A Yulia , A Wijesiriwardana

1. A Yulia, A Wijesiriwardana Department of Obstetrics and Gynaecology, Cumberland Infirmary Carlisle, North Cumbria University Hospital NHS Trust Introduction Alkaline phosphatases (ALP) are a group of isoenzyme produced by liver (isoenzymes ALP1-1), bones (isoenzymes ALP-2), kidneys, small intestine and placenta (isoenzymes ALP-3). Placenta ALP is physiologically produced by placenta at the brush border membranes of the syncytiotrophoblast. The major function of placental ALP is thought to aid in metabolism and facilitate transport across cell membranes. It appears in maternal serum between the 15th and the 26th weeks and increases during the third trimester. Usually, ALP production or diffusion in maternal serum is not major and total serum ALP level remains normal. Some cases of unusual elevation of placental ALP have been described. The mechanism of serum placental ALP increase is not well understood. In postpartum period, ALP isoenzyme activity decreases to the normal level at about 20 weeks after delivery. Marked elevation of serum ALP may be caused by liver or bone pathology such as malignancy, extrahepaticbiliary obstruction, and intrahepaticcholestasis. We report 2 cases of markedly elevated activity of heat-stable placental isoenzymes of ALP in the third trimester in otherwise uncomplicated pregnancies. In both cases, serum ALP returned to normal level after delivery. Case 1 A fit and well 29-year-old primigravida was reviewed due to itchy hands and suspicion of obstetric cholestasis at 36 weeks and 3 days gestations. Her obstetrics history was unremarkable. An extremely high serum ALP concentration was detected (5122 U/litre). Other laboratory tests were normal. No systemic immune disease was detected. Serum ALP electrophoresis showed normal ALP level of liver and bone origin, whereas placental isoenzymes were elevated. She was admitted to the antenatal ward for observation. Ultrasound scan of the fetus revealed normal growth, liquor volume and doppler flow. The fetus was monitored daily with cardiotocography. Abdominal and liver ultrasound scan was unremarkable. A gradual elevation of ALP level was noted on repeated blood tests. On the 38th week of pregnancy, a healthy girl was born by Caesarean section due to failed induction of labour. The histopathological examination revealed a 730 g placenta which showed mild chronic intervillositis of uncertain aetiology. The measurements of the placenta were adequate for the gestational age and neonate body weight. No area of infarction was observed. At the 3rd post-operative day, with a normal course of puerperium, the patient and baby were discharged home. A repeat serum ALP level one week post delivery showed marked decrease in ALP levels. Serum ALP level returned to normal at 6 weeks post-partum. Extremely high isolated maternal Alkaline Phosphatase serum concentration – 2 Case Reports and Literature Review Case 2 A fit and well 20-year-old primigravidae who was 36 weeks pregnant was reviewed due to generally feeling unwell. Her clinical history and examination was otherwise unremarkable. Blood tests were normal apart from single elevated serum ALP of 3017U/l. Five days previously, her ALP levels was 764 U/l. Abdominal and liver ultrasound examination showed no hepatic, biliary tract or renal abnormalities. Obstetrical ultrasonographic examination and Doppler blood flow remained normal. She was followed up for one week with daily fetal monitoring using cardiotocography. At that time, given the absence of any clinical or biochemical abnormalities, an isolated placental ALP elevation was suspected. Serum ALP electrophoresis showed normal ALP level of liver and bone origin, whereas placental isozyme was elevated. Labour was induced at 38 weeks and 1 day gestation using Prostin and she had a normal vaginal delivery of healthy female infant. At postpartum examination, placenta was mature, there was no evidence of infarction site or abnormality grossly. Histological examination of placenta did not reveal any abnormality. At postpartum 10 days, the alkaline level was 1010 U/L. Serum ALP level returned to normal at 6 weeks post-partum. Discussion The above two cases represents markedly elevated ALP levels, mainly due to placental origin. Review of the literature suggests a possible association between elevated ALP levels and several perinatal complications such as low birth weight, pre-eclampsia and preterm delivery. Although, there are two recent studies that have showed a significant association between elevated ALP levels and preterm delivery, further studies are needed to confirm these results. With regard to our cases, we have excluded liver, kidney, bone, and immunological diseases, in addition to thyroid and parathyroid dysfunction. Intrauterine growth restriction, pre-eclampsia, and Down’s syndrome were also ruled out. The mothers did not smoke and was not undergoing any drug treatments. There were slow decline in the serum ALP levels following delivery in both cases, and this finding is similar to one case described by Celik et al. They discussed that a slow decline in the serum ALP level following delivery is a typical characteristic of placental isoenzymes. Placental isoenzyme activity has the longest half-life of all the ALP isoenzymes with ~7 days, this is followed by liver isoenzyme and the last one is bone isoenzyme with half-life of 1-2 days. In conclusion, when markedly raised serum ALP concentration is present during pregnancy, differential diagnosis of important pathology must be systematically excluded. Elevation of serum ALP in pregnancy can originate not only form placenta but also from bone or hepatic tissue. The isoenzyme characterisation by electrophoresis must be performed to determine the origin of ALP. In such cases, the study would recommend precise monitoring of fetal and maternal conditions, histopathological examination of the placenta, and more attention to the follow up of declining ALP concentrations after delivery. One hypothesis we can derived from this report is that mild chronic infection of the placenta may be responsible for the markedly raised ALP level in pregnancy, however more research is needed to confirm this relationship. References: Lehmann FG. Human alkaline phosphatases. Evidence of three isoenzymes (placental, intestinal and liver-bone-kidney-type) by lectin-binding affinity and immunological specificity. BiochimBiophysActa 1980 Nov 6;616(1):41-59. Wojcicka-Bentyn J, et al. Extremely elevated activity of serum alkaline phosphatise in gestational diabetes: A case report. American Journal of Obstetrics and Gynaecology 2004; 190:566-7. Bashiri A, et al. Positive placental staining for alkaline phosphatise corresponding with extreme elevation of serum alkaline phosphatase during pregnancy. Arch GynecolObstet 2007; 275:211-214. Boronkai A, et al. Extremely high maternal alkaline phosphatise serum concentration with syncytiotrophoblastic origin. J ClinPathol 2005; 58:72-72. Celik H, et al. Markedly elevated serum alkaline phosphatase level in an uncomplicated pregnancy. The Journal of Maternal-Fetal and Neonatal Medicine 2009; 22(8):750-707. Delluc C, et al. Elevation of alkaline phosphatise in a pregnant patient with antiphospholipid syndrome: HELLP syndrome or not? Rheumatology 2008;47:554-555. Vongthavaravat V , Nurnberger MM, Balodimos N, et al. Isolated elevation of serum alkaline phosphatase level in an uncomplicated pregnancy: a case report. Am J ObstetGynecol 2000;183:505–6. Meyer R , Thompson S, Addy C, et al. Maternal serum placental alkaline phosphatase level and risk for preterm delivery. Am J ObstetGynecol 1995;173:181–6. Okesina AB, Donaldson D, Lascelles PT, Morris P. Effect of gestational age on levels of serum alkaline phosphataseisoenzymes in healthy pregnant women. Int J GynaecolObstet 1995;48:25-9. PN = Days post-natal Figure 1: Plot showing Alkaline Phosphatase levels for both Case 1 and Case 2.