Liver and Renal Disease in Pregnancy

1. Liver and Renal Disease in Pregnancy

2. Physiological changes • Pregnancy is associated with increased liver metabolism • ↓Protein concentrations (20-40 % fall in albumin due to hemodylution) • ↑fibrynogen, celuroplasmin, transferrin, TBG (thyroid BG), CBG(corticosteroid BG) • ↔Bilirubin • ↑Alkaline phosphatase ( due to placental production) upper limit in third trimester - 400 U/l • ↓fall in upper limit for AlAT, AspAT, SGOT

3. Liver Disease • Hyperemesis gravidarum • Cholestasis garvidarum • Acute fatty liver of pregnancy • HELLP syndrome • Viral hepatitis • Pre-existing liver disease • Gall bladder disease

4. Approach to Liver Disease in Pregnancy • Liver disease occurs in approximately 3% of deliveries • There are liver diseases which are specific to pregnancy • Hyperemesis gravidarum • Intrahepatic cholestasis of pregnancy • Acute fatty liver of pregnancy • HELLP syndrome • Liver dysfunction may also be seen in patients with hepatitis

5. Hyperemesis gravidarum • Severe vomiting in early pregnancy • Occurse in 0,1 –1% of pregnancies („Normal” nausea and vomiting are very common, up to 50% of pregnancies) • causing fluid, electrolyte and nutritional disturbance • May be associated with abnormal liver function in up to 50% cases

6. Hyperemesis gravidarum Clinical manifestation: • Vomiting up to 20 times a day, vamiting after eating, drinkig water, brushing teeth, spontaniously. Impossible to swallow saliva. Fatigue, fainting, weight loss, muscle wasting, • Dehydratation with hypotension and tachycardia Laboratory tests: • Hyponatremia, hypocaliemia, low serum urea, metabolic hypochloremic alkalosis, ketonuria, rised haematocrit, rised gravity of urine • Abnormal thyroid tests: ⇑FT 3 , FT4, ⇓ TSH( up to 66% cases) Patient is clinically euthyreoid, no antithyroid antibodies, no need for drugs, resolves as hyperemesis improves. • a moderate rise in transaminases ( 50 – 200U/l), slightly rised bilirubin, jaundice is uncommon

7. Hyperemesis gravidarum • Pathophysiology is poorly understood • Severity of hyperemesis is conected with hyperthyroidism • Level of hCG ( whitch shares £ - subunit with TSH) is conected with severity of vomiting • Increased incidence of hyperemeis in multiple pregnancy and hydatidiform mole (⇑hCG) • Psychological and behavioural thories • Usually there is rapid improvement on admission to hospital • Recurse in subsequent pegnacies

8. Hyperemesis gravidarum Maternal complications: • Vitamin deficiencies ( B1 – thiamine – Wernicke`s encephalopathy, B6 - pirydoxine and B12- cyanocobalamin – anaemia and perpheral neuropathy • Malnutrition • Mallory- Weiss tears of oesophagus • Severe hyponatremia cousing seisures, lethargy, respiratory arrest • Psychological problems (request for termiantion of pregnancy) • thrombosis

9. Hyperemesis gravidarum Fetal complications: • Feal death up to 40% associated with Wernicke`s encephalopathy • Lower birthweight

10. Hyperemesis gravidarum Treatment: • 0,9% NaCl (150 mmol/L Na), Hartmann solution ( 130mmol/L Na) • 30 - 40 mmol /L Potassium chloride • Enteral feeding / Total parenteral nutrition • Thiamine supplementation • Antiemetics: dopamine antagonist: metoclopramide, H1 receptor antagonist: promethasine - Diphergan, phenothiazines: Torecan • Corticosteroids – prednisolone 40-50 mg /d poor hydrocortisone 100 mg iv

11. Acute Fatty Liver in Pregnancy

12. Acute Fatty Liver of Pregnancy • Affects 1 in 10000 – 13000 pregnancies • maternal mortality of 10% • fetal mortality up to 45% • improved outcomes have been attributed to early recognition of the disorder followed by prompt delivery • association with nulliparity, twin gestations, male fetus and pre-eclampsia or eclampsia

13. Etiology • Remains unknown • These diseases are characterized by microvesicular fatty infiltration of hepatocytes without inflammation or necrosis

14. Clinical Manifestations • Generally occurs in the second half of pregnancy • Mean gestational age > 30 week

15. Clinical Manifestations • The duration of prodromal symptoms and signs is variable • Often presents with nausea and vomiting, followed by severe abdominal pain and headache

16. Clinical Manifestations • The right upper quadrant is generally tender, but the liver is not enlarged to palpation • Within a few days, jaundice appears, and the patient becomes somnolent and eventually comatose • Hematemesis and spontaneous bleeding result when the patient develops hypoprothrombinemia and DIC

17. Clinical Manifestations • Oliguria, metabolic acidosis, and eventually anuria occur in approximately 50 percent of patients • Diabetes insipidus may also accompany the disease, but may not manifest itself until postpartum

18. Clinical Manifestations • If the disease is allowed to progress, labor begins and the patient delivers a stillborn infant • Uteroplacental insufficiency may be the cause of fetal distress and fetal death in these patients.

19. Clinical Manifestations • During the immediate postpartum period, the mother becomes febrile, comatose and, without therapy, dies within a few days • DIC, renal failure, profound hypoglycemia, and occasionally pancreatitis are the most often cited immediate causes of death

20. Lab Investigations • Serum transaminases • elevated, but usually below 400 IU/L • ALP increases • Coagulation factors • INR increases before PTT because of vitamin K dependent clotting factors made in the liver • fibrinogen decreases, D-dimer increases with DIC • Bilirubin • mildly elevated

21. Lab Investigations • Serum ammonia - elevated • Serum glucose - decreased

22. Further Investigations • Liver Biopsy • liver biopsy not advised for diagnosis in most cases due to coagulopathy • pericentral microvesicular fatty change • minimal inflammatory cell infiltration or hepatic necrosis • periportal areas are usually preserved

23. Histology

24. Management • Once diagnosis is made, delivery should be carried out as soon as possible • Need to ensure patient is stable • Vaginal delivery is preferable • C/S can be performed if it appears vaginal delivery cannot be carried out in a timely fashion or if patient is deteriorating

25. Management • If delivery is carried out before hepatic encephalopathy and renal failure develop, patients recover rapidly • No long- term liver damage

26. Recurrence Risk • Little risk of recurrence in subsequent pregnancies

27. Intrahepatic Cholestasis of Pregnancy

28. Background • Incidence of 1 in 750-7,000 pregnancies • Uneven incidence worldwide • High incidence in Chile and Sweden • Seems to have a seasonal variation, peaking in November • association with twin gestations, old mothers, HCV infection

29. Pathogenesis • Cause is unknown • Evidence suggests both genetic and hormonal factors play a role • Decresed bile acides transport to bile (in hepatocite)

30. Clinical Manifestations • Generally occurs in second and third trimesters • Usually begins with pruritis at night • Pruritis is often generalized, but predominates on palms and soles of feet • Progresses to continuous pruritis

31. Clinical Manifestations • May have excoriations due to scratching • Abdominal pain is uncommon • Occasionally may have dark urine and pale stool

32. Clinical Manifestations • ~2 weeks after start of symptoms, jaundice develop in 50% • Accounts for 20-25% of cases of jaundice during pregnancy • Jaundice is usually mild, but persists until delivery • Symptoms usually abate about 2 days after delivery

33. cholestasis xerosis (dry skin) medications uremia iron deficiency leukemia HIV polycythemia lymphoma thyroid disorders diabetes visceral malignancies multiple sclerosis Differential Diagnosis for pruritis without a primary skin lesion

34. Lab Investigations • ALP • increases 5-10 fold • Serum total bile acids • may increase to more then 10x normal • Total bilirubin • mildly increased • AST, ALT • may increase - 200IU/L

35. Lab Investigations • GGT • normal or slightly elevated • Coagulation factors • INR • usually normal • may be increased scondary to Vitamin K deficiency due to cholestasis or due to the use of bile acid sequestrants

36. Diagnosis • Fasting serum bile acids must be more then 3 times the upper limit of normal • Clinical symptoms must also be present for diagnosis • Need to exclude other causes of jaundice and pruritus including viral hepatitis, primary biliary cirrhosis and biliary tract disease

37. Diagnosis • Ultrasound • reveals no biliary duct dilation, hepatic parenchyma appear normal • Liver Biopsy • rarely necessary for diagnosis • histologically shows: • centrilobular areas reveal dilated bile canaliculi • these changes tend to regress after pregnancy

38. Management • Cholestyramine • anion binding resin that interrupts the enterohepatic circulation, reducing reabsorption of bile acids • dose 8-28 g/day in three to four divided doses • may take up to 2 weeks to work, so should start as soon as pruritis is noted • check INR qweekly, as affects vitamin K absorption • may cause bloating and constipation, poorly tolerated • Intracranial heamorhage of the fetus??

39. Management • Ursodeoxycholic acid (UDCA) • Endogenous hydrophilic bile acid, reduces the proportion of hydrophobic = hepatotoxic bile acid,increases bile flow • causes significant decrease in pruritus and decrease liver function studies, decrease in total bile acid • dose 500 -1500mg per day • Fenobarbital • Induction of liver enzymes • Increase bile acides secreatio to bile • dose 60 mg / for night

40. Management • Dexametazon • prodiction of estrogens • decrease liver function studies • dose 12 mg/ per day – for 10 days • Antihistamines may help on reducing symptoms • Vit. K (10 mg/ d orally)

41. Management • Delivery • In most cases, delivery should be accomplished by 38 weeks • If cholestasis is severe, delivery should be considered at 36 weeks if fetal lung maturity is documented

42. Outcomes • Perinatal Outcome • Main complications are prematurity, meconuim-stained amniotic fluid and intrauterine demise • Probability of fetal complications is directly related to bile acid levels

43. Outcomes • Perinatal Outcome • Antepartum FHR testing and fetal surveillance should be undertaken • May induce labour at term, or when amniotic fluid studies indicate oligohydramnios

44. Outcomes • Maternal Outcome • Maternal prognosis is good • Pruritis usually begins to resolve around 2 days postpartum • There are generally no hepatic sequelae • Recurs in 60-70% of subsequent pregnancies • Recurrent episodes are variable in severity

45. Outcomes • Maternal Outcome • May be at increased risk for gallstones • OCP – administration rarely results in recurrent cholestasis

46. Differential Diagnosis • When patients present with signs of liver disease, appropriate workup needs to be undertaken to determine the cause • Generally a combination of clinical manifestations and lab results can help diagnose a patient • Rarely is invasive testing ie. liver biopsy necessary for diagnosis

47. Differential Diagnosis of Liver Disease in Pregnancy

48. Gall bladder disease • Gallsotnes are found in 8 % of nulliparus women and in 20 % of pluriparus women • ⇑risk: obesity, > 35 years of age • Gallsotne noeformation was documented in 3 – 8% of pregnant women • Acute cholecistitis occures in 0,1 % pregnancies • ⇑formation of cholesterol gallstones (estrogen related increased cholesterol saturation of bile and the rate of secretion of cholesterol), impaired gall bladder contractility leading to gall bladder stasis • Gall bladder disease are second common non-obstetrical couse of abdominal operations

49. Gall bladder disease Clinical manifestations of biliary colic: • Similar to non- pregnant • Pain in right upper quadrant of epigastrum, may radioate to the back and scapula • Nusea, vomiting and indigestion Clinical manifestations of aute cholecistitis: • More severe pain • High fever, shivers

50. Gall bladder disease Diagnosis: • Ultrasound – detection of gallstones, pericholecystis fluid, distention and thickening of gall bladder wall, ulrasound transduser- indused pain over gall bladder • aute cholecistitis - ⇧WBC, Abnormal liver function tests. Complications: • Jaundice • pancreatitis