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CLINICAL AND SYSTEMATIC REVIEWS 1

CME

Acute Fatty Liver Disease of Pregnancy: Updates in

REVIEW
Pathogenesis, Diagnosis, and Management
Joy Liu, MD1, Tara T. Ghaziani, MD2, 3 and Jacqueline L. Wolf, MD2

Acute fatty liver of pregnancy (AFLP) is an obstetric emergency characterized by maternal liver failure and may have
complications for the mother and fetus, including death. This review examines recent literature on the epidemiology,
pathogenesis, diagnosis, and treatment of acute fatty liver of pregnancy. Pathogenesis of this disease has been linked
to defects in fatty acid metabolism during pregnancy, especially in the setting of fetal genetic defects in fatty acid
oxidation. The value of screening all patients for these genetic defects remains to be determined. Distinguishing AFLP
from other high-risk liver diseases of pregnancy that have overlap features, such as HELLP and preeclampsia, can be
challenging. Although sensitive diagnostic tools such as the Swansea criteria have been developed, further work is
needed to diagnose AFLP more quickly. Although survival rates have improved in the past 30 years, delay in diagnosis
and treatment of AFLP has life-threatening consequences; an algorithmic approach to AFLP may be a valuable
resource for clinicians. Future epidemiological and long-term studies will improve our prediction of women at risk for
developing AFLP and determine the long-term consequences of this condition.
Am J Gastroenterol advance online publication, 14 March 2017; doi:10.1038/ajg.2017.54

INTRODUCTION outcomes for the mother and fetus, and management strategies.
Acute fatty liver of pregnancy (AFLP) is an uncommon but poten- The role of diagnostic tools such as the Swansea criteria, imaging
tially fatal disease unique to pregnancy that typically occurs in studies, and the role of liver biopsy will also be briefly discussed.
the third trimester (16). Standard texts give incidence values for We also describe a practical algorithmic approach to the diagnosis
AFLP of 1:700015,000 pregnancies (3,79). On rare occasions, and management of AFLP.
AFLP presents as early as 22 weeks of gestation; however, it gener-
ally manifests after 30 weeks of gestation (1013).
AFLP remains an obstetric emergency for both mother and EPIDEMIOLOGY AND RISK FACTORS
fetus. The mother often requires intensive care, ranging from AFLP is a relatively rare disease of pregnancy. The incidence of
blood transfusions to dialysis to orthotropic liver transplantation AFLP in recent epidemiological studies ranges between 1:7000
(7). The severity of this disease underscores the need for early diag- 15,000 although in one study in Southeastern Wales the incidence
nosis and treatment, which currently consists of early delivery of was as high as 1:1000 (8). In a recent epidemiological study, in
the fetus and supportive care (1416). Rochester, Minnesota, in a principally Caucasian population, the
With advances in supportive obstetric care, maternal and fetal incidence of AFLP was 1:15,000, much less frequent than preec-
deaths have declined. Morbidity and mortality may be higher in lampsia (134:15,000) or hemolysis, elevated liver enzymes, low
developing countries with less ability to provide intensive support- platelet count (HELLP) syndrome (72:15,000) (9).
ive obstetric care (14,17). Minimal available evidence suggests that Historically, ethnic composition and geography have not been
the maternal liver recovers quickly after delivery of the fetus (2). considered to be significant factors. Thirty years ago, Pockros
However, in contrast to our understanding of preeclampsia, the et al (4). concluded that it was doubtful that ethnic factors affect
long-term effects of AFLP on the mother remain unknown. the incidence or severity of AFLP. However, epidemiological
This paper will emphasize our current knowledge of the genetic studies beyond the United States and United Kingdom are lack-
and biochemical basis of the etiology of AFLP, its implications ing and could elucidate whether there are truly population-based
for identifying populations at greater risk for AFLP, long-term differences in incidence.

1
Department of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; 2Department of Medicine, Division of Gastroenterology,
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; 3Department of Medicine, Division of Gastroenterology, Liver Transplant Institute, Beth Israel
Deaconess Medical Center, Boston, Massachusetts, USA. Correspondence: Joy Liu, MD, Department of Internal Medicine, Beth Israel Deaconess Medical Center
(BIDMC), 330 Brookline Avenue, Boston, Massachusetts 02215, USA. E-mail:jliu16@bidmc.harvard.edu
Received 4 August 2016; accepted 3 February 2017

2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY


2 Liu et al.

Table 1. Risk factors for AFLP delivery of the fetus should be considered in the presence of liver
dysfunction and coagulopathy regardless of etiology (33). In the
Multigravid state (1820)
presence of coagulopathy, a transjugular liver biopsy is performed,
REVIEW

Male sex of fetus (3) which carries a lower risk of bleeding compared to a percutaneous
Co-existing diagnosis of other liver disease of pregnancy liver biopsy. The treatment of choiceemergent deliveryshould
(HELLP, preeclampsia) (9,11,21,22) not be delayed in patients whose clinical presentation, laboratory
Previous episode of AFLP (23,24) findings, and imaging results are compatible with AFLP.
AFLP, acute fatty liver of pregnancy; HELLP, hemolysis, elevated liver enzymes, It is important to note that AFLP manifests different histo-
low platelet count. pathology from other liver diseases of pregnancy, which suggests
a different underlying pathophysiology (Table 2). The hallmark
histologic finding of AFLP is microvesicular fatty infiltration of
hepatocytes classically involving the pericentral zone and sparing
Several risk factors have been identified for AFLP (Table 1). the periportal hepatocyte (1). Fat droplets are not always readily
Multigravidas are believed to be at greater risk because of increased apparent on H&E staining, or are too small to appreciate on light
fetal production of fatty acid metabolites by more than one fetus microscopy and instead give the appearance of ballooning or dila-
(21). Underlying maternal metabolic disorders, such as type 2 dia- tion. Microvesicular steatosis is confirmed on a special stain called
betes, a known risk factor for non-alcoholic fatty liver disease, have Oil-red-O which must be done on fresh-frozen sections.
been reported on a case report basis in the literature (25). Although fatty change is considered the diagnostic histologic
It is unclear if other liver diseases of pregnancy might predispose hallmark of AFLP, case series such as that conducted by Rolfes
women to AFLP or are merely associated (15). For example, AFLP and Ishak have reported other findings as well, such as giant mito-
has been diagnosed in a significant number of patients (2040%) chondria and lymphocytic infiltration (2). In that particular study,
who are also diagnosed with preeclampsia, a condition defined by AFLP was distinguished from other diseases of pregnancy such as
the development of hypertension in the second half of pregnancy preeclampsia and HELLP by lack of sinusoidal fibrin deposition.
and associated with proteinuria with or without other signs of Evidence of intrahepatic cholestasis, including bile canalicular
organ damage such as new thrombocytopenia, impaired hepatic plugs and acute cholangiolitis, was seen in two-thirds of cases (2).
or renal function, pulmonary edema, and visual disturbances However, microvesicular steatosis can be seen in other forms of
(7,9,26). Up to 20% of women with AFLP may also be diagnosed liver disease, including Reyes syndrome and drug-induced liver
with HELLP syndrome, which itself is associated with preeclamp- injury from tetracycline; histopathologic findings must be consid-
sia (7,27). Rarer associations have been reported, such as AFLP ered in the right clinical context.
and intrahepatic cholestasis of pregnancy (ICP) (28). The Swansea criteria have been proposed as a diagnostic tool for
AFLP (3,8). (Table 3) One study concluded that the Swansea crite-
ria had 100% sensitivity and 57% specificity with an 85% positive
CLINICAL MANIFESTATIONS AND DIAGNOSTIC predictive value and a 100% negative predictive value for a sample
TOOLS of 24 patients (18). These criteria (Table 3) are considered "posi-
AFLP shares symptoms with other liver diseases that are unique to tive" if at least 6 out of the 15 criteria are met. They are intended
pregnancy (13,27). Patients may present with non-specific symp- to be used in the absence of other diagnosis of liver dysfunction
toms such as nausea and vomiting, encephalopathy, abdominal pain, (that is, HELLP syndrome, preeclampsia), which makes applica-
jaundice, and polydipsia and polyuria that rapidly progress to acute tion challenging if multiple conditions co-exist.
liver failure marked by complications such as coagulopathy, hypo- There is no study that has demonstrated that use of the criteria
glycemia, and renal failure (27,29). Laboratory studies may reveal results in earlier time to diagnosis. In the study above, 8 of the 20
not just elevated liver enzymes, but true liver dysfunction, which patients later confirmed to have AFLP on biopsy also fulfilled
occurs in AFLP and not in other obstetric liver diseases (16,28,30). criteria for HELLP syndrome, clouding the accuracy of diagnosis
Clinical findings and laboratory data are the key tools in diag- (18). Minakami et al. point out that the Swansea criteria seem to be
nosing AFLP and distinguishing this rare but life-threatening dis- most helpful when women are critically ill, which undermines the
ease from other more common liver diseases in pregnancy such value of a diagnostic model (19,25). Furthermore, the use of the
as preeclampsia, HELLP syndrome, and intrahepatic cholestasis of Swansea criteria in the research literature has not been standard-
pregnancy (Table 2). AFLP may be distinguished from HELLP or ized. Some authors have required patients to have 9 instead of just
preeclampsia by such differences as hypoglycemia, elevated INR, 6 criteria in order to meet diagnosis of AFLP (29).
and signs of synthetic liver dysfunction such as encephalopathy A potential question is whether certain criteria might be
and disseminated intravascular coagulopathy (DIC) (27). How- weighted more heavily to provide a more accurate diagnosis. A
ever, the diagnosis of AFLP does not exclude the diagnosis of other recent Chinese study showed a statistically significant association
liver diseases of pregnancy, and vice versa. between hyperbilirubinemia and prolonged duration to recovery.
A liver biopsy is not necessary to make the diagnosis of Prothrombin time, plasma fibrinogen, and platelet count were also
AFLP in most cases and is only done to determine the need found to have significant bearing, while leukocytosis, hypoglyce-
for early delivery in indeterminate cases (32). An expedited mia, and AST showed no predictive value (20).

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Acute Fatty Liver Disease of Pregnancy 3

Table 2. Characteristic features and ndings of several liver disorders of pregnancy (31)

AFLP HELLP Preeclampsia ICP

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Clinical features Abdominal pain, vomiting, Abdominal pain, Abdominal pain, hypertension, Pruritis, jaundice (25%)
polydipsia/polyuria, vomiting, proteinuria, proteinuria, headache, blurred
encephalopathy headache, peripheral edema vision, peripheral edema
Ascites
Thrombocytopenia
Bilirubin Usually <10 mg/dl <5 mg/dl <5 mg/dl <5 mg/dl
(ULN 1.9 mg/dl)
Bile acids 30100x
Hypoglycemia
Proteinuria
Aminotransferases 510 1100 1100 15
Uric acid in 80%
Hemolysis
Creatinine
Histopathology Microvesicular Fibrin deposition, hemorrhage, Fibrin deposition, hemorrhage, Hepatocellular bile and canalicular
steatosis hepatocellular necrosis hepatocellular necrosis bile plugs, cholestasis
AFLP, acute fatty liver of pregnancy; HELLP, hemolysis, elevated liver enzymes, low platelet count; ICP, intrahepatic cholestasis of pregnancy.

found that women with AFLP had increased detectable fat on


Table 3. The Swansea criteria (5) MRI that disappeared within 2 weeks into the postpartum period.
Vomiting One woman who met six Swansea criteria and was later diagnosed
Abdominal pain with preeclampsia/HELLP did not have the same radiographic
findings such as a peripartum excess of fat detected on MRI (35).
Polydipsia/polyuria
Non-invasive imaging may become more accepted as part of the
Encephalopathy standard workup for AFLP in the future.
Bilirubin>0.8 mg/dl
Hypoglycemia<72 mg/dl
Elevated urea>950 mg/dl
AFLP AND DEFECTS IN MATERNAL AND FETAL FATTY
ACID OXIDATION
White blood cell count >11109/l
It is well established that certain inheritance patterns in mother
Ascites and fetus, such as long-chain 3-hydroxyacyl-CoA dehydrogenase
ALT >42 U/l (LCHAD) deficiency, are linked to fetal fatty oxidation defects
Ammonia >66 _ mol that may predispose to AFLP (3638). Although AFLP has also
AKI or Cr>1.7 mg/dl
been reported in cases not associated with genetic defects in fatty
acid oxidation, genetic associations may have implications for
Coagulopathy or PT >14 s
mothers with AFLP and their children.
Bright liver on ultrasound Fetal fatty acid oxidation defects (FAOD) are believed to be
Microvesicular steatosis on liver biopsy associated with the risk of AFLP. FAODs are caused by deficien-
Legend: A patient positive for at least 6 of the 15 criteria should be considered cies of specific enzymes involved in mitochondrial metabolism
for a diagnosis of AFLP. However, the Swansea criteria are meant to be applied of fatty acids. Clinical findings of FAOD in affected individu-
in cases where no other liver disease of pregnancysuch as HELLP or preec-
lampsiahas been diagnosed. als range from mild-to-multi-organ failure with encephalopathy,
cardiomyopathy, liver failure, severe hypoglycemia, and skeletal
myopathy. Although rates of AFLP may differ by ethnic group, the
internationally compiled data show the incidence of FAOD to be
Imaging may be helpful in supporting the diagnosis of AFLP around 1:9,300 in Caucasians but lower in Asians (39).
but its role remains unclear (22,23). Changes such as brightness One of the most-studied risk factors for AFLP is fetal long-chain
or fatty infiltration of the liver on ultrasound may be non-specific 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, which
or non-diagnostic (14,24,34). But advances in technology may is categorized within a group of disorders named fetal fatty acid
prove useful. An observational study in France of five patients oxidation defects (FAOD) (40). The carrier incidence for LCHAD

2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY


4 Liu et al.

deficiency has been reported as 1 in 675 in the United States (41). in the placenta as in the fetal liver (41). Because the fetus and
Although LCHAD deficiency has the most widely reported asso- placenta share a uniform genotype, when FAO fails in the fetus,
ciation with AFLP, it should be noted that any enzyme involved the placenta is similarly unable to proceed with normal meta-
REVIEW

in fatty acid oxidation may have a similar effect. The more com- bolic pathways. As shown in Figure 1, intermediate products of
mon FAODs in addition to LCHAD are medium-chain acyl- metabolism may accumulate in the placenta and the maternal
CoA dehydrogenase (MCAD), and very long-chain acyl-CoA blood, creating toxic effects in the mother (44).
dehydrogenase (VLCAD) deficiencies, although MCAD has rarely Defects in FAO become clinically evident as toxic metabolic
been associated and VLCAD has not been associated with AFLP. intermediates build up in maternal hepatocytes. Lipotoxicity from
Short-chain acyl-CoA dehydrogenase (SCAD) has also been rarely the accumulation of fatty acids and their metabolites in the mater-
associated with AFLP (36). nal blood creates an environment of increased reactive oxygen
FAODs affect the mother because of physiologic metabolic species (ROS) that have deleterious effects on hepatocytes such as
changes during pregnancy that result in increased demand activation of inflammatory pathways and cellular necrosis leading
for fatty acids. Animal studies have shown that pregnant mice to acute maternal hepatic failure, which may manifest as AFLP
naturally develop impaired mitochondrial beta-oxidation of fatty (38,45). This is demonstrated by cases of toxicity of arachidonic
acids, and it is possible that the hormonal changes during preg- acid and acetylsalicyclic acid (these inhibit long-chain fatty acid
nancy in women affect mitochondrial oxidation (42). During oxidation in mitochondria), which have been associated with
pregnancy, increased activity of maternal hormone-sensitive clinical manifestations and histopathologic findings similar to
lipase--found in adipose tissue, as well as the adrenal glands, AFLP (46,47).
gonads, and cardiac and skeletal muscle--in combination with The reduced capacity of heterozygous women to handle increased
gestational insulin resistance causes an increase in the levels of demand for FAO during the shift to ketogenesis in later stages of
triglycerides that are broken down into free fatty acids (FFA) in pregnancy may contribute to maternal liver disease (37,48). In
maternal blood. cases of fetal FAOD, the risk of maternal liver disease is increased
These FFA are also metabolized by the fetus and placenta for whether the fetus is a homozygote or compound heterozygote for
utilization in growth and development. The placenta contains one of the aforementioned enzymatic defects (22). A question
lipoprotein lipase that breaks down triglycerides into FFA, and that remains is how maternal carrier status affects disease: while
fatty acid-binding proteins and carnitine transporters that direct mothers heterozygous for LCHAD deficiency have been found
the flow of FFA to the fetus (43). It also contains enzymes involved to have higher risk of AFLP, it is unclear whether other defects of
in fatty acid oxidation (FAO), such as LCHAD and other enzymes FAO lead to the development of AFLP in carriers.
involved in fatty acid metabolism, whose levels are regulated The most important enzyme in the etiology of AFLP is long-chain
throughout pregnancy. These enzymes may contribute to overall 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (LCHAD) (49).
metabolic stress on the mother. In one study, the level of placental LCHAD is located on the C-terminal portion of the alpha-subunit
LCHAD activity during weeks 1219 of gestation was as high of the mitochondrial trifunctional protein (MTP) on the inner

Fetal liver

Long-chain fatty acids + CoA

TI
CP I Mitochondrial trifunctional AFLP, preeclampsia, HELLP
Carnitine + TI protein
CP
Acyl-CoA
MCAD
4
1 Liver dysfunction

2,3-enoyl-CoA Medium-chain
OXIDATION fatty acids +
3-ketoacyl-CoA
metabolites
3
1 = acyl-CoA dehydrogenase (MCAD, Oxidative stress
LCAD, VLCAD) 2
2 = 2,3-enoyl-CoA hydratase
LCHAD
3-hydroxyacyl-CoA
3 = 3-hydroxyacyl-CoA dehydrogenase
(SCHAD, LCHAD)
4 = 3-ketoacyl-CoA thiolase (SKAT,
LKAT) Long-chain fatty acids +
CPT I - Carnitine palmitotransferase I metabolites Maternal circulation
CPT II - Carnitine palmitotransferase I

Figure 1. Homozygous enzymatic defects in fetal and placental beta-oxidation of fatty acids as part of ketogenesis (causing clinical conditions such as
LCHAD and MCAD deciency in offspring) lead to accumulation of fatty acid chains that are transferred to a heterozygous mother, a proposed pathogenesis
for AFLP (35,40). Each step of the pathway may be catalyzed by homologous enzymes (for example, MCAD, LCAD, or VLCAD may create 2,3-enoyl-CoA).
The black x depicts the effect of an LCHAD or MCAD deciency that leads to accumulation of fatty acid metabolites that enter maternal circulation and
may contribute to maternal liver disease. A full color version of this gure is available at the American Journal of Gastroenterology website online.

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Acute Fatty Liver Disease of Pregnancy 5

Table 4. Fetal fatty acid oxidation defects reported to be associated with AFLP(36)

Incidence Symptoms in affected individuals (neonates) Diagnosis


(general population)

REVIEW
SCAD (34,58,59) 1:35,00050,000 Encephalopathy, progressive myopathy; ranging Increased butyrylcarnitine (C4) concentrations
from benign to severe in plasma and/or increased ethylmalonic acid
concentrations in urine under non-stressed
conditions (on at least two occasions)
MCAD (4,34,60) 1:10,0001:27,000 Hypoglycemia, hepatic encephalopathy, sudden Increased octanoylcarnitine (serum), medium-chain
death dicarboxylic acids and glycine derivatives such as
hexanoylglycine, suberylglycine, phenylpropionyl-
glycine (urine)
LCHAD/MTP Estimated 1:62,000 Cardiac and skeletal myopathy, hypoglycemia, Increased dicarboxylic acids with a hydroxy group
(34,35,50,51,61,62) acidosis, neuropathy/retinopathy, hyperammonemia, and their carnitine derivatives
sudden death
SCAD, short-chain acyl-CoA dehydrogenase; LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; MTP, mitochondrial
trifunctional protein.

mitochondrial membrane. It catalyzes the third step in oxidation Since there is clinical overlap between AFLP, HELLP and pre-
of long-chain fatty acids. There is a strong correlation between a eclampsia, women with an LCHAD heterozygous mutation are
recessively inherited defect in LCHAD in the infant and AFLP more likely to have received a concomitant diagnosis of HELLP or
in the mother (50,51). Mothers heterozygous for an FAOD and preeclampsia. This suggests that the genetic mechanisms identified
pregnant with a homozygous fetus have been found to develop in patients with AFLP may improve our understanding of other
preeclampsia and HELLP as well (50,52,53). In cases of fetuses diseases of pregnancy that affect the liver (52). However, these
with LCHAD, maternal liver disease including AFLP may occur in mechanisms are heterogeneous even in association with AFLP and
2070% of cases and is 50 times more likely to occur (36). In that the precise mechanisms remain unknown.
same study, mothers were 12 times more likely to develop AFLP if
there was a fetal fatty acid short or medium-chain oxidation defect.
The most common defect, associated with 6590% of LCHAD MANAGEMENT
patients, is a 1528 G >C mutation in exon 15 of the alpha-subu- As discussed above, there is no universal, standardized approach
nit, which results in the exchange of glutamic acid for glutamine at to diagnosis, but characteristic laboratory findings, imaging, find-
amino acid 474 called the E474Q mutation (54). In one study, 79% ings on biopsy, and use of tools like the Swansea criteria may be
of women carrying fetuses with the E474Q mutation had AFLP used for diagnosis when clinical suspicion is present (Figure 2).
or the HELLP syndrome (45). However, there is also evidence Delivery of the fetus is paramount. Treatment is largely supportive.
that fetal LCHAD deficiency is not always associated with AFLP However, fulminant liver failure due to AFLP may not be revers-
(5557). One retrospective examination of 10 cases of AFLP ible, underscoring the importance of early diagnosis.
showed that none of the fetuses had the G1528C mutation (58,59) In the immediate postpartum setting, the most common life-
and in one Japanese study, none of three fetuses had the mutation, threatening conditions associated with AFLP include acute liver
implying that there was some other cause of AFLP (60). failure with encephalopathy, disseminated intravascular coagu-
In fact, other mutations that cause mitochondrial trifunctional lation, acute renal failure, and gastrointestinal bleeding (6567).
protein (MTP) deficiency have been identified. These mutations Although hepatic rupture or infarction are more associated with
and others reported with AFLP are described in Table 4. Isaacs preeclampsia or HELLP, hepatic rupture, as well as hematoma, in
et al. (61) describe a method using single-stranded conforma- association with AFLP has been reported (68,69). Mothers may
tion variance and DNA sequence analysis for identifying other require admission to intensive care settings for frequent monitor-
mutations that may be associated with AFLP. Other deficiencies ing for coagulopathy and blood products, aggressive correction
of fetal and placental mitochondrial oxidation associated with of hypoglycemia, mechanical ventilation for acute respiratory
AFLP include fetal short-chain acyl-CoA dehydrogenase defi- distress syndrome (ARDS), dialysis, or plasmapheresis (70,71).
ciency and fetal carnitine palmitoyltransferase deficiency (62,63). N-acetylcysteine is often used, but there are no series or larger
In a case-control study comparing fetal oxidation defects with the observational studies to provide evidence for this approach (72).
occurrence of maternal liver disease during pregnancy, two cases Liver transplantation has been explored as a last measure, but
of medium chain acyl-CoA dehydrogenase deficiency associated its use remains controversial. AFLP is usually a reversible con-
with AFLP were noted (36). Most recently, Santos and colleagues dition, and women may be expected to recover normal func-
provided the first description of a normal fetus with a maternal tion within a week. If liver function worsens, it may be a sign of
FAO defect in medium-chain acyl-CoA dehydrogenase resulting concurrent sepsis or hypoxic-ischemic liver injury (7). Use of
in AFLP in the late third trimester (64). liver transplantation in AFLP has been reported for cases of

2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY


6 Liu et al.

Algorithm for diagnosis and management of AFLP

Transaminitis at >20
weeks of pregnancy
REVIEW

Review symptoms: CBC, INR, serum Consider imaging Workup for transaminitis: viral
abdominal pain, glucose, creatinine, (ultrasound) hepatitis, autoimmune
nausea/vomiting, bilirubin, bile acids, uric hepatitis, viral infection (such
polydipsia/polyuria, acid level, urinalysis as VZV), gallstone disease,
anorexia, lethargy (including urine protein) drug-induced toxicity,
ischemia, Budd-Chiari
syndrome

Consider AFLP as a diagnosis if:


- Consistent symptoms
- Consistent laboratory findings
including signs of liver dysfunction
- AST and ALT typically <1000
- AKI (creatinine increase >0.3 mg/dL)
- Ascites or encephalopathy
- Bright liver on ultrasound
- Consistent findings on liver biopsy

Diagnostic uncertainty Diagnosis of AFLP

Delivery of fetus and supportive care, consultation


with multidisciplinary team including high-risk
Consider Consider alternate
obstetrician, gastroenterologist
liver diagnosis
biopsy (preeclampsia,
HELLP,ICP) Worsening clinical picture or instability:
consider need for liver transplantation

Figure 2. AFLP is associated with ndings such as right upper quadrant abdominal pain, nausea/vomiting, polydipsia and/or polyuria, or clinical signs of
liver dysfunction such as encephalopathy and ascites. AST and ALT are usually <1000. Other laboratory ndings may include thrombocytopenia, elevated
INR, elevated uric acid level, and elevated creatinine suggesting AKI. Imaging may help support the diagnosis although ndings are non-specic. If there
is diagnostic uncertainty, liver biopsy is the gold standard of diagnosis and will show microvesicular steatosis. Therapy consists of immediate delivery of
the fetus and supportive care. Discussion with a high-risk obstetrician should be initiated. If liver function does not recover afterwards, transplantation may
need to be considered.

worsening clinical status, such as encephalopathy and lactic care unit stay, women who receive prompt and appropriate sup-
acidosis, and persistent liver failure despite maximal medical portive care have improvement over 13 weeks. Evidence of arrest
therapy (73). One Dutch case series found only two cases of liver of hepatic necrosis--decreasing LFTs--may occur within 12 days
transplantation between 1979 and 2012 in the Netherlands, one of delivery (2). Cholesterol and bilirubin levels lagged behind by
orthotopic and one auxiliary; both had good outcomes (72). There about 3 to 4 days. Acute kidney injury typically resolved within
are no official guidelines for determining which AFLP patients 710 days. Most often, histological changes resolve rapidly after
should be considered for transplantation. delivery. However, histological changes may occasionally persist
for up to 5 weeks (2). Other reports indicated that damage may
be more long-lasting, such as in a case of chronic pancreatitis that
SHORT AND LONG-TERM FETAL-MATERNAL lasted 3 months after delivery (10).
OUTCOMES IN AFLP; SCREENING While preeclampsia is known to recur, there is no demonstrated
RECOMMENDATIONS pattern of recurrence for women who have one pregnancy com-
Maternal mortality rates for AFLP have improved in the past plicated by AFLP. There are case reports of recurrent episodes of
few decades. Recent data show that maternal mortality rates in AFLP, but these are very few in number (75).
the United States for AFLP were around 85% in the 1980s and More work is needed to understand long-term maternal out-
dropped to 1015% by the 2000s (2,3,70,71). One recent survey comes, as many studies do not follow women past the immedi-
found that, worldwide mortality, once close to 100%, had decreased ate postpartum period. A recent study by Xiong et al. studied 25
to <10% (74). This has largely been attributed to greater recogni- women over a mean of 54 months post-delivery and found no
tion of AFLP and time to diagnosis with subsequent delivery of the major adverse events (76). Ultrasound findings were significant for
fetus and improvements in obstetric intensive care (6,7). increased echogenicity in about 40% of the patients, and another
The time frame needed for recovery depends on disease severity. 40% were normal. This preliminary work suggests that once AFLP
Although there is a risk of prolonged complications and intensive has resolved, patients may have a relatively benign course. And

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Acute Fatty Liver Disease of Pregnancy 7

yet, with recent findings that other diseases of pregnancy, such as comes, could be gleaned from further cohort studies. Due to the
preeclampsia, have profound implications for future health, such rarity of this condition, much of our understanding of AFLP is
as increased risk of cardiovascular disease and stroke for both currently based on small retrospective case series and more work

REVIEW
mother and fetus (26,77), it is imperative to follow women with needs to be done to understand AFLP at a population level.
AFLP for longer periods of time to see if there may be long-term Research examining risk factors for AFLP, such as environmen-
adverse implications to the mother (40,78). tal factors, preexisting maternal conditions like diabetes and obe-
Despite progress in maternal mortality rates, fetal mortality sity, and family history, may provide greater ability to risk-stratify
remains high. Fetal mortality has been estimated as high as 20%; women with AFLP. Could an occurrence of AFLP predispose
this may be due in part to maternal acidosis that has immediate women to developing chronic conditions such as diabetes, or to
detrimental effects on the fetus as well as the general complications developing other diseases of pregnancy such as preeclampsia or
of prematurity (15). In cases where FAOD can be identified, the HELLP in the future? The implications of genetic associations
effects of fatty acid oxidation defects on the offspring range from with fetal conditions such as LCHAD deficiency and other FAODs
mild to profound (see Table 4). In one follow-up of 50 children remains enticing, but it is essential to study whether these genetic
with LCHAD deficiency, there was a 38% mortality rate within 3 mutations are causative, highly associated, or not associated. Fur-
months of diagnosis as well as chronic issues such as retinopathy, ther studies at the population, individual, and genetic levels can
metabolic crises, and muscle pain and hypotonia (31). In cases contribute to more effective treatment and counseling for AFLP.
where no fatty oxidation defect can be identified, children appear
to have no adverse outcomes. CONFLICT OF INTEREST
Fetal/newborn screening for FAOD has been suggested, and in Guarantor of the article: Joy Liu, MD.
fact screening for several disorders including MCAD and VLCAD Specific author contributions: Joy Liu: article concept and design;
is done in multiple states in the United States (59). In the United drafting of manuscript. Jacqueline Wolf: article concept and design;
States, newborn screeningmass spectrometry using the dried critical revision of manuscript for important intellectual content;
blood spotis based on an acylcarnitine profile and does not supervision. Tara Ghaziani: critical revision of manuscript for
occur for all inborn errors of metabolism. The cost varies by state. important intellectual content.
(On the basis of the data for phenylketonuria and congenital adre- Financial support: None.
nal hyperplasia, it may range up to $59) (79,80). Abnormal results Potential competing interests: None.
trigger confirmatory testing, consisting of blood and urine sam-
ples, costing about $100, and genetic testing may be done within a
couple of months of birth with techniques such as gene panels or Study Highlights
next-generation sequencing.
Wilcken et al. (81,82) found that in Australia, the estimated cost WHAT IS CURRENT KNOWLEDGE
of a newborn screening assay for the more common FAODs is Acute fatty liver of pregnancy (AFLP) is an obstetric
about $0.70 but may help avoid long-term costs and have intan- emergency characterized by acute liver failure, which
gible benefits for parents. For example, screening for MTP, mito- distinguishes it from other conditions like preeclampsia or
the HELLP (hemolysis, elevated liver enzyme levels, and
chondrial trifunctional protein, which is very similar to LCHAD, low platelet levels) syndrome.
demonstrably reduced morbidity and mortality for a group of 11
WHAT IS NEW HERE
patients (83).
However, the recommendation to screen for FAOD across the
Liver biopsy may be useful if the diagnosis is uncertain,
but is not considered essential if the diagnosis can be
general population remains controversial (39,84). Two reason- made clinically.
able suggestions may be to screen obstetric patients for AFLP Defects in fetal fatty oxidation have been shown to
around the thirty-fourth week (85) and longitudinally monitor increase the risk of AFLP; it may be pragmatic to screen
children of mothers with AFLP for symptoms of LCHAD defi- women based on symptoms around the thirty-fourth week
ciency (86). and follow the offspring for metabolic disorders.
Mortality rates have improved in recent decades. Treatment
consists of immediate delivery of the fetus and multi-
disciplinary management in a closely monitored setting.
CONCLUSIONS
AFLP is an obstetric emergency that must be diagnosed as quickly
More work is needed to improve the diagnostic tools for
AFLP, and understanding of its epidemiology and long-term
as possible. Recent studies have suggested that certain criteria, maternal outcomes.
such as INR, platelets, and bilirubin, may be more useful for prog-
nostication, although more work is needed to determine which
diagnostic parameters are most specific, reliable, and relevant for
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