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Diagnostic Challenges in the Evaluation of Hepatic Grafts From Donors With HELLP Syndrome: Case Report and Review of the Literature
Diagnostic Challenges in the Evaluation of Hepatic Grafts From Donors With HELLP Syndrome: Case Report and Review of the Literature W.H. Kitchens, A.B. Adams, C.B. Hughes, and R.M. Subramanian ABSTRACT HELLP syndrome (hemolysis, elevated liver function tests, low platelets) is a rare complication of pregnancy that can result in severe complications such as hepatic infarction, subcapsular liver hematomas, and maternal brain death from cerebral hemorrhage. Recently, several investigators have described cases of successful transplantation using livers procured from donors who suffered brain death as a result of HELLP syndrome. However, this new class of marginal liver donors must be approached with caution. We report the case of a 28-year-old pregnant woman who suffered brain death due to HELLP syndrome and was subsequently evaluated for potential liver donation. Although her transaminitis and other liver function tests were markedly improving during the final days of her hospital course, her liver demonstrated segments of necrosis during attempted procurement, and the histology revealed extensive centrilobular necrosis. This case suggests that peak values of serum transaminases, as well as partial resolution of transaminitis, appear to have limited predictive ability in determining the suitability of the hepatic graft for transplantation. Thus, donors with HELLP syndrome should be approached with caution, even in the setting of laboratory values suggesting minimal or resolving hepatic injury. Furthermore, there should be an additional emphasis on obtaining and reviewing histology of the potential graft to determine its suitability for transplantation. HE CONSTELLATION OF SYMPTOMS known collectively as HELLP syndrome (hemolysis, elevated liver function tests, low platelets) develops in 0.17% to 0.85% of all pregnancies and is often associated with right upper-quadrant pain as a result of hepatic infarction and subcapsular liver hematomas.1 Liver transplantation has long been established as a potentially lifesaving intervention for some patients who develop HELLP syndrome and experience spontaneous rupture of these subcapsular hematomas.2,3 Among the most feared complications of HELLP syndrome is cerebral hemorrhage, with a resulting maternal mortality of 50% to 65%.1 Recently, several investigators have reported the successful transplantation of livers procured from donors with HELLP syndrome complicated by cerebral hemorrhage. However, this new class of potential liver donors must be approached with caution, as demonstrated by the following case of a patient with HELLP syndrome whose liver demonstrated large segments of centrilobular necrosis, despite reassuring laboratory values prior to procurement.
T
CASE REPORT A 28-year-old woman who had a 35-week gestational age pregnancy presented to her obstetrician’s office complaining of newonset nausea and constant sharp right upper-quadrant and epigastric abdominal pain of 24-hour duration. She had a history notable only for three previous pregnancies, all delivered preterm via caesarian section and all notable for pregnancy-induced hypertension. Her obstetrician referred her to a local emergency department, where her presenting blood pressure was 189/94, ultimately reaching 194/116 despite the administration of labetalol. Her platelets on admission were 93,000/L. Her additional laboratory values were significant for elevated transaminases (aspartate aminotransferase [AST] 186 IU/L, alanine aminotransferase [ALT] 174 IU/L), a serum bilirubin of 1.5 mg/dL, an international normalized ratio (INR) of 1.04 and a serum lactate dehydrogenase (LDH) of 720 IU/mL. She was diagnosed with HELLP syndrome and was transferred emergently to labor and delivery for prompt From the Departments of Medicine and Surgery, Emory University, Atlanta, Georgia Address reprint requests to Dr Ram Subramanian, MD, Emory University, 1365 Clifton Rd NE, Atlanta, GA. E-mail: rmsubra@ emory.edu
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.08.073
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
4010
Transplantation Proceedings, 43, 4010 – 4012 (2011)
DONORS WITH HELLP SYNDROME
4011
fetal delivery. While being evaluated, she had a seizure and experienced the onset of left hemiparesis. After undergoing an emergent caesarian section, she was taken to the intensive care unit postoperatively, where her pupils were noted to be fixed and dilated. Computed tomography scan of her brain revealed a 4.6 ⫻ 3.3-cm intraparenchymal hematoma in the right basal ganglia with extension into the ventricular system, marked midline shift, and severe cerebral edema. A repeat brain scan revealed no interval improvement and an electroencephalogram showed no activity. After failing an apnea test, brain death was declared 2 days after admission. At this stage, the patient was evaluated and consented for organ donation, and aggressive donor management in consultation with an intensivist was initiated. Following the declaration of brain death, the patient’s clinical course was characterized by a stable cardiopulmonary and renal status. Her liver function tests peaked 18 hours after admission with a total bilirubin of 8.7 mg/dL, AST 1488 IU/L, and ALT 1116 IU/L; the INR remained unchanged at 1.0. Over the remainder of her hospital course, her transaminitis began to resolve, reaching final values of an AST of 483 IU/L and ALT of 485 IU/L at the time of organ procurement. Despite improving liver function tests, the liver at the time of procurement was found to be congested, with segments of hepatocellular necrosis (Fig 1A). A liver biopsy revealed moderate centrilobular (zone 3) hepatocellular necrosis (Fig 1B). Given the operative and histological findings, the liver was not used for transplantation. The heart and one kidney from the donor were found suitable for transplantation.
DISCUSSION
While the use of kidneys from donors with HELLP syndrome is well established,4 recent case reports have emerged describing the successful transplantation of livers procured from this new class of marginal donors.5–9 To date, six liver transplants using a donor with HELLP syndrome have been described in the literature (Table 1), including a pair of transplants that utilized portions of a split liver from a single HELLP donor.5 In general, good patient outcomes have been reported, with four of six patients still alive at the time of publication (follow-up 28 days to 2 years posttransplant). Of the two recipients who died, one developed posttransplant lymphoproliferative disease 9 months posttransplant,7 and the other developed severe early graft dysfunction (with encephalopathy, dialysis-dependent renal failure, and an INR of 5.3 on postoperative day 2) before dying of sepsis on postoperative day 39.5 While these earlier cases demonstrate the clinical potential of HELLP syndrome donors, the current case report demonstrates that caution is mandated before using these marginal donors. The transaminitis in this patient was resolving at the time of procurement, and even at its peak it was comparable to those transplanted successfully in previous reports. Despite an encouraging trend in laboratory values, the liver showed evidence of gross injury at the time of attempted procurement, and histological evidence of marked centrilobular necrosis. Interestingly, two other reports of liver mottling resulting in graft discard have been published.7,10 In one of these, the liver appeared grossly normal upon procurement but upon rebiopsy immediately prior to implantation, approximately 30% of lobules had evidence of necrosis, suggestive of evolving injury during cold ischemia in these organs from HELLP patients.10 Concern regarding livers
Fig 1. Liver from a donor with HELLP syndrome (hemolysis, elevated liver function tests, low platelets) at the time of procurement. (A) Inspection of the organ revealed a congested liver with focal areas of necrosis. (B) Biopsy of the liver revealed extensive centrilobular necrosis.
from HELLP donors is also raised by the report of severe early graft dysfunction developing in at least two recipients.5 In conclusion, organs from donors who die of HELLP syndrome may be suitable for transplant, although extreme care should be given to screen them thoroughly pretransplant. Peak values of serum transaminases, as well as partial resolution of transaminitis, appear to have limited predictive ability in determining the suitability of the hepatic graft for transplantation. The liberal use of biopsy at the time of procurement is encouraged to avoid missing occult liver injury not reflected in serum laboratory values. Given reports of evolving liver injury during periods of cold ischemia, efforts should be made to minimize these times when using these marginal organs. REFERENCES 1. Mihu D, Costin N, Mihu CM, et al: HELLP syndrome—a multisystemic disorder. J Gastrointestin Liver Dis 16:419, 2007
4012
KITCHENS, ADAMS, HUGHES ET AL Table 1. Summary of the Published Experience Using Liver Grafts Obtained From Donors With HELLP Syndrome Donor age (y)
Recipient age (y)
Recipient indication
9 8
27 23
51 63
HBV PBC
7
30
37
5
42
5
42
6
30
32
10
37
7
24
Reference
Final AST (peak)*
Final ALT (peak)*
Final TBi (peak)†
Outcome
878 3⫻ normal (20⫻ normal) 40 (700)
592 3⫻ normal (20⫻ normal) 62 (405)
1.9 N/A
Alive 9 mo posttransplant Alive 5 mo posttransplant
1.9 (3.4)
16
14
0.5
HBV with 5 cm HCC
16
14
0.5
716 (2746)
1980 (2130)
3.41 (3.41)
N/A
Fulminant HBV/ deltavirus coinfection N/A
Died of PTLD 9 mo posttransplant Alive 2 y posttransplant after early dysfunction (INR 3.3 on POD 2) Died on POD 39 after developing severe early graft dysfunction (INR 5.3 on POD 2 with encephalopathy and ESRD) Alive 28 d posttransplant
(1419)
(435)
(2.3)
N/A
N/A
213 (1082)
216 (593)
1.2 (2.8)
1 (received segments 2/3) 64 (received right lobe)
Cryptogenic cirrhosis Biliary atresia
Liver procured, found to have ⬎30% necrosis on rebiopsy Liver mottled/congested, not procured
N/A, not available/applicable; TBi, total bilirubin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis; PTLD, posttransplant lymphoproliferative disease; ESRD, end-stage renal disease; HELLP syndrome, hemolysis, elevated liver function tests, low platelets; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio; POD, postoperative day. *Transaminases measured in IU/L. † TBi measured in mg/dL.
2. Zarrinpar A, Farmer DG, Ghobrial RM, et al: Liver transplantation for HELLP syndrome. Am Surg 73:1013, 2007 3. Shames BD, Fernandez LA, Sollinger HW, et al: Liver transplantation for HELLP syndrome. Liver Transpl 11:224, 2005 4. Flynn MF, Power RE, Murphy DM, et al: Successful transplantation of kidneys from a donor with HELLP syndrome-related death. Transpl Int 14:108, 2001 5. Yasutomi M, McCall J, Munn S, et al: In situ split liver transplantation using a donor with a recent history of HELLP syndrome. Transplantation 81:639, 2006 6. Moussavian MR, Kollmar O, Richter S, et al: Liver transplantation of a HELLP syndrome donor liver in acute fulminant hepatitis B with deltavirus coinfection. Transpl Int 19:1030, 2006
7. Briceno PJ, Ortiz JA, Manzarbeitia C, et al: Liver transplantation using an organ donor with HELLP syndrome. Transplantation 77:137, 2004 8. Baron PW, Ojogho ON, Chick W, et al: Successful liver transplantation using a HELLP syndrome donor. Transplantation 78:782, 2004 9. Nardo B, Montalti R, Beltempo P, et al: Successful liver transplantation from an eclamptic donor complicated by the HELLP syndrome. Transplantation 76:440, 2003 10. Woodside KJ, Knisely AS, Strauss AW, et al: Progression of hepatic damage during cold storage after procurement in a liver and kidney donor with HELLP syndrome. Transplantation 72: 1990, 2001
T
CASE REPORT A 28-year-old woman who had a 35-week gestational age pregnancy presented to her obstetrician’s office complaining of newonset nausea and constant sharp right upper-quadrant and epigastric abdominal pain of 24-hour duration. She had a history notable only for three previous pregnancies, all delivered preterm via caesarian section and all notable for pregnancy-induced hypertension. Her obstetrician referred her to a local emergency department, where her presenting blood pressure was 189/94, ultimately reaching 194/116 despite the administration of labetalol. Her platelets on admission were 93,000/L. Her additional laboratory values were significant for elevated transaminases (aspartate aminotransferase [AST] 186 IU/L, alanine aminotransferase [ALT] 174 IU/L), a serum bilirubin of 1.5 mg/dL, an international normalized ratio (INR) of 1.04 and a serum lactate dehydrogenase (LDH) of 720 IU/mL. She was diagnosed with HELLP syndrome and was transferred emergently to labor and delivery for prompt From the Departments of Medicine and Surgery, Emory University, Atlanta, Georgia Address reprint requests to Dr Ram Subramanian, MD, Emory University, 1365 Clifton Rd NE, Atlanta, GA. E-mail: rmsubra@ emory.edu
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.08.073
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
4010
Transplantation Proceedings, 43, 4010 – 4012 (2011)
DONORS WITH HELLP SYNDROME
4011
fetal delivery. While being evaluated, she had a seizure and experienced the onset of left hemiparesis. After undergoing an emergent caesarian section, she was taken to the intensive care unit postoperatively, where her pupils were noted to be fixed and dilated. Computed tomography scan of her brain revealed a 4.6 ⫻ 3.3-cm intraparenchymal hematoma in the right basal ganglia with extension into the ventricular system, marked midline shift, and severe cerebral edema. A repeat brain scan revealed no interval improvement and an electroencephalogram showed no activity. After failing an apnea test, brain death was declared 2 days after admission. At this stage, the patient was evaluated and consented for organ donation, and aggressive donor management in consultation with an intensivist was initiated. Following the declaration of brain death, the patient’s clinical course was characterized by a stable cardiopulmonary and renal status. Her liver function tests peaked 18 hours after admission with a total bilirubin of 8.7 mg/dL, AST 1488 IU/L, and ALT 1116 IU/L; the INR remained unchanged at 1.0. Over the remainder of her hospital course, her transaminitis began to resolve, reaching final values of an AST of 483 IU/L and ALT of 485 IU/L at the time of organ procurement. Despite improving liver function tests, the liver at the time of procurement was found to be congested, with segments of hepatocellular necrosis (Fig 1A). A liver biopsy revealed moderate centrilobular (zone 3) hepatocellular necrosis (Fig 1B). Given the operative and histological findings, the liver was not used for transplantation. The heart and one kidney from the donor were found suitable for transplantation.
DISCUSSION
While the use of kidneys from donors with HELLP syndrome is well established,4 recent case reports have emerged describing the successful transplantation of livers procured from this new class of marginal donors.5–9 To date, six liver transplants using a donor with HELLP syndrome have been described in the literature (Table 1), including a pair of transplants that utilized portions of a split liver from a single HELLP donor.5 In general, good patient outcomes have been reported, with four of six patients still alive at the time of publication (follow-up 28 days to 2 years posttransplant). Of the two recipients who died, one developed posttransplant lymphoproliferative disease 9 months posttransplant,7 and the other developed severe early graft dysfunction (with encephalopathy, dialysis-dependent renal failure, and an INR of 5.3 on postoperative day 2) before dying of sepsis on postoperative day 39.5 While these earlier cases demonstrate the clinical potential of HELLP syndrome donors, the current case report demonstrates that caution is mandated before using these marginal donors. The transaminitis in this patient was resolving at the time of procurement, and even at its peak it was comparable to those transplanted successfully in previous reports. Despite an encouraging trend in laboratory values, the liver showed evidence of gross injury at the time of attempted procurement, and histological evidence of marked centrilobular necrosis. Interestingly, two other reports of liver mottling resulting in graft discard have been published.7,10 In one of these, the liver appeared grossly normal upon procurement but upon rebiopsy immediately prior to implantation, approximately 30% of lobules had evidence of necrosis, suggestive of evolving injury during cold ischemia in these organs from HELLP patients.10 Concern regarding livers
Fig 1. Liver from a donor with HELLP syndrome (hemolysis, elevated liver function tests, low platelets) at the time of procurement. (A) Inspection of the organ revealed a congested liver with focal areas of necrosis. (B) Biopsy of the liver revealed extensive centrilobular necrosis.
from HELLP donors is also raised by the report of severe early graft dysfunction developing in at least two recipients.5 In conclusion, organs from donors who die of HELLP syndrome may be suitable for transplant, although extreme care should be given to screen them thoroughly pretransplant. Peak values of serum transaminases, as well as partial resolution of transaminitis, appear to have limited predictive ability in determining the suitability of the hepatic graft for transplantation. The liberal use of biopsy at the time of procurement is encouraged to avoid missing occult liver injury not reflected in serum laboratory values. Given reports of evolving liver injury during periods of cold ischemia, efforts should be made to minimize these times when using these marginal organs. REFERENCES 1. Mihu D, Costin N, Mihu CM, et al: HELLP syndrome—a multisystemic disorder. J Gastrointestin Liver Dis 16:419, 2007
4012
KITCHENS, ADAMS, HUGHES ET AL Table 1. Summary of the Published Experience Using Liver Grafts Obtained From Donors With HELLP Syndrome Donor age (y)
Recipient age (y)
Recipient indication
9 8
27 23
51 63
HBV PBC
7
30
37
5
42
5
42
6
30
32
10
37
7
24
Reference
Final AST (peak)*
Final ALT (peak)*
Final TBi (peak)†
Outcome
878 3⫻ normal (20⫻ normal) 40 (700)
592 3⫻ normal (20⫻ normal) 62 (405)
1.9 N/A
Alive 9 mo posttransplant Alive 5 mo posttransplant
1.9 (3.4)
16
14
0.5
HBV with 5 cm HCC
16
14
0.5
716 (2746)
1980 (2130)
3.41 (3.41)
N/A
Fulminant HBV/ deltavirus coinfection N/A
Died of PTLD 9 mo posttransplant Alive 2 y posttransplant after early dysfunction (INR 3.3 on POD 2) Died on POD 39 after developing severe early graft dysfunction (INR 5.3 on POD 2 with encephalopathy and ESRD) Alive 28 d posttransplant
(1419)
(435)
(2.3)
N/A
N/A
213 (1082)
216 (593)
1.2 (2.8)
1 (received segments 2/3) 64 (received right lobe)
Cryptogenic cirrhosis Biliary atresia
Liver procured, found to have ⬎30% necrosis on rebiopsy Liver mottled/congested, not procured
N/A, not available/applicable; TBi, total bilirubin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis; PTLD, posttransplant lymphoproliferative disease; ESRD, end-stage renal disease; HELLP syndrome, hemolysis, elevated liver function tests, low platelets; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio; POD, postoperative day. *Transaminases measured in IU/L. † TBi measured in mg/dL.
2. Zarrinpar A, Farmer DG, Ghobrial RM, et al: Liver transplantation for HELLP syndrome. Am Surg 73:1013, 2007 3. Shames BD, Fernandez LA, Sollinger HW, et al: Liver transplantation for HELLP syndrome. Liver Transpl 11:224, 2005 4. Flynn MF, Power RE, Murphy DM, et al: Successful transplantation of kidneys from a donor with HELLP syndrome-related death. Transpl Int 14:108, 2001 5. Yasutomi M, McCall J, Munn S, et al: In situ split liver transplantation using a donor with a recent history of HELLP syndrome. Transplantation 81:639, 2006 6. Moussavian MR, Kollmar O, Richter S, et al: Liver transplantation of a HELLP syndrome donor liver in acute fulminant hepatitis B with deltavirus coinfection. Transpl Int 19:1030, 2006
7. Briceno PJ, Ortiz JA, Manzarbeitia C, et al: Liver transplantation using an organ donor with HELLP syndrome. Transplantation 77:137, 2004 8. Baron PW, Ojogho ON, Chick W, et al: Successful liver transplantation using a HELLP syndrome donor. Transplantation 78:782, 2004 9. Nardo B, Montalti R, Beltempo P, et al: Successful liver transplantation from an eclamptic donor complicated by the HELLP syndrome. Transplantation 76:440, 2003 10. Woodside KJ, Knisely AS, Strauss AW, et al: Progression of hepatic damage during cold storage after procurement in a liver and kidney donor with HELLP syndrome. Transplantation 72: 1990, 2001