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Pathophysiology
Clinical meaning
Acute fatty liver of pregnancy (AFLP) is a rare but life-threatening obstetric emergency that occurs exclusively in the third trimester of pregnancy (typically between 30-38 weeks gestation), characterized by microvesicular fatty infiltration of hepatocytes leading to acute liver failure. The estimated incidence is 1 in 7,000 to 1 in 16,000 pregnancies, but the mortality rate has historically been 75-85% and, even with modern intensive care and prompt delivery, remains 7-18% for the mother and 9-23% for the fetus. The registered nurse must recognize the often subtle and nonspecific early symptoms of AFLP to facilitate rapid diagnosis and emergency delivery, which is the only definitive treatment.
The underlying pathogenesis of AFLP is linked to a defect in mitochondrial fatty acid oxidation, specifically a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) in the fetus. LCHAD is a key enzyme in the mitochondrial beta-oxidation pathway that breaks down long-chain fatty acids into acetyl-CoA for energy production. When the fetus is homozygous for an LCHAD mutation (the most common being the G1528C mutation in the HADHA gene), it cannot properly oxidize long-chain fatty acids. These unmetabolized fatty acid intermediates (long-chain 3-hydroxyacyl metabolites) accumulate in the fetal and placental circulation and are shunted into the maternal bloodstream. The mother, who is typically heterozygous for the same LCHAD mutation (carrier state with approximately 50% enzyme activity), has reduced capacity to metabolize these additional fatty acid intermediates, particularly during the third trimester when metabolic demands are highest.
The accumulating long-chain fatty acid metabolites are directly toxic to maternal hepatocytes. They are taken up by the liver and deposited as microvesicular fat droplets within the hepatocyte cytoplasm (as opposed to the macrovesicular steatosis seen in alcoholic liver disease or NAFLD, where a single large fat droplet displaces the nucleus). Microvesicular steatosis reflects mitochondrial dysfunction -- the hepatocytes have functioning rough endoplasmic reticulum and protein synthesis apparatus but their mitochondria cannot perform beta-oxidation. The accumulated fatty acids also impair mitochondrial oxidative phosphorylation, disrupting ATP production and further compromising hepatocyte function. As hepatocyte dysfunction progresses, all major hepatic functions deteriorate simultaneously.
Hepatic synthetic failure manifests as coagulopathy: decreased production of clotting factors (especially factors V, VII, and fibrinogen), leading to prolonged PT/INR, prolonged aPTT, and decreased fibrinogen levels. Fibrinogen levels below 300 mg/dL in pregnancy are abnormal (normal pregnancy elevates fibrinogen to 400-600 mg/dL) and fibrinogen below 150 mg/dL indicates severe coagulopathy. Many AFLP patients develop overt disseminated intravascular coagulation (DIC), with the combination of hepatic synthetic failure and consumptive coagulopathy creating a devastating hemorrhagic diathesis.
Hepatic metabolic failure produces hypoglycemia (the liver cannot maintain gluconeogenesis or glycogenolysis), hyperammonemia (the liver cannot convert ammonia to urea via the urea cycle), and lactic acidosis (impaired hepatic lactate clearance). Hypoglycemia can be profound and life-threatening, requiring continuous dextrose infusion. Hyperammonemia causes hepatic encephalopathy with progressive confusion, somnolence, asterixis (flapping tremor), and eventually coma.
Hepatic excretory failure causes conjugated (direct) hyperbilirubinemia and jaundice as the liver cannot excrete bilirubin into bile. Serum transaminases (AST, ALT) are elevated but typically only modestly (300-500 U/L, rarely above 1000), which is disproportionately low compared to the severity of liver dysfunction. This is because microvesicular steatosis causes hepatocyte dysfunction rather than massive hepatocyte necrosis (which produces very high transaminase levels in conditions like acetaminophen toxicity or viral hepatitis). The relatively modest transaminase elevation despite severe liver failure is a characteristic feature of AFLP.
Renal failure complicates 50-60% of AFLP cases through multiple mechanisms: hepatorenal syndrome (functional renal failure from splanchnic vasodilation and renal vasoconstriction), direct fatty acid toxicity to renal tubular cells, hypovolemia from hemorrhage and third-spacing, and DIC-mediated renal microvascular thrombosis.
The Swansea criteria provide a standardized diagnostic framework for AFLP, requiring six or more of the following features in the absence of another explanation: vomiting, abdominal pain, polydipsia/polyuria, encephalopathy, elevated bilirubin (above 14 micromol/L), hypoglycemia (below 4 mmol/L), elevated uric acid (above 340 micromol/L), leukocytosis (above 11 x 10^9/L), ascites or bright liver on ultrasound, elevated transaminases (above 42 U/L), elevated ammonia (above 47 micromol/L), renal impairment (creatinine above 150 micromol/L), coagulopathy (PT above 14 seconds), and microvesicular steatosis on liver biopsy. Liver biopsy, while histologically definitive, is rarely performed due to coagulopathy risk and is not required for clinical diagnosis.
AFLP exists on a spectrum with two other third-trimester hepatic disorders: HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) and severe preeclampsia with hepatic involvement. These conditions share some pathophysiological mechanisms (endothelial dysfunction, microangiopathy) and clinical features, making differentiation challenging. Key distinguishing features of AFLP include more prominent hypoglycemia, lower fibrinogen, more severe coagulopathy, higher ammonia levels, and the characteristic microvesicular steatosis pattern. In practice, the clinical management is similar for all three: immediate delivery.
The definitive treatment for AFLP is immediate delivery of the fetus and placenta, which removes the source of toxic fatty acid metabolites. Vaginal delivery is preferred if maternal and fetal conditions allow rapid delivery, but cesarean section is often necessary due to maternal instability, fetal distress, or unfavorable cervical status. After delivery, hepatic function typically begins to improve within 48-72 hours, although complete recovery may take weeks to months. Some patients develop fulminant liver failure requiring liver transplantation despite delivery.
Exam Focus
Exam relevance
Risk factors:
- Primigravida (first pregnancy) -- AFLP is more common in first pregnancies, possibly due to higher metabolic demands and lack of prior metabolic adaptation
- Male fetus (AFLP occurs more frequently when the fetus is male, though the mechanism is not fully understood)
- Multiple gestation (twin or higher-order pregnancies) increasing the metabolic load of fatty acid intermediates from multiple placentas
- Fetal LCHAD deficiency (homozygous G1528C mutation in HADHA gene) with maternal heterozygous carrier status -- the primary pathogenic mechanism
- Pre-eclampsia or HELLP syndrome (may coexist with or predispose to AFLP; shared endothelial dysfunction pathways)
- Low maternal body mass index (reduced hepatic fat storage capacity may increase susceptibility to fatty acid metabolite toxicity)
- Third trimester beyond 30 weeks gestation (AFLP almost never occurs before 26 weeks; peak incidence 34-37 weeks)
Diagnostics:
- Swansea diagnostic criteria: six or more of 14 clinical and laboratory features (vomiting, abdominal pain, polydipsia/polyuria, encephalopathy, elevated bilirubin, hypoglycemia, elevated uric acid, leukocytosis, ascites/bright liver on US, elevated AST/ALT, elevated ammonia, renal impairment, coagulopathy, microvesicular steatosis on biopsy)
- Liver function tests: AST/ALT elevated but typically modest (300-500 U/L, rarely above 1000); total bilirubin elevated (conjugated predominant); albumin decreased; this pattern of moderate transaminase elevation with severe synthetic dysfunction is characteristic of AFLP
- Coagulation studies: PT/INR prolonged, aPTT prolonged, fibrinogen critically low (below 300 mg/dL in pregnancy is abnormal; below 150 mg/dL indicates severe coagulopathy); D-dimer markedly elevated indicating DIC
- Blood glucose: hypoglycemia may be profound and life-threatening; check bedside glucose every 1-2 hours; maintain continuous dextrose infusion if glucose falls below 60 mg/dL
- Serum ammonia: elevated due to impaired urea cycle function; correlates with hepatic encephalopathy severity; levels above 100 micromol/L indicate severe hepatic failure
- Abdominal ultrasound: may show bright (echogenic) liver consistent with fatty infiltration, ascites, and normal hepatic vasculature (excludes Budd-Chiari syndrome); however, sensitivity of ultrasound for AFLP is only 50-60% -- a normal ultrasound does NOT exclude AFLP
Core concept
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Clinical scenario
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