Maternal and perinatal outcome in severe pregnancy-related liver disease.

Maternal and Perinatal Outcome in Severe Pregnancy-Related Liver Disease STEPHEN P. PEREIRA,1 JOHN O’DONOHUE,2 JULIA WENDON,2

Acute fatty liver of pregnancy (AFLP) and the syndrome of hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) are rare but major disorders of the third trimester of pregnancy. Over a 10-year period, 46 women (median age, 30 years; range, 17-41 years) developed hepatic dysfunction severe enough to require transfer to our Liver Failure Unit. Three quarters of the women were nulliparous, and 5 had twin pregnancies; the median gestational age was 35 weeks (range, 24-40 weeks). At admission, 32 patients (70%) were preeclamptic and 21 (46%) were encephalopathic and/or ventilated. Thirty-two patients (70%) had clinical features and laboratory values consistent with AFLP, and 7 (15%) had HELLP syndrome. One patient had preeclamptic liver rupture requiring liver transplantation. In 6 other patients, causes of severe liver dysfunction unrelated to pregnancy were found. Infectious complications occurred in 17 of the patients with AFLP (53%) and in 2 of those with HELLP syndrome (29%). Major intra-abdominal bleeding occurred in 12 women (10 with AFLP), 9 of whom required laparotomies for clot evacuation. Four patients with AFLP (12.5%) had a fatal outcome, with a corresponding perinatal mortality rate of 9%. There were no maternal or perinatal deaths associated with HELLP syndrome. In contrast to results of many previous studies, the results of this large series suggest a relatively favorable maternal and perinatal outcome in severe AFLP and HELLP syndrome. Further improvements in outcome are likely to be achieved through the prevention of the bleeding and infectious complications associated with these disorders. (HEPATOLOGY 1997;26:1258-1262.) Preeclampsia and the associated HELLP syndrome (hemolysis, elevated serum liver enzyme levels, and low blood platelet count), as well as the rare acute fatty liver of pregnancy (AFLP), represent major causes of maternal and perinatal morbidity and mortality. AFLP occurs in approximately 1 in 13,000 pregnancies compared with 1 to 6 per 1,000 deliveries for the HELLP syndrome,1-4 and it usually results in a more severe degree of liver impairment. Other complications of the third trimester of pregnancy, such as preeclamp-

Abbreviations: HELLP, hemolysis, elevated liver enzyme levels, and low platelet count; AFLP, acute fatty liver of pregnancy; INR, international normalized ratio; LCHAD, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase. From the 1Gastroenterology Unit, Guy’s Hospital, London, and the 2Institute of Liver Studies, King’s College School of Medicine and Dentistry, London, UK. Received March 7, 1997; accepted June 17, 1997. Address reprint requests to: R. Williams, M.D., Institute of Hepatology, University College London Medical School, 69-75 Chenies Mews, London WC1E 6HX, UK. Fax: 44-171-380-0405. Copyright q 1997 by the American Association for the Study of Liver Diseases. 0270-9139/97/2605-0026$3.00/0

AND

ROGER WILLIAMS2

tic liver infarction or rupture, are even rarer and also often fatal.3,5,6 Causes of liver failure unrelated to pregnancy may also present during this time and may be difficult to distinguish from severe pregnancy-related disease.1,5 Before 1980, maternal and infant mortality rates associated with AFLP were generally greater than 80%,7 with reported figures for HELLP syndrome of approximately 25%.8 In more recent series, maternal and infant mortality rates for AFLP and HELLP syndrome have been less than 20%, although most of these studies have involved small numbers of patients, often with only minor degrees of liver impairment.3,9 The aims of the present study were to describe the clinical features, complications, and maternal/perinatal mortality in a large group of 46 patients seen in a single center over a 10-year period, who presented with hepatic dysfunction in late pregnancy severe enough to require admission to a Liver Failure Unit. PATIENTS AND METHODS Patients. The Liver Failure Unit of King’s College Hospital is a tertiary intensive care unit that accepts approximately 200 patients with acute liver failure per year. In recent years, acetaminophininduced acute liver failure has accounted for approximately two thirds of admissions, with pregnancy-related liver disease responsible for less than 5% of cases. Over a 10-year period from April 1986 to December 1996, a total of 46 women (median age, 30 years; range, 17-41 years) who developed severe hepatic dysfunction in late pregnancy were transferred to the Liver Failure Unit. The HELLP syndrome was defined according to standard criteria4,10; the diagnosis of AFLP was based on the development of jaundice in the third trimester of pregnancy together with features of acute liver failure, such as coagulopathy, hypoglycemia, and/or encephalopathy, whether or not preeclampsia was present. Causes of severe liver dysfunction unrelated to pregnancy, such as acute viral hepatitis or fulminant autoimmune hepatitis, were excluded. In thrombocytopenic patients, laboratory evidence of disseminated intravascular coagulation (including low fibrinogen concentrations, positive fibrin degradation products, and prolonged prothrombin and partial thromboplastin times) was also sought. In all patients, Doppler ultrasonography of the liver was performed at admission and when clinically indicated thereafter. Abdominal computed tomography was requested when major intra-abdominal bleeding was suspected and laparotomy was being considered. In cases of diagnostic uncertainty, a liver biopsy was performed. Methods. Patient care followed a standard protocol for acute liver failure. Central venous access was obtained via the internal jugular route, and central venous pressures were maintained between /10 and /14 mm Hg with infusion of 4.5% human albumin solution. Dopamine was infused if oliguria persisted despite adequate intravascular filling, and intermittent venovenous hemodiafiltration was instituted in anuric or oliguric patients with a serum creatinine level of ú400 mmol/L. A pulmonary artery flotation catheter was inserted, and inotropic support with adrenaline or noradrenaline was commenced in any patient with a mean arterial pressure of

1258

AID

Hepa 0020

/

5p27$$$381

10-13-97 19:29:32

hepa

WBS: Hepatology

HEPATOLOGY Vol. 26, No. 5, 1997

PEREIRA ET AL.

TABLE 1. Clinical Features and Laboratory Values at Admission in Patients With AFLP or HELLP Syndrome AFLP (n Å 32)

Median age, yr (range) Week of gestation No. with preeclampsia (%) No. encephalopathic/ventilated (%) Platelet count (normal, 150-450 1 109/L) Creatinine (normal, 45-120 mmol/L) Bilirubin (normal, 3-20 mmol/L) AST (normal, 10-50 IU/L) Alkaline phosphatase (normal, 30-150 IU/L) g-Glutamyl transferase (normal, 5-55 IU/L)

30 36 16 20 123 245 142 99

HELLP Syndrome (n Å 7)

(17-40) 31 (23-41) (28-40) 34 (27-38) (50)* 7 (100)* (63)* 1 (14)* (26-262)* 39 (19-89)* (99-758) 102 (63-526) (63-646)* 34 (19-124)* (25-911) 342 (60-328)

293 (92-716)

126 (61-526)

67 (16-237)

28 (13-87)

* P õ .01, AFLP vs. HELLP syndrome.

õ60 mm hg despite adequate intravascular filling. Broad-spectrum antibiotics were administered intravenously. In preeclamptic patients, hydralazine or nifedipine was used to control hypertension, and magnesium sulfate was infused.11 Fresh-frozen plasma and platelets were also given to maintain an international normalized ratio (INR) of õ1.5 and a platelet count of ú50 1 109/L. Since 1990, the standard regimen has also included intravenous N-acetylcysteine to maintain microcirculatory flow.12,13 Data are expressed as medians with ranges. The significance of differences in results between groups was tested with Student’s t test (two-tailed) or the Mann-Whitney nonparametric method, as appropriate. Differences in proportions were compared either by the x2 or by Fisher’s Exact Test. A P value of õ.05 was considered to be significant. RESULTS

Of the 46 patients, 33 (71%) were nulliparous, and only 3 had had more than one previous pregnancy. Five women (11%) had twin pregnancies. Twenty-three (50%) developed symptoms between 28 and 36 weeks’ gestation, whereas 17 (37%) presented after 36 weeks, and 4 (9%) presented at õ28 weeks. In 26 patients (57%), the presenting symptoms were related to the preeclamptic triad of hypertension, proteinuria, and edema. Half also complained of nausea and vomiting. Sixteen women (35%) developed concomitant abdominal pain (usually epigastric or right upper quadrant discomfort), and 8 (17%) had a viruslike prodrome in the preceding week. Thirty-seven patients (80%) delivered at their local hospital within 24 to 48 hours of admission, 82% by emergency cesarian section and 18% by spontaneous or induced vaginal delivery. The 9 remaining patients delivered (by cesarean section in 8) within 24 hours of transfer. The HELLP syndrome was diagnosed in 7 patients, all of whom had preeclampsia. At admission, 1 patient was encephalopathic and 2 were clinically jaundiced, with a median bilirubin concentration in the 7 patients of 34 mmol/L (range, 19-124 mmol/L). Three patients had renal impairment, with a median serum creatinine concentration overall of 102 mmol/L (range, 63-526 mmol/L). The INR was normal or only mildly elevated (õ1.5) in all patients. The median platelet count was 39 1 109/L (range, 19-89 1 109/L), which decreased to a nadir of 31 1 109/L (7-66 1 109/L) at a median of 2 days after admission (Table 1). Thirty-two of the 46 patients (70%) had AFLP. In contrast

AID

Hepa 0020

/

5p27$$$381

10-13-97 19:29:32

1259

to the 7 patients with HELLP syndrome, only 16 of the 32 with AFLP (50%) had preeclampsia (P õ .02), a condition complicated by seizures in 4 patients. At admission, 14 patients (44%) were in grade I-II encephalopathy, and 6 others (19%) were mechanically ventilated. All were clinically jaundiced, with a median bilirubin concentration of 142 mmol/L (range, 63-646 mmol/L), a significantly higher level than in those with HELLP syndrome (P õ .01). Eighteen patients (56%) were hypoglycemic. All but 1 patient (97%) had an elevated serum creatinine concentration, 16 of whom required renal support with dopamine and/or continuous venovenous hemodiafiltration. Twenty-nine patients (91%) had a raised INR (median, 1.7; range, 1.0-3.4) despite fresh-frozen plasma support in most cases. At admission, the median platelet count of 123 1 109/L was significantly higher (P õ .01) than that associated with HELLP syndrome, but it decreased to a median of 53 1 109/L (range, 16-163 1 109/ L) at day 2, usually in association with other features of acute liver failure, bacterial sepsis, and/or disseminated intravascular coagulation. Overall, 29 (91%) of the AFLP group developed thrombocytopenia at some point during their admission (Table 1). Eleven of the 32 patients underwent liver biopsy a median of 18 days after admission (range, 5-40 days), which confirmed the diagnosis of AFLP in all instances. The patients with AFLP also had a greater number of complications than did those with HELLP syndrome, although the median hospital stay of 11 days was identical in the two groups. Infectious complications with sepsis syndrome and/ or laboratory evidence of disseminated intravascular coagulation occurred in 17 of the patients with AFLP (53%) and in 2 with HELLP syndrome (29%). Major intra-abdominal bleeding, resulting in hypotension, anemia, and abnormal ultrasonographic findings, occurred in 10 women with AFLP (31%) and in 2 with HELLP syndrome, all of whom had undergone delivery by cesarean section. Nine of these patients required repeat laparotomies for evacuation of pelvic or abdominal hematomas. In contrast, none of the 8 patients with AFLP or HELLP syndrome who had vaginal deliveries developed bleeding complications. Furthermore, the median hospital stay in the 8 patients who delivered vaginally was 5 days, compared with 13 days in those who delivered via cesarean section (P õ .05). Maternal and Perinatal Outcome. Four of the 32 patients with AFLP died, corresponding to a maternal mortality rate of 12.5%. The first death in the series was in a 19-year-old woman with preeclampsia, grade II encephalopathy, and an INR of 2.3 who underwent emergency cesarean section because of fetal distress and was transferred to the Liver Failure Unit the same day. Immediately after arrival, the patient had a fatal hypovolemic arrest. Postmortem examination revealed hemorrhage into the peritoneal cavity. The second patient, a 35-year-old woman who required multiple laparotomies for recurrent intra-abdominal bleeding, developed severe acute pancreatitis complicated by necrotizing fasciitis of the abdominal wall and died of multiorgan failure 2 weeks after admission. The third was a 34-year-old multigravida with preeclampsia and severe AFLP who died on day 8 after developing gram-negative septicemia complicated by acute respiratory distress syndrome and cardiac dysfunction. The fourth death was in a 22-year-old primipara with AFLP who developed liver rupture and a large subcapsular hematoma requiring surgical evacuation. She remained critically ill and was

hepa

WBS: Hepatology

1260 PEREIRA ET AL.

HEPATOLOGY November 1997

HELLP syndrome, 4 of the 6 presented before the third trimester of pregnancy, at 24 to 26 weeks’ gestation, whereas the remaining 2 developed symptoms at 28 to 30 weeks. None of the 6 were encephalopathic; 5 had normal platelet counts (median, 256 1 109/L; range, 67-409 1 109/L), and only 1 had an elevated serum creatinine concentration. Liver function test abnormalities were unhelpful in distinguishing these patients from those with pregnancy-related liver disease, apart from the one with acute hepatitis A, who had an AST concentration of 2,542 IU/L, which was considered to be uncharacteristically high for AFLP or HELLP syndrome. DISCUSSION

FIG. 1. Abdominal computed tomography scan after intravenous administration of contrast medium in a patient with preeclampsia and hepatic rupture, showing an extensive right subcapsular hematoma surrounding a nonperfused right lobe of the liver. The portal vein is patent, but the right hepatic vein cannot be seen. Ascites are also present.

listed for liver transplantation, but died 3 days later before a liver became available. In contrast, none of the 7 patients with HELLP syndrome died, and all 7 infants (6 girls and 1 boy) survived. In the 32 patients with AFLP, there were 3 perinatal deaths in 37 deliveries (5 twin births; 12 girls, 25 boys), corresponding to an infant mortality rate in AFLP of 9%. Other Causes of Liver Disease. In 7 patients with an initial diagnosis of AFLP or HELLP syndrome, other causes of severe liver dysfunction were subsequently proved. One of these patients, a 21-year-old primigravida, presented with preeclampsia at 33 weeks, complicated by the sudden development of abdominal pain and hypotension immediately before emergency cesarean section and delivery of a live baby girl. Postoperatively, the patient’s serum aspartate transaminase (AST) concentration increased to 3,104 IU/L, and computed tomography of the abdomen confirmed the presence of a large right subcapsular hematoma surrounding a nonperfused right liver lobe, consistent with the clinical diagnosis of preeclamptic liver rupture. After the development of hepatic encephalopathy, acute renal failure, worsening coagulopathy, and severe metabolic acidosis, she underwent liver transplantation 48 hours later. Histological examination of the explant revealed an infarcted left lobe and extensive focal necrosis of the right lobe. She had an uncomplicated course posttransplantation and was discharged 3 weeks later (Fig. 1). The other 6 patients were found to have causes of liver impairment unrelated to their pregnancies. Hepatic infiltration by tumor or lymphoma was found in 2 cases; choledochal cyst with stones was found in 1 case, alcohol-induced fatty liver and severe acute pancreatitis in 1 case, veno-occlusive disease secondary to antiphospholipid syndrome in 1 case, and acute hepatitis A in 1 case (Table 2). All 6 patients had symptoms suggestive of AFLP or HELLP syndrome (vomiting, abdominal pain, and jaundice), but only 1 had preeclampsia. In contrast to the patients with AFLP or

AID

Hepa 0020

/

5p27$$$381

10-13-97 19:29:32

In contrast to many previous series, which have involved only small numbers of patients with relatively mild pregnancy-related liver disease, the present series comprised a large group of 46 women with severe hepatic dysfunction in late pregnancy. By the time of admission to King’s College Hospital, almost two thirds had evidence of preeclampsia, half of the patients were encephalopathic or mechanically ventilated, and 90% had developed acute renal failure. Overall, severe infections or bleeding complications occurred in two thirds of patients, 20% required laparotomies for clot evacuation or control of intra-abdominal bleeding, and 2 patients were listed for emergency liver transplantation, one of whom was successfully transplanted. However, despite the high frequency of complications, the maternal and infant mortality rates in those with AFLP were only 12.5% and 9%, respectively, and there were no deaths associated with the HELLP syndrome. The reasons for this improvement in mortality over earlier and comparable series of severe cases are likely to be better recognition and treatment of these syndromes by prompt delivery and appropriate intensive-care management. The majority of women in the present series had presented to their local hospital within a week of their initial symptoms, and more than three quarters delivered within 24 hours of admission. Thereafter, most patients showed evidence of improvement in hepatic function within 24 to 48 hours. Four patients with AFLP died as a result of complications related to bleeding and/or sepsis. It is notable that none of the 8 patients with AFLP or HELLP syndrome who delivered vaginally developed bleeding complications. In contrast, 30% of those who underwent cesarean section had major intra-abdominal bleeds postoperatively, and most of them required repeat laparotomies for clot evacuation. There is controversy about whether the three diseases of late pregnancy—preeclampsia or eclampsia with hepatic involvement, AFLP, and HELLP syndrome—are separate clinical entities or part of a spectrum of the same illness.14 In the present series, preeclampsia, characterized by the triad of hypertension, proteinuria, and edema, was present in half of the patients with a clinical diagnosis of AFLP and in all of those with HELLP syndrome. Moreover, most patients with AFLP developed low platelet counts comparable with those with HELLP syndrome at some time during their admission, although the thrombocytopenia was usually in association with laboratory evidence of disseminated intravascular coagulopathy and/or ongoing liver failure rather than hemolysis alone.2 In acute liver failure of any cause, platelet counts decrease to below 100 1 109/L in approximately two thirds of patients.15 Furthermore, lesser degrees of microvesicular fatty infiltration of the liver—the histological

hepa

WBS: Hepatology

HEPATOLOGY Vol. 26, No. 5, 1997

PEREIRA ET AL.

1261

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

Age (yr)

Parity (n)

Symptom Onset (wk)

Diagnosis

Maternal Outcome

Perinatal Outcome

1 2 3 4 5 6

23 31 20 33 26 28

2 2 2 1 1 4

25 26 24 30 24 24

Metastatic adenocarcinoma with unknown primary Choledochal cyst with stones, sepsis syndrome Alcohol-induced fatty liver and acute pancreatitis Veno-occlusive disease/anti-phospholipid syndrome Non-Hodgkin’s lymphoma Acute hepatitis A

Died Survived Survived Survived Died Survived

Survived Died Stillborn Survived Died Survived

hallmark of AFLP—have also been observed in some patients with HELLP syndrome or preeclampsia alone,16-18 suggesting that these conditions may be part of a spectrum of pregnancyinduced microvesicular fatty disease of the liver, with AFLP the most severe form. In the present series, those with a clinical diagnosis of AFLP had a higher frequency of encephalopathy, a more complicated hospital course, and a higher mortality rate than those with HELLP syndrome. The severity of liver disease in AFLP is also likely to be the reason why a larger number of patients referred for intensive care support had AFLP rather than HELLP syndrome, although AFLP is at least 10 times less common than HELLP syndrome.1-4 In an earlier series from King’s College Hospital, of 14 patients who presented with acute liver disease in late pregnancy, 8 had pregnancy-related liver disease, whereas 6 had severe hepatic dysfunction due to presumed viral hepatitis or gram-negative septicemia.5 In the present series, a smaller proportion of patients (6 of 46, or 13%) referred with presumed AFLP or HELLP syndrome was found to have liver disease unrelated to pregnancy. Nevertheless, these cases highlight the need to exclude other causes of liver impairment in patients with clinical features of pregnancy-related liver disease. The pathogenesis of preeclamptic liver disease remains unclear, but it is related in part to sympathetic overactivity and a marked increase in peripheral vascular resistance, which, in turn, causes the increase in blood pressure.19,20 As a result of endothelial cell injury and activation of the coagulation and fibrinolytic pathways in preeclampsia, intravascular deposition of fibrin also occurs and contributes to end-organ damage and the microangiopathic hemolytic anemia of the HELLP syndrome.14 Experimental evidence suggests that nitric oxide deficiency may also play a role in the development of endothelial dysfunction, although recent clinical studies of NO donors in preeclampsia have yielded conflicting results.20-23 Conversely, some cases of AFLP may have a distinct pathophysiological mechanism to preeclamptic liver disease, mediated through a defect in the intramitochondrial oxidation of fatty acids. In this regard, AFLP may be similar to Reye’s syndrome or the other microvesicular fatty infiltration diseases, such as medium-chain acyl-coenzyme A dehydrogenase deficiency.1 Recently, a deficiency in pediatric long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency, as a result of mutations in the gene encoding for the LCHAD subunit, has been reported in association with maternal AFLP.24-26 Although early recognition and prompt delivery in patients with severe pregnancy-related liver disease by local obstetricians is crucial to a successful outcome, further improvements in outcome are likely to be achieved only if major

AID

Hepa 0020

/

5p27$$$381

10-13-97 19:29:32

infectious and bleeding complications are in some way prevented or better treated. While the natural history of pregnancy-related liver disease is for improvement to occur usually within 24 to 48 hours of delivery, it is recommended that the care of patients who are critically ill at the time of presentation to their local hospital, who develop complications, or who continue to deteriorate despite emergency delivery, should be discussed with a liver center. In the present series, it was not always possible to distinguish patients with AFLP from those with severe HELLP syndrome (or causes of severe liver dysfunction unrelated to pregnancy) at the time of referral. Patients with AFLP were more likely than those with HELLP to have encephalopathy and renal impairment and were less likely to have preeclampsia and thrombocytopenia, but there was often an overlap. We would therefore recommend that referral criteria be based primarily on the severity of liver disease rather than on the presumed underlying diagnosis. Patients with tests showing deteriorating liver function despite early delivery, and/or patients who develop encephalopathy, coagulopathy, hypoglycemia, or other features of severe liver dysfunction, should be referred early to a specialist liver center for intensive care management. The present results, and those of others,8,9,27 indicate that intra-abdominal bleeding, which in our experience occurred only after emergency cesarean section, is another major adverse prognostic factor in severe pregnancy-related liver disease. We would suggest that, whenever possible, vaginal delivery rather than cesarean section be considered, together with broad-spectrum antibiotic therapy and the administration of fresh-frozen plasma and platelets to maintain an INR of õ1.5 and a platelet count of ú50 1 109/L. In other causes of acute liver failure, fresh-frozen plasma supplementation in the absence of bleeding is usually contraindicated because it does not reduce the frequency of hemorrhage and because it will partially correct the INR, an important dynamic marker of hepatic function and part of the selection criteria for emergency transplantation.15,28 However, in pregnancyrelated acute liver failure, postpartum hemorrhage is common and liver transplantation is only rarely required.6,29-32 In the present series, 1 patient with liver rupture secondary to AFLP died before a donor liver became available, but another, with preeclamptic liver rupture for whom an organ was obtained, underwent successful transplantation and made a rapid postoperative recovery. Thus, in our experience, liver transplantation should probably be reserved for those with liver rupture complicated by hepatic necrosis, as indicated by computed tomographic findings, the presence of hepatic encephalopathy, and a severe metabolic acidosis, together with a worsening coagulopathy, and/or fresh-frozen plasma requirements.

hepa

WBS: Hepatology

1262 PEREIRA ET AL.

HEPATOLOGY November 1997

Acknowledgment: The authors thank N. Heaton and M. Rela of the Liver Transplant Surgical Service, members of the Department of Obstetrics and Gynecology, and other colleagues at King’s College Hospital involved in the care of the patients in this study. REFERENCES 1. Riely CA. Hepatic disease in pregnancy. Am J Med 1994;96:18s-22s. 2. Castro MA, Goodwin TM, Shaw KJ, Ouzounian JG, McGehee WG. Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. Am J Obstet Gynecol 1996;174:211216. 3. Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med 1996; 335:569-576. 4. Sibai BM, Ramadan MK, Chari RS, Friedman SA. Pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): subsequent pregnancy outcome and long-term prognosis. Am J Obstet Gynecol 1995;172:125-129. 5. Davies MH, Wilkinson SP, Hanid MA, Portmann B, Brudenell JM, Newton JR, Williams R. Acute liver disease with encephalopathy and renal failure in late pregnancy and the early puerperium–a study of fourteen patients. Br J Obstet Gynaecol 1980;87:1005-1014. 6. Hunter SK, Martin M, Benda JA, Zlatnik FJ. Liver transplant after massive spontaneous hepatic rupture in pregnancy complicated by preeclampsia. Obstet Gynecol 1995;85:819-822. 7. Kaplan MM. Acute fatty liver of pregnancy. N Engl J Med 1985;313: 367-370. 8. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol 1993;169:1000-1006. 9. Reyes H, Sandoval L, Wainstein A, Ribalta J, Donoso S, Smok G, Rosenberg H, et al. Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients. Gut 1994;35:101-106. 10. Usta IM, Barton JR, Amon EA, Gonzalez A, Sibai BM. Acute fatty liver of pregnancy: an experience in the diagnosis and management of fourteen cases. Am J Obstet Gynecol 1994;171:1342-1347. 11. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995;345:1455-1463. 12. Keays R, Harrison PM, Wendon JA, Gimson AE, Alexander GJ, Williams R. Intravenous acetylcysteine in paracetamol-induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991;303:1026-1029. 13. Harrison PM, Wendon JA, Gimson AE, Alexander GJ, Williams R. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852-1858. 14. Sibai BM, Kustermann L, Velasco J. Current understanding of severe preeclampsia, pregnancy-associated hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, hemolysis, elevated liver enzymes, and low platelet syndrome, and postpartum acute renal failure: different clinical syndromes or just different names? Curr Opin Nephrol Hypertens 1994;3:436-445. 15. Pereira SP, Langley PG, Williams R. The management of abnormalities of hemostasis in acute liver failure. Semin Liver Dis 1996;16:403-414.

AID

Hepa 0020

/

5p27$$$381

10-13-97 19:29:32

16. Minakami H, Oka N, Sato T, Tamada T, Yasuda Y, Hirota N. Preeclampsia: a microvesicular fat disease of the liver? Am J Obstet Gynecol 1988; 159:1043-1047. 17. Barton JR, Riely CA, Adamec TA, Shanklin DR, Khoury AD, Sibai BM. Hepatic histopathologic condition does not correlate with laboratory abnormalities in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). Am J Obstet Gynecol 1992;167:1538-1543. 18. Dani R, Mendes GS, Medeiros J, Peret FJ, Nunes A. Study of the liver changes occurring in preeclampsia and their possible pathogenetic connection with acute fatty liver of pregnancy. Am J Gastroenterol 1996; 91:292-294. 19. Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE. Preeclampsia—a state of sympathetic overactivity. N Engl J Med 1996;335:14801485. 20. Mushambi MC, Halligan AW, Williamson K. Recent developments in the pathophysiology and management of pre-eclampsia. Br J Anaesth 1996;76:133-148. 21. Seligman SP, Buyon JP, Clancy RM, Young BK, Abramson SB. The role of nitric oxide in the pathogenesis of preeclampsia. Am J Obstet Gynecol 1994;171:944-948. 22. Barton JR, Sibai MS, Ahokas RA, Whybrew D, Mercer BM. Magnesium sulfate therapy in preeclampsia is associated with increased urinary cyclic guanosine monophosphate excretion. Am J Obstet Gynecol 1992; 167:931-934. 23. de Belder A, Lees C, Martin J, Moncada S, Campbell S. Treatment of HELLP syndrome with nitric oxide donor. Lancet 1995;345:124-125. 24. Wilcken B, Leung K-C, Hammond J, Kamath R, Leonard JV. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet 1993;341:407-408. 25. Treem WR, Rinaldo P, Hale DE, Stanley CA, Millington DS, Hyams JS, Jackson S, et al. Acute fatty liver of pregnancy and long-chain 3hydroxyacyl-coenzyme A dehydrogenase deficiency. HEPATOLOGY 1994; 19:339-345. 26. Sims HF, Brackett JC, Powell CK, Treem WR, Hale DE, Bennett MJ, Gibson B, et al. The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proc Natl Acad Sci U S A 1995;92:841-815. 27. Rolfes DB, Ishak KG. Acute fatty liver of pregnancy: a clinicopathologic study of 35 cases. HEPATOLOGY 1985;5:1149-1158. 28. Bismuth H, Samuel D, Castaing D, Williams R, Pereira SP. Liver transplantation in Europe for patients with acute liver failure. Semin Liver Dis 1996;16:415-425. 29. Amon E, Allen SR, Petrie RH, Belew JE. Acute fatty liver of pregnancy associated with preeclampsia: management of hepatic failure with postpartum liver transplantation. Am J Perinatol 1991;8:278-279. 30. Ockner SA, Brunt EM, Cohn SM, Krul ES, Hanto DW, Peters MG. Fulminant hepatic failure caused by acute fatty liver of pregnancy treated by orthotopic liver transplantation. HEPATOLOGY 1990;11:5964. 31. Erhard J, Lange R, Niebel W, Scherer R, Kox WJ, Philipp T, Eigler FW. Acute liver necrosis in the HELLP syndrome: successful outcome after orthotopic liver transplantation. A case report. Transplant Int 1993;6: 179-181. 32. Chenard-Neu MP, Boudjema K, Bernuau J, Degott C, Belghiti J, Cherqui D, Costes V, et al. Auxiliary liver transplantation: regeneration of the native liver and outcome in 30 patients with fulminant hepatic failure: a multicenter European study. HEPATOLOGY 1996;23:1119-1127.

hepa

WBS: Hepatology