Dr Anil Arora address the liver diseases that are specific during pregnancy. The presentation contains case discussions on diagnosis, treatments & take home messages

1. PREGNANCY AND LIVER DISEASE
PROF ANIL ARORA
DM(GASTRO),AIIMS,FRCP(EDINBURGH),FRCP(LONDON),FIAMS,FSGIE
PRESIDENT
INDIAN ASSOCIATION FOR STUDY OF LIVER
DIRECTOR
INSTITUTE OF LIVER, GASTROENTEROLOGY AND
PANCREATICOBILIARY SCIENCES
SIR GANGA RAM HOSPITAL
NEW DELHI
1

2. 2
Sir Ganga Ram HospitalSGRH

3. Liver diseases in Pregnancy
• Specific to pregnancy
– Hyperemesis gravidarum
– Intrahepatic cholestasis of pregnancy
– Preeclampsia/ HELLP
– Acute fatty liver of pregnancy
• Pregnancy worsens the severity
– Cholelithiasis
– Budd Chiari syndrome
– HEV infection
• Pregnancy in preexisiting chronic liver disease

4. 1st Trimester 2nd Trimester 3rd Trimester
Total Protein
Albumin
Sr.Alkaline Phosphate
Total Bilirubin
Gamma Glutamyl
Transferase
Lab Tests not affected by pregnancy
SGOT, SGPT
PT-INR
Serum Bile Acids
Lactate Dehydrogenase
LFT in Normal Pregnancy

5. Case discussion : 1
• 26/F primigravida
• 10th week of pregnancy
• Persistent nausea and vomiting since 2 weeks
• Weight loss of 5 kgs in 2 weeks
• No abdominal pain, distension, fever, jaundice
• Slightly decreased urine output
• O/E
– Patient slightly dehydrated
– Pulse : 106/min, BP : 100/60 mm Hg
– P/S : Non distended, soft

6. Case discussion : 1
Lab Parameter Value
S. Bilirubin (T) (mg%) 1.8
S. Bilirubin (D) (mg%) 0.9
SGPT (IU/L) 96
SGOT (IU/L) 75
SAP (IU/L) 34
GGT (IU/L) 18
PT-INR 0.9
Sr.Albumin (gm%) 3.2
Sr.Creatinine (mg%) 1.2
Urine Routine Normal
Urine Ketones Positive
Sr. Amylase 326
Sr.Lipase 40
Sr.TSH 0.1

7. Case discussion : 1
• Diagnosis ?
–Acute viral hepatitis
–Hyperthyroidism
–Hyperemesis gravidarum
–Acute biliary pancreatitis

8. Hyperemesis Gravidarum
• 60-70% of pregnant women complain of some nausea.
• 40% complain of vomiting.
0
1
2
3
4
5
6
4 8 12 16 20 24 28 32 36
Nausea

9. Hyperemesis Gravidarum
• Definition : (apart from intractable vomiting)
– Ketonuria
– Weight loss > 5% of pre-pregnancy weight.
• Risk factors
– H/O hyperemesis in previous pregnancy
– Family H/O hyperemesis
– Female fetus
– Maternal Hp infection
– Increased HCG states
• Mutiple gestation
• Gestational trophoblastic disease
• Trisomy 21
• Hydrops fetalis

10. Hyperemesis
gravidarum
Genetic predisposition
• Familial clustering
Hormones
• Estrogens : more
in obese
• HCG : more in 
HCG states
• Thyroid
hormones : abN
TFT in 66% pts.
Alfa subunit of
HCG has TSH like
activity. Hence
T4 levels
increase. No Rx
reqd.
Hp infection : some pts
show improvement with
Hp eradication
Psychogenic
• Triggered by
olfactory, visual
and auditory
stimuli
Pathogenesis

11. Hyperemesis Gravidarum
• Maternal complications
– Mallory Weiss tears
– Boerhaave’s syndrome
– Wernicke’s encephalopathy +/- Korsakoff psychosis
– Central pontine myelinolysis
– Retinal hemorrhage
– Spontaneous mediastinum
• Fetal complications (occur especially if maternal weight gain is
<7 kg of pre pregnancy weight)
– Low birth weight, Small for gestational age, poor APGAR scores

12. Hyperemesis Gravidarum
• Dietary advise
– Frequent small meals
– High carbohydrate, low fat diet
– Avoid empty stomach
– Avoid offensive odours
– Separate ingestion of solid and liquid foods
• Medical treatment
– Phenothiazines (chlorpromazine, prochlorperazine) / Dopamine
antagonist (metoclopramide, pyridoxine) / 5HT3 antagonist
(ondansetron)
– Inj.Thiamine
– IV Fluids

13. Pregnancy-unique quantification of
emesis and nausea (PUQE) scorePUQE score (pregnancy unique quantification of nausea
and emesis)

15. • Nausea/vomiting persisting in/beyond 2nd trimester : rule out
– Hyperthyroidism
– Hypercalcemia/hyperparathyroidism
– PIH / Raised ICP
– AFLP
– Gastroenteritis
– Migraine / labyrinthitis
– PUD
– GOO

16. Case discussion : 2
• 26/F primigravida
• 30th week of pregnancy
• Severe generalized pruritis
• No jaundice, abdominal pain, distension, fever
• O/E
– Patient healthy
– Few ecchymosis on lower limbs, scratch marks all over
– Pulse : 70/min, BP : 110/70 mm Hg
– P/S : Non distended, soft

17. Case discussion : 2
Lab Parameter Value
S. Bilirubin (T) (mg%) 1.2
S. Bilirubin (D) (mg%) 0.9
SGPT (IU/L) 780
SGOT (IU/L) 564
SAP (IU/L) 112
GGT (IU/L) 54
PT-INR 1.6
Sr.Albumin (gm%) 3.2
Sr.Creatinine (mg%) 1.2
Urine Routine Normal
HIV/HBsAg/HCV Negative
S. Bile Acids 15 mcmol/L
USG Abdo Liver N, Gall stones+

18. Case discussion : 2
• Diagnosis ?
–Acute viral hepatitis
–Choledocholithiasis
–Primary sclerosing cholangitis
–Intrahepatic cholestasis of pregnancy

20. Intrahepatic cholestasis of pregnancy
• Etiopathogenesis
– Mutations of MDR3(ABCB4) gene in 15% pts
– ABCB11 gene, ATP8B1 gene also responsible
– Role of estrogen/progesterone : predisposed women may have
itching later on Rx with OCP.
– Environmental factors : In Chile (max incidence of ICP ~ 20%); more
episodes in colder months, relationship seen to mean blood
selenium levels.
• Bland cholestasis on liver biopsy

21. IHCP pathogenesis

22. Intrahepatic cholestasis of pregnancy
• Seen in 3rd trimester
• Most characteristic symptom is pruritis. More on palms and
soles. More at night.
• Jaundice is rare (10-25%)
• LFT pattern is atypical of adult cholestasis (rather resembles
PFIC/Bylers syndrome)
– SGOT/PT elevated (sometimes = 1000 IU/L)
– Only modest elevations of SAP
– GGT normal or only mildly elevated
– Mild hyperbilirubinemia

23. Intrahepatic cholestasis of pregnancy
• Scoring for pruritis
– 0 : absent pruritis
– 1 : occasional prurutis; not everyday
– 2 : daily pruritis but < 50% of time
– 3 : daily pruritis but > 50% of time
– 4 : continuous pruritis
• Monitoring pruritis only helps for assessing efficacy of Rx.
• No correlation of pruritis to disease severity or fetal/maternal
outcomes.

24. Intrahepatic cholestasis of pregnancy
• Maternal outcomes
– Increased risk of gallstone disease, cholecystitis, pancreatitis
– 60-70% develop cholestasis in subsequent pregnancies
– May also develop cholestatic symptoms on later OCP use
– Fat soluble vitamin deficiencies
– Increased risk of PPH if Vit K deficiency
• Fetal outcomes
– Fetal hypoxia and meconium staining in 19% of patients with IHCP;
correlating strongly to Bile Acid > 40 mcmol/L
– Sudden intrauterine fetal death
– Prematurity

25. Intrahepatic cholestasis of pregnancy
• Serum Bile Acids > 10 mcmol/L clinch the
diagnosis
• Serum Bile Acids > 40 mcmol/L : fetal
distress, unexplained stillbirth.

26. Intrahepatic cholestasis of pregnancy
• Medical management
– Ursodeoxycholic acid : 15mg/kg/day as useful as higher doses
• Improves patient symptoms
• Improves fetal outcome
– Cholestyramine : may aggravate fat soluble vitamin deficiency
– Phenobarbitone : may affect the fetus
– S Adenosyl methionine : mixed results. Used in combination with
UDCA may show better outcomes
– Short course of steroid : few case reports showed good symptom
improvement
• Obstetric management
– Planned early delivery after maturation of fetal lungs
– Earlier delivery if severe pruritus and SBA > 40 mcmol/L

27. • Cholestasis of ICP should resolve soon after delivery
• If prolonged cholestasis occurs, then rule out
– PBC
– PSC
• ICP also has been associated with some cases of preeclampsia
and AFLP
• Prudent to rule out Hepatitis C in patients with ICP

28. Case discussion : 3
• 33/F primigravida, previously healthy
• 28th week of pregnancy, multiple gestations
• c/o headache, nausea and vomiting since 2 weeks
• Right upper quadrant/epigastric abdominal pain
• Swelling over B/L feet
• O/E
– Patient conscious, oriented
– Pulse : 86/min, BP : 140/90 mm Hg
– P/S : Distended, soft

29. Case discussion : 3
Lab Parameter Value
S. Bilirubin (T) (mg%) 1.7
S. Bilirubin (D) (mg%) 0.9
SGPT (IU/L) 210
SGOT (IU/L) 198
SAP (IU/L) 34
GGT (IU/L) 18
PT-INR 0.9
Sr.Albumin (gm%) 3.2
Sr.Creatinine (mg%) 1.3
Urine Routine Albumin 1+
Platelet count 65000
Peripheral smear Scistocytes
Sr.LDH 610
USG Abdomen N

30. Case discussion : 3
• Diagnosis ?
–Acute cholecystitis
–Preeclampsia/HELLP
–Migraine
–Acute biliary pancreatitis

31. Preeclampsia
• Preeclampsia complicates 3-10% of pregnancies.
• Occurs in 2nd half of pregnancy or puerperium
• M.C in primiparous women with multiple gestations
• Criteria for diagnosis
– Sustained BP of >=140/90 mm Hg after the 20th week of pregnancy
in a previously normotensive woman
– Proteinuria (≥300 mg/24 hr) [equivalent to a random urine protein
concentration of 30 mg/dL (“1+ dipstick”)]

32. Preclamptic disorders in pregnancy
Preeclampsia
occurs in around
10% of the
pregnancies
HELLP occurs almost always
in setting of preeclmapsia
; in 12% cases.
Preeclampsia is
an associated
diagnosis in 21-61
% cases of AFLP:
Preeclampsia
HELLP
AFLP

33. Preeclampsia pathogenesis
Preeclampsia
Normal placentation
Fetal cytotrophoblasts
fail to adopt invasive
phenotype
Invasion of spiral
arteries is shallow
Remain small caliber
resistance vessels

34. HELLP syndrome
• Occurs in 0.2-0.8% of all pregnancies; in 12% of patients with
severe preeclampsia.
• In addition to hypertension and pedal edema as seen in
preeclampsia, other frequent presentations are
– Chest, epigastric and right upper quadrant abdominal pain
– Nausea, vomiting
– Headache
– Blurred vision
– Malaise
• Most affected individuals seek treatment after week 27 of
gestation, 11% may do so earlier, 30% present after delivery
(preeclampsia is absent intrapartum in these pts)

35. Sibai BH, Ramadan MK, Usta I, et al. Maternal morbidity and mortality in 442
pregnancies with hemolysis, elevated liver enzymes and low platelets
(HELLP)syndrome. Am J Obstet Gynecol 1993
HELLP syndrome

36. HELLP syndrome
• Tennessee Classification
1. Microangiopathic hemolytic anemia with abnormal blood smear, low
serum haptoglobin, and elevated serum LDH levels
2. Serum LDH level >600 IU/L or twice the laboratory upper limit of normal
and serum AST level >70 IU/L or twice the laboratory upper limit of
normal, or serum bilirubin level more than >1.2 mg/dL
3. Platelet count <100,000/μL
4. Incomplete HELLP syndrome is defined as the presence of only 1 or 2 of
these abnormalities and may be less severe)
• Mississippi Triple-Class Classification
– Class I: platelet count nadir ≤50,000/mm3
– Class II: platelet count nadir >50,000/mm3 and ≤100,000/mm3
– Class III: platelet count nadir >100,000/mm3 and ≤150,000/mm3

37. HELLP syndrome
Portal triad
Pockets of
hemorrage
Fibrin
deposition

38. HELLP syndrome
• Treatment principles
– Monitor in intensive care setting
– Mainly supportive care required : maintain hydration, platelet
transfusion if very low, hemodialysis if AKI
– Glucocorticoids for fetal lung maturation
– Prompt delivery

39. Hepatic rupture/hematoma

40. Hepatic rupture
• Spontaneous hepatic rupture may complicate severe
preeclampsia or HELLP syndrome patients.
• Usually occurs very near term or early postpartum.
• In contrast to preeclamptic patients, patients who have
hepatic rupture are older and have had multiple previous
pregnancies.
• High index of suspicion if
– Sudden severe increase in abdominal pain/distension
– Cardiovascular collapse
• Diagnosis confirmed by imaging (US/CT/MRI) or aspiration of
blood on paracentesis

41. Hepatic rupture
• Management
– Contained subcapsular hematoma with no progression
• Careful monitoring
• Transfusion of blood and blood products
– Partially contained subcapsular hematoma with hemodynamic
stability
• Hepatic artery embolization
• Rapid delivery of the fetus
– Uncontained rupture with hemoperitoneum/shock
• Emergent hepatectomy/transplantation

42. Case discussion : 4
• 28/F primigravida with 38 weeks gestation
• Vague abdominal pain in right upper quadrant, epigastrium
• Nausea and vomiting since 5 days
• Felt decreased fetal movements since 1 day
• P/V bleeding since last 4 hours
• Confused behavior since 4 hours
• O/E
– Patient disoriented
– Pulse : 106/min, BP : 90/60 mm Hg
– Mild icterus present
– P/A : Right hypochondriac tenderness

43. Case discussion : 4
Lab Parameter Value
S. Bilirubin (T) (mg%) 2.2
S. Bilirubin (D) (mg%) 1.6
SGPT (IU/L) 450
SGOT (IU/L) 412
SAP (IU/L) 34
GGT (IU/L) 18
PT-INR 2.6
Sr.Albumin (gm%) 3.0
Sr.Creatinine (mg%) 1.8
Platelet count 1,60,000
TLC 16000
Uric Acid 10.5
RBS 55
Sr.Ammonia 206

44. Case discussion : 4
• Diagnosis ?
–HELLP
–Acute Viral Hepatitis with ALF
–Sepsis with DIC
–Acute Fatty Liver of Pregnancy

45. Acute Fatty Liver of Pregnancy
• Swansea criteria for diagnosis of AFLP (>=6 of the following without
any other attributable cause)
1. Abdominal pain
2. Ascites or bright liver on hepatic US
3. Coagulopathy (PT > 14 seconds or aPTT > 34 seconds)
4. Elevated serum ammonia levels (>47 μmol/L)
5. Elevated serum AST or ALT levels (>42 IU/L)
6. Elevated serum bilirubin levels (> 0.8 mg/dL)
7. Elevated serum urate levels (> 5.7 mg/dL)
8. Encephalopathy
9. Hypoglycemia (< 72 mg/dL)
10. Leukocytosis (> 11,000/mm3)
11. Microvesicular steatosis on liver biopsy
12. Polydipsia/polyuria
13. Renal impairment (creatinine > 1.7 mg/dL)
14. Vomiting

46. Acute Fatty Liver of Pregnancy
• Occurs in 1 of 6700 third trimester pregnancies
• Presents late in pregnancy usually between 34-37 weeks
• More common in primigravida, twin pregnancies and male
fetus

47. Acute Fatty Liver of Pregnancy
• Histologic hallmark : microvesicular fatty infiltration which is
most prominent in periveinular hepatocytes (zone 3)

48. Acute Fatty Liver of Pregnancy
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) catalyses the third
step in the β oxidation of fatty acids in mitochondria (the formation of 3-
ketoacyl-CoA from 3-hydroxyacyl-CoA). The accumulation of long-chain 3-
hydroxyacyl metabolites produced by the fetus or placenta is toxic to the
liver
Cycle of mitochondrial oxidation

49. Acute Fatty Liver of Pregnancy
• Precise mechanism by which LCHAD deficiency in a fetus
causes severe liver disease in mother is unclear.
• Hypothesized that because the mutation is recessive, under
normal physiological conditions the mother does not have
abnormal fatty acid oxidation.
• However, when both parents are heterozygous for this
abnormality and the fetus acquires both of these mutations,
the fetus will be unable to oxidize long-chain fatty acids.
• The unmetabolized free fatty acids return via the placenta to
the mother’s circulation, which strains maternal hepatic
activity and overwhelms any diminished maternal hepatic
enzyme activity, resulting in the symptoms of AFLP.

50. Acute Fatty Liver of Pregnancy
Mother

51. Acute Fatty Liver of Pregnancy
• Management
– Close monitoring in intensive care setting
– Infusion of blood products
– Infusion of dextrose to prevent hypoglycemia
– Antibiotic therapy
– Anti-encephlopathy measures
– Mechanical ventilation/hemodialysis for organ failure
– Prompt fetal delivery

52. Acute Fatty Liver of Pregnancy
• Monitoring of patients with AFLP diagnosis
– In all cases of AFLP, the mother, father, and child should be tested for
the G1528C LCHAD mutation.
– Risk of recurrence in subsequent pregnancies, hence further
pregnancy should be closely monitored
– Infants with a LCHAD deficiency can present a metabolic crisis, or
suffer a sudden unexpected death at a few months of age; hence
they have to be monitored closely.

53. Summary

54. The golden rule
• As a rule hepatic disorders arising as a consequence of
pregnancy are always seen in the 3rd trimester or just after
delivery.
• Most of the disorders are common in primigravida, especially if
associated with multiple gestations (twins)
• Except hepatic rupture is M.C in pts with multiple previous
pregnancies.
• PIH is seen more common in elderly primi.
• IHCP more common with female fetus.
• AFLP more common with male fetus.

55. Drug categories in pregnancy
FDA category Animal study Human Study
A Conducted
NO risk
Conducted
NO risk
B Conducted
NO risk
Not conducted
C Conducted
YES risk
Not conducted
D Conducted
YES risk
Conducted
Risk < Benefits
X Conducted
YES risk
Conducted
Risk > Benefits

57. Thank You