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{{Infobox medical condition (new)
{{Infobox_Disease |
Name = {{PAGENAME}} |
| name = Acute fatty liver of pregnancy
Image = |
| synonyms =
Caption = |
| image =
DiseasesDB = 32879 |
| caption =
ICD10 = |
| pronounce =
| field = [[Obstetrics]], <br />[[Perinatology]], <br />[[Hepatology]]
⚫
ICD9 = |
ICDO = |
| symptoms =
| complications = [[Death]], [[Disseminated intravascular coagulation]]
⚫
OMIM = |
| onset = Third trimester of pregnancy
⚫
MedlinePlus = |
| duration =
⚫
eMedicineSubj = |
| types =
⚫
eMedicineTopic = |
| causes = [[Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency]]
| risks =
| diagnosis = [[Clinical history]] and [[physical examination]] <br /> [[Liver biopsy]] (rarely needed)
| differential =
| prevention =
| treatment = Prompt delivery of the infant, <br /> Intensive supportive care <br />[[Liver transplantation]]
| medication =
| prognosis =
| frequency = 1 in 7,000 to 1 in 15,000 pregnancies
| deaths = 18%<ref name="HinHinKo" />
}}
}}
'''Acute fatty liver of pregnancy''' is a rare life-threatening complication of [[pregnancy]] that occurs in the third trimester or the immediate period after delivery.<ref name=HinHinKo>Ko HH, Yoshida EM. Acute fatty liver of pregnancy. ''Can J Gastroenterol.'' 2006 Jan;20(1):25-30. PMID 16432556 </ref> It is thought to be caused by a disordered metabolism of [[fatty acid]]s by [[mitochondria]] in the fetus, caused by [[Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency|deficiency in the '''LCHAD''']] (long-chain 3-hydroxyacyl-coenzyme A dehydrogenase) [[enzyme]].<ref name=Bellig>Bellig LL. Maternal acute fatty liver of pregnancy and the associated risk for long-chain 3-hydroxyacyl-coenzyme a dehydrogenase (LCHAD) deficiency in infants. ''Adv Neonatal Care''. 2004 Feb;4(1):26-32. PMID 14988877.</ref> The condition was previously thought to be universally fatal <ref name=Mjahed>Mjahed K, Charra B, Hamoudi D, Noun M, Barrou L. Acute fatty liver of pregnancy. ''Arch Gynecol Obstet.'' 2006 Jul 26 (electronic) PMID 16868757</ref>, but aggressive treatment by stabilizing the mother with [[intravenous]] fluids and [[blood]] products in anticipation of early [[delivery]], has improved [[prognosis]].<ref name=ACG>Riely CA. Liver disease in the pregnant patient. American College of Gastroenterology guidelines. ''Am J Gastroenterol'' 1999 Jul;94(7):1728-32. PMID 10406228 </ref>
'''Acute fatty liver of pregnancy''' is a rare life-threatening complication of [[pregnancy]] that occurs in the third trimester or the immediate period after delivery.<ref name="HinHinKo">{{Cite journal |vauthors=Ko H, Yoshida EM |year=2006 |title=Acute fatty liver of pregnancy |journal=Canadian Journal of Gastroenterology |volume=20 |issue=1 |pages=25–30 |doi=10.1155/2006/638131 |pmc=2538964 |pmid=16432556 |doi-access=free}}</ref> It is thought to be caused by a disordered metabolism of [[fatty acid]]s by [[mitochondria]] in the fetus, caused by [[long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency]].<ref name="Bellig">{{Cite journal |last=Bellig LL |year=2004 |title=Maternal acute fatty liver of pregnancy and the associated risk for long-chain 3-hydroxyacyl-coenzyme a dehydrogenase (LCHAD) deficiency in infants |journal=Advances in Neonatal Care |volume=4 |issue=1 |pages=26–32 |doi=10.1016/j.adnc.2003.12.001 |pmid=14988877 |s2cid=29356240}}</ref> This leads to decreased metabolism of long chain fatty acids by the feto-placental unit, causing subsequent rise in hepatotoxic fatty acids in maternal plasma. The condition was previously thought to be universally fatal,<ref name="Mjahed">{{Cite journal |vauthors=Mjahed K, Charra B, Hamoudi D, Noun M, Barrou L |year=2006 |title=Acute fatty liver of pregnancy |journal=Archives of Gynecology and Obstetrics |volume=274 |issue=6 |pages=349–353 |doi=10.1007/s00404-006-0203-6 |pmid=16868757 |s2cid=24784165}}</ref> but aggressive treatment by stabilizing the mother with [[intravenous]] fluids and [[blood]] products in anticipation of early [[Childbirth|delivery]] has improved [[prognosis]].<ref name="ACG">{{Cite journal |last=Riely CA |year=1999 |title=Liver disease in the pregnant patient. American College of Gastroenterology |journal=The American Journal of Gastroenterology |volume=94 |issue=7 |pages=1728–1732 |doi=10.1111/j.1572-0241.1999.01199.x |pmid=10406228 |s2cid=36694459 |doi-access=free}}</ref>


==Signs and symptoms==
==Clinical manifestations==
Acute fatty liver of pregnancy (or hepatic lipidosis of pregnancy) usually manifests in the third trimester of pregnancy, but may occur any time in the second half of pregnancy, or in the [[puerperium]], the period immediately after delivery.<ref name=HinHinKo/> On average, the disease presents during the 35th or 36th week of pregnancy.<ref name=Riely>Riely CA. Acute fatty liver of pregnancy. ''Semin Liver Dis.'' 1987 Feb;7(1):47-54. PMID 3296215 </ref>. The usual symptoms in the mother are non-specific including [[nausea]], [[vomiting]], [[anorexia (symptom)|anorexia]] (or lack of desire to eat) and abdominal pain <ref name=Riely/>; however, [[jaundice]] and [[fever]] may occur in as many as 70% of patients.<ref name=HinHinKo/><ref>Riely CA, Latham PS, Romero R, Duffy TP. Acute fatty liver of pregnancy. A reassessment based on observations in nine patients. ''Ann Intern Med.'' 1987 May;106(5):703-6. PMID 3565968.</ref>
Acute fatty liver of pregnancy (or hepatic lipidosis of pregnancy) usually manifests in the third trimester of pregnancy, but may occur any time in the second half of pregnancy, or in the [[puerperium]], the period immediately after delivery.<ref name=HinHinKo/> On average, the disease presents during the 35th or 36th week of pregnancy.<ref name="Riely">{{Cite journal |last=Riely CA |year=1987 |title=Acute fatty liver of pregnancy |journal=Seminars in Liver Disease |volume=7 |issue=1 |pages=47–54 |doi=10.1055/s-2008-1040563 |pmid=3296215}}</ref> The usual symptoms in the mother are non-specific including [[nausea]], [[vomiting]], [[anorexia (symptom)|anorexia]] (or lack of desire to eat) and abdominal pain; excessive thirst may be the earliest symptom without overlap with otherwise considered normal pregnancy symptoms;<ref name=Riely/> however, [[jaundice]] and [[fever]] may occur in as many as 70% of patients.<ref name=HinHinKo/><ref>{{Cite journal |vauthors=Riely CA, Latham PS, Romero R, Duffy TP |year=1987 |title=Acute fatty liver of pregnancy. A reassessment based on observations in nine patients |journal=Annals of Internal Medicine |volume=106 |issue=5 |pages=703–6 |doi=10.7326/0003-4819-106-5-703 |pmid=3565968}}</ref>


In more patients with more severe disease, [[pre-eclampsia]] may occur, which involves [[hypertension|elevation of blood pressure]] and accumulation of fluid (termed [[edema]]).<ref name=Riely/> This may progress to involvement of additional systems, including [[acute renal failure]],<ref>Koroshi A, Babameto A. Acute renal failure during acute fatty liver of pregnancy. ''Nephrol Dial Transplant''. 2002 Jun;17(6):1110-2. PMID 12032205</ref> [[hepatic encephalopathy]],<ref>Aggarwal R. Hepatic encephalopathy in pregnancy. ''Indian J Gastroenterol.'' 2003 Dec;22 Suppl 2:S78-80. PMID 15025263</ref> and [[pancreatitis]].<ref name=Pancreas>Moldenhauer JS, O'brien JM, Barton JR, Sibai B. Acute fatty liver of pregnancy associated with pancreatitis: a life-threatening complication. ''Am J Obstet Gynecol.'' 2004 Feb;190(2):502-5. PMID 14981397</ref> There have also been reports of [[diabetes insipidus]] complicating this condition.<ref>Kennedy S, Hall PM, Seymour AE, Hague WM. Transient diabetes insipidus and acute fatty liver of pregnancy. ''Br J Obstet Gynaecol'' 1994 May;101(5):387-91. PMID 8018608.</ref>
In patients with more severe disease, [[pre-eclampsia]] may occur, which involves [[hypertension|elevation of blood pressure]] and accumulation of fluid (termed [[oedema]]).<ref name=Riely/> This may progress to involvement of additional systems, including [[acute kidney failure]],<ref>{{Cite journal |vauthors=Koroshi A, Babameto A |year=2002 |title=Acute renal failure during acute fatty liver of pregnancy |journal=Nephrology Dialysis Transplantation |volume=17 |issue=6 |pages=1110–1112 |doi=10.1093/ndt/17.6.1110 |pmid=12032205 |doi-access=free}}</ref> [[hepatic encephalopathy]],<ref>{{Cite journal |last=Aggarwal R |year=2003 |title=Hepatic encephalopathy in pregnancy |journal=Indian Journal of Gastroenterology |volume=22 Suppl 2 |pages=S78–80 |pmid=15025263}}</ref> and [[pancreatitis]].<ref name="Pancreas">{{Cite journal |vauthors=Moldenhauer JS, O'brien JM, Barton JR, Sibai B |year=2004 |title=Acute fatty liver of pregnancy associated with pancreatitis: a life-threatening complication |journal=American Journal of Obstetrics and Gynecology |volume=190 |issue=2 |pages=502–505 |doi=10.1016/j.ajog.2003.09.022 |pmid=14981397}}</ref> There have also been reports of [[diabetes insipidus]] complicating this condition.<ref>{{Cite journal |vauthors=Kennedy S, Hall PM, Seymour AE, Hague WM |year=1994 |title=Transient diabetes insipidus and acute fatty liver of pregnancy |journal=BJOG: An International Journal of Obstetrics and Gynaecology |volume=101 |issue=5 |pages=387–91 |doi=10.1111/j.1471-0528.1994.tb11909.x |pmid=8018608 |s2cid=11869406}}</ref>


Many laboratory abnormalities are seen in acute fatty liver of pregnancy. [[Liver function tests|Liver enzymes]] are elevated, with the AST and ALT enzymes ranging from minimal elevation to 1000 IU/L, but usually staying in the 300-500 range.<ref name=HinHinKo/> [[Bilirubin]] is almost universally elevated. [[Alkaline phosphatase]] is often elevated in [[pregnancy]] due to production from the [[placenta]], but may be additionally elevated.<ref name=ACG/> Other abnormalities may include an elevated [[white blood cell count]], [[hypoglycemia]], elevated coagulation parameters, including the [[international normalized ratio]], and decreased [[fibrinogen]].<ref name=HinHinKo/> <ref name=ACG/> <ref name=Riely/> Frank [[disseminated intravascular coagulation]], or DIC, may occur in as many as 70% of patients.<ref name=HinHinKo/>
Many laboratory abnormalities are seen in acute fatty liver of pregnancy. [[Liver function tests|Liver enzymes]] are elevated, with the AST and ALT enzymes ranging from minimal elevation to 1000 IU/L, but usually staying in the 300-500 range.<ref name=HinHinKo/> [[Bilirubin]] is almost universally elevated. [[Alkaline phosphatase]] is often elevated in [[pregnancy]] due to production from the [[placenta]], but may be additionally elevated.<ref name=ACG/> Other abnormalities may include an elevated [[white blood cell count]], [[hypoglycemia]], elevated coagulation parameters, including the [[international normalized ratio]], and decreased [[fibrinogen]].<ref name=HinHinKo/><ref name=ACG/><ref name=Riely/> Frank [[disseminated intravascular coagulation]], or DIC, may occur in as many as 70% of people.<ref name=HinHinKo/>


Abdominal [[ultrasound]] may show fat deposition in the [[liver]], but, as the hallmark of this condition is [[fatty liver|microvesicular steatosis]] (see pathology below), this may not be seen on ultrasound.<ref>Castro MA, Ouzounian JG, Colletti PM, Shaw KJ, Stein SM, Goodwin TM. Radiologic studies in acute fatty liver of pregnancy. A review of the literature and 19 new cases. ''J Reprod Med.'' 1996 Nov;41(11):839-43. PMID 8951135</ref> Rarely, the condition can be complicated by rupture or [[necrosis]] of the liver, which may be identified by ultrasound.
Abdominal [[ultrasound]] may show fat deposition in the [[liver]], but, as the hallmark of this condition is [[fatty liver|microvesicular steatosis]] (see pathology below), this is not seen on ultrasound.<ref>{{Cite journal |vauthors=Castro MA, Ouzounian JG, Colletti PM, Shaw KJ, Stein SM, Goodwin TM |year=1996 |title=Radiologic studies in acute fatty liver of pregnancy. A review of the literature and 19 new cases |journal=The Journal of Reproductive Medicine |volume=41 |issue=11 |pages=839–43 |pmid=8951135}}</ref> Rarely, the condition can be complicated by rupture or [[necrosis]] of the [[liver]], which may be identified by [[medical ultrasonography|ultrasound]].{{cn|date=March 2022}}

⚫
==Pathophysiology==
⚫
[[Image:LCHAD deficiency.svg|right|thumb|200px|Schematic demonstrating [[mitochondria]]l [[fatty acid]] beta-[[oxidation]] and effects of LCHAD deficiency, a hallmark of acute fatty liver of pregnancy]]

The understanding of the causes of acute fatty liver of pregnancy
⚫
has been improved by advances in mitochondrial [[biochemistry]]. Deficiency of LCHAD (3-hydroxyacyl-CoA dehydrogenase) leads to an accumulation of medium and long chain [[fatty acid]]s. When this occurs in the [[foetus]], the unmetabolized fatty acids will re-enter the maternal circulation through the placenta, and overwhelm the beta-oxidation enzymes of the mother.<ref name=Tein/> The [[gene]] responsible for LCHAD has been isolated, and the most common mutation found in acute fatty liver of pregnancy is the E474Q [[missense mutation]].<ref>{{Cite journal |vauthors=IJlst L, Oostheim W, Ruiter JP, Wanders RJ |year=1997 |title=Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations |url=https://pure.uva.nl/ws/files/3860305/3217_29884y.pdf |journal=Journal of Inherited Metabolic Disease |volume=20 |issue=3 |pages=420–422 |doi=10.1023/A:1005310903004 |pmid=9266371 |s2cid=23046057}}</ref> LCHAD deficiency is [[autosomal recessive]] in inheritance and mothers are often found to be [[heterozygous]] for the affected mutation.<ref>{{Cite journal |vauthors=Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, IJlst L |year=1999 |title=Disorders of mitochondrial fatty acyl-CoA beta-oxidation |journal=Journal of Inherited Metabolic Disease |volume=22 |issue=4 |pages=442–487 |doi=10.1023/A:1005504223140 |pmid=10407780 |s2cid=35795159}}</ref>


==Diagnosis==
==Diagnosis==
The diagnosis of acute fatty liver of pregnancy is usually made on clinical grounds by the treating physician, but differentiation from other conditions affecting the [[liver]] may be difficult.<ref name=HinHinKo/> The diagnosis of acute fatty liver of pregnancy is suggested by jaundice with a lesser elevation of liver enzymes, elevated white blood cell count, disseminated intravascular coagulation, and a clinically more unwell patient.<ref name=ACG/>
The diagnosis of acute fatty liver of pregnancy is usually made on clinical grounds by the treating physician, but differentiation from other conditions affecting the [[liver]] may be difficult.<ref name=HinHinKo/> The diagnosis of acute fatty liver of pregnancy is suggested by jaundice with a lesser elevation of liver enzymes, elevated white blood cell count, disseminated intravascular coagulation, and a clinically unwell patient.<ref name=ACG/>


A liver [[biopsy]] can provide a definitive diagnosis, <ref>Brunt EM. Liver biopsy interpretation for the gastroenterologist. ''Curr Gastroenterol Rep''. 2000 Feb;2(1):27-32. PMID 10981000</ref> but is not always done, due to the increased chance of bleeding in acute fatty liver of pregnancy.<ref>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 Jan;174(1 Pt 1):211-6. PMID 8572009</ref> Often testing will be done to exclude more common conditions that present in a similar fashion, including [[hepatitis|viral hepatitis]],<ref>Pang WW, Lei CH, Chang DP, Yang TF, Chung YT, Huang MH. Acute jaundice in pregnancy: acute fatty liver or acute viral hepatitis? ''Acta Anaesthesiol Sin.'' 1999 Sep;37(3):167-70. PMID 10609353.</ref> [[pre-eclampsia]],<ref name=Riely/> [[HELLP syndrome]],<ref name=ACG/> [[cholestasis|intrahepatic cholestasis of pregnancy]],<ref name=HinHinKo/> and [[autoimmune hepatitis]].<ref name=Mjahed/>
A [[liver biopsy]] can provide a definitive diagnosis,<ref>{{Cite journal |last=Brunt EM |year=2000 |title=Liver biopsy interpretation for the gastroenterologist |journal=Current Gastroenterology Reports |volume=2 |issue=1 |pages=27–32 |doi=10.1007/s11894-000-0048-2 |pmid=10981000 |s2cid=39207958}}</ref> but is not always done, due to the increased chance of bleeding in acute fatty liver of pregnancy.<ref>{{Cite journal |vauthors=Castro MA, Goodwin TM, Shaw KJ, Ouzounian JG, McGehee WG |year=1996 |title=Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy |journal=American Journal of Obstetrics and Gynecology |volume=174 |issue=1 Pt 1 |pages=211–216 |doi=10.1016/S0002-9378(96)70396-4 |pmid=8572009}}</ref> Often testing will be done to exclude more common conditions that present in a similar fashion, including [[hepatitis|viral hepatitis]],<ref>{{Cite journal |vauthors=Pang WW, Lei CH, Chang DP, Yang TF, Chung YT, Huang MH |year=1999 |title=Acute jaundice in pregnancy: acute fatty liver or acute viral hepatitis? |journal=Acta Anaesthesiologica Sinica |volume=37 |issue=3 |pages=167–70 |pmid=10609353}}</ref> [[pre-eclampsia]],<ref name=Riely/> [[HELLP syndrome]],<ref name=ACG/> [[cholestasis|intrahepatic cholestasis of pregnancy]],<ref name=HinHinKo/> and [[autoimmune hepatitis]].<ref name=Mjahed/>

===Pathology===
⚫
If a liver [[biopsy]] is needed for diagnosis of the condition, the mother should be appropriately stabilized and treated to reduce bleeding related complications. The diagnosis can be made by a frozen-section (as opposed to a specimen in formalin) that is stained with the '''Oil red O''' stain, that shows microvesicular steatosis (or small collections of [[fat]] within the liver cells). The microvesicular steatosis usually spares zone one of the liver, which is the area closest to the [[hepatic artery]]. On the regular trichrome stain, the liver cell [[cytoplasm]] shows a foamy appearance due to the prominence of fat. [[Necrosis]] is rarely seen. The diagnosis can be enhanced by [[electron microscopy]] which can be used to confirm the presence of microvesicular steatosis, and specifically the presence of megamitochondria and paracrystalline inclusions.<ref>{{Cite journal |last=Bacq Y |year=1998 |title=Acute fatty liver of pregnancy |journal=Seminars in Perinatology |volume=22 |issue=2 |pages=134–140 |doi=10.1016/S0146-0005(98)80045-1 |pmid=9638907}}</ref><ref name="Reyes">{{Cite journal |last=Reyes H |last2=Sandoval L |last3=Wainstein A |last4=Ribalta |first4=J |last5=Donoso |first5=S |last6=Smok |first6=G |last7=Rosenberg |first7=H |last8=Meneses |first8=M |display-authors=3 |name-list-style=vanc |year=1994 |title=Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients |journal=Gut |volume=35 |issue=1 |pages=101–106 |doi=10.1136/gut.35.1.101 |pmc=1374642 |pmid=8307428}}</ref> Liver diseases with similar appearances include [[Reye's syndrome]], drug-induced hepatitis from agents with mitochondrial toxicity, including [[nucleoside reverse transcriptase inhibitors]] used to treat [[HIV]],<ref>{{Cite journal |vauthors=Montessori V, Harris M, Montaner JS |year=2003 |title=Hepatotoxicity of nucleoside reverse transcriptase inhibitors |journal=Seminars in Liver Disease |volume=23 |issue=2 |pages=167–172 |doi=10.1055/s-2003-39947 |pmid=12800069}}</ref> and a rare condition known as [[Jamaican vomiting sickness]] which is caused by the eating of the unripened [[Ackee]] fruit.<ref>{{Cite journal |vauthors=Hautekeete ML, Degott C, Benhamou JP |year=1990 |title=Microvesicular steatosis of the liver |journal=Acta Clinica Belgica |volume=45 |issue=5 |pages=311–26 |doi=10.1080/17843286.1990.11718105 |pmid=2177300}}</ref>


==Treatment==
==Treatment==
Acute fatty liver of pregnancy is best treated in a centre with expertise in [[hepatology]], high-risk [[obstetrics]], maternal-fetal medicine and [[neonatology]]. The physicians who treat this condition will often consult with experts in [[liver transplantation]] in severe cases. Admission to the [[intensive care unit]] is recommended.<ref name=HinHinKo/>
Acute fatty liver of pregnancy is best treated in a centre with expertise in [[hepatology]], high-risk [[obstetrics]], maternal-fetal medicine and [[neonatology]]. The physicians who treat this condition will often consult with experts in [[liver transplantation]] in severe cases. Admission to the [[intensive care unit]] is recommended.<ref name=HinHinKo/>


Initial treatment involves supportive management with [[intravenous]] fluids, intravenous [[glucose]] and blood products, including [[fresh frozen plasma]] and [[cryoprecipitate]] to correct DIC. The [[fetus]] should be monitored with [[cardiotocography]]. After the [[mother]] is stabilized, arrangements are usually made for delivery. This may occur vaginally, but, in cases of severe bleeding or compromise of the mother's status, a [[caesarian section]] may be needed.<ref name=HinHinKo/>
Initial treatment involves supportive management with [[intravenous]] fluids, intravenous [[glucose]] and blood products, including [[fresh frozen plasma]] and [[cryoprecipitate]] to correct DIC. The [[foetus]] should be monitored with [[cardiotocography]]. After the [[mother]] is stabilized, arrangements are usually made for delivery. This may occur vaginally, but, in cases of severe bleeding or compromise of the mother's status, a [[caesarian section]] may be needed.<ref name=HinHinKo/> Often AFLP is not diagnosed until the mother and baby are in trouble, so it is most likely that an emergency C-section is needed.{{citation needed|date=November 2017}}


The complications of acute fatty liver of pregnancy may require treatment after delivery, especially pancreatitis.<ref name=Pancreas/> Liver transplantation is rarely required for treatment of the condition, but may be needed for mothers with severe DIC, those with rupture of the liver, or those with severe [[encephalopathy]].<ref>Pereira SP, O'Donohue J, Wendon J, Williams R. Maternal and perinatal outcome in severe pregnancy-related liver disease. ''Hepatology''. 1997 Nov;26(5):1258-62. PMID 9362370.</ref>
The complications of acute fatty liver of pregnancy may require treatment after delivery, especially if pancreatitis occurs.<ref name=Pancreas/> Liver transplantation is rarely required for treatment of the condition, but may be needed for mothers with severe DIC, those with rupture of the liver, or those with severe [[encephalopathy]].<ref>{{Cite journal |vauthors=Pereira SP, O'Donohue J, Wendon J, Williams R |year=1997 |title=Maternal and perinatal outcome in severe pregnancy-related liver disease |journal=Hepatology |volume=26 |issue=5 |pages=1258–1262 |doi=10.1002/hep.510260525 |pmid=9362370 |doi-access=free}}</ref>


==Pathology==
==Epidemiology==
⚫
Acute fatty liver of pregnancy is a rare condition and occurs in approximately one in 7,000 to one in 15,000 pregnancies.<ref name=Mjahed/><ref name=Reyes/> The mortality from acute fatty liver of pregnancy has been reduced significantly to 18%, and is now related primarily to complications, particularly DIC (Disseminated Intravascular Coagulation) and infections.<ref name=HinHinKo/><ref name=Mjahed/> After delivery, most mothers do well, as the stimulus for fatty acid overload is removed. The disease can recur in future pregnancies, with a calculated genetic chance of 25%; the actual rate is lower, however.<ref name="Tein">{{Cite journal |last=Tein I |year=2000 |title=Metabolic disease in the foetus predisposes to maternal hepatic complications of pregnancy |journal=Pediatric Research |volume=47 |issue=1 |pages=6–8 |doi=10.1203/00006450-200001000-00005 |pmid=10625076 |doi-access=free}}</ref> Mortality of the foetus has also diminished significantly, but still remains 23%,<ref>{{Cite journal |vauthors=Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM |year=2005 |title=Acute fatty liver of pregnancy in 3 tertiary care centers |journal=American Journal of Obstetrics and Gynecology |volume=192 |issue=5 |pages=1416–1419 |doi=10.1016/j.ajog.2004.12.035 |pmid=15902124}}</ref> and may be related to the need for premature delivery.<ref name=HinHinKo/>
⚫
If a liver [[biopsy]] is needed for diagnosis of the condition, the mother should be appropriately stabilized and treated to reduce bleeding related complications. The diagnosis can be made by a frozen-section (as opposed to a specimen in formalin) that is stained with the '''Oil red O''' stain, that shows microvesicular steatosis (or small collections of [[fat]] within the liver cells). The microvesicular steatosis usually spares zone one of the liver, which is the area closest to the [[hepatic artery]]. On the regular trichrome stain, the liver cell [[cytoplasm]] shows a foamy appearance due to the prominence of fat. [[Necrosis]] is rarely seen. The diagnosis can be enhanced by [[electron microscopy]] which can be used to confirm the presence of microvesicular steatosis, and specifically the presence of megamitochondria and paracrystalline inclusions.<ref>Bacq Y. Acute fatty liver of pregnancy. ''Semin Perinatol.'' 1998 Apr;22(2):134-40. PMID 9638907</ref><ref name=Reyes>Reyes H, Sandoval L, Wainstein A, Ribalta J, Donoso S, Smok G, Rosenberg H, Meneses M. Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients. ''Gut'' 1994 Jan;35(1):101-6. PMID 8307428></ref> Liver diseases with similar appearances include [[Reye's syndrome]], drug-induced hepatitis from agents with mitochondrial toxicity, including [[nucleoside reverse transcriptase inhibitors]] used to treat [[HIV]],<ref>Montessori V, Harris M, Montaner JS. Hepatotoxicity of nucleoside reverse transcriptase inhibitors. ''Semin Liver Dis.'' 2003 May;23(2):167-72. PMID 12800069</ref> and a rare condition known as Jamaican vomiting syndrome.<ref>Hautekeete ML, Degott C, Benhamou JP. Microvesicular steatosis of the liver. ''Acta Clin Belg.'' 1990;45(5):311-26. PMID 2177300</ref>

==Epidemiology and prognosis==
⚫
Acute fatty liver of pregnancy is a rare condition and occurs in approximately one in 7,000 to one in 15,000 pregnancies.<ref name=Mjahed/> <ref name=Reyes/> The mortality from acute fatty liver of pregnancy has reduced significantly to 18%, and is now related primarily to complications, particularly DIC and infections.<ref name=HinHinKo/><ref name=Mjahed/> After delivery, most mothers do well, as the stimulus for fatty acid overload is removed. The disease can recur in future pregnancies, with a calculated genetic chance of 25%; the actual rate is lower, however.<ref name=Tein>Tein I. Metabolic disease in the fetus predisposes to maternal hepatic complications of pregnancy. ''Pediatr Res''. 2000 Jan;47(1):6-8. PMID 10625076</ref> Mortality of the fetus has also diminished significantly, but still remains 23%,<ref>Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM. Acute fatty liver of pregnancy in 3 tertiary care centers. ''Am J Obstet Gynecol.'' 2005 May;192(5):1416-9. PMID 15902124.</ref> and may be related to the need for premature delivery.<ref name=HinHinKo/>

⚫
==Pathophysiology==
⚫
[[Image:LCHAD deficiency.jpg|right|thumb|200px|Schematic demonstrating [[mitochondria]]l [[fatty acid]] beta-[[oxidation]] and effects of LCHAD deficiency, a hallmark of acute fatty liver of pregnancy]]
⚫
The understanding of the causes of acute fatty liver of pregnancy has been ameliorated by advances in mitochondrial [[biochemistry]]. Deficiency of LCHAD (3-hydroxyacyl-CoA dehydrogenase) leads to an accumulation of medium and long chain [[fatty acid]]s. When this occurs in the [[fetus]], the unmetabolized fatty acids will re-enter the maternal circulation through the placenta, and overwhelm the beta-oxidation enzymes of the mother.<ref name=Tein/> The [[gene]] responsible for LCHAD has been isolated, and the most common mutation found in acute fatty liver of pregnancy is the E474Q [[missense mutation]].<ref>IJlst L, Oostheim W, Ruiter JP, Wanders RJ. Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations. ''J Inherit Metab Dis.'' 1997 Jul;20(3):420-2. PMID 9266371</ref> The disease is [[autosomal recessive]] in inheritance and mothers are often found to be [[heterozygous]] for the affected mutation.<ref>Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, IJlst L. Disorders of mitochondrial fatty acyl-CoA beta-oxidation. ''J Inherit Metab Dis.'' 1999 Jun;22(4):442-87. PMID 10407780</ref>


==History==
==History==
The disease was first described in [[1940]] by H. L. Sheehan as an "acute yellow atrophy" of the liver, and thought to be related to delayed [[chloroform]] poisoning.<ref name=HinHinKo/><ref name=Sheehan> Sheehan HL. The pathology of acute yellow atrophy and delayed chloroform poisoning. ''J Obstet Gynaecol Br. Emp.'' 1940;47:49-62.</ref>
The disease was first described in 1940 by H. L. Sheehan as an "acute yellow atrophy" of the liver, then thought to be related to delayed [[chloroform]] poisoning.<ref name=HinHinKo/><ref name="Sheehan">{{Cite journal |last=Sheehan HL |year=1940 |title=The pathology of acute yellow atrophy and delayed chloroform poisoning |journal=Journal of Obstetrics and Gynaecology of the British Empire |volume=47 |pages=49–62 |doi=10.1111/j.1471-0528.1940.tb14731.x |s2cid=72493420}}</ref>

==See also==
* [[Fatty liver]]


==References==
==References==
{{Reflist}}
<div class="references-small"><references /></div>


== External links ==
{{Medical resources
| DiseasesDB = 32879
| ICD10 = {{ICD10|O|26|6|o|20}}
| ICD9 = {{ICD9|646.7}}
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| ICDO =
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| OMIM = 609016
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| MedlinePlus =
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| eMedicineSubj =
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| eMedicineTopic =
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{{Gastroenterology}}
{{Gastroenterology}}
{{Pathology of pregnancy, childbirth and the puerperium}}
{{Fatty-acid metabolism disorders}}


{{DEFAULTSORT:Acute Fatty Liver Of Pregnancy}}
[[Category:Gastroenterology]]
[[Category:Pregnancy]]
[[Category:Diseases of liver]]
[[Category:Genetic disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Maternal disorders predominantly related to pregnancy]]
[[Category:Fatty-acid metabolism disorders]]

Latest revision as of 12:21, 20 October 2024

Acute fatty liver of pregnancy
SpecialtyObstetrics,
Perinatology,
Hepatology
ComplicationsDeath, Disseminated intravascular coagulation
Usual onsetThird trimester of pregnancy
CausesLong-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
Diagnostic methodClinical history and physical examination
Liver biopsy (rarely needed)
TreatmentPrompt delivery of the infant,
Intensive supportive care
Liver transplantation
Frequency1 in 7,000 to 1 in 15,000 pregnancies
Deaths18%[1]

Acute fatty liver of pregnancy is a rare life-threatening complication of pregnancy that occurs in the third trimester or the immediate period after delivery.[1] It is thought to be caused by a disordered metabolism of fatty acids by mitochondria in the fetus, caused by long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.[2] This leads to decreased metabolism of long chain fatty acids by the feto-placental unit, causing subsequent rise in hepatotoxic fatty acids in maternal plasma. The condition was previously thought to be universally fatal,[3] but aggressive treatment by stabilizing the mother with intravenous fluids and blood products in anticipation of early delivery has improved prognosis.[4]

Signs and symptoms

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Acute fatty liver of pregnancy (or hepatic lipidosis of pregnancy) usually manifests in the third trimester of pregnancy, but may occur any time in the second half of pregnancy, or in the puerperium, the period immediately after delivery.[1] On average, the disease presents during the 35th or 36th week of pregnancy.[5] The usual symptoms in the mother are non-specific including nausea, vomiting, anorexia (or lack of desire to eat) and abdominal pain; excessive thirst may be the earliest symptom without overlap with otherwise considered normal pregnancy symptoms;[5] however, jaundice and fever may occur in as many as 70% of patients.[1][6]

In patients with more severe disease, pre-eclampsia may occur, which involves elevation of blood pressure and accumulation of fluid (termed oedema).[5] This may progress to involvement of additional systems, including acute kidney failure,[7] hepatic encephalopathy,[8] and pancreatitis.[9] There have also been reports of diabetes insipidus complicating this condition.[10]

Many laboratory abnormalities are seen in acute fatty liver of pregnancy. Liver enzymes are elevated, with the AST and ALT enzymes ranging from minimal elevation to 1000 IU/L, but usually staying in the 300-500 range.[1] Bilirubin is almost universally elevated. Alkaline phosphatase is often elevated in pregnancy due to production from the placenta, but may be additionally elevated.[4] Other abnormalities may include an elevated white blood cell count, hypoglycemia, elevated coagulation parameters, including the international normalized ratio, and decreased fibrinogen.[1][4][5] Frank disseminated intravascular coagulation, or DIC, may occur in as many as 70% of people.[1]

Abdominal ultrasound may show fat deposition in the liver, but, as the hallmark of this condition is microvesicular steatosis (see pathology below), this is not seen on ultrasound.[11] Rarely, the condition can be complicated by rupture or necrosis of the liver, which may be identified by ultrasound.[citation needed]

Pathophysiology

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Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of LCHAD deficiency, a hallmark of acute fatty liver of pregnancy

The understanding of the causes of acute fatty liver of pregnancy has been improved by advances in mitochondrial biochemistry. Deficiency of LCHAD (3-hydroxyacyl-CoA dehydrogenase) leads to an accumulation of medium and long chain fatty acids. When this occurs in the foetus, the unmetabolized fatty acids will re-enter the maternal circulation through the placenta, and overwhelm the beta-oxidation enzymes of the mother.[12] The gene responsible for LCHAD has been isolated, and the most common mutation found in acute fatty liver of pregnancy is the E474Q missense mutation.[13] LCHAD deficiency is autosomal recessive in inheritance and mothers are often found to be heterozygous for the affected mutation.[14]

Diagnosis

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The diagnosis of acute fatty liver of pregnancy is usually made on clinical grounds by the treating physician, but differentiation from other conditions affecting the liver may be difficult.[1] The diagnosis of acute fatty liver of pregnancy is suggested by jaundice with a lesser elevation of liver enzymes, elevated white blood cell count, disseminated intravascular coagulation, and a clinically unwell patient.[4]

A liver biopsy can provide a definitive diagnosis,[15] but is not always done, due to the increased chance of bleeding in acute fatty liver of pregnancy.[16] Often testing will be done to exclude more common conditions that present in a similar fashion, including viral hepatitis,[17] pre-eclampsia,[5] HELLP syndrome,[4] intrahepatic cholestasis of pregnancy,[1] and autoimmune hepatitis.[3]

Pathology

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If a liver biopsy is needed for diagnosis of the condition, the mother should be appropriately stabilized and treated to reduce bleeding related complications. The diagnosis can be made by a frozen-section (as opposed to a specimen in formalin) that is stained with the Oil red O stain, that shows microvesicular steatosis (or small collections of fat within the liver cells). The microvesicular steatosis usually spares zone one of the liver, which is the area closest to the hepatic artery. On the regular trichrome stain, the liver cell cytoplasm shows a foamy appearance due to the prominence of fat. Necrosis is rarely seen. The diagnosis can be enhanced by electron microscopy which can be used to confirm the presence of microvesicular steatosis, and specifically the presence of megamitochondria and paracrystalline inclusions.[18][19] Liver diseases with similar appearances include Reye's syndrome, drug-induced hepatitis from agents with mitochondrial toxicity, including nucleoside reverse transcriptase inhibitors used to treat HIV,[20] and a rare condition known as Jamaican vomiting sickness which is caused by the eating of the unripened Ackee fruit.[21]

Treatment

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Acute fatty liver of pregnancy is best treated in a centre with expertise in hepatology, high-risk obstetrics, maternal-fetal medicine and neonatology. The physicians who treat this condition will often consult with experts in liver transplantation in severe cases. Admission to the intensive care unit is recommended.[1]

Initial treatment involves supportive management with intravenous fluids, intravenous glucose and blood products, including fresh frozen plasma and cryoprecipitate to correct DIC. The foetus should be monitored with cardiotocography. After the mother is stabilized, arrangements are usually made for delivery. This may occur vaginally, but, in cases of severe bleeding or compromise of the mother's status, a caesarian section may be needed.[1] Often AFLP is not diagnosed until the mother and baby are in trouble, so it is most likely that an emergency C-section is needed.[citation needed]

The complications of acute fatty liver of pregnancy may require treatment after delivery, especially if pancreatitis occurs.[9] Liver transplantation is rarely required for treatment of the condition, but may be needed for mothers with severe DIC, those with rupture of the liver, or those with severe encephalopathy.[22]

Epidemiology

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Acute fatty liver of pregnancy is a rare condition and occurs in approximately one in 7,000 to one in 15,000 pregnancies.[3][19] The mortality from acute fatty liver of pregnancy has been reduced significantly to 18%, and is now related primarily to complications, particularly DIC (Disseminated Intravascular Coagulation) and infections.[1][3] After delivery, most mothers do well, as the stimulus for fatty acid overload is removed. The disease can recur in future pregnancies, with a calculated genetic chance of 25%; the actual rate is lower, however.[12] Mortality of the foetus has also diminished significantly, but still remains 23%,[23] and may be related to the need for premature delivery.[1]

History

[edit]

The disease was first described in 1940 by H. L. Sheehan as an "acute yellow atrophy" of the liver, then thought to be related to delayed chloroform poisoning.[1][24]

See also

[edit]

References

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  1. ^ a b c d e f g h i j k l m n Ko H, Yoshida EM (2006). "Acute fatty liver of pregnancy". Canadian Journal of Gastroenterology. 20 (1): 25–30. doi:10.1155/2006/638131. PMC 2538964. PMID 16432556.
  2. ^ Bellig LL (2004). "Maternal acute fatty liver of pregnancy and the associated risk for long-chain 3-hydroxyacyl-coenzyme a dehydrogenase (LCHAD) deficiency in infants". Advances in Neonatal Care. 4 (1): 26–32. doi:10.1016/j.adnc.2003.12.001. PMID 14988877. S2CID 29356240.
  3. ^ a b c d Mjahed K, Charra B, Hamoudi D, Noun M, Barrou L (2006). "Acute fatty liver of pregnancy". Archives of Gynecology and Obstetrics. 274 (6): 349–353. doi:10.1007/s00404-006-0203-6. PMID 16868757. S2CID 24784165.
  4. ^ a b c d e Riely CA (1999). "Liver disease in the pregnant patient. American College of Gastroenterology". The American Journal of Gastroenterology. 94 (7): 1728–1732. doi:10.1111/j.1572-0241.1999.01199.x. PMID 10406228. S2CID 36694459.
  5. ^ a b c d e Riely CA (1987). "Acute fatty liver of pregnancy". Seminars in Liver Disease. 7 (1): 47–54. doi:10.1055/s-2008-1040563. PMID 3296215.
  6. ^ Riely CA, Latham PS, Romero R, Duffy TP (1987). "Acute fatty liver of pregnancy. A reassessment based on observations in nine patients". Annals of Internal Medicine. 106 (5): 703–6. doi:10.7326/0003-4819-106-5-703. PMID 3565968.
  7. ^ Koroshi A, Babameto A (2002). "Acute renal failure during acute fatty liver of pregnancy". Nephrology Dialysis Transplantation. 17 (6): 1110–1112. doi:10.1093/ndt/17.6.1110. PMID 12032205.
  8. ^ Aggarwal R (2003). "Hepatic encephalopathy in pregnancy". Indian Journal of Gastroenterology. 22 Suppl 2: S78–80. PMID 15025263.
  9. ^ a b Moldenhauer JS, O'brien JM, Barton JR, Sibai B (2004). "Acute fatty liver of pregnancy associated with pancreatitis: a life-threatening complication". American Journal of Obstetrics and Gynecology. 190 (2): 502–505. doi:10.1016/j.ajog.2003.09.022. PMID 14981397.
  10. ^ Kennedy S, Hall PM, Seymour AE, Hague WM (1994). "Transient diabetes insipidus and acute fatty liver of pregnancy". BJOG: An International Journal of Obstetrics and Gynaecology. 101 (5): 387–91. doi:10.1111/j.1471-0528.1994.tb11909.x. PMID 8018608. S2CID 11869406.
  11. ^ Castro MA, Ouzounian JG, Colletti PM, Shaw KJ, Stein SM, Goodwin TM (1996). "Radiologic studies in acute fatty liver of pregnancy. A review of the literature and 19 new cases". The Journal of Reproductive Medicine. 41 (11): 839–43. PMID 8951135.
  12. ^ a b Tein I (2000). "Metabolic disease in the foetus predisposes to maternal hepatic complications of pregnancy". Pediatric Research. 47 (1): 6–8. doi:10.1203/00006450-200001000-00005. PMID 10625076.
  13. ^ IJlst L, Oostheim W, Ruiter JP, Wanders RJ (1997). "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations" (PDF). Journal of Inherited Metabolic Disease. 20 (3): 420–422. doi:10.1023/A:1005310903004. PMID 9266371. S2CID 23046057.
  14. ^ Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, IJlst L (1999). "Disorders of mitochondrial fatty acyl-CoA beta-oxidation". Journal of Inherited Metabolic Disease. 22 (4): 442–487. doi:10.1023/A:1005504223140. PMID 10407780. S2CID 35795159.
  15. ^ Brunt EM (2000). "Liver biopsy interpretation for the gastroenterologist". Current Gastroenterology Reports. 2 (1): 27–32. doi:10.1007/s11894-000-0048-2. PMID 10981000. S2CID 39207958.
  16. ^ Castro MA, Goodwin TM, Shaw KJ, Ouzounian JG, McGehee WG (1996). "Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy". American Journal of Obstetrics and Gynecology. 174 (1 Pt 1): 211–216. doi:10.1016/S0002-9378(96)70396-4. PMID 8572009.
  17. ^ Pang WW, Lei CH, Chang DP, Yang TF, Chung YT, Huang MH (1999). "Acute jaundice in pregnancy: acute fatty liver or acute viral hepatitis?". Acta Anaesthesiologica Sinica. 37 (3): 167–70. PMID 10609353.
  18. ^ Bacq Y (1998). "Acute fatty liver of pregnancy". Seminars in Perinatology. 22 (2): 134–140. doi:10.1016/S0146-0005(98)80045-1. PMID 9638907.
  19. ^ a b Reyes H, Sandoval L, Wainstein A, et al. (1994). "Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients". Gut. 35 (1): 101–106. doi:10.1136/gut.35.1.101. PMC 1374642. PMID 8307428.
  20. ^ Montessori V, Harris M, Montaner JS (2003). "Hepatotoxicity of nucleoside reverse transcriptase inhibitors". Seminars in Liver Disease. 23 (2): 167–172. doi:10.1055/s-2003-39947. PMID 12800069.
  21. ^ Hautekeete ML, Degott C, Benhamou JP (1990). "Microvesicular steatosis of the liver". Acta Clinica Belgica. 45 (5): 311–26. doi:10.1080/17843286.1990.11718105. PMID 2177300.
  22. ^ Pereira SP, O'Donohue J, Wendon J, Williams R (1997). "Maternal and perinatal outcome in severe pregnancy-related liver disease". Hepatology. 26 (5): 1258–1262. doi:10.1002/hep.510260525. PMID 9362370.
  23. ^ Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM (2005). "Acute fatty liver of pregnancy in 3 tertiary care centers". American Journal of Obstetrics and Gynecology. 192 (5): 1416–1419. doi:10.1016/j.ajog.2004.12.035. PMID 15902124.
  24. ^ Sheehan HL (1940). "The pathology of acute yellow atrophy and delayed chloroform poisoning". Journal of Obstetrics and Gynaecology of the British Empire. 47: 49–62. doi:10.1111/j.1471-0528.1940.tb14731.x. S2CID 72493420.
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