Diagnostic Challenges in Acute Fatty Liver of Pregnancy: Fever as a Key Symptom in Case Series from Indonesia

Introduction

Acute Fatty Liver of Pregnancy (AFLP) is a rare and catastrophic disease in pregnancy, with studies demonstrating incidences ranging from 1 in 4000 to 1 in 20 000 pregnancies. AFLP, originally known as “acute yellow atrophy of the liver,” is an obstetrical and medical emergency that is characterized by microvesicular fatty infiltration of hepatocytes [1,2]. A 2014 study at Dr. Hasan Sadikin General Hospital Indonesia showed that the AFLP prevalence in 2010–2013 was 1 per 1538 births [3].

The Swansea criteria are used to establish the diagnosis of AFLP. The majority of women with AFLP are diagnosed in the third trimester of pregnancy, but the condition can last up to 26 weeks postpartum [4,5]. AFLP can manifest at various clinical levels; thus, early identification of this condition is challenging. This leads to variation in clinical results. Differential diagnosis for AFLP includes several conditions that present with overlapping symptoms and laboratory findings, making accurate diagnosis crucial for appropriate management. AFLP featuring hemolysis, elevated liver enzymes, and low platelet counts (HELLP) is a syndrome that can mimic AFLP’s hepatic abnormalities and requires urgent delivery if severe. Acute liver failure presents with more pronounced systemic symptoms, including coagulopathy and altered mental status, necessitating immediate intervention to prevent severe complications. Gestational hypertension and preeclampsia can also present similarly, emphasizing the importance of distinguishing these conditions to guide management strategies focused on maternal and fetal safety. Drug-induced liver injury may further complicate the clinical picture, particularly if recent medications have been introduced. Cholestasis of pregnancy, while typically associated with elevated bile acids and pruritus rather than significant liver enzyme elevation, can cause diagnostic confusion. Lastly, acute hepatitis from viral infections can lead to elevated transaminases, a condition that overlaps with AFLP findings. Misdiagnosis among these conditions can lead to severe maternal and fetal implications, including increased morbidity and mortality, emphasizing the need for a thorough evaluation and an interdisciplinary approach to care. Timely and accurate diagnosis is essential to initiate appropriate interventions, ensuring the best outcomes for both mother and child [6,7].

Non-specific symptoms, including anorexia, nausea, vomiting, discomfort, exhaustion, headaches, and stomach pain, are frequently experienced by patients. More than 70% of AFLP patients had fever and jaundice during physical assessment [5,8]. However, fever is not included in the Swansea criteria. AFLP typically presents with symptoms such as abdominal pain, nausea, vomiting, and liver dysfunction indicators (elevated liver enzymes, hypoglycemia, and coagulopathy). Fever can occur in various conditions, including infections or other inflammatory processes, and its presence may not be directly related to the liver dysfunction characteristic of AFLP [9]. The inclusion of fever could lead to misdiagnosis or confusion with other conditions, such as infections or intra-abdominal complications, which may present similarly [9]. Moreover, AFLP is also an obstetrical and medical emergency that is characterized by rapid decline in the patient’s condition. “Rapid birth” remains the best management, even if the causes of pathophysiology are still enigmatic [7]. In this study, we would like to report 3 cases of AFLP with atypical signs or symptoms.

Case Reports

CASE 1:

The patient in Case 1 was a 37-year-old woman, G4P2A1, at 33 weeks 4 days of gestation, referred with singleton/intrauterine fetal death (IUFD) and dengue hemorrhagic fever. She had a history of fever 5 days before hospitalization, gum bleeding, articular pain, nausea, and vomiting. She had no comorbidities and had a normal obstetric history. The patient came in to our clinic with jaundice and encephalopathy. A decrease in consciousness was found but her other vital signs were within normal limits. Fetal ultrasonography showed no fetal heart beat and other signs of IUFD. Laboratory investigations revealed thrombocytopenia, leukocytosis, reactivity for NS-1 and dengue IgG, liver dysfunction, coagulopathy, hypoalbuminemia, hypofibrinogenemia, hypoglycemia, hyperbilirubinemia, and elevated lactate dehydrogenase (LDH) level. Abdominal ultrasound revealed hepatomegaly and ascites. The Swansea score for AFLP was 8, confirming the AFLP diagnosis. An emergency cesarean-section was performed due to maternal complications. During the postpartum period and general improvement, our patient developed several complications, including pneumonia, acute kidney injury, electrolyte imbalance, and wound dehiscence due to massive ascites and prolonged immobilization. A thorough repair of the surgical wound was performed. Due to the prolonged immobilization, there was also a decubitus ulcer in the gluteal region, which was treated by plastic surgery. The patient used 20 packs of red blood cells, 10 packs of thrombocyte concentrate, 19 packs of fresh frozen plasma, and 4 packs of cryoprecipitate. She finally improved after 34 days.

CASE 2:

In Case 2, a 31-year-old woman, G2P1A0, 36 weeks of gestation, was referred with thrombocytopenia due to AFLP, with dengue hemorrhagic fever as a differential diagnosis. She had a history of fever 6 days before hospitalization, gum bleeding, nausea, and vomiting. She had no comorbidities and had a normal obstetric history. Her vital signs were within normal limits. Fetal ultrasound was normal. Laboratory investigations revealed thrombocytopenia, leukocytosis, negative IgM and IgG for dengue, liver dysfunction, coagulopathy, hyperbilirubinemia, hypoalbuminemia, elevated creatinine, and lactate dehydrogenase (LDH). Abdominal ultrasound revealed hepatomegaly and ascites. The Swansea score for AFLP was 6, confirming the AFLP diagnosis. An emergency cesarean section was performed due to maternal complications. The patient improved over the course of 8 days.

CASE 3:

In Case 3, a 28-year-old woman, G3P0A2, 33 weeks of gestation, was referred from the regional hospital with thrombocytopenia due to HELLP syndrome diagnosed as AFLP, immune thrombocytopenia purpura (ITP), preeclampsia, and multiple congenital anomalies in the fetus. She had a normal obstetric history previous to 33 weeks of gestation. She had a history of fever 5 days before hospitalization, gum bleeding, nausea, and vomiting. Her laboratory test results revealed thrombocytopenia, NS-1, liver dysfunction, coagulopathy, hyperbilirubinemia, elevated LDH, and were negative for dengue IgM and IgG. The Swansea score for AFLP was 4. During misoprostol termination, the patient’s condition suddenly deteriorated, with cardiac arrest and respiratory failure that was suspected to be due to transfusion-associated circulatory overload, with transfusion-related acute lung injury as the differential diagnosis. Thus, an emergency resuscitation was performed. This condition could have been related to her comorbidities, including ITP. The patient did not improve and was declared dead.

The laboratory findings and other findings for all the cases at admission are summarized in Table 1.

Discussion

AFLP remains a serious disease with high mortality, ranging from 16.5% to 26.7%. We used the Swansea criteria to diagnose AFLP. Our patients were mostly in their late third trimester, 33–36 weeks pregnancy, when the AFLP became apparent. Two journals from the Hasan Sadikin Hospital previously reported data that showed an increase in the number of cases with fever complaints, reaching 30% and 80%, respectively [3,4]. Those case reports also confirmed that fever was the main symptom experienced by the patients who were hospitalized. Other common initial symptoms were nausea, vomiting, jaundice, and encephalopathy.

Fever is not part of the Swansea criteria because AFLP usually manifests with symptoms like abdominal pain, nausea, vomiting, and signs of liver dysfunction, such as elevated liver enzymes, hypoglycemia, and coagulopathy. While fever can occur in a range of conditions, including infections and other inflammatory issues, it may not be directly linked to the liver dysfunction seen in AFLP. Including fever in the criteria could result in misdiagnosis or confusion with other disorders that present similarly, such as infections or intra-abdominal complications [9].

The etiology of AFLP entails abnormalities in the mitochondria that lead to a deficit of long-chain enzyme 3-hydroxyacyl-CoA dehydrogenase (LCHAD) in the fetus, which disrupts the metabolism of fatty acids. These alterations lead to hepatocyte swelling, inflammation, and necrosis, which impairs liver function and results in AFLP. Symptoms and complications emerge predominantly because of decreased liver cell metabolism, suggesting extensive liver damage [10,11].

We present 3 cases that were preceded by fever, which led to confusion among the clinicians in the early diagnosis and treatment. Many clinicians initially diagnosed this condition as dengue hemorrhagic fever, which resulted in inappropriate treatment and delayed referral to a specialist hospital. The difference between AFLP and HELLP is mainly that AFLP causes more coagulopathy with no significant drop in platelet counts. Fever is considered an integral part of HELLP syndrome. In our cases, patients had an overlap of both syndromes and probably that is why fever was present. This eventually made treatment at our local tertiary hospital more challenging, required a longer time for recovery, and led to the emergence of various complications, including death. Clearly, if AFLP is diagnosed early, treatment will be more effective and the patient can recover rapidly. In our cases, laboratory tests revealed liver dysfunction, coagulopathy, hypoglycemia, thrombocytopenia, leukocytosis, and elevated bilirubin, creatinine, and LDH levels. Ultrasound revealed ascites and hepatomegaly. Clinical symptoms in conjunction with laboratory and ultrasound data are key tools for the diagnosis of AFLP [4,12].

The diagnosis of dengue infection significantly impacts management decisions, especially regarding the mode of delivery, due to the potential risk of hemorrhage associated with thrombocytopenia. Positive serology for dengue confirms the infection and helps differentiate it from other causes of thrombocytopenia. Similar to the current study, a previous case series conducted in Sri Lanka also reported an increased likelihood of HELLP syndrome and complications related to hypertensive disorders in pregnancy. The overlap of thrombocytopenia and elevated transaminases in both conditions, which was found in our cases, can complicate differentiation. Evidence of hemolysis and positive dengue serology are critical for accurate diagnosis. Secondary dengue infections are known to lead to more severe outcomes, such as severe dengue (dengue hemorrhagic fever/dengue shock syndrome), according to the latest WHO classification. These severe outcomes are often associated with infection with a different serotype. This can trigger a cross-reactive immune response through antibody-dependent enhancement, resulting in complement activation, endothelial dysfunction, platelet destruction, and consumptive coagulopathy. However, the current study did not analyze the relationship between disease severity and secondary dengue infections [13,14].

To date, only 2 similar case reports [15,16] have been documented. In those cases, the patients exhibited significant proteinuria on urine microscopy, underwent normal vaginal delivery within 6 hours of admission, and experienced seizures during birth. In contrast, our patient in Case 1 presented with features suggestive of dengue fever and mild proteinuria. When her platelet counts failed to improve and her liver function worsened, we considered a diagnosis of masquerading HELLP syndrome. It’s possible that her initially normal blood pressure was influenced by the combined effects of HELLP and dengue fever. We cannot rule out the possibility that she might have had normotensive HELLP. Dengue fever and HELLP share overlapping features, making it challenging to differentiate between them in normotensive patients. Overlooking the potential for HELLP in such cases can result in delayed treatment and can pose a serious risk to the patient’s life [15,16].

Early diagnosis, immediate delivery, and comprehensive supportive treatment are the mainstays of the management of AFLP [3,4,11]. All 3 of our cases had the same characteristic complaints, preceded by fever, before admission into our hospital. All of the above cases were initially treated as dengue hemorrhagic fever due to fever and thrombocytopenia. In Case 3, there was a rapid deterioration in the condition of both mother and fetus, that was largely due to the lack of accuracy in establishing a diagnosis, such that the treatment for AFLP came too late. Delayed treatment prolongs the duration of healing and can result in the emergence of various complications.

Accurate diagnosis and rapid and precise handling can prevent maternal and infant mortality. To minimize maternal and fetal death in AFLP, it is suitable to combine the choice to terminate the pregnancy immediately with a cesarean section as the delivery mode [4,8,17]. Due to their blood coagulation condition, people with AFLP are more prone to experience bleeding after delivery [18], which requires hemodynamic monitoring, as was the case in our patients. Pancreatitis, sepsis, renal failure, and gastrointestinal bleeding are the most common causes of death in individuals with AFLP, which has a fatality rate of around 18% [19]. Clinical recovery usually occurs within a few weeks and there are no long-term effects, even if altered liver histology might persist for several months [20].

Conclusions

We report 3 cases of AFLP in which patients initially presented with fever, which misled the first physician and led to delayed referral. This delay resulted in a longer healing time and various complications. We suggest that fever be considered for inclusion in the Swansea criteria, although further research with prospective studies or multi-center trials is needed. Early diagnosis and timely delivery are crucial, as hepatic injury associated with AFLP can be reversed. Prompt identification, diagnosis, and comprehensive supportive care, and specific recommendations for clinicians to avoid diagnostic delays, are essential for improving maternal and infant outcomes in AFLP cases.