Maternal and Perinatal Outcome in Severe Pregnancy-RelatedLiver Disease

STEPHEN P. PEREIRA,1 JOHN ODONOHUE,2 JULIA WENDON,2 AND ROGER WILLIAMS2

Acute fatty liver of pregnancy (AFLP) and the syndrome of tic liver infarction or rupture, are even rarer and also oftenfatal.3,5,6 Causes of liver failure unrelated to pregnancy mayhemolysis, elevated liver enzyme levels, and low platelet

count (HELLP) are rare but major disorders of the third tri- also present during this time and may be difficult to distin-guish from severe pregnancy-related disease.1,5 Before 1980,mester of pregnancy. Over a 10-year period, 46 women (me-

dian age, 30 years; range, 17-41 years) developed hepatic maternal and infant mortality rates associated with AFLPwere generally greater than 80%,7 with reported figures fordysfunction severe enough to require transfer to our Liver

Failure Unit. Three quarters of the women were nulliparous, HELLP syndrome of approximately 25%.8 In more recentseries, maternal and infant mortality rates for AFLP andand 5 had twin pregnancies; the median gestational age was

35 weeks (range, 24-40 weeks). At admission, 32 patients HELLP syndrome have been less than 20%, although mostof these studies have involved small numbers of patients,(70%) were preeclamptic and 21 (46%) were encephalopathic

and/or ventilated. Thirty-two patients (70%) had clinical fea- often with only minor degrees of liver impairment.3,9

The aims of the present study were to describe the clinicaltures and laboratory values consistent with AFLP, and 7(15%) had HELLP syndrome. One patient had preeclamptic features, complications, and maternal/perinatal mortality in

a large group of 46 patients seen in a single center over aliver rupture requiring liver transplantation. In 6 other pa-tients, causes of severe liver dysfunction unrelated to preg- 10-year period, who presented with hepatic dysfunction in

late pregnancy severe enough to require admission to a Livernancy were found. Infectious complications occurred in 17 ofthe patients with AFLP (53%) and in 2 of those with HELLP Failure Unit.syndrome (29%). Major intra-abdominal bleeding occurred in

PATIENTS AND METHODS12 women (10 with AFLP), 9 of whom required laparotomiesPatients. The Liver Failure Unit of Kings College Hospital is afor clot evacuation. Four patients with AFLP (12.5%) had a

tertiary intensive care unit that accepts approximately 200 patientsfatal outcome, with a corresponding perinatal mortality ratewith acute liver failure per year. In recent years, acetaminophin-of 9%. There were no maternal or perinatal deaths associatedinduced acute liver failure has accounted for approximately twowith HELLP syndrome. In contrast to results of many previousthirds of admissions, with pregnancy-related liver disease responsi-

studies, the results of this large series suggest a relatively ble for less than 5% of cases. Over a 10-year period from April 1986favorable maternal and perinatal outcome in severe AFLP and to December 1996, a total of 46 women (median age, 30 years;HELLP syndrome. Further improvements in outcome are range, 17-41 years) who developed severe hepatic dysfunction inlikely to be achieved through the prevention of the bleeding late pregnancy were transferred to the Liver Failure Unit. The

HELLP syndrome was defined according to standard criteria4,10; theand infectious complications associated with these disorders.diagnosis of AFLP was based on the development of jaundice in(HEPATOLOGY 1997;26:1258-1262.)the third trimester of pregnancy together with features of acute liverfailure, such as coagulopathy, hypoglycemia, and/or encephalopa-Preeclampsia and the associated HELLP syndrome (he-thy, whether or not preeclampsia was present. Causes of severe liver

molysis, elevated serum liver enzyme levels, and low blood dysfunction unrelated to pregnancy, such as acute viral hepatitis orplatelet count), as well as the rare acute fatty liver of preg- fulminant autoimmune hepatitis, were excluded. In thrombocytope-nancy (AFLP), represent major causes of maternal and peri- nic patients, laboratory evidence of disseminated intravascular coag-natal morbidity and mortality. AFLP occurs in approximately ulation (including low fibrinogen concentrations, positive fibrin

degradation products, and prolonged prothrombin and partial1 in 13,000 pregnancies compared with 1 to 6 per 1,000thromboplastin times) was also sought. In all patients, Dopplerdeliveries for the HELLP syndrome,1-4 and it usually resultsultrasonography of the liver was performed at admission and whenin a more severe degree of liver impairment. Other complica-clinically indicated thereafter. Abdominal computed tomographytions of the third trimester of pregnancy, such as preeclamp-was requested when major intra-abdominal bleeding was suspectedand laparotomy was being considered. In cases of diagnostic uncer-tainty, a liver biopsy was performed.

Methods. Patient care followed a standard protocol for acute liverAbbreviations: HELLP, hemolysis, elevated liver enzyme levels, and low plateletcount; AFLP, acute fatty liver of pregnancy; INR, international normalized ratio; failure. Central venous access was obtained via the internal jugularLCHAD, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase. route, and central venous pressures were maintained between /10

From the 1Gastroenterology Unit, Guys Hospital, London, and the 2Institute of and /14 mm Hg with infusion of 4.5% human albumin solution.Liver Studies, Kings College School of Medicine and Dentistry, London, UK. Dopamine was infused if oliguria persisted despite adequate intra-

Received March 7, 1997; accepted June 17, 1997.vascular filling, and intermittent venovenous hemodiafiltration was

Address reprint requests to: R. Williams, M.D., Institute of Hepatology, Universityinstituted in anuric or oliguric patients with a serum creatinineCollege London Medical School, 69-75 Chenies Mews, London WC1E 6HX, UK.level of 400 mmol/L. A pulmonary artery flotation catheter wasFax: 44-171-380-0405.inserted, and inotropic support with adrenaline or noradrenalineCopyright q 1997 by the American Association for the Study of Liver Diseases.

0270-9139/97/2605-0026$3.00/0 was commenced in any patient with a mean arterial pressure of

1258

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HEPATOLOGY Vol. 26, No. 5, 1997 PEREIRA ET AL. 1259

TABLE 1. Clinical Features and Laboratory Values at Admission in to the 7 patients with HELLP syndrome, only 16 of the 32Patients With AFLP or HELLP Syndrome with AFLP (50%) had preeclampsia (P .02), a condition

complicated by seizures in 4 patients. At admission, 14 pa-HELLPAFLP Syndrome tients (44%) were in grade I-II encephalopathy, and 6 others

(n 32) (n 7) (19%) were mechanically ventilated. All were clinically jaun-diced, with a median bilirubin concentration of 142 mmol/LMedian age, yr (range) 30 (17-40) 31 (23-41)

Week of gestation 36 (28-40) 34 (27-38) (range, 63-646 mmol/L), a significantly higher level than inNo. with preeclampsia (%) 16 (50)* 7 (100)* those with HELLP syndrome (P .01). Eighteen patientsNo. encephalopathic/ventilated (%) 20 (63)* 1 (14)* (56%) were hypoglycemic. All but 1 patient (97%) had anPlatelet count (normal, 150-450 1 109/L) 123 (26-262)* 39 (19-89)* elevated serum creatinine concentration, 16 of whom re-Creatinine (normal, 45-120 mmol/L) 245 (99-758) 102 (63-526) quired renal support with dopamine and/or continuous veno-Bilirubin (normal, 3-20 mmol/L) 142 (63-646)* 34 (19-124)*

venous hemodiafiltration. Twenty-nine patients (91%) had aAST (normal, 10-50 IU/L) 99 (25-911) 342 (60-328)raised INR (median, 1.7; range, 1.0-3.4) despite fresh-frozenAlkaline phosphataseplasma support in most cases. At admission, the median(normal, 30-150 IU/L) 293 (92-716) 126 (61-526)platelet count of 123 1 109/L was significantly higher (Pg-Glutamyl transferase

(normal, 5-55 IU/L) 67 (16-237) 28 (13-87) .01) than that associated with HELLP syndrome, but itdecreased to a median of 53 1 109/L (range, 16-163 1 109/

* P .01, AFLP vs. HELLP syndrome.L) at day 2, usually in association with other features of acuteliver failure, bacterial sepsis, and/or disseminated intravascu-lar coagulation. Overall, 29 (91%) of the AFLP group devel-

60 mm hg despite adequate intravascular filling. Broad-spectrum oped thrombocytopenia at some point during their admissionantibiotics were administered intravenously. In preeclamptic pa- (Table 1). Eleven of the 32 patients underwent liver biopsytients, hydralazine or nifedipine was used to control hypertension, a median of 18 days after admission (range, 5-40 days), whichand magnesium sulfate was infused.11 Fresh-frozen plasma and

confirmed the diagnosis of AFLP in all instances.platelets were also given to maintain an international normalizedThe patients with AFLP also had a greater number of com-ratio (INR) of 1.5 and a platelet count of 50 1 109/L. Since

plications than did those with HELLP syndrome, although1990, the standard regimen has also included intravenous N-acetyl-cysteine to maintain microcirculatory flow.12,13 the median hospital stay of 11 days was identical in the two

Data are expressed as medians with ranges. The significance of groups. Infectious complications with sepsis syndrome and/differences in results between groups was tested with Students t or laboratory evidence of disseminated intravascular coagula-test (two-tailed) or the Mann-Whitney nonparametric method, as tion occurred in 17 of the patients with AFLP (53%) andappropriate. Differences in proportions were compared either by in 2 with HELLP syndrome (29%). Major intra-abdominalthe x2 or by Fishers Exact Test. A P value of .05 was considered

bleeding, resulting in hypotension, anemia, and abnormalto be significant.ultrasonographic findings, occurred in 10 women with AFLP(31%) and in 2 with HELLP syndrome, all of whom hadRESULTSundergone delivery by cesarean section. Nine of these pa-Of the 46 patients, 33 (71%) were nulliparous, and onlytients required repeat laparotomies for evacuation of pelvic3 had had more than one previous pregnancy. Five womenor abdominal hematomas. In contrast, none of the 8 patients(11%) had twin pregnancies. Twenty-three (50%) developedwith AFLP or HELLP syndrome who had vaginal deliveriessymptoms between 28 and 36 weeks gestation, whereas 17developed bleeding complications. Furthermore, the median(37%) presented after 36 weeks, and 4 (9%) presented athospital stay in the 8 patients who delivered vaginally was28 weeks. In 26 patients (57%), the presenting symptoms5 days, compared with 13 days in those who delivered viawere related to the preeclamptic triad of hypertension, pro-cesarean section (P .05).teinuria, and edema. Half also complained of nausea and

Maternal and Perinatal Outcome. Four of the 32 patients withvomiting. Sixteen women (35%) developed concomitant ab-AFLP died, corresponding to a maternal mortality rate ofdominal pain (usually epigastric or right upper quadrant dis-12.5%. The first death in the series was in a 19-year-oldcomfort), and 8 (17%) had a viruslike prodrome in the pre-woman with preeclampsia, grade II encephalopathy, and anceding week. Thirty-seven patients (80%) delivered at theirINR of 2.3 who underwent emergency cesarean section be-local hospital within 24 to 48 hours of admission, 82% bycause of fetal distress and was transferred to the Liver Failureemergency cesarian section and 18% by spontaneous or in-Unit the same day. Immediately after arrival, the patient hadduced vaginal delivery. The 9 remaining patients delivereda fatal hypovolemic arrest. Postmortem examination revealed(by cesarean section in 8) within 24 hours of transfer.hemorrhage into the peritoneal cavity. The second patient,The HELLP syndrome was diagnosed in 7 patients, all ofa 35-year-old woman who required multiple laparotomies forwhom had preeclampsia. At admission, 1 patient was enceph-recurrent intra-abdominal bleeding, developed severe acutealopathic and 2 were clinically jaundiced, with a medianpancreatitis complicated by necrotizing fasciitis of the ab-bilirubin concentration in the 7 patients of 34 mmol/L (range,dominal wall and died of multiorgan failure 2 weeks after19-124 mmol/L). Three patients had renal impairment, with aadmission. The third was a 34-year-old multigravida withmedian serum creatinine concentration overall of 102 mmol/Lpreeclampsia and severe AFLP who died on day 8 after devel-(range, 63-526 mmol/L). The INR was normal or only mildlyoping gram-negative septicemia complicated by acute respi-elevated (1.5) in all patients. The median platelet countratory distress syndrome and cardiac dysfunction. The fourthwas 39 1 109/L (range, 19-89 1 109/L), which decreased todeath was in a 22-year-old primipara with AFLP who devel-a nadir of 31 1 109/L (7-66 1 109/L) at a median of 2 daysoped liver rupture and a large subcapsular hematoma requir-after admission (Table 1).

Thirty-two of the 46 patients (70%) had AFLP. In contrast ing surgical evacuation. She remained critically ill and was

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1260 PEREIRA ET AL. HEPATOLOGY November 1997

HELLP syndrome, 4 of the 6 presented before the third tri-mester of pregnancy, at 24 to 26 weeks gestation, whereasthe remaining 2 developed symptoms at 28 to 30 weeks.None of the 6 were encephalopathic; 5 had normal plateletcounts (median, 256 1 109/L; range, 67-409 1 109/L), andonly 1 had an elevated serum creatinine concentration. Liverfunction test abnormalities were unhelpful in distinguishingthese patients from those with pregnancy-related liver dis-ease, apart from the one with acute hepatitis A, who had anAST concentration of 2,542 IU/L, which was considered tobe uncharacteristically high for AFLP or HELLP syndrome.

DISCUSSION

In contrast to many previous series, which have involvedonly small numbers of patients with relatively mild preg-nancy-related liver disease, the present series comprised alarge group of 46 women with severe hepatic dysfunction inlate pregnancy. By the time of admission to Kings CollegeHospital, almost two thirds had evidence of preeclampsia,

FIG. 1. Abdominal computed tomography scan after intravenous admin- half of the patients were encephalopathic or mechanicallyistration of contrast medium in a patient with preeclampsia and hepatic

ventilated, and 90% had developed acute renal failure. Over-rupture, showing an extensive right subcapsular hematoma surrounding aall, severe infections or bleeding complications occurred innonperfused right lobe of the liver. The portal vein is patent, but the right

hepatic vein cannot be seen. Ascites are also present. two thirds of patients, 20% required laparotomies for clotevacuation or control of intra-abdominal bleeding, and 2patients were listed for emergency liver transplantation, oneof whom was successfully transplanted. However, despite thehigh frequency of complications, the maternal and infantlisted for liver transplantation, but died 3 days later before

a liver became available. mortality rates in those with AFLP were only 12.5% and 9%,respectively, and there were no deaths associated with theIn contrast, none of the 7 patients with HELLP syndrome

died, and all 7 infants (6 girls and 1 boy) survived. In the HELLP syndrome.The reasons for this improvement in mortality over earlier32 patients with AFLP, there were 3 perinatal deaths in 37

deliveries (5 twin births; 12 girls, 25 boys), corresponding and comparable series of severe cases are likely to be betterrecognition and treatment of these syndromes by promptto an infant mortality rate in AFLP of 9%.

Other Causes of Liver Disease. In 7 patients with an initial delivery and appropriate intensive-care management. Themajority of women in the present series had presented todiagnosis of AFLP or HELLP syndrome, other causes of se-

vere liver dysfunction were subsequently proved. One of their local hospital within a week of their initial symptoms,and more than three quarters delivered within 24 hours ofthese patients, a 21-year-old primigravida, presented with

preeclampsia at 33 weeks, complicated by the sudden devel- admission. Thereafter, most patients showed evidence of im-provement in hepatic function within 24 to 48 hours. Fouropment of abdominal pain and hypotension immediately be-

fore emergency cesarean section and delivery of a live baby patients with AFLP died as a result of complications relatedto bleeding and/or sepsis. It is notable that none of the 8girl. Postoperatively, the patients serum aspartate transami-

nase (AST) concentration increased to 3,104 IU/L, and com- patients with AFLP or HELLP syndrome who delivered vagi-nally developed bleeding complications. In contrast, 30% ofputed tomography of the abdomen confirmed the presence

of a large right subcapsular hematoma surrounding a nonper- those who underwent cesarean section had major intra-ab-dominal bleeds postoperatively, and most of them requiredfused right liver lobe, consistent with the clinical diagnosis of

preeclamptic liver rupture. After the development of hepatic repeat laparotomies for clot evacuation.There is controversy about whether the three diseases ofencephalopathy, acute renal failure, worsening coagulopathy,

and severe metabolic acidosis, she underwent liver trans- late pregnancypreeclampsia or eclampsia with hepaticinvolvement, AFLP, and HELLP syndromeare separateplantation 48 hours later. Histological examination of the

explant revealed an infarcted left lobe and extensive focal clinical entities or part of a spectrum of the same illness.14

In the present series, preeclampsia, characterized by the triadnecrosis of the right lobe. She had an uncomplicated courseposttransplantation and was discharged 3 weeks later (Fig. of hypertension, proteinuria, and edema, was present in half

of the patients with a clinical diagnosis of AFLP and in all1).The other 6 patients were found to have causes of liver of those with HELLP syndrome. Moreover, most patients

with AFLP developed low platelet counts comparable withimpairment unrelated to their pregnancies. Hepatic infiltra-tion by tumor or lymphoma was found in 2 cases; chole- those with HELLP syndrome at some time during their ad-

mission, although the thrombocytopenia was usually in asso-dochal cyst with stones was found in 1 case, alcohol-inducedfatty liver and severe acute pancreatitis in 1 case, veno-occlu- ciation with laboratory evidence of disseminated intravascu-

lar coagulopathy and/or ongoing liver failure rather thansive disease secondary to antiphospholipid syndrome in 1case, and acute hepatitis A in 1 case (Table 2). All 6 patients hemolysis alone.2 In acute liver failure of any cause, platelet

counts decrease to below 100 1 109/L in approximately twohad symptoms suggestive of AFLP or HELLP syndrome(vomiting, abdominal pain, and jaundice), but only 1 had thirds of patients.15 Furthermore, lesser degrees of

microvesicular fatty infiltration of the liverthe histologicalpreeclampsia. In contrast to the patients with AFLP or

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HEPATOLOGY Vol. 26, No. 5, 1997 PEREIRA ET AL. 1261

TABLE 2. Age, Parity, Gestational Age at Onset of Symptoms, and Outcome of 6 Patientsin Whom Hepatic Impairment Was Unrelated to Pregnancy

Parity Symptom Maternal PerinatalPatient Age (yr) (n) Onset (wk) Diagnosis Outcome Outcome

1 23 2 25 Metastatic adenocarcinoma with unknown primary Died Survived2 31 2 26 Choledochal cyst with stones, sepsis syndrome Survived Died3 20 2 24 Alcohol-induced fatty liver and acute pancreatitis Survived Stillborn4 33 1 30 Veno-occlusive disease/anti-phospholipid syndrome Survived Survived5 26 1 24 Non-Hodgkins lymphoma Died Died6 28 4 24 Acute hepatitis A Survived Survived

hallmark of AFLPhave also been observed in some patients infectious and bleeding complications are in some way pre-vented or better treated. While the natural history of preg-with HELLP syndrome or preeclampsia alone,16-18 suggesting

that these conditions may be part of a spectrum of pregnancy- nancy-related liver disease is for improvement to occur usu-ally within 24 to 48 hours of delivery, it is recommendedinduced microvesicular fatty disease of the liver, with AFLP

the most severe form. In the present series, those with a that the care of patients who are critically ill at the time ofpresentation to their local hospital, who develop complica-clinical diagnosis of AFLP had a higher frequency of encepha-

lopathy, a more complicated hospital course, and a higher tions, or who continue to deteriorate despite emergency de-livery, should be discussed with a liver center. In the presentmortality rate than those with HELLP syndrome. The severity

of liver disease in AFLP is also likely to be the reason why series, it was not always possible to distinguish patients withAFLP from those with severe HELLP syndrome (or causesa larger number of patients referred for intensive care support

had AFLP rather than HELLP syndrome, although AFLP is of severe liver dysfunction unrelated to pregnancy) at thetime of referral. Patients with AFLP were more likely thanat least 10 times less common than HELLP syndrome.1-4

In an earlier series from Kings College Hospital, of 14 those with HELLP to have encephalopathy and renal impair-ment and were less likely to have preeclampsia and thrombo-patients who presented with acute liver disease in late preg-

nancy, 8 had pregnancy-related liver disease, whereas 6 had cytopenia, but there was often an overlap. We would there-fore recommend that referral criteria be based primarily onsevere hepatic dysfunction due to presumed viral hepatitis

or gram-negative septicemia.5 In the present series, a smaller the severity of liver disease rather than on the presumedunderlying diagnosis. Patients with tests showing deteriorat-proportion of patients (6 of 46, or 13%) referred with pre-

sumed AFLP or HELLP syndrome was found to have liver ing liver function despite early delivery, and/or patients whodevelop encephalopathy, coagulopathy, hypoglycemia, ordisease unrelated to pregnancy. Nevertheless, these cases

highlight the need to exclude other causes of liver impair- other features of severe liver dysfunction, should be referredearly to a specialist liver center for intensive care manage-ment in patients with clinical features of pregnancy-related

liver disease. ment. The present results, and those of others,8,9,27 indicatethat intra-abdominal bleeding, which in our experience oc-The pathogenesis of preeclamptic liver disease remains

unclear, but it is related in part to sympathetic overactivity curred only after emergency cesarean section, is another ma-jor adverse prognostic factor in severe pregnancy-related liverand a marked increase in peripheral vascular resistance,

which, in turn, causes the increase in blood pressure.19,20 disease. We would suggest that, whenever possible, vaginaldelivery rather than cesarean section be considered, togetherAs a result of endothelial cell injury and activation of the

coagulation and fibrinolytic pathways in preeclampsia, intra- with broad-spectrum antibiotic therapy and the administra-tion of fresh-frozen plasma and platelets to maintain an INRvascular deposition of fibrin also occurs and contributes to

end-organ damage and the microangiopathic hemolytic ane- of1.5 and a platelet count of50 1 109/L. In other causesof acute liver failure, fresh-frozen plasma supplementationmia of the HELLP syndrome.14 Experimental evidence sug-

gests that nitric oxide deficiency may also play a role in in the absence of bleeding is usually contraindicated becauseit does not reduce the frequency of hemorrhage and becausethe development of endothelial dysfunction, although recent

clinical studies of NO donors in preeclampsia have yielded it will partially correct the INR, an important dynamicmarker of hepatic function and part of the selection criteriaconflicting results.20-23 Conversely, some cases of AFLP may

have a distinct pathophysiological mechanism to preeclamp- for emergency transplantation.15,28 However, in pregnancy-related acute liver failure, postpartum hemorrhage is com-tic liver disease, mediated through a defect in the intramito-

chondrial oxidation of fatty acids. In this regard, AFLP may mon and liver transplantation is only rarely required.6,29-32

In the present series, 1 patient with liver rupture secondarybe similar to Reyes syndrome or the other microvesicularfatty infiltration diseases, such as medium-chain acyl-coen- to AFLP died before a donor liver became available, but

another, with preeclamptic liver rupture for whom an organzyme A dehydrogenase deficiency.1 Recently, a deficiency inpediatric long-chain 3-hydroxyacyl-coenzyme A dehydroge- was obtained, underwent successful transplantation and

made a rapid postoperative recovery. Thus, in our experi-nase (LCHAD) deficiency, as a result of mutations in thegene encoding for the LCHAD subunit, has been reported in ence, liver transplantation should probably be reserved for

those with liver rupture complicated by hepatic necrosis, asassociation with maternal AFLP.24-26

Although early recognition and prompt delivery in patients indicated by computed tomographic findings, the presenceof hepatic encephalopathy, and a severe metabolic acidosis,with severe pregnancy-related liver disease by local obstetri-

cians is crucial to a successful outcome, further improve- together with a worsening coagulopathy, and/or fresh-frozenplasma requirements.ments in outcome are likely to be achieved only if major

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1262 PEREIRA ET AL. HEPATOLOGY November 1997

16. Minakami H, Oka N, Sato T, Tamada T, Yasuda Y, Hirota N. Preeclamp-Acknowledgment: The authors thank N. Heaton and M.sia: a microvesicular fat disease of the liver? Am J Obstet Gynecol 1988;Rela of the Liver Transplant Surgical Service, members of159:1043-1047.

the Department of Obstetrics and Gynecology, and other 17. Barton JR, Riely CA, Adamec TA, Shanklin DR, Khoury AD, Sibai BM.colleagues at Kings College Hospital involved in the care of Hepatic histopathologic condition does not correlate with laboratory

abnormalities in HELLP syndrome (hemolysis, elevated liver enzymes,the patients in this study.and low platelet count). Am J Obstet Gynecol 1992;167:1538-1543.

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