Liver Disease in Pregnancy



Liver Disease in Pregnancy


Juan Ignacio Pereira

Gustavo F. Leguizamón



Introduction

Approximately 3% of all pregnancies are complicated by liver disorders.1 These infrequent conditions pose a great diagnostic challenge for the obstetrician. In this chapter, we address liver diseases exclusive to pregnancy, including preeclampsia, HELLP syndrome, acute fatty liver of pregnancy (AFLP), and intrahepatic cholestasis; as well as those that coexist with pregnancy like biliary lithiasis, viral hepatitis, autoimmune and vascular disorders.


Physiological Changes in Liver in Normal Pregnancy

During normal pregnancy, many physiological and hormonal changes occur, some of which may mimic liver disease (Table 34.1). Heart rate and cardiac output increase, and plasma volume rises with reduction in peripheral vascular resistance. These changes result in a hyperdynamic state, which is also observed in patients with decompensated chronic liver disease.2 Because the liver moves upward into the thorax secondary to increasing uterine size, liver palpation is difficult. Hepatomegaly is not a normal finding and should prompt evaluation.3 Gallbladder motility decreases, whereas the risk of developing gallstones is enhanced.4 By the end of the second trimester, small esophageal varices without clinical significance can be present in 50% of pregnant women. This occurs due to compression of the inferior vena cava (IVC) by the gravid uterus, with subsequent reduction of venous return.2








Laboratory values are frequently modified secondary to hemodilution. Total protein decreases during pregnancy, mainly because of reduced serum albumin.3 Maternal alkaline phosphatase (AP) is enhanced due to its placental origin and as a result of fetal bone development. Therefore, the measurement of serum AP activity is not accurate for the diagnosis of cholestasis during the third trimester.5 Because alpha fetoprotein is produced by the fetal liver, its concentration increases in gestation. In general, serum alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transferase activities, as well as serum bilirubin and total bile acid concentrations, remain below the upper normal limits during pregnancy.6 Increases of these values should be considered abnormal and should prompt further evaluation.5


Liver Diseases Unique to Pregnancy


Hyperemesis Gravidarum


Epidemiology

Although nausea and vomiting during pregnancy (NVP) affects 50% to 80% of pregnant women,7 90% resolve by 20 weeks of gestation. In contrast, hyperemesis gravidarum (HG) is a complication
rather than a normal finding8 and occurs in 0.3% to 3% of pregnancies.9 It is the most common cause of hospitalization in the first trimester10 and is more prevalent among young, primiparous mothers who are non-Caucasian and nonsmokers.9


Etiology

The etiology of HG is unknown. Endocrine, infectious, psychological, and genetic factors have been proposed. Human chorionic gonadotropin (hCG) is a strong emetogenic stimulus, especially when levels are significantly enhanced such as in multiple or molar gestations. NVP and hyperemesis are also more common when estradiol levels are increased. Estrogen can decrease gastric emptying and overall intestinal transit time.11 Other theories suggest that NVP is an evolutionary adaptation to protect the mother and her fetus from food-borne diseases.12 Helicobacter pylori as a causative factor of HG has also been addressed. In fact, according to American College of Obstetricians and Gynecologists (ACOG) recommendations, H. pylori treatment could be beneficial in refractory cases.11 Psychogenic theories have been proposed, but data to support this approach are lacking. The development of depression, anxiety, and posttraumatic stress disorder may be an effect rather than a cause of HG.9 Finally, history of HG in a previous pregnancy, history of motion sickness, migraine headaches, and women carrying female fetuses8 have been identified as risk factors.



Diagnosis

The diagnosis of HG is based on characteristic clinical findings and is achieved after the exclusion of other conditions that may also present with excessive NVP. Typical signs and symptoms include vomiting not related to other causes and an objective measure of acute starvation such as large ketonuria and weight loss.11 Hypochloremic alkalosis, hypokalemia, hyponatremia, and mild elevation of amylase, lipase, and liver function enzymes are common laboratory abnormalities.13 Frequently, signs of dehydration are also present, including orthostatic hypotension, tachycardia, dry skin, mood changes, and lethargy.9 The differential diagnosis includes gastroenteritis, cholecystitis, hepatitis, biliary tract diseases, drug abuse/misuse, and migraine headaches. Infrequent causes include diabetic ketoacidosis, intracranial lesions, and intestinal obstruction.9

Laboratory tests commonly included in the initial assessment are complete blood count and serum metabolic panels, amylase/lipase, hCG level for evaluation of possible molar or multiple gestations, and urinalysis for ketones.9 The 2018 ACOG guidelines recommend that serum thyroid function studies should be obtained only in the presence of other signs of hyperthyroidism such as palpable goiter.11 Because gastric ulcers can be a contributing factor to refractory HG, testing for H. pylori infection has also been recommended.11


Maternal-Fetal Implications

Most women with HG receiving supportive care have good outcomes. Occasionally, serious maternal complications can occur. Severe dehydration and malnutrition can rarely lead to complications, including Wernicke encephalopathy, metabolic disturbances, and venous thromboembolism.14,15,16 Wernicke encephalopathy (caused by vitamin B1 deficiency) has been associated with permanent neurologic disability or maternal death. Esophageal laceration associated with Mallory-Weiss syndrome may result from repetitive wrenching. Rupture of the esophagus (Boerhaave syndrome) and pneumomediastinum have also been described and may require surgical intervention.9 HG can also have psychosocial consequences, such as social isolation, feeling of guilt, suicidal ideation, and pressure to terminate pregnancy.17 Fetal risks include low birthweight, preterm labor, and small for gestational age infants. No significant association of HG with congenital anomalies has been demonstrated.18 Finally, recurrence risk varies from 15% to 80%.19 Prophylactic interventions started before the onset of NVP may reduce the duration and severity of symptoms in subsequent pregnancies. Early prescription of antiemetics that proved effective in the first pregnancy is encouraged.20



Nonpharmacologic Treatment

Common recommendations include rest and avoidance of sensory stimuli such as odors, heat, humidity, noise, and flickering lights.11 Two studies found that women who were taking multivitamin supplements at the time of fertilization were less likely to require medical assistance for vomiting.21,22 Therefore, taking prenatal vitamins for 1 month before pregnancy could reduce the incidence and severity of NVP.11 Dietary modifications include avoiding spicy or fatty foods, excluding iron supplements, and eating bland or dry foods and high-protein snacks.11



Pharmacologic Therapies

Early treatment of NVP is recommended to prevent progression to HG. Treatment of NVP with vitamin B6 (pyridoxine) alone or plus doxylamine is safe and effective and should be considered the first-line pharmacotherapy.11 A multicenter randomized controlled trial (RCT) evaluating this combination, found significant symptomatic improvement.23 Relief of NVP with dopamine antagonists (metoclopramide, promethazine, prochlorperazine, or chlorpromazine) given orally, rectally, intramuscularly, or intravenously has been demonstrated in large groups of patients.11 Antihistamines, such as dimenhydrinate and diphenhydramine, have been shown to be effective and are frequently used.11 Evidence is limited on the safety and efficacy of the serotonin 5-HT3 inhibitor, ondansetron. In a small double-blind RCT, ondansetron was found to be more effective than the combination of doxylamine and vitamin B6 (pyridoxine).24 However, serious adverse effects such as QT interval prolongation, especially in patients with underlying heart problems, hypokalemia, or hypomagnesemia, have been reported.25 The risk of birth defects in the first trimester is still a matter of debate. Thus, women should be counseled weighing the risks and benefits of ondansetron use before 10 weeks.11 Corticosteroids for HG should be used with caution and avoided as first-line agents, especially before 10 weeks of gestation, as studies have reported an association between oral cleft and methylprednisolone.26 The use of antidepressants has been suggested for refractory HG. Mirtazapine was found to be beneficial in cases of HG in the context of depression.9

Hospitalization is recommended if oral intolerance is a concern or there is lack of response to outpatient management, a change in vital signs or in mental status, and if persistent weight loss occurs.11 Intravenous hydration should be used. Correction of ketosis and vitamin deficiency should be considered. Dextrose and vitamins should be included, and in severe cases thiamine should be administered before dextrose infusion to prevent Wernicke encephalopathy.27 Additionally, serum electrolytes must be monitored and corrected accordingly.9 Enteral tube feeding (nasogastric or nasoduodenal) should be used to provide nutritional support in woman with HG who cannot maintain appropriate weight, especially if malnutrition is present.11


Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease.28,29,30 Its clinical presentation is usually in the third trimester and consists of pruritus of the palms and soles, abnormal liver function tests, and elevated serum bile acid (SBA) levels.28 ICP is consistently associated with adverse pregnancy outcomes, including spontaneous and iatrogenic preterm birth, nonreassuring fetal status, meconium staining of the amniotic fluid, and stillbirth.28,29


Epidemiology

The incidence of ICP is between 0.2% and 2% but varies with ethnicity and geographic location. It is most common in South America and Northern Europe.28,29 In Chile, the incidence in the Araucan Indian group is as high as 15.6%.31 In the United States, reported incidence rates range from 0.32% in a Connecticut mainly Caucasian cohort to 5.6% in a Los Angeles Latino populations.29 Risk factors for ICP include multiple gestations, in vitro fertilization, advanced maternal age, history of prior affected pregnancy, family history, and hepatitis C infection.28,29,30 Moreover, women with ICP are more likely to develop hepatobiliary disease, including fibrosis, gallstone disease, or hepatitis.28,29


Etiology and Pathogenesis

The etiology of ICP appears to be related to the cholestatic effect of reproductive hormones in genetically susceptible women.28 Estrogen reduces the expression of hepatic biliary transport proteins and contributes to the internalization of the bile acid transporter bile salt export pump.28 Progesterone metabolites can also impair hepatic bile acid homeostasis by reducing the function of the main hepatic bile acid receptor.29,32,33 Therefore, the transport of bile salts from the liver to the gallbladder is disrupted and there is compensatory transport from the hepatocytes into the blood.28 Fetal complications are directly related to the toxic effect of bile acids, which accumulate in the fetal compartment.28 Some studies suggested an association of ICP with low dietary selenium34 as well as low vitamin D35 levels.



Clinical Features and Diagnosis

The classical feature of ICP is pruritus without rash or any specific dermal lesion,29 typically occurring in the third trimester.28 Approximately 80%
of women manifest this symptom after 30 weeks of gestation, but occasionally it can present as early as the seventh week.28,36 Pruritus typically affects the palms and soles but may occur anywhere, and characteristically disturbs the sleep pattern. It is often worse at night and may deteriorate as pregnancy advances.28 Excoriation marks secondary to scratching are usually observed.28 Systemic symptoms of cholestasis may be present, including dark urine and pale stools. Some women may also present as jaundiced, but this is rarely observed.28

The diagnosis is confirmed after demonstration of abnormal liver function tests and especially maternal SBA above 10 to 14 µmol/L.28 Liver transaminases can also be elevated.28,29 AP is not useful in the diagnosis of ICP, because it is produced in large quantities by the placenta.28 Bilirubin is increased in 10% of women with ICP.28 Finally, liver ultrasound scanning is useful to rule out other causes of cholestasis, such as gallstones.28


Fetal Concerns

ICP increases the risk of adverse perinatal outcomes, probably secondary to accumulation of SBA in the fetal compartment.28 Spontaneous and iatrogenic preterm birth, meconium staining, stillbirth, and neonatal intensive care unit (NICU) admission are consistently associated with this condition.36,37 Several investigators observed a relationship between maternal SBA level and adverse outcomes.28,36,37 These studies reported an elevated risk of stillbirth with SBA levels greater than 40 µmol/L,37 with the highest risk being observed when levels are greater than 100 µmol/L.29,38,39



Pharmacologic Treatment

ICP is commonly treated with ursodeoxycholic acid (UDCA). Randomized trials showed significant improvements in pruritus and liver function tests with UDCA therapy.28,40,41 Although UDCA therapy decreases fetal levels of SBA,29 there is no evidence to support improved perinatal outcomes when compared with placebo.41 Finally, the dose of UDCA can be titrated to symptoms and usually ranges from 500 mg to 2 g daily.28

Other drugs have been used to treat ICP, but they are less effective and, therefore, are not considered as first-line therapy. Patients not responding to monotherapy with UDCA can benefit from a combined treatment with rifampicin, an antibiotic with choleretic properties.28 Cholestyramine is an anion exchange resin that may be effective in reducing pruritus but fails to improve SBA levels or liver function.42 Given the reduced intestinal absorption of fat-soluble vitamins and the subsequent higher risk of intrapartum or postpartum hemorrhage, cholestyramine is no longer considered a first-line treatment in ICP.28 Antihistamines and topical emollients, such as aqueous cream with 2% menthol, may improve symptoms but have no effect on liver function.28



Fetal Monitoring

It has been hypothesized that bile acids may cause sudden fetal death secondary to arrhythmia and vasoconstriction of placental vessels, leading to acute anoxia.28

There is no proven effective antenatal monitoring strategy to prevent stillbirth in ICP.28,29,43 However, clinicians may find it reassuring to have regular cardiotocography, biophysical profile, and fetal growth scans. Women with ICP should also be counseled on the increased risk of stillbirth and the limitations of testing.29


Elective Early Delivery

To reduce the risk of stillbirth, many authors have advocated for elective early delivery.28,30 In a large retrospective cohort study involving over 1.5 million subjects, Puljic et al43 compared women with diagnosis of ICP (n = 5545) between 34 and 40 weeks of gestation to women without ICP. For each week of gestation, they assessed the risk of stillbirth, the risk of delivery, and the composite risk of expectant management. The authors found that the risk of delivery was lower than the risk of expectant management at 36 weeks of gestation (4.7 per 10,000 vs 19.2 per 10,000). After 36 weeks, the risk of expectant management remained higher than delivery, and continued to rise at each subsequent week of gestation.43 Although relevant, these data do not consider neonatal morbidity and are limited by the retrospective design. A strategy of universal delivery at 36 weeks of gestation would lead to intubation of 10 newborns or 80 admissions to the NICU, to prevent 1 stillbirth.43 We emphasize, however, that no randomized studies have established the optimal timing of delivery for pregnancies complicated by ICP.28 Algorithm 34.1 depicts a possible management approach to patients with ICP based on the current literature and the author’s experience.








Postnatal Follow-Up and Preconception Counseling

The biochemical abnormalities associated with ICP typically resolve rapidly after delivery.28 Because higher incidence of hepatobiliary disease is observed later in life,44 women with ICP should have their liver function and SBAs checked 6 to 8 weeks postnatally.28 This condition can recur with oral contraceptives; therefore, alternative methods to oral contraception should be advised.45 Approximately 90% of women will have ICP recurrence in subsequent pregnancies.28,29


Liver Involvement in Hypertensive Disorders of Pregnancy


Preeclampsia

Hepatic involvement affects approximately 10% of women with severe preeclampsia, and frequently presents with epigastric or right upper quadrant pain.46 Transaminases are significantly increased, whereas bilirubin concentrations are rarely enhanced. Complications can include subcapsular hematoma and hepatic rupture.30 Liver biopsy is not indicated.1 Characteristic microscopic changes involve periportal areas with identifiable sinusoidal fibrin thrombi, hemorrhage, and hepatocellular necrosis. Portal thrombosis and hemorrhage can also occur.1 Liver biochemical profile usually normalizes within 2 weeks of delivery.1


HELLP Syndrome

HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome is characterized by hemolytic anemia, elevated liver enzymes, and low platelet count. It complicates 0.5% to 0.9% of all pregnancies47 and 10% of gestations with severe preeclampsia.30 Liver injury is secondary to intravascular fibrin deposition, hypovolemia, and increased sinusoidal pressure.1,48

Patients with HELLP syndrome may be asymptomatic or present with right upper quadrant and epigastric pain, nausea, vomiting, and malaise.1,48 Although hypertension and proteinuria are present
in 85% of women with this condition,1 HELLP syndrome can occasionally occur without a previous diagnosis of preeclampsia. Usually, HELLP syndrome is complete. Hemolysis is manifested by enhanced lactate dehydrogenase, decreased haptoglobin, and increased unconjugated bilirubin. In its complete form, thrombocytopenia and elevated aminotransferases are also evident; partial forms with only one or two alterations have also been described.1,48 Liver biopsy remains a high-risk procedure due to thrombocytopenia and should be avoided.


Hepatic Infarction, Hematoma, and Rupture

An extremely rare and potentially fatal complication of HELLP syndrome is hepatic infarction. It is usually focal and less common because of the dual blood supply of the liver (20% hepatic artery and 80% portal vein).47 Computed tomography (CT) scan may show nonhomogenous wedge-shaped areas with enhanced vessels coursing through these areas.47

Subcapsular liver hematoma is a life-threatening condition complicating 1 in 25,000 to 1 in 40,000 pregnancies49 and occurs in 0.9% to 1.6% of gestations complicated by HELLP syndrome.50 Its rupture is the most catastrophic complication with maternal mortality rates as high as 50%.51



Diagnosis

Symptoms include right upper quadrant or epigastric pain, severe right shoulder pain, NVP, and hypotension and shock. Abdominal distention from hemoperitoneum is seen when hepatic rupture occurs.49 Differential diagnoses are pulmonary embolism, adnexal torsion, rupture of adnexal cyst, cholelithiasis, hepatitis, pancreatitis, peptic ulcer, myocardial infarction, pyelonephritis, and nephrolithiasis.49,52 Laboratory alterations include increased transaminases in excess of 3000 U/L, leukocytosis, pyrexia, and anemia. Clinical suspicion should prompt further evaluation. Ultrasound is a reasonable initial approach,49 but findings need to be confirmed with either CT scan or magnetic resonance imaging (MRI).1,30,49 Complications include acute respiratory distress syndrome, acute kidney injury, and hypovolemic shock.1


Management of Liver Hematoma in Pregnancy

Unruptured subcapsular liver hematoma in a hemodynamically stable patient can be conservatively managed.1,30,49 Maternal condition should be closely monitored and, if present, coagulopathy must be corrected. Even mild trauma to the liver, such as abdominal palpation, must be avoided because it can lead to the rupture and catastrophic bleeding.49 Serial ultrasound or CT scans should be performed to monitor the size of the hematoma, and if it increases or the maternal condition becomes unstable, surgical evaluation is mandatory.49 Complete resolution of the hematoma can take several months.49 Hemodynamically unstable patients with the suspicion of ruptured hematoma require invasive hemostatic measures. Arterial embolization of the hepatic artery or surgical exploration to achieve hemostasis through packing of the bleeding bed is mandatory.1,30,53,54 Liver transplant could be considered if refractory hemorrhage leads to acute hepatic failure.1,30,47,49


Acute Fatty Liver of Pregnancy

AFLP is an uncommon but potentially fatal disease unique to pregnancy that typically occurs after 30 weeks of gestation.30,55,56 It is more frequent among nulliparous, multiple gestations, and pregnancies with a male fetus.3 AFLP is characterized by microvesicular fatty infiltration of hepatocytes, and it remains a common cause of liver failure during gestation.57 This entity is an obstetric emergency for both mother and fetus. Therefore, the severity of this condition underscores the need for early diagnosis and treatment, which consists of prompt delivery and supportive care.55 Maternal mortality due to AFLP has decreased significantly in the last decades, and it is currently about 12%.57



Pathophysiology

The exact pathophysiology is unknown.3 It has been hypothesized that a fetal mutation in the gene encoding for the mitochondrial trifunctional protein results in long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency, leading to long-chain fatty acid oxidation defects (FAODs) in the fetal mitochondria. The aberrant fatty acid oxidation in the fetal compartment leads to an accumulation of hepatotoxic metabolites in the maternal circulation and liver.3,55,58


Diagnosis and Clinical Presentation

Diagnosis is primarily based on clinical and laboratory findings. The most common initial symptoms are nonspecific: anorexia, malaise, nausea, vomiting, and headache. Additional features may include epigastric pain, jaundice, hypertension, and
disseminated intravascular coagulation (DIC).3,30,55 AFLP and HELLP syndrome are coexistent in approximately 50% of patients.3,30,55

Laboratory alterations include moderate elevations in ALT and AST. Bilirubin, blood urea nitrogen, uric acid, and creatinine are also mildly elevated. Hypoglycemia is common and a valuable finding in the differential diagnosis with preeclampsia and HELLP syndrome.3,30,55 However, the absence of hypoglycemia should not rule out AFLP.3 Although liver biopsy can confirm the diagnosis of AFLP, this test is rarely indicated because of the risks involved in critically ill patients.3,55


Management in Pregnancy

Delivery should not be delayed in patients whose clinical presentation and laboratory findings are consistent with AFLP. The most common life-threatening conditions include acute liver failure with encephalopathy, DIC, acute renal failure, and gastrointestinal bleeding.55 Treatment is largely supportive.55 Liver biopsy is rarely indicated because of the risks involved in critically ill patients.55 Patients are expected to recover normal liver function within a week. Xiong et al57 followed up 25 women over a mean of 54 months postdelivery and found no major adverse events. This observation suggests that once AFLP has resolved, patients may have a relatively benign course. Liver transplantation in AFLP has been reported in cases of clinical worsening and persistent liver failure despite medical supportive care.59 Offspring of women with AFLP should be monitored for manifestations of LCHAD deficiency. Affected infants often show involvement of heart, liver, and skeletal muscle.30 In a follow-up study including 50 children with LCHAD deficiency, den Boer et al60 reported a 38% mortality rate within 3 months of the diagnosis, and complications such as retinopathy, metabolic crises, muscle pain, and hypotonia.60 Finally, children with no FAODs appear to have good outcomes.55 Table 34.2 depicts differential features relevant to liver disorders in pregnancy.


Liver Disease Concurrent to Pregnancy


Biliary Disease

Cholelithiasis is the most common biliary condition in pregnancy, complicating approximately 3.5% of all gestations. Gallstones are more frequent because of increased cholesterol secretion, increased bile lithogenicity, and decreased gallbladder motility.1,30 Approximately 10% to 12% of all pregnant women develop either gallstones or biliary sludge.61,62 Although some pregnant patients experience uncomplicated cholelithiasis, an important proportion develops complications such as acute cholecystitis, choledocholithiasis, cholangitis, and gallstone pancreatitis.63

Acute cholecystitis is the second most common surgical condition in pregnancy and occurs in 1 in 6000 to 1 in 10,000 gestations.30,64 Furthermore, it is the major nonobstetric cause for hospitalization in the first year postpartum.63 Symptomatic gallstone disease in pregnancy is associated with increased mortality for both the mother and fetus and may result in complications such as spontaneous abortion, fetal abnormalities, preterm labor, and even death.62,63,64



Diagnosis

Cholelithiasis is frequently asymptomatic but may also present with right upper abdominal or epigastric pain, with colic features, that is worsened by fat-rich meals. NVP is frequently present.

Cholecystitis is a more serious condition. Although similar symptoms usually occur, fever, tachycardia, and the characteristic murphy sign (pain with abdominal palpation below the inferior costal margin at the level of the right midclavicular line, during deep inspiration) are generally present. Furthermore, increased leukocyte count and mildly elevated liver function tests could be observed. Abdominal ultrasound is a useful tool to confirm clinical suspicion of cholelithiasis. Presence of gallstones, ultrasound murphy sign, gallbladder wall thickening, and pericholecystic fluid are characteristic ultrasound finding in cholecystitis. Endoscopic retrograde cholangiopancreatography (ERCP) safety has been reported in multiple series, with some reports of increased pancreatitis risk.30 Fetal exposure to radiation should be reduced by limiting fluoroscopy time, external fetal shielding, and adjustment of patient position.30 When performed in the first trimester, ERCP was found to be associated with higher risk of preterm delivery and low birthweight.62


Management in Pregnancy

Although few patients with mild symptoms of cholelithiasis or cholecystitis can be managed conservatively, most women will benefit from surgical treatment. Medical management consists of intravenous hydration, fasting, analgesics, and antibiotics.








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Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Liver Disease in Pregnancy

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