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Acute Fatty Liver Disease of Pregnancy: Updates in Pathogenesis, Diagnosis, and Management Joy Liu , MD1 , Tara T. Ghaziani , MD2 , 3 and Jacqueline L. Wolf , MD2 Am J Gastroenterol 2017; 112:838–846; doi: 10.1038/ajg.2017.54 دکتر مسعود دینوری فلوی گوارش و کبد بالغین 1396/9/9

INTRODUCTION Acute fatty liver of pregnancy (AFLP) is an uncommon but potentially fatal disease unique to pregnancy that typically occurs in the third trimester Standard texts give incidence values for AFLP of 1:7000–15,000 pregnancies On rare occasions,AFLP presents as early as 22 weeks of gestation; however, it generally manifests after 30 weeks of gestation Morbidity and mortality may be higher in developing countries with less ability to provide intensive supportive obstetric care Minimal available evidence suggests that the maternal liver recovers quickly after delivery of the fetus .However, in contrast to our understanding of preeclampsia, the long-term effects of AFLP on the mother remain unknown.

EPIDEMIOLOGY AND RISK FACTORS AFLP is a relatively rare disease of pregnancy. The incidence of AFLP in recent epidemiological studies ranges between 1:7000–15,000 although in one study in South eastern Wales the incidence was as high as 1:1000 Historically, ethnic composition and geography have not been considered to be significant factors

Multigravidas are believed to be at greater risk because of increased fetal production of fatty acid metabolites by more than one fetus Underlying maternal metabolic disorders, such as type 2 diabetes,a known risk factor for non-alcoholic fatty liver disease, have been reported on a case report basis in the literature It is unclear if other liver diseases of pregnancy might predispose women to AFLP or are merely associated Up to 20% of women with AFLP may also be diagnosed with HELLP syndrome, which itself is associated with preeclampsia. Rarer associations have been reported, such as AFLP and intrahepatic cholestasis of pregnancy (ICP)

CLINICAL MANIFESTATIONS AND DIAGNOSTIC TOOLS AFLP shares symptoms with other liver diseases that are unique to pregnancy Patients may present with non-specific symptoms such as nausea and vomiting,encephalopathy, abdominal pain,jaundice, and polydipsia and polyuria that rapidly progress to acute liver failure marked by complications such as coagulopathy, hypoglycemia and renal failure Laboratory studies may reveal not just elevated liver enzymes, but true liver dysfunction, which occurs in AFLP and not in other obstetric liver diseases Clinical findings and laboratory data are the key tools in diagnosing AFLP and distinguishing this rare but life-threatening disease from other more common liver diseases in pregnancy such as preeclampsia, HELLP syndrome, and intrahepatic cholestasis of pregnancy

AFLP may be distinguished from HELLP or preeclampsia by such differences as hypoglycemia, elevated INR, and signs of synthetic liver dysfunction such as encephalopathy and disseminated intravascular coagulopathy (DIC) . However, the diagnosis of AFLP does not exclude the diagnosis of other liver diseases of pregnancy, and vice versa. A liver biopsy is not necessary to make the diagnosis of AFLP in most cases and is only done to determine the need for early delivery in indeterminate cases The hallmark histologic finding of AFLP is microvesicular fatty infiltration of hepatocytes classically involving the pericentral zone and sparing the periportal hepatocyte Although fatty change is considered the diagnostic histologichal halmark of AFLP, case series such as that conducted by Rolfesand Ishak have reported other findings as well, such as giant mitochondria and lymphocytic infiltration AFLP was distinguished from other diseases of pregnancy such as preeclampsia and HELLP by lack of sinusoidal fibrin deposition Evidence of intrahepatic cholestasis, including bile canalicular plugs and acute cholangiolitis, was seen in two-thirds of cases microvesicular steatosis can be seen in other forms of liver disease, including Reyes syndrome and drug-induced liver injury from tetracycline; histopathologic findings must be consideredin the right clinical context

Imaging may be helpful in supporting the diagnosis of AFLP but its role remains unclear. Changes such as brightness or fatty infiltration of the liver on ultrasound may be non-specific or non-diagnostic . But advances in technology may prove useful. An observational study in France of five patients found that women with AFLP had increased detectable fat on MRI that disappeared within 2 weeks into the postpartum period.

AFLP AND DEFECTS IN MATERNAL AND FETAL FATTY ACID OXIDATION It is well established that certain inheritance patterns in mother and fetus, such as long-chain 3-hydroxyacyl-CoA dehydrogenase(LCHAD) deficiency, are linked to fetal fatty oxidation defects that may predispose to AFLP. Fetal fatty acid oxidation defects (FAOD) are believed to be associated with the risk of AFLP. FAODs are caused by deficiencies of specific enzymes involved in mitochondrial metabolism of fatty acids. Clinical findings of FAOD in affected individuals range from mild-to-multi-organ failure with encephalopathy,cardio myopathy, liver failure, severe hypoglycemia, and skeletal myopathy. FAODs affect the mother because of physiologic metabolic changes during pregnancy that result in increased demand for fatty acids.

During pregnancy, increased activity of maternal hormone-sensitive lipase--found in adipose tissue, as well as the adrenal glands,gonads, and cardiac and skeletal muscle--in combination with gestational insulin resistance causes an increase in the levels of triglycerides that are broken down into free fatty acids (FFA) in maternal blood. Defects in FAO become clinically evident as toxic metabolic intermediates build up in maternal hepatocytes. Lipotoxicity from the accumulation of fatty acids and their metabolites in the maternal blood creates an environment of increased reactive oxygen species (ROS) that have deleterious effects on hepatocytes such as activation of inflammatory pathways and cellular necrosis leading to acute maternal hepatic failure, which may manifest as AFLP.

MANAGEMENT there is no universal, standardized approach to diagnosis, but characteristic laboratory findings, imaging, findings on biopsy, and use of tools like the Swansea criteria may be used for diagnosis when clinical suspicion is present. Delivery of the fetus is paramount. Treatment is largely supportive.However, fulminant liver failure due to AFLP may not be reversible,underscoring the importance of early diagnosis. In the immediate postpartum setting, the most common life threatening conditions associated with AFLP include acute liver failure with encephalopathy, disseminated intravascular coagulation,acute renal failure, and gastrointestinal bleeding .Although hepatic rupture or infarction are more associated with preeclampsia or HELLP, hepatic rupture, as well as hematoma, in association with AFLP has been reported . Mothers may require admission to intensive care settings for frequent monitoring for coagulopathy and blood products, aggressive correction of hypoglycemia, mechanical ventilation for acute respiratory distress syndrome (ARDS), dialysis, or plasma pheresis .

N-acetylcysteine is often used, but there are no series or larger observational studies to provide evidence for this approach . Liver transplantation has been explored as a last measure, but its use remains controversial. AFLP is usually a reversible condition,and women may be expected to recover normal function within a week. If liver function worsens, it may be a sign of concurrent sepsis or hypoxic-ischemic liver injury . Use of liver transplantation in AFLP has been reported for cases of worsening clinical status, such as encephalopathy and lactic acidosis, and persistent liver failure despite maximal medical therapy . There are no official guidelines for determining which AFLP patients should be considered for transplantation.

SHORT AND LONG-TERM FETAL-MATERNALOUTCOMES IN AFLP; SCREENING RECOMINDATIONS: Recent data show that maternal mortality rates in the United States for AFLP were around 85% in the 1980s and dropped to 10–15% by the 2000s . One recent survey found that, worldwide mortality, once close to 100%, had decreased to <10% . The time frame needed for recovery depends on disease severity.Although there is a risk of prolonged complications and intensive care unit stay, women who receive prompt and appropriate supportive care have improvement over 1–3 weeks. Evidence of arrest of hepatic necrosis--decreasing LFTs--may occur within 1–2 days of delivery . Cholesterol and bilirubin levels lagged behind by about 3 to 4 days. Acute kidney injury typically resolved within7–10 days. Most often, histological changes resolve rapidly after delivery. However, histological changes may occasionally persist for up to 5 weeks . Other reports indicated that damage may be more long-lasting, such as in a case of chronic pancreatitis that lasted 3 months after delivery . While preeclampsia is known to recur, there is no demonstrated pattern of recurrence for women who have one pregnancy complicated by AFLP. There are case reports of recurrent episodes of AFLP, but these are very few in number

the recommendation to screen for FAOD across the general population remains controversial . Two reasonable suggestions may be to screen obstetric patients for AFLP around the thirty-fourth week and longitudinally monitor children of mothers with AFLP for symptoms of LCHAD deficiency .

CONCLUSIONS AFLP is an obstetric emergency that must be diagnosed as quickly as possible. Recent studies have suggested that certain criteria,such as INR, platelets, and bilirubin, may be more useful for prognostication,although more work is needed to determine which diagnostic parameters are most specific, reliable, and relevant for prognosis. Research examining risk factors for AFLP, such as environmental factors, preexisting maternal conditions like diabetes and obesity,and family history, may provide greater ability to risk-stratify women with AFLP.

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