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Acute fatty liver of pregnancy (AFLP)

Rare, potentially fatal complication of pregnancy that occurs in the 3rd trimester or early postpartum period, characterized by a microvesicular fatty infiltration or steatosis of hepatocytes, which can precipitate coagulopathy, electrolyte imbalance, and multi-organ failure.

Acute fatty liver of pregnancy (AFLP) histology
Acute fatty liver of pregnancy (AFLP) histology: Purple = hepatocyte nuclei. Surrounding white around nuclei = lipid droplets (steatosis). | Liver disease in pregnancy - The Lancet. (2017). Accessed: March 12, 2017: http://www.thelancet.com/cms/attachment/2019854554/2039785456/gr5_lrg.jpg.

Rare, potentially fatal complication of pregnancy that occurs in the 3rd trimester or early postpartum period, characterized by a microvesicular fatty infiltration or steatosis of hepatocytes, which can precipitate coagulopathy, electrolyte imbalance, and multi-organ failure.

Pregnancy-associated liver diseases:

  1. Preeclampsia with hepatic impairment
  2. Haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome
  3. Hyperemesis gravidarum
  4. Intrahepatic cholestasis of pregnancy
  5. Acute fatty liver of pregnancy (AFLP)

History:

“Acute yellow atrophy of the liver,” a rare and fatal complication of pregnancy, was first described by Stander and Cadden in 1934.

The first documented inherited disorder of fatty acid oxidation was described in 1973 of a muscle carnitine palmitoyl transferase (CPT) deficiency. Since then, more than 20 different disorders that affect β-oxidation have been identified. LCHAD deficiency was first described in 1989. MTP deficiency was first reported in 1992, which cleared the confusion of interpreting the combined defects of LCEH, LCHAD, and LKAT.

Pathophysiology

Mitochondrial β-oxidation of fatty acids:

Complex process that consists of multiple transport steps and 4 enzymatic reactions resulting in the sequential removal of 2-carbon, acetyl-coenzyme A units.
Classical β-oxidation pathway in the mitochondria
Classical β-oxidation pathway in the mitochondria: Fatty acids (FAs) are activated to form fatty acyl CoA by the acyl CoA synthetase present in the outer mitochondrial membrane. To import FA into mitochondrial matrix, fatty acyl carnitine is formed by carnitine acyl transferase I and the carnitine translocase helps in transporting it into the mitochondrial matrix. Carnitine acyl transferase II converts fatty acyl carnitine back to fatty acyl CoA. β-Oxidation starts with the action of acyl-CoA dehydrogenase activity. The mitochondrial trifunctional protein, which consists of enoly CoA hydratase, hydroxyl acyl CoA dehydrogenase and thiolase activities leads to the formation of an acyl CoA molecule with two carbons less and acetyl CoA as products | Natarajan, S. K., Thangaraj, K. R., Goel, A., Eapen, C. E., Balasubramanian, K. A., & Ramachandran, A. (2011). Acute fatty liver of pregnancy: an update on mechanisms. Obstetric medicine, 4(3), 99–103. https://doi.org/10.1258/om.2011.100071

Fatty acid oxiadtion (FAO) disorders:

Category of inborn errors of metabolism that are inherited in an autosomal recessive pattern which cause defects in mitochondrial β-oxidation
  • Long chain hydroxyacyl CoA dehydrogenase (LCHAD) deficient fetus (M/C, 20% cases)
  • Mitochondrial trifunctional protein (MTP) deficient fetuses

In the latter stages of pregnancy, the primary source of energy for the mother shifts to fats, while glucose is the primary energy substrate for the fetus. In an inherited defect in fat metabolism, this defect would be expected to become clinically manifest in late pregnancy, when the maternal dependence on fats as the primary source of energy is at its peak.

Hypothesis illustrating the possible role of fetal and maternal MTP mutations in developing AFLP
Hypothesis illustrating the possible role of fetal and maternal MTP mutations in developing AFLP: Carrying an LCHAD deficient fetus (A) is the major determining factor in the development of maternal illness. Hepatotoxic metabolites produced by the fetus and/or placenta may cause liver disease in the obligate heterozygous mother when combined with the metabolic stress of the third trimester. Environmental stress (B) may lead to the further accumulation of toxic metabolites in the genetically susceptible mother causing maternal liver disease. | Ibdah J. A. (2006). Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World journal of gastroenterology, 12(46), 7397–7404. https://doi.org/10.3748/wjg.v12.i46.7397

Other risk factors:

  • First pregnancy
  • Male foetus
  • Materal obesity

Presentation

Severe coagulopathy, jaundice, hepatic encephalopathy, ascitis, hypoglycemia, and a mild to moderate elevation of transaminase levels are the key features of AFLP.

Initial manifestations: Nonspecific

  • Headache, fatigue
  • Nausea and vomiting (70%)
  • Right upper quadrant (RUQ) or epigastric pain (50%-80%)
  • Hypertension, proteinuria, oedema (ovelapping HELLP/preeclampsia)

Complications

AFLP can be complicated at an early stage due to the decreased liver production of coagulation factors and/or DIC
  • Disseminated intravascular coagulopathy (DIC)
  • Upper gastrointestinal hemorrhage (due to coagulation abnormalities)
  • Acute renal failure
  • Infection
  • Pancreatitis
  • Hypoglycemia
  • Hepatic encephalopathy (late complication)
  • Hepatorenal syndrome (late complication)
  • Postpartum hemorrhage (PPH) (high postpartum risk)
  • Complications during recovery phase:
    • Diabetes insipidus
    • Pancreatitis

Diagnosis

Swansea criteria:

predictor of hepatic microvesicular steatosis
Swansea diagnostic criteria for AFLP
Swansea diagnostic criteria for acute fatty liver of pregnancy | Ch’ng CL, Morgan M, Hainsworth I, Kingham JG. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 2002;51:876‐880.

Lab investigations:

  • ↑AST & ALT
  • ↑ S. bilirubin
  • Hypoglycemia
  • Hypoalbuminemia
  • Thrombocytopenia
  • ↑ S. urea, uric acid, creatinine
  • Elevated ammonia and white blood cell count may be present.
  • Coagulopathy: ↑ PT, ↑ INR, ↓ fibrinogen.

Differential diagnosis:

  • HELLP syndrome
  • Preeclampsia
Overlap syndromes with liver dysfunction
Overlap syndromes with liver dysfunction | Ryan, J.M. and Heneghan, M.A. (2014), Pregnancy and the liver. Clinical Liver Disease, 4: 51-54. doi:10.1002/cld.361

Management

Treatment of AFLP entails a combination of maternal stabilization and prompt delivery of the fetus regardless of gestational age.

Immediate termination of pregnancy

Irrespective of gestational age

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