A 39-year-old black woman, gravida 1, para 0, with an intrauterine pregnancy of 34 weeks and three days (according to last menstrual period and nine-week ultrasound) presented to her Ob-Gyn office for a routine prenatal visit. She was found to have an elevated blood pressure with new onset of 2+ proteinuria. The patient was sent to the labor and delivery unit at the adjoining hospital for serial blood pressure readings, laboratory work, and fetal monitoring.
The patient’s previous medical history was limited to sinusitis. She was taking no prescription medications, and her only listed allergy was to pineapple. Initial lab studies revealed elevations in liver enzymes, lactate dehydrogenase (LDH), uric acid, and serum creatinine, as well as thrombocytopenia (see Table 11-5). She also had a critically low blood glucose level, which conflicted with a normal follow-up reading.
At this point, the patient was thought to have HELLP syndrome6 (ie, hemolysis, elevated liver enzymes, low platelet count), or possibly acute fatty liver of pregnancy (AFLP).2,4,7-11 Additional labs were drawn immediately to confirm or rule out AFLP. These included repeat serum glucose (following a second reading with normal results), a serum ammonia level, prothrombin time (PT), and partial thromboplastin time (PTT). The most reliable values to distinguish AFLP from HELLP are profound hypoglycemia (found in 94% of women with AFLP12) and an elevated serum ammonia level.4
Given the serious nature of either diagnosis, immediate delivery of the infant was deemed necessary. Because the patient’s cervix was not found favorable for induction, she underwent low-transverse cesarean delivery without complications. She was noted to have essentially normal anatomy with the exception of a small subserosal fibroid posteriorly. Meconium-stained amniotic fluid was present. A male infant was delivered, weighing 5 lb with 1-minute and 5-minute Apgar scores of 8 and 9, respectively.
Postoperatively, the patient remained in the recovery area, where she received intensive monitoring. She experienced fluctuations in blood glucose, ranging from 33 to 144 mg/dL; she was started on 5% dextrose in lactated Ringer’s solution and treated with IV dextrose 50 g. While the patient was in surgical recovery, results from the second set of labs, drawn before surgery, were returned; findings included an elevated ammonia level and an abnormal coagulation panel, including PT of 25.3 sec, PTT of 48.4 sec, and a fibrinogen level of 116 mg/dL, confirming the suspected diagnosis of AFLP.
Magnesium sulfate, which had been started immediately postop, was discontinued on confirmation of the diagnosis of AFLP. The patient was initially somnolent as a result of general anesthesia but gradually returned to a fully normal sensorium by early morning on postop day 1. Postoperatively, the patient’s hemoglobin was found to be low (8.6 g/dL; reference range, 13.5 to 18.5 g/dL), so she was transfused with two units of packed red blood cells (PRBCs) and given fresh frozen plasma (FFP) to correct this coagulopathy. The patient’s platelets were also low at 82,000/mm3 (reference range, 140,000 to 340,000/mm3).
On postop day 1, the patient’s serum creatinine rose to 4.2 mg/dL and her total bilirubin increased to 14.4 mg/dL (reference ranges, 0.6 to 1.2 mg/dL and < 1.0 mg/dL, respectively). Given the multiple systems affected by AFLP and the need for intensive supportive care, the patient was transferred to the ICU.
On her arrival at the ICU, the patient’s vital signs were initially stable, and she was alert and oriented. However, within the next few hours, she became hypotensive and encephalopathic. She required aggressive fluid resuscitation and multiple transfusions of PRBCs and FFP due to persistent anemia and coagulopathy. Her vital signs were stabilized, but she continued to need blood transfusions.
Postop day 2, the patient became less responsive and was soon unable to follow commands or speak clearly. Her breathing remained stable with just 3 L of oxygen by nasal cannula, but in order to prevent aspiration and in consideration of a postoperative ileus, it was necessary to place a nasogastric tube with low intermittent suction. This produced a bloody return, but no intervention other than close monitoring and transfusion was performed at that time.
Abdominal ultrasound showed ascites and mild left-sided hydronephrosis with no gallstones. The common bile duct measured 3 mm in diameter.
Although liver biopsy is considered the gold standard for a confirmed diagnosis of AFLP,13,14 this procedure was contraindicated by the patient’s coagulopathy. Concern was also expressed by one consultant that the patient might have thrombotic thrombocytopenic purpura (TTP) in addition to AFLP. TTP can manifest with similar findings, such as anemia, thrombocytopenia, neurologic symptoms, and renal abnormalities, but usually fever is involved, and the patient was afebrile. A catheter was placed for hemodialysis and therapeutic plasma exchange (TPE). Given that TTP-associated mortality is significantly decreased by use of TPE,15 this intervention was deemed prudent. The patient underwent TPE on three consecutive days, postop days 2 through 4.
The patient’s mental status began to improve, and by postop day 6, she was able to follow commands and engage in brief conversations. By postop day 9, she had returned almost completely to her baseline mental status.
The patient’s liver function test results and total bilirubin, ammonia, and creatinine levels all improved over the first few postoperative days but began to rise again by day 6. In response to worsening renal and hepatic functioning, the decision was made on postop day 9 to transfer the patient to a hospital with liver transplantation capabilities, should this procedure become necessary.
AFLP is a rare condition specific to pregnancy, affecting 1/7,000 to 1/20,000 pregnancies. Due to the low incidence of this disease, randomized controlled trials to study it are not possible. Instead, clinicians must learn either from individual case studies or from retrospective syntheses of cases reported over time.1,2,7 Fortunately, the wealth of information gleaned over the past 30 years has significantly reduced AFLP-associated maternal and fetal mortality and morbidity rates. In the 1980s, maternal and fetal mortality rates as high as 85% were reported.3 Worldwide, maternal mortality associated with AFLP has decreased significantly to 7% to 18%, whereas the fetal mortality rate has fallen to between 9% and 23%.1,16,17
Common trends among women who have developed AFLP include nulliparity, multiparity, and advanced maternal age. One retrospective study of 57 women who had developed AFLP revealed that 35 cases (61%) involved first-time pregnancies. It also showed that 10 (18%) of the women had twins, and 14 (25%) were older than 35.2 In another study of 35 cases of AFLP, 40% of the women were nulliparous, and 11.4% were multiparous, including one triplet gestation.12 In a third, smaller study, 80% of women affected by AFLP were multiparous.10 Currently, there is no known evidence linking any maternal behavior to development of AFLP.
Women who present with AFLP often experience vague, nonspecific symptoms, leading to misdiagnosis or delayed diagnosis. Objective measurements, including physical exam findings, laboratory studies, and other diagnostic tests, will help with a diagnosis. The most frequent initial symptoms are nausea and vomiting (in 70% of patients) and abdominal pain (50% to 80%), epigastric or right upper-quadrant.3 Other common symptoms include fatigue, malaise, anorexia, weight gain, polyuria, and polydipsia.2,3,9,18,19
Because the presenting symptoms in AFLP can be vague, clinicians should complete a thorough physical exam to differentiate accurately among conditions associated with pregnancy. Physical signs present in women with AFLP can include jaundice, ascites, edema, confusion, abdominal tenderness, and fever. More severe cases can present with multisystem involvement, including acute renal failure, gastrointestinal bleeding, pancreatitis, coagulopathy, and hepatic encephalopathy.3,4,9,18
Relevant laboratory tests include a complete blood count (CBC), liver studies, chemistry, coagulation studies, and urinalysis (see Table 1). Viral causes should be ruled out by way of a hepatitis panel.3 In AFLP, the CBC may show elevated white blood cells, decreased hemoglobin and hematocrit, and decreased platelets. Liver studies show elevated hepatic aminotransferase, bilirubin, LDH, and ammonia levels. Chemistry results show elevated blood urea nitrogen and creatinine, and decreased blood glucose. Coagulation factors are affected, and prolonged PTT, decreased fibrinogen, and proteinurea may also be found.9
Though invasive and not often necessary4,13 (and not possible for the case patient), the definitive diagnostic test for AFLP is liver biopsy.13,14 Biopsy reveals a microvesicular fatty infiltration of the hepatocytes as minute fat droplets surrounding a centrally located nucleus. These fatty infiltrates stain with oil red O, specific for fat. Inflammation is present in 50% of cases. There may also be a picture similar to cholestasis with bile thrombi or deposits within the hepatocytes.20
Due to the risk for hemorrhage and the critical status of women with AFLP, biopsy is often not possible. Ultrasonography may show increased echogenicity; CT may show decreased or diffuse attenuation in the liver. These imaging studies, though possibly helpful in severe cases, often yield false-negative results.3,20
In the absence of another explanation for the patient’s symptoms, the Swansea criteria are used for diagnosis of AFLP.1 Six or more of the following criteria must be present to confirm this diagnosis: vomiting, abdominal pain, polydipsia or polyuria, encephalopathy, leukocytosis, elevated bilirubin, elevated liver enzymes, elevated ammonia, hypoglycemia, renal dysfunction, coagulopathy, elevated uric acid, ascites on ultrasound, and microvesicular steatosis on liver biopsy.1,2,5
Normal functions of the liver include metabolism, protein synthesis, and manufacturing of blood coagulation proteins. These functions are disturbed in the presence of AFLP. Thus, women with this disease experience signs and symptoms related directly to the dysfunction of these processes.20-22
Disturbances in the hepatocytes due to excess fatty acids impair the liver’s ability to convert unconjugated bilirubin into conjugated bilirubin, causing plasma levels of unconjugated bilirubin to rise. This increase in bilirubin explains the jaundiced appearance of women with AFLP. AFLP is often thought to occur in conjunction with preeclampsia in many, but not all, patients. Thrombocytopenia in these patients is felt to be secondary to peripheral vascular consumption. Conjugated bilirubin levels may also be increased due to decreased flow of conjugated bilirubin into the common bile duct.21
Another liver function that is disrupted is that of glycogen storage and conversion to glucose, and the liver’s ability to convert nutrients into glycogen is also impaired. Decreased storage of glycogen, along with the liver’s inability to break down previously stored glycogen, causes a decrease in serum glucose levels. Women with AFLP often require treatment with IV dextrose in response to marked hypoglycemia.16,21,23
The liver dysfunction associated with AFLP reduces adequate production of clotting factors and coagulation proteins. Thrombocytopenia, elevated clotting times, and bleeding are all problems seen in AFLP. Mild to moderate elevations in serum aminotransferases and elevated LDH also occur in patients with AFLP.23,24
There is little known about the etiology of AFLP, although recent data point to a genetic component that was found in as many as 62% of mothers in one study and in 25% of infants in another study.20-22 Fatty acid oxidation (FAO) is one of the processes of hepatic mitochondria, a process that relies on several enzymes. When FAO is interrupted, fatty acids are deposited in the liver cells, as seen in histologic studies of AFLP.25,26 The common thread in women with this disease is a mutation in one of the enzymes needed for FAO. This enzyme is the long-chain 3-hydroxyacyl-CoA dehydrogenase. Deficiencies in this enzyme are common in mothers with AFLP and their infants.3,16,20,23,27
Several complications of pregnancy that involve the liver may, on presentation, mimic AFLP.16,20,23,24,28 The most common are hyperemesis gravidarum and intrahepatic cholestasis of pregnancy23 (see Table 216,20,23,24,28); others are preeclampsia/eclampsia and HELLP syndrome. It is important to distinguish between the signs and symptoms associated with each of these disorders in order to provide the most effective treatment. Hepatitis serologies are important in the differential diagnosis when liver enzyme levels are exceptionally high.4,16,22,28
The most effective treatment for AFLP is delivery of the infant; often, this alone causes the signs and symptoms of AFLP to resolve.8,21,27,29 In two of three cases in a small study by Aso et al,8 early delivery of the fetus led to complete resolution of symptoms and return to normal liver function. One of these patients was sent home four days after delivery; the other, 14 days later. Other patients may require more invasive treatment and support.8
Management in the ICU is often required to provide appropriate supportive care to the mother after delivery. Acute respiratory distress syndrome, pancreatitis, hemorrhage, encephalopathy, renal failure, and continual liver failure are among the severe complications associated with AFLP.4,8,10 Many women require intubation, dialysis, fluid resuscitation, blood product transfusion, and vasopressor therapy.3,8,11 Prophylactic antibiotics, IV steroids, and glucose may all be required in the supportive care and recovery of a mother with AFLP.3,8,11
TPE has also been useful in instances of severe complications.1,3,6 In one retrospective study, Martin et al1 recommended administration of TPE in patients with AFLP under the following circumstances:
(1) Deteriorating central nervous system abnormalities, such as sensorium changes or coma;
(2) Persistent coagulopathy requiring continued and aggressive blood product support with plasma, red cells, and/or cryoprecipitate;
(3) Advanced renal dysfunction that compromised fluid management;
(4) Progressive cardiopulmonary compromise; and/or
(5) Ongoing fluid management concerns, including significant ascites, edema, anuria/oliguria, and/or fluid overload.1
In rare cases, liver transplantation is needed in patients with AFLP. Westbrook et al18 reviewed 54 cases of liver disease in pregnancy in one UK hospital between 1997 and 2008. Of these, six patients with encephalopathy or elevated lactate were listed for liver transplant, including just one with a diagnosis of AFLP. This woman never actually underwent transplant but recovered in response to medical management alone.18 According to data reported in June 2011 by the Organ Procurement and Transplantation Network,30 liver transplantation was needed in only three US patients with AFLP between 2000 and 2011. Further retrospective studies on outcomes from transplant versus medical management should be considered to guide future decision making involving this invasive therapy.
The Case Patient
This 39-year-old patient presented during a routine prenatal visit with proteinuria and hypertension, possibly indicative of preeclampsia. Because of the serious nature of this potential diagnosis in pregnancy, she was admitted for monitoring and further testing. Although the diagnosis of AFLP was not confirmed until later, the patient’s preliminary lab studies showed elevated liver enzymes and low platelet counts, signifying the need for prompt intervention and delivery of the infant. At this point, the patient met criteria for HELLP syndrome, but AFLP was suspected after the initial finding of profound hypoglycemia led to further testing.
As an older mother experiencing pregnancy for the first time, this patient fit the profile for AFLP. She initially responded well after delivery of her infant but continued to experience complications. On the days that the patient was treated with TPE, her total bilirubin and liver enzymes were at their lowest. Perhaps this treatment should be considered in more cases of AFLP.
The patient was transferred to a hospital with liver transplantation capabilities, but she ultimately recovered without undergoing transplant.
For the primary obstetric care provider, being aware of the possible complications associated with pregnancy is important. Though uncommon, AFLP is a serious complication that should be ruled out in women who present with vague symptoms such as nausea, vomiting, and abdominal pain in the third trimester of pregnancy. The reduction in AFLP-associated morbidity and mortality during the past 20 years is a direct result of increased early recognition and therapeutic delivery.
Referral to a maternal fetal medicine specialist, gastroenterologist, hematologist, and/or nephrologist may be necessary and appropriate in the management of a woman with AFLP. Further study is indicated for use of TPE in more severe cases of AFLP, particularly in women affected by persistent thrombocytopenia and anemia.
The author would like to thank C. Leanne Browning, MD, obstetrics/gynecology, for her invaluable guidance and advice on this project.
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