Acute fatty liver of pregnancy

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Acute fatty liver of pregnancy
Classification and external resources
ICD-10 O26.6
ICD-9 646.7
OMIM 609016
DiseasesDB 32879

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 mother, caused by deficiency in the LCHAD (long-chain 3-hydroxyacyl-coenzyme A dehydrogenase) enzyme.[2] 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]

Clinical manifestations[edit]

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;[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 edema).[5] This may progress to involvement of additional systems, including acute renal 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 patients.[1]

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

Diagnosis[edit]

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,[12] but is not always done, due to the increased chance of bleeding in acute fatty liver of pregnancy.[13] Often testing will be done to exclude more common conditions that present in a similar fashion, including viral hepatitis,[14] pre-eclampsia,[5] HELLP syndrome,[4] intrahepatic cholestasis of pregnancy,[1] and autoimmune hepatitis.[3]

Treatment[edit]

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 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.[1]

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.[15]

Pathology[edit]

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.[16][17] 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,[18] and a rare condition known as Jamaican vomiting sickness which is caused by the eating of the unripened Ackee fruit.[19]

Epidemiology and prognosis[edit]

Acute fatty liver of pregnancy is a rare condition and occurs in approximately one in 7,000 to one in 15,000 pregnancies.[3][17] 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.[20] Mortality of the fetus has also diminished significantly, but still remains 23%,[21] and may be related to the need for premature delivery.[1]

Pathophysiology[edit]

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 fetus, the unmetabolized fatty acids will re-enter the maternal circulation through the placenta, and overwhelm the beta-oxidation enzymes of the mother.[20] 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.[22] LCHAD deficiency is autosomal recessive in inheritance and mothers are often found to be heterozygous for the affected mutation.[23]

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]

References[edit]

  1. ^ a b c d e f g h i j k l m Ko H, Yoshida EM (2006). "Acute fatty liver of pregnancy". Can. J. Gastroenterol. 20 (1): 25–30. 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". Adv Neonatal Care 4 (1): 26–32. doi:10.1016/j.adnc.2003.12.001. PMID 14988877. 
  3. ^ a b c d Mjahed K, Charra B, Hamoudi D, Noun M, Barrou L (2006). "Acute fatty liver of pregnancy". Arch. Gynecol. Obstet. 274 (6): 349–353. doi:10.1007/s00404-006-0203-6. PMID 16868757. 
  4. ^ a b c d e Riely CA (1999). "Liver disease in the pregnant patient. American College of Gastroenterology". Am. J. Gastroenterol. 94 (7): 1728–1732. doi:10.1111/j.1572-0241.1999.01199.x. PMID 10406228. 
  5. ^ a b c d e Riely CA (1987). "Acute fatty liver of pregnancy". Semin. Liver Dis. 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". Ann. Intern. Med. 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". Nephrol. Dial. Transplant. 17 (6): 1110–1112. doi:10.1093/ndt/17.6.1110. PMID 12032205. 
  8. ^ Aggarwal R (2003). "Hepatic encephalopathy in pregnancy". Indian J Gastroenterol. 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". Am. J. Obstet. Gynecol. 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". Br J Obstet Gynaecol 101 (5): 387–91. doi:10.1111/j.1471-0528.1994.tb11909.x. PMID 8018608. 
  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". J Reprod Med 41 (11): 839–43. PMID 8951135. 
  12. ^ Brunt EM (2000). "Liver biopsy interpretation for the gastroenterologist". Curr Gastroenterol Rep 2 (1): 27–32. doi:10.1007/s11894-000-0048-2. PMID 10981000. 
  13. ^ Castro MA, Goodwin TM, Shaw KJ, Ouzounian JG, McGehee WG (1996). "Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy". Am. J. Obstet. Gynecol. 174 (1 Pt 1): 211–216. doi:10.1016/S0002-9378(96)70396-4. PMID 8572009. 
  14. ^ 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 Anaesthesiol. Sin. 37 (3): 167–70. PMID 10609353. 
  15. ^ 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. 
  16. ^ Bacq Y (1998). "Acute fatty liver of pregnancy". Semin. Perinatol. 22 (2): 134–140. doi:10.1016/S0146-0005(98)80045-1. PMID 9638907. 
  17. ^ 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. 
  18. ^ Montessori V, Harris M, Montaner JS (2003). "Hepatotoxicity of nucleoside reverse transcriptase inhibitors". Semin. Liver Dis. 23 (2): 167–172. doi:10.1055/s-2003-39947. PMID 12800069. 
  19. ^ Hautekeete ML, Degott C, Benhamou JP (1990). "Microvesicular steatosis of the liver". Acta Clin Belg 45 (5): 311–26. PMID 2177300. 
  20. ^ a b Tein I (2000). "Metabolic disease in the fetus predisposes to maternal hepatic complications of pregnancy". Pediatr. Res. 47 (1): 6–8. doi:10.1203/00006450-200001000-00005. PMID 10625076. 
  21. ^ Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM (2005). "Acute fatty liver of pregnancy in 3 tertiary care centers". Am. J. Obstet. Gynecol. 192 (5): 1416–1419. doi:10.1016/j.ajog.2004.12.035. PMID 15902124. 
  22. ^ IJlst L, Oostheim W, Ruiter JP, Wanders RJ (1997). "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations". J. Inherit. Metab. Dis. 20 (3): 420–422. doi:10.1023/A:1005310903004. PMID 9266371. 
  23. ^ Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, IJlst L (1999). "Disorders of mitochondrial fatty acyl-CoA beta-oxidation". J. Inherit. Metab. Dis. 22 (4): 442–487. doi:10.1023/A:1005504223140. PMID 10407780. 
  24. ^ Sheehan HL (1940). "The pathology of acute yellow atrophy and delayed chloroform poisoning". J Obstet Gynaecol Br. Emp. 47: 49–62. doi:10.1111/j.1471-0528.1940.tb14731.x.