosis of AFLP. However, imaging assists in excluding other potential causes of hepatic failure such as obstruction, infarct or hematoma. A description of fatty infiltration of the liver is not indicative of AFLP. Fatty infiltration of the liver (steatosis) is identified in approximately one third of the general population, but may be found in 80% of obese patients.

Liver biopsy will differentiate AFLP from other causes of hepatic failure. However, most cases can be diagnosed clinically without the need for biopsy and the potential risks this procedure entails. Routine liver biopsy to confirm the diagnosis is not recommended. If biopsy is performed, the presence of microvesicular fatty infiltration is the hallmark. Additional studies (electron microscopy or oil red O on frozen section) on the tissue sample may also assist in diagnosis if the initial evaluation is nondiagnostic.

Differential diagnosis

When elevated liver enzymes are identified in a pregnant patient, the differential diagnosis should include HELLP syndrome, intrahepatic cholestasis or a non-obstetric hepatic process such as hepatitis or obstruction. Hemolytic uremic syndrome or thrombocytopenic purpura may also be considered in the differential but are also rare.

HELLP syndrome shares a number of overlapping features with AFLP. Features common to both diagnoses include elevated transaminases, elevated creatinine, proteinuria and hypertension. Hyperbilirubinemia is possible in HELLP syndrome due to hemolysis; however, it rarely exceeds 2 mg/dL. Thrombocytopenia is generally not seen in AFLP unless the patient develops hemorrhage. Coagulopathy is a hallmark of AFLP, but does not typically occur in HELLP syndrome in the absence of hemorrhage or abruption. Hypoglycemia and encephalopathy are unique to AFLP and not HELLP syndrome. Both will demonstrate resolution after delivery.

Intrahepatic cholestasis is a more common diagnosis during pregnancy. Elevated transaminases and hyperbilirubinemia are possible with this disorder; however, the characteristic pruritus with cholestasis is not found in AFLP. Coagulopathy and hypoglycemia are also not expected with cholestasis.

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) may present similarly to AFLP with renal insufficiency, thrombocytopenia, mental status changes and microangiopathy. In this case, HUS and TTP are distinguished by the absence of coagulopathy as demonstrated by a normal fibrinogen, PT and antithrombin III levels. The degree of renal insufficiency is typically more severe in patients with HUS or TTP.

Viral hepatitis should also be considered. Patients with acute viral hepatitis often have transaminase levels that are much higher than AFLP (exceeding 1000 U/L) in addition to hyperbilirubinemia. Coagulopathy is possible, depending on the degree of hepatic dysfunction. It is easily distinguished from AFLP once viral serology studies are obtained.

Biliary obstruction may lead to symptoms of pain, nausea, vomiting, malaise and elevated transaminases and hyperbilirubinemia. Imaging of the upper abdomen with ultrasound or CT should identify an obstructive process, most commonly cholelithiasis. This rarely results in hepatic dysfunction to a degree that coagulopathy or hypoglycemia would be expected.

Consultation with maternal fetal medicine and hepatology or gastroenterology subspecialists is recommended if the diagnosis is suspected. Once diagnosed, the patient may require admission to an intensive care unit.

3. Management

A definitive treatment for AFLP is not known. Initial management should focus on maternal stabilization. Clinicians may be falsely reassured by laboratory values that do not adequately reflect disease severity, such as mildly elevated transaminases. Consideration should be given to admitting the patient to an intensive care unit, depending on her condition.

Management consists primarily of delivery in conjunction with maternal supportive therapy. The condition is reversible following delivery, but may take several weeks until complete resolution. Frequent assessment of maternal condition and vital signs is mandatory. The patient is at risk for deterioration of mental status due to severe hypoglycemia and/or encephalopathy and may require respiratory support. Supportive care should initially focus on correction of hypoglycemia and correction of coagulopathy. Many patients will require continuous infusion of a 10% dextrose solution with intermittent boluses of D50 to maintain blood glucose greater than 60 mg%. Frequent glucose monitoring is recommended.

Correction of coagulopathy may be required with repeated infusions of blood products. Cryoprecipitate and fresh frozen plasma should be administered to correct hypofibrinogenemia and prolongation of PT/PTT as needed, particularly if the patient requires surgical intervention or develops clinical evidence of coagulopathy with mucosal or surgical site bleeding.

Cesarean delivery should be reserved for the usual obstetrical indications, as the majority of hemorrhagic complications occur in patients undergoing operative procedures. However, cesarean delivery may be the most prudent course of action if maternal status is rapidly deteriorating and the patient is remote from delivery. Correction of coagulopathy should be achieved preoperatively. If regional anesthesia is precluded due to coagulopathy and general anesthesia required, potentially hepatotoxic inhalation agents, such as halothane, should be avoided.

Intraoperatively, meticulous attention to hemostasis and avoidance of unnecessary dissection should be undertaken to minimize risk of postoperative hematoma formation. Consideration should be given to placing a surgical drain into the peritoneal space. Many patients will present in labor and deliver vaginally within 24 hours of admission. Episiotomy should be avoided due to the risk of developing a vaginal or vulvar hematoma in a coagulopathic patient.

Continuous fetal monitoring is recommended in a viable gestation as fetal heart rate abnormalities are common. Maternal lactic acidosis may develop due to hepatotoxicity and impaired clearance of serum lactate, leading to fetal acidosis.

Management summary

  • Consider admission to ICU.

  • Maternal fetal medicine, gastroenterology, anesthesia consultation.

  • Assess vital signs.

  • Establish IV with D10 solution.

  • Serial assessment of mental status.

  • Evaluate and establish airway, if needed.

  • Fetal monitoring and ultrasound.

  • Prepare for delivery.

  • Avoid hepatotoxic medications.

  • Serial glucose levels, give supplemental D50 bolus as needed to maintain glucose greater than 60 mg%.

  • Correct coagulopathy if operative procedure expected or evidence of bleeding.

  • Administer lactulose to lower ammonia levels if encephalopathic.

  • Provide stress ulcer prophylaxis.

  • Avoid surgical procedures including cesarean section and episiotomy. However, this may not be possible.

  • Avoid hypovolemia to protect renal function.

  • Follow electrolytes; rare patients will require dialysis.

  • dDAVP may be necessary for small subset of patients that develop central diabetes insipidus.

  • Close surveillance for infection.

4. Complications

Profound hypoglycemia and hemorrhagic complications related to coagulopathy are the two most immediate risks to the patient with AFLP and are addressed in the sections above. Additionally, pancreatitis may develop and place the patient at further risk for infection and pancreatic pseudocyst formation, hence the need for surveillance of amylase and lipase levels. Acute renal failure and need for dialysis is rare and more likely to develop as the result of a hemorrhagic event. Renal insufficiency will reverse postpartum for the majority of patients. Polyuria should raise suspicion for central diabetes insipidus.

Encephalopathy related to elevated serum ammonia should be anticipated. Prophylactic lactulose should be considered. These patients are at risk for airway compromise and should be watched carefully.

Infectious complications are well described. Close surveillance for infection is recommended, including cultures when indicated. Pneumonia, urinary tract infections, pancreatitis and wound infections are common sources. Liver capsule rupture with hepatic necrosis is also described.

Neonates may be at risk for complications related to LCHAD deficiency homozygosity, including cardiomyopathy, hepatic failure, and death. Therefore, informing the neonatal caregivers of the maternal diagnosis and the possibility of a neonatal inborn error of metabolism is essential.

5. Prognosis and outcome

The average gestational age at delivery is 35-36 weeks, although one case has been reported as early as 22 weeks. Perinatal mortality is approximately 10%.

Maternal mortality related to AFLP has declined in recent years and now appears to be around 1.8%. Liver transplantation is very rare and unlikely if diagnosed early, delivery accomplished and appropriate supportive care is provided. Most patients will demonstrate evidence of improvement within the first week postpartum, although worsening of laboratory parameters may occur in the first few days postpartum. With supportive care, a complete recovery is possible without residual liver dysfunction.

Recurrence in subsequent pregnancies is uncommon but has been reported. The exact incidence is unknown as many patients may have opted or been advised to avoid future pregnancies. Recurrence risk may be increased in the setting of maternal heterozygosity for LCHAD deficiency; however, recurrences have been reported in women negative for the mutation. Therefore, accurate prediction of future pregnancy outcome is limited.

6. What is the evidence for specific management and treatment recommendations

Castro, MA, Fassett, MJ, Reynolds, TB, Shaw, KJ, Goodwin, TM. “Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases”. Am J Obstet Gynecol. vol. 181. 1999. pp. 389-95. (Provides detail on clinical presentation of 28 patients cared for in a single facility.)

Knight, M, Nelson-Piercy, C, Kurinczuk, JJ, Spark, P, Brocklehurst, P. “A prospective national study of acute fatty liver of pregnancy in the UK”. Gut. vol. 57. 2008. pp. 951-6. (Largest population-based study that was published recently. Describes clinical findings and suggests improved neonatal and maternal outcomes.)