HG

Nausea and vomiting are not uncommon during pregnancy, with symptoms ranging from mild morning sickness to severe disease requiring hospitalization. Morning sickness is a common occurrence, occurring in 50% to 90% of all pregnant women, and is almost an accepted physiologic phenomenon of pregnancy. On the other hand, HG can significantly affect a pregnant woman’s quality of life. This topic is discussed in another article by Saha and colleagues elsewhere in this issue and so is only briefly addressed here.

HG is an idiopathic syndrome of severe intolerable nausea and vomiting in the first trimester of pregnancy, usually before 10 weeks of gestation, occurring in approximately 0.3% of pregnancies. Objectively, HG is defined as persisting vomiting accompanied by weight loss exceeding 5% of prepregnancy body weight and ketonuria unrelated to other causes. The pathophysiology is poorly understood but immunologic, hormonal, and psychological factors are thought to play a role. The risk factors for HG are noted in Box 1 .

Approximately 50% of women are hospitalized with HG. Half of these patients have liver dysfunction with minimal to several fold elevation in aminotransferase levels, mild unconjugated hyperbilirubinemia (up to 4 mg/dL), or pruritus. The true incidence of abnormal liver function tests in HG is difficult to predict because the incidence is related to the severity of symptoms. The hepatic dysfunction is thought to be related to dehydration, malnutrition, and electrolyte abnormalities. There may be elevation in amylase levels, likely from a salivary source and not pancreatic. Symptoms usually resolve at 14 to 18 weeks of gestation; however, they may continue until the third trimester in 15% to 20% or even until delivery in 5% of patients.

The diagnosis is usually made on clinical grounds. It remains a diagnosis of exclusion after other pathologic conditions, such as gastrointestinal disorders (gastroenteritis, viral hepatitis, pancreatitis, cholelithiasis, peptic ulcer disease), genitourinary tract disorders, metabolic disturbances (diabetes, porphyria), neurologic diseases (migraine, tumor, vestibular lesions), drug toxicity, and psychological problems, have been ruled out. Rarely, a liver biopsy need to be performed only to exclude other more serious diseases. The hepatic histologic appearance is generally normal or shows bland cholestasis, mild fatty change, or no abnormality.

Treatment is symptomatic, focuses on alleviating vomiting, and includes bowel rest and intravenous fluids. Antiemetics, such as metoclopramide, promethazine, ondansetron, or droperidol, have been reported to be safe and useful in the treatment; however, no medications are currently approved by the US Food and Drug Administration (FDA). Dietary management generally consists of frequent high-carbohydrate, low-fat, small meals. Fluids are better tolerated if they are cold, clear, and carbonated and if taken in small amounts between meals. Thiamine supplementation should be given to patients with prolonged vomiting to prevent Wernicke encephalopathy. Patients who are not able to maintain their weight because of excessive vomiting may need enteral feeding.

HG may rarely lead to serious complications, including Wernicke encephalopathy, renal damage, retinal hemorrhage, immunosuppression, pneumomediastinum, and spontaneous esophageal rupture. Mild hyperthyroidism may be associated with HG likely because of the high serum concentrations of human chorionic gonadotrophin, which increases thyroid-stimulating activity in pregnant women. With adequate supportive treatment, the pregnancy outcome is favorable.

ICP

ICP is characterized by pruritus and elevated serum bile acid levels, which occur in the second and third trimester of pregnancy. The disorder resolves after delivery but often recurs in subsequent pregnancies. ICP was initially described in the Scandinavian countries, and the incidence in the region is 1% to 2%. However, the incidence varies significantly, and there are clear ethnic and racial differences. In the United States, the population prevalence varies from 0.3% to 5.6% in a primarily Latin population in Los Angeles. The highest incidence is found in Chile and Bolivia with rates ranging from 4% to 22%. The cause for the disorder is unknown; however, genetic, hormonal, and environmental factors may play a role.

The association with ethnic background supports the presence of a genetic component. Some women have defects in the ABCB 4 (adenosine triphosphate–binding cassette subfamily B member 4) gene, which codes for the multidrug-resistance P-glycoprotein 3 (MDR 3). MDR 3 is a hepatocellular phospholipid transporter, transporting phospholipids across the canalicular membrane, and mutations may result in loss of function and increased bile acid levels as a secondary effect. At least 10 different MDR 3 mutations have been identified in ICP, and MDR 3 mutations may account for 15% of cases of ICP. Some genes encoding other canalicular transport proteins or their regulator may also play a role in the pathogenesis of ICP. Sex hormones have known cholestatic effects and are thought to play a role in causing ICP. There is increased hormonal activity in the third trimester and in twin pregnancies, which may lead to ICP because it is more common in these situations. Estrogens and progesterones can impair the function of bile transporters (such as MDR 3), saturating the hepatic transport systems, in some genetically predisposed women. Progesterone treatment in pregnant women for the prevention of premature labor can lead to symptoms of ICP, and it is recommended that progesterone be avoided in patients with a history of ICP or stopped immediately if the patients develop symptoms of cholestasis while on progesterone therapy.

A new hypothesis for the pathogenesis of ICP was proposed in a recent study. It was found that patients with ICP had increased intestinal permeability, and it has been hypothesized that a leaky gut can increase the intestinal absorption of endotoxins and contribute to the pathogenesis of the disease. Environmental factors are certainly thought to play a role because of the climatic and geographic variability. Selenium deficiency has also been implicated in a study from Chile where the increased levels of selenium over the years especially during the summers has led to a decrease in the incidence of ICP.

The disease is manifested by pruritus, at times severe and intractable, in the third trimester; however, symptoms as early as the first trimester have been noted. The pruritus is usually generalized, starting peripherally and spreading centrally, but it may be present more on the palms and soles and gets more intense at night. There is no clear rash, but there may be excoriations on various areas because of scratching. Jaundice is fairly uncommon, occurring in less than 15% of patients with ICP. Jaundice usually occurs 2 to 4 weeks after the onset of pruritus, and if it precedes pruritus, other causes of liver disease should be investigated. Patients may also develop diarrhea or steatorrhea.

Fasting levels of TBAs, particularly conjugated bile acids and especially cholic acid, are elevated. These increased levels may be the first or only laboratory abnormality seen and are the most sensitive and specific markers of the disease. There is mild, predominantly conjugated hyperbilirubinemia. Transaminase levels are usually 2 to 10 fold above normal levels (in 20%–60% of cases with pruritus), serum alkaline phosphatase level is modestly elevated (not specific because of production of the placental isoenzyme), and GGT level is normal. Liver biopsy is usually not necessary and if done, shows bland cholestasis with minimal or no inflammation. Bile plugs in hepatocytes and canaliculi predominate in zone 3, and the portal tracts are unaffected. Ultrasonographically, the liver appears normal and the biliary ducts are not dilated.

The treatment of ICP is focused on reducing the debilitating symptoms, improving biochemical test results, and preventing maternal and fetal complications. There is no associated maternal mortality; however, there may be significant fetal morbidity and mortality. The risks for the fetus include fetal prematurity, meconium-stained amniotic fluid, intrauterine demise, and increased risk of fetal respiratory distress syndrome. The rate of fetal demise ranges from 1% to 3% but can be as high as 5%. There is no ideal method for fetal surveillance, and even though biophysical profile testing and nonstress tests are recommended by some physicians, their role in predicting the risk of fetal demise is very limited. It has been suggested that fetal complications increase with increasing serum bile acid levels, with significant complications arising when the levels are more than 40 μmol/L. However, this method is very impractical because of delay in reported results. The delivery of the fetus leads to resolution of symptoms but may not be feasible until fetal lung maturity is established.

Ursodeoxycholic acid (UDCA) has shown efficacy in the treatment of ICP in multiple trials, improving the symptoms, bile flow, and biochemical test results. There are no significant adverse maternal or fetal effects reported; however, the effect of UDCA in reducing fetal complications is unknown. UDCA seems to restore the transport capabilities of the placenta, which are affected in ICP, and it also helps normalize the maternal serum bile acid concentration to that of a healthy pregnant woman. A study compared UDCA dose of 8 to 10 mg/kg/d in divided doses versus cholestyramine. Pruritus and biochemical studies significantly improved with UDCA compared with cholestyramine, and the babies were delivered closer to term. There were no adverse effects noted. With all the supporting data, UDCA is considered to be a first-line therapy for ICP. The dosage is not clearly defined but the usual dose is 10 to 15 mg/kg/d in divided doses. However, even when used in higher doses, UDCA is completely safe for the fetus.

Other drugs that are used include antihistamines, such as hydroxyzine; cholestyramine; and S-adenosylmethionine (SAMe). Cholestyramine works by decreasing ileal absorption of bile salts and increasing fecal elimination. Cholestyramine has not shown benefit over UDCA in clinical trials and may lead to significant steatorrhea. If cholestyramine is used, vitamin K should be administered along with it because it can lead to exacerbation of vitamin K deficiency, leading to postpartum bleeding. Antihistamines may aggravate respiratory difficulties in preterm babies. SAMe is a glutathione precursor and when used alone has not shown benefit but if combined with UDCA, may have an additive effect. Cholestasis can lead to deficiency of fat-soluble vitamins; hence, vitamin K should be given to all patients with jaundice to decrease postpartum bleeding.

Cholestasis recurs in 60% to 70% of the patients, and affected women are also at an increased risk of having gallstones. It is prudent to check patients for underlying liver disease. Liver function tests should also be checked a few months after delivery to confirm normalization. Use of oral contraceptives is associated with a small risk of recurrence of pruritus; however, low-dose estrogen contraception can be used safely after liver function tests have normalized.

AFLP

AFLP is a sudden catastrophic illness characterized by microvesicular steatosis associated with mitochondrial dysfunction. When described in 1940, AFLP was thought to be universally fatal, but now with early diagnosis and prompt delivery, the prognosis has significantly improved, with maternal mortality being a rarity. AFLP occurs in approximately 1 out of 10,000 pregnancies and is a disease of the third trimester; however, there are patients presenting in the late second trimester or who are diagnosed after delivery. Approximately half of the patients are nulliparous, with an increased incidence in twin pregnancies and preeclamptic patients. There is no ethnic, geographic, or age distribution.

There is a strong association with defects in the mitochondrial beta-oxidation pathway, particularly in the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). The LCHAD, 1 of the 4 enzymes responsible for long-chain fatty acid oxidation (FAO) in the liver, is part of a larger enzyme complex on the mitochondrial inner membrane called mitochondrial trifunctional protein. Defects in the LCHAD lead to accumulation of long-chain 3-hydroxyacyl metabolites produced by the fetus or placenta. These metabolites are hepatotoxic and can lead to liver disease. The most common mutations are Glu474Gln and G1548C. The risk of developing AFLP in mothers of infants with LCHAD homozygosity is very high. There is also increased risk of developing HELLP syndrome in mothers of babies with LCHAD mutations. This strong association supports the need to screen for this defect in the fetuses of mothers with AFLP. Testing for the known genetic variants of LCHAD is available and should be performed in affected women, their infants, and fathers. However, LCHAD deficiencies may not be the only defects leading to AFLP, and other defects in the mitochondrial beta-oxidation pathway may play a role, including short- and medium-chain fatty acid defects. Factors such as carnitine deficiency or other dietary factors may also play a role.

The diagnosis of AFLP is made by a combination of clinical presentation, laboratory findings, and imaging. Presentation of AFLP may range from asymptomatic elevation in aminotransferases to fulminant hepatic failure. Patients usually have 1 or 2 weeks of nonspecific symptoms, such as anorexia, nausea and vomiting, headache, and right upper quadrant pain. The patients may develop progressive jaundice with the bilirubin level usually being less than 5 mg/dL, but pruritus is rare. Aminotransferases vary from near normal to 1000s, with the majority being in the 300 to 500 range. If the levels are very high, other diagnoses, such as hepatic ischemia and viral hepatitis, should also be entertained. Other laboratory studies may show a normochromic normocytic anemia, leukocytosis, normal to low platelet levels, coagulopathy with or without disseminated intravascular coagulation (DIC), metabolic acidosis, renal dysfunction, hypoglycemia, high ammonia levels, and biochemical pancreatitis with elevated amylase and lipase. As the disease progresses, patients appear ill with worsening jaundice and development of complications such as hypertension, edema, ascites, polyuria and polydipsia caused by transient diabetes insipidus, oliguric renal failure, gastrointestinal bleeding, intra-abdominal bleeding, and hepatic encephalopathy.

Definitive diagnosis is made histologically; however, it is not always required because doing a biopsy may prove hazardous in a pregnant patient. If done, the biopsy shows microvesicular fatty infiltration predominantly in zone 3 within hepatocytes. The fat droplets surround centrally located nuclei, giving the cytoplasm a foamy appearance. There is lobular disarray, and there might be mild inflammation with cholestasis. The frozen section can be stained with oil red O stain or can be viewed under electron microscopy, which shows evidence of cytoplasmic fat and can be helpful if the fat is not obvious on regular hematoxylin-eosin staining.

Differential diagnosis includes acute viral hepatitis, especially hepatitis E; herpes simplex virus disease; drug-induced hepatitis; HELLP syndrome; and biliary tract disorders. Features of AFLP may overlap with HELLP syndrome, making the distinction between the two very difficult at times. But in AFLP, the degree of hepatic impairment is much more significant. Even though AFLP can culminate in severe disease, early recognition and diagnosis with immediate delivery of the fetus and aggressive supportive care has increased both maternal and fetal survival, with fetal mortality being less than 15%.

Patients generally improve clinically and biochemically shortly after delivery; however, there may be cases with transient worsening followed by definitive improvement. There are no reports of improvement before delivery. The method of delivery is dependent on obstetric assessment. Vaginal delivery can be attempted in a stable patient if it can be achieved in a rapid controlled fashion within 24 hours. Vaginal delivery decreases the incidence of major intra-abdominal bleeding caused by coagulopathy. However, in most cases, a cesarean section is the mode of delivery. Supportive care is of the utmost importance, especially in severe cases or when the diagnosis was delayed. Mechanical ventilation, blood products to correct coagulopathy, glucose infusion, dialysis, parenteral nutrition, or even surgery to treat bleeding may be required. Lactulose therapy can be used for hepatic encephalopathy associated with elevated ammonia levels. Occasionally, liver transplant may be required.

Patients typically recover without any clinical sequelae, even after severe liver disease. The disease recurs in approximately 25% of pregnancies, even though there might be negative testing for LCHAD deficiencies. Patients need counseling regarding risks, and if they decide to proceed with another pregnancy, they should be closely followed up at a tertiary referral center by a high-risk obstetrician.

Preeclampsia and HELLP Syndrome

Preeclampsia is a triad of hypertension, edema, and proteinuria seen in the third trimester of 5% to 7% of pregnancies. Liver involvement is not common but when present signifies severe disease. The mechanism of injury involves vasospasm and precipitation of fibrin in the liver. Histologically, there is periportal hemorrhage, ischemic lesions, and microvesicular fat deposition. Clinically, the patients may have nausea, vomiting, and right upper quadrant abdominal pain. Liver enzyme levels may be elevated 10- to 20-fold, and this elevation reflects the development of HELLP syndrome. In the most severe cases, it may progress to subcapsular hemorrhage or hepatic rupture. Prompt delivery is indicated to avoid progressing to eclampsia and hepatic complications as mentioned earlier.

HELLP syndrome is characterized by microangiopathic hemolytic anemia, elevated liver enzyme levels, and low platelet counts. This syndrome complicates 2% to 12% of cases with severe preeclampsia and about 0.2% to 0.6% of all pregnancies. Although preeclampsia may lead to development of HELLP syndrome, there are patients without hypertension and proteinuria but with defining criteria of HELLP syndrome, leading many experts to believe that it is a separate entity. Most women present antepartum, usually in the third trimester, with most cases being diagnosed in the 28 to 36 weeks of gestation. Up to 30% of women may present in the postpartum period, ranging from 48 hours after delivery to as long as 7 days after childbirth.

The precipitating injury is not known. There is some overlap with AFLP and FAO defects; however, this association is not well established. Although families with FAO deficiencies have an increased incidence of HELLP, the babies born to women with HELLP do not necessarily have an increased risk of having FAO deficiencies. HELLP is a disease of abnormal hepatic endothelial reactivity or disruption. Initially, abnormal trophoblastic implantation may lead to reduced tissue perfusion and endothelial dysfunction, which leads to platelet activation and aggregation along with activation of the complement and coagulation cascades, increased vascular tone, and alteration of the thromboxane to prostacyclin ratio. The endothelial injury results in microangiopathic hemolytic anemia with schistocytes seen on peripheral smear. The liver enzymes are elevated because of periportal hepatic necrosis.

It is difficult to clinically distinguish HELLP from preeclampsia. Most women have right upper quadrant abdominal pain and tenderness, nausea and vomiting, malaise, headache, edema, and weight gain. Most patients have hypertension and proteinuria; however, 15% of patients can have absence of either one or both even with severe HELLP syndrome. Jaundice is only seen in 5% of patients. HELLP is more common in older, white, multiparous women but can occur in any parity and age.

Diagnosis is made by changes in complete blood cell count, peripheral smear, and transaminase levels. Patients have anemia with schistocytes on peripheral smear, elevated lactate dehydrogenase level (more than 600 IU/L), and platelet count usually less than 100,000 cells/μL. The transaminase levels are elevated, with the AST levels being at least 70 IU/L. Patients who fulfill all 3 criteria usually have severe disease and are considered to have “true” HELLP syndrome, whereas some patients may only have “partial” HELLP. These include patients with “ELLP,” in which hemolysis is absent; “EL,” in which severe preeclampsia is present; or “HEL,” in which platelet counts are normal. Patients may also develop DIC.

Radiological imaging is considered when complications are suspected because of pain radiating to the shoulder or neck. CT or MRI scans can show subcapsular hematomas, intraparenchymal hemorrhage, or infarction or hepatic rupture. These findings usually correlate with platelet counts less than 20,000 but not with liver dysfunction. Liver biopsy is rarely necessary and can be dangerous because of coagulopathy. However, if biopsy is done, it shows periportal hemorrhage and fibrin deposition. Certain other conditions can have a similar presentation as HELLP. In particular, some features of AFLP may overlap with those of HELLP, but in AFLP, the degree of hepatic impairment is much more significant. Thrombocytopenia can be caused by gestational thrombocytopenia, immune thrombocytopenia or thrombotic thrombocytopenia (TTP), and hemolytic uremic syndrome (HUS). These conditions do not have elevated liver enzyme levels, and HELLP lacks the neurologic and renal manifestations found in patients with TTP and HUS.

Delivery is the only definitive therapy because there can be rapid progressive maternal deterioration. Mortality is as high as 3%, and serious morbidity can include DIC, abruption placenta, acute renal failure, pulmonary edema, subcapsular liver hematoma, and retinal detachment. Pregnant women with HELLP should be hospitalized immediately for antepartum stabilization and transferred to a tertiary referral center if needed. A limited-view hepatic CT scan should also be obtained in deteriorating or critical patients to rule out hepatic complications. Temporizing measures, such as magnesium sulfate for seizure prophylaxis, and vasodilators (labetalol; hydralazine; nifedipine; or, in severe cases, sodium nitroprusside) should be administered and may improve fetal and neonatal as well as maternal outcomes. If there are no obstetric complications or DIC and if the pregnancy is at term, well-established labor should be allowed to proceed. However, most patients require caesarean section. Usually, there is resolution of HELLP after delivery with platelet levels normalizing in 5 days; however, some patients may develop persistent thrombocytopenia or hemolysis or may have complications of HELLP. In these situations, more aggressive therapy is indicated, including plasmapheresis, plasma volume expansion, antithrombotic agents, steroids, plasma exchange with fresh frozen plasma, or dialysis.

There may be an indication to proceed with liver transplant in rare situations, such as persistent bleeding from a hematoma or hepatic rupture or liver failure from extensive necrosis. Hepatic hemorrhage without rupture is managed conservatively with close hemodynamic monitoring, correction of coagulopathy, and immediate intervention for any maternal deterioration or expansion of hematoma on hepatic imaging. Any stressful situation, such as abdominal palpation, unnecessary transportation, convulsions, or emesis, should be avoided. Rarely, hepatic hemorrhage may lead to hepatic rupture. Hepatic hemorrhage is associated with severe thrombocytopenia and occurs primarily in the right lobe, occurring just before or after delivery. Diagnosis is made on finding intraperitoneal blood during emergency caesarean section or by imaging. Operative management includes packing; drainage; hepatic artery ligation; resection; angiographic embolization; or, rarely, transplant.

Perinatal mortality is high (7%–20%) because of prematurity, dysmaturity due to placental insufficiency, or the consequences of severe maternal complications. If the maternal condition is stable and the pregnancy is not at term, options include conservative management until fetal lung maturity is achieved or corticosteroids to help achieve fetal lung maturity. However, the longer the conservative management, the higher the risk of deterioration with resultant increase in fetal loss. Despite lacking randomized trials, the National Institutes of Health Consensus Development Panel recommends using corticosteroids for fetal lung maturity at less than 34 weeks gestation and consequently improving perinatal outcome. Using steroids may also improve the maternal platelets. High-dose intravenous dexamethasone is preferable to intramuscular betamethasone for 24 to 48 hours, with delivery thereafter. Surviving babies have the same outcome as other babies of similar gestational age. Subsequent pregnancies carry a high risk of complications and recurrence occurs in 2% to 6%. No long-term effects have been noted.

HG

Nausea and vomiting are not uncommon during pregnancy, with symptoms ranging from mild morning sickness to severe disease requiring hospitalization. Morning sickness is a common occurrence, occurring in 50% to 90% of all pregnant women, and is almost an accepted physiologic phenomenon of pregnancy. On the other hand, HG can significantly affect a pregnant woman’s quality of life. This topic is discussed in another article by Saha and colleagues elsewhere in this issue and so is only briefly addressed here.

HG is an idiopathic syndrome of severe intolerable nausea and vomiting in the first trimester of pregnancy, usually before 10 weeks of gestation, occurring in approximately 0.3% of pregnancies. Objectively, HG is defined as persisting vomiting accompanied by weight loss exceeding 5% of prepregnancy body weight and ketonuria unrelated to other causes. The pathophysiology is poorly understood but immunologic, hormonal, and psychological factors are thought to play a role. The risk factors for HG are noted in Box 1 .

Approximately 50% of women are hospitalized with HG. Half of these patients have liver dysfunction with minimal to several fold elevation in aminotransferase levels, mild unconjugated hyperbilirubinemia (up to 4 mg/dL), or pruritus. The true incidence of abnormal liver function tests in HG is difficult to predict because the incidence is related to the severity of symptoms. The hepatic dysfunction is thought to be related to dehydration, malnutrition, and electrolyte abnormalities. There may be elevation in amylase levels, likely from a salivary source and not pancreatic. Symptoms usually resolve at 14 to 18 weeks of gestation; however, they may continue until the third trimester in 15% to 20% or even until delivery in 5% of patients.

The diagnosis is usually made on clinical grounds. It remains a diagnosis of exclusion after other pathologic conditions, such as gastrointestinal disorders (gastroenteritis, viral hepatitis, pancreatitis, cholelithiasis, peptic ulcer disease), genitourinary tract disorders, metabolic disturbances (diabetes, porphyria), neurologic diseases (migraine, tumor, vestibular lesions), drug toxicity, and psychological problems, have been ruled out. Rarely, a liver biopsy need to be performed only to exclude other more serious diseases. The hepatic histologic appearance is generally normal or shows bland cholestasis, mild fatty change, or no abnormality.

Treatment is symptomatic, focuses on alleviating vomiting, and includes bowel rest and intravenous fluids. Antiemetics, such as metoclopramide, promethazine, ondansetron, or droperidol, have been reported to be safe and useful in the treatment; however, no medications are currently approved by the US Food and Drug Administration (FDA). Dietary management generally consists of frequent high-carbohydrate, low-fat, small meals. Fluids are better tolerated if they are cold, clear, and carbonated and if taken in small amounts between meals. Thiamine supplementation should be given to patients with prolonged vomiting to prevent Wernicke encephalopathy. Patients who are not able to maintain their weight because of excessive vomiting may need enteral feeding.

HG may rarely lead to serious complications, including Wernicke encephalopathy, renal damage, retinal hemorrhage, immunosuppression, pneumomediastinum, and spontaneous esophageal rupture. Mild hyperthyroidism may be associated with HG likely because of the high serum concentrations of human chorionic gonadotrophin, which increases thyroid-stimulating activity in pregnant women. With adequate supportive treatment, the pregnancy outcome is favorable.

ICP

ICP is characterized by pruritus and elevated serum bile acid levels, which occur in the second and third trimester of pregnancy. The disorder resolves after delivery but often recurs in subsequent pregnancies. ICP was initially described in the Scandinavian countries, and the incidence in the region is 1% to 2%. However, the incidence varies significantly, and there are clear ethnic and racial differences. In the United States, the population prevalence varies from 0.3% to 5.6% in a primarily Latin population in Los Angeles. The highest incidence is found in Chile and Bolivia with rates ranging from 4% to 22%. The cause for the disorder is unknown; however, genetic, hormonal, and environmental factors may play a role.

The association with ethnic background supports the presence of a genetic component. Some women have defects in the ABCB 4 (adenosine triphosphate–binding cassette subfamily B member 4) gene, which codes for the multidrug-resistance P-glycoprotein 3 (MDR 3). MDR 3 is a hepatocellular phospholipid transporter, transporting phospholipids across the canalicular membrane, and mutations may result in loss of function and increased bile acid levels as a secondary effect. At least 10 different MDR 3 mutations have been identified in ICP, and MDR 3 mutations may account for 15% of cases of ICP. Some genes encoding other canalicular transport proteins or their regulator may also play a role in the pathogenesis of ICP. Sex hormones have known cholestatic effects and are thought to play a role in causing ICP. There is increased hormonal activity in the third trimester and in twin pregnancies, which may lead to ICP because it is more common in these situations. Estrogens and progesterones can impair the function of bile transporters (such as MDR 3), saturating the hepatic transport systems, in some genetically predisposed women. Progesterone treatment in pregnant women for the prevention of premature labor can lead to symptoms of ICP, and it is recommended that progesterone be avoided in patients with a history of ICP or stopped immediately if the patients develop symptoms of cholestasis while on progesterone therapy.

A new hypothesis for the pathogenesis of ICP was proposed in a recent study. It was found that patients with ICP had increased intestinal permeability, and it has been hypothesized that a leaky gut can increase the intestinal absorption of endotoxins and contribute to the pathogenesis of the disease. Environmental factors are certainly thought to play a role because of the climatic and geographic variability. Selenium deficiency has also been implicated in a study from Chile where the increased levels of selenium over the years especially during the summers has led to a decrease in the incidence of ICP.

The disease is manifested by pruritus, at times severe and intractable, in the third trimester; however, symptoms as early as the first trimester have been noted. The pruritus is usually generalized, starting peripherally and spreading centrally, but it may be present more on the palms and soles and gets more intense at night. There is no clear rash, but there may be excoriations on various areas because of scratching. Jaundice is fairly uncommon, occurring in less than 15% of patients with ICP. Jaundice usually occurs 2 to 4 weeks after the onset of pruritus, and if it precedes pruritus, other causes of liver disease should be investigated. Patients may also develop diarrhea or steatorrhea.

Fasting levels of TBAs, particularly conjugated bile acids and especially cholic acid, are elevated. These increased levels may be the first or only laboratory abnormality seen and are the most sensitive and specific markers of the disease. There is mild, predominantly conjugated hyperbilirubinemia. Transaminase levels are usually 2 to 10 fold above normal levels (in 20%–60% of cases with pruritus), serum alkaline phosphatase level is modestly elevated (not specific because of production of the placental isoenzyme), and GGT level is normal. Liver biopsy is usually not necessary and if done, shows bland cholestasis with minimal or no inflammation. Bile plugs in hepatocytes and canaliculi predominate in zone 3, and the portal tracts are unaffected. Ultrasonographically, the liver appears normal and the biliary ducts are not dilated.

The treatment of ICP is focused on reducing the debilitating symptoms, improving biochemical test results, and preventing maternal and fetal complications. There is no associated maternal mortality; however, there may be significant fetal morbidity and mortality. The risks for the fetus include fetal prematurity, meconium-stained amniotic fluid, intrauterine demise, and increased risk of fetal respiratory distress syndrome. The rate of fetal demise ranges from 1% to 3% but can be as high as 5%. There is no ideal method for fetal surveillance, and even though biophysical profile testing and nonstress tests are recommended by some physicians, their role in predicting the risk of fetal demise is very limited. It has been suggested that fetal complications increase with increasing serum bile acid levels, with significant complications arising when the levels are more than 40 μmol/L. However, this method is very impractical because of delay in reported results. The delivery of the fetus leads to resolution of symptoms but may not be feasible until fetal lung maturity is established.

Ursodeoxycholic acid (UDCA) has shown efficacy in the treatment of ICP in multiple trials, improving the symptoms, bile flow, and biochemical test results. There are no significant adverse maternal or fetal effects reported; however, the effect of UDCA in reducing fetal complications is unknown. UDCA seems to restore the transport capabilities of the placenta, which are affected in ICP, and it also helps normalize the maternal serum bile acid concentration to that of a healthy pregnant woman. A study compared UDCA dose of 8 to 10 mg/kg/d in divided doses versus cholestyramine. Pruritus and biochemical studies significantly improved with UDCA compared with cholestyramine, and the babies were delivered closer to term. There were no adverse effects noted. With all the supporting data, UDCA is considered to be a first-line therapy for ICP. The dosage is not clearly defined but the usual dose is 10 to 15 mg/kg/d in divided doses. However, even when used in higher doses, UDCA is completely safe for the fetus.

Other drugs that are used include antihistamines, such as hydroxyzine; cholestyramine; and S-adenosylmethionine (SAMe). Cholestyramine works by decreasing ileal absorption of bile salts and increasing fecal elimination. Cholestyramine has not shown benefit over UDCA in clinical trials and may lead to significant steatorrhea. If cholestyramine is used, vitamin K should be administered along with it because it can lead to exacerbation of vitamin K deficiency, leading to postpartum bleeding. Antihistamines may aggravate respiratory difficulties in preterm babies. SAMe is a glutathione precursor and when used alone has not shown benefit but if combined with UDCA, may have an additive effect. Cholestasis can lead to deficiency of fat-soluble vitamins; hence, vitamin K should be given to all patients with jaundice to decrease postpartum bleeding.

Cholestasis recurs in 60% to 70% of the patients, and affected women are also at an increased risk of having gallstones. It is prudent to check patients for underlying liver disease. Liver function tests should also be checked a few months after delivery to confirm normalization. Use of oral contraceptives is associated with a small risk of recurrence of pruritus; however, low-dose estrogen contraception can be used safely after liver function tests have normalized.

AFLP

AFLP is a sudden catastrophic illness characterized by microvesicular steatosis associated with mitochondrial dysfunction. When described in 1940, AFLP was thought to be universally fatal, but now with early diagnosis and prompt delivery, the prognosis has significantly improved, with maternal mortality being a rarity. AFLP occurs in approximately 1 out of 10,000 pregnancies and is a disease of the third trimester; however, there are patients presenting in the late second trimester or who are diagnosed after delivery. Approximately half of the patients are nulliparous, with an increased incidence in twin pregnancies and preeclamptic patients. There is no ethnic, geographic, or age distribution.

There is a strong association with defects in the mitochondrial beta-oxidation pathway, particularly in the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). The LCHAD, 1 of the 4 enzymes responsible for long-chain fatty acid oxidation (FAO) in the liver, is part of a larger enzyme complex on the mitochondrial inner membrane called mitochondrial trifunctional protein. Defects in the LCHAD lead to accumulation of long-chain 3-hydroxyacyl metabolites produced by the fetus or placenta. These metabolites are hepatotoxic and can lead to liver disease. The most common mutations are Glu474Gln and G1548C. The risk of developing AFLP in mothers of infants with LCHAD homozygosity is very high. There is also increased risk of developing HELLP syndrome in mothers of babies with LCHAD mutations. This strong association supports the need to screen for this defect in the fetuses of mothers with AFLP. Testing for the known genetic variants of LCHAD is available and should be performed in affected women, their infants, and fathers. However, LCHAD deficiencies may not be the only defects leading to AFLP, and other defects in the mitochondrial beta-oxidation pathway may play a role, including short- and medium-chain fatty acid defects. Factors such as carnitine deficiency or other dietary factors may also play a role.

The diagnosis of AFLP is made by a combination of clinical presentation, laboratory findings, and imaging. Presentation of AFLP may range from asymptomatic elevation in aminotransferases to fulminant hepatic failure. Patients usually have 1 or 2 weeks of nonspecific symptoms, such as anorexia, nausea and vomiting, headache, and right upper quadrant pain. The patients may develop progressive jaundice with the bilirubin level usually being less than 5 mg/dL, but pruritus is rare. Aminotransferases vary from near normal to 1000s, with the majority being in the 300 to 500 range. If the levels are very high, other diagnoses, such as hepatic ischemia and viral hepatitis, should also be entertained. Other laboratory studies may show a normochromic normocytic anemia, leukocytosis, normal to low platelet levels, coagulopathy with or without disseminated intravascular coagulation (DIC), metabolic acidosis, renal dysfunction, hypoglycemia, high ammonia levels, and biochemical pancreatitis with elevated amylase and lipase. As the disease progresses, patients appear ill with worsening jaundice and development of complications such as hypertension, edema, ascites, polyuria and polydipsia caused by transient diabetes insipidus, oliguric renal failure, gastrointestinal bleeding, intra-abdominal bleeding, and hepatic encephalopathy.

Definitive diagnosis is made histologically; however, it is not always required because doing a biopsy may prove hazardous in a pregnant patient. If done, the biopsy shows microvesicular fatty infiltration predominantly in zone 3 within hepatocytes. The fat droplets surround centrally located nuclei, giving the cytoplasm a foamy appearance. There is lobular disarray, and there might be mild inflammation with cholestasis. The frozen section can be stained with oil red O stain or can be viewed under electron microscopy, which shows evidence of cytoplasmic fat and can be helpful if the fat is not obvious on regular hematoxylin-eosin staining.

Differential diagnosis includes acute viral hepatitis, especially hepatitis E; herpes simplex virus disease; drug-induced hepatitis; HELLP syndrome; and biliary tract disorders. Features of AFLP may overlap with HELLP syndrome, making the distinction between the two very difficult at times. But in AFLP, the degree of hepatic impairment is much more significant. Even though AFLP can culminate in severe disease, early recognition and diagnosis with immediate delivery of the fetus and aggressive supportive care has increased both maternal and fetal survival, with fetal mortality being less than 15%.

Patients generally improve clinically and biochemically shortly after delivery; however, there may be cases with transient worsening followed by definitive improvement. There are no reports of improvement before delivery. The method of delivery is dependent on obstetric assessment. Vaginal delivery can be attempted in a stable patient if it can be achieved in a rapid controlled fashion within 24 hours. Vaginal delivery decreases the incidence of major intra-abdominal bleeding caused by coagulopathy. However, in most cases, a cesarean section is the mode of delivery. Supportive care is of the utmost importance, especially in severe cases or when the diagnosis was delayed. Mechanical ventilation, blood products to correct coagulopathy, glucose infusion, dialysis, parenteral nutrition, or even surgery to treat bleeding may be required. Lactulose therapy can be used for hepatic encephalopathy associated with elevated ammonia levels. Occasionally, liver transplant may be required.

Patients typically recover without any clinical sequelae, even after severe liver disease. The disease recurs in approximately 25% of pregnancies, even though there might be negative testing for LCHAD deficiencies. Patients need counseling regarding risks, and if they decide to proceed with another pregnancy, they should be closely followed up at a tertiary referral center by a high-risk obstetrician.

Preeclampsia and HELLP Syndrome

Preeclampsia is a triad of hypertension, edema, and proteinuria seen in the third trimester of 5% to 7% of pregnancies. Liver involvement is not common but when present signifies severe disease. The mechanism of injury involves vasospasm and precipitation of fibrin in the liver. Histologically, there is periportal hemorrhage, ischemic lesions, and microvesicular fat deposition. Clinically, the patients may have nausea, vomiting, and right upper quadrant abdominal pain. Liver enzyme levels may be elevated 10- to 20-fold, and this elevation reflects the development of HELLP syndrome. In the most severe cases, it may progress to subcapsular hemorrhage or hepatic rupture. Prompt delivery is indicated to avoid progressing to eclampsia and hepatic complications as mentioned earlier.

HELLP syndrome is characterized by microangiopathic hemolytic anemia, elevated liver enzyme levels, and low platelet counts. This syndrome complicates 2% to 12% of cases with severe preeclampsia and about 0.2% to 0.6% of all pregnancies. Although preeclampsia may lead to development of HELLP syndrome, there are patients without hypertension and proteinuria but with defining criteria of HELLP syndrome, leading many experts to believe that it is a separate entity. Most women present antepartum, usually in the third trimester, with most cases being diagnosed in the 28 to 36 weeks of gestation. Up to 30% of women may present in the postpartum period, ranging from 48 hours after delivery to as long as 7 days after childbirth.

The precipitating injury is not known. There is some overlap with AFLP and FAO defects; however, this association is not well established. Although families with FAO deficiencies have an increased incidence of HELLP, the babies born to women with HELLP do not necessarily have an increased risk of having FAO deficiencies. HELLP is a disease of abnormal hepatic endothelial reactivity or disruption. Initially, abnormal trophoblastic implantation may lead to reduced tissue perfusion and endothelial dysfunction, which leads to platelet activation and aggregation along with activation of the complement and coagulation cascades, increased vascular tone, and alteration of the thromboxane to prostacyclin ratio. The endothelial injury results in microangiopathic hemolytic anemia with schistocytes seen on peripheral smear. The liver enzymes are elevated because of periportal hepatic necrosis.

It is difficult to clinically distinguish HELLP from preeclampsia. Most women have right upper quadrant abdominal pain and tenderness, nausea and vomiting, malaise, headache, edema, and weight gain. Most patients have hypertension and proteinuria; however, 15% of patients can have absence of either one or both even with severe HELLP syndrome. Jaundice is only seen in 5% of patients. HELLP is more common in older, white, multiparous women but can occur in any parity and age.

Diagnosis is made by changes in complete blood cell count, peripheral smear, and transaminase levels. Patients have anemia with schistocytes on peripheral smear, elevated lactate dehydrogenase level (more than 600 IU/L), and platelet count usually less than 100,000 cells/μL. The transaminase levels are elevated, with the AST levels being at least 70 IU/L. Patients who fulfill all 3 criteria usually have severe disease and are considered to have “true” HELLP syndrome, whereas some patients may only have “partial” HELLP. These include patients with “ELLP,” in which hemolysis is absent; “EL,” in which severe preeclampsia is present; or “HEL,” in which platelet counts are normal. Patients may also develop DIC.

Radiological imaging is considered when complications are suspected because of pain radiating to the shoulder or neck. CT or MRI scans can show subcapsular hematomas, intraparenchymal hemorrhage, or infarction or hepatic rupture. These findings usually correlate with platelet counts less than 20,000 but not with liver dysfunction. Liver biopsy is rarely necessary and can be dangerous because of coagulopathy. However, if biopsy is done, it shows periportal hemorrhage and fibrin deposition. Certain other conditions can have a similar presentation as HELLP. In particular, some features of AFLP may overlap with those of HELLP, but in AFLP, the degree of hepatic impairment is much more significant. Thrombocytopenia can be caused by gestational thrombocytopenia, immune thrombocytopenia or thrombotic thrombocytopenia (TTP), and hemolytic uremic syndrome (HUS). These conditions do not have elevated liver enzyme levels, and HELLP lacks the neurologic and renal manifestations found in patients with TTP and HUS.

Delivery is the only definitive therapy because there can be rapid progressive maternal deterioration. Mortality is as high as 3%, and serious morbidity can include DIC, abruption placenta, acute renal failure, pulmonary edema, subcapsular liver hematoma, and retinal detachment. Pregnant women with HELLP should be hospitalized immediately for antepartum stabilization and transferred to a tertiary referral center if needed. A limited-view hepatic CT scan should also be obtained in deteriorating or critical patients to rule out hepatic complications. Temporizing measures, such as magnesium sulfate for seizure prophylaxis, and vasodilators (labetalol; hydralazine; nifedipine; or, in severe cases, sodium nitroprusside) should be administered and may improve fetal and neonatal as well as maternal outcomes. If there are no obstetric complications or DIC and if the pregnancy is at term, well-established labor should be allowed to proceed. However, most patients require caesarean section. Usually, there is resolution of HELLP after delivery with platelet levels normalizing in 5 days; however, some patients may develop persistent thrombocytopenia or hemolysis or may have complications of HELLP. In these situations, more aggressive therapy is indicated, including plasmapheresis, plasma volume expansion, antithrombotic agents, steroids, plasma exchange with fresh frozen plasma, or dialysis.

There may be an indication to proceed with liver transplant in rare situations, such as persistent bleeding from a hematoma or hepatic rupture or liver failure from extensive necrosis. Hepatic hemorrhage without rupture is managed conservatively with close hemodynamic monitoring, correction of coagulopathy, and immediate intervention for any maternal deterioration or expansion of hematoma on hepatic imaging. Any stressful situation, such as abdominal palpation, unnecessary transportation, convulsions, or emesis, should be avoided. Rarely, hepatic hemorrhage may lead to hepatic rupture. Hepatic hemorrhage is associated with severe thrombocytopenia and occurs primarily in the right lobe, occurring just before or after delivery. Diagnosis is made on finding intraperitoneal blood during emergency caesarean section or by imaging. Operative management includes packing; drainage; hepatic artery ligation; resection; angiographic embolization; or, rarely, transplant.

Perinatal mortality is high (7%–20%) because of prematurity, dysmaturity due to placental insufficiency, or the consequences of severe maternal complications. If the maternal condition is stable and the pregnancy is not at term, options include conservative management until fetal lung maturity is achieved or corticosteroids to help achieve fetal lung maturity. However, the longer the conservative management, the higher the risk of deterioration with resultant increase in fetal loss. Despite lacking randomized trials, the National Institutes of Health Consensus Development Panel recommends using corticosteroids for fetal lung maturity at less than 34 weeks gestation and consequently improving perinatal outcome. Using steroids may also improve the maternal platelets. High-dose intravenous dexamethasone is preferable to intramuscular betamethasone for 24 to 48 hours, with delivery thereafter. Surviving babies have the same outcome as other babies of similar gestational age. Subsequent pregnancies carry a high risk of complications and recurrence occurs in 2% to 6%. No long-term effects have been noted.