12.2 Acute Fatty Liver of Pregnancy (AFLP / Swansea Criteria) & Acute Kidney Injury
Key Takeaways
- Acute Fatty Liver of Pregnancy (AFLP) is a life-threatening third-trimester hepatorenal emergency caused by an autosomal recessive defect in fetal mitochondrial fatty acid beta-oxidation (most commonly Long-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD] G1528C mutation), leading to accumulation of toxic fetal/placental fatty acids that cause maternal microvesicular hepatic steatosis.
- The diagnosis of AFLP is established clinically using the validated Swansea Criteria (requiring >=6 of 14 clinical and laboratory criteria in the absence of an alternative explanation), including vomiting, abdominal pain, polydipsia/polyuria, encephalopathy, elevated bilirubin, hypoglycemia (<72 mg/dL), elevated uric acid, leukocytosis, bright liver on ultrasound, elevated transaminases, hyperammonemia, renal impairment (Cr >1.7 mg/dL), and coagulopathy (PT >14s).
- Profound hypoglycemia, marked hyperuricemia, severe coagulopathy/DIC with antithrombin III deficiency (<50%), and hyperammonemia distinguish AFLP from HELLP syndrome and severe preeclampsia; liver biopsy is rarely necessary and contraindicated in severe coagulopathy.
- Definitive management requires immediate multidisciplinary maternal stabilization followed by prompt delivery regardless of gestational age, aggressive correction of hypoglycemia with IV dextrose, blood product replacement (cryoprecipitate for fibrinogen >150-200 mg/dL, FFP, platelets), and postnatal genetic testing of the infant for LCHAD deficiency.
- Acute Kidney Injury (AKI) in pregnancy is defined by a serum creatinine >=0.3 mg/dL rise in 48h or >=1.5x baseline; because normal pregnancy baseline creatinine is 0.4 to 0.6 mg/dL due to gestational hyperfiltration, a serum creatinine of 1.0 mg/dL represents substantial renal impairment.
Acute Fatty Liver of Pregnancy (AFLP / Swansea Criteria) & Acute Kidney Injury
Acute Fatty Liver of Pregnancy (AFLP) and Acute Kidney Injury (AKI) represent severe, rapidly progressive medical emergencies unique to late pregnancy and the early puerperium. AFLP affects approximately 1 in 7,000 to 1 in 20,000 pregnancies. Historically associated with maternal and perinatal mortality exceeding 70%, early recognition using the Swansea Criteria and prompt delivery have reduced maternal mortality to under 5% to 10% in modern intensive care settings.
1. Pathophysiology & Molecular Genetics of AFLP
AFLP is a classic paradigm of maternal-fetal metabolic interdependence. It arises from an inherited autosomal recessive defect in fetal mitochondrial fatty acid beta-oxidation.
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| MOLECULAR PATHOGENESIS OF AFLP (LCHAD DEFECT) |
| |
| • FETAL GENETIC DEFECT: |
| - The fetus is homozygous for a mutation in the mitochondrial trifunctional protein (MTP), |
| most commonly the **G1528C mutation** in the alpha-subunit encoding **Long-chain 3-hydroxy- |
| acyl-CoA dehydrogenase (LCHAD)**. |
| |
| • MATERNAL CARRIER STATUS: |
| - The mother is an obligate heterozygous carrier with ~50% normal LCHAD enzyme activity. |
| - In non-pregnant states, maternal liver capacity easily handles normal fatty acid loads. |
| |
| • THIRD-TRIMESTER METABOLIC COLLAPSE: |
| - In late pregnancy, maternal metabolism shifts toward lipolysis to supply fetal energy. |
| - The homozygous LCHAD-deficient fetus and placenta cannot oxidize long-chain fatty acids, |
| releasing massive amounts of toxic intermediate metabolites (long-chain 3-hydroxy fatty acids)|
| into the maternal circulation. |
| - The overwhelmed heterozygous maternal liver accumulates triglycerides and free fatty acids, |
| inducing diffuse **microvesicular steatosis** (fat droplets crowding hepatocytes without |
| displacing the nucleus), mitochondrial dysfunction, hepatocyte ballooning, and acute liver |
| failure with secondary multiorgan dysfunction. |
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2. Clinical Presentation & Swansea Diagnostic Criteria
Clinical Manifestations
AFLP typically presents in the third trimester (between 30 and 38 weeks of gestation) or occasionally in the immediate postpartum period. Initial symptoms are insidious and frequently mistaken for common viral gastroenteritis or normal late-pregnancy complaints:
- Prodrome (1 to 2 weeks): Persistent nausea, vomiting (70%), anorexia, malaise, headache, and epigastric or right upper quadrant (RUQ) abdominal pain (50–80%).
- Progressive Hepatorenal Failure: Jaundice (scleral icterus/dark urine), polydipsia and polyuria (nephrogenic diabetes insipidus-like state caused by elevated circulating placental vasopressinase from impaired hepatic clearance).
- Severe Complications: Profound hypoglycemia (hepatic glycogen depletion and impaired gluconeogenesis), hepatic encephalopathy (asterixis, lethargy, confusion, coma), severe disseminated intravascular coagulation (DIC), gastrointestinal hemorrhage, acute renal failure, and ascites.
The Swansea Diagnostic Criteria
The Swansea Criteria provide a validated, non-invasive standard for establishing the diagnosis of AFLP. A diagnosis requires the presence of 6 or more of the following 14 criteria in the absence of another explanation (e.g., viral hepatitis, biliary obstruction, drug-induced liver injury):
| No. | Swansea Diagnostic Criterion | Diagnostic Threshold / Definition |
|---|---|---|
| 1 | Vomiting | Persistent antepartum or peripartum nausea/vomiting |
| 2 | Abdominal Pain | Epigastric or right upper quadrant tenderness |
| 3 | Polydipsia / Polyuria | Excessive thirst and high urine output (transient diabetes insipidus) |
| 4 | Encephalopathy | Lethargy, confusion, asterixis, cognitive blunting, or coma |
| 5 | Elevated Total Bilirubin | Total bilirubin >0.8 mg/dL (>14 µmol/L) |
| 6 | Hypoglycemia | Serum glucose <72 mg/dL (<4.0 mmol/L) |
| 7 | Elevated Uric Acid | Serum uric acid >5.7 mg/dL (>340 µmol/L) |
| 8 | Leukocytosis | White blood cell count >11,000 /µL (frequently >20,000–30,000 /µL) |
| 9 | Ascites or Bright Liver | Ascites on ultrasound/CT or diffuse increased echogenicity ("bright liver") |
| 10 | Elevated Transaminases | Serum AST or ALT >42 IU/L (typically 200–500 IU/L, rarely >1,000) |
| 11 | Elevated Serum Ammonia | Serum ammonia >47 µmol/L (leads to cerebral edema and encephalopathy) |
| 12 | Renal Impairment | Serum creatinine >1.7 mg/dL (>150 µmol/L) |
| 13 | Coagulopathy | Prothrombin Time (PT) >14 seconds, aPTT >34 seconds, or low Fibrinogen |
| 14 | Microvesicular Steatosis | Microvesicular fat on Oil Red O staining of liver biopsy (rarely needed) |
Clinical Rule: A liver biopsy is rarely required to initiate treatment; when clinical suspicion is high (>=6 Swansea criteria), urgent delivery must not be delayed for invasive histological confirmation, which carries a severe hemorrhage risk due to coagulopathy.
3. Differential Diagnosis: AFLP vs. HELLP vs. Viral Hepatitis vs. TTM
Distinguishing AFLP from HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) syndrome, severe preeclampsia, acute viral hepatitis, and thrombotic microangiopathies (TTP/aHUS) is critical for clinical decision-making.
| Diagnostic Parameter | Acute Fatty Liver of Pregnancy (AFLP) | HELLP Syndrome / Severe Preeclampsia | Acute Viral Hepatitis (A, B, E, HSV) | Thrombotic Thrombocytopenic Purpura (TTP) |
|---|---|---|---|---|
| Gestational Timing | 3rd trimester / early postpartum | Late 2nd or 3rd trimester | Any trimester | Any trimester (often 2nd/3rd or postpartum) |
| Hypoglycemia | Severe & Profound (<72 mg/dL; hallmark) | Rare / absent | Occurs only in fulminant liver failure | Absent |
| Coagulopathy / DIC | Severe early DIC (prolonged PT/PTT, Fibrinogen <150, AT-III <50%) | Late/mild DIC (usually normal PT/PTT unless severe abruption) | Normal until end-stage liver necrosis | Normal PT/PTT (pure microvascular platelet aggregation) |
| Transaminases (AST/ALT) | Moderate elevation (200–500 IU/L; rarely >1,000) | Moderate elevation (100–500 IU/L; rarely >1,000) | Massive elevation (1,000–10,000+ IU/L) | Normal or mildly elevated |
| Hyperbilirubinemia | Elevated conjugated bilirubin (>5–15 mg/dL) | Mild elevation (usually <5 mg/dL, mostly unconjugated) | Markedly elevated direct/indirect | Mild indirect hyperbilirubinemia from hemolysis |
| Thrombocytopenia | Moderate to severe (50k–100k/µL) | Severe (<100k/µL by definition; often <50k) | Normal unless fulminant failure | Profound (<20k–30k/µL) with abundant schistocytes |
| Key Distinguishing Feature | Hypoglycemia + Encephalopathy + Coagulopathy + Polyuria | Hypertension + Proteinuria + Hemolysis + Normal PT | AST/ALT in thousands + Viral serologies + Fever | Severe hemolytic anemia + ADAMTS13 activity <10% |
4. Emergency Management Protocol for AFLP
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| STEP-BY-STEP AFLP EMERGENCY PROTOCOL |
| |
| STEP 1: IMMEDIATE MATERNAL STABILIZATION IN AN INTENSIVE CARE UNIT (ICU) |
| • Airway & Encephalopathy: Secure airway with endotracheal intubation if Grade III/IV hepatic |
| encephalopathy develops. Administer Lactulose (20-30 g orally/rectally) to reduce ammonia. |
| • Correct Hypoglycemia: Administer immediate IV bolus of 50% Dextrose (D50W 50 mL), followed by |
| a continuous infusion of **10% to 20% Dextrose** (maintain blood glucose 100-150 mg/dL). |
| Check point-of-care blood glucose hourly. |
| • Aggressive Coagulopathy Correction: |
| - **Cryoprecipitate (10 to 20 units):** First-line to maintain Fibrinogen >=150 to 200 mg/dL. |
| - **Fresh Frozen Plasma (FFP, 15-20 mL/kg):** Correct prolonged PT/INR and aPTT. |
| - **Platelets:** Transfuse to maintain count >50,000/µL for delivery (>70,000-80,000 for CS). |
| - Avoid regional anesthesia if severe coagulopathy or thrombocytopenia is present. |
| |
| STEP 2: PROMPT DELIVERY (DEFINITIVE TREATMENT) |
| • Delivery is the only definitive cure for AFLP. Once maternal coagulopathy and glucose are |
| stabilized, proceed directly to delivery regardless of gestational age. |
| • Route of Delivery: |
| - Vaginal induction is appropriate if maternal/fetal conditions are stable, cervix is favorable|
| and delivery is expected within a reasonable timeframe. |
| - Cesarean delivery is indicated for obstetric indications, fetal distress, or failing maternal|
| hemodynamic/metabolic status. |
| |
| STEP 3: POSTPARTUM ICU MONITORING & POST-DELIVERY LAG |
| • Clinical "Lag Phase": Maternal hepatic and renal function frequently **worsen for 48 to 72 |
| hours postpartum** before regeneration occurs. Maintain aggressive glucose and coagulopathy |
| management. |
| • Plasmapheresis / Renal Replacement Therapy (RRT): Indicated for refractory lactic acidosis, |
| severe hyperammonemia, or progressive multiorgan failure. Liver transplantation is rarely |
| required for irreversible necrosis. |
| |
| STEP 4: NEONATAL SCREENING & CARE |
| • The infant is at high risk for fatal hypoketotic hypoglycemia, cardiomyopathy, hepatic failure,|
| and sudden infant death syndrome (SIDS). |
| • Immediately avoid prolonged infant fasting; initiate **high-carbohydrate, medium-chain |
| triglyceride (MCT) formula** feedings and perform genetic testing for LCHAD mutations. |
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5. Acute Kidney Injury (AKI) in Pregnancy
Renal Physiology of Pregnancy & Diagnostic Red Flags
During normal gestation, renal blood flow and glomerular filtration rate (GFR) increase by 50%, causing baseline serum creatinine to drop to 0.4 to 0.6 mg/dL (35 to 55 µmol/L). Therefore:
- A serum creatinine >=0.8 to 1.0 mg/dL (70 to 90 µmol/L) indicates significant renal impairment in pregnancy.
- A serum creatinine >1.2 mg/dL represents marked renal failure.
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| ETIOLOGICAL CLASSIFICATION OF PREGNANCY AKI |
| |
| 1. PRERENAL ETIOLOGIES (40% to 50%): |
| • Hyperemesis gravidarum (1st trimester severe volume depletion). |
| • Massive Obstetric Hemorrhage: Placental abruption, uterine rupture, placenta accreta |
| spectrum, uterine atony. |
| • Septic shock (chorioamnionitis, septic abortion, severe pyelonephritis). |
| |
| 2. INTRINSIC RENAL ETIOLOGIES: |
| • Preeclampsia with Severe Features & HELLP Syndrome (Glomerular endotheliosis). |
| • Acute Tubular Necrosis (ATN): Prolonged ischemia secondary to uncorrected prerenal shock. |
| • Acute Fatty Liver of Pregnancy (AFLP): Hepatorenal syndrome and tubular fatty infiltration. |
| • Thrombotic Microangiopathies: Atypical Hemolytic Uremic Syndrome (aHUS, complement- |
| mediated) and TTP. |
| • **Bilateral Renal Cortical Necrosis (BRCN):** |
| - Catastrophic, irreversible ischemic necrosis of the renal cortex triggered by severe |
| abruptio placentae, DIC, or massive septic shock. |
| - Presents with prolonged absolute anuria, gross hematuria, and severe flank pain. |
| - Carries poor prognosis: >80% require permanent lifelong hemodialysis or renal transplant. |
| |
| 3. POSTRENAL ETIOLOGIES (5%): |
| • Ureteral compression by massive polyhydramnios or overdistended gravid uterus. |
| • Iatrogenic ureteral injury/ligation during emergency cesarean hysterectomy. |
| • Retroperitoneal or broad ligament hematoma compressing the urinary tract. |
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Emergent Management & Dialysis Indications in Pregnancy
- Fluid Resuscitation: For prerenal AKI, administer isotonic crystalloid (balanced crystalloid or normal saline) with careful monitoring of maternal lung fields (pregnant patients are highly vulnerable to pulmonary edema due to reduced colloid oncotic pressure).
- Avoid Nephrotoxins: Discontinue NSAIDs, ACE inhibitors/ARBs (fetotoxic), and aminoglycosides.
- Indications for Emergent Renal Replacement Therapy (AEIOU):
- Acidosis: Refractory severe metabolic acidosis (pH <7.15).
- Electrolytes: Severe refractory hyperkalemia (K >6.0–6.5 mEq/L with ECG changes).
- Ingestions: Toxic alcohols, lithium, salicylates.
- Overload: Volume overload / pulmonary edema refractory to diuretics.
- Uremia: Uremic encephalopathy, pericarditis, or BUN >80–100 mg/dL (high urea concentrations are toxic to the developing fetus and cause polyhydramnios/fetal distress).
A 33-year-old G1P0 at 35 weeks of gestation is admitted with a 5-day history of persistent nausea, vomiting, epigastric pain, and progressive jaundice. Laboratory evaluation reveals: AST 280 IU/L, ALT 310 IU/L, Total Bilirubin 4.8 mg/dL, Blood Glucose 44 mg/dL, Serum Creatinine 2.1 mg/dL, Uric Acid 8.2 mg/dL, WBC 24,500 /µL, PT 19 seconds, INR 1.8, and Fibrinogen 110 mg/dL. Maternal ultrasound shows an echogenic 'bright' liver and mild ascites. Which underlying fetal enzymatic disorder is most strongly linked to this condition?
A 29-year-old G2P1 at 36 weeks of gestation is diagnosed with Acute Fatty Liver of Pregnancy (AFLP) based on meeting 8 Swansea criteria, including marked hypoglycemia (blood glucose 48 mg/dL), encephalopathy with asterixis, and profound coagulopathy (fibrinogen 95 mg/dL, PT 18.5 seconds). The patient is lethargic but hemodynamically stable. Continuous fetal monitoring shows a category I tracing. What is the most appropriate next clinical step?
A 25-year-old G1P0 at 38 weeks of gestation suffers a catastrophic grade 3 placental abruption with 2,500 mL postpartum hemorrhage and severe DIC. Following resuscitative hysterotomy and massive transfusion, she is admitted to the ICU. Over the next 48 hours, her urine output drops to 0 mL/hour despite fluid resuscitation, vasopressors, and high-dose loop diuretics. Serum creatinine rises from a baseline of 0.5 mg/dL to 5.4 mg/dL, and gross hematuria is noted from the Foley catheter. Renal biopsy confirms diffuse, irreversible ischemic coagulative necrosis of the renal cortex sparing the medulla. What is the diagnosis?
A 31-year-old G1P1 who delivered 24 hours ago following an emergency cesarean for Acute Fatty Liver of Pregnancy (AFLP) remains in the ICU. The neonatology team is establishing the post-delivery care plan for her vigorous term infant. What critical dietary and diagnostic protocol must be instituted immediately for the newborn?