Chapter: Liver Disease in Pregnancy

Patricia Dalby, M.D.

OUTLINE:

Introduction

General Approach

Hypertensive Disorders of Pregnancy

Cirrhotic Liver Disease and Portal Hypertension

Maternal Hepatitis

Cholestatic Liver Disease

Liver Transplantation and Pregnancy

Introduction:

Isolated liver disease rarely occurs during pregnancy, and most of the life-threatening ones are the variants of the late gestational hypertensive disorders. The syndrome of hemolysis, elevated liver function tests, and low platelets (HELLP ), acute fatty liver of pregnancy (AFLP), and acute hepatic rupture associated with severe preeclampsia are examples of these. Progressive disorders such as intrahepatic cholestasis, cholecystitis, and hepatitis can affect the pregnancy to varying degrees and require treatment during pregnancy. In other cases, preexisting conditions such as liver transplantation and alcoholic liver dysfunction may affect outcome. Mild liver disease in pregnancy often does not affect fetal outcome, but severe disease can lead to fetal morbidity due to placental insufficiency, transmission of infection, and hyperbilirubinemia associated neurologic defects. Fetal mortality is higher with liver failure in pregnancy.

General approach:

In uncomplicated pregnancies normal physiologic changes and laboratory test abnormalities may mimic liver disease. Skin changes such as palmar erythema and telangiectasia, abdominal distension and discomfort, nausea, and pruritis are liver disease symptoms that occur in a significant percentage of normal pregnancies. Normally in pregnancy the liver size stays the same, but the percentage of cardiac output perfusing the liver is reduced 35%, preferentially perfusing the uterus. Jaundice, hepatomegaly, ascites, and right upper quadrant pain are definitely abnormal in pregnancy and warrant investigation. Esophageal varices are more likely to hemorrhage during pregnancy due to the increased blood volume. The laboratory test variations associated with normal pregnancies and in women with various liver disorders are shown in Table 1.

Table 1: LFT in normal pregnancy and disease states compared to normal non-pregnant females:

Diagnosis

Normal pregnancy

IHC

Cirrhosis

Acute hepatitis

Preeclampsia

HELLP

AFLP

Onset		3^rd trimester	Precedes Pregnancy	Any time	After 20 weeks	After 20 weeks	After 20 weeks
Albumin	- 10-60 %	0	- to - -				- -
Total protein	- 15 %	0	-		-		-
Total Bilirubin	Normal Range	+		0 to +++		0 to ++	+ to ++
Bilirubin direct	Normal Range	+		+ marked
Bilirubin indirect	Normal Range	+
AST / SGOT	0	0 or mild +	0 to ++	0 to ++++	0 to ++	+ to ++	++ to +++
ALT / SGPT	0	0 or mild +	0 to ++	0 to ++++	0 to ++		+ to ++
Total Alkaline Phosphatase	+ 200 to 400 %	0 or slight +	++				0 or ++
Glucose	0	0	- to - -	0 or -		0	-
Ammonia	0	0	+ with porto-systemic shunting	0 or rarely +	-	0	+
Platelets	0 or slight -	0	- with 2^o hyper-splenism	0	-	- to - -	- to - -
Fibrinogen	+ 50 %	0	-	+/-
Prothrombin time	Normal	0 if + then Rx with Vit K	0 to ++	0 to ++	0 to ++	0 to ++	++

Legend for Table 1:

IHC = Intrahepatic Cholestasis; HELLP = syndrome of hemolysis, elevated liver enzymes, and low platelets; AFLP = Acute Fatty Liver of Pregnancy

Once it is known that a parturient has hepatic disease, then the next logical step is determine the etiology of the disease and assess how sever the liver dysfunction is. A common approach to the severity of liver disease is based on the system (Table 2) described by Turcotte-Child for patients undergoing esophageal transections for bleeding varices. ^{[ 1]} Liver disease may affect the coagulation system, cardiac and pulmonary systems. Preanesthetic and predelivery efforts should focus on optimization of these systems. Operative delivery is often associated with high morbidity in severe liver disease because of the propensity to hemorrhage and coagulopathy. These conditions may also preclude the use of regional anesthesia. Pulmonary hypertension can occur in patients with cirrhosis. Many of the muscle relaxants including rocuronium and vecuronium have prolonged pharmacokinetic profiles in severe liver disease. All drugs that undergo hepatic metabolism should be considered potentially fixed agents.

Table 2: Child-Turcotte classification with Pugh modification of Liver Disease

Albumin (g/dl)	> 3.5	3.0 – 3.5	< 3.0
Bilirubin (mg/dl)	< 2.0	2.0 -3.0	> 3.0
Ascites	None	Controlled	Uncontrolled
Encephalopathy	None	Minimal	Coma
Nutrition *	Excellent	Good	Wasted
PT prolongation (s) *	< 4.0	4.0 – 6.0	> 6.0
Operative Mortality	0 - 10 %	4 - 31 %	19 - 76 %

The Pugh modification replaces nutrition with PT prolongation.

Acute hepatic failure can occur in pregnancy from multiple etiologies and liver biopsy may be the best diagnostic modality. The clinical features associated with acute liver failure in pregnancy are given in Table 3. The diagnosis may be delayed due insidious onset until encephalopathy and hyperventilation has developed due to hyperammonemia.

Table 3: Acute Liver Failure in Pregnancy:

	Acute Fatty Liver of Pregnancy	HELLP Syndrome	Acute Hepatitis
Abdominal Pain	50% of women	Almost 100%	Greater than 50%
Jaundice	All women	Less than 50%	All women
Serum Transaminases (elevation)	Less than 10 fold	Greater than 10 fold	Greater than 10 fold
Scans	Diffuse changes	Focal abnormalities	Diffuse changes
Coexisting Preeclampsia	50% of women	100% of women	Less than one quarter of women
Liver Biopsy	Microvesicular Fat	Sinusoidal fibrin	Acute hepatocyte inflammation
Liver Failure	Present	Usually absent	Variable

Hyperammonemia, impaired glucose metabolism, and lactic acidosis may develop and require treatment with the therapeutic modalities listed in Table 4. Cardiopulmonary deterioration may require supportive care, and renal failure may develop rapidly requiring dialysis. TIPPS (Transjugular intrahepatic portal-systemic shunts) have been advocated as a means of reducing esophageal venous pressures in pregnancy since unshunted parturients are more likely to have severe hemorrhagic events. ^[2]

Table 4:Treatment of Acute Liver Failure:

Treatment options for acute liver failure:

Correct underlying cause if possible

TIPPS early in the course: Prophylactic variceal sclerotherapy if indicated

Altered Low protein diet with enriched branched chain amino acids

Neomycin if necessary (controversial)

Vitamin B6, Folate, and Thiamin supplementation

Close monitoring of blood glucose levels for hypoglycemia, correction if indicated

Ascites present: Low salt diet, fluid restriction, and spironolactone.

Volume expansion with salt poor albumin carefully; risk of variceal bleed with aggressive rehydration

Variceal Bleeding present: Emergent sclerotherapy

Transfusion of blood products as indicated by clinical situation: packed red blood cells, platelets, and clotting factors (fresh frozen plasma)

Isolated coagulopathy present ; Treatment based on lab values and the anticipated intervention; consider Vitamin K supplementation

Consideration of liver biopsy if etiology unclear

Hypertensive disorders of Pregnancy

This encompasses a group of related pregnancy associated disorders manifesting hepatic dysfunction including severe preeclampsia, the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP), acute fatty liver of pregnancy (AFLP), hepatic hematoma, and hepatic infarction.

Severe Preeclampsia:

This is discussed comprehensively elsewhere on this web manual. However, the majority of the maternal deaths in this population are due to hepatic disease secondary only to central nervous system complications. Usually this occurs in association with one of the following disorders.

Hepatic Hematoma and Subsequent Rupture:

This occurs in the setting of severe preeclampsia and the hematoma is usually subcapsular. Nausea and vomiting with associated right upper quadrant pain in a hypertensive mother may be later followed by cardiovascular collapse if rupture occurs. Mortality of both mother and baby are very high, and the bleeding source at laparotomy often is elusive. Ultrasonography is diagnostic, and treatment involves embolization techniques, surgery, or occasionally conservative treatment. Treatment consists of delivery, often by cesarean section to avoid maternal pushing efforts. If rupture occurs blood loss is enormous, and disseminated intravascular coagulopathy will probably develop. Invasive monitors are indicated in the perioperative period in an intensive care environment.

Hepatic Infarction:

This rare phenomenon is also associated with preeclampsia, and presents in the third trimester with fever, abdominal pain, and severely abnormal liver function tests. Diagnosis is by CT and liver biopsy. Management modalities are similar to hepatic hematoma.

HELLP Syndrome:

This syndrome occurs in 10% of preeclamptic pregnancies and current morbidity figures are low. The hallmark of the disease is severe depression of platelet counts in a parturient following other vague viral illness like nonspecific complaints. Hypertension and liver dysfunction are often not profound. Treatment is delivery and the disease may worsen for several days postpartum. Regional anesthesia, which is the preferred anesthetic choice in preeclamptic patients, may not be feasible in this population. Transfusion of platelets is not advocated prior to delivery in these patients.

Acute fatty Liver of Pregnancy (ALFP):

This is an obstetrical emergency thought by many to represent a variant of severe preeclampsia. Severe liver failure with coagulopathy occurs over the course of one to two weeks of nausea, vomiting, and abdominal pain. AFLP may be confused with hepatitis, but profound liver failure develops more acutely. It may belong to a group of microvascular fat diseases such as Reyes syndrome, and congenital urea cycle defects. ^[3] Treatment is that of delivery and that provided for acute liver failure, with liver transplantation being the only hope for some mothers.

Cirrhotic Liver Disease and Portal hypertension

Hepatic cirrhosis is an irreversible fibrotic chronic injury to the liver. Post necrotic cirrhosis resulting from chronic viral hepatitis is the most common cause of this disorder in parturients, but alcoholic liver disease is the most common etiology in the general population. Portal hypertension connotes severe liver impairment, and is rare in parturients except for some notable exceptions. Cases of pregnant women with portal hypertension are reported with coexisting Wilson’s disease, focal nodular hyperplasia, liver cell adenoma, hereditary hemorrhagic telangiectasia and Budd-Chiari syndrome. Esophageal varices develop in these women and forceps use or vacuum extraction are often advocated to avoid further increases in portal pressures with prolonged maternal straining efforts. Regional anesthesia is advocated unless liver disease is so severe as to affect coagulation.

Alcoholic Cirrhosis:

If the etiology of the cirrhosis is due to alcoholic liver disease, concomitant alcohol intoxication may confound anesthetic management. Acute intoxication will decrease demands for general anesthetic agents, and will lead to an increased propensity to vomit and aspirate. Also the acutely intoxicated mother may be uncooperative with regional anesthesia. Chronic intoxication is associated with maternal immune incompetence, cardiomyopathy, bleeding disorders and poor wound healing. These women can also develop alcoholic withdrawal syndromes during their hospitalization. Fetal alcohol syndrome is described in infants born to these mothers and is comprised of abnormal facies, hypotonicity, tremulousness, and associated cardiac septal defects.

Maternal Hepatitis:

Maternal hepatitis is the most common cause of jaundice in pregnancy and most often of viral etiology. A serious infectious risk to the neonate and the caregivers may be imposed by the parturient with hepatitis depending on the cause of the hepatitis. Hepatitis viruses A through E predominates as causal agents, but other viruses and drugs can be responsible. Laboratory analysis of the jaundiced mother should include specific viral markers. Hepatitis can be a chronic disease that predates pregnancy or can contracted during pregnancy, and treatment regimens vary for neonatal prophylactic regimens. Maternal viral hepatitis disease can be quiescent during the pregnancy, but maternal viral hepatitis E disease is usually adversely affected. Maternal mortality with Hepatitis E is 15-20 %. ^[4]

Cholestatic Liver Disease:

This disorder generally occurs late in the pregnancy and includes intrahepatic cholestasis of pregnancy, primary biliary cirrhosis, hepatoxic drug reactions, and rarely exacerbation’s of Dubin-Johnson syndrome. Pruritis, jaundice, or both are the main presentations of the disease. Right upper quadrant pain and fever usually accompany biliary tract disease; often involving gall stones and occurs throughout pregnancy. Such disease may require operative intervention during pregnancy. Stangely hyperemesis gravidarum has been included in this category, but also occurs throughout pregnancy. ^[5]

Intrahepatic Cholestasis:

The implications of this disease are more severe for the fetus than the mother. IHC has been associated with preterm labor, meconium staining, and a high incidence of abnormal fetal heart rate tracings. The pathogenesis of the disease may involve an enzyme deficiency or a maternal hypersensitivity to estrogen. Mothers have been treated with anion exchange resin agents to bind bile acids, but these may further interfere with vitamin K metabolism that is already defective in this disorder. Coagulation disorders may need to be corrected prior to regional anesthesia administration for labor and delivery.

Liver Transplantation and Pregnancy:

Liver transplantation is performed rarely during pregnancy or immediately after delivery for various indications, but it is usually precipitated by acute hepatic failure and as a last resort effort to save the parturient. There are less than 40-reported cases on an acute basis secondary to hepatic rupture, AFLP, fulminant hepatitis, Budd Chiari Syndrome and other causes with much better maternal than fetal survival. Normal infants have been delivered from mothers that underwent transplantation earlier in the pregnancy. General anesthesia is used for these operations following accepted techniques, with the utilization of left lateral uterine displacement if the pregnancy is still in-utero.

A more common management encountered is that of the pregnant prior transplant recipient. Pregnancy is usually delayed for six months, but then if graft rejection is not apparent, fertility is the rule. ^[6] Such parturients should be evaluated for residual maternal end organ disease and there are reports of these mothers developing hypertension, preeclampsia, anemia, and preterm delivery. These mothers are also on immunosuppressant medication regimens that must be continued and these drugs have pregnancy implications (Table 5). Since 1991 the National Transplantation Pregnancy Registry has evaluated pregnancy outcomes in liver transplant parturients. Biopsy proven acute rejection poses the greatest risk on outcome for both the mother and neonate. In the stable parturient with a prior liver transplant, anesthesia choices should be based on obstetrical indications. By ways of insuring that the patient is not entering a rejection episode baseline laboratory studies are often available for these patients are often followed by a transplantation service. If general anesthesia need be employed for an urgent cesarean section, then airway management may be complicated by cushionoid changes, and the anesthesiologist should be aware that cyclosporine may prolong the effect of muscle relaxants, especially with coadministration of magnesium. For additional information, please see the chapter on “Parturients with Transplanted Organs”.

Table 5:Liver Transplantation Antiregection Agents

Immunosuppressive Medications:	Maternal concerns:	Fetal concerns:
Steroids	Hypertension, Cushion’s Syndrome, Wound healing problems, Hyperglycemia	Premature rupture of membranes, Fetal lung immaturity,
Azothiaprine	Pancytopenia, Decreased muscle relaxant requirement	Intrauterine growth retardation, Chromosomal aberrations
Cyclosporine	Nephrotoxicity, Hypertension, Insulin sensitivity, Neurologic deficits	Intrauterine growth retardation, No evidence teratogenesis
Tracolimus (FK-506)	Nephrotoxicity, block IL production and T-cell proliferation
Rapamycin	Same as FK-506
OKT3	Serum sickness syndrome, Vulnerable to cytomegalovirus infection	CMV infection from maternal transmission
Antilymphocyte Globulin	Leukopenia, Thrombocytopenia, Serum sickness syndrome

Bibliography:

[1] Pugh R, Murray-Lyon I, Dawson J, et al. Transection of the esophagus for bleeding esophageal varices. Br J Surg 1973; 60:646-9.

[2] Conn HO. Transjugular Intrahepatic Portal-systemic Shunts: The State of the Art. Hepatology 1993; 17:148-158.

[3] Strauss AW, Benett MJ, Sims HE. Inherited long chain 3-hydroxyl acyl-co A dehydrogenase deficiency and a fetal-maternal interaction causing maternal liver disease and other pregnancy complications. Semin Perinatol 1999; 2:100-112.

[4] Anonymous. ACOG Educational Bulletin Number 248: Viral Hepatitis in Pregnancy. 1998; Chicago: ACOG. 248:

[5] Rioseco AJ, Ivankovic MB, Germain AM. Intrahepatic Cholestasis of Pregnancy: A Retrospective Case-Control Study of Perinatal Outcome. Am J Obstet Gynecol 1994; 170:890-895.

[6] Riley T. Obstetric Management of Patients with Transplants. Int Anesthesiol Clin 1995; 33:125-140.

Author: Patricia L. Dalby, M.D.