PREGNANCY AND LIVER DISEASE

PROF ANIL ARORADM(GASTRO),AIIMS,FRCP(EDINBURGH),FRCP(LONDON),FIAMS,FSG

IEPRESIDENT

INDIAN ASSOCIATION FOR STUDY OF LIVERDIRECTOR

INSTITUTE OF LIVER, GASTROENTEROLOGY AND PANCREATICOBILIARY SCIENCES

SIR GANGA RAM HOSPITAL NEW DELHI

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Sir Ganga Ram HospitalSuper specialty & Research Block

SG RH

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

1st Trimester 2nd Trimester 3rd Trimester

Total Protein

Albumin

Sr.Alkaline Phosphate

Total Bilirubin

Gamma Glutamyl Transferase

Lab Tests not affected by pregnancySGOT, SGPT

PT-INR

Serum Bile Acids

Lactate Dehydrogenase

LFT in Normal Pregnancy

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

Case discussion : 1

Lab Parameter ValueS. Bilirubin (T) (mg%) 1.8S. Bilirubin (D) (mg%) 0.9

SGPT (IU/L) 96SGOT (IU/L) 75SAP (IU/L) 34GGT (IU/L) 18

PT-INR 0.9Sr.Albumin (gm%) 3.2

Sr.Creatinine (mg%) 1.2Urine Routine NormalUrine Ketones Positive

Sr. Amylase 326Sr.Lipase 40

Sr.TSH 0.1

Case discussion : 1

• Diagnosis ? –Acute viral hepatitis–Hyperthyroidism–Hyperemesis gravidarum–Acute biliary pancreatitis

Hyperemesis Gravidarum

• 60-70% of pregnant women complain of some nausea.• 40% complain of vomiting.

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Nausea

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

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

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

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

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

and emesis)

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

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

Case discussion : 2

Lab Parameter ValueS. Bilirubin (T) (mg%) 1.2S. Bilirubin (D) (mg%) 0.9

SGPT (IU/L) 780SGOT (IU/L) 564SAP (IU/L) 112GGT (IU/L) 54

PT-INR 1.6Sr.Albumin (gm%) 3.2

Sr.Creatinine (mg%) 1.2Urine Routine Normal

HIV/HBsAg/HCV NegativeS. Bile Acids 15 mcmol/LUSG Abdo Liver N, Gall stones+

Case discussion : 2

• Diagnosis ? –Acute viral hepatitis–Choledocholithiasis–Primary sclerosing cholangitis–Intrahepatic cholestasis of pregnancy

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

IHCP pathogenesis

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

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.

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

Intrahepatic cholestasis of pregnancy

• Serum Bile Acids > 10 mcmol/L clinch the diagnosis

• Serum Bile Acids > 40 mcmol/L : fetal distress, unexplained stillbirth.

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

• 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

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

Case discussion : 3

Lab Parameter ValueS. Bilirubin (T) (mg%) 1.7S. Bilirubin (D) (mg%) 0.9

SGPT (IU/L) 210SGOT (IU/L) 198SAP (IU/L) 34GGT (IU/L) 18

PT-INR 0.9Sr.Albumin (gm%) 3.2

Sr.Creatinine (mg%) 1.3Urine Routine Albumin 1+Platelet count 65000

Peripheral smear ScistocytesSr.LDH 610

USG Abdomen N

Case discussion : 3

• Diagnosis ? –Acute cholecystitis–Preeclampsia/HELLP–Migraine–Acute biliary pancreatitis

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”)]

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

Preeclampsia pathogenesis

Preeclampsia

Normal placentation

Fetal cytotrophoblasts fail to adopt invasive phenotype

Invasion of spiral arteries is shallow

Remain small caliber resistance vessels

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)

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

HELLP syndrome

• Tennessee Classification1. Microangiopathic hemolytic anemia with abnormal blood smear, low

serum haptoglobin, and elevated serum LDH levels2. 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/μL4. 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

HELLP syndrome

Portal triad

Pockets of hemorrage

Fibrin deposition

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

Hepatic rupture/hematoma

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

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

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

Case discussion : 4

Lab Parameter ValueS. Bilirubin (T) (mg%) 2.2S. Bilirubin (D) (mg%) 1.6

SGPT (IU/L) 450SGOT (IU/L) 412SAP (IU/L) 34GGT (IU/L) 18

PT-INR 2.6Sr.Albumin (gm%) 3.0

Sr.Creatinine (mg%) 1.8Platelet count 1,60,000

TLC 16000Uric Acid 10.5

RBS 55Sr.Ammonia 206

Case discussion : 4

• Diagnosis ? –HELLP–Acute Viral Hepatitis with ALF–Sepsis with DIC–Acute Fatty Liver of Pregnancy

Acute Fatty Liver of Pregnancy

• Swansea criteria for diagnosis of AFLP (>=6 of the following without any other attributable cause)1. Abdominal pain2. Ascites or bright liver on hepatic US3. 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. Encephalopathy9. Hypoglycemia (< 72 mg/dL)10. Leukocytosis (> 11,000/mm3)11. Microvesicular steatosis on liver biopsy12. Polydipsia/polyuria13. Renal impairment (creatinine > 1.7 mg/dL)14. Vomiting

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

Acute Fatty Liver of Pregnancy

• Histologic hallmark : microvesicular fatty infiltration which is most prominent in periveinular hepatocytes (zone 3)

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

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.

Acute Fatty Liver of Pregnancy

Mother

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

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.

Summary

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.

Drug categories in pregnancy

FDA category Animal study Human Study

A Conducted NO risk

ConductedNO risk

B ConductedNO risk

Not conducted

C ConductedYES risk

Not conducted

D ConductedYES risk

ConductedRisk < Benefits

X Conducted YES risk

ConductedRisk > Benefits

Thank You