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ORIGINAL ARTICLE

Acute Liver Failure at 26 Weeks Gestation in aPatient with Sickle Cell DiseaseMara Greenberg,1 Tami J. Daugherty,2 Arvand Elihu,3 Ravi Sharaf,2 Waldo Concepcion,3

Maurice Druzin,1 and Carlos O. Esquivel31Department of Obstetrics and Gynecology, 2Division of Gastroenterology and Hepatology, and 3Divisionof Transplantation Surgery, Stanford University School of Medicine, Stanford, CA

Orthotopic liver transplantation (OLT) for acute liver failure (ALF) during pregnancy is an uncommon occurrence with variable

outcomes. In pregnancy-related liver failure, prompt diagnosis and immediate delivery are essential for a reversal of the underlying

process and for maternal and fetal survival. In rare cases, the reason for ALF during pregnancy is either unknown or irreversible, and

thus OLT may be necessary. This case demonstrates the development of cryptogenic ALF during the 26th week of pregnancy in awoman with sickle cell disease. She underwent successful cesarean delivery of a healthy male fetus at 27 weeks with concurrent

OLT. This report provides a literature review of OLT in pregnancy and examines the common causes of ALF in the pregnant patient.

On the basis of the management and outcome of our case and the literature review, we present an algorithm for the suggested

management of ALF in pregnancy. Liver Transpl 15:1236-1241, 2009. 2009 AASLD.

Received February 13, 2009; accepted April 27, 2009.

Acute liver failure (ALF) occurring during pregnancymay be coincidental or secondary to a pregnancy-re-lated disorder such as HELLP (hemolysis, elevated liverenzymes, and low platelets) syndrome or acute fatty

liver of pregnancy (AFLP). Previous reports have sug-gested that orthotopic liver transplantation (OLT) is asafe and effective therapeutic option for this life-threat-ening condition, either as an antepartum procedure orafter delivery.1-3 We report a case of cryptogenic ALF at26 weeks gestation that was successfully managed viaOLT concurrently with cesarean delivery, and we pro-pose an algorithm for the management of ALF in preg-nancy.

CASE REPORT

A 30-year-old African American woman (gravida 2 para1) had been followed in the high-risk obstetric clinic

because of a history of sickle cell disease. In the 26thweek of her pregnancy with a single fetus, she was

admitted to our institution with the acute onset of 1 to

2 days of thigh pain, nausea, and vomiting. During this

pregnancy, the patient had baseline hemoglobin rang-

ing from 7.7 to 8.9 g/dL and unremarkable prenatal

laboratory studies. She was crisis-free and in goodhealth until this admission. She denied abdominal

pain, decreased fetal movement, vaginal bleeding, con-

tractions, rupture of membranes, pruritus, jaundice,

toxin ingestion, travel, and sick contacts. She had

taken acetaminophen for pain relief in the 24 hours

prior to admission with a total dose of 1650 mg.

Her past medical history was notable for the diagno-

sis of sickle cell disease at age 6, carpal tunnel syn-

drome, left breast lumpectomy of a benign growth at age

22, and right knee arthroscopy at age 23. Allergies were

to diphenhydramine and eggs, which caused swelling

and rash, respectively. Medications included prenatal

vitamins, folic acid, oxycodone, and acetaminophen asneeded. Her family history was significant for sickle cell

Abbreviations: AFLP, acute fatty liver of pregnancy; Ag, antigen; ALF, acute liver failure; ALT, alanine aminotransferase; AMA,antimitochondrial antibody; ANA, antinuclear antibody; ASMA, antismooth muscle antibody; AST, aspartate aminotransferase;CMV, cytomegalovirus; Cr, creatinine; EBV, Epstein-Barr virus; FHF, fulminant hepatic failure; HBV, hepatitis B virus; HCV, hepatitisC virus; HELLP, hemolysis, elevated liver enzymes, and low platelets; HEV, hepatitis E virus; HSV, herpes simplex virus; ICU, intensivecare unit; IgG, immunoglobulin G; IgM, immunoglobulin M; INR, international normalized ratio; OLT, orthotopic liver transplantation;PCR, polymerase chain reaction; TB, total bilirubin.Address reprint requests to Carlos O. Esquivel, M.D., Ph.D., Division of Transplantation, Stanford University School of Medicine, 750 Welch Road,Suite 319, Palo Alto, CA 94304-1510. Telephone: 650-498-5689; FAX: 650-498-5690; E-mail: [email protected]

DOI 10.1002/lt.21820Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 15:1236-1241, 2009

2009 American Association for the Study of Liver Diseases.

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disease, rheumatoid arthritis, type 2 diabetes, coronaryartery disease, cerebrovascular accident, and hyper-tension. The patient was a married homemaker. Sheendorsed no tobacco, alcohol, or drug exposure.

With respect to her sickle cell disease, she experi-enced 2 to 3 crises per year, most recently 10 monthsprior to the current presentation. Her first pregnancy

was complicated by 5 sickle crises, the last of which wasat 35 weeks gestation. At that time, she was noted tohave new proteinuria (1.3 g/L) and transaminitis [peakalanine aminotransferase (ALT), 232 U/L; peak aspar-tate aminotransferase (AST), 436 U/L] without hyper-tension, coagulopathy, or thrombocytopenia. With sup-portive care and blood transfusion, laboratory andclinical abnormalities resolved. A healthy baby girl was

born at 39 weeks via cesarean delivery, which was per-formed for fetal intolerance of labor.

On examination, her temperature was noted to beelevated to 39.2C with normal blood pressure, heartrate, and oxygen saturation. Fetal heart rate tracing

was within normal limits. She was in moderate distress,with normal cardiac and respiratory examinations. Hersclera was nonicteric. The liver was not palpable, andher abdomen was soft and nontender with appropriatefundal height. Her extremity examination was negativefor edema and hyperreflexia. There was no evidence ofhepatic encephalopathy or stigmata of chronic liver dis-ease.

A laboratory evaluation revealed the following: whiteblood cell count, 12.3 K/L; hemoglobin, 8.7 g/dL;hematocrit, 26.4%; platelet count, 761 K/L; creati-nine, 0.7 mg/dL; serum glucose, 83 mg/dL; total bili-rubin level, 3.4 mg/dL (with a direct-to-indirect ratio of2 to 1); AST, 791 U/L; and ALT, 349 U/L. Her interna-

tional normalized ratio (INR) was 1.8. Amylase andlipase were normal, and the lactate dehydrogenase level

was 522 U/L. Hemoglobin S fractionation was 80%,hemoglobin F fractionation was 15%, the uric acid con-centration was 2.7 mg/dL, the haptoglobin concentra-tion was 7 mg/dL, and the reticulocyte count was8.77%. An initial blood smear revealed only Howell-Howell-Jolly bodies and target cells. Urinalysis demon-strated new 1 proteinuria. A chest X-ray revealed in-creased pulmonary vascularity in the upper lobes withmild cardiomegaly. An ultrasound examination re-

vealed a singleton appropriate for a gestational-age fe-tus with an estimated fetal weight of 1030 g, normal

amniotic fluid volume, and placentation.The presumptive diagnosis was sickle cell crisis withhepatic involvement as the patient was not demonstrat-ing signs of HELLP syndrome. The patient was treated

with oxygen, intravenous fluids, narcotics, and antibi-otics. Transfusion of packed red blood cells was initi-ated. On hospital day 2, the patients liver enzymes roseas follows: AST, 4092 U/L; ALT, 1168 U/L; total biliru-

bin, 11.1 mg/dL; and INR, 2.6. She received a course ofcorticosteroids for induction of fetal lung maturity. Thepatient began to experience oxygen desaturation andhad radiographic findings of concern for acute chestsyndrome. She was transferred to the intensive careunit, where she received an exchange transfusion with

8 units of packed red blood cells. The posttransfusionhemoglobin S level was 26%. Her oxygen needed to bestabilized.

The laboratory workup for the etiology for ALF wasnegative, as listed in Table 1. A duplex ultrasound of theliver showed normal hepatic echo texture with patenthepatic and portal veins and appropriate flow and

waveforms in the hepatic arteries. Transjugular liverbiopsy performed on hospital day 2 showed extensivehepatocyte necrosis without histopathological evidenceof microsteatosis to suggest AFLP or sickled erythro-

cytes in the sinusoids to suggest sickle cell hepatopa-thy. There were no viral inclusions to suggest viral hep-atitis, cytomegalovirus, or adenovirus; herpes simplex

virus immunostains were negative; and there was noplasma cell infiltrate.

Despite full supportive measures, the patient contin-ued to manifest worsened hepatic function evidenced

by progressive coagulopathy requiring transfusions offresh frozen plasma to maintain INR 3.0 and stage IIIto IV encephalopathy requiring intubation for airwayprotection on hospital day 4. Following an expeditedevaluation for OLT, she was considered a suitable can-didate for liver transplantation. She became anuric and

developed acute renal failure secondary to hepatorenalsyndrome necessitating continuous venovenous hemo-dialysis. Intensive care unit management also includedelectroencephalogram monitoring to rule out seizureactivity and noninvasive intracranial pressure monitor-ing with transcranial Doppler ultrasound, which re-mained normal.

On hospital day 5 (27 weeks gestation), an appropri-ate liver allograft became available, and she was takento the operating room for combined cesarean deliveryand OLT. The patient received a high transverse cesar-ean section via an infraumbilical vertical midline inci-sion. Delivery was of a viable cephalic male weighing1156 g with Apgar scores of 7 and 8 at 1 and 5 minutes,

TABLE 1. Laboratory Testing for the Evaluation of

Acute Liver Failu re

Negative Serology Negative PCR

ANA HBV DNAASMA HCV RNA

AMA CMV DNAHEV Ag HSV-1/2 DNA HEV IgG EBV DNA HEV IgM Adenovirus DNA

NOTE: HCV antibody was equivocal; iron studies werenormal. The ceruloplasmin level was 55 mg/dL (18-36); thealpha 1-antitrypsin level was 239 mg/dL (100-190).Abbreviations: Ag, antigen; AMA, antimitochondrialantibody; ANA, antinuclear antibody; ASMA, antismoothmuscle antibody; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus;HEV, hepatitis E virus; HSV, herpes simplex virus; IgG,immunoglobulin G; IgM, immunoglobulin M; PCR,polymerase chain reaction.

ACUTE LIVER FAILURE WITH SICKLE CELL DISEASE 1237

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

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respectively. Immediately after delivery, the patient un-

derwent OLT using the standard technique with venousbypass. Measures taken to prevent sickling during im-plantation of the liver included avoidance of hypother-mia, anemia, and hypoxia. Intraoperatively, the patientreceived 10 units of fresh frozen plasma and 5 units ofpacked red blood cells. A histological examination of theliver explant confirmed the biopsy findings of extensivehepatic necrosis, with less than 1% viable hepatocytes,and there was no evidence of vaso-occlusive disease orfeatures of AFLP (Fig. 1). Placental pathology revealedmaternal vasculopathy with sickled red cells identified.

The patient required mechanical ventilation for thefirst 3 postoperative days, during which her mentalstatus steadily improved to her baseline. She continued

to progress well with full recovery of hepatic and renalfunction (Fig. 2). Her immunosuppressive regimen in-cluded tacrolimus, methylprednisolone, and dacli-zumab. Her recovery was complicated by a sickle cellcrisis that was successfully managed with hydration,

blood transfusion, oxygen therapy, and pain control.Hemoglobin S saturation remained 30% without fur-ther exchange transfusion during her entire postoper-ative course. The patient was discharged home on post-

transplant day 28.The postnatal course for the infant was notable for

hyperbilirubinemia on day of life 1, which responded toan exchange transfusion. He had normal liver functionthereafter and otherwise received routine treatment inthe intensive care nursery for extreme prematurity withno evidence of significant intracranial hemorrhage. Theinfant was tested for evidence of inborn errors of me-tabolism, including long-chain 3 hyroxyacyl coenzyme

A dehydrogenase and medium chain acyl coenzyme Adehydrogenase deficiencies, which were within normallimits. He has subsequently been discharged home inexcellent health.

DISCUSSION

This case demonstrates the development of ALF at 26weeks gestation successfully managed via cesarean de-livery at 27 weeks with concurrent OLT. After an exten-sive workup, the etiology of this patients liver failureremained unknown. In the United States, the mostcommon cause of ALF in adults is acetaminophen tox-icity. According to a prospective study conducted by the

Acute Liver Failure Study Group of 17 US centers from1998 to 2001, acetaminophen overdose constituted39% of cases, and it was followed by indeterminatecauses (17%), idiosyncratic drug reactions (13%), and

Figure 1. (A) Histological examination of the liver biopsy andexplanted liver (shown here) demonstrated mild portal chronicinflammation without significant plasma cells. The portal

tracts and central veins showed no evidence of sickle cell

thrombosis or veno-occlusive disease (hematoxylin and eosin,200 ). (B) Massive hepatocyte necrosis was characterized byconfluent hepatocyte death and dropout with less than 1%

residual viable hepatocytes. The necrotic hepatocytes werecharacterized by bright eosinophilic cytoplasm and pyknotic,hyperchromatic nuclei. Mild lobular chronic inflammation

was also present. No significant plasma cell infiltrate wasidentified (hematoxylin and eosin, 200 ).

Figure 2. Serum chemistries during time points before, dur-ing, and after OLT. Time 0 is the day of OLT. Abbreviations:

ALT, alanine aminotransferase (U/L); Cr, creatinine (mg/dL;

on continuous venovenous hemodialysis or hemodialysis at alltime points except day 28); INR, international normalizedratio; OLT, orthotopic liver transplantation; TB, total biliru-

bin (mg/dL).

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viral hepatitis A or B (12%).4 When our patient pre-sented in the first week of the third trimester of preg-

nancy with evidence of sickle cell crisis and rapidlyrising aminotransferases, 2 less common causes, vaso-occlusive hepatopathy due to acute sickle crises andpregnancy-related liver disease such as AFLP or HELLPsyndrome, were considered in the etiology of her ALF.

As these etiologies would be treated very differently andhad different implications for continuing the pregnancy

versus terminating the pregnancy, liver biopsy was es-sential to aid us in determining the cause of ALF and inmaking a treatment plan.

The experience of OLT for sickle cellinduced liverfailure is limited, and the results are mixed. Acute liverinjury from sickle cell crisis is the result of vascularocclusion from sickle cell thrombi and sinusoidal ex-

pansion and congestion.5The subsequent clinical spec-trum ranges from benign liver enzyme abnormalities to

hepatic necrosis and/or acute cholestasis. The clinicalpresentation is characterized by acute right upperquadrant pain, nausea, tender hepatomegaly, elevatedlevels of AST and ALT (usually300 U/L but possibly6000 U/L), and hyperbilirubinemia (from mild to se-

vere). This acute liver injury can resolve with treatmentof the sickle crisis or, depending on the amount ofhepatic necrosis, can lead to progressive liver failure. Inone small case series examining patients with sickle celldisease and liver dysfunction, of the 20 patients whopresented with acute liver injury, 8 died during theirfirst admission.6 Liver transplant for the managementof ALF due to an acute sickle crisis has variable out-comes, with a high incidence of demise of the patient in

Figure 3. Proposed algorithmfor the management of acuteliver failure in pregnancy.Abbre-viations: AFLP, acute fatty liverof pregnancy; FHF, fulminanthepatic failure; HELLP, hemoly-

sis, elevated liver enzymes, andlow platelets; ICU, intensive careunit; OLT, orthotopic liver

transplantation.



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the postoperative period or failure of the transplantedliver secondary to vaso-occlusion.7-9Those authors rec-ommended maintaining the hemoglobin S fraction be-low 30% after OLT to decrease the risk of future crisesand thus subsequent graft injury. This patient did notpresent with right upper quadrant pain or hepatomeg-aly, and liver biopsy, although showing extensive ne-

crosis, failed to demonstrate the findings of acute sicklehepatopathy as described previously.

There is very little information on the management ofALF during pregnancy. We have created an algorithmfor the management of this condition, realizing that thetreatment must be individualized on the basis of thelength and evolution of the pregnancy and the degree ofliver failure (Fig. 3). First, a pregnant patient with liverdysfunction must be referred to a tertiary care centerthat offers OLT. The importance of establishing preg-nancy-related ALF is paramount, as delivery is thetreatment for this condition and most often results in arapid return to baseline hepatic function. HELLP syn-

drome is a variant of severe pre-eclampsia, which isconsidered an endothelial cell disorder characterized byhemolysis, mild to moderately elevated liver enzymes,and low platelets, usually in the setting of elevated

blood pressures and proteinuria. It is associated withsignificant maternal and fetal morbidity and rarely withsevere outcomes such as subcapsular liver hematomaand hepatic rupture. Maternal mortality is rare, andprompt treatment with delivery is curative. Althoughthis patient demonstrated hemolysis and proteinuria,in the absence of hypertension and thrombocytopenia,

we were not able to conclusively diagnose an endothe-lial cell disorder. To complicate the presentation fur-ther, both the hemolysis and proteinuria can also be

attributed to her sickle disease and ongoing crisis.AFLP is a rare but severe condition with maternal

mortality rates as high as 12% and perinatal mortalityup to 66% in some reports.10,11 Patients often present

with right upper quadrant pain and moderate trans-aminitis (1000 U/L) and can progress to acute renalfailure, acute pancreatitis, hypoglycemia, and infec-tion. Maternal or fetal fatty acid oxidation defects have

been suggested as common associated factors. As withHELLP syndrome, early diagnosis and timely deliveryare lifesaving for both the mother and fetus, but con-tinued hepatic failure and subsequent liver transplan-tation occur if the degree of hepatocyte necrosis is ad-

vanced. Although liver biopsy to prove the presence ofAFLP is not considered standard of care prior to deliveryof the fetus, in our case, liver biopsy was a necessarypart of our decision-making process. Without a defini-tive diagnosis of a pregnancy-related cause of liver fail-ure, pretransplantation delivery of the fetus from a pa-tient in a virtually anhepatic state almost assuredly willalso lead to her demise.

In this case, transjugular liver biopsy demonstratedan absence of microvesicular fatty infiltration, did notshow evidence of vaso-occlusive disease, and displayedmassive necrosis with less than 1% viable hepatocytes.On the basis of these findings, it was concluded that thepatient did not have pregnancy-related liver disease,

and the decision was made to allow the pregnancy tocontinue while she awaited OLT.

The timing of fetal delivery with respect to the time ofOLT in cases in which delivery will not likely contributeto improving the patients condition is controversial.

There have been several reports of OLT while the fetusis maintained in utero, although few have been at a

postviable gestational age. Most describe previable pro-cedures with variable fetal outcomes.12 Three caseshave been reported of previable transplantation thatresulted in live-born infants post-viability.13-15 Theseprocedures were performed at 20 to 22 weeks gesta-tion, and at delivery, the gestational age range was 27 to30 weeks. Moreno et al.2 described 1 case of a postvi-ability transplant that resulted in a successful fetaloutcome, with transplant at 27 weeks for cryptogenic

ALF and subsequent scheduled cesarean delivery of ahealthy infant at 39 weeks gestation. In other reports,postviability OLT performed between 26 and 27 weeksgestation has resulted in delivery and neonatal death 2

to 14 days after transplant.

1,16,17

We are aware of 1other successful case of combined OLT and cesareansection reported in the peer-reviewed literature. Theprocedure was performed at 32 weeks gestation forBudd-Chiari syndrome.3

In conclusion, the availability of expert care in trans-plant surgery, hepatology, intensivist medicine, inter-

ventional radiology, perinatology, and neonatologymust be considered when one is presented with a preg-nant patient in ALF. The continual improvement of neo-natal intensive care at the extremes of prematurity in atertiary center is a factor that may affect the use of thisalgorithm in the future to maximize potential outcomesfor both the patient and fetus.

REFERENCES

1. Laifer SA, Abu-Elmgard K, Fung J. Hepatic transplanta-tion during pregnancy and the puerperium. J Matern-Fetal Med 1997;6:40-44.

2. Moreno EG, Garcia GI, Gomez SR, Gonzalez-Pinto I,Loinaz SC, Ibanez AJ, et al. Fulminant hepatic failureduring pregnancy successfully treated by orthotopic livertransplantation. Transplantation 1991;52:923-926.

3. Valentine JM, Parkin G, Pollard SG, Bellamy MC. Com-bined orthotopic liver transplantation and caesarean sec-tion for the Budd-Chiari syndrome. Br J Anaesth 1995;75:105-108.

4. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, DavernTJ, Han SH, et al. Results of a prospective study of acuteliver failure at 17 tertiary care centers in the United States.Ann Intern Med 2002;137:947-954.

5. Mills LR, Mwakyusa D, Milner PF. Histopathologic fea-tures of liver biopsy specimens in sickle cell disease. ArchPathol Lab Med 1988;112:290-294.

6. Berry PA, Cross TJS, Thein SL, Portmann BC, Wendon JA,Karani JB, et al. Hepatic dysfunction in sickle cell disease:a new system of classification based on global assessment.Clin Gastroenterol Hepatol 2007;5:1469-1476.

7. Emre S, Kitibayashi K, Schwartz ME, Ahn J, Birnbaum A,Thung SN, Miller CM. Liver transplantation in a patientwith acute liver failure due to sickle cell intrahepatic cho-lestasis. Transplantation 2000;69:675-676.

8. Baichi N, Arifuddin RM, Mantry PS, Bozorgzadeh A, Ryan C.

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Liver transplantation in sickle cell anemia: a case of acutesickle cell intrahepatic cholestasis and a case of sclerosingcholangitis. Transplantation 2005;80:1630-1632.

9. van den Hazel SJ, Metselaar HJ, Tilanus HW, IjzermansJN, Groenland TH, Visser L, de Man RA. Successful livertransplantation in a patient with sickle-cell anaemia.Transpl Int 2003;16:434-436.

10. Hepburn IS, Schade RR. Pregnancy associated liver disor-

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12. Laifer SA, Darby MJ, Scantlebury VP, Harger JH, CaritisSN. Pregnancy and liver transplantation. Obstet Gynecol1990;76:1083-1088.

13. Fair J, Klein AS, Feng T, Merrit WT, Burdick JF. Intrapar-tum orthotopic liver transplantation with successful out-come of pregnancy. Transplantation 1990;50:534-535.

14. Catnach SM, McCarthy M, Jauniaux E, Fitt S, Tan K,Nicolaides K, Williams R. Liver transplantation duringpregnancy complicated by cytomegalovirus infection.Transplantation 1995;60:510-511.

15. Jarufe N, Soza A, Perez-Ayuso RM, Poblete JA, Gonzalez R,Guajardo M, et al. Successful liver transplantation anddelivery in a woman with fulminant hepatic failure occur-ring during the second trimester of pregnancy. Liver Int

2006;26:494-497.16. Morris CV, GoldsteinRM, Cofer JB, Solomon H, Klintmalm GB.

An unusual presentation of fulminant hepatic failure sec-ondary to propylthiouracil therapy. In: Terasaki PI, ed. Clin-ical Transplants. Published by UCLA Tissue Typing Labora-tory, Los Angeles, CA; 1989:311.

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