Liver troubles in pregnancy Dr. PERIHAN SALEM Assistant Professor of Hepatology Hepatobiliary Department Alexandria University

Acute fatty liver of pregnancy (AFLP): It is a very rare condition which affects 1:20 000 pregnancies with high maternal mortality rate (up to 18%), more common in 1st pregnancies, male babies & twins. The onset is usually late in 3rd trimester between 34th-36th week (earlier presentation is exceptional and alternative diagnosis should be considered). AFLP is a rare autosomal recessive disorder linked to an inherited mitochondrial enzyme deficiency called: Long Chain Acyl-CoA Dehydrogenase (LCHAD) in the baby. This deficiency will make the baby unable to metabolize FAs, which will return from the baby via the placenta to the mother, these FAs overwhelm the beta-oxidation enzymes of the mother producing hepatic stress & fat infiltration of the mother. AFLP can be regarded as a member of the mitochondrial cytopathy family.

Clinically: Non-specific manifestations as: N, V, fatigue, lack of appetite, abdominal pain. Jaundice & fever (up to 70%). Severe disease may present with elevated blood pressure, edema, RF, HE, pancreatitis, DIC, micro- vesicular fat infiltration in various organs. US: diffuse fatty liver with increased echogenicity. However, normal US doesn’t exclude the diagnosis. Laboratory findings: Increased liver enzymes, bilirubin, alkaline P. Leucocytosis, thrombocytopenia (linked inversely). High serum urea; creatinine; uric acid; ammonia levels, hypoglycemia together with lactic acidosis. Coagulopathy (diminished fibrinogen, DIC)

Treatment: Once diagnosis is confirmed, the baby should delivered as quickly as possible. The mother should be carefully followed as full clinical recovery of the mother usually occurs within several weeks without long term sequelae. However, recurrence of AFLP in the subsequent pregnancies can occur (25%).

toxemia of Pregnancy : I) pre-eclampsia & eclampsia It occurs after 20th week of pregnancy. The etiology of pre-eclampsia is unknown, it is marked by generalized vasospasm with increased systemic vascular resistance and enhanced responses to endogenous vasoconstrictors, leading to endothelial cell injury and damage which may decrease the release of endothelial dependent vasodilators & increase production of vasoconstrictors coming from both endothelial calls and platelets.

Vascular endothelial injury and damage will lead to increase vascular permeability with edema and hemorrhage. Vascular endothelial injury and damage leads to platelet deposition; thrombocytopenia and fibrin deposition in sinusoids resulting in hepatocellular necrosis, areas of infarction & hemorrhages. Hepatic involvement shows: elevated transaminases (more than 10 folds), elevated alkaline phosphatase, jaundice and rarely rupture of the liver.

II) HELLP syndrome: It is a rare variant of pre-eclampsia occurs in the last trimester (8% present after delivery), consists of hemolysis; elevated liver enzymes and low platelet count. The exact cause of HELLP is unknown, but activation of the coagulation cascade is considered the main underlying problem. Fibrin forms cross linked networks in the small blood vessels leading to destruction of RBCs & consumption of platelets. The liver appears to be the main site of this process leading to ischemia/Hg/rupture (other organs can be similarly affected). Thus, HELLP syndrome leads to a variable combination of DIC & bleeding.

Clinically: Malaise, nausea, vomiting, abdominal pain (epigastric/Rt hypochondrial). HTN (may be mild), headache, blurred vision, paraesthesia, edema. Severe form may present with: RF, pulmonary edema, DIC/Hg (in different organs), convulsions, coma, rupture liver. Laboratory findings: * CBC (hemolysis, thrombocytopenia). “class 1 ≤50.000, class 2 between 50.000-100.000, class 3 between 100.000-150.000”. Some sources recommend monitoring platelet count in pregnant females, as the level decreases just before HELLP syndrome become manifest. * Coagulation panel, FDP, D-dimer (if positive in pre-eclampsia it can predict HELLP). * Liver enzymes, bilirubin. * Renal function tests, electrolytes. * LDH >600 IU/L. * Proteinuria.

The only effective treatment is termination of the pregnancy & delivery of the baby. Several medications have been investigated for the treatment of HELLP syndrome, but evidences are conflicting as magnesium sulfate decreases the risk of seizures and progress to eclampsia. The DIC is treated with fresh frozen plasma to replenish the coagulation proteins, and the anemia may require blood transfusion. In mild cases, corticosteroids and antihypertensive may be sufficient. Intravenous fluids are generally required. The University of Mississippi standard protocol for treatment of HELLP syndrome includes corticosteroids. However, others found "no conclusive evidence" supporting corticosteroid therapy and no clear evidence of any effect of corticosteroids on the clinical outcomes either for the mothers or for the newborns”.

Intrahepatic cholestasis of pregnancy (ICP): It is common in the last trimester, but can start as early as the second or third month. Unknown etiology, theories include genetic predisposition vs pregnancy hormones. Genetic changes in the ABC B11 or the ABC B4 gene can increase a woman's likelihood of developing ICP: i) The ABC B11 gene provides instructions for making a protein called the bile salt export pump (BSEP), its main role is to move bile salts out of liver cells, which is important for the normal release of bile. Changes in the ABC B11 gene reduce the amount & function of the BSEP protein resulting in impaired bile secretion with the features of ICP. ii) The ABC B4 gene provides instructions for making a protein that helps move phospholipids across cell membranes and release them into bile. Phospholipids bind to bile acids, thus the lack of phospholipids available to bind to bile acids leads to accumulation of toxic bile acids that can impair liver function with impaired bile flow.

General health is preserved with variable degrees of weight loss with no abdominal pain. Liver and spleen are impalpable. The urine is dark with pale stool (steatorrhea which correlates with severity). Jaundice is rarely deep (rarely exceeding 100 µmol/L= 5.84 mg/dl) and usually associated with pruritis. After delivery, jaundice and pruritis disappears within weeks, however it can return in later pregnancies. There are increased levels of conjugated bilirubin, alkaline phosphatase & GGT with normal or mildly elevated transaminases. Prothrombin time is prolonged due to vitamin K deficiency.

This condition is associated with an increased risk of premature delivery and stillbirth. Additionally, some infants born with a slow heart rate (fetal distress). Treatment lines are supportive including: appropriate nutritional support with diminished intake of fats, vitamin K supplements (at least 6 hours before delivery) as the risk of post partum hemorrhage is increased, Ursodeoxycholic acid (safe dose is up to 2g/day) which relieves pruritis and improves liver function and also reduce fetal mortality, cholestyramine. Although dexamethasone helps in fetal lung maturation, its effectiveness in ICP remains debatable.

Budd-Chiari syndrome: Pregnancy is a pro-coagulant state with increased fibrinogen, factor VIII, factor IX and factor XII levels. Budd-Chiari syndrome and hepatic micro-thrombi may complicate pregnancy, especially in patients with lupus anticoagulants, anticardiolipin antibodies, antithrombin III deficiency, factor V Leiden mutation. Moreover, infections may be a precipitating factor. Supportive treatment (anticoagulant therapy as unfractionated heparin; LMWH), TIPS, LT may be needed with high maternal mortality. Warfarin crosses the placenta and can cause fetal bleeding and teratogenicity, with the latter occurring mainly during the first trimester. Neither UFH nor LMWH cross the placenta; therefore, these agents don't cause fetal bleeding or teratogenicity, although bleeding at the utero-placental junction and fetal wastage are possible.

Pregnancy and infections: Hepatitis A: Pregnant women exposed should receive immunoglobulins and vaccine. Hepatitis B: 1- Pregnant women in close contact with HBV positive persons (even carrier), must receive HBV vaccine which is safe in pregnancy. 2- In HBV positive pregnant women with high viral load (>10 [6] copies/ml) treatment depends on lamivudine or tenofovir (high potency, high genetic barrier for resistance) in the last trimester to prevent intrauterine & perinatal transmission. 3- The baby must receive HBVIGs immediately after birth (dose is 100 IU, IM, 12-48 hs). Also, the baby must receive HBV vaccine (within 24 hs- 7days).

Centers for disease control & prevention Pregnancy is not a contraindication to HBV vaccination: Limited data suggest that developing fetuses are not at risk for adverse events when hepatitis B vaccine is administered to pregnant women. Available vaccines contain noninfectious HBsAg and should cause no risk of infection to the fetus. Pregnant women who are identified as being at risk for HBV infection during pregnancy: e.g., having more than one sex partner during the previous 6 months, been evaluated or treated for an STD, recent or current injection drug use, or having had an HBsAg-positive sex partner should be vaccinated. Centers for disease control & prevention Guidelines for vaccinating pregnant woman 2014   Hepatitis A vaccine is an inactivated vaccine, and similar to HBV vaccines, is recommended for pregnant woman if high risk condition is present.

Hepatitis C: The chances of HCV transmission to the baby are small (during pregnancy & labor), however, the risk is increased if the mother has a high titre of HCV RNA. Vertical transmission was NOT reported in any Egyptian study. HCV antibodies may pass the placenta and remain positive for 6 months (lifespan of circulating maternal antibodies), thus the baby must screened at 1 month for HCV RNA. Breast feeding has NOT been associated with vertical transmission of HCV. (cracks???) Interferon & ribavirin (category x) are contraindicated during pregnancy. Sovaldi (category B, not adequately studied in pregnant humans, but don’t appear to cause harm to the fetus in animal studies).

* Hepatitis E: It is associated with up to 30% maternal & 50% fetal mortality. The mother may present with acute liver failure, where the severity of liver disease is correlated with the viral load. * Herpes simplex virus: The hepatitis is marked by very high serum transaminase levels together with herpetic lesions (can alert the clinician to the diagnosis).

GB diseases: During pregnancy, the bile become more lithogenic and GB emptying is impaired (by the relaxing effect of pregnancy hormones). Immediate post-partum GB US examination showed sludge in up to 26.2% and stone in up to 5.2%. Although symptoms of GB diseases are rare during pregnancy, ERCP & sphincterotomy can be performed safely as early as the 2nd trimester. Also, cholecystectomy whether open or laparoscopic can be performed during pregnancy.

Pre-existing liver disease: Pregnancy in women with cirrhosis carries an increased risk of maternal/fetal morbidity & mortality. However, liver cirrhosis per se is not an indication for termination. Recently, maternal & fetal outcomes are better than previously reported, with the ability to give anti-viral therapy for chronic HBV infection, non- selective B- blockers as prophylaxis for variceal bleeding (safe in pregnancy), banding of varices (during 2nd trimester).

Chronic cholestatic liver diseases: UDA , unabsorbed anti- pruritic therapy (anion exchange resin; Cholestyramin), regular plasma pheresis. Autoimmune hepatitis: Those taking Prednisone &/or Azathioprine prior to pregnancy can safely stay on but doses must be reduced. Placenta is a relative barrier for Azathioprine & its metabolites. Also, breast feeding is allowed. Wilson’s disease: Chelating agents as D- penicillamine/trientine must not stopped. Birth defects are described with high doses of D-penicillamine (1.5-2 g/day), but not with lower doses or with trientine.

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Case report Acute fulminate hepatitis (Alf) 21 years old female in 42nd w of pregnancy (2nd) presented a day after her CS with: Clinically: * V, Mild elevation of BP (returns normal on R). * Disturbed level of consciousness, agitation and disorientation. * Jaundice (start 5 days before delivery ???) Laboratory: Hb 8.2 g/dl, WBCs 28.000, platelets 114.000. Total bilirubin 9.5 mg/dl, direct 7.3 mg/dl, (17 mg/dl). Urea 30, creatinine 2.5 (4.4) with oliguria. LDH 1202, CRP 36.9 Elevated liver enzymes (AST 262, ALT 224). Serum albumin 1.6 INR 1.8 (2.8), prothrombin activity 26% Na 128, K 3.3, Ca 7.7 FBG: Normal

Viral markers: -ve Autoimmune markers: -ve Culture blood & urine : -ve CT brain: unremarkable (repeated) US abdomen: free except for fatty liver & minimal pelvic collection. DD: * Acute Fatty Liver of Pregnancy: With: Timing, V, jaundice, HE, fatty liver by US, elevated BP, increased liver enzymes & creatinine, leucocytosis, thrombocytopenia, coagulopathy. * Pre-eclampsia: With: Elevated BP (although mild, controlled), jaundice, thrombocytopenia, increased liver enzymes (although mild), coagulopathy, impaired renal function. * HELLP: With: Elevated liver enzymes, thrombocytopenia (although without hemolysis), jaundice, V, HTN, impaired renal function, coagulopathy, high LDH. * ICP: With: Jaundice, elevated liver enzymes, coagulopathy.

Treatment: Adequate hydration (IV fluids). Anti-hypertensive drugs. Empirical broad spectrum antibiotics. Anti-encephalopathy measures (lactulose, enema, branched chain amino acids). Glypressin (ampoule/6h). Corticosteroids (Dexa 20 mg/12h). Plasma & packed RBCs transfusion.

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