Acute fatty liver versus Acute fatty liver versus HELLP syndrome in HELLP syndrome in

obstetric ICU:obstetric ICU: why and how to why and how to

differentiate?differentiate?

BYBY

Bahaa-El-Din Ewees MDBahaa-El-Din Ewees MD

Physiological changes in liver tests during normal Physiological changes in liver tests during normal pregnancypregnancy

TestTest Normal RangeNormal Range

BilirubinBilirubin Unchanged or Unchanged or slightly decreaseslightly decrease

AminotransferasesAminotransferases UnchangedUnchanged

Prothrombin timeProthrombin time UnchangedUnchanged

Alkaline phosphataseAlkaline phosphatase Increases 2 to 4-foldIncreases 2 to 4-fold

FibrinogenFibrinogen Increases 50%Increases 50%

GlobulinGlobulin Increases in α and ß globulinsIncreases in α and ß globulins

α -fetoproteinα -fetoprotein Moderate riseModerate rise, esp. with twins, esp. with twins

WBCWBC IncreasesIncreases

CeruloplasminCeruloplasmin IncreasesIncreases

CholesterolCholesterol Increases 2-foldIncreases 2-fold

TriglyceridesTriglycerides IncreasesIncreases

GlobulinGlobulin Decreases in gamma-globulinDecreases in gamma-globulin

HemoglobinHemoglobin Decrease in later pregnancyDecrease in later pregnancy

Abnormal liver function tests Abnormal liver function tests occur inoccur in 3 - 5%3 - 5% of pregnancies for of pregnancies for different reasonsdifferent reasons

Liver diseases in pregnancyLiver diseases in pregnancy

liver disorders that occur liver disorders that occur only inonly in the the setting of setting of pregnancypregnancy

liver disorders that occur liver disorders that occur coincidentallycoincidentally with pregnancywith pregnancy

Liver diseases in pregnancy

Only in thesetting of pregnancy

coincidental with pregnancy

Preeclampsia-associated

Chronic liver diseases e.g.: cholestatic liver disease,

autoimmune hepatitis,Wilson disease,

viral hepatitis, etc…

not associated withpreeclampsia

The preeclampsiaitself

HELLP-syndrome

AFLP

Hyperemesisgravidarum

Intrahepatic cholestasisof pregnancy

HELLP syndromeHELLP syndrome

Severe preeclampsia is complicated in Severe preeclampsia is complicated in 2-12% of cases (0.2-0.6% of all 2-12% of cases (0.2-0.6% of all pregnancies) by hemolysis (pregnancies) by hemolysis (HH), ), elevated liver tests (elevated liver tests (ELEL), and low ), and low platelet count (platelet count (LPLP), the ), the HELLP HELLP syndromesyndrome..

Etiology:Etiology: microangiopathic hemolytic microangiopathic hemolytic anemia anemia ++ vascular endothelial injury vascular endothelial injury fibrin deposition in blood vessels fibrin deposition in blood vessels ++ platelet activation & consumption, platelet activation & consumption, small to diffuse areas of small to diffuse areas of hemorrhage and necrosis hemorrhage and necrosis large hematomas large hematomas ++ capsular tears capsular tears ++ intraperitoneal bleeding.intraperitoneal bleeding.

Clinical Features and Clinical Features and DiagnosisDiagnosis

Most patients: 27 - 36 weeks’ Most patients: 27 - 36 weeks’ gestation,gestation,

butbut 25% in postpartum period. 25% in postpartum period.

Can occur with any parity and age Can occur with any parity and age butbut commoner in white, multiparous commoner in white, multiparous & older pts.& older pts.

Clinical Picture:Clinical Picture:

Most patientsMost patientsLess commonlyLess commonly

upper abd. painupper abd. pain & tenderness& tenderness

NauseaNauseavomitingvomiting

MalaiseMalaiseheadacheheadache

EdemaEdemaweight gainweight gain

jaundicejaundiceuncommon (5%)uncommon (5%)

HypertensionHypertensionproteinuriaproteinuria

renal failurerenal failure

+ uric acid+ uric acid

DIDI

AntiphospholipidAntiphospholipidsyndromesyndrome

some patients have some patients have no obviousno obvious preeclampsia preeclampsia

•DiagnosisDiagnosis requires the presence requires the presence of of all 3 laboratory criteria:all 3 laboratory criteria:

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.

H ……………………H ……………………

Hemolysis Hemolysis EL…………………EL…………………

Elevated Liver Tests Elevated Liver Tests LP……………LP……………

Low Platelets Low Platelets

LDH>600 U/LLDH>600 U/L

↑ ↑ indirect bilirubin indirect bilirubin AST> 70U/L AST> 70U/L <150,000 <150,000

AminotransferaseAminotransferase: variable, from mild to : variable, from mild to 10 – 20 fold,10 – 20 fold,

BilirubinBilirubin: usually < 5 mg/dL.: usually < 5 mg/dL.

Liver CTLiver CT: : subcapsular hematomas,subcapsular hematomas, intra-parenchymal hemorrhage, or infarctionintra-parenchymal hemorrhage, or infarction hepatic rupture.hepatic rupture.

HistologicallyHistologically: focal hepatocyte necrosis, : focal hepatocyte necrosis, periportal hemorrhage, and fibrin deposits.periportal hemorrhage, and fibrin deposits.

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).

TreatmentTreatment

Hospitalization & ICU careHospitalization & ICU care for: for:o antepartum stabilization of BP and DIC,antepartum stabilization of BP and DIC,o seizure prophylaxis,seizure prophylaxis,o fetal monitoring.fetal monitoring.

pregnancy is > 34 wk gestational age

24-34 wk

immediate induction

corticosteroids for 48 h(fetal lung maturity)

delivery

The only definitive treatment is deliveryThe only definitive treatment is delivery

Corticosteroids which cross the placenta(betamethasone or dexamethasone,)

for 24-48 hours

fetal lung maturity improves maternalplatelet count.

Tried treatment modalities for patients with ongoing or newly developing symptoms

Antithrombotics(Heparin, aspirin)

plasmapheresis

plasma exchangewith FFP dialysis

After deliveryAfter delivery continue close monitoring of the mothercontinue close monitoring of the mother

Up to 48 h postpartum

worsening thrombocytopeniaworsening thrombocytopenia& increasing LDH levels& increasing LDH levels

Most lab. values normalizeMost lab. values normalize

After 48 h

persistent or worseningpersistent or worseninglab. Abnormalitieslab. Abnormalities

by 4by 4thth postpartum day postpartum day

PostpartumPostpartumcomplicationscomplications

May be

normalization of plateletsnormalization of platelets

5 5 daysdays

RARELY

Fate & complicationsFate & complications

ReportedReported maternal mortalitymaternal mortality isis 1%1%

Perinatal mortalityPerinatal mortality rate ranges rate ranges fromfrom 7%-22%7%-22% and may be due to:and may be due to:• premature detachment of placenta,premature detachment of placenta,• intrauterine asphyxia,intrauterine asphyxia,• prematurity.prematurity.

Other complicationsOther complications::

No long-term effect on renal No long-term effect on renal function noted.function noted.

•abruptio abruptio placentaeplacentae•DICDIC•ARFARF•ARDSARDS

•pulmonary pulmonary edemaedema

•strokestroke•liver failureliver failure•hepatic hepatic infarctioninfarction

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

Acute fatty liverAcute fatty liver

Acute fatty liver of pregnancy (Acute fatty liver of pregnancy (AFLPAFLP) is a) is a rarerare butbut seriousserious maternal illness that maternal illness that occurs in theoccurs in the third trimesterthird trimester of of pregnancy.pregnancy.

Incidence:Incidence: 1/10 000 to 1/15 0001/10 000 to 1/15 000 pregnancies.pregnancies.

Maternal mortality:Maternal mortality: 18%18%

Fetal mortality:Fetal mortality: 23%23%..

More common inMore common in nulliparous womennulliparous women and and withwith multiple gestationmultiple gestation..

PathophysiologyPathophysiology Defects in intramitochondrial fatty acid beta-Defects in intramitochondrial fatty acid beta-

oxidation (enzymatic mutations in fatty acid oxidation (enzymatic mutations in fatty acid oxidation).oxidation).

Heterozygous woman gets a homozygous Heterozygous woman gets a homozygous fetus fetal fatty acids accumulatefetus fetal fatty acids accumulate

return to the mother’s circulationreturn to the mother’s circulation extra load of long-chain fatty acidsextra load of long-chain fatty acids triglyceride accumulation triglyceride accumulation

hepatic fat deposition & impaired hepatic fat deposition & impaired maternal hepatic function.maternal hepatic function.

Clinical Features and Clinical Features and DiagnosisDiagnosis

Typical presentation:Typical presentation:

a 1 - 2 wk history of nausea, a 1 - 2 wk history of nausea, vomiting, abdominal pain & fatigue,vomiting, abdominal pain & fatigue,

Jaundice (frequent),Jaundice (frequent), moderate to severe hypoglycemia,moderate to severe hypoglycemia, hepatic encephalopathy,hepatic encephalopathy, coagulopathy.coagulopathy.

Laboratory Laboratory findingsfindings aminotransferase levels (from mild aminotransferase levels (from mild

elevation to 1000 IU/L, usually elevation to 1000 IU/L, usually 300 - 300 - 500500).).

Bilirubin: frequently Bilirubin: frequently > 5mg/dL> 5mg/dL.. Commonly: leukocytosis, anemia.Commonly: leukocytosis, anemia. With progress: thrombocytopenia (With progress: thrombocytopenia (±±

DIC) & hypoalbuminemia.DIC) & hypoalbuminemia. May be: rising uric acid, renal May be: rising uric acid, renal

impairment, metabolic acidosis, impairment, metabolic acidosis, ammonia & biochemical pancreatitis.ammonia & biochemical pancreatitis.

Laboratory findings (Cont.)Laboratory findings (Cont.)

liver biopsy

most definitive test

often not doned. t. coagulopathy

swollen, pale hepatocytesin the central zones

microvesicular fatty infiltration(frozen section with oil red staining)

findings

Imaging studies (US & CT)

Inconsistent

So, diagnosis

is

usually

based on

clinica

l & la

b. findings

(B) Hematoxylin-eosin stain (high power) shows hepatocytes stuffed with microvesicular fat (free fatty acids) and centrally located nuclei.

Histological appearance of the liver in AFLPHistological 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.

TreatmentTreatment

If no obstetric indication, normal delivery is If no obstetric indication, normal delivery is preferred to CS ( % of major intra-preferred to CS ( % of major intra-abdominal bleeding)abdominal bleeding)

Careful attention to the infant: risk ofCareful attention to the infant: risk of cardiomyopathycardiomyopathy, , neuropathyneuropathy, , myopathymyopathy, , nonketotic hypoglycemianonketotic hypoglycemia, , hepatic failurehepatic failure, , and and death.death.

Treatment involves

early recognition & diagnosis immediate terminationof pregnancy +

Fate & complicationsFate & complications

Usually By 2 - 3 dayspostpartum

liver enzymes & encephalopathy

improve

Sometimeslaboratory abnormalities

persist after delivery& may initially worsen during

first postpartum week

Rarelypatients progress to fulminant hepatic failure

with need for liver transplantation.

Most patients improve in 1 to 4 weeks postpart

With advances in supportive With advances in supportive management, the maternal mortality management, the maternal mortality is now 7%-18% and fetal mortality is now 7%-18% and fetal mortality 9%-23%.9%-23%.

Complications:Complications:• Infectious and bleeding remain the Infectious and bleeding remain the

most life threatening.most life threatening.

Liver transplantation has a very Liver transplantation has a very limited role because of the great limited role because of the great potential for recovery with delivery.potential for recovery with delivery.

HOW TO HOW TO DIFFERENTIATEDIFFERENTIATE

HELLPHELLP AFLPAFLP

% % PregnanciesPregnancies

0.2%–0.6%0.2%–0.6% 0.005%–0.01%0.005%–0.01%

Onset/Onset/trimestertrimester

3 or postpartum3 or postpartum 3 or 3 or postpartumpostpartum

Family Family historyhistory

NoNo OccasionallyOccasionally

Presence of Presence of preeclampsiapreeclampsia

YesYes 50%50%

Typical Typical clinical clinical featuresfeatures

Hemolysis Hemolysis (anemia)(anemia)

ThrombocytopeniThrombocytopenia (50,000 often)a (50,000 often)

Liver failure Liver failure with with coagulopathy, coagulopathy, encephalopathyencephalopathy

hypoglycemia, hypoglycemia, DICDIC

AminotransfeAminotransfer-asesr-ases

MildMild, but may be , but may be up to 10-20-fold up to 10-20-fold riserise

300-500 typical300-500 typical but variablebut variable

HELLPHELLP AFLPAFLP

BilirubinBilirubin <5<5 mg/dL unless mg/dL unless massive necrosismassive necrosis

often often >5>5 mg/dL, higher mg/dL, higher if severeif severe

Hepatic Hepatic imagingimaging

Hepatic infarctsHepatic infarcts

Hematomas, Hematomas, rupturerupture

Fatty infiltrationFatty infiltration

HistologyHistology Patchy/extensivePatchy/extensive

necrosis, necrosis, periportal hge, periportal hge, fibrin depositsfibrin deposits

Microvesicular fat in Microvesicular fat in zone 3zone 3

Maternal Maternal mortalitymortality

1%–25%1%–25% 7%–18%7%–18%

Fetal/Fetal/perinatal perinatal mortalitymortality

11%11% 9%–23%9%–23%

Recurrence in Recurrence in subsequentsubsequent

PregnanciesPregnancies

4%–19%4%–19% fatty acid oxidation defect fatty acid oxidation defect 25%25%

No fatty acid oxidation defect No fatty acid oxidation defect rare rare

WHY TO WHY TO DIFFERENTIATEDIFFERENTIATE

Major Risks

Infections & bleeding(most life threatening).

Hypoglycemia

AFLP HELLP

Pancreatitis (develop after onset of hepatic & renal dysfunction

need serial screeningof serum lipase and amylase

for several days afterhepatic dysfunction)

DIC

ARF

ARDS

pulmonary edema

stroke & seizures

liver hges(most life-threatening)

Therapeutic Options

AFLP HELLP

FFP

glucose

Liver transplant(limited role)

Antithrombotics:(heparin, antithrombin,

low dose aspirin)

Steroids: rapid clinical &lab. improvement

Blood transfusion

Early Late

Plasmapheresis

Liver transplantMore definite role role

Follow-up Precautions:Follow-up Precautions:A deficiency in long chain 3-hydroxyacyl-A deficiency in long chain 3-hydroxyacyl-

CoA dehydrogenase (LCHAD) is thought CoA dehydrogenase (LCHAD) is thought to be associated with the development to be associated with the development of AFLP.of AFLP.

Under normal circumstances, an Under normal circumstances, an individual that is heterozygous for individual that is heterozygous for enzymatic mutations in fatty acid enzymatic mutations in fatty acid oxidation will not have abnormal fatty oxidation will not have abnormal fatty oxidation.oxidation.

Affected patients should be screened Affected patients should be screened for defects in fatty acid oxidation as for defects in fatty acid oxidation as recurrence in subsequent children is recurrence in subsequent children is 25%, and recurrence of AFLP in 25%, and recurrence of AFLP in mothers is also possible.mothers is also possible.

Presymptomatic diagnosis of FAOD Presymptomatic diagnosis of FAOD withwith The application of tandem mass The application of tandem mass spectrometry to newborn screening spectrometry to newborn screening is an effective way to identify most is an effective way to identify most FAOD patients presymptomaticallyFAOD patients presymptomatically

reduce morbidity and avoid mortalityreduce morbidity and avoid mortality

Current management of pts with Current management of pts with FAOD includes long-term dietary FAOD includes long-term dietary therapy of:therapy of: fasting avoidance,fasting avoidance, low-fat/high-carbohydrate dietlow-fat/high-carbohydrate diet restriction of long-chain fatty acid restriction of long-chain fatty acid

intake and substitution with medium-intake and substitution with medium-chain fatty acids.chain fatty acids.

These dietary approaches appear These dietary approaches appear promising in the short-term, but not promising in the short-term, but not the long-term outcome.the long-term outcome.

In conclusionIn conclusion

Important to diff. AFLP from HELLPImportant to diff. AFLP from HELLP Diff. mainly based on lab. + imaging Diff. mainly based on lab. + imaging

(CT-MRI)(CT-MRI) Diff. because AFLP needs:Diff. because AFLP needs:

o Maternal follow-up for recurrenceMaternal follow-up for recurrenceo Baby follow-up for FAOD needing Baby follow-up for FAOD needing

dietary controldietary controlo Next pregnancies for presymptomatic Next pregnancies for presymptomatic

diagnosisdiagnosis