Fulminant acute fatty liver of pregnancy presenting with multi-organ failure: A case series

Abstract

Liver disease in pregnancy can be classified into pregnancy-related, liver disease coincident with pregnancy or preexisting liver disease. Acute fatty liver of pregnancy (AFLP) is a rare liver disorder that is caused by defects in mitochondrial beta (β) oxidation of fatty acids. In view of its fulminant presentation and rapid progression to multiple organ failure (MOF), AFLP carries high maternal and fetal mortality. These patients are commonly present in the third trimester of pregnancy with gastrointestinal symptoms and complications such as hypoglycemia, lactic acidosis, hyperammonemia, leukocytosis, liver dysfunction, coagulopathy, and renal dysfunction. Diagnosis is mostly based on the Swansea diagnostic criteria and by excluding other etiologies of liver dysfunction. Liver biopsy is rarely performed owing to underlying coagulopathy and thrombocytopenia. In this case series, we intend to share our experience of managing four cases of AFLP that were admitted to the intensive care unit with fetal demise and MOF.

INTRODUCTION

Acute fatty liver of pregnancy (AFLP) is a rare and life-threatening, liver disorder that occurs in the third trimester of pregnancy with a prevalence of 1:7,000–1:20,000 pregnancies.[1,2] Diagnosis of AFLP is based on the Swansea criteria, after excluding other potential etiologies of liver dysfunction in pregnancy. Liver biopsy, although confirmatory, is not feasible in clinical settings due to underlying coagulopathy.[3] Early termination of pregnancy and intensive care unit (ICU) management is essential to ensure a better outcome. We hereby describe four cases of AFLP that presented to ICU with multi-organ failure (MOF).

CASE SERIES

Case 1

A 24-year-old female, primigravida, G₃P_1L0A_1, with no comorbidities, was referred to ICU at 33 weeks of gestation with acute hepatic dysfunction, intrauterine fetal death (IUFD), postpartum hemorrhage (PPH), and MOF. In the third trimester, she had developed loose stools on and off, followed by fever, altered sensorium, and decreased fetal movements. Ultrasonography (US) pelvis revealed IUFD. Immediately after the termination of pregnancy, she developed PPH which was managed with multiple blood products and uterine packing. At ICU admission, she was afebrile, restless and agitated, tachypneic (Respiratory rate (RR) 35/min), blood oxygen saturation (SpO2 98% [on room air]), tachycardia (heart rate [HR] 114/min), and normotensive (blood pressure [BP] 106/67 mm Hg). Her abdomen was soft but distended, urine output was reduced, and bleeding was present from the episiotomy wound.

Laboratories at admission showed anemia, thrombocytopenia, leukocytosis, coagulopathy, hypoglycemia, and deranged liver and renal functions [Table 1].US abdomen revealed a bulky uterus and no significant retained products of conception. 2-D echocardiography was normal. The general blood picture showed anisocytosis, hypochromia, microcytosis, thrombocytopenia, severe leukocytosis, and neutrophilia with no evidence of hemolysis. Viral serology for hepatotropic viruses (Hepatitis A virus, hepatitis B virus, hepatitis C virus, and Hepatitis E virus), tropical causes for acute febrile illness (dengue, malaria, typhoid, scrub typhus, and leptospirosis) were ruled-out and workup for autoimmune hepatitis was also negative. Noncontrast computed tomography head showed diffuse cerebral edema secondary to acute hepatic dysfunction. Cerebral protection strategy (head-up position, deep sedation, mannitol, hypertonic saline, and normocarbia) was initiated along with invasive mechanical ventilation (MV), hemodynamic support (vasopressors), antimicrobials, and blood component therapy. She improved within 48–72 h of delivery, and tracheal extubation was done after 2 weeks of ICU stay.

Table 1.

Case descriptions

	Case 1	Case 2	Case 3	Case 4
Age (years)	24	22	25	25
GPA	G1P1L0A1	G1P0	G3P1L0A2	G1P0
Trimester	3rd	3rd	3rd	3rd
IUFD	Yes (male)	Yes (male)	Yes (male)	No
PPH	Yes	-	Yes	Yes
SOFA admission	16	10	18	18
Laboratories at admission
Hb (g/dL)	4.8	6.5	4.6	8.0
TLC (×103/mm3)	13.2	13	18.7	25.7
PLT (/mm3)	82,000	82,000	1.1 lacs	60,000
INR	2.5	3.8	2.9	1.97
T.bil/D.bil (mg/dL)	9/6.5	15.6/12.7	11/7.5	14/9.67
SGOT/SGPT (IU/L)	41/36	850/729	138/56	339/283
Alkaline phosphatase	279	-	1403	1407
RBS (mg/dl)	70	77	58	45
Serum albumin (g/dl)	2.5	-	2.8	-
Serum ammonia (micromol/L)	-	97	256	45
Urea (mg/dl)	60	96	82	26.5
Serum creatinine (mg/dl)	2.5	2.8	3.9	1.63
Na/K (mEq/L)	129/3.9	131/3.8	125/3.8	131/3.8
LDH (IU/L)	1376	833	1898	-
Clinical profile at admission
Encephalopathy	Yes	Yes	Yes	Yes
NCCT head	Cerebral edema (early)	Normal (late in illness)	Not done	Not done
Cerebral protection strategy	Yes	Yes	Yes	No
MV days	13	7	12	2
Shock days	6	2-3	10	2
AKI	Yes	Yes	Yes	Yes
RRT	No	No	Yes	No
DIC	Yes	Yes	Yes	Yes
Blood products	7 PRBCs, 22 FFPs, 4 RDPs, 1 SDP, 3 CPPs	2PRBCs, 2FFPs	5 PRBCs, 10 FFPs, 6 RDPs, 10 CPPs	3 PRBCs, 6 FFPs, 6 RDPs
LOS ICU (days)	20	14	22	3
Outcome	Survivor	Survivor	Survivor	Survivor

ICU: Intensive care unit, GPA: Gravida parity abortion, IUFD: Intrauterine fetal death, PPH: Postpartum hemorrhage, SOFA: Sequential organ failure assessment, NCCT head: Noncontrast CT head, MV: Mechanical ventilation, Shock days: Number of days on vasopressors, AKI: Acute kidney injury, RRT: Renal replacement therapy, DIC: Disseminated intravascular coagulation, PRBCs: Packed red blood cells, FFPs: Fresh frozen plasmas, RDPs Random donor platelets, SDP: Single-donor apheretic platelet, CPPs Cryoprecipitates, LOS ICU: Length of stay in ICU, Hb: Hemoglobin, TLC: Total leukocyte count, PLT: Platelet count, INR: International normalized ratio, T Bil: Total bilirubin, D bil: Direct bilirubin, SGOT: Serum glutamate oxalate transferase, SGPT: Serum glutamate pyruvate transferase, RBS: Random blood sugar, LDH: Lactate dehydrogenase, Na: Sodium, K: Potassium, Mg: Magnesium, US: Ultrasonography

Case 2

A 22-year-old female, primigravida, with no comorbidities, was transferred to ICU from the labor room after vaginal delivery of intrauterine fetal demise (IUFD) at 35 weeks of gestation. Her antenatal course was uneventful till the third trimester when she developed jaundice for 10 days and headache for 2 days, followed by diarrhea, oral bleeding, and altered sensorium. At ICU admission, she was afebrile, sedated, hypotensive (BP 80/50 mm Hg), tachycardia (HR 130/min), oliguric, and had deranged liver and kidney functions [Table 1]. 2-D echocardiography was normal. Organ support therapies such as cerebral protection strategy, hemodynamic support, and invasive MV were administered. Over the next 48 h, there was progressive improvement in organ functions. She got extubated on ICU day 7 and was ultimately discharged home.

Case 3

A 25-year-old female, G3P1 L0A2, with no comorbidities, was admitted to the labor room at 34 weeks of gestation with low-grade fever intermittently for a month with high-grade fever and scleral icterus for 1 week, multiple episodes of vomiting and abdominal pain for 2 days and altered behavior for 1 day. At ICU admission, she was disoriented, agitated, tachycardia (HR 105/min), BP 126/70 mmHg (no vasopressors), tachypneic (RR 30/min), SpO2 98% (without supplemental oxygen), and oliguric. US pelvis revealed IUFD. Postvaginal delivery of the fetus, she had PPH that was managed with uterine packing and blood products. Laboratories are mentioned in Table 1. In view of progressively worsening sensorium, the airway was secured, and a cerebral protection strategy was instituted along with invasive MV, hemodynamic optimization, and renal replacement therapy. Within 72–96 h posttermination of pregnancy, she improved clinically and tracheal extubation was done on the 10^th day of ICU stay.

Case 4

A 25-year-old female, a primigravida with twin pregnancy, presented to ICU following an emergency lower segment cesarean section at 36 weeks of gestation for fetal distress. She had a history of pain abdomen, vomiting, jaundice for 1 week, and altered sensorium for 2–3 days before getting admitted to the hospital. Issues at ICU admission were encephalopathy, hypoglycemia, and shock, for which supportive management was done. Thereafter, the patient improved clinically and was subsequently discharged home from ICU.

Table 1 shows a description of these four cases.

DISCUSSION

AFLP is a rare but lethal disorder that occurs in the third trimester of pregnancy.[3,4] It is a medical and obstetric emergency that leads to high fetal and maternal mortality. The pathophysiological basis of AFLP is defective mitochondrial beta (β) oxidation of fatty acids, which results in microvesicular fatty infiltration of hepatocytes.[4] AFLP is generally diagnosed by excluding other etiologies of liver dysfunction in pregnancy, especially those presenting in the third trimester. Figure 1 depicts an algorithmic approach to tackle varied etiologies of liver dysfunction in pregnancy and Table 2 shows the common third-trimester etiologies of liver dysfunction in pregnancy.

Figure 1.

Algorithmic approach to liver dysfunction in pregnancy. HAV: Hepatitis A virus, HEV: Hepatitis E virus, HCV: Hepatitis C virus, IPC: intrahepatic cholestasis of pregnancy, HELLP: Hemolytic anemia, Elevated Liver Enzymes, and Low Platelets syndrome, AFLP: Acute fatty liver of pregnancy, GBP: General blood picture, CBC: Complete blood count, BMP: Basic metabolic panel, LFT: Liver function test, RBS: Random blood sugar, LDH: Lactate dehydrogenase, INR: International normalized ratio, USG: Ultrosonongraphy, ICP: Intracranial pressure, PPH: Postpartum hemorrhage, IUFD: Intrauterine fetal death, DIC: Disseminated intravascular coagulation, MODS: Multiorgan dysfunction syndrome

Table 2.

Common third trimester etiologies of liver dysfunction in pregnancy

	Viral hepatitis	Preeclampsia/eclampsia	TTP/HUS or aHUS	HELLP±preeclampsia		AFLP
Risk factors	Poor sanitation, sexual history, IV drug use, contact with an infected person	Primiparity, family history, age <16 and >45 years, preexisting hypertension	Contaminated food, Predisposing conditions, medications	Advanced maternal age, multiparity, white ethnic origin		Primiparity, twin pregnancy, male fetus
C/f	Fever, pain abdomen Nausea/vomiting	Pain abdomen, nausea/vomiting, hypertension	Fever, anemia, AKI, neurological symptoms, gastrointestinal symptoms	Pain abdomen, nausea/vomiting, hypertension		Pain abdomen, nausea/vomiting, loose stools
Diagnosis	Viral markers   Hepatitis A IgM antibody   IgM anti-HEV, HEV PCR   HBsAg, HBV DNA, HBcAbIgM, HBeAg   IgM anti-HCV, HCV RNA   CMV, EBV, HSV, VZV	Hypertension (>140/90) and proteinuria   After 20 weeks gestation and/or Within 48 h after delivery	MAHA	Mississippi system   Class 1     PLT <50,000     SGOT or SGPT >70     LDH >600   Class 2     PLT 50,000-1 lac     SGOT or SGPT >70     LDH >600   Class 3     PLT 1-1.5 lacs     SGOT or SGPT >70     LDH >600	Tennessee system   Complete     PLT<1 lac     LDH>600 SGOT>70   Partial     Any 1 or 2 features of the above	Swansea criteria (≥6 points) and absence of other causes Liver biopsy if no contraindications
LFT[4]	LFT: 10 fold↑in aminotransferases; Bilirubin raised	LFT: 10 fold↑in aminotransferases; Bilirubin rarely raised	LFT derangement is not common; ↑ LDH	T Bil 1.5-10 times raised SGPT 2-30 times raised LDH ≥600		T Bil 3-15 times raised Aminotransferases <1000 IU/L
GBP	-	MAHA	MAHA	MAHA		-
Organ failures	Fulminant hepatitis: ALF with↑ICP with MOF	Hypertensive crisis, AKI, hepatic rupture, Hematological dysfunction, seizures	Neurological dysfunction, AKI, hemolysis, thrombocytopenia	Hepatic hematoma/rupture/infarction INR is generally normal, normal fibrinogen HELLP generally improves after the termination of pregnancy unlike HUS/TTP		Encephalopathy (↑ ICP) Hypoglycemia AKI DIC Hyperammonemia MOF

C/f: Clinical features, IV: Intravenous, HEV: Hepatitis E Virus, HBV Hepatitis B virus, HBsAg: Hepatitis B surface antigen, HBeAg: Hepatitis B e-antigen, HBcAg: Hepatitis B core antigen, HCV: Hepatitis C virus, CMV: Cytomegalovirus, EBV: Epstein Barr virus, HSV: Herpes simplex virus, VZV: Varicella-zoster virus, PLT: Platelet count, SGOT: Serum glutamate oxalate transaminase, SGPT: Serum glutamate pyruvate transaminase, LDH; Lactate dehydrogenase, LFT: Liver function test, T. Bil: Total bilirubin, MAHA: Microangiopathic hemolytic anemia, HUS: Hemolytic uremic syndrome, TTP: Thrombotic thrombocytopenic purpura, aHUS: Atypical HUS, GBP: General blood picture, HELLP: Hemolytic anemia, Elevated Liver Enzymes, and Low Platelets syndrome, AFLP: Acute fatty liver of pregnancy, ICP: Intracranial pressure, AKI: Acute kidney injury, DIC: Disseminated intravascular coagulation, MOF: Multiple organ failure, ALF: Acute liver failure, PCR: Polymerase chain reaction

Hemolysis, elevated liver enzymes, and low platelets syndrome is an important differential diagnoses of AFLP.[5] Points in favor of AFLP include gastrointestinal (GI) symptoms at the onset of disease, fulminant course with MOF including encephalopathy, acute kidney injury, disseminated intravascular coagulation, hypoglycemia, hyperammonemia, and ascites.[5,6] Liver biopsy is rarely feasible in clinical settings due to underlying coagulopathy. Hence, AFLP is usually diagnosed by Swansea criteria (with 100% sensitivity, 57% specificity, 100% negative predictive value, and 85% positive predictive value)[7,8,9,10] ≥6 Swansea criteria qualify for the diagnosis. Clues favoring AFLP in our cases were third-trimester onset, initial GI symptoms, fulminant presentation with MOF, and ≥ 6 Swansea criteria [Table 3]. Aggressive ICU care and early termination of pregnancy are quintessential for the management of AFLP.

Table 3.

Diagnosis of acute fatty liver of pregnancy using Swansea criteria

	Case 1	Case 2	Case 3	Case 4
Swansea criteria: AFLP: ≥6 of following in absence of any other explanation
Pain abdomen	Yes	-	Yes	Yes
Vomiting	Yes	-	Yes	Yes
Encephalopathy	Yes	Yes	Yes	Yes
Hypoglycemia <4 mmol/L (<72 mg/dl)	Yes (70)	Yes (77; on dextrose)	Yes (58)	Yes (50)
TLC>11,000	Yes (13,200)	Yes (13,000)	Yes (18,700)	Yes (25,700)
Coagulopathy; PT >14 s	Yes (2.3)	Yes (3.8)	Yes (2.9)	Yes (1.97)
Hyperammonemia >47 µmol/L	-	Yes (97)	Yes (256)	Yes (97)
↑ Serum urea >14 µmol/L	Yes (60)	Yes (96)	Yes (82)	Yes (26.5)
↑ Serum creatinine >150 µmol/L (>1.7 mg/dl)	Yes (2.5)	Yes (2.8)	Yes (3.7)	Yes (1.63)
Hyperbilirubinemia >14 micromol/L (> 0.82 mg/dl)	Yes (9.5)	Yes (15.6)	Yes (11)	Yes (14)
Transaminitis >42 IU/L	-	Yes (850/729)	Yes (138/56)	Yes (339/283)
↑Serum urate >340 µmol/L	-	-	-	-
Ascites or bright liver on USG	Yes (ascites)	Yes (ascites, mild hepatomegaly)	Yes (ascites, mild hepatomegaly)	Yes (ascites)
Microvesicular steatosis on liver biopsy	-	-	-	-
How was AFLP diagnosed in all four cases?	Common 3rd trimester and other etiologies ruled out:   Viral hepatitis (HAV, HEV, HBV, HCV), drug-related (no history of any drug ingestion), tropical illness (dengue, malaria, typhoid, scrub typhus, and leptospirosis), MAHA: HELLP, HUS/TTP, autoimmune liver disease   ≥6 Swansea criteria positive     Clues to diagnosis: Gastrointestinal symptoms at the onset of disease, fulminant course of illness with MODS, male fetus, encephalopathy, AKI, DIC, hypoglycemia, hyperammonemia, and ascites (in absence of other liver disorders)

TLC: Total leukocyte count, Na: Sodium, K: Potassium, Mg: Magnesium, US: Ultrasonography, AFLP: Acute fatty liver of pregnancy, HAV: Hepatitis A virus, HEV: Hepatitis E virus, HBV: Hepatitis B virus, HCV: Hepatitis C virus, MAHA: Microangiopathic hemolytic anemia, HELLP syndrome: Hemolytic anemia, elevated liver enzymes, low platelets syndrome, TTP: Thrombotic thrombocytopenic Purpura, HUS: Hemolytic uremic syndrome, AKI: Acute kidney injury, DIC: Disseminated intravascular coagulation, MODS: Multi-organ dysfunction, US: Ultrasonography

CONCLUSION

AFLP is a fulminant medical and obstetric condition that presents in the third trimester of pregnancy and culminates in MOF and fetal demise. Swansea criteria are helpful in the timely diagnosis of AFLP. Early diagnosis and ICU management with a multidisciplinary approach are pivotal to improving the outcome of patients.

Research quality and ethics statement

This case series did not require approval by the Institutional Review Board/Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the CARE guidelines, during the conduct of this research project.

Declaration of patient consent

The authors certify that each subject provided written informed consent for the publication of de-identified findings, but that anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.