Acute Fatty Liver of Pregnancy (AFLP): Comprehensive Analysis

Overview

Epidemiology

• Incidence: Approximately 1 in 6,700 to 1 in 16,000 pregnancies; a large UK national prospective cohort (1.1 million deliveries) found 5.0 cases per 100,000 pregnancies
• Gestational age: Most commonly presents between 34-37 weeks, though cases as early as 19-20 weeks have been reported; rarely presents postpartum
• Risk factors:
  • Primiparity (first pregnancy)
  • Multiple gestations (twin pregnancies independently identified as a risk factor)
  • Low BMI (<20)
  • Male fetus (affected patients have a significantly greater than expected proportion of male fetuses)
  • Pre-existing fatty acid oxidation disorders in the fetus (LCHAD deficiency - see Pathogenesis)
• Co-existing preeclampsia: Present in 21-64% of AFLP cases, reflecting shared pathophysiologic mechanisms and overlapping risk factors
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 661
• Yamada's Textbook of Gastroenterology, p. 831

Pathogenesis

LCHAD Deficiency and Beta-Oxidation Defects

1. The fetus inherits two mutant copies of the HADHA gene (encoding LCHAD), making it homozygous deficient
2. The mother and father are each obligate heterozygous carriers - insufficient for disease outside pregnancy
3. The enzyme deficiency causes the fetus and placenta to spill unmetabolized long-chain 3-hydroxyacyl fatty acid metabolites into the maternal circulation
4. These metabolites accumulate in the mother's liver, causing hepatotoxicity and the clinical syndrome of AFLP
5. This represents one of the rare instances where the fetus causes metabolic disease in the mother

Note: Not all AFLP cases are explained by LCHAD deficiency. An intensive search has failed to identify a single toxin responsible, and other unknown mechanisms likely exist.

Relationship to Preeclampsia

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. (pathogenesis section)
• Sleisenger and Fordtran's GI and Liver Disease, p. 661-662
• Comprehensive Clinical Nephrology, 7th Ed., p. 633

Pathology / Histology

Zonal Pattern

• Steatosis is most prominent in zone 3 hepatocytes (perivenular/centrilobular) and spares zone 1 hepatocytes surrounding portal areas
• The distribution is relatively homogeneous on light microscopy

Staining Challenges

• Microvesicular fat has a relatively homogeneous, pale appearance on H&E and may be difficult to discern
• Confirmation requires:
  • Oil-Red O stain on frozen tissue (stains fat red-orange)
  • Electron microscopy on glutaraldehyde-fixed specimen (shows characteristic mitochondrial pleomorphism)

Other Histologic Findings

• Lobular disarray (may mimic viral hepatitis)
• Hepatocyte dropout with reticulin collapse
• Biliary ductular proliferation
• Cholestasis may be present
• Notable for: relative absence of inflammation and necrosis in early disease (distinguishing from viral hepatitis)
• Sleisenger and Fordtran's GI and Liver Disease, p. 661
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. (morphology)

Clinical Presentation

Timing

• Late pregnancy, usually 34-37 weeks (third trimester)
• Rarely before 20 weeks or postpartum

Prodromal Symptoms (Days to Weeks Before Diagnosis)

• Nausea and vomiting (most common)
• Abdominal pain (often right upper quadrant or epigastric)
• Malaise, anorexia
• Polydipsia/polyuria (may reflect early transient diabetes insipidus)
• Pruritus (overlap with intrahepatic cholestasis of pregnancy - rare)

Established Disease

Severe Complications

• DIC with vaginal bleeding or post-cesarean hemorrhage
• Acute pancreatitis (16% in one cohort)
• Ascites and pleural effusion
• Respiratory failure
• Acute renal failure (75% had creatinine ≥1.5 mg/dL in one series; 2% required dialysis)
• Sepsis/infection
• Rare: myocardial infarction, pulmonary fat emboli

Outcomes Data (cohort of 51 women)

• Blood product transfusion: 55%
• Pancreatitis: 16%
• ICU admission: 14%
• Maternal death: 4%
• Stillbirth: 12%
• Acute renal failure requiring average 8-9 days to return to baseline creatinine
• Creasy & Resnik's Maternal-Fetal Medicine, p. 1375
• Sleisenger and Fordtran's GI and Liver Disease, p. 661

Diagnosis

Clinical Diagnosis: The Swansea Criteria

Typical Lab Profile

• AST/ALT: Moderately elevated (typically ~750 U/L) - rarely very high or even normal
• Bilirubin: Elevated (jaundice in majority)
• PT/aPTT: Prolonged
• Fibrinogen: Decreased (hypofibrinogenemia)
• Platelet count: May be low (thrombocytopenia)
• Creatinine/BUN: Elevated (renal dysfunction)
• Uric acid: Elevated
• Glucose: Low (hypoglycemia - critical finding)
• Ammonia: Elevated
• WBC: Leukocytosis

Imaging

• Hepatic ultrasound may show increased echogenicity ("bright liver") consistent with steatosis
• CT scan can confirm hepatic steatosis
• Imaging is important to exclude hepatic hematoma, rupture, and infarction

Liver Biopsy

• Usually unnecessary if clinical and laboratory features are typical
• Indicated when: the obstetrician has reservations about delivery, or diagnosis remains uncertain
• Coagulopathy may necessitate transvascular (transjugular) sampling rather than percutaneous
• Histologic results are pathognomonic when present
• Comprehensive Clinical Nephrology 7th Ed., p. 633-634
• Yamada's Textbook of Gastroenterology, p. 831

Differential Diagnosis

Importantly, AFLP, HELLP, and severe preeclampsia all mandate prompt delivery, so the practical urgency to distinguish them is somewhat reduced - though recognizing hepatic hematoma and rupture is critically important.

Management

Principles

1. Expedited delivery - the definitive treatment
2. Aggressive supportive care in an ICU or high-dependency unit
3. Correction of coagulopathy
4. Prevention and treatment of complications

Step-by-Step Management

• Admit to ICU/high-dependency care
• Multidisciplinary team: maternal-fetal medicine obstetricians, intensivists, hepatologists, neonatologists, anesthesiologists
• Establish IV access; continuous monitoring of maternal vital signs and fetal status

• Prompt delivery is imperative regardless of gestational age
• Mode: Cesarean section is common (74% in the UK cohort), though vaginal delivery is not contraindicated if clinically feasible
• Coagulopathy must be corrected prior to delivery to reduce hemorrhagic risk

• Fresh frozen plasma (FFP) - to replace clotting factors
• Cryoprecipitate - for fibrinogen replacement
• Platelet transfusions as needed
• Blood products as required (55% of patients required transfusion)

• Hypoglycemia: Continuous dextrose infusion; frequent glucose monitoring (at-risk patients with altered CNS function should be presumed hypoglycemic until proven otherwise)
• Hyperammonemia: Treat encephalopathy

• Monitor urine output and creatinine closely
• Renal replacement therapy (dialysis) in severe AKI (~2% require)
• Pathology multifactorial: hepatorenal syndrome, TMA, preeclampsia co-existing

• Mechanical ventilation as needed for respiratory failure

• Treat/prevent infection (sepsis is a major complication)
• Monitor for pancreatitis

Postpartum Course

• Disease typically remits after delivery with no residual hepatic or renal impairment
• Recovery of renal function takes average 8-9 days
• Patients may remain critically ill for days-weeks postpartum while hepatic function recovers
• Liver transplantation has been required in rare refractory cases (1 case in the UK cohort)
• Sleisenger and Fordtran's GI and Liver Disease, p. 662
• Creasy & Resnik's Maternal-Fetal Medicine, p. 1375

Fetal and Neonatal Implications

• Perinatal mortality: Historically high (7-58% in early retrospective series); in the UK prospective cohort: 104 per 1,000 births (approximately 10%)
• Stillbirth risk: ~12%
• Neonatal LCHAD screening: Infants born after AFLP-affected pregnancies should be screened for fatty acid oxidation disorders including LCHAD deficiency - deficient babies develop nonketotic hypoglycemia and obtundation after birth
• Genetic testing: In all cases of AFLP, the mother, father, and child should be tested for the G1528C LCHAD mutation
• Prenatal genetic diagnosis is feasible via chorionic villus sampling in families with known mutations

Recurrence and Future Pregnancies

• Recurrence of AFLP in subsequent pregnancies has been documented, particularly in women with confirmed LCHAD deficiency
• Women with AFLP in one pregnancy are not universally at risk for recurrence, but counseling and close monitoring in future pregnancies is warranted
• Some cases have resolved normally in subsequent pregnancies even after prior AFLP

Prognosis

• Earlier recognition (Swansea criteria)
• Availability of intensive care and liver support
• Multidisciplinary obstetric management
• Blood product availability

Key Points Summary

Recent Evidence Update

• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, pp. 660-662
• Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice, p. 1375
• Comprehensive Clinical Nephrology, 7th Ed., pp. 633-634
• Yamada's Textbook of Gastroenterology, 7th Ed., pp. 830-831
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 1443-1445
• Goldman-Cecil Medicine (AFLP entry)
• Terrault NA, Williamson C. Pregnancy-Associated Liver Diseases. Gastroenterology 2022;162(7):1947-1963. [PMID: 35276220]