Hepatic Dysfunction During Pregnancy Ayman Mokhtar Kamaly, MD Professor of Anesthesiology kamaly3@hotmail.com

Most pregnant women are young & healthy. Liver disease is a rare complication of pregnancy, but when it occurs it may be so dramatic & in a tragic fashion for both mother & infant.

Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes: Coincidental to Pregnancy Underlying Chronic Liver Disease Diseases Unique to Viral hepatitis Chronic hepatitis B or C Hyperemesis gravidarum Gallstones Autoimmune hepatitis Intrahepatic cholestasis of pregnancy Drugs 1ry sclerosing cholangitis Preeclampsia Sepsis Wilson disease HELLP syndrome Budd-Chiari* 1ry biliary cirrhosis (rare) Acute fatty liver of Cirrhosis (uncommon)

Normal liver in pregnancy Physiological changes in pregnancy: 40% increase in plasma volume, Increase in CO & HR (peaks at 32 wks), Hepatic Bl flow remains the same or even decreases (35% of CO in non-pregnant Vs 28% in pregnants).

Abnormal LFT During Pregnancy ‘normal for pregnancy’ AST ALT GGT BIL ALP Triglycerides Cholesterol Transferrin α1, α2 globulins 20% ↓ ↑ Reduced serum albumin, urea and uric acid concentrationsin the 3rd trimester ALP = Alkaline Phosphatase ↓ Alb Urea Uric acid

(I) Liver Diseases Unique to Pregnancy

Hyperemesis Gravidarum (HG) Occurs in 0.3% of pregnancies (1st trimester), Sever enough to indicate IV hydration, Risk factors: Hyperthyroidism, Molar pregnancy, Pre-existing DM, Multiple pregnancies.

LFT: Mild ↑ Bil (< 4mg%), related to malnutrition & impaired excretion of Bil. ALP ↑ twice N. AST/ALT ↑ 20-fold Biopsy: Histological normal. Management: Rehydration, nutrition, antiemetics (± steroids).

Intrahepatic Cholestasis of Pregnancy (ICP) 3rd trimester disease (25-30 wks), ↑ bile acid [BA] (due to defective biliary transport) & Pruritus Etiology: Hormonal: Sex hormones have known cholestatic effects Genetic: Certain ethnic groups (gene associated ICP) Exogenous: seasonal, geographical, selenium deficiency

Clinical Features and Diagnosis: Pruritus: Affects all parts of the body, Worse @ night, Severe cases→ patient may be suicidal. Obstructive Jaundice: 2-4 wks post pruritus (20-60% of pts.), Pale stools & dark urine, Diarrhea or steatorrhea, Sudden fetal death, (due to ↑ fetal levels of BA).

Labs (= Biliary obst): ↑ Bil. (< 5 mg%) ↑ ALP x 4 ↑ ALT/AST: 2-10 fold ↑ B.A. (most specific): 10-100 fold.

Cholestyramine, 10-12 g/day, Prophylactic Vitamin K. Management: Symptomatic therapy for mother + close monitoring & early delivery for the fetus. Urso-deoxy-cholic acid (UDCA), 10-15 mg/kg (ttt of choice, completely safe) Dexamethasone (12 mg/day for 1 wk) has the advantage of promoting fetal lung maturity Cholestyramine, 10-12 g/day, Prophylactic Vitamin K. Prophylactic parenteral Vitamin K

Outcome of pts. with ICP: Pruritus & liver dysfunction resolve immediately after delivery. 45-70% recurrence in subsequent preg. or with oral contraceptives. More liable to: Gallstones, Cholecystitis, Hepatitis C, Nonalcoholic pancreatitis, Nonalcoholic cirrhosis.

Preeclampsia and Eclampsia Triad (hypertension + edema + proteinuria), 5-10% of pregnancies in the 3rd trimester. Liver involvement, always indicates severe preeclampsia. Etiology: Placental hypoperfusion, with alteration of vasomotor tone, initiation of the coagulation cascade. Nitric oxide has role, (upregulation of NO-synthase in normal pregnancy) Imbalance of prostacyclin (PGI2) : thromboxane ratio increase systemic resistance. Etiology (unknown): Placental hypoperfusion leads to activation of the endothelium, with alteration of vasomotor tone, initiation of the coagulation cascade, increased adhesiveness to platelets and greater thrombogenicity. Nitric oxide has role, and upregulation of the nitric oxide synthase pathways has been demonstrated in normal pregnancy Imbalance of prostacyclin(PGI2) : thromboxane ratio increased systemic resistance.

Hepatic Involvement: Abnormal LFT in 20–30% of pts due to VC of hepatic vascular bed. ALP (which is often elevated in pregnancy), may be further ↑, Transaminases: 10-20 fold ↑, Bilirubin < 5 mg%, Complications: Subcapsular hematoma & rupture, infarction, & fulminant failure.

Acute Hepatic Hemorrhage of the Rt Lobe with a Subcapsular Hematoma.

Extensive necrosis throughout the Rt lobe with patchy necrosis in the Lt lobe

Autopsy of a eclamptic woman shows multiple regions of hepatic infarction (pale zones).

Unfortunately; No specific therapy for the hepatic involvement of preeclampsia, It is only significant as an indicator of severity & need for immediate delivery to avoid eclampsia, hepatic rupture, or necrosis.

HELLP Syndrome HELLP is a complication of severe preeclampsia in 2-12% of cases (Hemolysis, Elevated Liver tests, & Low Platelet). Key abnormalities: V.C, platelet activation & consumption, Thromboxane : Prostacyclin ratio alteration, Activation of complement & coagulation cascade causing microangiopathic hemolytic anemia, elevated liver enzymes with periportal and hepatic necrosis. V.C = increased vascular tone,

Clinical Features & Diagnosis There are no distinguished clinical features from preeclampsia (upper abdominal pain, nausea & vomiting, headache, edema, hypertension, and proteinuria). Diagnosis requires the all 3 laboratory criteria: (1) Hemolysis (↑ indirect bil.), (2) ↑ Transaminases (10-20 fold + bil. < 5 mg%), (3) Thrombocytopenia (<150000).

Classification of HELLP: Mississippi Class System: Class 1: Platelets < 50000 Class 2: Platelets 50-100000 Class 3: Platelets 100-150000 + Hemolysis + ↑liver enzymes (LDH>600) Tennessee System Complete syndrome: AST &/or ALT > 40 Platelets <100000 LDH > 600 IU/L AST > 70 Incomplete syndrome: Any 1 or 2 of the above

Differential Diagnoses of HELLP Thrombotic disorders Thrombotic thrombocytopaenic purpura, Hemolytic uremic syndrome, Sepsis & DIC, Drug-induced hemolytic anemias. Consumptive disorders Acute fatty liver of pregnancy, Sepsis and DIC, Hemorrhage. Others Connective tissue disease, SLE, Antiphospholipid syndrome, Procoagulant disorders.

Management: Hospitalization for stabilization (hypertension & DIC, seizure prophylaxis, fetal monitoring), Delivery is the only definitive therapy (< 34 wk → steroids for lung & plt), Outcome @ < 34 wk is better when steroids (dexamethasone, which cross the placenta) are used for 24-48 hr (main benefit is lung maturity & platelet count). outcome at less than 34 weeks’ is better when steroids (betamethasone or dexamethasone, which cross the placenta) are used for 24 to 48 hours; the main benefit of this therapy is fetal lung maturity but it also improves the maternal platelet count.

Complications of HELLP DIC, ARF, eclampsia, pulm edema, ARDS, Indications for liver transplantation are very limited (persisting bleeding from a hepatic hematoma or hepatic rupture or liver failure - necrosis). Hepatic hemorrhage or rupture due to exogenous trauma (abdominal palpation, convulsions, emesis & unnecessary transportation)

(compare perfusion with the normal spleen). Lt lobe Large subcapsular hematoma. Rt lobe has widespread necrosis a (heterogeneous, hypodense appearance), with “sparing” of Lt lobe.

Acute Fatty Liver of Pregnancy (AFLP) Rare fatal complication of preg. (3rd trimester). ChCh: microvesicular fatty infiltration → encephalopathy & hepatic failure with up to 10% mortality. Etiology: Enzyme mutation (mitochondria fatty acid oxidation) 20% of babies for mothers with AFLP are +ve for the enzyme . FAO = fatty acid oxidation

Clinical Features and Diagnosis 40%-50% of pts with AFLP are in their 1st preg, with twin. Presentation: vary from asymptomatic, nonspecific symptoms, to fulminant liver failure. Transaminases : 300-500, Bil. < 5 mg% Presumptive diagnosis is made on compatible clinical and lab features. Definitive diagnosis is histological.

AFLP: Diffuse fatty infiltration (A): (low power), (B):(high power)

Management: Immediate termination of pregnancy, Vaginal Vs CS according to INR (< 1.5) & plt (> 50000), Outcome: before 1980, both maternal & fetal mortality were 85%, With advance of supportive care, mortality went down to 7-18%.

(II) Liver Diseases Occurring Coincidentally in a Pregnant Patient

Viral Hepatitis 40% of jaundice in pregnant women in USA. Hepatitis A, B, C, D, E, Herpes, CMV, Epstein-Barr viruses. Management of pt with acute viral hepatitis is supportive, Viral hepatitis is NOT an indication for termination of pregnancy, caesarean section, or discouragement for breastfeeding

Pregnants with -ve HBV antibodies, & @ high risk (e. g Pregnants with -ve HBV antibodies, & @ high risk (e.g., +ve partner) can be vaccinated safely with little fetal risk. HBV transmission is NOT transplacental, but only during delivery. HCV mother to infant transmission is only 1-5%.

Gallstones & Biliary Disease Cholesterol secretion ↑ in the 2nd & 3rd trimesters > bile acids & phospholipids, → to supersaturated bile, Surgery is indicated when not responding to conservative measure (1st trimester (risk of abortion), & in 3rd trimester (risk of prematurity) ideally: Laproscopic . ERCP for impacted CBD stone (fluoroscopy minimization)

(III) The Pregnant Patient with Chronic Liver Disease

In HCV, aminotransferases may fall & viral RNA ↑ during pregnancy. Unfortunately, the optimal management of pregnancy with cirrhosis and portal hypertension in the modern era of obstetrics is undefined. Most patients with advanced cirrhosis are amenorrheic & infertile due to hypothalamic -pituitary dysfunction.

B-blocker is indicated for Pts with large varices, despite fetal effects, Acute variceal bleeding is managed endoscopically (as in non-preg), however; Vasopressin is contraindicated. In Pts with known large varices, avoidance of CS is recommended to avoid ↑ in portal pressure.

Conclusion