Gastrocon 2016 - Pregnancy & Liver Disease

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

Gastrocon 2016 - Pregnancy & Liver Disease

Gastrocon 2016 - Pregnancy & Liver Disease

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