This document discusses various physiological changes in pregnancy and how they relate to common pregnancy-related liver conditions. It begins by outlining relevant increases in body water, cardiac output, and plasma volume during pregnancy. It then examines specific conditions like hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, HELLP syndrome, and acute viral hepatitis-E. For each condition, it discusses etiology, clinical features, management, and outcomes. The document provides a concise yet informative review of how physiology and pathology intersect in relation to the liver during pregnancy.

1. Dr. (Maj) Ajay Kandpal
MD MEDICINE, DNB MEDICINE
DM PG (Gastro enterology) STANLEY MEDICAL COLLEGE
CHENNAI, INDIA
kandykilroy@gmail.com

2. WHEN PHYSIOLOGY MEETS PATHOLOGY

3. Layout
 Relevant physiological changes
 Common conditions
 Approach in some specific conditions

4. CVS
• Increased body water ~ 20% - hemodilution ,hematocrit fall
• Cardiac output increases by 40 % and and plasma volume by
30%.
• Blood flow to liver remain constant
Physiological changes in pregnancy

5. Hormonal changes
 High serum level of estrogen

6. Effects to liver
 Histology is normal
 Procoagulant state ( factors I II V VII X XII and
fibrinogen increased
 Others
 Small insignificant varices in 2nd /3rd trimester.
 Relative immune tolerance

7. Albumin
Bilirubin Reduced
ϒ-globulin
Ggt
ALT/AST
Prothrombin time Unchanged
Total bile acid (Fasting)
Alk. phosphatase
Lipids
Cholesterol Elevated
AFP
Ceruloplasmin
5 nucleotidase
Physiological changes in pregnancy

8. What indicates a pathology
• Palpable liver
• Splenomegaly
• Elevated
- bilirubin
- transaminases (ALT/AST)
- fasting serum bile acid.

9. Pregnancy related liver
disease
Non pregnancy related liver disease
Hyperemesis gravidarum Pre existing liver
disease
Coincidentally
with pregnancy
Intrahepatic cholesatasis of
pregnancy
Viral Autoimmune
Hypertension related liver
diseases
Cirrhosis and portal
hypertension
Viral
- Preeclampsia/ eclampsia Post liver
transplantation
Vascular
-HELLP syndrome Autoimmune Drug induced
hepatotoxicity
-Infarction / rupture
Acute fatty liver of pregnancy
Rachel H. Westbrook . Journal of Hepatology 2016 vol. 64 j 933–945

10. Chang et al, 2002 (n=148)
• Pre-eclampsia 48%
• HELLP syndrome
Partial 04%
Complete 18%
• Intrahepatic cholestasis 16%
• Hyperemesis gravidarum 08%
• Acute fatty liver 04%
• Unexplained 10%
Gut 2002;51:876–880
Abnormal LFT in pregnancy

11. Abnormal LFT in pregnancy
Suspected cause Rathi et al
2007 (n=107)
Preg. induced HTN 36
Intrahepatic cholestasis 10
H.gravidarum 5
AFLP 2
HEV 15
HBV 4
Unexplained 5
Indian J Gastroenterol 2007. 26(2): 59-63

12. Clinical conditions
• Hyperemesis gravidarum
• Intrahepatic cholestasis of pregnancy
• Acute fatty liver of pregnancy
• HELLP syndrome
• Acute viral hepatitis-E

13. Hyperemesis gravidarum
• 1.5%
• Natural history
• Risk factors
• Maternal
• Fetal

15. LFT
• Elevation in transaminase
- up to 50% of cases
- commonly up to 2-3 times ULN
- may rise up to 20 times ULN
• Increase in bilirubin can occur
• Transient hyperthyrodism

16. Complications
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

17. Management
 Electrolytes and acid base balanace rehydration (iv
fluids)and gut rest followed by a diet rich in carbohydrates
and low in fat,frequent small meals
 High dose Thiamine ( 150mg) , Metoclopramide 10 QID,
Domperidone 10 QID, prochlorperazine 10 TDS helpful.
 Refractory cases- Ondanseteron and steroids.

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

21. Intrahepatic cholestasis of pregnancy
0.3% to 5.6%
Characterised by
– Pruritis and elevated bile acid levels
– appear in the second and third trimester
– disappear after delivery
– typically to recur in subsequent pregnancies.

22. ICP – risk factors
Known risk factor
- history in previous pregnancy, anticipation (50-70%)
- positive family history
- h/o pruritis with OCP use
Genetic predisposition
- familial aggregation
- high rates in certain ethnic groups
- mutation in ABCB4 (MDR3), ABCB11 (BSEP) genes with ICP
Proposed risk factors
- winter season
- twin pregnancy
- in vitro fertilization

23. Intrahepatic cholestasis of pregnancy
Clinical features:
 Pruritus
 25 to 32 wks
 Body parts effected, night
 Occasionally complicated by diarrhea or steatorrhea.
 Jaundice (10%-25%) 2-4 wks later.

24. ICP – laboratory
• Conjugated hyper bilirubinemia
- seen in 10-25% usually <5 mg/dL
- follows pruritis in 2-4 weeks
• Raised serum alkaline phosphatase
• GGT elevated in 30% only
• Transaminase elevation -2-4x. ( max upto 20x)
• Bile acids > 10umol/L( upto 100X)
A relation ship between maternal serum bile acids and fetal
distress has been found

25. ICP – neonatal outcome
ICP severity
Mild BA 10-39 mic mol/L
Moderate BA 40-99 mic mol/L
Severe BA >100 mic mol/L
Neonatal morbidity or mortality
- premature birth
- stillbirth (TBA>100 mic mol/L)
- fetal hypoxia
- fetal distress
- meconium aspiration syndrome (TBA>40 mic mol/L)

26. Outcomes
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

27. ICP- Etiopathogenesis

28.  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 :dexamethasone 12mg/day for 7days 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

29.  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

30. Acute fatty liver of pregnancy
• Yellow acute atropy of liver.
• Rare, sudden catastrophic illness
• almost exclusively in the third trimester 34-37wks
• microvesicular fatty infiltration
• encephalopathy and hepatic failure,coagulopathy with no prior
history of liver disease
• significant perinatal and maternal mortality
• requires early diagnosis and intervention.

31. 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

32. Risk factors
• Associated with primiparous
• Twin pregnancies(multiple gestation) and male foetus
• About 50% of patients with AFLP have preeclampsia, and there is
some overlap with the HELLP syndrome

33. Clinical features
• Symptomatic to fulminant liver failure.
• 1 to 2 weeks of anorexia, nausea and vomiting
• Headache
• right upper quadrant pain
• Pruritus
• hypertension
• Edema
• Ascites
• small liver
• Hepatic encephalopathy.

34. Laboratory features- AFLP
 Hypoglycemia
 high ammonia
 Aminotransferases – 300-500
 Bilirubin is < 5
 Normochromic normocytic anemia high TLC.
 Normal to low Platelets
 coagulopathy with or without DIC
 metabolic acidosis
 renal dysfunction (often progressing to oliguric renal failure)
 bio-chemical pancreatitis

35. AFLP- Histology
J. Eileen Hay, HEPATOLOGY, March 2008
Definitive diagnosis is histological—microvesicular fatty infiltration (free
fatty acids) predominantly in zone 3 with lobular disarray and mild
portal inflammation with cholestasis

36.  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.

37. Cycle of mitochondrial oxidation

38. 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
 2 to 3 days after delivery, the aminotransferases and
encephalopathy will improve.
 Most patients improve in 1 t o 4 weeks postpartum.
 cholestatic phase- rising bilirubin and alkaline phosphatase may
persist.
 Infectious and bleeding complications - life threatening.
 Liver transplantation - continues to deteriorate with advancing
fulminant hepatic failure after the first 1 to 2 days postpartum.

39. 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, non ketotic hypoglycemia or suffer a sudden
unexpected death at a few months of age; hence they have
to be monitored closely.

40. 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”)]

42. Preeclampsia pathogenesis

43. HELLP syndrome
 Occurs in 0.2-0.8% of all pregnancies; in 12% of patients with
severe preeclampsia.
 In addition to hypertension and Proteinuria (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)

45. 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

46. Liver biopsy
 Periportal hemorrhage, intrasinusoidal fibrin deposition,
and irregular areas of liver cell necrosis with mild reactive
hepatitis, findings characteristic of preeclampsia
 Imaging(ct/mri) should be performed in patients with
complaints of severe abdominal pain, neck or shoulder
pain, or a sudden drop in blood pressure (intrahepatic
hemorrhage and infarction)

47. Risk factors
 Female relatives, including the mothers of patients with
preeclampsia
 Women with a hypercoagulable condition (e.g., with factor
V Leiden or anticardiolipin antibodies)
 Excessive release of soluble fms-like tyrosine kinase 1 (sFlt1)
into the circulation develops hellps syndrome
 sFlt1 is a potent antagonist of vascular endothelial growth
factor (VEGF), placental growth factor (PlGF), and soluble
endoglin (sEng), an inhibitor of capillary formation,

48. 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

49. Hepatic rupture/hematoma
 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

50. 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

51. J. Eileen Hay, HEPATOLOGY, March 2008
Features ICP HELLP AFLP
% Pregnancies 0.1 0.2-0.6 0.005-0.01
Onset - wks 25-32 3/Post partum 3/Post partum
Family history Often No Occasionally
Preeclampsia No Yes 50%
Clinical features Pruritis, mild
jaundice , ^ B acids
Hemolysis, low
platelet
Liver failure-
coagulopathy,HE, DIC
Aminotransferases Mild – 10-20x Mild – 10-20x 300-500, variable
Bilirubin <5 <5 unless massive
necrosis
<5
Imaging Normal Infarcts, hematoma,
rupture
Fatty infiltration
Histology Normal to mild
cholestasis
Patchy necrosis and
hemorrhage
Microvesicular fat in
zone 3
Maternal mortality 0% 1-25% 7-18%
Perinatal mortality 0.4-1.4% 11 9-23
Recurrrence 45-70% 4-19% LCHAD defect - yes

52. Viral hepatitis-Perinatal transmission

53. Hepatitis E
• Endemic areas- exposure is particularly risky for pregnant women.
• During out-breaks- higher risk of developing symptomatic disease
( 2nd and 3rd trimester)
• Larger proportion progress to ALF.
• Mortality is much more common.
• Risks of IUD and abortion can occur in any trimester
• Their newborns are at risk of acquiring HEV infection, through
vertical materno fetal transmission
– anicteric / icteric hepatitis
– Hypoglycemia
– neonatal death .
• Increased incidence and severity is not observed in developed
countries.

54. HEV infection during pregnancy -
Pathogenesis
 Excess of circulating progesterone, estrogen, and human chorionic
gonadotropin- influence immune function and cellular responses
 Pregnancy -reduction in number and cytotoxic activity of NK cells in the
peripheral blood .
 Mononuclear cells from pregnant women with acute HEV infection
have poorer lymphoproliferative responses → high viral titres.
 Balance between T helper cell 1 & T helper cell 2 (Th2) is lost.
 Bias toward Th2 response during pregnancy might facilitate increased
multiplication of HEV in the host liver and thus more marked liver
injury

56. Pregnancy drug risk categories

57. Drugs used in pregnancy

58. Drugs used in pregnancy

59. Walker I, Chappell LC, Williamson C ‘‘Abnormal
Liver function tests in pregnancy” BMJ 2013 Oct 25:34 .
SYMPTOM LIKELY DIAGNOSIS OTHER POSSIBLE DIAGNOSIS
Pruritis ICP Pre eclampsia, AFLP, biliary
obstruction, preexisting hepatobiliary
disease ( PBC,PSC ) DILI
Epigastric pain
Nausea and vomiting
( 2& 3 trimester)
Headache
Visual disturbance
Pre eclampsia,
HELLP, AFLP
Gall bladder disease, Cholangitis, Viral
Hepatitis.
Nausea and vomting Hyperemesis
gravidarum
Viral hepatitis
Jaundice Viral Hepatitiss. HELLP symdrome, GB disease,
Cholangitis, DILI, rarely ICP, AFLP,
Preeclampsia
Pale stool and Urine Gall stone and
biliary obstruction
ICP, Cholangitis, Virla hepatitis, other

60. Algorithm for evaluation of abnormal LFTs
during pregnancy
The American Academy of Family Physicians-1999
Fever,Leucocytosis,RUQ
pain,+/- Jaundice
No Yes
Exclude
DILI
New onset
pruritis
ICP
Exclude
cholelithiasis /
Abscess
RUQ
pain
AMINOTRANSFERASES
Rule out viral hepatitis
yes
ALT <
1000U/l
ALT>
1000U/l
Renal
failure,Hypog
lycemia,DIC
Preeclampsia
, DIC,
hemolysis
Fever,leucocytosis,
RUQ pain +/_
Jaundice
Stones/
Abscess
DILI,
Hyperemesis
garvidarum
Toxins
Hypotensive
episode
Infarction/ rupture
HELLP AFLP
Prompt delivery
CHOLESTASIS

61. OTHER HEPATIC DISORDERS
AND PREGNANCY
 VIRAL HEPATITIS HAV,HBV,HDV,HCV AND HSV
 Chronic Liver Disease and Portal Hypertension
 Wilson Disease
 Autoimmune Liver Diseases
 Hepatic Tumors and Mass Lesions
 Hepatic Vein Thrombosis (Budd-Chiari Syndrome)
 Pregnancy after Liver Transplantation

62. THANK YOU