Acute fatty liver versus HELLP syndrome in obstetric ICU: why and how to differentiate? BY Bahaa-El-Din Ewees MD

Physiological changes in liver tests during normal pregnancy Normal Range Bilirubin Unchanged or slightly decrease Aminotransferases Unchanged Prothrombin time Alkaline phosphatase Increases 2 to 4-fold Fibrinogen Increases 50% Globulin Increases in α and ß globulins α -fetoprotein Moderate rise, esp. with twins WBC Increases Ceruloplasmin Cholesterol Increases 2-fold Triglycerides Decreases in gamma-globulin Hemoglobin Decrease in later pregnancy

Abnormal liver function tests occur in 3 - 5% of pregnancies for different reasons Liver diseases in pregnancy liver disorders that occur only in the setting of pregnancy liver disorders that occur coincidentally with pregnancy

Liver diseases in pregnancy coincidental with pregnancy Only in the setting of pregnancy Chronic liver diseases e.g.: cholestatic liver disease, autoimmune hepatitis, Wilson disease, viral hepatitis, etc… not associated with preeclampsia Preeclampsia- associated The preeclampsia itself Hyperemesis gravidarum HELLP-syndrome Intrahepatic cholestasis of pregnancy AFLP

HELLP syndrome

Severe preeclampsia is complicated in 2-12% of cases (0. 2-0 Severe preeclampsia is complicated in 2-12% of cases (0.2-0.6% of all pregnancies) by hemolysis (H), elevated liver tests (EL), and low platelet count (LP), the HELLP syndrome. Etiology: microangiopathic hemolytic anemia + vascular endothelial injury fibrin deposition in blood vessels + platelet activation & consumption, small to diffuse areas of hemorrhage and necrosis large hematomas + capsular tears + intraperitoneal bleeding.

Clinical Features and Diagnosis

Most patients: 27 - 36 weeks’ gestation, but 25% in postpartum period. Can occur with any parity and age but commoner in white, multiparous & older pts.

some patients have no obvious preeclampsia Clinical Picture: Most patients Less commonly upper abd. pain & tenderness jaundice uncommon (5%) renal failure + uric acid Nausea vomiting DI Hypertension proteinuria Malaise headache Antiphospholipid syndrome Edema weight gain some patients have no obvious preeclampsia

Diagnosis requires the presence of all 3 laboratory criteria: Hemolysis EL………………… Elevated Liver Tests LP…………… Low Platelets LDH>600 U/L ↑ indirect bilirubin AST> 70U/L <150,000 Based on platelet count, may be: severe/ Class 1 (platelets 50,000), moderate/Class 2 (50 –99,000), mild/Class 3 (100 –150,000). Lately, DIC, pulmonary edema, placental abruption, and retinal detachment may be present.

Aminotransferase: variable, from mild to 10 – 20 fold, Bilirubin: usually < 5 mg/dL. Liver CT: subcapsular hematomas, intra-parenchymal hemorrhage, or infarction hepatic rupture. Histologically: focal hepatocyte necrosis, periportal hemorrhage, and fibrin deposits.

CT abdomen of a woman with severe HELLP syndrome (39 weeks) CT abdomen of a woman with severe HELLP syndrome (39 weeks). A large subcapsular hematoma extends over the Lt lobe; Rt lobe has heterogeneous, hypodense appearance due to widespread necrosis, with “sparing” of the areas of lt lobe (compare perfusion with the normal spleen).

Treatment

The only definitive treatment is delivery Hospitalization & ICU care for: antepartum stabilization of BP and DIC, seizure prophylaxis, fetal monitoring. The only definitive treatment is delivery gestational age 24-34 wk pregnancy is > 34 wk corticosteroids for 48 h (fetal lung maturity) immediate induction delivery

Corticosteroids which cross the placenta (betamethasone or dexamethasone,) for 24-48 hours fetal lung maturity improves maternal platelet count. Tried treatment modalities for patients with ongoing or newly developing symptoms plasmapheresis Antithrombotics (Heparin, aspirin) plasma exchange with FFP dialysis

continue close monitoring of the mother After delivery continue close monitoring of the mother Up to 48 h postpartum RARELY persistent or worsening lab. Abnormalities by 4th postpartum day worsening thrombocytopenia & increasing LDH levels May be After 48 h Most lab. values normalize Postpartum complications 5 days normalization of platelets

Fate & complications

Reported maternal mortality is 1% Perinatal mortality rate ranges from 7%-22% and may be due to: premature detachment of placenta, intrauterine asphyxia, prematurity.

Other complications: No long-term effect on renal function noted. abruptio placentae DIC ARF ARDS pulmonary edema stroke liver failure hepatic infarction

Recurrence : Subsequent pregnancies carry a high risk of complications pre-eclampsia, recurrence, prematurity, IUGR, abruptio placentae, perinatal mortality.

Acute fatty liver

Acute fatty liver of pregnancy (AFLP) is a rare but serious maternal illness that occurs in the third trimester of pregnancy. Incidence: 1/10 000 to 1/15 000 pregnancies. Maternal mortality: 18% Fetal mortality: 23%. More common in nulliparous women and with multiple gestation.

Pathophysiology Defects in intramitochondrial fatty acid beta-oxidation (enzymatic mutations in fatty acid oxidation). Heterozygous woman gets a homozygous fetus fetal fatty acids accumulate return to the mother’s circulation extra load of long-chain fatty acids triglyceride accumulation hepatic fat deposition & impaired maternal hepatic function.

Clinical Features and Diagnosis

Typical presentation: a 1 - 2 wk history of nausea, vomiting, abdominal pain & fatigue, Jaundice (frequent), moderate to severe hypoglycemia, hepatic encephalopathy, coagulopathy.

Laboratory findings Bilirubin: frequently > 5mg/dL. aminotransferase levels (from mild elevation to 1000 IU/L, usually 300 - 500). Bilirubin: frequently > 5mg/dL. Commonly: leukocytosis, anemia. With progress: thrombocytopenia (± DIC) & hypoalbuminemia. May be: rising uric acid, renal impairment, metabolic acidosis, ammonia & biochemical pancreatitis.

Laboratory findings (Cont.) liver biopsy Imaging studies (US & CT) most definitive test Inconsistent often not done d. t. coagulopathy swollen, pale hepatocytes in the central zones So, diagnosis is usually based on clinical & lab. findings findings microvesicular fatty infiltration (frozen section with oil red staining)

Histological appearance of the liver in AFLP. (A) Sudan stain (low power) shows diffuse fatty infiltration (red staining) involving predominantly zone 3, with relative sparing of periportal areas. (B) Hematoxylin-eosin stain (high power) shows hepatocytes stuffed with microvesicular fat (free fatty acids) and centrally located nuclei.

Treatment

Treatment involves early recognition & diagnosis immediate termination of pregnancy + If no obstetric indication, normal delivery is preferred to CS ( % of major intra-abdominal bleeding) Careful attention to the infant: risk of cardiomyopathy, neuropathy, myopathy, nonketotic hypoglycemia, hepatic failure, and death.

Fate & complications

Usually Sometimes Rarely By 2 - 3 days postpartum liver enzymes & encephalopathy improve laboratory abnormalities persist after delivery & may initially worsen during first postpartum week Sometimes patients progress to fulminant hepatic failure with need for liver transplantation. Rarely Most patients improve in 1 to 4 weeks postpart

With advances in supportive management, the maternal mortality is now 7%-18% and fetal mortality 9%-23%. Complications: Infectious and bleeding remain the most life threatening. Liver transplantation has a very limited role because of the great potential for recovery with delivery.

HOW TO DIFFERENTIATE

HELLP AFLP % Pregnancies 0.2%–0.6% 0.005%–0.01% Onset/trimester 3 or postpartum Family history No Occasionally Presence of preeclampsia Yes 50% Typical clinical features Hemolysis (anemia) Thrombocytopenia (50,000 often) Liver failure with coagulopathy, encephalopathy hypoglycemia, DIC Aminotransfer-ases Mild, but may be up to 10-20-fold rise 300-500 typical but variable

<5 mg/dL unless massive necrosis HELLP AFLP Bilirubin <5 mg/dL unless massive necrosis often >5 mg/dL, higher if severe Hepatic imaging Hepatic infarcts Hematomas, rupture Fatty infiltration Histology Patchy/extensive necrosis, periportal hge, fibrin deposits Microvesicular fat in zone 3 Maternal mortality 1%–25% 7%–18% Fetal/perinatal mortality 11% 9%–23% Recurrence in subsequent Pregnancies 4%–19% fatty acid oxidation defect 25% No fatty acid oxidation defect rare

WHY TO DIFFERENTIATE

Major Risks AFLP HELLP DIC Infections & bleeding (most life threatening). DIC ARF Hypoglycemia ARDS pulmonary edema Pancreatitis (develop after onset of hepatic & renal dysfunction need serial screening of serum lipase and amylase for several days after hepatic dysfunction) stroke & seizures liver hges (most life-threatening)

Therapeutic Options AFLP HELLP Late Early FFP Plasmapheresis glucose Antithrombotics: (heparin, antithrombin, low dose aspirin) Liver transplant (limited role) Liver transplant More definite role role Steroids: rapid clinical & lab. improvement Blood transfusion

Follow-up Precautions: A deficiency in long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) is thought to be associated with the development of AFLP. Under normal circumstances, an individual that is heterozygous for enzymatic mutations in fatty acid oxidation will not have abnormal fatty oxidation.

Affected patients should be screened for defects in fatty acid oxidation as recurrence in subsequent children is 25%, and recurrence of AFLP in mothers is also possible. Presymptomatic diagnosis of FAOD with The application of tandem mass spectrometry to newborn screening is an effective way to identify most FAOD patients presymptomatically reduce morbidity and avoid mortality

Current management of pts with FAOD includes long-term dietary therapy of: fasting avoidance, low-fat/high-carbohydrate diet restriction of long-chain fatty acid intake and substitution with medium-chain fatty acids. These dietary approaches appear promising in the short-term, but not the long-term outcome.

In conclusion Important to diff. AFLP from HELLP Diff. mainly based on lab. + imaging (CT-MRI) Diff. because AFLP needs: Maternal follow-up for recurrence Baby follow-up for FAOD needing dietary control Next pregnancies for presymptomatic diagnosis

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