Preeclampsia‐induced Liver Dysfunction, HELLP syndrome, and acute fatty liver of pregnancy

Watch a video presentation of this article

Watch the interview with the author

Answer questions and earn CME

Abbreviations

GCCR

glucocorticoid receptor gene

HELLP

hemolysis, elevated liver function tests, low platelet counts

LCHAD

long chain 3‐hydroxyacyl‐CoA dehydrogenase

LDH

lactate dehydrogenase

PET

plasma exchange therapy

TLR4

toll‐like receptor 4 gene

Preeclampsia‐induced Liver Dysfunction and HELLP Syndrome

Definition and Epidemiology

Preeclampsia‐induced liver disease is a disorder unique to pregnancy and is frequently seen in the third trimester. Severe preeclampsia is defined by extreme elevation in systemic blood pressure and evidence of organ compromise. HELLP syndrome is a unique liver‐related disorder of pregnancy that was first described by Weinstein in 1982 as a constellation of clinical and laboratory abnormalities in pregnant women in their third trimester.1 This disorder was termed HELLP syndrome, with (H) for hemolysis, (EL) for elevated liver functions tests, and (LP) for low platelet counts.

The incidence of HELLP syndrome is approximately 0.6% of all pregnancies and is considered a variant of severe preeclampsia. Seventy percent of cases occur between weeks 27 and 37, with 20% occurring within 48 hours of delivery. Features of preeclampsia occur in the majority of patients presenting with HELLP syndrome. Ten percent to 20% of patients with severe preeclampsia will develop HELLP. Liver involvement in preeclampsia is not common, however, if present signifies severe disease. Table 1 lists the prevalence of liver disorders unique to pregnancy throughout the gestation period and their association with preeclampsia.2

Table 1.

Liver Diseases Unique to Pregnancy

Pathogenesis

Vascular remodeling, uteroplacental ischemia, defects in the formation of the placenta, and immune‐mediated mechanisms have been proposed. Several gene variants such as glucocorticoid receptor gene (GCCR), toll‐like receptor 4 gene (TLR4), vascular endothelial growth factor gene, FAS gene, cluster of differentiation 95 (CD95), and the coagulation factor V Leiden mutation are associated with increased risk of HELLP compared to healthy women. Inadequate vascular placental invasion has been the leading hypothesis in the etiology of preeclampsia‐eclampsia and HELLP syndrome. Thrombotic microangiopathy leads to microangiopathic hemolytic anemia and liver damage in patients with HELLP. HELLP syndrome has also been reported in a few cases to be associated with defects in β‐oxidation of fatty acids.

Clinical Presentation

Affected pregnant women typically present with nonspecific symptoms of weight gain, right upper quadrant pain (90%), nausea or vomiting (50%), or nonspecific viral‐like illness. Jaundice is seen in 40% of patients. Concomitant signs and symptoms of preeclampsia may or may not be present. Severe right upper‐abdominal pain may herald impending hepatic rupture. Other causes of right upper‐quadrant pain must be sought such as acute cholecystitis, acute pancreatitis, peptic ulcer disease, and acute fatty liver disease of pregnancy. Pregnant women with preeclampsia/HELLP may present with involvement of other organs, resulting in cerebral or visual symptoms, pulmonary edema, and renal insufficiency.

Diagnosis

Table 2 shows both the Tennessee and Mississippi classifications for the diagnosis of HELLP. Liver enzyme abnormalities are seen in up to 10% of pregnant women with severe preeclampsia. These include two‐ to three‐fold elevation in alanine and aspartate aminotransferases. The frequency and severity of elevation of liver aminotransferases are much higher in HELLP syndrome than in severe preeclampsia.3 Thus, elevation in liver transaminases, lactate dehydrogenase (LDH), and uric acid in the setting of severe preeclampsia might indicate a progression to HELLP syndrome. Hemolysis is the hallmark of the triad of HELLP syndrome. The presence of an abnormal peripheral smear (microangioplastic anemia with schistocytosis); thrombocytopenia; and elevated levels of aspartate aminotransferase, alanine aminotransferase, bilirubin, and LDH are diagnostic.4 Liver transaminases are typically > 500 U/L. The Mississippi classification has been proposed for assessment of the severity of the pathologic process of HELLP. Class 1 denotes worse prognosis and longer hospital stay. The trends in platelet count and serum LDH levels are predictive of speed of recovery.5 Other causes that simulate HELLP syndrome are acute viral hepatitis, hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), antiphospholipid syndrome, and AFLP. The classic hepatic lesion associated with the HELLP syndrome is periportal or focal parenchymal necrosis (Fig. 1A, 1B).6

Table 2.

Diagnostic Criteria for HELLP Syndrome

Tennessee Classification	Mississippi Classification
Complete syndrome:	Class 1: platelets ≤ 50 × 109/L
Platelets ≤ 100 × 109/L	1. AST or ALT ≥ 70 units/L
AST ≥ 70 units/L	2. LDH ≥ 600 units/L
LDH ≥ 600 units/L
Incomplete syndrome:
Any one or two of the above
	Class 2: platelets ≤ 100 × 109/L
	1. ≥ 50 × 109/L
	2. AST or ALT ≥ 70 units/L
	3. LDH ≥ 600 units/L
	Class 3: platelets ≤ 150 × 109/L
	1. ≥ 100 × 109/L
	2. AST or ALT ≥ 40 units/L
	3. LDH ≥ 600 units/L

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Figure 1.

Liver in HELLP syndrome. (A) Periportal patchy hemorrhage and necrosis (arrow). (B) Sinusoidal deposition of fibrin (arrow); hematoxylin and eosin stain. Reproduced with permission from Hammoud.13

Management

Bed rest and control of hypertension is mandatory for all women with HELLP syndrome. All women diagnosed with preeclampsia and HELLP syndrome should receive IV‐infused magnesium sulfate for the prevention of eclamptic seizures and cerebral changes. Prompt delivery is indicated if the syndrome develops after 34 weeks of gestation, or earlier if there is multiorgan dysfunction, disseminated intravascular coagulation (DIC), liver infarction or hemorrhage, renal failure, suspected abruption placentae, or nonreassuring fetal status.

Corticosteroids improve laboratory abnormalities but do not alter the natural progression of liver disease.7, 8 Plasma exchange therapy (PET) has been used in the management of severe cases with HELLP syndrome and organ failure refractory to conservative management.9 PET is generally started on the day of delivery or postpartum until improvement in laboratory parameters.10

Hepatic rupture, although rare, is perhaps the most catastrophic complication of HELLP syndrome. Surgical and interventional radiologic procedures such as hepatic artery ligation, hepatic packing or lobectomy, arterial embolization, and liver transplantation have been described. HELLP syndrome can recur in subsequent pregnancies and is associated with a high risk of complications such as fetal prematurity and intrauterine growth retardation.

Acute Fatty Liver of Pregnancy

Definition and Epidemiology

Acute fatty liver of pregnancy (AFLP) is a serious and rare maternal liver disease unique to pregnancy that occurs in the third trimester. It was first described as a specific clinical entity in 1900.11 It carries a significant perinatal and maternal mortality. AFLP has an incidence of one per 7,270 to 13,000 deliveries. AFLP is more frequent in primaparous than multiparous women but can occur after multiple uneventful pregnancies.

Pathogenesis and Clinical Implications

There is a strong association between AFLP and mitochondrial long chain 3‐hydroxyacyl‐CoA dehydrogenase (LCHAD) deficiency in the fetus.12 LCHAD is part of a complex mitochondrial enzyme alpha subunit, the mitochondrial trifunctional protein, and its deficiency is known to be secondary to a common G1528C mutation. LCHAD deficiency in the fetus likely causes accumulation of long chain 3‐hydroxy‐fatty acyl metabolites particularly toxic to the liver. The interaction between the affected fetus and the mother may result from passage of these metabolites from the fetus to the maternal circulation. In addition, metabolic and environmental stresses in the third trimester can lead to further accumulation of hepatotoxic LCHAD‐metabolites in the maternal circulation (Fig. 2).13

Figure 2.

Hypothesis illustrating the possible role of fetal and maternal mitochondrial trifunctional protein mutations in developing AFLP. (A) Carrying an LCHAD‐deficient fetus is the major determining factor in the development of maternal illness. Hepatotoxic metabolites produced by the fetus and/or placenta may cause liver disease in the obligate heterozygous mother when combined with the metabolic stress of the third trimester. (B) Environmental stress may lead to the further accumulation of toxic metabolites in the genetically susceptible mother, causing maternal liver disease. Reproduced with permission from Hammoud.13

This association between AFLP and the common LCHAD G1528C mutation in the fetus is significant.

Approximately 20% of women who develop AFLP carry LCHAD‐deficient fetuses.14 Thus, screening the offspring of women who develop AFLP at birth for this mutation can be lifesaving.14, 15 Most newborns who are LCHAD‐deficient present with a metabolic crisis in the first year of life and can suffer a sudden unexpected death at a few months of age. Thus, genetic counseling and screening newborns for LCHAD deficiency in pregnancies complicated by AFLP should be sought as early as possible after delivery.14, 15 LCHAD‐deficient newborns can be treated by dietary modifications, with dramatic reduction in morbidity and mortality.

Clinical Presentation

The initial manifestations are nonspecific and include headache, fatigue, nausea and vomiting (70%), right upper quadrant or epigastric pain (50%‐80%), and jaundice (70%). Maternal morbidity includes hypoglycemia, renal failure, and coagulopathy, which can be seen in up to 90% of cases. Hepatic encephalopathy occurs later in the disease and should immediately alert the physician to the possibility of AFLP. Hypertension, edema, and ascites may be present. Half of the patients may have associated preeclampsia.16 Upper gastrointestinal hemorrhage due to coagulation abnormalities may be seen in some cases. In severe untreated cases, progression is rapid over a few hours or days to hepatic failure with coma, hypoglycemia, hyperammonemia, renal failure, and severe coagulopathy, with hemorrhage leading to death of the mother and fetus.

Diagnosis

Peripheral blood smears may demonstrate thrombocytopenia. Disseminated intravascular coagulopathy is common. Prothrombin time, partial thromboplastin time, and fibrinogen maybe abnormal. Urine analysis may reveal ketones, protein, or bilirubin. Blood urea nitrogen and creatinine may be elevated, and uric acid is increased. Histologically, AFLP is characterized microscopically by microvesicular hepatic steatosis (Fig. 3). The centrally located nuclei are dense, widespread inflammation or necrosis is absent, and mitochondrial dense bodies are present.

Figure 3.

Acute fatty liver of pregnancy. Fat accumulation is greater in pericentral hepatocytes (arrow) compared with periportal hepatocytes (arrowhead); hematoxylin and eosin stain. Reproduced with permission from Hammoud.13

Distinguishing HELLP From AFLP

Table 3 lists the overlap distinguishing and clinical, laboratory, histological, and imaging features between HELLP syndrome and AFLP.

Table 3.

Distinguishing Features of HELLP and AFLP

Features	HELLP	AFLP
Incidence in pregnancy	0.2%‐0.6%	0.005%‐0.01%
Onset during pregnancy	Third trimester or postpartum	Third trimester or postpartum
Presence of preeclampsia	Yes	> 50%
Abdominal pain	Common	Common
Clinical features	Hemolysis, thrombocytopenia, hyperuricemia	Liver failure with coagulopathy, encephalopathy, hypoglycemia, hyperuricemia, and DIC
Aminotransferases	Typically > 500 units/L	Typically 300‐500 units/L but could be > 1000 unites/L
Alkaline phosphatase	Exceeds those normally observed in pregnancy	3‐10 fold upper limit
Bilirubin	< 5 mg/dL	< 5 mg/dL
LDH	Markedly elevated	Elevated
Peripheral smear	Schistocystes, spherocytes, reticulocytes	Thrombocytopenia, normoblasts
Renal impairment	Mild increase in BUN/creatinine	Mild to moderate increase in BUN/creatinine
Imaging	May show hepatic rupture or infarction	May show fatty infiltrate
Histology	Periportal hemorrhage, extensive necrosis, and hemorrhage	Microvesicular steatosis in zone 3
Immunohistologic	Cytokine and immune‐mediated	Reactive oxygen species‐mediated mitochondrial apoptosis
Perinatal/fetal outcomes	Perinatal mortality, prematurity	Fetal mortality 9‐23%

Abbreviation: BUN, blood urea nitrogen.

Management

Timely delivery after initial maternal stabilization is a cure. Prothrombin time improvement is the first sign of hepatic recovery. Liver transplantation is an option if the patient did not improve after delivery due to liver failure.

Conclusion

HELLP syndrome and AFLP are both rare and serious disorders unique to pregnancy. These disorders are seen in the third trimester of pregnancy and carry significant perinatal and maternal morbidity and mortality. Preeclampsia is associated with both disorders. Expedited delivery when fetal maturity is optimal is the main stay of therapy in both conditions.