Acute Fatty Liver of Pregnancy Case File

Acute Fatty Liver of Pregnancy Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 14

A 23-year-old G1P0 at 34 weeks’ gestation by first-trimester sonography presents with a 3-day history of malaise, anorexia, nausea, and vomiting. Her prenatal course has been uncomplicated to date. She denies a history of medical problems and surgeries.

On physical examination, the patient appears ill, with jaundice. Vitals: temperature, 98.9°F; BP, 120/78 mm Hg; pulse, 105 bpm; respiratory rate, 18 breaths per minute, lungs clear, cardiac regular rhythm. HR, 99 beats per minute with grade 2/4 systolic ejection murmur. Fundal height is 33 cm; epigastric tenderness is noted without guarding or rebound. Extremities are without edema or tenderness. The fetal heart rate tracing shows a baseline of 150 seconds, moderate variability, positive accelerations, no decelerations. Irregular contractions every 10 to 25 minutes are noted on tocodynamometer, although the patient does not perceive them. Her cervix is closed and long on digital examination. Bedside ultrasound shows fetal biometry consistent with 34 weeks, anterior placenta, and normal amniotic fluid.

During the evaluation, the patient has three episodes of emesis. Intravenous fluids with potassium repletion are started and antiemetics are administered. Laboratory results are as follows: Hgb 12 mg/dL, Hct 33%, WBC 19 × 103/μL, platelet count 127,000/mm3, AST 482 IU/L, ALT 402 IU/L, conjugated bilirubin 5.2 mg/dL, total bilirubin 6.0, LDH 302, serum creatinine 1.1 mg/dL, serum glucose 51 mg/dL, K+ 3.0 mEq/L. Amylase, lipase, ammonia, uric acid, and coagulation studies are within normal range. Urine analysis is only remarkable for specific gravity 1.03 and large ketones but otherwise negative.

➤ What is the differential diagnosis?

➤ What is the most likely diagnosis?

➤ What are the maternal risks associated with this diagnosis?

➤ What are the fetal risks associated with this diagnosis?

ANSWERS TO CASE 14:

Acute Fatty Liver of Pregnancy

Summary: This is a 23-year-old G1 at 34 0/7 weeks’ gestation with malaise, nausea, vomiting, abdominal tenderness as well as clinical and laboratory evidence of liver dysfunction.

➤ Differential diagnosis: In the second and third trimester, acute fatty liver of pregnancy (AFLP), intrahepatic cholestasis of pregnancy (IHCP), and severe preeclampsia with HELLP (hemolysis, elevated liver enzymes, low platelets) should be considered in a patient with evidence of liver dysfunction. Other conditions that may occur at any gestational age include viral hepatitis, pancreatitis, drug toxicity, cholelithiasis or rarely, malignancy. Conditions associated with nausea, vomiting, and abdominal pain that should also be considered in the differential include pyelonephritis, appendicitis, and hyperemesis gravidarum (HEG), however, these are less likely in this case.

➤ Most likely diagnosis: The most likely diagnosis is AFLP given this patient’s symptoms, evidence of liver dysfunction, and hypoglycemia.

➤ Maternal risks associated with this diagnosis: Maternal complications include pulmonary edema, coagulopathy, acute renal failure, infection, pancreatitis, diabetes insipidus (DI), hepatic encephalopathy, coma, liver transplantation, and maternal death.

➤ Fetal risks associated with this diagnosis: Fetal demise is a potential complication with AFLP if the diagnosis is delayed and delivery is not expedited. Prematurity complications are increased due to risk of both spontaneous and iatrogenic preterm birth. The fetus may also be affected with a fatty acid oxidation disorder.

ANALYSIS

Objectives

1. Recognize the clinical presentation of AFLP.
2. Become familiar with the evaluation and management.
3. Understand genetic implications associated with AFLP.

Considerations

It is not uncommon for pregnant women to present with nonspecific symptoms of nausea, vomiting, and malaise. In most instances, these symptoms may be attributed to normal pregnancy or hyperemesis gravidarum (HEG), especially during first trimester. Other times symptoms are secondary to a benign, self-resolving process such as a viral syndrome. On rare occasions such as this, nonspecific symptoms may represent a serious and potentially lifethreatening condition.

Acute fatty liver of pregnancy (AFLP) should always be in the differential for any patient who presents in the third trimester with nausea, vomiting, and abdominal pain. Although the incidence of AFLP is reportedly 1 in 7000 to 1 in 16,000 pregnancies1-10 (Level III), this may very well be an overestimation from published case series derived from tertiary referral centers.

Often times, there is a delay in diagnosis as there are overlapping clinical and laboratory findings of AFLP with other conditions. The major diagnosis that must be excluded is preeclampsia (HELLP syndrome). Although the frequency of hypoglycemia is variable with AFLP, its presence may help to distinguish it from HELLP syndrome. Another laboratory abnormality seen with AFLP that is not seen with HELLP syndrome is a markedly reduced antithrombin III levels. However, routine testing for antithrombin III is not practical since it may take several days to obtain results. In the absence of hypertension and proteinuria, the diagnosis of HELLP syndrome is also less likely; however, it is important to note that approximately 15% and 10% of HELLP syndrome occurs in the absence of hypertension and proteinuria, respectively. Hemolysis occurs in both conditions but is more common with HELLP syndrome than with AFLP. On the other hand, jaundice, coagulopathy, and impaired renal function are more common with AFLP than with HELLP syndrome. Liver biopsies from cases of HELLP syndrome reveal periportal hemorrhage and fibrin deposition which is in contrast to the microvesicular fatty infiltration seen with AFLP11 (Level III). Fortunately, the management of both conditions is similar in that delivery is indicated when either is suspected.

Another pregnancy-specific condition associated with liver dysfunction that needs to be considered in the third trimester is intrahepatic cholestasis of pregnancy (IHCP). The predominant symptom with IHCP is pruritus (without a rash) which helps to distinguish it from AFLP. Other conditions that need to be considered that are coincidental to pregnancy and can occur at any gestational age include viral hepatitis, cholelithiasis, pancreatitis, druginduced toxicity, and, rarely, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). It is also important to note that pyelonephritis and acute appendicitis must be considered with any patient that presents with nausea, vomiting, and abdominal pain. Because management strategies and outcomes differ among these conditions, obtaining the correct diagnosis is of the utmost importance.

The diagnosis of AFLP is most commonly made by clinical symptoms and laboratory findings. In this ill-appearing patient with emesis, abdominal tenderness, jaundice, liver impairment, and hypoglycemia, the most likely diagnosis is AFLP. Renal insufficiency, hemolysis, hemoconcentration, and leukocytosis are also evident in this patient and are not uncommon with AFLP. Hospitalization is indicated as this condition is progressive and sudden deterioration of both mother and fetus may occur at any time. The ultimate treatment is delivery after maternal stabilization. As long as maternal and fetal status is stable and reassuring, this patient is a good candidate to undergo induction of labor. Cesarean delivery should be reserved for the usual obstetrical indications or if delivery is not affected within a reasonable time and maternal and/or fetal status deteriorates.

APPROACH TO

Acute Fatty Liver of Pregnancy

AFLP affects women of all ages, race, and geographic areas. It is more common in nulliparas with a male fetus and in multiple gestations1,11 (Level III). It usually manifests in the third trimester with onset between 28 to 38 weeks’ gestation2-6,13 (Level III). Although rare, earlier cases have been reported in the second trimester12-14 (Level III). Less often, symptoms may not develop until the first few days of the postpartum period2,10 (Level III).

The typical patient appears ill with nonspecific symptoms for 1 to 2 weeks. The most common symptoms are nausea and vomiting (75%), abdominal pain (50%), jaundice (37%), and malaise (31%)2,6,7,10(Level III). Half of women with AFLP may also have preeclampsia at presentation or at some point during their disease course7,10 (Level III). Patients occasionally present with altered mental status due to hepatic encephalopathy. On physical examination, the patient may have hypertension, tachycardia (secondary to dehydration), low-grade fever, mild jaundice, and/or epigastric tenderness. In cases of severe coagulopathy, bleeding may be evident from multiple sites. Although less common (15%-20% cases), patients may actually be asymptomatic at the time of presentation or they may present for other reasons11 (Level III). Some patients may present with preterm contractions/labor or with decreased fetal movement (secondary to maternal acidosis).

As the disease progresses, additional complications may arise. Marked hypoglycemia may occur with variable frequency, developing in 17% to 100% of women due to impaired gluconeogenesis from liver dysfunction2,6,7 (Level III). A recent review of 16 cases of AFLP from three tertiary centers showed a 50% incidence of hypoglycemia10 (Level III). Hypoglycemia has also been found to be more common in the postpartum period. Additional maternal complications are hepatic encephalopathy (60%), acute renal failure (50%), disseminated intravascular coagulopathy (DIC) (55%), pulmonary edema/acute respiratory distress syndrome (ARDS) (25%), and infection2,6,7,10 (Level III). Acute pancreatitis may complicate 15% of cases and confers a poor prognosis. This complication may occur later in the disease process and is associated with hyperglycemia9 (Level III). Transient central diabetes insipidus in first week after delivery has also been reported. The mechanism for this is unknown but it is presumably from elevated vasopressinase levels which results in prodigious urine output15 (Level III).

Laboratory evaluation usually reveals parameters consistent with liver dysfunction. Prolonged clotting times, reduced fibrinogen as well as antithrombin III levels are associated with coagulopathy. Hyperbilirubinemia is usually of the conjugated type and has been reported to be in the range of 5 to 10 mg/dL. Liver enzymes (aspartate transaminase, alanine transaminase) are mildly elevated, rarely exceeding 1000 U/L. Endothelial exudation activation may cause hemoconcentration, leukocytosis, and thrombocytopenia. Hemolysis is likely from impaired cholesterol synthesis which contributes to erythrocyte membrane damage. LDH levels may vary from 250 to 4000 IU/L. As renal failure progresses, metabolic acidosis with elevated creatinine and uric acid levels is common. Either hypoglycemia or hyperglycemia may be present with the latter occurring in association with pancreatitis. In 12 cases of AFLP complicated by pancreatitis, the average peak for amylase was 552 U/L (range 26-113 U/L) and lipase 1866 U/L (range 100-5869 U/L)9 (Level III). Elevated ammonia levels are more common with progressive liver failure. Table 14–1 shows a summary of laboratory findings of 169 women with AFLP taken from six published studies.

Computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound imaging of the liver have limited usefulness and therefore the diagnosis of AFLP is made by clinical and laboratory evaluation. Hepatic imaging is helpful in excluding other disorders that may be confused with AFLP when the diagnosis is unclear. It is useful in detecting suspected complications of AFLP such as a pancreatic pseudocyst or hemorrhagic pancreatitis. The finding of fat on CT or ultrasound has been reported in cases of AFLP. This finding is nonspecific16 (Level III). The gold standard for diagnosis is the presence of microvesicular fatty infiltration of hepatocytes on liver biopsy. In patients without this diagnostic feature, special staining with oil red O on frozen section or electron microscopy can help to confirm the diagnosis of AFLP11 (Level III). Liver biopsy may be considered after coagulopathy has been corrected in those in whom the diagnosis remains in question; however, it is rarely used in clinical practice.

Once the diagnosis of AFLP is made, delivery is recommended regardless of gestational age. Antenatal corticosteroids to induce lung maturity can be administered as soon as preterm birth is anticipated if gestational age < 34 weeks. Delivery should not be delayed to complete a full course of antenatal steroids once the diagnosis is made as maternal and fetal status may deteriorate trying to accomplish this. Consultation with maternal-fetal medicine and neonatology is advised. Although there is no definitive treatment, maternal stabilization with supportive care is a mainstay of management.

aMean values

bMedian values

It is important to monitor vital signs and repeat laboratory tests every 6 to 8 hours or more frequent as needed. Transfusion of blood products may be necessary for correction of clinical coagulopathy and anemia. Serial glucose monitoring is also recommended with intravenous glucose infusion in order to maintain blood glucose levels > 60 mg/dL. It also is important to correct any electrolyte abnormalities and reduce high ammonia levels with lactulose when necessary. Continuous fetal monitoring to asses fetal well-being is also recommended. It is important to note that the fetal status may deteriorate rapidly, likely secondary to maternal acidosis or uteroplacental insufficiency or both11 (Level III).

Induction of labor is very reasonable in the absence of other indications that may preclude vaginal delivery. Vaginal delivery is optimal in a patient with AFLP who is at very high risk of hemorrhage and postoperative complications from AFLP. Cesarean delivery should be considered for the usual obstetrical indications or if maternal/fetal status deteriorates necessitating expeditious delivery. Anesthesia should be based on coexisting coagulopathy. If preeclampsia develops, magnesium sulfate should be administered for seizure prophylaxis.

Intensive care unit admission may be necessary intrapartum or postpartum for several reasons including maternal stabilization as well as close monitoring of laboratory abnormalities and complications that may develop in the postpartum period. Although clinical improvement is expected 2 to 3 days after delivery, laboratory abnormalities may continue for 7 to 10 days7 (Level III). Fulminant liver failure and need for liver transplant is very rare but has been reported.

The maternal mortality rate in older studies was reportedly in the order of 60% to 70%. In more recent case series, the maternal mortality rate has been found to be lower, in the range of 1.8% to 20%3,4,9,10,17(Level III, Level II-2). Prompt diagnosis and aggressive treatment of associated complications may contribute to improved maternal outcome. Perinatal mortality is approximately 13% based on the most recent literature10 (Level III); however, neonatal morbidity remains high due to prematurity complications.

Molecular advances have improved our understanding of the pathogenesis of AFLP. Several reports have provided evidence to support an association between AFLP and an inherited fatty acid oxidation disorder of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency in the fetus. This enzyme catalyzes the third step in the β-oxidation of fatty acids in mitochondria by facilitating the formation of 3-ketoacyl-CoA from 3-hydroxyacyl- CoA. With deficiency of the enzyme, the latter metabolite accumulates in the fetus and enters the maternal circulation causing hepatic fat deposition and impaired liver function.

The most common mutation of LCHAD deficiency associated with AFLP that has been studied is E474Q (or GC1528C). In a study of 24 families, Ibdah and colleagues examined the association between LCHAD deficiency in children and severe liver disease in their mothers. Of the 19 children that were found to be homozygous for E474Q or compound heterozygous (E474Q plus a different mutation on the other allele), the majority of these mothers developed AFLP, HELLP syndrome, or both during their pregnancy involving these children. Thus based on this study, carrying a fetus with LCHAD deficiency is associated with a 79% risk of developing AFLP or HELLP syndrome with the former having a stronger association than the latter18 (Level II-2). A subsequent prospective study confirmed this association and it is suggested that 1 in 5 women who develop AFLP may carry an LCHAD deficient fetus19 (Level II-2). Whether the pathogenesis of AFLP and HELLP syndrome is related remains unclear. At present, 17 mutations of β-oxidation have been identified raising the possibility that other defects may be associated with ALFP but are less well studied to date.

Molecular testing for the most common mutation, E474Q, and known genetic variants are available for women who develop AFLP, their partner, or their infants. This information is important for counseling a couple regarding their risk of having an affected fetus with LCHAD deficiency. With an autosomal recessive pattern of inheritance, a heterozygous couple has a 25% chance of having an affected fetus. Prenatal diagnosis by enzyme assay of amniocytes or chorionic villus samples may be available for an at-risk couple. Infants or children with LCHAD deficiency are at risk of developing fatal nonketotic hypoglycemia, defects in urea cycle formation, cardiomyopathy, or progressive neuromyopathy18 (Level II-2). The recurrence risk of AFLP in subsequent pregnancies (whether or not there is an associated inherited fatty acid oxidation defect) is likely to be increased but difficult to quantify based on the available literature.

Comprehension Questions

14.1 A 35-year-old woman G1P0 at 35 weeks’ gestation is noted to have BP in the 160/100 range and 3+ proteinuria. Her blood pressures during pregnancy were 120/70. The SGOT is 80 IU/L and SGPT 100 IU/L. The serum bilirubin is 0.2 mg/dL and serum glucose level is 90 mg/dL. The hemoglobin level is 12 g/dL and platelet count 120,000/mm3. Which of the following is the most likely diagnosis?

A. Acute fatty liver of pregnancy

B. Acute cholestasis of pregnancy

C. HELLP syndrome

D. Hepatitis

E. Preeclampsia

14.2. A 29-year-old G2P1 woman at 34 weeks’ gestation presents with fatigue, nausea and vomiting, and abdominal pain. The patient has an evaluation and is diagnosed with acute fatty liver of pregnancy. Which of the following is thought to be the etiology of this condition?

A. Estrogen effect on the liver decreasing transport of bile salts

B. Sludge in the gall bladder leading to delayed transit

C. Long chain fatty acid metabolism defect

D. Variant of preeclampsia

ANSWERS

14.1. D. This scenario is most consistent with preeclampsia. In acute fatty liver of pregnancy, the liver function tests usually show an elevated bilirubin and the glucose is low. Acute cholestasis is not usually associated with hypertension. HELLP syndrome would have thrombocytopenia (platelets < 100,000), and hepatitis is associated with transaminase enzymes in the 1000s.

14.2. C. AFLP is thought to be due to an inherited fatty acid oxidation disorder of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency in the fetus. This enzyme catalyzes the third step in the β-oxidation of fatty acids in mitochondria by facilitating the formation of 3-ketoacyl-CoA from 3-hydroxyacyl-CoA. With deficiency of the enzyme, the latter metabolite accumulates in the fetus and enters the maternal circulation causing hepatic fat deposition and impaired liver function. Although many patients with AFLP have preeclampsia, it is not thought to be a variant of preeclampsia.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ AFLP is a rare condition in the third trimester associated with significant maternal and perinatal morbidity (Level III).

➤ The major diagnosis that must be excluded is preeclampsia (HELLP syndrome) (Level III).

➤ Although there is no definitive treatment, maternal stabilization with supportive care is a mainstay of management (Level III).

➤ One in five women who develop AFLP may carry an LCHAD deficient fetus (Level II-3).

➤ Molecular testing for the most common mutation, E474Q, and known genetic variants should be offered for women who develop AFLP, their partner, or their infants (Level III).

REFERENCES

1. Davidson KM, Simpson LL, Knox TA, D’Alton ME. Acute fatty liver of pregnancy in triplet gestation. Obstet Gynecol. 1998;91:806-808. (Level III) 

2. Usta IM, Barton JR, Amon EA, Gonzalez A, Sibai BM. Acute fatty liver of pregnancy: An experience in the diagnosis and management of fourteen cases. Am J Obstet Gynecol. 1999;181:389-395. (Level III) 

3. Vigil-De Garcia P, Lavergne JA. Acute fatty liver of pregnancy. Int J Gynaecol Obstet. 2001;72:193-195. (Level III) 

4. Pereira SP, O’Donohue J, Wendon J, Williams R. Maternal and perinatal outcome in severe pregnancy related liver disease. Hepatology. 1997;26:1258-1262. (Level III) 

5. Reyes H. Acute fatty liver of pregnancy. A cryptic disease threatening mother and child. Clin Liver Dis. 1999;3:69-81. (Level III) 

6. Castro MA, Fasset 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. 1999;181:389-395. (Level III) 

7. Reyes H, Sandoval L, Wainstein A, et al. Acute fatty liver of pregnancy: A clinical study of 12 episodes in 11 patients. Gut. 1994;35:101. (Level III) 

8. Mabie WC. Acute fatty liver of pregnancy. Gastroenterol Clin North Am. 1992;21: 951-959. (Level III) 

9. Moldenhauer JS, O’Brien JM, Barton JR, Sibai B. Acute fatty liver of pregnancy associated with pancreatitis: a life-threatening complication. Am J Obstet Gynecol. 2004;190:502-505. (Level III) 

10. Fesenmeir MF, Coppage KH, Lambers DS, Barton JR, Sibai BM. Acute fatty liver in 3 tertiary care centers. Am J Obstet Gynecol. 2005;192:1416-1419. (Level III) 

11. Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol. 2007;109(4):956-966. This is an excellent review of the different conditions that share many of the clinical and laboratory findings of patients with severe preeclampsia-eclampsia (Level III). 

12. Buytaert IM, Elewaut GP, Van Kets HE. Early occurrence of acute fatty liver in pregnancy. Am J Gastroenterol. 1996;91:603-604. (Level III) 

13. Monga M, Katz AR. Acute fatty liver in the second trimester. Obstet Gynecol. 1999;93:811-813. (Level III) 

14. Suzuki S, Watanabe S, Araki T. Acute fatty liver of pregnancy at 23 weeks of gestation. BJOG. 2001;108:223-224. (Level III) 

15. Kennedy S, Hall PM, Seymour AE, Haque W. Transient diabetes insipidus and acute fatty liver of pregnancy. Br J Obset Gynecol. 1994;101:387. (Level III) 

16. Castro M, Ouzounian J, Colletti P, et al. Radiologic studies in acute fatty liver of pregnancy. A review of the literature and 19 new cases. J Reprod Med. 1996;41:839. (Level III) 

17. Knight M, Nelson-Percy C, Kurinczuk JJ, and on behalf of UK obstetric surveillance system (UKOSS). A prospective national study of acute fatty liver of pregnancy in the UK. Gut. 2008;57:951-956. This is the largest population-based study of a cohort of women with AFLP which showed improved maternal and fetal outcomes than previously reported (Level II-2). 

18. Ibdah JA, Bennett MJ, Rinaldo P, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med. 1999;340:1723-1731. A cohort of 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency underwent DNA amplification and nucleotide-sequence analyses to identify the alpha subunit of the trifunctional protein. Seventy-nine of heterozygous mothers developed AFLP or HELLP syndrome while carrying fetuses with Glu474Gln mutation (Level II-2). 

19. Yang Z, Yamada J, Zhao Y, Strauss AW, Ibdah JA. Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease. JAMA. 2002;288:2163-2166. A cohort study of 108 samples of maternal blood from women who developed AFLP or HELLP syndrome was tested. Mutations causing LCHAD deficiency were detected in 19% of women with a history of AFLP but only one with HELLP syndrome. The authors concluded that in approximately one out of five pregnancies complicated by AFLP the fetus had LCHAD deficiency (Level II-2).

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