Hepatic Disorders During Pregnancy

Key Abbreviations

Acute fatty liver of pregnancy	AFLP
Autoimmune hepatitis	AIH
Acute intermittent porphyria	AIP
Alanine transaminase	ALT
Aspartate transaminase	AST
Budd-Chiari syndrome	BCS
Complete blood count	CBC
Centers for Disease Control and Prevention	CDC
Cytomegalovirus	CMV
Computed tomography	CT
Disseminated intravascular coagulopathy	DIC
Epstein-Barr virus	EBV
Esophagogastroduodenoscopy	EGD
Endoscopic retrograde cholangiopancreatography	ERCP
Fetal alcohol syndrome	FAS
Focal nodular hyperplasia	FNH
Gestational diabetes	GDM
Gastrointestinal esophageal reflux disease	GERD
Gamma glutamyl transpeptidase	GGTP
Gastrointestinal	GI
Hepatocellular carcinoma	HCC
Human chorionic gonadotropin	hCG
Hemolysis, elevated liver enzymes, low platelets	HELLP
Hyperemesis gravidarum	HG
Human immunodeficiency virus	HIV
Herpes simplex virus	HSV
Intrahepatic cholestasis of pregnancy	ICP
Intensive care unit	ICU
Intrauterine growth restriction	IUGR
Liver function test	LFT
Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase	LCHAD
Mycophenolate mofetil	MMF
Magnetic resonance angiography	MRA
Magnetic resonance cholangiopancreatography	MRCP
Magnetic resonance imaging	MRI
Nonalcoholic fatty liver disease	NAFLD
Primary biliary cirrhosis	PBC
Polymerase chain reaction	PCR
Primary sclerosing cholangitis	PSC
Right upper quadrant	RUQ

Obstetricians, hepatologists, surgeons, and primary care physicians should be familiar with hepatic, biliary, and pancreatic disorders that can present in pregnancy and how these conditions affect pregnancy and may be altered due to pregnancy. This chapter reviews these conditions with a focus on features unique to pregnancy. Some liver diseases are unique to pregnancy, including hyperemesis gravidarum (HG); intrahepatic cholestasis of pregnancy (ICP); preeclampsia, hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; and acute fatty liver of pregnancy (AFLP). Others such as cholelithiasis, cholecystitis, and viral hepatitis can frequently occur in reproductive age women. With advances in management of chronic liver disease, more women are achieving pregnancy and will need a multidisciplinary team approach during pregnancy. This chapter reviews these conditions with a focus on features unique to pregnancy.

Physiologic Effects of Pregnancy and Assessment of Liver Disease

Abdominal assessment is modified during pregnancy. The expanding gravid uterus can displace abdominal viscera and may conceal an abdominal mass on physical examination. Pregnancy does not affect the liver span. The liver may be pushed cephalad by the gravid uterus, but a liver span greater than 12 cm, when appreciated, remains a valid indicator of hepatomegaly. Spider angiomata and palmar erythema, cutaneous lesions often associated with chronic liver disease, may appear transiently during normal pregnancy without underlying liver disease, presumably because of hyperestrogenemia during pregnancy. Most of these resolve after delivery. Although nausea and vomiting are common, especially in early pregnancy, jaundice and generalized pruritis are not normal features of pregnancy. During pregnancy, the serum alkaline phosphatase level normally increases mildly as a result of placental synthesis; the serum albumin level also declines, primarily from hemodilution and secondarily from decreased hepatic synthesis. Serum bilirubin levels tend to change little during pregnancy because of the effect of mildly impaired hepatic excretion balanced by the opposing effects of hemodilution and hypoalbuminemia. Serum bile acids tend to mildly increase during gestation because of impaired hepatic transport and biliary secretion. Serum levels of cholesterol, triglycerides, and phospholipids increase moderately during pregnancy as a result of increased hepatic synthesis. The serum aminotransferase levels are largely unaffected by pregnancy. Changes of serum levels of common blood tests during pregnancy are summarized in Table 52.1 . The incidence of abnormal liver tests in pregnancy is 3% to 5%. Any abnormality of transaminases or bilirubin requires further evaluation.

TABLE 52.1

Normal Physiologic Changes in Liver Tests in Pregnancy by Trimester

Test	First Trimester	Second Trimester	Third Trimester
Albumin	↓	↓	↓
ALT	↔	↔	↔
AST	↔	↔	↔
Alkaline phosphatase	↔	↑	↑
GGT	↔	↓	↓
Total bile acids	↔	↔	↔
Prothrombin time	↔	↔	↔

ALT, Alanine transaminase; AST, aspartate transaminase; GGT, γ-glutamyl transferase.

Differential Diagnosis of Hepatobiliary Symptoms and Conditions During Pregnancy

Maternal Jaundice

As in the general population, acute viral hepatitis is the most common cause of jaundice during pregnancy. The differential diagnosis of jaundice during the first and second trimesters of pregnancy also includes drug hepatotoxicity and gallstone disease such as acute cholecystitis , choledocholithiasis, ascending cholangitis, or gallstone pancreatitis . In addition to these disorders, the differential of jaundice during the third trimester includes pregnancy-related causes such as ICP, AFLP, and HELLP syndrome. Moderate direct hyperbilirubinemia without jaundice during the third trimester may also be due to preeclampsia, eclampsia, and Budd-Chiari syndrome (BCS). Predominantly indirect hyperbilirubinemia during pregnancy is usually due to hemolysis related to either HELLP syndrome or Gilbert syndrome.

Right Upper Quadrant Abdominal Pain

The differential diagnosis of right upper quadrant (RUQ) abdominal pain is extensive during pregnancy ( Box 52.1 ). In addition to disorders related to pregnancy, it includes disorders that occur in the nonpregnant state ( Box 52.2 ). A detailed medical history is warranted. In addition, characterization of the pain including intensity, temporal pattern, radiation pattern, exacerbating factors, and alleviating factors help to delineate the differential diagnosis. Biliary colic produces a waxing and waning intensity of pain. Acute cholecystitis is associated with RUQ pain, often with radiation to the right shoulder. Women with acute pancreatitis often describe a pain that is boring in quality, located in the abdominal midline, and radiating to the back. Women with HELLP syndrome can also experience similar symptoms. After a detailed medical history, physical examination of the abdomen should be performed including inspection, palpation, and auscultation, which can further help in diagnosing the cause of the pain. Laboratory evaluation of abdominal pain routinely includes a complete blood count (CBC) with differential, serum electrolytes, and liver function tests (LFTs). Additional studies may be warranted, including serum lipase and amylase as well as coagulation studies. In evaluating the laboratory results, gestational changes in normative values, as mentioned earlier, must be considered. Radiologic studies are often needed to aid in diagnosis. The choice of radiologic imaging must be considered related to the pregnancy, as discussed later in this chapter. RUQ pain and elevated LFTs the setting of new-onset hypertension in the second or third trimester of pregnancy should strongly suggest preeclampsia with hepatic involvement. RUQ pain and abnormal LFTs in the setting of thrombocytopenia and microangiopathic hemolysis, as demonstrated by the presence of schistocytes in a peripheral blood smear, should strongly suggest the HELLP syndrome.

Box 52.1

Differential Diagnosis of Right Upper Quadrant Abdominal Pain During Pregnancy

Hepatic Disorders

Hepatitis
Hepatic vascular engorgement
Hepatic hematoma
Hepatic malignancy

Biliary Tract Disease

Biliary colic
Choledocholithiasis
Cholangitis
Cholecystitis

Diseases Related to Pregnancy

Preeclampsia or eclampsia
Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome
Acute fatty liver of pregnancy
Hepatic hemorrhage or rupture

Renal Disorders

Pyelonephritis
Nephrolithiasis

Gastrointestinal Disorders

Peptic ulcer disease
Perforated duodenal ulcer
Pancreatitis

Other Conditions

Rib fracture
Shingles

Referred Pain From Another Disease

Pneumonia
Pulmonary embolus or infarct
Pleural effusion
Radiculopathy
Inferior wall myocardial infarction
Gastric cancer
Colon cancer

Box 52.2

Hepatic Diseases and Their Association With Pregnancy

Liver Diseases Affected by Pregnancy

Hepatic adenomas
Liver transplantation
Budd-Chiari syndrome
Portal hypertension
Acute intermittent porphyria
Sickle cell hemoglobinopathies

Liver Diseases Not Affected by Pregnancy

Acute viral hepatitis
Chronic hepatitis B
Chronic hepatitis C
Autoimmune hepatitis
Hepatic hemangiomas
Wilson disease
Primary biliary cirrhosis
Primary sclerosing cholangitis

Liver Diseases Related to Pregnancy

Hyperemesis gravidarum
Intrahepatic cholestasis of pregnancy
Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome
Acute fatty liver of pregnancy
Herpes simplex hepatitis

Nausea and Vomiting

Nausea and vomiting are common symptoms of early pregnancy. Also known as morning sickness, it occurs in up to 50% of all pregnancies. It typically begins at approximately 6 weeks and resolves at approximately 18 weeks. Symptoms are often attributed to the rising hCG and estrogen levels. In contrast, HG occurs in only 1.5% of all pregnancies. HG is a serious and potentially life-threatening form of nausea and vomiting in pregnancy associated with loss of more than 5% of the pregravid weight and electrolyte imbalance or ketonuria. HG is a diagnosis of exclusion and is typically not associated with other symptoms. The differential diagnosis of nausea and vomiting during pregnancy also includes acute pancreatitis, viral hepatitis, cholelithiasis, acute cholecystitis, HELLP syndrome, AFLP, and occasionally ICP. Other gastrointestinal (GI) disease causes include gastroesophageal reflux disease (GERD), peptic ulcer disease, viral gastroenteritis, appendicitis, gastroparesis, and GI obstruction.

Pruritus

The differential diagnosis of pruritus during pregnancy includes ICP, cholestatic viral hepatitis, PSC, PBC, and mechanical choledochal obstruction from benign or malignant strictures. Pruritus sometimes occurs physiologically during pregnancy; this pruritus is typically mild, localized, unassociated with other symptoms, and unassociated with abnormal LFTs. Intense pruritis that begins in the late second or third trimester of pregnancy, affecting mostly the hands and feet, in the absence of abdominal pain should lead to an evaluation of ICP. Laboratory blood work including LFTs and bile acids should be drawn.

Hepatic Lesions

Hepatic lesions identified on abdominal imaging studies are classified as cystic or solid. The differential of cystic hepatic lesions includes simple hepatic cysts, hepatic cysts associated with polycystic kidney disease, Caroli disease (a rare inherited disorder characterized by dilation of the intrahepatic bile ducts), bacterial abscesses, amoebic abscesses, intraparenchymal hemorrhage, hemangiomas, echinococcal cysts, and rarely hepatic malignancies. The differential of a solid hepatic mass includes hepatic adenoma, focal nodular hyperplasia (FNH), hepatocellular carcinoma (HCC), and hepatic metastases.

Ascites

Ascites is rare in pregnancy. Hepatic causes include cirrhosis, AFLP, BCS, portal vein thrombosis, hepatic fibrosis, and HCC. Other causes of ascites during pregnancy include ovarian cancer, abdominal tuberculosis, cardiac failure, protein-losing nephropathy, and severe protein malnutrition.

Abdominal Imaging During Pregnancy

The choice of diagnostic imaging in pregnancy must take the fetus into consideration. Ultrasonography is the preferred abdominal imaging modality during pregnancy due to lack of radiation exposure. Magnetic resonance imaging (MRI) is also safe in pregnancy. Although gadolinium, which is used in MRI with contrast, has not been associated with adverse fetal outcomes, data in the first trimester is limited. MRI is preferable to computed tomography (CT) scanning during pregnancy to avoid ionizing radiation, but gadolinium administration should be avoided during MRI in the first trimester.

CT scans are associated with increased risk of teratogenicity and childhood hematologic malignancies but can be used with minimized radiation protocols (2 to 5 rad) if necessary. Large doses of radiation (>100 rad) have been associated with adverse fetal outcomes such as malformations, growth restriction, and microcephaly. Both timing of exposure and radiation dosage are important when assessing fetal risk. Greatest fetal risk is associated with radiation exposure at 8 to 15 weeks of gestation and a cumulative dosage of 5 rad or greater. Common studies used in the evaluation of GI diseases, including an abdominal plain film (100 mrad), small bowel series (2 to 4 rad), and CT of maternal abdomen (3.5 rad), are all less than this critical threshold. Miscarriage risk is greatest during the first 2 weeks after conception. Fetal radiation exposure should be minimized by shielding the pelvis whenever feasible.

Therapeutic Endoscopy During Pregnancy

Endoscopy With Variceal Sclerotherapy or Banding

Endoscopy is most commonly used to assess and treat esophageal varices in pregnancy. When performing endoscopy in pregnancy, specific attention should be taken to ensure hemodynamic stability and oxygenation to preserve fetal oxygenation. This can be achieved with left lateral supine positioning, avoiding maternal hypotension or hypoxia, and ensuring adequate intravenous (IV) hydration. A multidisciplinary team approach including a maternal fetal medicine specialist, a hepatologist, and an anesthesiologist is beneficial. Esophageal varices occur in women with portal hypertension. Portal hypertension may occur related to autoimmune hepatitis (AIH), PSC, or cirrhosis . Endoscopic ligation (banding) or sclerotherapy are the primary therapies used for acute variceal bleeding during pregnancy. Endoscopic banding is preferred over sclerotherapy in the general population. Endoscopic banding has been associated with favorable perinatal outcomes compared with untreated disease. Sclerotherapy has also been shown to successfully treat acute variceal bleeding successfully without significant maternal or fetal risk. Esophagogastroduodenoscopy (EGD) can also be performed during pregnancy with relatively low fetal risks and should be considered when strongly indicated, such as for acute upper GI hemorrhage or significant gastritis or peptic ulcer disease. Both propofol and meperidine can be used for sedation during endoscopy. Propofol is preferred due to its short half-life and rapid recovery time.

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