View source for Acute fatty liver of pregnancy

{{Infobox_Disease |
  Name           = {{PAGENAME}} |
  Image          = |
  Caption        = |
  DiseasesDB     = 32879 |
  ICD10          = {{ICD10|O|26|6|o|20}} |
  ICD9           = {{ICD9|646.7}} |
  ICDO           = | 
  OMIM           = 609016 |
  OMIM_mult      = {{OMIM2|600890}} |
  MedlinePlus    = |
  eMedicineSubj  = |
  eMedicineTopic = |
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{{SI}}
{{CMG}} '''Assosciate Editor(s)-In-Chief:''' [[User: Prashanthsaddala|Prashanth Saddala M.B.B.S]]
==Overview==
'''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>
==Historical Perspective==
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>
==Epidemiology and Demographics==
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==
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>
[[Image:LCHAD deficiency.jpg|framed|400px|center|Schematic demonstrating [[mitochondria]]l [[fatty acid]] beta-[[oxidation]] and effects of LCHAD deficiency, a hallmark of acute fatty liver of pregnancy]]
[[Image:autorecessive.jpg|left|thumb|200pxAcute fatty liver of pregnancy is inherited in an [[Recessive gene|autosomal recessive]] pattern.]]
===Histopathology===
On the regular trichrome stain, the liver cell [[cytoplasm]] shows a foamy appearance due to the prominence of fat.  [[Necrosis]] is rarely seen. On [[electron microscopy]], microvesicular steatosis, megamitochondria and paracrystalline inclusions are seen.<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>
==Differential Diagnosis==
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/>
==Natural history, Complications and Prognosis==
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>
==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/>
===History and Symptoms===
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> 
===Laboratory tests===
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/>
===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 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.
===Liver Biopsy===
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> 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>
==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/>

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/>

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>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>

==References==
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