Liver diseases unique to pregnancy

Best Practice & Research Clinical Gastroenterology Vol. 21, No. 5, pp. 771–792, 2007 doi:10.1016/j.bpg.2007.05.004 available online at http://www.sciencedirect.com

2 Liver diseases unique to pregnancy Vivian A. Schutt *

MD

Assistant Professor Department of Obstetrics and Gynecology, University of Buenos Aires, Buenos Aires, Argentina

Gerald Y. Minuk1

MD. FRCP

Professor of Medicine and Pharmacology and Therapeutics Department of Medicine, University of Manitoba, Health Science Centre, John Buhler Research Centre, Room 803F-715 McDermot Avenue, Winnipeg, Manitoba R3E 3P4, Canada

Liver injury and dysfunction in a pregnant woman may be caused by intrinsic features of the pregnancy itself, disorders that are coincidental with pregnancy or pre-existing liver disease that is exacerbated by pregnancy. The clinical setting, gestational age and standard liver biochemistry testing are useful tools in helping to establish a diagnosis. Prompt recognition of the signs of liver disease in pregnant patients leads to timely management and may save the life of both mother and baby. This review summarises the incidence, risk factors, pathogenesis, clinical presentation, diagnosis, treatment and outcome of those liver diseases unique to pregnancy. Key words: Pregnancy; Liver; Hyperemesis gravidarum; Vomiting; Dehydration; Weight loss; Intrahepatic; Cholestasis; Cholestatic; Bile acids; MDR3; ABCB4; Itching; Pruritus; Icterus; ALT; AST; Cholestyramine; Ursodeoxycholic acid; Vitamin K; Antipruritics; Preeclampsia; Eclampsia; Hypertension; Edema; Proteinuria; HELLP; Hemolysis; Enzymes; Thrombocytopenia; Acute fatty liver; Fatty acids; Oxidation; E474Q; G1528C; Hypoglycemia; Budd-Chiari; Venous occlusion; Thrombotic; Thrombectomy; Hematoma; Rupture; Hepatic; Infarction.

INTRODUCTION Liver disease during pregnancy can be divided into disorders unique to pregnancy, those coincidental with pregnancy and pre-existing liver diseases exacerbated by pregnancy. This review will largely focus on those disorders unique to pregnancy. Readers * Corresponding author. University of Manitoba, Health Science Centre, John Buhler Research Centre, Room 806-715 McDermot Avenue, Winnipeg, Manitoba R3E 3P4, Canada. Tel.: þ1 204 977 5619; Fax: þ1 204 977 5693. E-mail addresses: [email protected] (V.A. Schutt), [email protected] (G.Y. Minuk). 1 Tel.: þ1 204 789 3529; Fax: þ1 204 977 5693. 1521-6918/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.

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are referred to recent reviews of liver disease coincidental with pregnancy and the impact of pregnancy on women with chronic liver disease for additional information on these topics.1,2 LIVER DISEASES UNIQUE TO PREGNANCY Hyperemesis gravidarum Intrahepatic cholestasis of pregnancy Peeclampsia/eclampsia HEELP (haemolysis, elevated liver enzymes, low platelets) syndrome Acute fatty liver of pregnancy Budd-Chiari syndrome Hepatic haematoma and rupture Hepatic infarction Primary hepatic pregnancy HYPEREMESIS GRAVIDARUM Definition Hyperemesis gravidarum (HG) can be defined as vomiting during pregnancy of sufficient severity to produce a minimum of 5% weight loss, dehydration, hypokalemia and metabolic acidosis or alkalosis.3 Incidence The reported incidence of HG ranges between 0.3 and 2% or approximately 1 in 100 pregnant mothers.4,5 HG is the most common indication for hospital admission during early pregnancy.6 Risk factors A number of risk factors have been associated with HG including: nulliparity, low maternal age, multiple gestation, foetal anomalies, previous pregnancy complicated by hyperemesis (although the risk here decreases with a change in paternity), female infant sex, psychiatric conditions, both high and low maternal pregnancy weight, hyperthyroidism, diabetes, asthma, long intervals between births, chronic liver diseases, history of oral contraceptive induced sickness, motion sickness, migraine headaches, and a positive family history of hyperemesis.5–9 On the other hand, smoking and advanced maternal age have been associated with a reduced risk of HG.4,6–8 Pathogenesis The precise pathogenesis of HG remains unclear but is thought to be multifactorial.4,10 One of the more common theories involves human chorionic gonadotrophin (hCG). The basis for the hCG hypothesis includes the following; (1) hCG is a potent stimulant of gastrointestinal tract secretion; (2) it mimics thyroid stimulating hormone and

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thereby induces a self limiting hyperthyroid state which can be associated with severe and protracted vomiting; (3) there is a temporal relationship between the onset of nausea and vomiting and hCG production (both peaking between 12 and 14 weeks); and (4) the nausea and vomiting of pregnancy are more pronounced in women with conditions associated with high hCG levels such as molar pregnancies, multiple gestation, Down’s syndrome and pregnancies of female foetuses. None-the-less, it must be noted that the correlation between hCG levels and severity of HG is not strong, perhaps reflecting the various biological activities of the different forms of hCG.3,10,11 Other somewhat less common factors implicated in the pathogenesis of HG are excess estrogen and/or progesterone levels,12 adrenal cortex insufficiency,13 an overactive immune system,14 Helicobacter Pylori infection,15 thyrotoxicosis,16 high intake of macronutrients (carbohydrates, fats, proteins and kilocalories), the consumption of certain foods (meat, fish, poultry and eggs more so than plant foods)17 and underlying psychological disorders.18 Clinical presentation The average gestational age for HG mothers admitted to hospital is 11.3 weeks.4 In addition to the nausea, vomiting, weight loss, dehydration and acid/base disturbances that by definition are uniformly present, an estimated 67% of HG patients have liver enzyme abnormalities. Typically, the enzyme abnormalities reflect an ischemic, hepatocellular injury pattern with more marked elevations of aspartate (AST) than alanine (ALT) aminotransferase levels. The enzyme abnormalities are most commonly found with late onset HG, in those with more severe ketonuria and when HG is associated with hyperthyroidism.5 They promptly return to normal when vomiting resolves and/or with restoration of adequate hydration and nutrition. When liver biopsies have been performed, either normal or non-specific findings have been described histologically.19 Complications of HG are rare but on occasion, can serve as the presenting complaint. These include; epigastric pain from oesophageal tears or rupture, left upper quadrant pain from splenic avulsion, shortness of breath from a pneumothorax and peripheral neuropathy due to vitamin B6 and/or B12 deficiency.20 Diagnosis The diagnosis of HG is based on the typical presentation described above and absence of other disorders that could explain these findings.10 The use of gestational age serves as the best guide to diagnosis as HG is the only pregnancy- related liver disease that occurs during the first trimester of pregnancy. Other conditions that warrant consideration include; gallstone disease, viral hepatitis, drug induced hepatitis and autoimmune disorders of the liver.2 With the exception of gallstone disease which unless associated with choledocholithiasis is not accompanied by liver enzymes abnormalities, the AST/ALT ratio in these other conditions tends to be less than one. Treatment The treatment of HG depends on the severity of symptoms. Mothers should be instructed to have frequent but small meals with high carbohydrate but low fat

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content. Foods with offensives odours should be avoided. Citrus drinks are better tolerated than water and can be useful for retching.3 Common antiemetics such as the phenothiazines (e.g. prochlorperazine, promethazine and chlorpromazine) reduce nausea and vomiting. Metoclopramide has also been used to treat HG by improving gastric emptying and correcting gastric dysrhythmias.21 Ondasetron has also been used but limited safety data area available for this agent.22 Antihistamines and anticholinergics such as meclizine and diphenhydramine may be tried.23 If nausea and vomiting do not respond to dietary modification and antiemetics, intravenous hydration and nutritional support may be necessary.24 Keeping the gut empty for the first 24 h is usually recommended. Initial intravenous therapy consists of crystalloid solutions (usually dextrose), normal saline, or Ringer’s lactate to correct dehydration, electrolyte deficiencies and acid-base disturbances. Multivitamin supplements should be added to the intravenous solutions for 24–48 h while the patient remains without oral intake. If dextrose solutions are used, thiamine should be administered to prevent Wernike’s encephalopathy. Parenteral thiamine supplementation is warranted in patients with severe HG lasting more than 3 weeks, especially those with abnormal liver function.19 In rare cases when neither oral nor enteral routes are available, total parenteral nutrition (TPN) has been used. However, TPN can be associated with serious complications and should be used sparingly.21,24 Outcome As a rule, HG resolves by the 20th week, regardless of therapy.19 In developing nations or where access to modern health care facilities is limited, HG has been associated with foetal growth retardation and deaths.6 The adverse infant outcomes with HG are a consequence of and mostly limited to women with poor maternal weight gain.25 Where access to modern health care is not an issue, the outcome from HG is good with no adverse effects for the mother and no increase in foetal prematurity or birth defects.2 The liver enzymes abnormalities associated with HG promptly resolve with rehydratation and/or resolution of the disorder.19 INTRAHEPATIC CHOLESTASIS OF PREGNANCY Intrahepatic cholestasis of pregnancy (ICP) is a benign cholestasic liver disorder of uncertain aetiology that most often develops during late pregnancy and almost invariable, resolves spontaneously after delivery of the foetus.26 Incidence The incidence of ICP varies depending on the patient’s genetic make-up, geography, and environmental factors. In populations where the risk is considered low such as North America and Southern Europe, the incidence is 1–2/1000 pregnant women. In high risk areas such as Chile, Bolivia, the Scandinavian countries and Poland, the incidence is 10 times higher.26,27 ICP is second only to viral hepatitis as the most common cause of jaundice during pregnancy.28

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Risk factors As indicated above, ICP is most common in Chile, Bolivia, The Scandinavian countries and Poland. It is also more frequent in older, multiparous women, in these with twin gestation and tends to occur most frequently during the winter months.27 As many as 40–69% of women with a history of ICP and those with cholestasis while on oral contraceptives will develop this condition. Those women with a positive family history for ICP and/or a family history of contraceptive-induced cholestasis are also at increased risk of developing ICP.26 Recently, ICP has been described in association with Acute Fatty Liver of Pregnancy (AFLP) but whether AFLP represents a true risk factor for ICP (or vice versa) remains to be determined.29 Pathogenesis Historically, ICP has been explained by the changes in serum estrogen and progesterone levels that occur during pregnancy.30 That high estrogen levels are of etiologic importance is supported by the fact that women with multiple gestations (a high estrogen state) have an increased risk of developing ICP. Moreover, estradiol acts on the basolateral membranes of hepatocytes to decrease membrane permeability and fluidity. This in turns leads to a decrease in Na/K ATPase pump activity, a decrease in the sodium gradient and thereby, less sodium-dependent bile acid transport by hepatocytes. By inhibiting glucuronyltransferase, (which results in impaired estrogen clearance by the liver), progesterone may amplify the cholestatic effects of the high estrogen state. Perhaps also relevant to the pathogenesis of ICP are differences in bile acid metabolism in women with this condition. Specifically, ICP women synthesise more sulphated progesterone metabolites which results in saturation of hepatic transport systems.31 Other potential etiologic factors include an increase in intestinal permeability to bacterial endotoxins, enhanced enterohepatic circulation of cholestastic metabolites of bile salts and sex hormones, dyslipidemia and low selenium concentrations.32,33 Most recently, researchers have focused on mutations that have been described in the hepatobiliary transport genes responsible for certain forms of genetic cholestasis. To date, mutations in the hepatic phospholipid transporters (MDR3, ABCB4), aminophospholipid transporter ATP8B1 and bile salt export pump (BSEP, ABCB11) have been reported in mothers with ICP. The most common of these is the MDR3 mutation which may account for up to 15% of all ICP cases.34,35 It should be noted however, that the patients described in these studies were heterogeneous with some being diagnosed during the first trimester of pregnancy while others had clear evidence of underlying chronic liver disease. Thus, it is conceivable that the mutations described may not have been responsible, and perhaps merely contributed to the cholestasis in these women.36 Finally, the pathogenesis of ICP may be a combination of hormonal, genetic and inflammatory factors that impair bile secretory function.30 Clinical presentation ICP usually presents during the third trimester of pregnancy, by the 30th week. The most common presenting complaint is moderate to severe itching without a rash.

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An estimated 80% of patients have pruritus alone while the remaining 20% have both pruritus and jaundice. The pruritus begins on the palms and soles and tends to extend proximally in an ascending pattern. It may be of sufficient severity that gross excoriations are present on physical examination. It is most prominent and irritating at night and if constant, sleep deprivation and irritability may ensue. Occasionally and perhaps because the same neuronal pathways are activated, the pruritus of ICP may mimic the sensation of pain or discomfort. Jaundice when it occurs develops 1–4 weeks after the onset of pruritus. ICP with jaundice but without pruritus is rare.26 Diagnosis In the earlier, mild stages (prior to hyperbilirubinemia) the biochemical findings of ICP can be difficult to appreciate. For example, the typical features of cholestasis (increased serum alkaline phosphatase and gamma glutamyl transferase (GGT levels) are often difficult to detect because of placental contributions to total serum alkaline phosphatase levels and decreased hepatic release of GGT during pregnancy. Indeed, only approximately 30% of ICP cases have been reported with elevated GGT levels.30 Serum ALT and AST activity is variable. In most ICP patients, ALT and AST levels are normal or only mildly elevated. However, on occasion they can be strinkingly abnormal to an extent that acute viral hepatitis and other causes of hepatocellular injury must be ruled out. The more marked elevations in serum ALT and AST levels may be caused by an unexplained increase in hepatocyte membrane permeability.36 Of more diagnostic value than serum liver enzyme determinations (although more difficult to obtain), are serum bile acid levels. These are markedly elevated in ICP with chenodeoxycholic acid and cholic acid levels being 10–100 times higher than levels reported in healthy pregnant women. Although not recommended, a liver biopsy will often reveal normal hepatic parenchyma or slight widening of the bile canaliculi.29,37 Recently, the measurement of serum glutathione-S-transferase, a marker of hepatocellular integrity, has been proposed to distinguish ICP from the non-liver related condition ‘benign pruritus gravidarum’.38 Treatment The treatment of ICP should be focused on reducing symptoms in the mother and providing adequate obstetrical management to prevent foetal distress. Mild pruritus may respond to emollients and topical antipruritics. Although antihistamines are rarely effective, an evening dose of hydroxyzine may help to alleviate itching and improve sleep. Cholestyramine and other cholesterol-lowering agents are considered the next line of treatment but recently, enthusiasm for the former has waned because of its limited efficacy and potential side effects which include constipation and vitamin K deficiency (two conditions that pregnant women are predisposed to developing). Ursodeoxycholic acid (UDCA) has been reported to be of value in the treatment of ICP.39 This agent should be considered in patients with moderate or severe pruritus, those that have failed to respond to earlier interventions and those with a history of ICP-related complications during previous pregnancies. UDCA may improve both the pruritus and biochemical evidence of cholestasis, particularly in patients with severe

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ICP.39 A synergistic effect may result from a combination of UDCA and S adenosyl-Lmethionine. The same combination has also been reported to improve foetal outcome by lowering premature-birth and stillbirth rates.40,41 When ICP is severe and non-responsive to the above measures, early delivery of the foetus is the only strategy to have been demonstrated to improve clinical outcomes. Delivery is usually delayed until 37–38 weeks of gestation to enable near complete maturation of the foetus, but should not be delayed if the mother or foetus exhibits signs of instability.29 Levels of bile acids have been proposed as a guide to clinicians on when to induce delivery. For example, the risk of foetal loss has been reported to increase substantially when fasting serum bile acid levels exceed 40 mM.37 Regardless of the agent selected for the treatment of pruritus, all patients with ICP should receive supplemental vitamin K therapy.26 The need for supplementation with other fat soluble vitamins (A, D and E) has yet to be demonstrated.42

Outcome Maternal outcomes from ICP are favourable. Signs, symptoms and laboratory abnormalities tend to resolve within days to 2 weeks after delivery. However, cases reports exist describing ICP that persisted for up to three months following delivery of the foetus.25,43 Recently it has been suggested that an association may exist between ICP and the subsequent development of severe, chronic hepatobiliary disease and cirrhosis.44 Whether these reports represent related or chance findings has yet to be determined but until resolved, it would be prudent to initiate long-term follow up with annual liver biochemistry testing (serum AST, ALT, alkaline phosphatase and GGT) in ICP mothers.44 Regarding the foetus, ICP can be associated with increased rates of preterm deliveries, perinatal mortality, intrapartum foetal heart dysrhythmias and meconium-stained amniotic fluid. The perinatal mortality can range from 11–20% with most deaths resulting from acute anoxic events rather than chronic utero-placental insufficiency (Table 1).39

PREECLAMPSIA/ECLAMPSIA Preeclampsia is considered part of a spectrum of conditions referred to as ‘hypertensive disorders of pregnancy.’ It can be defined as hypertension and proteinuria appearing after 20 weeks gestation and regressing in the post pregnancy period. There is no general agreement as to whether edema should be considered part of the diagnosis of preeclampsia. Preeclamptic mothers who develop seizures for otherwise unexplained reasons are considered to have progressed to eclampsia.45

Incidence Preeclampsia is relatively common, affecting 2–8% of all pregnancies.46

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Table 1. Summary: clinical presentation and outcomes from intrahepatic cholestasis of pregnancy. Clinical presentation Second or third trimester Generalised pruritus with no rash Marked increases in serum alkaline phosphatase and bilirubin levels Normal or slight increases in GGT levels

Maternal outcome

Foetal outcome

Pruritus and abnormal laboratory tests resolve with delivery Recurs with subsequent gestations (40e60%) Increased risk for caesarean delivery due to foetal compromise Can recur with the subsequent use of oral contraceptives and hormonal fluctuations

Increase risk for prematurity, stillbirth, spontaneous preterm labour and delivery, foetal compromise, foetal cardiac dysrhythmias, meconium stained amniotic fluid, and intrauterine foetal death

Mild increases in serum aminotransferase levels Marked increases in serum bile acid levels

Risk factors Risk factors for the hypertensive disorders of pregnancy include pre-existing hypertension, first pregnancy, multiple pregnancies, molar pregnancies, extreme childbearing ages and increased body mass index (BMI). There is also an increase in the frequency of preeclampsia in women with pre-existing medical conditions that are characterised by microvascular disorders such as diabetes, hypertension and collagen vascular diseases.47,48 Pathogenesis Preeclampsia/eclampsia is a multisystemic syndrome characterised by vasoconstriction, endothelial dysfunction, activation of coagulation cascades, metabolic changes, and increased inflammatory responses. The cause for these findings remains unclear. A common theory suggests that uteroplacental ischemia results in endothelial cell activation, initiation of various coagulation cascades, increased platelet adhesiveness and greater thrombogenicity. Elevated levels of nitric oxide, thromboxane, isoprostanes and lipid peroxidases, together with reduced prostacyclin 2 (PGI 2) levels may contribute to this increase in vascular sensitivity.47,49 Another theory involves abnormal placentation and excess placental production of the antiangiogenic soluble factor fms-like tyrosine kinase-1 (sFlt-1) and agonistic auto antibodies to the angiotensin II type 1 receptor.50,51 Genetic factors have been implicated on the basis of increased occurrences in females from the same family and documented compatibility in the human leucocyte antigen (HLA) between preeclamptic women and their spouses.52 Finally, other observations suggest an immune mediated cause with the placenta being considered the autoantigen.53 The pathogenesis of the liver injury in preeclampsia/eclampsia is believed to involve a combination of hepatic arterial vasospasm and precipitation of fibrin within the portal and periportal areas of the liver lobule. Together, these changes result in lobular ischemia and hepatocyte necrosis.50

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Clinical presentation The most common symptoms and signs of hypertensive disorders of pregnancy are persistent and severe headaches, visual disturbances such as blurred vision, diplopia and floating spots, epigastric pain, vomiting and peripheral edema. Seizures, strokes, cerebral edema and cortical blindness have also been reported. In the kidneys, cortical and medular necrosis have been described. Laryngeal and pulmonary edema may be manifestations of respiratory involvement. Disseminated intravascular coagulation and microangiopathic haemolysis can be seen on haematologic testing. Finally, radiological imaging of the placenta may reveal evidence of infarction and abruption.46 Diagnosis In addition to the symptoms and signs listed above, systemic blood pressures are increased beyond 140/90 mmHg. Typical laboratory findings include proteinuria (greater than 300 mg/day) or at least 130 mg/mmol of urine in a single specimen or greater than 1þ protein on dipstick, elevated serum creatinine levels, low platelet counts, evidence of microangiopathic anaemia and hyperuricemia (the latter being a more common finding in eclampsia than preeclampsia). Between 20% and 30% of women with preeclamsia/eclampsia have abnormal liver enzymes. Serum aminotransferase levels are most often elevated and tend to be in the mild to moderate range (1.5–5 normal), much less than those seen with HELLP, subcapsular bleeding or hepatic rupture. Serum alkaline phosphatase levels may be slightly elevated beyond the increases seen with pregnancy itself. Hepatic function (conjugated bilirubin, albumin and PT or INR levels) tend to remain unaltered.46 Liver histology shows deposition of fibrin in the hepatic sinusoids, periportal haemorrhage, hepatocyte necrosis and in severe cases, hepatic infarction.50 Treatment For mild to moderate hypertension, antihypertensive drugs will help prevent a hypertensive crisis. Women with severe hypertension should be admitted to hospital for prompt control of their blood pressure. Magnesium sulphate can be used to prevent and treat the seizures associated with eclampsia.46,54 Although the treatment of preeclampsis/eclampsia should extend beyond reducing blood pressure to include ameliorating the syndrome itself, no such agents have yet been developed. More success has been realised with preventive measures.47 Specifically, low dose aspirin reduces the risk of preeclampsia and calcium supplements have moderate benefits for women with low dietary calcium intake.46,54 Antioxidants have also been reported to decrease the incidence of preeclampsia. The liver condition associated with preclampsia/eclampsia tends not to be progressive and does not require specific therapy.55 Outcome Hypertensive disorders of pregnancy remain a leading cause of maternal and perinatal morbidity and mortality, particularly in developing nations.54 Although all laboratory abnormalities including liver enzyme and function tests tend to resolve with treatment

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of the hypertension, women with early onset and/or severe preeclampsia and those with recurrent preeclampsia should be considered at increased risk for future development of cardiovascular diseases.47,46,54,56 The most common complications from preeclampsia/eclampsia for the newborn are preterm birth, intrauterine growth restriction and death.46 Of note, after the first pregnancy with early onset preeclampsia, outcomes of subsequent pregnancies are generally favourable.56 HELLP SYNDROME The HELLP syndrome consists of haemolysis, elevated liver enzymes and low platelets. Although sometimes considered a complication of severe preeclampsia, HELLP has sufficiently unique features to be considered a distinct clinical entity.57 Incidence HELLP occurs in 0.1–0.6% of all pregnancies. Approximately 5–10% of women with severe preeclampsia experience HELLP.57,58 Risk factors Affected women tend to be older (mean age 25) than in those with preeclampsia alone. They also tend to be white, more often multiparous and have a past history of HELLP.57,59 Pathogenesis Like preeclampsia, the pathogenesis of HELLP is thought to involve aberrant placental development, activation of complement and coagulation cascades, increased vascular tone, platelet aggregation and alterations of the thromboxane-prostacyclin ratio. These changes induce generalised endothelial and microvascular injury resulting in microangiopathic haemolytic anaemia, periportal hepatic necrosis and thrombocytopenia.57,58 There are also data suggesting that HELLP represents a vasculophathy mediated by an abnormal concentration of vascular growth factors.60 The liver injury occurs as a result of intravascular fibrin deposition, vascular congestion and increased sinusoidal pressure.61 An alternative but not mutually exclusive explanation for the liver disease involves placental derived proteins. These yet to be identified proteins are thought to damage hepatocytes, in a manner analogous to that ascribed to the systemic inflammatory response syndrome (SIRS).58 Clinical presentation HELLP may present at any time during the second or third trimester of pregnancy. Approximately 20% of patients develop manifestations of HELLP within two days after delivery. Of these, 90% have antepartum preeclampsia. Most patients present with flu like symptoms, malaise, nausea, vomiting and right upper quadrant pain or discomfort. In 20% there is no hypertension. If hepatic haemorrhage occurs, the patient may also complain of neck and shoulder pain due to diaphragmatic irritation.57

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Other presenting problems can include disseminated intravascular coagulation, abruptio placentae, acute renal failure, pulmonary edema and hepatic rupture.58 By definition, signs of haemolysis, elevated liver enzymes and low platelet counts are consistent laboratory findings. The haemolysis is manifest by characteristic schistocytes and burr cells on peripheral blood smear. The liver enzyme abnormalities consist of increases in serum aminotransferases (AST/ALT >1) reflecting impaired hepatic perfusion.2,60 Hepatic function (albumin, conjugated bilirubin and PT/INR) tend to be preserved. Thrombocytopenia may be modest to severe.60 On liver biopsy periportal and focal parenchymal necrosis is present on liver biopsy. In advanced cases, hepatic necrosis and haemorrhage can lead to hepatic rupture.60 Treatment Blood pressure control and seizure prophylaxis are important therapeutic measures but definitive treatment consists of delivery of the foetus. If the patient is far from term (less than 34 weeks), conservative management should be employed.68 Antenatal and/or postpartum corticosteroids have been recommended for improvement or at least stabilisation of the clinical and laboratory abnormalities.58 Although steroid treatment is not considered curative it may provide sufficient stabilisation for further foetal maturation.61 Outcome Maternal mortality ranges between 1 and 3.5%. The majority of these deaths result from haemorrhage and shock. Only rarely is the cause of death liver failure.62 Most patients require careful observation for 48 h post delivery. During this time, haematologic parameters in particular should be monitored.57 Perinatal morbidity and mortality rates are higher with HELLP complicated by severe preeclampsia, primarily because of the required preterm delivery of the foetus. Foetal outcomes are more related to gestational age at delivery than the severity of HELLP in the mother.58 The risk of recurrent HELLP in subsequent pregnancies is 2–6%.59 ACUTE FATTY LIVER OF PREGNANCY Acute fatty liver of pregnancy (AFLP) is a rare but often serious condition that occurs in the third trimester of pregnancy. Emerging data suggest that at least a portion of AFLP may result from defects in maternal and foetal fatty acid metabolism. The condition carries a significant maternal and perinatal mortality. Early diagnosis and appropriate therapy can improve the prognosis.63 Incidence The incidence of AFLP has been estimated to be 1:10,000–15,000 pregnancies.46 However, this likely represents an underestimate as women with AFLP are often diagnosed with other liver diseases that share similar presentations such as HELLP and pregnancy induced hypertension (PIH).64

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Risk factors Approximately 15–20% of AFLP pregnancies are multiple. AFLP is also more common in the setting of male pregnancies, preeclampsia, and primiparas women. However, AFLP can occur after many uneventful pregnancies. The disorder affects women of all ages and races. There are no epidemiologic features that implicate a specific geographic area or ethnic group. The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased risk of developing AFLP.65

Pathogenesis Recent molecular advances suggest that AFLP may result from mitochondrial dysfunction in the foetal liver. Compared to healthy newborn controls, long chain fatty acid oxidation defects are 50 times and short or medium chain defects 12 times more common in the foetuses of mothers with AFLP.66 Of particular importance is a defect in long chain fatty acid oxidation which has been linked to a deficiency in the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). LCHAD is one of four enzymes responsible for breaking down long-chain fatty acids within the mitochondria of cells. A deficiency in its activity results in an increased accumulation of long-chain fatty acids in the foetal followed by maternal circulation. Because the mother is heterozygote for this enzyme, her liver’s ability to metabolise long chain fatty acids is impaired and hepatotoxicity ensues. The most common mutation responsible for the LCHAD deficiency is a G to C mutation at nucleotide position 1528 (E474Q amino acid substitution) E474Q mutation in 20% of cases. This mutation exists on chromosome 2 and results in altered mitochondrial trifunctional complex activity. To date, AFLP has been documented in 30–80% of pregnancies where the foetus was found to have an LCHAD deficiency. It remains unclear as to why some mothers who give birth to a child with fatty acid oxidation defects develop AFLP whereas others do not. Also unclear is why surviving homozygous infants born to mothers with AFLP do not develop significant liver disease either in utero or thereafter.64,65

Clinical presentation The onset of AFLP occurs between the 30th and 38th weeks of gestation. Only rare reports exist of AFLP occurring prior to or following this gestational age. The initial manifestations are non-specific. The most common symptoms include anorexia, nausea and vomiting (70%) and upper abdominal pain (50–80%). Thereafter, signs and symptoms of acute liver failure appear. However, only a minority of patients will develop jaundice. The size of the liver is initially normal or only slightly enlarged but as the condition progresses, it can become small on physical examination.65–67 Approximately 50% of patients have signs of preeclampsia.68 AFLP patients may also present with upper gastrointestinal haemorrhaging (due to portal hypertension and coagulation abnormalities), acute renal failure, sepsis, pancreatitis, hypoglycaemia or metabolic acidosis. Hepatic encephalopathy tends to occur late in the disease.67

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Diagnosis AFLP patients have only moderately elevated serum aminotransferase levels with ALT exceeding AST values. Serum alkaline phosphatase levels are mildly elevated but can be as high as 3–4 times normal. The plasma ammonia level may also be elevated.65 Hypoglycemia occurs in up to 40% of cases. Peripheral blood smears reveal a normocytic anaemia, slightly increased white blood cell counts and mild thrombocytopenia. Disseminated intravascular coagulopathy is relatively common. Prothrombin (PT) and partial thromboplastin (PTT) times are prolonged and plasma fibrinogen levels decreased. Blood urea nitrogen and creatinine levels tend to be elevated as are uric acid levels. The tendency towards hypoglycaemia, hyperammonemia and prolongation of PT and PTT times help to distinguish AFLP from HELLP.67,69,70 The diagnosis of AFLP can be confirmed by liver biopsy. Histologically, it is characterised by microvesicular fatty infiltration of the liver (seen to advantage by Oil Red O staining) without associated inflammation or necrosis. The microvesicular fatty infiltration is most prominent in the pericentral and mid-zones of the liver (acinar zones 2 and 3) and usually spare periportal (zone 1) cells. However, a liver biopsy is not routinely performed because of the advanced stage of the pregnancy and frequently associated coagulopathy. Ultrasound, computerised tomography and magnetic resonance imaging have been utilised as non-invasive tools for diagnosing AFLP but their value remains limited with false negative results being most common. Indeed, a recent study revealed that computed tomography findings were normal in 50% of patients with AFLP.70 Thus in clinical practice, particularly when severe cases can often be diagnosed on the basis of the clinical presentation and results of routine laboratory testing, the decision to deliver the foetus should not be delayed by the time required to obtain or the results of these radiologic examinations.70 On occasion, the diagnosis of AFLP can be difficult to distinguish from acute viral hepatitis and viral serology is required.64,65,67 Treatment AFLP is a medical and obstetrical emergency. Early recognition and treatment can improve both maternal and foetal survival. The cornerstone of treatment is prompt delivery of the infant. Appropriate supportive measures (blood transfusions, glucose administration, etc.) are required while preparing for foetal delivery.70 If the patient is at high risk for multisystem organ failure, admission to the intensive care unit is warranted. Liver transplantation has been performed in mothers with AFLP but only rarely and most often in the setting of continued deterioration despite delivery of the foetus.71 An earlier aspect of treatment is recognition and close observation of high risk mothers. Women with a history of AFLP and those with a child diagnosed with a fatty acid oxidation defect disorder or who died unexpectedly or with Reyes syndrome-like illness during their first two years of life should be referred promptly to a high-risk obstetrician and gynaecologist and genetic specialist for screening and counselling. At risk women should be instructed to maintain a high-carbohydrate, low fat diet. Fasting should be avoided as should the use of NSAIDS, salicylates, tetracyclines and valproic acid as each of these agents may interfere with oxidation of fatty acids.64 Regarding the infant, screening for LCHAD deficiency should be performed on all babies born to mothers with a diagnosis of AFLP. Those who are positive for reducing substances in the urine should undergo formal genetic testing. These babies should

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also be managed with high carbohydrate, low fat diets and not allowed to fast for more than four hours.72 Outcome Over the past 50 years, maternal mortality rates from AFLP have decreased from 85% to less than 5%.67,68 Identifying women at risk, early detection of AFLP and prompt intervention are thought to be responsible for the improved outcome.66,72 However, foetal mortality rates remain high (23%–66%). Surviving children born with LCHAD deficiency may develop, cardiomyopathy, hypoglycaemia or sudden death. Hepatic failure can also occur but is rare. Later presentations in these children include failure to thrive, episodic myopathy, neuropathy, retinopathy and cardiac arrhythmia. Several reports have documented recurrence of AFLP.63–65,68,73,74 BUDD-CHIARI The Budd-Chiari syndrome or hepatic vein occlusion occurs as a result of thrombotic or non-thrombotic obstruction of the hepatic venous system. The obstruction may develop at any point along the vascular tree from terminal hepatic venules to the left atrium of the heart.75–79 Incidence The incidence of Budd-Chiari syndrome in pregnancy is unknown.75–78 Risk factors Women with an underlying hypercagulable state are at increased risk of developing the Budd-Chiari syndrome during pregnancy.76 Pathogenesis As indicated above, in many instances an underlying hypercoagulable state exists. Hypercoagulability due to estrogen excess has been suggested. During pregnancy there is also a reduced concentration of the anti-coagulants protein C and S which predisposes to hypercoagulation. Several other reports suggest that the Budd-Chiari syndrome in pregnancy is associated with an underlying procoagulant state such as occurs in the presence of antiphospholipid or anticardiolipin antibodies, factor V Leiden mutations or polycythemia vera.77 Clinical presentation The Budd-Chiari syndrome can occur at any time during pregnancy or in the early puerperium. It can present as fulminant, acute, subacute or chronic hepatitis. Less commonly, it will present as inactive cirrhosis (months or years following delivery). An acute presentation is more common in women than men who develop this condition. The clinical presentation is dependent on the rate and extent of venous occlusion. Most often, pain in the upper abdomen is rapidly followed by abdominal

Liver diseases unique to pregnancy 785

distention and the development of ascites. Fever, vomiting, and jaundice may occur but are not as frequent.76,79 Diagnosis The diagnosis of Budd-Chiari syndrome can be established by non-invasive procedures. Most helpful are Duplex colour flow Doppler ultrasonography and magnetic resonance imaging. Liver biopsies can also be helpful but are rarely performed. A centrilobular zonal congestion with haemorrhage and necrosis are characteristic histologic findings.76,77 Treatment Direct surgical thrombectomy and thrombolitic therapies are rarely successful because of the extent of the thrombosis and difficulty in exposing the hepatic veins. Transjugular intrahepatic portal systemic (TIPS) or surgical side-to-side portacaval shunts ameliorate the portal hypertension and ascites. These interventions are recommended for patients with stable liver function. Orthotropic liver transplantation should be offered to those with fulminat hepatic failure or end stage chronic liver disease.75 Non-transplant candidates must be managed more conservatively with supportive care and treatment of the underlying cause for the thrombosis.79 Outcome The course of patients with major occlusions of the hepatic venous system is one of rapid deterioration, development of portal hypertensive bleeding, high protein content ascites, hepato-renal syndrome and/or hepatic encephalopathy. Rarely, patients with chronic Budd-Chiari syndrome will remain clinically stable for up to 22 years.75,79 HEPATIC HAEMATOMA AND RUPTURE Hepatic haematoma leading to spontaneous rupture of the liver is a catastrophic event in pregnancy resulting in high maternal and foetal mortality rates.80,81 Incidence The highest incidence of spontaneous rupture of the liver is in women with HELLP where rates are approximately 1%. The incidence associated with other causes of hepatic haematoma and rupture are unknown.1 Risk factors The majority of hepatic haematoma and ruptures result from complicated courses of preeclampsia, eclampsia, HELLP and rarely AFLP. Most women (88%) are multiparous.1,81,82 Clinical presentation The average age of women with hepatic haematoma and rupture is 32 years.1 Although the majority of ruptures occur in the late second or third trimester of pregnancy,

786 V. A. Schutt and G. Y. Minuk

some cases have been reported in the postpartum period. Typically, the rupture results from a subcapsular haematoma involving the right lobe. The initial symptom is related to haematoma induced stretching and irritation of the liver capsule and/or diaphragm, with pain in the right upper quadrant or right lower chest. If the expanding haematoma causes the capsule to rupture, free haemorrhage occurs into the peritoneum. At this point, the patient presents with severe pain, abdominal distension, perhaps shoulder pain, pleural effusions, a shock-like state and often a dead foetus. After resuscitation, the hypertension frequently associated with the underlying condition may become evident.48,83 Diagnosis The diagnosis of haematoma of the liver requires imaging of the abdomen. Ultrasonography may demonstrate the collection of the blood but more complete information such as impending or early rupture can be gained by computed tomography or magnetic resonance imaging. Hemoperitoneum can be confirmed by peritoneal aspiration. During the development of haematoma, biochemical evidence of ischemic hepatocellular liver injury is evident (AST/ALT >1) Once developed, extrinsic compression of adjacent bile ducts by the haematoma may result in a more cholestatic enzyme pattern.1,84 Treatment If the patient has a hepatic haematoma without rupture, conservative management and observation in an intensive care unit (ICU) is the management of choice. ICU management should involve close monitoring of the patient’s hemodynamic and coagulation status. If the capsule has ruptured, immediate surgery is warranted. Resuscitation should consist of blood transfusions and correction of the coagulophathy with fresh frozen plasma and platelets. Many options have been described at laparotomy including packing with gelform or an omental pedicle and drainage. Others have suggested surgical ligation or radiologic embolization of the hepatic artery that involve the affected segment. To date, data do not favour one therapeutic intervention over another.82,83 Outcome Even with appropriate treatment, maternal and foetal mortality rates from a ruptured haematoma remain at approximately 50%. Recurrence of hepatic haematoma has also been reported.82,83 HEPATIC INFARCTION Another clinical scenario associated with preeclampsia and HELLP is hepatic infarction. Mothers with the anti-phospholipid antibody syndrome are at increased risk of developing this complication of pregnancy.84 Affected patients present with fever and abdominal pain. Laboratory testing reveals thrombocytopenia and marked elevations in serum aminotransferase levels (AST/ALT >1). Hepatic failure can occur in more severe cases. Hepatic infarction should be considered in preeclamptic patients who present with acute abdominal pain and biochemical evidence of acute, severe hepatitis.85 CT scanning is the diagnostic method of choice revealing punched-out, poorly vascularised areas, often in more than one lobe of the liver.86

Liver diseases unique to pregnancy 787

The histology of hepatic infarction consists of intralobular haemorrhage with neutrophilic infiltration of the areas adjacent to the infarction. Prompt delivery of the foetus is indicated as is supportive care in the ICU. Continuous hemodiafiltration in conjunction with corticosteroid therapy has been reported to improve maternal outcome in severe cases.87

PRIMARY HEPATIC PREGNANCY On rare occasions, the inferior surface of the right lobe of the liver is the site for ectopic pregnancy implantation. Patients with this condition may present early in gestation with hemoperitoneum resulting from hepatic haemorrhage. If the pregnancy progresses, the patient may present with a mass in the liver. Primary hepatic pregnancy can be diagnosed by careful physical examination, ultrasound, computed tomography or magnetic resonance imaging. Termination of the pregnancy during laparotomy is recommended in view of the high risk of hepatic rupture.88

SUMMARY Although liver diseases unique to pregnancy are uncommon, they should always be suspected because of the potential for acute liver failure and mortality in both mother and foetus. One of the more useful diagnostic tools is the gestational age at the time of onset of the liver disease with HG beginning in the early part of the first trimester, ICP not until the second or third trimester, preeclampsia during the second half of the pregnancy and HELLP/AFLP in the third trimester or post partum. Hepatic infarction, haematoma and rupture are more common complications of preeclampsia and HELLP syndrome and therefore, tend to occur in the latter half of pregnancy. Finally, the Budd-Chiari syndrome can occur at any time during pregnancy. Other diagnostic clues include the pattern of liver enzymes abnormalities. HG, preeclampsia, HELLP, AFLP, hepatic infarction and the Budd-Chiari syndrome tend to present with an hepatocellular injury pattern (serum aminotransferases elevated to a greater extent than alkaline phosphatase levels) while ICP and occasionally, hepatic haematoma present as predominantly cholestatic disorders. Further refinement of the differential diagnosis can come from consideration of the AST/ALT ratio. A ratio greater than one suggests ischemic liver injury as occurs with HG, preeclampsia, HELLP, hepatic infarction and the Budd-Chiari syndrome while a ratio less than one is in keeping with AFLP or non-pregnancy related conditions such as viral, drugs or autoimmune hepatitis. Assessment of pregnant women with liver disease may also require imaging of the liver. Here ultrasonography is the imaging modality of choice because of its safety, accessibility and relatively low cost. Regarding treatment, drug therapy is often required and clinicians need to be familiar with which drugs are safe and which are potentially dangerous during pregnancy. In most instances, delivery of the foetus is the most effective therapeutic intervention available. In conclusion, the liver diseases unique to pregnancy their incidence, presentation, diagnostic findings, treatment and outcome are summarised in Table 2.

HG Incidence Presentation

<2% st

1 trimester

Symptoms Nausea vomiting and complications Ketosis

Laboratory

ICP

Preeclampsia/eclampsis

HELLP

AFLP

<10%

2e8%

0.1e0.6%

1:10,000e15,000

3rd trimester

2nd or 3rd trimester

2nd or 3rd trimester or after delivery

3rd trimester

Pruritus Jaundice

High blood pressure Proteinuria Edema Seizure Renal Failure Pulmonary Edema Hepatic haematoma/rupture

Abdominal pain Renal dysfunction Hypertension Hepatic Hematoma/rupture Liver infarction

Nausea/vomiting Abdominal pain Jaundice Hepatic failure

Low platelets Proteinuria increased uric acid

Low platelets Hemolysis Markedly elevated aminotransferases

Low platelets Hypoglycemia Mild-moderate elevated aminotransferases

Prompt delivery

Prompt delivery

Elevated Increased serum alkaline aminotransferases phosphatase and bile acid levels

mildly elevate aminotransferases Treatment

Supportive

Delivery at foetal maturity Ursodeoxycholic acid

Blood pressure control

Outcome

Benign for mother and foetus

Subsequent increase in liver and Maternal death rate 1% biliary tract disease may recur with subsequent pregnancies. No increase in maternal No increase in foetal death rate. death rate Prematury foetal death rate 11e20%.

Maternal death rate 3.5% Maternal death rate <5%

Foetal death rate 1e30% Foetal death rate 1e23%

788 V. A. Schutt and G. Y. Minuk

Table 2. Liver diseases unique to pregnancy.

Liver diseases unique to pregnancy 789

Clinical practice points  restoration of fluid balance will result in normalisation of the liver enzyme abnormalities associated with hyperemesis gravidarum  stepwise progression from applied creams to antihistamines to ursodeoxycholic acid to serotonin reuptake inhibitors to delivery of the foetus should be considered for intrahepatic cholestasis of pregnancy  the foetus should be delivered when HELLP/AFLP progresses to biochemical evidence of hepatic dysfunction (increases in serum conjugated bilirubin or PT/INR)  expectant management and supportive measures are required for liver haematoma but surgery should be consulted for impending or established hepatic rupture  the Budd-Chiari syndrome should be considered in the differential diagnosis of acute or fulminant hepatitis in pregnant women

Research agenda  define the prevalence of those genetic mutations that have been implicated in the pathogenesis of ICP and HELLP/AFLP  develop long term follow-up studies to document the prevalence and nature of liver disease in AFLP mothers and their offspring  identify a sensitive and specific test for predicting the progressive form of HELLP/AFLP  develop prospective trials that target the elevated levels of moderate- and long-chain fatty acids as treatment for HELLP/AFLP

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