Pregnancy-Associated Liver Disorders

Abstract

Liver disorders associated with pregnancy include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP), and acute fatty liver of pregnancy (AFLP). These conditions are relatively common and unique to pregnancy and are more likely to occur at certain terms of gestation specific to each condition. They can be associated with significant maternal and fetal morbidity and mortality. Although managing such patients may be very challenging, spontaneous resolution of the disease occurs shortly after termination of the pregnancy, usually without hepatic sequellae. Early diagnosis and timely treatment is a key to therapeutic success. This article explores the clinical features, pathophysiology, and management of these disorders.

Background

Liver disorders associated with pregnancy include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP), and acute fatty liver of pregnancy (AFLP). These conditions are relatively common and unique to pregnancy and are more likely to occur at certain terms of gestation specific to each condition. They can be associated with significant maternal and fetal morbidity and mortality. Although managing such patients may be very challenging, spontaneous resolution of the disease occurs shortly after termination of the pregnancy, usually without hepatic sequellae (see Table 1).

Table 1 Liver conditions in pregnancy [1–7]

Pregnancy is associated with many changes that alter maternal physiology. It often unmasks a genetically predetermined propensity for certain conditions.

HG is the most severe illness within the spectrum of nausea and vomiting in pregnancy; symptoms are protracted and severe and may result in abnormalities in liver enzymes. The reported prevalence of HG varies from 0.3 to 2% of pregnancies. Risk factors include young maternal age, obesity, first pregnancy, multiple gestation, pregnancy with female fetus, and trophoblastic disease. Liver involvement occurs in approximately 50–60% of patients with HG. Treatment is mainly supportive; promethazine is a first-line agent used for management of nausea and vomiting. In resistant cases, several other agents have been tried.

ICP is a relatively common cholestatic complication of pregnancy that occurs in approximately 0.5–1% of pregnancies in the USA. The exact etiology is unknown, but it is suspected that genetic and hormonal factors play a major role in the development of ICP. Most commonly, it is characterized by insidious onset of pruritus, nausea, malaise, and rarely jaundice in the third trimester of pregnancy. Laboratory evaluation shows cholestasis with elevation of bile salts, transaminases, and bilirubin. This condition is benign for the mother, but fetal complications and death are not uncommon. Therapy with ursodeoxycolic acid (UDCA) offers the most relief for maternal symptoms and is thought to somewhat improve fetal prognosis, although the ultimate therapy is prompt delivery.

Preeclampsia is a derangement of the third trimester of pregnancy that may lead to severe maternal and fetal complications. Liver involvement is not common and occurs predominantly in severe cases. HELLP syndrome, hemolysis, elevated liver enzymes and low platelets, occurs in approximately 10% of patients with preeclampsia and is associated with significant morbidity and mortality for both mother and fetus. The onset of the disease is insidious and the initial presentation can be very nonspecific, often leading to misdiagnosis and loss of valuable time.

Hepatic hematoma and rupture in pregnancy usually occurs in the setting of the HELLP syndrome, although cases without antecedent HELLP have been reported. The patient usually presents with acute abdominal pain and unstable hemodynamics. In the past this condition was universally fatal. Modern diagnostic and treatment methods with a multidisciplinary approach have improved prognosis significantly, but morbidity remains very high.

AFLP is another rare and potentially fatal complication of pregnancy that has been linked to fatty acids oxidation enzyme deficiencies in the fetus. The patient may present with nonspecific symptoms of nausea, vomiting, and malaise, which develop into a full picture of hepatic failure with encephalopathy, hypoglycemia, and coagulopathy. There is no treatment and emergency delivery is indicated. Both maternal and perinatal mortality remain high. All neonates from pregnancies complicated with AFLP should be tested for fatty acids oxidation (FAO) enzyme defects.

Purpose

To familiarize care providers with the important spectrum of pregnancy-associated liver diseases.

Methods

PubMed, MIDLINE, Ovid, and ScienceDirect were searched for articles relating to pregnancy complicated with liver disease. Bibliographies and the web sites of multiple international journals were reviewed (Gut, Gastroenterology, British Medical Journal, American Journal of Obstetrics and Gynecology, Hepatology, New England Journal of Medicine, American Journal of Gastroenterology, and Journal of American Medical Association).

Discussion

Pregnancy is a unique state that alters maternal physiology in many ways. Although a physiological state, pregnancy is a stressful period for the woman’s body. Physiological changes can interact with inherited or acquired predispositions to disease to precipitate pregnancy complications [8]. Physicians, confronted with signs and symptoms of newly developing liver disease in pregnant woman, should be careful not to overlook several pregnancy-associated liver disorders. Also, some common conditions that are well understood in nonpregnant patients can be difficult to diagnose and treat in pregnant patients. This may lead to significant morbidity and mortality and impose additional pressure on consulting internists not familiar with the management of the pregnant patient with comorbidities. While liver disease is not a very common complication of pregnancy, when it occurs outcomes may be tragic. An often insidious onset is followed by rapid deterioration with multiorgan failure and death; some of these conditions were almost uniformly lethal in the past. Prompt diagnosis and early delivery with modern supportive care can ensure better outcomes for both mother and infant.

Physiological changes in pregnancy

It is necessary to have a good understanding of the physiological changes during normal pregnancy to be able to interpret data obtained from the pregnant patient with a suspected liver abnormality.

Physical exam

Spider angiomas, teleangiectasias, and palmar erythema are normal findings that occur in 60% of normal pregnancies. As in liver conditions, in pregnancy these findings are thought to be induced by higher circulating estrogen levels. These changes generally spontaneously disappear after delivery.

The liver is pushed up into the chest cavity by the gravid uterus, making liver examination rather difficult. Finding a palpable liver in the pregnant patient is strongly suspicious of hepatomegaly and is abnormal.

Laboratory data

The plasma volume increases after 6 weeks of pregnancy and expands by 50% by the third trimester. This is accompanied by a lesser increase of red blood cells (RBC) mass (20%), and therefore some degree of dilutional anemia is expected. The serum concentration of albumin decreases significantly as well [9]. In normal pregnancy most liver enzyme tests are unchanged. However, levels of alkaline phosphatase are significantly elevated (2–4 times) due to placental production and increased bony isomer and should not be used for assessment of cholestasis. Total and fractionated bilirubin values are low-normal due to hemodilution. Serum values of 5′-nucleotidase, gamma-glutamyl transpeptidase (GGTP), bile salts, international normalized ratio, prothrombin and partial prothrombin times remain normal. A small increase of alanine aminotransferase (ALT) is observed in the second trimester of pregnancy when compared with healthy nonpregnant women, but values still remained within the normal range. There is no change in aspartate aminotransferase (AST) levels.

Significant elevations of cholesterol and triglycerides have been observed in pregnancy; therefore lipid profiles of pregnant women can be misleading. These changes normalize rapidly 4–6 weeks postpartum [10].

Ultrasonographic examination of the liver during normal pregnancy reveals normal parenchymal architecture and no biliary tree dilatation, but increased fasting gallbladder volume and residual volume after contraction is common. Of note, this delayed gallbladder emptying has been attributed to increased levels of circulating progestins and has been also implicated in pathogenesis of gallstones [11].

Both hepatocellular and cholestatic liver dysfunction are common in pregnancy: they were detected in up to 3% of all pregnancies by some reports [12]. Liver diseases unique to pregnancy include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia complicated with liver disorders, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP), and acute fatty liver of pregnancy (AFLP). The term of gestation at which a patient presents with a liver problem is important in the differential diagnosis. HG, though it may persist throughout the entire pregnancy, is much more common in the first trimester; in contrast AFLP and HELLP syndrome are more common at the end of the third trimester, although they can occur in the second trimester.

Pruritus is a distinctive feature of only a few liver conditions and its presence is helpful in differentiating those as well. When consulting on a pregnant patient with suspected liver disease, one should keep in mind that pregnant women are as susceptible to common liver diseases, such as viral and drug-induced hepatitis, as anyone else and these should be considered in the differential diagnosis. Pregnancy may also precipitate some conditions (gallstones) and aggravate the course of others (viral and autoimmune hepatitis) [13]. Usually pregnancy-associated liver conditions resolve spontaneously soon after the termination of the pregnancy.

Hyperemesis gravidarum

Case

A 22-year-old female was admitted to the emergency room complaining of intractable nausea and vomiting for the past 4 weeks. She informed the emergency room physician that she had a positive pregnancy test 5 weeks ago and had recently returned from a trip to Mexico. The patient also reported unintentional weight loss of approximately 10 lbs and diffuse abdominal pain. She denied alcohol use, hematemesis, diarrhea or melena, but admitted to salivating excessively and feeling weak and dizzy. Her nausea was exacerbated by strong odor, teeth brushing, and spicy foods.

On examination, the patient was found to be mildly obese and had icteric sclerae. The thyroid gland was slightly enlarged. Her blood pressure and pulse were, respectively, 115/67 and 107 while lying down, and 90/53 and 137 while standing. Her abdomen was slightly tender to palpation across the epigastrium and both right and left upper quadrants. Her liver was not enlarged or tender, and Murphy’s sign was negative. No gravid uterus was palpated on abdominal examination. Her reflexes were normal and there was no tremor.

The laboratory work up revealed elevated transaminases (AST 195 U/l and ALT 207 U/l), alkaline phosphatase (178 mU/ml), bilirubin (2.4 mg/dl), and serum beta-hCG (346,000 mIU/ml). Her thyroid-stimulating hormone (TSH) was suppressed (0.2 mcIU/ml) and free thyroxin was elevated (2.3 ng/dl). She had normal amylase, lipase, cell counts, prothrombin time, and international normalized ratio.

Abdominal ultrasound demonstrated no hepatosplenomegaly, a slightly enlarged and distended gallbladder with biliary sludge, but no choledocolithiasis or bile duct dilatation. Ultrasound of the uterus showed twin gestation with a normal placenta. Viral serology for hepatitis A, B, and C, Epstein–Barr virus, cytomegalovirus, and herpes simplex virus were negative.

The patient was given intravenous fluids and promethazine. Her symptoms resolved in a few days and laboratory recovery was observed as well.

Various degrees of nausea with or without vomiting are observed in 50–90% of all pregnancies. Most commonly the onset of symptoms occurs at about 4–6 weeks of gestation and resolve at 16–18 weeks. However, in a minority of cases, symptoms may persist until the third trimester or delivery. The symptoms resolve completely with the end of the pregnancy and there are no hepatic sequellae.

The syndrome of HG is the most severe illness within the spectrum of nausea and vomiting in pregnancy; symptoms are protracted and severe and may result in abnormalities in liver enzymes. The reported prevalence of HG varies from 0.3 to 2% of pregnancies. Risk factors include young maternal age, obesity, first pregnancy, multiple gestation, pregnancy with female fetus, and trophoblastic disease [14, 15]. Liver involvement occurs in approximately 50–60% of patients with HG. There is a mild hyperbilirubinemia in one-third of the patients and mild elevation of transaminases in one-fourth of the patients.

Maternal complications

Rarely HG can lead to severe thiamine deficiency and Gayet–Wernicke encephalopathy, which manifests as a classic devastating triad of ataxia, ocular dysfunction, and confusion [16–18]. Diagnosis is made clinically and can be confirmed by brain magnetic resonance imaging (MRI), revealing peri-aqueductal, thalamic, and mamillary bodies changes [18, 19]. Complete remission of the disease occurs in less than half of the patients and the proportion of the patients with permanent deficits is large. One should pay great attention to vitamin supplementation in a patient who has vomited for more than 3 weeks. Thiamine 100 mg IV or IM daily for 5 days should be given to prevent this devastating disease [17, 19]. Anaphylaxis and bronchospasm are the side effects of thiamine, but they are rarely seen.

If vomiting is severe enough, esophageal rupture is a threat with potentially high morbidity and mortality, if not diagnosed promptly [20–22].

Cases of HG-associated pancreatitis and acute renal failure due to vomiting-induced volume contraction have also been reported [23, 24].

Fetal outcomes

In the report of a large foreign study, congenital malformations are seen in pregnancies with HG slightly more often than expected. The most common fetal abnormalities were undescended testicles, hip dysplasia, and Down’s syndrome [14]. Other reports suggested that maternal malnutrition may lead to congenital abnormalities of the central nervous system (CNS) and skeleton in the fetus: gray matter heterotopias and brachytelephalangic chondrodysplasia punctata that were thought to be related to vitamin K deficiency [25]. Infants born to mothers who experienced HG are more likely to have a lower birth weight, be small for gestational age, and have longer hospital stay, but this had no effect on perinatal survival [26, 27]. Decreased risk of miscarriage has been reported [28].

Pathogenesis

Multiple theories have been proposed as an explanation of this disorder, but it remains poorly understood and is sometimes difficult to treat. Multiple organs and symptoms are involved, including thyroid and liver [29, 30]. Most likely this condition arises as a result of a complex interplay of psychological, hormonal, and genetic factors. Estrogen seems to play a role. Often the same patients who develop nausea and vomiting in pregnancy experience the same symptoms with estrogen therapy. However the fact that HG is more prevalent in the first trimester, and estrogen levels peak in the third trimester, contradict this hypothesis. By some reports, lower levels of prolactin along with higher levels of estradiol are suspected to be the cause [31]. Another pregnancy-related hormone, human chorionic gonadotropin (beta-hCG), is thought to be involved in pathogenesis of HG. The highest levels of this hormone are seen in the patients with multiple gestation and trophoblastic disease and coincide with higher risk of HG. Also women with HG were found to have elevated levels of leptin when compared with healthy pregnant women [32–34]. Decreased levels of total cholesterol, low-density lipoproteins (LDL) cholesterol, apo-A, and apo-B were observed in hyperemetic patients, but their significance is not clear [35].

It has been speculated that immune and inflammatory mechanisms contribute to the development of HG. Proinflammatory cytokines (IL-6) can stimulate release of beta-hCG. Even though normal pregnancy is accompanied by a shift from the Th1 dominance to Th2, this shift is more pronounced in HG and may be related to the increase of progesterone and estrogen levels [36–38].

Serum and uterine decidua of patients with HG were found to contain naked fetal DNA and have higher activity of natural killers and cytotoxic T cells when compared with normal pregnancies [39]. Significant elevation of serum adenosine deaminase is observed in HG and this also confirms activated cell mediated immunity.

Other theories, prominently including psychological or behavioral abnormalities, have been proposed to explain this syndrome. Olfactory stimuli can be nausea provoking, cognitive processing of these stimuli is altered in pregnancy in a nonuniform fashion, often leading to unpredictable response. It has been noted that women with complete anosmia almost never develop nausea and vomiting during the pregnancy [40, 41]. Psychological factors such as marital stress, undesired/unplanned pregnancy, and history of poor relationships between the patient and her own mother in the patient’s childhood are speculated to be implicated in the development of HG as well [42, 43]. A history of eating disorder has also been suspected to be a risk factor [44].

Helicobacter pylori was suspected to play a role, but the results of the studies are contradictory and additional investigation is needed [16, 45–48].

Gastric motility may be abnormal in the HG, but studies of gastric motility in these patients have shown conflicting results. Although incompletely defined, one mechanism of the effects of pregnancy on motility may be progesterone-induced inhibition of the mobilization of intracellular calcium within smooth-muscle cells [11].

Liver involvement is expected in about 50–60% of patients with HG [49]. It has been hypothesized that women heterozygous for fatty acid oxidation (FAO) defects develop HG associated with liver disease while carrying fetuses with FAO defects due to accumulation of fatty acids in the placenta and subsequent generation of reactive oxygen species [50]. Alternatively, it is possible that starvation leading to peripheral lipolysis and an increased load of fatty acids in the maternal–fetal circulation, combined with a reduced capacity of the mitochondria to oxidize the fatty acids in mothers heterozygous for FAO defects, can also cause HG and liver injury while carrying nonaffected fetuses [50].

Thyroid function should be measured in women with HG, since thyroid dysfunction is common in pregnancy and hyperthyroidism is diagnosed in approximately 60% of patients with HG. It is unclear whether beta-hCG has thyrotropic properties, or, if it is metabolic products can stimulate the thyroid gland, but a transient hyperthyroid state often occurs at the beginning of pregnancy [51, 52].

Transient gestational thyrotoxicosis has to be distinguished from Graves’ disease. The latter is associated with potential maternal and fetal complications if uncontrolled, whereas the former usually has a favorable outcome. In transient hyperthyroidism of hyperemesis gravidarum, thyroid function normalizes by the middle of the second trimester without antithyroid treatment. Clinically overt hyperthyroidism and thyroid antibodies are usually absent [53].

Jaundice is rare in HG but can occur in severe cases and is associated with conjugated hyperbilirubinemia. Other causes of jaundice must be excluded prior to making the diagnosis. Interestingly, jaundice in HG is frequently associated with hyperthyroidism, which suggests that it is a possible factor of cholestasis in patients with HG. Elevation of bilirubin and alkaline phosphatase, and mild elevation of transaminases are seen in such patients [54]. The fact that jaundice resolves when vomiting subsides points toward the diagnosis as well. Pancreatitis is an uncommon complication of cholestatic jaundice in HG, but has been reported. There are reports of recurrent HG with jaundice in consecutive pregnancies [30, 51, 55–57]. The risk of reoccurrence is approximately 16% and is lesser with a change of paternity (10%), suggesting the involvement of genetic factors.

Diagnostic evaluation

There are no strict diagnostic criteria for HG. Nausea and vomiting in a pregnant woman are considered pathological when it leads to weight loss of 5% or greater, compared with the most recent pre-illness weight value.

An initial evaluation of the pregnant woman presenting with nausea and vomiting should include assessment of volume status (tissue turgor, orthostatic BP) and weight changes, measurement of serum and urine electrolytes, and ketones, and evaluation of thyroid function, including free T4. Elevation of transaminases can be quite significant, ranging from hundreds to greater than a thousand by some reports [58].

Liver biopsy is not useful since there is no distinct histopathological picture. When biopsy was performed, the histopathology was either normal or revealed nonspecific necrotic changes in hepatocytes, bile plugs, centrilobular vacuolization, and steatosis [55]. In fatal cases, hepatic histology demonstrated acute yellow atrophy or centrilobular fatty infiltration.

Ultrasound might be useful for the diagnosis of twin pregnancies, trophoblastic disease, and gallbladder disease, and for maternal reassurance.

Differential diagnosis

Other causes of nausea and vomiting need to be ruled out prior to arriving at the diagnosis of HG.

Intestinal intussusceptions, cholecystitis, pancreatitis, and appendicitis may initially present with an insidious onset of nausea and vomiting. In the case of the “surgical abdomen”, pregnant patients do not develop peritoneal signs until later in the disease process, and the abdominal pain associated with peritoneal irritation is often vague. This may lead to delay in diagnosis and adverse outcomes for both mother and fetus.

Infectious causes of nausea and vomiting should be ruled out (viral or bacterial gastroenteritis, viral hepatitis). It is important to distinguish HG and hyperthyroidism. Both conditions may have a similar presentation; however the former does not require correction of the endocrine abnormalities, but the latter needs treatment to prevent maternal and fetal complications.

Presence of fever, diarrhea, constipation, goiter, hypertension, neurological changes, headache or abdominal pain point away from the diagnosis of HG. The onset of HG after 10–12 weeks of pregnancy is uncommon. Preeclampsia, HELLP syndrome, and AFLP can also have an initial presentation with nausea and vomiting, but they occur later in pregnancy.

Treatment

Treatment of nausea and vomiting in pregnancy is primarily supportive. The patient should be advised to avoid triggers that provoke nausea (strong odors, teeth brushing, etc.). Consumption of small, frequent, high-carbohydrate low-fat meals, avoidance of spicy, salty, high-protein foods may be helpful in some patients. Satisfaction of gustatory cravings is occasionally helpful as well.

In some studies, acupuncture and acupressure were found to be as effective as medication therapy in improving discomfort of HG [59]. Pressure wristbands are commercially available and do not require prescription. Ginger powder and pyridoxine supplementation are successfully used by some patients, but study reports on their effectiveness are contradictory. Since acid reflux is very common in pregnancy and it may contribute to nausea, a trial of acid-suppressing medications is warranted.

HG requires prompt treatment with intravenous fluids, thiamine and folate supplementation, and appropriate antiemetic therapy [17, 60]. Antihistamines such as promethazine are favored as first-line agents, with prochlorperazine being used as a second-line drug. However, there is no clear data as to the most appropriate drug if these are ineffective. In a study of 174 singleton pregnancies with nausea and vomiting, combined therapy with pyridoxine and metoclopramide was found to be superior to monotherapy with either promethazine or prochlormethazine [61].

In a case series of six patients with HG resistant to standard therapy levomepromazine 6.25 mg tid was used to control HG successfully without significant maternal or fetal complications [62]. Others report using mirtazapine for intractable nausea and vomiting in several cases, but further studies are needed to confirm the efficacy and safety of this regiment [63, 64].

Inspired by the effectiveness of steroids in chemotherapy-induced nausea, a short course of steroid therapy with a subsequent taper (hydrocortisone 300 mg IV Qday or methylprednisone) has been successfully used for controlling intractable HG [65–68].

Ondansetron is the most commonly used 5HT3-receptor antagonist; it did not produce teratogenicity in animals and appears to be safe in human pregnancy by the results of small studies [1, 2, 69] (see Table 2).

Table 2 Drugs used for treatment of hyperemesis gravidarum [60–64, 68–74]

Nasojejunal enteral feeding can be an effective option, if the HG persists despite intravenous fluids and antiemetic drugs. Oral eating and drinking is encouraged along the tube after vomiting subsides, usually after 3–4 days of nasojejunal feeding. Usually symptoms do not reoccur after the tube is removed [75].

Severe dehydration and volume depletion may lead to acute renal failure and the need for hemodialysis.

Total parenteral nutrition (TPN) is used occasionally in severe cases when significant weight loss and malnutrition are observed, but the incidence of complications directly linked to TPN is great in pregnant women. This treatment modality should be used cautiously and is reserved for severe cases only [76–78].

Intrahepatic cholestasis of pregnancy

Case

A 26-year-old woman in the 29th week of her third pregnancy was complaining of worsening itching of the skin that began 10 days earlier. Initially only her palms and soles were itchy; now pruritus involved her entire body and was worse at night. She had tried various over-the-counter lotions with no relief. Her first pregnancy ended in a miscarriage at 5 weeks of gestation. She experienced similar symptoms during her second pregnancy, when she developed generalized pruritus at 30 weeks of gestation and had a premature delivery at 32 weeks of gestation with intranatal death of the fetus. Autopsy demonstrated hyaline membranes in the fetal lungs and mild hepatomegaly. Her family history was significant for cholelithiasis in her mother. Laboratory tests at that time showed mild elevation of transaminases, total and direct bilirubin, and bile salts. Detailed evaluation did not show any underlying liver disease in the patient. On physical examination, the patient demonstrated multiple skin excoriations, but no other skin lesions or icterus. She was afebrile and normotensive with a heart rate of 76. There was no abdominal tenderness or hepatosplenomegaly. Laboratory tests showed elevated transaminases (AST 360 U/l, ref 13–45 U/l, ALT480 U/l, ref 5–57 U/l), total bilirubin (4.5 mg/dl, ref 0.2–1.2 mg/dl), total bile salts (12 μg/dl, ref <10 μg/dl), normal amylase, lipase, protrombin time, and cell counts. Serological testing was negative for hepatitis B virus (HBV), hepatitis A virus (HAV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). The biophysical profile of the fetus was reassuring. The patient was started on ursodiol; her labs and fetal biological profile were monitored weekly. Some improvement in pruritus was observed and her AST, ALT, bilirubin, and bile salt levels continued to decrease slowly. At 36 weeks of gestation she delivered a small for gestational age male fetus after premature rupture of the amniotic membranes.

Intrahepatic cholestasis of pregnancy (ICP) is the most common cholestatic liver disease affecting pregnant women; it is also the second most common cause of jaundice in pregnant patients after viral hepatitis. Although ICP has a fairly benign course for the mother, fetal outcomes can be devastating. It is a known cause of prematurity, meconium staining of amnionic fluid, fetal respiratory distress, and stillbirth [79]. Originally reported in 1883 by Ahlfeld [80] in Germany and later by Eppinger [81] and Thorling [82], this liver derangement remains poorly understood and underreported. The exact incidence of ICP is unknown, but ranges anywhere between 0.1 and 15% of full-term pregnancies by various reports [83]. Wide regional and ethnic variations of incidence have been observed: it is reported more frequently from Scandinavia, Baltic countries, Chile, Bolivia, and China.

Pathogenesis

ICP is peculiar to pregnancy and seems to be multifactorial in origin; there is a significant genetic component, but environmental factors, patient age, and parity play a role. Multiple factors interact with a genetic predisposition to alter the membrane composition of bile ducts and hepatocytes and increase their sensitivity to sex steroids [83, 84].

Genetic predisposition seems to be a major factor. Familial cases of ICP have been reported and are usually more severe [85]. The mode of inheritance can be autosomal dominant, autosomal recessive, or X-linked dominant. Also there is higher incidence of cholestatic liver disease and cholecystolithiasis in family members of women with ICP. A single-nucleotide polymorphism on the bile salt export pump gene (BSEP, also known as ABCB11) has been linked to susceptibility to ICP [86–88].

A small proportion of ICP cases have demonstrated a heterozygous mutation in the multidrug resistance-3 (MDR3) gene, also known as ABCB4, and the ATP8B1 (alias FIC1) gene that encodes for hepatobiliary phospholipid transporters [85, 87, 89, 90]. During first year of life monozygous children presented with progressive familial intrahepatic cholestasis (PFIC) types 3 and 1, respectively, whereas mothers had severe cases of ICP [83, 84, 88, 89, 91–93]. More frequently, however, ICP occurs in patients without a known history of PFIC. In these patients, a heterozygous missense mutation in the MDR3 gene that led to impaired protein trafficking and alteration of bile salt export was identified [91, 94–96]. Placental bile acid transporters are also altered in women with ICP, leading to impaired clearance of fetal bile acids [83, 84].

Genetic predisposition may also make the biliary tract more susceptible to the influence of pregnancy-induced hormonal changes. Patients with ICP have similar concentrations of total progesterone in their serum, but ratios between concentrations of progesterone metabolites differ from those in normal pregnancies: there is an increase in the concentration of mono- and disulfated metabolites with a normal concentration of glucoronidated compounds. Insufficient liver capacity to metabolize the high load of placenta-derived sex hormones could be a factor, since incidence and severity of ICP are higher in multiple gestations. Several estrogens and progesterone metabolites are able to induce transinhibition of the bile salt export pump and cause accumulation of bile acids, which may play a role in the etiopathogenesis of ICP [97]. The fact that ICP is more common in multiple pregnancies, where serum sex steroid hormones concentrations are higher than in singleton pregnancies, also suggests a connection between ICP and hormonal causes [97].

Bile acid synthesis appears to be reduced in patients with ICP, in whom primary conjugated bile acids are retained in the blood. The major bile acid in blood and urine of these patients is cholic acid instead of chenodeoxycholic acid as is present in normal pregnancies [98]. The abundance of circulating estrogens promotes cholestasis as well. This sensitivity to sex steroids is also confirmed by the cases of cholestasis provoked by oral contraceptive pill use or hormone replacement therapy. Progesterone given to delay preterm delivery has been associated with ICP as well [99]. Environmental factors may play a role since ICP has a higher prevalence in the cooler seasons. Selenium deficiency has also been suspected to be a contributing factor [100, 101].

It has been speculated that infection may be implicated in the pathogenesis of ICP through inflammatory cytokine interference with the activity of both the sinusoidal and canalicular transporting systems [102]. Interestingly, urinary tract infection can cause cholestasis or worsen intrahepatic cholestasis of pregnancy [103]. Sepsis and some viral infections (HSV, EBV, and CMV) are known causes of cholestasis [104]. Also, increased bowel wall permeability with enhanced absorption of potentially hepatotoxic bacterial endotoxins have been linked to the development of ICP [105].

ICP often reoccurs in subsequent pregnancies (40–60% of patients); increasing incidence of ICP has also been observed with advancing maternal age [85].

Clinical presentation and diagnostic evaluation

ICP is characterized by cholestasis-induced pruritus and elevation of bile acids and transaminases that spontaneously resolve after delivery. Presence of these criteria is essential for diagnosis.

ICP usually develops after 20 weeks of pregnancy, most commonly in the third trimester. Earlier onset is usually observed in familial cases of ICP and is associated with more severe disease, combined genetic defects, and worse fetal outcome [87]. Insidious in onset, pruritus begins on the palms and soles and gradually progresses to the arms, legs, and trunk; more pronounced at night, it may cause significant discomfort and sleep disturbance. Anorexia, malaise, dark urine, nausea, and steatorrhea may develop and cause nutritional deficiencies and weight loss. One should be especially watchful for vitamin K deficiency that could be quite hazardous in the light of future delivery and potential bleeding. Jaundice is an uncommon presenting feature, but can occur later (10–20% of patients) and is usually mild [3, 106].

Although abdominal discomfort may occur, severe abdominal or right upper quadrant pain, as well as fever, are uncommon and should prompt further investigation. Patients with ICP do not develop encephalopathy.

Serum bile acids elevation >10 μM/l occurs and the severity of pruritus is in direct proportion to the degree of hypercholangemia. Serum cholic acid increases more than chenodeoxycholic acid, resulting in a marked elevation of the cholic/chenodeoxycholic acid ratio compared to pregnant women without ICP; a simultaneous decrease in the glycine/taurine conjugates ratio also occurs [107]. The frequency of fetal complications rises with serum bile acid concentrations greater than 40 μM/l [70, 108, 109]. Serum transaminase elevation usually accompanies hypercholangemia and reaches three- to fourfold above the upper limit of normal, although in severe cases 100-fold elevations have been reported. Alkaline phosphatase should not be used for assessment of the pregnant patient with suspected cholestasis, since there is a physiological elevation of alkaline phosphatase due to increased production by the placenta and bone. Glutathione S-transferase-alpha (GSTA, a specific marker of hepatocellular integrity) is significantly elevated in women with ICP, when compared with healthy pregnancies. Also, it is helpful in differentiating between ICP and pruritus gravidarum, a benign condition with no elevation of fetal risk [110]. Serum gamma-glutamyl transpeptidase (GGT) and 5′-nucleotidase activity are normal or only mildly increased. Hyperbilirubinemia is also observed, but total bilirubin rarely exceeds 6 mg/dl. Interestingly, concomitant urinary tract infection makes ICP worse and is more frequently associated with jaundice. Coagulation studies are almost always normal. However in cases of very severe ICP or associated with cholestyramine administration prothrombin time (PT) prolongation has been observed. This has been attributed to vitamin K deficiency due to intestinal malabsorption of this lipid-soluble vitamin.

ICP is associated with dyslipidemia with a significant increase of LDL, apolipoprotein B-100, total cholesterol values and decreased high-density lipoproteins (HDL). These changes occur before the patient becomes symptomatic and may prove to be useful biomarkers [111] (see Table 3).

Table 3 Manifestations of intrahepatic cholestasis of pregnancy [106, 112]

Even though ICP can the make the mother’s condition very uncomfortable, in most cases it is not a major threat to her health. In contrast, fetal wellbeing is threatened much more in the setting of ICP. The list of potential fetal complications includes prematurity, meconial amniotic fluid staining, asphyxia, respiratory distress syndrome (RDS), and intrauterine fetal demise. The mechanisms of fetal impairment are not clear. It has been proposed that high bile acid concentrations decrease surfactant formation and impair lung maturation [79]. Direct correlations between the degree of elevation of bile acids and increased fetal risk have been observed. Fetal complications are rare with levels of total bile acids less than 40 μM/l [108]. Sudden intrauterine fetal death may occur without any early signs of fetal distress on fetal monitoring. To date, no ideal screening test has been established for antenatal fetal monitoring in the setting of ICP [106]. The total serum bile acid level seems to be a better predictor of fetal distress than biophysical profile or nonstress testing. Sudden fetal death occurs in 1–2% of cases, but it is rare before the last month of pregnancy [113].

Differential diagnosis

Diagnosis is usually made based on history and laboratory data revealing a cholestatic picture. Ultrasound is used to rule out biliary obstruction by gallstones. Liver biopsy is rarely needed for diagnosis. When obtained, histopathology demonstrates pure cholestasis without inflammation or necrosis with bile plugs in the hepatocytes and canaliculi predominantly present in zone 3.

ICP should be distinguished from other cholestatic conditions that may present in the late terms of pregnancy. Although rare, the Dubin–Johnson syndrome can be exacerbated by pregnancy and present as jaundice in the second or third trimester. Usually it is not accompanied by pruritus but is associated with mild conjugated hyperbilirubinemia with otherwise normal liver enzyme values. Cholecystolithiasis can be exacerbated or precipitated by pregnancy and should be considered as a part of the differential diagnosis. It is usually accompanied by right upper quadrant pain, jaundice, and fever. Endoscopic ultrasound can be used to identify common biliary duct (CBD) stones. Endoscopic retrograde cholangiopancreatogram (ERCP) can relieve CBD obstruction with minimal fetal radiation exposure. Other causes of pruritus and jaundice that require exclusion include primary biliary cirrhosis, sclerosing cholangitis, viral hepatitis, autoimmune chronic active hepatitis, and drug hepatotoxicity. Hepatosplenomegaly, encephalopathy, and fever do not occur in ICP and suggest other causes.

Primary biliary cirrhosis (PBC) is usually diagnosed later in life at the end of reproductive age or after menopause. It may present as cholestatic jaundice shortly after the pregnancy. There are very few case reports of pregnancy in the setting of PBC. In these pregnancies levels of bilirubin increase toward the end of pregnancy and remain elevated after it. Most women with PBC have a history of uncomplicated pregnancies, suggesting that pregnancy in the setting of asymptomatic primary biliary cirrhosis is uncomplicated. Antimitochondrial antibodies are helpful in confirming the diagnosis of PBC [114].

Wilson’s disease is a rare autosomal-recessive condition that may present in adolescence or early adulthood. A combination of neurological and hepatic dysfunction is the most common initial presentation, although psychiatric and hematological symptoms are common as well. Classical findings of a Kayser–Fleischer ring on eye slit-lamp examination, low serum cerruloplasmin levels, and high tissue copper concentration are helpful in confirming the diagnosis. However, cerruloplasmin production is increased by estrogen and might reach normal levels in these patients during pregnancy. Successful pregnancies have been reported in women with Wilson’s disease. Although d-penicillamine has some teratogenic effect, it is imperative to continue treatment during the pregnancy since rapid hepatic decompensation and hemolysis can occur and have been observed in pregnant patients who have discontinued treatment [114].

Pruritus gravidarum (PG) has a milder course and does not lead to severe fetal complications. Serum bile acids, bilirubin, and transaminases are only mildly changed in PG, whereas glutathione S-transferase alpha remains normal [110].

Treatment of ICP

Early diagnosis and careful interdisciplinary monitoring are a must to ensure favorable maternal and fetal outcomes. Delivery before projected term, preferably after confirming lung maturity, may be necessary to prevent sudden antenatal death.

When expedited delivery is not advisable, medical treatment should be employed. Many agents have been tried for both symptom relief and in the hope of normalizing laboratory abnormalities and improving fetal outcome.

Hydroxizine was somewhat effective in decreasing pruritus, but it can potentially cause respiratory depression in a newborn when administered near delivery.

Ursodeoxycolic acid (UDCA) administration has been helpful in normalizing the bile acid ratio in maternal serum, decreasing total bile acid concentration, and facilitating placental transport of bile acids from the fetal to the maternal compartment [107]. Fetal benefits include facilitation of closer to term delivery and reduction of bile acid concentration in the colostrum. It is usually well tolerated and no adverse effects to the fetus or teratogenicity with UDCA administration has been reported [71–73, 106].

S-adenosyl-methionine (SAMe, a glutathione precursor) has been observed to reverse estrogen-induced cholestasis in experimental animals, but has shown only small improvement in laboratory values and pruritus in women with ICP.

The combination of UDCA and SAMe has demonstrated a synergistic effect in decreasing serum bile acids concentration and transaminases, but it is unclear whether fetal outcomes improve with this therapy. SAMe administration alone was inferior to UDCA alone in alleviating symptoms of ICP [115, 116].

Cholestyramine was not effective in reducing pruritus and worsened steatorrhea, making vitamin K deficiency even more likely.

Dexamethasone administration does not improve pruritus or transaminases, and is less effective than UDCA in reducing bile acid and bilirubin levels [70].

Ondansetron, a 5-hydroxytryptamine 3 receptor antagonist, was reported to be effective in controlling pruritus associated with ICP, but no changes of laboratory values were reported with this therapy.

Use of plasmapheresis for treatment of intractable pruritus has been reported, and total bile acid concentration was decreased immediately after the procedure. However, reoccurrence of hypercholangemia and pruritus was observed several days later and the procedure had to be repeated [117].

Recommendations

UDCA 15 mg/kg/day (500 mg BID) is recommended.

Close monitoring of the serum total bile acid concentration, transaminases, bilirubin, and coagulation studies is needed, as well as close fetal surveillance. Vitamin supplementation may be needed in cases of severe steatorrhea.

Delivery should be accomplished by 38 weeks. In severe cases, when jaundice is present or total bile acid concentration is greater than 40 μM/l, delivery as early as 36 weeks is advisable, if lung maturity permits [106, 118].

Women with a history of ICP should be cautioned about possible reoccurrence of cholestasis with future pregnancies or hormonotherapy, and liver function tests should be monitored once such therapy is initiated.

ICP and maternal health

Women with a history of ICP are significantly more likely to be diagnosed with gallbladder stones, nonalcoholic pancreatitis, nonalcoholic cirrhosis, and hepatitis C [83]. They may experience reoccurrence of cholestasis with oral contraceptives use or hormone replacement therapy, but this is a rare complication and, while a prior history of ICP is not a contraindication to therapy with sex steroids, close monitoring is advised [83, 85, 119]. There are case reports of MDR3 mutation-linked biliary cirrhosis in middle-aged patients who have a history of ICP [119].

Toxemia of pregnancy and syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome)

The syndrome of preeclampsia and eclampsia is well described in the literature. The diagnostic criteria for this condition are defined as presence of the edema, proteinuria, and hypertension above 140/90 in a previously normotensive patient or worsening hypertension in the patient with pre-existing vascular hypertension in the second or third trimester of pregnancy. The term “toxemia” is a misnomer in this case, since no toxin causing the constellation of the symptoms of edema, hypertension, and proteinuria in the pregnant patient has ever been found. Multiple theories have been proposed as an explanation of this condition, but the exact cause remains unknown and the ultimate cure is still delivery [120]. Most women with preeclampsia do not develop liver disease. However, at least 10% of patients with severe degrees of preeclampsia exhibit liver involvement and 70% of women who have died from eclampsia show liver involvement [121].

The liver involvement in preeclampsia includes the syndrome of microangiopathic hemolitic anemia, elevated liver enzymes, and low platelets (HELLP syndrome). This condition has been described in the literature both with and without symptoms of preeclampsia. In addition, liver involvement in preeclampsia may include periportal hemorrhage, hematoma formation, and liver rupture without a complete picture of the HELLP syndrome. The question of whether the HELLP syndrome exists as a distinct entity or is a part of preeclampsia remains a subject of debate among obstetricians and internists [54].

First described in the literature in 1982 [122], HELLP syndrome is a part of the spectrum of pregnancy complications that can be life threatening to both the mother and fetus. The associated liver disease may be severe and may progress to the point that liver transplantation may become necessary. The incidence of the HELLP syndrome is approximately 0.6% of deliveries and 3.1–12% of patients with preeclampsia [123, 124]. In 70–92% of patients it occurs ante partum and in 8–30% postpartum; 9–11% patients develop symptoms before 27 weeks of gestation and 25–80% at term [2, 125]. Up to 15–20% of the patients with HELLP syndrome do not have antecedent symptoms of preeclampsia. HELLP is extremely rare in the first trimester, but such cases have been reported as well [4, 126].

Case

A 28-year-old woman (G3P2) was admitted at 32 weeks of gestation with seizures, severe headache, and epigastric pain radiating to the right shoulder. During initial assessment her blood pressure was 86/58 and her heart rate was 146. Fetal heart tones were not detected. Her abdomen was diffusely tender to palpation with more pronounced tenderness on palpation of the right upper quadrant. Her uterus was hypertonic and very tender to palpation.

The laboratory evaluation was significant for hemoglobin of 8.2 g/dl, white blood cell count of 11,000/dl, platelet count of 87,000/dl, AST level 1,856 U/l, ALT 2,100 U/l, lactate dehydrogenase (LDH) 1,543 U/l, international normalized ratio (INR) 1.4, PT 46 s, and partial thromboplastin time (PTT) 86 s.

The clinical diagnosis of abruptio placenta was made and the patient underwent an emergency Caesarean section. A male fetus with American pediatric gross assessment record (APGAR) scores 5 and 7 was delivered. During the surgery intra-abdominal bleeding due to hepatic rupture was detected. Hepatic artery ligation was performed with subsequent repair of the hepatic lesion and cholecystectomy. During and after surgery, the patient received five units of packed red blood cells, three units of fresh frozen plasma, one unit of cryoprecipitate, and intravenous fluid resuscitation. Her postoperative course was complicated with acute renal failure that resolved with supportive care. Serial abdominal ultrasound examinations revealed development of a postoperative hepatic hematoma that remained stable and resolved spontaneously after several weeks of observation.

Pathogenesis

Many theories have been proposed to explain the pathophysiology of HELLP syndrome. Most likely it represents a severe and distinct form of preeclampsia, although a large proportion of the patients do not have antecedent hypertension and proteinuria.

Structural and functional changes in the systemic vasculature have been proposed to play a major role in the development of the HELLP syndrome. In a prospective study of total hepatic blood flow in patients with severe preeclampsia, the authors demonstrated that observed decrease of hepatic blood flow was predictive of the subsequent development of HELLP syndrome in these patients [127].

Another theory is that placenta-derived proteins mediate apoptosis of liver cells. It has been demonstrated in animal models that interaction of placenta-derived CD95 (APO-1, Fas) with its ligand, CD95L (FasL), induces apoptosis in hepatic cells. A new therapeutic agent (LY498919) that blocks CD95-induced apoptosis is being investigated [128].

Inflammation has been suspected to play a role in the development of the HELLP syndrome, since a reverse correlation between the degree of the leukocytosis and thrombocytopenia has been observed [129].

Clinical presentation of HELLP syndrome

Patients typically present in the early third trimester with upper abdominal or right upper quadrant pain, nausea, and vomiting. There may or may not be concomitant signs and symptoms of preeclampsia (hypertension, proteinuria, and edema), therefore initial misdiagnosis is not uncommon. The complaints are often nonspecific, such as malaise (90%), nausea and vomiting (50%), and sometimes flu-like symptoms [130]. Jaundice is a presenting feature in fewer than 5% of the cases, and bleeding due to thrombocytopenia is a very uncommon mode of presentation. Right upper quadrant pain may be severe, radiating to the neck or shoulder when complications of HELLP syndrome such as hepatic hematoma or hepatic rupture develop.

Diagnosis

Diagnosis is based on finding laboratory abnormalities comprising the name of the syndrome, but there are no uniform criteria for the degree of these abnormalities.

Usually, diagnosis is based on finding hemolytic anemia, an abnormal peripheral smear (microangioplastic anemia with schistocytosis), thrombocytopenia, and elevated AST, ALT, bilirubin, and LDH [131].

The Mississippi classification system, based on the degree of thrombocytopenia and elevation of transaminases and LDH, has been proposed for assessment of severity of the pathological process as shown in Table 4. The platelet count and serum LDH levels are found to be moderately predictive of severity of the disease and the speed of recovery [132]. Patients with class I HELLP syndrome have a worse prognosis and longer hospital stay; they require more transfusions, and a longer time for both laboratory and clinical recovery [125].

Table 4 Mississippi classification of the HELLP syndrome [132]

Differential diagnosis

There are several conditions that need to be distinguished from HELLP syndrome. Acute viral hepatitis is the most common cause of transaminase elevation in pregnancy and the initial presentation of the HELLP syndrome can easily be confused with it. Other conditions that have to be differentiated from the HELLP syndrome include gastroenteritis, appendicitis, cholecystitis, idiopathic thrombocytic purpura, lupus, antiphospholipid syndrome, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS), and acute fatty liver of pregnancy (see Table 5).

Table 5 Differential diagnosis of HELLP syndrome, TTP/HUS, and AFLP [4, 52, 54, 114, 133–138]

Acute fatty liver of pregnancy (AFLP), another severe liver disease associated with the gravid state, may be confused with HELLP syndrome. Both conditions occur in the later terms of pregnancy and have similar presentations. Liver dysfunction is usually more profound in AFLP and is more frequently associated with coagulopathy, hypoglycemia, and renal failure. The coagulopathy of the AFLP is due to liver failure, whereas in HELLP coagulopathy develops as a part of disseminated intravascular coagulation (DIC) syndrome. The coagulation abnormalities are also different in these disorders. HELLP is associated with thrombocytopenia, and in severe cases there may be DIC and prolongation of the prothrombin and partial thromboplastin time, decreased fibrinogen and coagulation factors especially factors V and VIII. In contrast, TTP/HUS is associated with isolated platelet consumption; thus, although thrombocytopenia is seen, the other findings are typically absent [139].

Management of HELLP syndrome

The clinical course of the patient with HELLP syndrome can take a route of very rapid and sudden deterioration. Since mortality and morbidity is so high for both mother and the fetus, many authors consider the diagnosis of HELLP syndrome an indication for immediate delivery [2, 122, 125, 140, 141]. However, due to increased awareness of this condition and improved diagnostic technology and treatment modalities prognosis is slightly improved. Although controversial, expectant management may be recommended in rare cases when the patient is stable and the term of gestation is nonfavorable for fetal survival [122, 131, 133, 142, 143].

The first step in the management of the HELLP syndrome is to stabilize the patient, assess fetal condition, and make the decision about time and method of the delivery.

Immediate delivery is indicated if term of gestation is greater than 34 weeks or fetal testing results are non-reassuring. Maternal indications for the immediate delivery include presence of multiorgan dysfunction, DIC, liver infarction or hematoma, renal failure or abruptio placentae. In these cases, treatment includes prophylaxis of seizures with magnesium sulfate, control of blood pressure, stabilization of the patient, and prompt delivery [131].

Before 34 weeks of pregnancy, if both mother and fetus are stable, corticosteroids for acceleration of fetal lung maturity should be administered [131, 143, 144]. Delivery is usually performed within 48 h. Some authors say that corticosteroids are beneficial for both mother and the fetus in the setting of HELLP syndrome and should be given at any term including postpartum [143, 145–147]. Reported maternal benefits of corticosteroids include improvement of the laboratory values, urine output, blood pressure, greater rate of local anesthesia use, and shorter hospital stay [141, 145–147]. Higher than usual doses of steroids are required to reach maximal benefit. Proposed treatment is two doses of betamethasone given 12 h apart [144, 148]. The greatest benefit from steroid administration was demonstrated in the patients with class I HELLP syndrome. However, only a few randomized studies have been reported that demonstrated an improvement of maternal laboratory values and renal output with use of dexamethasone but with no difference in serious maternal morbidity (need for transfusion, pulmonary edema, renal failure, and hepatic complications). Platelet transfusion is recommended in the case of bleeding or of severe thrombocytopenia (platelet count less than 20,000 cell/dl) [149].

After delivery, initial worsening of laboratory values with subsequent spontaneous recovery is observed. Speed of recovery depends upon the severity of initial presentation and the presence of complications [132].

Complications

With modern treatment, maternal prognosis and outcomes have improved significantly, but morbidity remains very high (see Table 6).

Table 6 Complications of the HELLP syndrome [122, 124, 150–152]

The most frequent maternal complication of HELLP is disseminated intravascular coagulopathy (30%). Development of abruptio placentae (16%) and acute renal failure (7.7%) correlate with occurrence of DIC. Pulmonary edema (6%), aspiration pneumonia (7%), cardiopulmonary arrest (4%), cerebral hemorrhage (1.2%), and retinal detachment (0.9%) are other potential complications [1, 2]. Of note, neurological complications are more common in patients with preeclampsia that presented postpartum [150].

Most frequently severe maternal complications and maternal mortality were observed in the patients with class I HELLP syndrome (85%) [125, 151]. The perinatal mortality approximates from 7 to 22.6% and maternal mortality is 1%.

One of the potentially deadly complications of HELLP syndrome is development of subcapsular hepatic hematoma and/or hepatic rupture. The first case report was published by Abercrombie in the London Medical Gazette in 1877 [153]. It occurs in 0.9% of patients with HELLP and often requires surgical management. The mortality rate historically is very high (18–86% by some reports) [2, 123].

Spontaneous hepatic rupture is a rare life-threatening complication that is most commonly associated with HELLP. It also has been reported in association with preeclampsia/eclampsia, AFLP, and DIC [154]. Simultaneous splenic and hepatic rupture in HELLP syndrome has been reported [155]. Failure to promptly identify it is invariably fatal. Coincident renal hematomas are described as well [156]. Cases of hepatic hematomas not associated with HELLP or preeclampsia have been reported as well [156, 157]. In the latter cases, it has usually been associated with poor management of preeclampsia and an absence of prenatal care. The incidence of spontaneous hepatic rupture in pregnancy is reported to be from 1 in 45,000 to 1 in 225,000 deliveries [123, 156]. Patients usually present with vaginal bleeding, epigastric or right upper quadrant pain, severe right shoulder pain, nausea, vomiting, abdominal distension, and hypovolemic shock. Laboratory findings include elevated transaminases (usually between 200 and 500 U/l, but higher values have been reported), sudden drop in hemoglobin, thrombocytopenia (<100,000/mm³), and LDH elevation (>600 U/l) [5, 114, 123]. HELLP syndrome can lead to hepatic failure as well, although it occurs less frequently than in AFLP.

Hepatic infarction is another potential complication of preeclampsia. These patients usually present in the late third trimester or puerperium with right upper quadrant pain and a fever, usually, but not invariably, accompanied by the signs and symptoms of preeclampsia. Although, hepatic infarction in pregnancy is most frequently observed in patients with preeclampsia, it may occur as a separate entity and in those cases is usually associated with antiphospholopid syndrome [158]. Laboratory findings include leukocytosis, anemia, high LDH, prolonged PT, and significant transaminase elevation (≥3,000 U/l). Abdominal CT confirms the presence of the liver infarct most commonly located in the left liver lobe. Management is mainly supportive and normally there is no hepatic sequellae after delivery [3, 5, 114, 159].

Diagnostic studies in HELLP syndrome

Hepatic ultrasound, computer tomography, and MRI are routinely used to confirm the diagnosis. The most frequent imaging abnormality is the finding of subcapsular hepatic hematoma or frank intra-abdominal hemorrhage. No correlation between the degree of transaminase elevation and the probability of hepatic hematoma has been found. However, the degree of thrombocytopenia correlates with the probability of finding hepatic hematoma during imaging studies [160].

CT scanning, particularly contrast-enhanced CT, is accurate in localizing the site and extent of liver injuries, providing vital information for treatment. Spiral CT is the preferred scanning technique if available. Multidetector-row CT offers the further advantages of fast scanning times (allowing scanning during specific phases of intravenous contrast enhancement) and the acquisition of thin sections over a large area (allowing high-quality multiplanar reconstruction). CT without intravenous contrast enhancement is of limited value in hepatic trauma, but it can be useful in identifying or following up a hemoperitoneum [156, 161].

Iodinated contrast agents are safe in pregnancy (pregnancy category B), although contrast studies in pregnant patient should be used judiciously [162].

Liver biopsy is very risky and not necessary for diagnosis of HELLP syndrome. Even in mild preeclampsia the histopathological picture reveals fibrin deposition along hepatic sinusoids and bleeding into the space of Disse. Modest fatty infiltration may occur in preeclamptic patients as well. Similar but more pronounced changes with extensive fibrinous thrombi and hemorrhages are seen in the liver of patients with HELLP [3, 114, 163].

Management of the hepatic hematoma

The degree of hepatic involvement varies from a stable hematoma that may be managed conservatively, to various degrees of hepatic parenchymal lacerations that may be quite extensive at times and require emergent surgical intervention. Most hepatic lesions are found in the larger right lobe. Smaller lacerations can be managed with suturing and omental patching. In other cases, hepatic artery ligation is an option [123]. Cholecystectomy is frequently performed at the same time to avoid gallbladder necrosis due to associated vascular disease. In severe cases with involvement of larger portions of hepatic parenchyma emergency liver transplantation may be required [133]. The optimal management of these cases is very difficult to establish and the decision on when to proceed to surgery has to be made based on the clinical findings and availability of a hepatic surgeon. The most commonly used approach is to proceed to surgery if there is any evidence of hemodynamic instability, continued blood loss, increasing pain, documented expansion or infection of the hepatic hematoma [123, 157]. Percutaneous transcatheter embolization of one of the hepatic arteries has been used successfully in some cases: introduction of this procedure has led to further decreases in maternal mortality [114, 164].

The most common cause of maternal death in this setting is DIC and acute renal failure [123]. All patients with this serious pathology require intensive supportive measures, including intravenous fluids, multiple blood transfusions, cryoprecipitate, and plasma [165]. A combination of surgical treatment with hepatic artery ligation and omental patching with supportive measures can be effective in decreasing mortality rates [123]. However, the perinatal mortality remains very high.

Recommendations

Considering the extreme importance of early diagnosis for ensuring favorable maternal and fetal outcomes, one should always pay great attention to the pregnant patient with elevated transaminases and keep the HELLP syndrome in mind as one of the likely diagnoses. The incidence of this condition is less than 1% of all deliveries and approximately 10% of cases with severe preeclampsia and eclampsia.

Diagnostic features of HELLP syndrome include presence of microangiopathic hemolytic anemia, elevation of transaminases and thrombocytopenia. Of note, marked elevation of transaminases is not characteristic of HELLP syndrome and, if present, is suggestive of development of hepatic complications (liver infarction, hematoma or rupture). The development of abdominal and right shoulder pain in a pregnant woman with preeclampsia/eclampsia or HELLP syndrome is an ominous sign and careful screening for a possible hepatic lesion should be performed.

Abdominal ultrasound, CT scanning, and MRI are useful and safe modalities for confirmation of the diagnosis.

Management includes prompt delivery after initial stabilization. If magnesium sulfate is given for seizure prophylaxis, the infusion should be continued for 24 h postpartum or until remission is achieved. Blood pressure control should be achieved with use of labetalol, hydralasine or sodium nitroprusside in severe and resistant cases. Immediate delivery is indicated if severe maternal complications are present, in cases of non-reassuring fetal monitoring findings or if term of gestation is greater than 34 weeks.

If term of gestation is less than 34 weeks and both mother and fetus are stable, intravenous steroids should be administered for acceleration of fetal lung maturity. In these cases delivery should be performed 24 h after the last dose of steroids. Data regarding maternal benefits from steroid use in the HELLP syndrome remains controversial. Vaginal route of delivery is preferred, if possible. Local anasthesia has fewer complications than general anasthesia in patients with HELLP syndrome.

Expectant management of stable patients with HELLP syndrome is experimental.

The approach to the patient with such a complex problem should be multidisciplinary. Early diagnosis and timely delivery is a key to the successful management of this condition almost uniformly fatal in the past.

Subsequent pregnancy outcomes and long-term prognosis after HELLP syndrome

In a large study of pregnancy outcomes it has been reported that normotensive patients with a history of HELLP syndrome are at a higher risk of preeclampsia (19%), preterm delivery (21%), intrauterine growth restriction (12%), abruptio placentae (2%), perinatal death (4%), and recurrence of HELLP (3%). However, women with pre-existing hypertension and HELLP syndrome had much higher rates of complications [1] (see Table 7). Other authors report much higher risk of complications and reoccurrence of HELLP [4].

Table 7 Subsequent pregnancy outcomes in women with HELLP syndrome [1, 2, 4, 122, 125, 133, 166]

Acute fatty liver of pregnancy

Acute fatty liver of pregnancy is a rare and potentially fatal condition. It was first described as “yellow acute atrophy of the liver” in 1934 by Stander [167] and in 1940 by Sheehan [168]. It has been thought that this condition is rare and usually takes a devastating course with significant morbidity and mortality [103, 169]. Modern advances in diagnostic capabilities have given us a better understanding of the pathological process, and many cases with a milder clinical course as well as subclinical cases have been reported [3, 6, 134]. The relationship between AFLP and preeclampsia is not clearly defined, but data suggest that most women with AFLP have some degree of preeclampsia.

The reported incidence of AFLP is from 1 in 7,270 to 1 in 13,000 of deliveries [7, 134, 169]. There is no ethnic or regional variability. Most commonly onset occurs between 30 and 38 weeks of gestation, but cases as early as 26 weeks have been reported. There are a few reports of AFLP in the second trimester. This condition is more common in primiparous women, but cases of AFLP after multiple uncomplicated pregnancies are documented as well [169]. The frequency of multiple gestations is higher in patients with AFLP than in the average population (14–19% versus 1%). Some reports suggest that it is more common in gestations with male fetuses [5]. AFLP may reoccur with subsequent pregnancies [5].

Case

A 42-year-old primigravida with twin gestation at 38 weeks was admitted to the emergency room complaining of painful uterine contractions for the past 6 h and bloody vaginal discharge. She received routine prenatal care, and the course of her pregnancy was complicated by moderate to severe preeclampsia. She had no significant past medical history. Review of systems revealed nausea, vomiting, malaise, and yellow discoloration of the skin for the past week; there was gum bleeding for the past few days and abdominal pain in the right upper quadrant. There was no history of hematemesis, melena, hematochezia, headache, dizziness, seizures or loss of consciousness. There was no recent history of travel, sick contacts, use of illicit drugs or alcohol.

During initial examination, her blood pressure was 142/90, heart rate was 89, and she was afebrile. The icteric sclerae and skin were noted. Her abdomen was tender to palpation all over; uterus was hypertonic and painful. The size of the uterus was appropriate for dates. No hepatosplenomegaly, Murphy sign or asterixis was found. On vaginal examination closed cervical os was detected with a moderate amount of bloody vaginal discharge with few clots; the uterus was slightly smaller than expected for dates. Fetal monitor tracings showed tachycardia with multiple decelerations.

Laboratory work up was significant for elevated transaminases (AST 125 U/l and ALT 167 U/l), bilirubin (9.2 mg/dl), alkaline phosphatase (339 U/l), createnine (1.7 mg/dl), blood urea nitrogen (BUN) (18 mg/dl), prothrombin time (32 s), INR (1.4), and partial thromboplastin time (49 s). Her platelet count was 59,000 μl; urine was positive for protein. Viral serology for viral hepatitis A, B, and C were negative.

A clinical diagnosis of abruptio placenta was made and confirmed by bedside ultrasound; acute fatty liver of pregnancy was strongly suspected. Emergency Caesarean section with intraoperative liver biopsy was performed. Postoperatively, the patient experienced worsening jaundice with further elevation of the bilirubin, transaminases, BUN, and createnine. She became encephalopathic and hypoglycemic. Her serum ammonia level was 97 mg/dl; amylase and lipase were elevated as well and a diagnosis of pancreatitis was made.

Intraoperative liver biopsy results demonstrated marked centrilobular microvesicular fatty infiltration and a mild degree of cholestasis.

After the delivery, the patient required intensive care unit hospitalization, multiple transfusions of blood products, and intravenous fluids. Her postoperative recovery was prolonged, but her liver and renal function recovered completely and her encephalopathy and pancreatitis resolved as well.

Presentation

The patient with AFLP usually presents in the late term of pregnancy, most commonly in the third trimester. Initial presentation with malaise, nausea, vomiting, and headache is very nonspecific and can be easily misdiagnosed. Right upper quadrant pain and epigastric pain are common (50–80%) [169, 170]. Fever, headache, diarrhea, back pain suggestive of acute pancreatitis, and myalgias on presentation are reported occasionally. Some patients may present with frank liver failure and acute bleeding due to liver-failure-induced coagulopathy, but more commonly these symptoms are seen 1–2 weeks later. Vaginal bleeding, hematemesis, and mucosal bleeding may occur. About 50% of patients have concomitant preeclampsia [7, 170]. Occasionally, the patient may present with signs and symptoms of eclampsia (agitation, increased thirst, premature labor, seizures). Hypertension is not severe or may be absent due to the offset of preeclampsia-induced blood pressure elevation by a decrease of peripheral vascular resistance associated with hepatic failure. Rarely AFLP may present as asymptomatic elevation of transaminases [5]. Jaundice is seen on initial presentation in severe cases [133, 171].

Physical findings are often minimal. Early in the disease, right upper quadrant tenderness may be the only abnormality found. The liver is usually nonpalpable. As the disease progresses, jaundice, altered mentation, ascites, and edema arise.

Early complications of AFLP include acute renal failure, acute pancreatitis, hypoglycemia, and infection. Hepatic encephalopathy usually occurs later in the course. Any combination of these complications may be deadly to the mother, and intrauterine fetal demise occurs frequently. Fetal demise is related to the severe maternal illness, premature delivery, frequent development of placental insufficiency with fetal asphyxia and DIC. Delivery is often complicated with severe postpartum bleeding. Diabetes insipidus may complicate AFLP [7, 171, 172].

AFLP is a medical and obstetric emergency, and prompt diagnosis and treatment are imperative to ensure maternal and fetal survival. Reported maternal mortality ranges between 3 and 12.5% [133] and perinatal mortality is 66%. Previous reports suggest even higher mortality rates [140] (see Table 8).

Table 8 Complications of acute fatty liver of pregnancy [5, 133, 166, 170, 171]

Diagnosis and laboratory data

Initial diagnosis is made clinically, based on presentation and can be confirmed with a liver biopsy. Although liver biopsy is a gold standard for diagnosis of AFLP, it is not routinely done due to the urgency of the clinical situation and danger of coagulopathic bleeding. Early in the disease or in mild cases of AFLP, when diagnosis is not clear, liver biopsy is very helpful. Special staining is required to demonstrate the fatty changes in the hepatocytes (Oil Red O stain, reticulin stain, etc.). Frozen section rather than formalin-fixed specimen is used [169]. If a liver biopsy is performed, it usually shows cytoplasmic vacuolisation predominantly in the central zones with microvesicular fatty infiltration [7, 114, 173]. In severe cases lobular disarray is seen with cell dropout. Portal inflammatory changes can be seen as well, suggestive of cholangitis; therefore histopathology should be interpreted with the consideration of clinical presentation [3].

A moderate elevation of the transaminases is usually seen, although widely variable values ranging from just slightly above normal to greater than a 1,000 U/l have been reported. The degree of transaminase elevation does not reflect accurately the severity of liver dysfunction. Normocytic anemia and leukocytosis, that is not associated with an infectious process, are seen as well. Thrombocytopenia is common when DIC is present; otherwise it is unusual in AFLP. Coagulation studies show a pattern of DIC in many cases. The peripheral smear contains nucleated red blood cells and, in cases with DIC, fragmented erythrocytes and Burr cells. Elevation of BUN and creatinine is observed as a reflection of emerging acute renal failure. As liver function worsens, encephalopathy, hypoglycemia, and elevated ammonia are seen.

Imaging studies are of little value in diagnosis of AFLP [166, 169]. Both liver ultrasound (US) and CT were inconsistent in detecting fatty infiltration of the liver in patients with AFLP; the role of MRI and spectroscopy in particular requires further investigation [174, 175]. However, imaging studies are useful to exclude other pathological processes in the liver (for example, hepatic ischemia, infarct, Budd-Chiary syndrome or hepatic hematoma/rupture).

Differential diagnosis

Many conditions present with transaminase elevation in late terms of pregnancy. AFLP poses an imminent threat to maternal and fetal wellbeing and early diagnosis is very important. Sometimes AFLP can be confused with fulminant liver failure due to viral hepatitis. A history of exposure to an individual the hepatitis and viral serologic testing are the key in making the diagnosis in these cases. The degree of transaminase elevation is much higher in patients with acute viral hepatitis than in AFLP and DIC is uncommon.

Clinical findings in AFLP vary and its diagnosis is complicated with significant overlap of clinical and laboratory features with the HELLP syndrome. Both conditions present in later terms of pregnancy in patients with background preeclampsia. Nevertheless, these two entities appear to be distinct on the grounds of both clinical hallmarks and histology. Presence of hypoglycemia and prolongation of prothrombin time is suggestive of AFLP [169]. Frank hepatic failure, although possible, is rare in HELLP syndrome. Also patients with preeclampsia associated liver disease and HELLP have more profound hematological abnormalities (see Table 5).

Histopathology is also different in these pathological processes. While extensive hepatocellular necrosis is virtually nonexistent in AFLP, it is a common histological feature of HELLP syndrome. Most commonly HELLP syndrome is characterised by periportal hemorrhages and fibrin deposits, whereas the histopathology of AFLP is characterised by microvesicular fatty infiltration [169, 173]. A mixed histological picture can be observed and it should be interpreted in clinical context.

Management

Prompt diagnosis is the key to a successful outcome in this severe and largely unpredictable condition [103]. Patients are usually very ill and require intensive care unit or hepatic failure unit hospitalization with multidisciplinary team management [173]. Timely delivery after initial patient stabilization is a cure, as in most pregnancy-associated liver diseases [171, 173, 176]. Depending on the presence of the complications, complete recovery from AFLP may take anywhere from days to weeks. Since clotting factors have short half-life, prothrombin time improvement is the first sign of recovery of hepatic function [3]. Patients may require dialysis for management of acute renal failure, or multiple transfusions for correction of coagulopathy, DIC, and anemia. Mechanical ventilation may be needed in patients with respiratory compromise. Intravenous infusion of 10% glucose solution may be needed for treatment of hypoglycemia that might be profound and severe. In general, if the patient does not succumb to complications, there are no hepatic sequellae postpartum after AFLP [177]. Rarely, liver transplantation is needed for management of severe acute hepatic failure in the setting of AFLP [178]. The mortality of patients with the AFLP dropped significantly with modern diagnostic capabilities, but morbidity remains very high [5, 171].

Pathogenesis

For a very long time the etiology and pathogenesis of AFLP remained a complete mystery. Recent data suggest that deficiencies in the enzymes of mitochondrial beta-oxidation of fatty acids (FAO) may play a role in the development of this condition. It has been observed that maternal liver disease occurs in 16% of pregnancies with FAO defects compared with 0.88% in general population [179, 180]. The precise mechanism by which FAO enzyme deficiencies cause AFLP is not known. It has been hypothesized that a heterozygous mother who is carrying a homozygous fetus with FAO enzyme deficiency develops AFLP as a result of an impaired maternal ability to handle an increased load of fatty acids due to pregnancy-associated increase in lipolysis. The most commonly reported enzyme deficiency associated with AFLP is a long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. The defect is present in the alpha-subunit of the mitochondrial trifunctional protein (MTP) and is associated with G1528C or E474Q mutation [169, 180, 181]. It has been observed that approximately one in five women with AFLP may carry a fetus with LCHAD deficiency [169]. There are a few reports that suggest that other enzymes of FAO may be involved as well [179, 182]. Fetal hepatic carnitine palmytoiltransferase (CPT I) deficiency was reported to cause maternal AFLP in two successive pregnancies. CPT I deficiency usually presents as a Reye’s-like syndrome in children ages 8–18 months. There is one case report of recurrent AFLP and hyperemesis gravidarum in two successive pregnancies in a patient whose offspring were diagnosed with CPT I deficiency [183]. A different author reported pre-existing undiagnosed maternal medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the patient with AFLP, who delivered a baby without enzyme abnormalities [182]. The results of a study that looked at the incidence of maternal liver disease in pregnancies with fetal FAO defects suggested that fetal long-chain defects are 50 times more likely to develop a liver disease in pregnancy when compared with healthy controls; and short- and medium-chain FAO defects are 12 times more likely to develop liver disease [179]. Overall, the prevalence of maternal liver disease in all fatty acid oxidation defect pregnancies was 16%, compared with the general population 0.88% [179].

There are reports suggesting that FAO defects may be associated with hyperemesis gravidarum as well [183]; data regarding HELLP syndrome is contradictory [179, 181, 184].

Recommendations

The strong association of the AFLP with LCHAD deficiency in the fetus suggests a necessity of neonatal testing for enzymatic defects of FAO. Testing for known genetic variants of LCHAD deficiency is available and should be utilized in affected patients and their family [180, 181]. These genetic defects are autosomal recessive, and the chance of reoccurrence in subsequent children is 25%. Neonatal LCHAD deficiency presents with Reye-like syndrome and is potentially lethal by 6 months of age if left untreated. Early diagnosis and dietary intervention is lifesaving. Genetic counselling for the family is needed. In addition, there are other forms of FAO defects that present as cardiomyopathy and neuromuscular degenerative disease. In the subsequent pregnancy, patients with a history of AFLP should be monitored by high-risk pregnancy experts, since reoccurrence of the condition is possible in subsequent gestations [169].