Short ReportTHE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 15, No.6, 2002
Acute fatty liver of pregnancy: A report oftwo cases
G. LOGANATHAN, C. E. EAPEN, RACHEL G. CHANDY,PADMINI JASPER, MATTHEWS MATHAI, LAKSHMISESHADRI, BANUMATHI RAMAKRISHNA, ATANUKUMAR JANA, GEORGE JOHN, GEORGE M. CHANDY
ABSTRACTAcute fatty liver of pregnancy is an uncommon, potentially fataldisorder. Between 1998 and 2000, two patients with acute fattyliver of pregnancy presented at the Christian Medical CollegeHospital, Vellore. Both patients were in the thirty-sixth week ofpregnancy. Jaundice and encephalopathy were the predominantsymptoms. Both the mothers died after they delivered a stillborninfant each. The maternal deaths were due to multiorgan failureand/or postpartum haemorrhage and sepsis. The route ofdelivery was vaginal in both the patients. Extrahepatic andmetabolic complications in both cases included renal failure,sepsis, hypoglycaemia, disseminated intravascular coagulationand gastrointestinal bleeding. Liver biopsy done in both patientswas consistent with the diagnosis of acute fatty liver of pregnancy.To the best of our knowledge, this is the first report from Indiaon acute fatty liver of pregnancy.Natl Med J India 2002; 15:336-8
INTRODUCTIONAcute fatty liver of pregnancy (AFLP) is an uncommon, com-pletely reversible, yet potentially fatal disorder. It occurs in thethird trimester of pregnancy and has well-defined clinical, labora-tory and histopathological features, which are not pathognomonic.An early diagnosis, rapid delivery of the foetus, availability oftrained personnel and intensive care facilities have been shown toresult in improved maternal and foetal survival. We. report ourexperience of two patients with AFLP, the first such report fromIndia, to the best of our knowledge.
THE CASESBetween 1998 and 2000, 23 pregnant women with acute hepaticdysfunction presented at the Christian Medical College Hospital,Vellore. Ofthese, 18 patients satisfied the standard criteria for thediagnosis of AFLP (see Box). However, consent to perform a liver
Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, IndiaG. LOGANATHAN, C. E. EAPEN, GEORGE M. CHANDY
Department of Gastrointestinal SciencesRACHELG.CHANDY, PADMINIJASPER, MATTHEWS MATHAI,
LAKSHMI SESHADRI Department of Obstetrics and GynaecologyBANUMATHIRAMAKRISHNA Department of General PathologyAT ANU KUMAR JAN A Department of NeonatologyGEORGE JOHN Department of Medical Intensive Care Unit
biopsy was obtained in only 4 patients. Two of these 4 biopsieswere obtained post mortem and were consistent with the diagnosisof AFLP.
Patient 1 was a 21-year-old second gravida, who had onset ofsymptoms in the thirty-sixth week of pregnancy with jaundice andencephalopathy. She did not have predominant cholestatic symp-toms or polydipsia. She had undergone a vaginal delivery 6 daysafter the onset of symptoms and had delivered a stillborn girl child.Following the delivery, she was referred to our hospital.
Patient 2 was a 17-year-old first gravida, who also had onset ofsymptoms in the thirty-sixth week of pregnancy and was referredto our hospital. A vaginal delivery was conducted on day 5 after theonset of symptoms. Her predominant' symptoms also were jaun-dice and encephalopathy and she had ascites at the time ofpresentation to our hospital. A history of consanguinity waspresent. The outcome of the delivery was a stillborn girl child.Both mothers died 2-4 days after delivery.
The following tests were done on both the patients at admissionand serially when required: haemoglobin, total white cell count,differential count, blood picture, work-up for disseminated intra-vascular coagulation (DIC), platelet count, liver function tests,serum creatinine, lactate dehydrogenase, serum electrolytes, se-rum caeruloplasmin, serum copper, antinuclear antibody, bloodsugar, uric acid, serum amylase and routine analysis of urine.
Hepatitis B surface antigen (HBsAg), HIV, VDRL, IgM hepa-titis A virus, IgM hepatitis E virus, and hepatitis C virus (third-generation EIA) antibodies were tested in both patients and werefound negative. Both patients were managed in the intensive carefacility.
Fresh frozen plasma, platelet-rich concentrate and packed celltransfusions were given to maintain an international normalizedratio (INR) of <1.5, platelets of >50x 109/L and a haemoglobin of>8 g/dl, respectively. Antibiotics (ampicillin, ciprofloxacin andmetronidazole) were started before delivery and the patientsreceived 10% dextrose infusion. On documentation of hypo-glycaemia, 50% dextrose boluses were added till normalization ofblood sugar:
Table I gives the laboratory findings. Both patients had directhyperbilirubinaemia with serum bilirubin values of> 15 mg/dl.The serum albumin was low and the aspartate aminotransferase,
LOGANATHAN et at. : ACUTE FATTY LIVER OF PREGNANCY
TABLEI. Laboratory findings
Laboratory parameter Patient 1 Patient 2
Serum bilirubin (mg/dl)TotalDirect
Serum albumin (g/dl)Aspartate aminotransferase (UIL)Alanine aminotransferase (UIL)Alkaline phosphatase (UIL)Random blood sugar (mg/dl)*Serum creatinine (mg/dl)Prothrombin time in seconds (patient/control)*Platelet count (cmm) *
15.910.72.22702755581063.2
60110126000
38.028.02.72801801332451.9
6011169000
·worst values within 72 hours of delivery. All other values at admissionNormal values: total bilirubin: 0.2-1 mgldl; direct bilirubin: 0.2~.5 mgldl; serum albumin:3.7-4.9 gldl; alanine aminotransferase: 540 UIL; aspartate aminotransferase: 540 UIL;alkaline phosphatase: 40-125 UIL; serum creatinine: 0.5-1.4 mgldl
alanine aminotransferase and alkaline phosphatase were elevated.A high uric acid level was seen in the second patient. Neitherpatient had albuminuria. At admission, the prothrombin time wasprolonged and platelets were low (<150 OOO/cmm)in both pa-tients.
Abdominal ultrasound showed a fatty liver and ascites in bothpatients. Splenomegaly and biliary obstruction were absent inboth patients.
Hospital courseLeucocytosis was present in both patients. Patient 1 had culture-negative neutrocytic ascites. Patient 2 required a therapeuticparacentesis. Patient 1 had schistocytes and Burr cells, andderanged coagulation parameters strongly suggestive of DIC.Patient 2 had bleeding from venepuncture sites, schistocytes onperipheral smear, prolonged coagulation parameters but a nega-tive paracoagulation test. She received cryoprecipitate transfu-sion. Both patients had elevated creatinine levels. Hypoglycaemiawas seen in Patient 2. Both required ventilatory support. Patient 1developed gastrointestinal bleeding due to reflux oesophagitis.Patient 2 had atonic postpartum haemorrhage. Patient 1developedrenal failure, gross ascites, right-sided pleural effusion, spontane-ous bacterial peritonitis, DIC and severe metabolic acidosis. Shedied on the fourth day after delivery. Patient 2 had atonic postpar-tum haemorrhage, DIC, renal failure and severe metabolic acido-sis. She died on the second day. We received the patients inmulti organ dysfunction with severe metabolic acidosis. Probablythe late presentation after the onset of illness resulted in death.
Histopathological findings of liver biopsiesThe liver biopsy was obtained in both these patients post mortem.The biopsies showed diffusely swollen hepatocytes with micro-vesicular fatty change (Fig. 1), which was more prominent in theperivenular region, extramedullary haemopoiesis, mild lobularand portal inflammation, ceroid-laden Kupffer cells and macroph-ages and, in one patient, diffuse canalicular and mild hepatocyticcholestasis. Bile ductular proliferation was present in one biopsy.The histological features were in keeping with AFLP.
DISCUSSIONAcute fatty liver of pregnancy is classified under acute hepaticfailure-not otherwise classified. I Its incidence ranges from 1 in7000 to 1in 15 000 deliveries. 2 AFLP has been reported to be morecommon in multiple gestations and with male foetuses. Jaundice
and encephalopathy are the common presenting symptoms. Theabsence of jaundice and occurrence of polydipsia and pruritushave been reported:" however, these symptoms were not seen inour patients.
A low albumin.v' a greater than 5-fold elevation of alkalinephosphatase':' and amoderate elevation of transaminasest+' havebeen reported. A prolonged prothrombin time, essential to thediagnosis of AFLP, was seen in both patients. An elevatedcreatinine value, which is seen in the majority of patients withAFLP and is to be considered as 'forme fruste' of AFLP, 5 was foundin both patients. Portal hypertension" and spontaneous bacterialperitonitis' have been documented in this disorder. One of ourpatients developed culture-negative neutrocytic ascites and onehad gastrointestinal bleeding. The causes of gastrointestinal bleed-ing described in various reports include oesophageal varicealbleed'? in addition to Mallory-Weiss syndrome, acute gastric orduodenal lesions and as a manifestation of coagulopathy.sv"Disseminated intravascular coagulation was seen in both patientsas well as hypoglycaemia, which is a common manifestation asreported in other studies.'
Fatty liver on ultrasound was seen in both our patients. Theusefulness of various imaging modalities in the diagnosis andmanagement of AFLP has been described." The standard criteriafor the diagnosis of AFLP, 2.10 the indications for liver biopsy? andthe histopathological findings on liver biopsy" have been welldocumented.
The differential diagnosis in a patient who presents withfeatures of AFLP includes acute viral hepatitis and pre-eclampsia.The difficulty in differentiating AFLP from acute viral hepatitis II
and the differentiating features between AFLP and HELLP(Haemolysis, Elevated Liver enzymes, Low Platelets) syndrome 12
have also been described.Early recognition, early termination ofpregnancy ,availability of
well-equipped intensive medical care units, provision of aggressivesupportive care ofli ver failure and management of complications ofliver failure have resulted in 100% maternal survival as comparedto the high maternal mortality and morbidity reported earlier. 2.13 Thecauses of foetal mortality include pre-term delivery and maternalDie. The rationale of early delivery based on good clinical judge-
338
ment seems to be supported by the finding that no patient has yetrecovered from AFLP before deli very. 2,4,14,15The route of deli very inpatients with AFLP is controversial. The advantages and disadvan-tages of a caesarean section and vaginal delivery have been ad-dressed. 13We advocate that labour should be induced if AFLP is oneof the differential diagnoses in the patient. AFLP and pre-eclampsiapresent with a poorly defined overlap of clinical symptoms andsigns6,16,17and recurrence of AFLP has been reported.v"-"
The pathogenesis of AFLP is not clear. A defect in theintramitochondrial beta-oxidation of fatty acids has been found tobe responsible for the manifestations of AFLP. Vomiting, comaand hyperammonaemia are common to all mitochondrial hepato-pathies. Children with defects in the early stages of the intra-mitochondrial pathway present with severe energy deficiency anddie before 2 years oflife, while those with defects in the later stagespresent with symptoms of failure to thrive."
Long chain 3-hydroxyacyl coenzyme A dehydrogenase(LCHAD) deficiency has been demonstrated in skin fibroblastculture in patients diagnosed to have AFLP.21 LCHAD deficiencyhas been identified to be due to mutations at G 1528C. AFLP ismanifest when the foetus is homozygous for the defect in a motherwho is heterozygous for the defect. Mothers who carry heterozy-gous foetuses do not develop the disease." Consanguinity wasseen in one of our patients. Genetic studies will help identifyspecific mutations in our population and are useful for the prenataldiagnosis of foetal homozygosity for LCHAD deficiency. Suchstudies are also useful in diagnosing the disease and for offeringappropriate dietary advice for newborns.
The absence of recurrence of AFLP in every pregnancy, absenceof geographic or ethnic clustering and familial accumulation do notsupport a genetic cause. The identification of the defect in a motherwith a prenatal diagnosis of homozygosity of the foetus will helpreduce complications and ensure improved maternal survival.
The major clinical manifestation of inherited mitochondrialdisorders ofFAO include hepatic steatosis, elevated aminotrans-ferase levels, coagulopathy, hyperammonaemia, hypoglycaemiaand hypoketosis, cardiomyopathy, congestive heart failure, car-diac arrhythmia, sudden infant death, rhabdomyolysis, vomiting,lethargy, coma, encephalopathy, increased lactate and uric acid,myoglobinuria, renal tubular acidosis, failure to thrive and pancre-atitis."
AFLP has not been reported from the Indian subcontinent and,.to the best of our knowledge, this is the first report of two patients.
ACKNOWLEDGEMENTWe thank Professor Robert G. Batey, Director and Head, Department of
THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 15, NO. 6, 2002
Gastroenterology, John Hunter Hospital, New South Wales, Australia forreviewing the manuscript and for offering valuable suggestions and advice.
REFERENCESTandon BN, Bernauau J. O'Grady J. Gupta SO, Krisch RE, Liaw YF, et al.Recommendations of the International Association for the Study of the LiverSubcommittee on nomenclature of acute and subacute liver failure. J GastroenterolHepatoI1999;14:403-4.
2 Reyes H, Sandoval L, Wainstein A, RibaltaJ, Donoso S, SmokG, et al. Acute fatty liverof pregnancy: A clinical study of 12 episodes in I I patients. Gut 1994;35: IO 1-6.
3 Rolfes DB, Ishak KG. Acute fatty liver of pregnancy: A clinicopathologic study of35patients. Hepatology 1985;5: I 149-58.
4 Davies MH, Wilkinson SP, Hanid MA, Portmann 8, Brudenell JM, Newton JR, et al.Acute liver disease with encephalopathy and renal failure in late pregnancy and the earlypuerperium-a study of fourteen patients. Br J Obstet Gynaecol1980; 87: 1005- I4.Castro MA, Fasset MJ, Reynolds TB, Shaw KJ. Goodwin TM. Reversible peripartumfailure: A new perspective on the diagnosis, treatment and cause of acute fatty liver ofpregnancy based on 28 consecutive cases. Am J Obstet GynecoI1999;181:389-95.
7 Cano RI, Delman MR, Pitchumoni CS, Lev R, Rosenthal WS. Acute fatty liver ofpregnancy: Complication by disseminated intravascular coagulation. JAMA1975;231:159-61.Liebman HA,McGehee WG, Patch MJ, Feinstein DL Severe depression of antithrombinIII associated with disseminated intravascular coagulation in women with fatty liverofpregnancy. Ann Intern Med 1983;98:330-3.
. 9 Castro MA, Ouzounaian JG, Colletti PM, Shaw KJ, Stein SM, Goodwin TM.Radiologic studies in acute fatty liver of pregnancy: A review ofliterature and 19 newcases. J Reprod Med 1996;41:839-43.
10 Treem WR, Shoup ME, Hale DE, BennettMJ, Rinaldo P, Millington OS, et al, Acutefatty liver of pregnancy, hemolysis, elevated Iiverenzymes, and low platelets syndrome,and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Am JGastroenteroI1996;91:2293-300.
II Hamid SS, Jafri SM, Khan H, Shah H, Abbas Z, Fields H. Fulminant hepatic failure inpregnant women: Acute fatty liver or acute viral hepatitis? J HepatoI1996;25:20-7.
12 Barton RJ, Sibai BM. HELLP and the liver diseases of pre-eclampsia. Clin Liver Dis1999;3:31-48.
13 Pereira SP, O'Donohue J, Wendon J, Williams R. Maternal and perinatal outcome insevere pregnancy-related liver disease. Hepatology 1997 ;26: 1258-62.
14 EbertEC, Sun EA, Wright SH, Decker JP,Librizzi RJ, BologneseRJ, et al. Does earlydiagnosis and deli very in acute fatty liver of pregnancy lead to improvement in maternaland infant survival? Dig Dis Sci 1984;29:453-5.
15 Hou SH, Levin S, Ahola S, Lister J, Omicioli V, Dandrow R, et al. Acute fatty liverof pregnancy: Survival with early caesarean section. Dig Dis Sci 1984;29:449-52.
16 Minakami H, Oka N, Sato T, Tamada T, Yasuda Y, Hirota N. PreeclarnpsiarAmicrovesicular fat disease of the liver? Am J Obstet GynecoI1988;159: 1043-7.
17 Dani R, Mendes GS, MedeirosJ de L, PeretFJ, Nunes A. Study ofthe liver changesoccurring in preeclampsia and their possible pathogenetic connection with acute fattyli ver of pregnancy. Am J Gastroenterol 1996;91 :292-4.
18 Barton JR, Sibai BM, Mabie WC, Shanklin DR. Recurrent acute fatty liver ofpregnancy. Am J Obstet GynecoI1990;l63:534-8.
19 Schoeman MN, Batey RG, Wilcken B. Recurrent acute fatty liver of pregnancyassociated with a fatty acid oxidation defect in the offspring. Gastroenterology1991;100:544-8 .
20 Treem WR. Beta oxidation defects. Clin Liver Dis 1999;3:49-67.21 Tyni T, Ekholm E, Pihko H. Pregnancy complications are frequent in long-chain 3
hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Obstet Gynecol1998;178:603-60.
