Introduction
Acute Fatty Liver of Pregnancy (AFLP) is a rare but severe complication arising in the late stages of pregnancy or shortly after childbirth. While its precise causes remain under investigation, AFLP is strongly associated with disruptions in how a fetus processes fatty acids. Diagnosing AFLP early can be complex, as its symptoms often overlap with more common pregnancy-related conditions such as pre-eclampsia, viral hepatitis, and intrahepatic cholestasis of pregnancy. However, a thorough medical history, careful physical examination, and specific laboratory and imaging findings are usually enough for Aflp Diagnosis. Liver biopsy is seldom necessary. The cornerstone of managing AFLP is supportive care and prompt delivery of the baby, which are critical for improving outcomes for both mother and child.
AFLP, sometimes referred to as acute yellow atrophy of the liver, involves the buildup of tiny droplets of fat in liver cells, without significant inflammation or cell death. It affects approximately 1 in 10,000 to 15,000 pregnancies. Historically, AFLP was associated with very high rates of death for both mothers (75%) and babies (85%). However, thanks to advances in diagnosis and treatment, these rates have significantly decreased to around 18% and 23% respectively. Despite ongoing research, the exact mechanisms leading to AFLP are still not fully understood. Currently, the best approach to treatment involves supportive medical care and delivering the baby as quickly as possible. This article provides a detailed overview of AFLP, covering its causes, how it develops, clinical signs, aflp diagnosis, and treatment strategies.
Clinical Presentation of AFLP
AFLP typically manifests in the third trimester of pregnancy, with most cases occurring around 35 to 36 weeks of gestation, although it can range from 28 to 40 weeks. There are documented cases of AFLP appearing as early as 26 weeks and even in the immediate postpartum period. In rare instances, it has been diagnosed as early as 22 weeks. The varied nature of AFLP’s symptoms and its overlap with other late-pregnancy conditions make early aflp diagnosis challenging.
Initial symptoms are often nonspecific and can include loss of appetite, nausea, vomiting, general discomfort, fatigue, headache, and abdominal pain. Upon physical examination, patients frequently present with fever and jaundice, a yellowing of the skin and eyes, which is a common sign, occurring in over 70% of AFLP cases as the condition progresses. Tenderness may be present in the upper right abdomen or the mid-abdominal area. Notably, the liver is usually normal in size or small and not easily felt during examination.
In severe cases, AFLP can lead to widespread organ dysfunction, including acute kidney failure, brain dysfunction (encephalopathy), gastrointestinal bleeding, inflammation of the pancreas (pancreatitis), and blood clotting problems (coagulopathy). Some women with AFLP may also develop pre-eclampsia, characterized by edema and high blood pressure. Conditions like HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), pre-eclampsia, thrombotic thrombocytopenia purpura, and AFLP are thought to be related and possibly part of a spectrum of the same underlying disease process. Although rare, transient diabetes insipidus, a condition affecting fluid balance, can also occur.
The prevalence of common signs and symptoms for aflp diagnosis is detailed in Table 1.
AFLP also poses risks to the fetus. Maternal metabolic acidosis, resulting from the liver’s reduced ability to clear lactate from the blood, is a significant complication. This acidosis directly impacts the fetus’s acid-base balance. Therefore, quickly correcting metabolic acidosis in the mother is vital for the fetus’s well-being, and prompt delivery may be necessary.
Laboratory Findings for AFLP Diagnosis
Laboratory tests play a crucial role in aflp diagnosis. Table 2 summarizes typical laboratory abnormalities seen in AFLP. Patients often exhibit an elevated white blood cell count (above 15 × 109/L), while hematocrit levels are usually normal unless significant bleeding has occurred. Hemolysis and decreased platelet counts (thrombocytopenia) may also be present. Blood clotting tests typically show prolonged prothrombin and partial thromboplastin times, and fibrinogen levels are often reduced. Disseminated intravascular coagulopathy (DIC), a serious clotting disorder, is indicated by the presence of fibrin split products in about 75% of patients.
Liver function tests reveal elevated serum aminotransferases (AST and ALT), typically in the range of 300 U/L to 500 U/L, but levels can vary from normal to as high as 1000 U/L. Elevated aminotransferases may be accompanied by increased serum ammonia, amino acid levels, lactic acidosis, uric acid, elevated bilirubin (hyperbilirubinemia), and low blood sugar (hypoglycemia) due to impaired liver glycogen breakdown. Alkaline phosphatase levels may be significantly elevated, up to ten times normal, although it’s important to note that alkaline phosphatase can also increase normally in the third trimester of pregnancy. Kidney function may also be affected, with elevated blood urea nitrogen and creatinine levels, and acute kidney failure can occur in severe cases.
Differential Diagnosis of AFLP
Aflp diagnosis can be challenging because its initial symptoms are often nonspecific and can mimic several other conditions. The patient’s medical history, clinical signs, and biochemical abnormalities may resemble acute viral hepatitis, pre-eclampsia, HELLP syndrome, intrahepatic cholestasis of pregnancy, and other liver disorders. Given the rarity of AFLP, when evaluating a pregnant woman with liver dysfunction, it is essential to first rule out more common causes.
Pre-eclampsia, a common multiorgan disease in late pregnancy, is a primary consideration in differential aflp diagnosis. While pre-eclampsia can coexist with AFLP, patients with pre-eclampsia alone typically do not present with jaundice or hypoglycemia, which are characteristic of AFLP. Furthermore, AFLP often develops more rapidly than pre-eclampsia, which can progress over days or weeks. Severe coagulopathy, such as DIC, is also less common in pre-eclampsia alone.
Acute viral hepatitis must also be excluded in pregnant women showing signs of liver dysfunction. Viral hepatitis usually presents with much higher serum transaminase levels, often exceeding 1000 U/L, and viral serology tests will be positive. Additionally, uric acid levels are typically not elevated in fulminant hepatitis, and signs of pre-eclampsia are absent.
Intrahepatic cholestasis of pregnancy, another condition causing jaundice, is characterized by intense itching (pruritus) and elevated alkaline phosphatase. It is not typically associated with abdominal pain, nausea, vomiting, liver failure, or DIC, which are more common in AFLP. Key characteristics that aid in the differential aflp diagnosis of common liver diseases in pregnancy are summarized in Table 3.
Imaging studies, such as ultrasound and computed tomography (CT) scans, may show fatty infiltration of the liver, but their sensitivity and specificity are not high enough to definitively confirm aflp diagnosis. False negative results are frequent. Historically, liver biopsy was considered necessary for aflp diagnosis, dating back to 1955 when AFLP was difficult to distinguish from severe infectious hepatitis. However, liver biopsy carries risks, especially in the presence of coagulopathy. Today, with available serological markers for viral hepatitis and characteristic clinical and biochemical findings for AFLP, liver biopsy is generally not required for diagnosis and is rarely performed clinically.
While AFLP shares features with other more common illnesses, a careful medical history, physical examination, and supportive laboratory and imaging results are usually sufficient to establish aflp diagnosis. Liver biopsy is not recommended to confirm AFLP or differentiate it from severe pre-eclampsia, as the management for both conditions is similar. Liver biopsy might be considered in cases where liver function does not improve after delivery or when a definitive diagnosis is needed urgently in the early stages of AFLP to justify immediate delivery. Microscopic examination of liver tissue in AFLP reveals microvesicular steatosis, predominantly in zone 3 of the liver lobule, with less involvement in zone 1. There is pericentral pallor, lobular disarray, and vacuolization of hepatocytes in the centrizonal region. Special stains, like oil red O on fresh-frozen specimens, are needed to visualize the fat. Patchy hepatocellular necrosis may be present, but widespread necrosis or inflammation is typically absent.
Management Strategies for AFLP
The cornerstones of AFLP management are early aflp diagnosis, prompt delivery of the fetus, and intensive supportive care. Because laboratory findings may not always reflect the severity of AFLP, a high degree of clinical suspicion and a low threshold for hospital admission for monitoring are essential. Patients at high risk of multisystem organ failure and death should be admitted to the intensive care unit (ICU).
Prior to delivery, maternal stabilization is paramount. This includes managing the airway, treating hypertension, and correcting hypoglycemia, electrolyte imbalances, and coagulation abnormalities. Careful administration of intravenous fluids and blood products, frequent monitoring of vital signs, and assessment of mental status changes are crucial. Simultaneous fetal monitoring is also necessary. Effective management requires a multidisciplinary approach involving specialists from intensive care, gastroenterology, and perinatology.
Once the mother is stable, delivery of the fetus is the next critical step. Vaginal delivery is preferred if it is safe and feasible; however, cesarean delivery is often necessary due to rapidly deteriorating maternal or fetal conditions. Postpartum care in AFLP is equally important. Hemodynamic monitoring is essential due to the increased risk of bleeding from coagulopathy. Transfusions of fluids and blood products may be required. Patients remain at risk for hypoglycemia, necessitating glucose infusions. Furthermore, potential complications like pancreatitis, which can develop after liver and kidney dysfunction, should not be overlooked. The development of pseudocysts or hemorrhagic pancreatitis can be challenging to manage, especially with existing coagulopathy. Therefore, serial monitoring of serum lipase and amylase levels for several days after the onset of hepatic dysfunction may be beneficial. Imaging studies like CT or MRI can be useful in evaluating for pseudocysts or hemorrhagic pancreatitis.
Liver transplantation is a rare intervention for AFLP. A review of the American United Network for Organ Sharing (UNOS) database from 1987 to 2003 identified only eight liver transplants performed for pregnancy-associated liver conditions, including HELLP syndrome. However, case reports indicate that liver transplantation can be life-saving in fulminant hepatic failure due to AFLP, reversing multisystem organ failure. Liver transplantation should be considered for women with severe liver failure from AFLP who show signs of irreversible liver damage despite delivery and aggressive supportive care, particularly those with hepatic encephalopathy, severe metabolic acidosis, worsening coagulopathy, or liver rupture with necrosis.
Etiology and Pathophysiology of AFLP
Recent research points to mitochondrial dysfunction as a key factor in the etiology of AFLP. The process of mitochondrial fatty acid beta-oxidation, which breaks down fatty acids for energy, involves several transport steps and enzymatic reactions. A deficiency in the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) can lead to the accumulation of medium- and long-chain fatty acids. LCHAD deficiency is an autosomal recessive disorder, and heterozygous LCHAD deficiency has been found in some women who develop AFLP.
In 1991, an association was reported between recurrent AFLP and LCHAD deficiency, suggesting that some women may have an inherited defect in beta-oxidation, predisposing them to AFLP. Subsequent studies in the early 1990s further linked maternal AFLP or HELLP syndrome to LCHAD deficiency in their children. Retrospective studies have also shown a correlation between LCHAD deficiency and AFLP.
The gene for LCHAD was identified in 1995, and specific genetic mutations associated with this deficiency were found. The most common mutation, 1528G→C in the alpha-unit of the trifunctional protein gene, results in an amino acid substitution (E474Q). This mutation accounts for 65% to 90% of LCHAD-deficient patients. The exact mechanism by which fetal LCHAD deficiency causes severe liver disease in the mother is not fully understood. The prevailing hypothesis is that mothers who are heterozygous for the LCHAD mutation do not typically have impaired fatty acid oxidation under normal conditions. However, if the fetus inherits two copies of the mutated gene (one from each heterozygous parent), the fetus becomes unable to effectively process long-chain fatty acids. These unmetabolized fatty acids then cross the placenta into the mother’s circulation, overloading her liver and leading to the clinical manifestations of AFLP. Delivery removes the metabolic stress from the mother, which may explain why liver function usually normalizes after childbirth.
However, the link between AFLP and LCHAD deficiency is not universally accepted, as some studies have not confirmed this association. One possible explanation is that only specific LCHAD mutations increase the risk of AFLP. Studies have shown that the E474Q mutation is particularly associated with pregnancy complications. Approximately 15% to 20% of mothers with AFLP give birth to children with LCHAD deficiency, while fetal LCHAD deficiency is less commonly associated with HELLP syndrome.
LCHAD deficiency in infants can have serious consequences. The buildup of toxic products from impaired fatty acid oxidation can cause muscle degeneration and fatty infiltration, affecting both skeletal and cardiac muscle. The liver becomes enlarged with lipid deposits. Infants may develop progressive jaundice and impaired bilirubin metabolism. Inherited LCHAD deficiency typically presents in the newborn period or early childhood, often triggered by fasting or viral illnesses. Symptoms can include severe liver failure, cardiomyopathy, and hypoketotic hypoglycemic encephalopathy, which can be difficult to treat. Management usually involves a diet low in long-chain fatty acids and supplemented with medium-chain triglycerides. While dietary therapy can improve long-term outcomes, it may not prevent all complications, such as ophthalmological changes.
LCHAD deficiency can be life-threatening, especially during illnesses involving fasting or vomiting, when the body relies more on lipid metabolism for energy. Due to the potential severity of LCHAD deficiency, genetic testing for this condition is recommended for infants of mothers with AFLP, as well as for the mothers and fathers themselves. Testing for the E474Q mutation may be sufficient, as fetuses of affected mothers often carry this mutation.
In AFLP, the pathophysiology involves a progressive accumulation of fat within liver cells. Normally, the liver contains about 5% fat, but in AFLP, this can increase to 13% to 19%. This fat accumulation, along with ammonia production by hepatocytes, contributes to coagulopathy and hypoglycemia, ultimately leading to liver failure. The liver often appears small, soft, and yellow, likely due to hepatocyte damage and atrophy. Microvesicular fat infiltration can also occur in other organs, including the kidneys, pancreas, brain, and bone marrow.
Risk Factors for AFLP
Besides LCHAD deficiency, other factors have been identified as potential risk factors for AFLP, including first pregnancies (primigravidity), pre-eclampsia, carrying a male fetus, and multiple gestations. However, a direct causal link between these factors and AFLP has not been established. One hypothesis suggests that multiple pregnancies might increase the risk of AFLP due to the increased production of fatty acid metabolites from multiple fetuses. Ethnicity does not appear to be a risk factor for AFLP. Certain drugs have also been proposed as potential triggers for AFLP. One case report linked acetylsalicylic acid (aspirin) use to AFLP. It is hypothesized that nonsteroidal anti-inflammatory drugs (NSAIDs), including salicylates, can inhibit trifunctional protein and long-chain fatty acid oxidation in mitochondria, potentially precipitating AFLP in mothers heterozygous for LCHAD mutation carrying a homozygous fetus.
Maternal and Fetal Outcomes in AFLP
Maternal Outcomes
The mortality rate associated with AFLP is approximately 18%, with deaths typically resulting from sepsis, kidney failure, circulatory collapse, pancreatitis, or gastrointestinal bleeding. In survivors, liver function tests may continue to worsen for up to a week postpartum before gradually improving. Similarly, liver volume, as seen on CT scans, will decrease and then recover over time after delivery. Resolution of AFLP is indicated by the initial improvement in liver dysfunction, with liver enzymes, ammonia levels, and coagulation studies starting to normalize, followed by a decrease in serum creatinine, provided there is no permanent kidney damage. Full clinical recovery usually occurs within several weeks without long-term health issues, although histological changes in the liver may persist for months.
Recurrence of AFLP in subsequent pregnancies is possible but uncommon. Although the theoretical risk of recurrence is 25% when a mother carries a homozygous mutant or compound heterozygous fetus, documented cases are rare. This may be underreported, as many women may choose to avoid future pregnancies after experiencing AFLP. However, women who have had AFLP should be informed of the potential recurrence risk, counseled, and tested for LCHAD deficiency, along with their affected infants. If a woman with a history of AFLP becomes pregnant again, close monitoring for early signs of acute fatty liver is crucial.
Fetal Outcomes
Historically, neonatal mortality rates in AFLP were as high as 85%. However, with improved early aflp diagnosis and treatment, this rate has decreased significantly to around 23%. Despite improved perinatal survival, fetal distress and neonatal complications remain common, even when the mother appears clinically stable. The reasons for increased fetal distress and neonatal death in the absence of maternal decompensation are not entirely clear but may be related to the necessity for urgent, often premature, delivery. Therefore, close fetal monitoring and specialized neonatal care are essential in cases of AFLP.
Conclusion
AFLP is a rare but life-threatening condition that develops in late pregnancy or the early postpartum period. Early aflp diagnosis can be challenging due to overlapping symptoms with other pregnancy-related disorders like pre-eclampsia, viral hepatitis, and cholestasis of pregnancy. However, a detailed medical history, physical examination, and compatible laboratory and imaging findings are typically sufficient for aflp diagnosis, and liver biopsy is rarely needed. Prompt delivery of the infant and intensive supportive medical care remain the primary treatments for AFLP, significantly improving outcomes for both mothers and their babies.
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