Glutathione S –Transferase and Liver Function in Intrahepatic Cholestasis of Pregnancy and Pruritus Gravidarum

Dann, A T; Kenyon, A; Seed, Paul; Poston, Lucilla; Shennan, Andrew; Tribe, Rachel M.

doi:10.1002/hep.20473

Cited by 43 publications

(31 citation statements)

References 36 publications

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“…Impaired sulfation and abnormalities in progesterone metabolism have been found in ICP. 4 The recognition of familial cases and high incidence in certain ethnic groups have long suggested a genetic predisposition to ICP. Pedigree analysis of family members of a child with progressive familial intrahepatic cholestasis has identified a mutation in the MDR3 (ABCB4) gene associated with ICP.…”

Section: Intrahepatic Cholestasis Of Pregnancymentioning

confidence: 99%

Liver disease in pregnancy

2008

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Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes, including coincidental liver disease (most commonly viral hepatitis or gallstones) and underlying chronic liver disease. However, most liver dysfunction in pregnancy is pregnancy-related and caused by 1 of the 5 liver diseases unique to the pregnant state: these fall into 2 main categories depending on their association with or without preeclampsia. The preeclampsiaassociated liver diseases are preeclampsia itself, the hemolysis (H), elevated liver tests (EL), and low platelet count (LP) (HELLP) syndrome, and acute fatty liver of pregnancy. Hyperemesis gravidarum and intrahepatic cholestasis of pregnancy have no relationship to preeclampsia. Although still enigmatic, there have been recent interesting advances in understanding of these unique pregnancy-related liver diseases. Hyperemesis gravidarum is intractable, dehydrating vomiting in the first trimester of pregnancy; 50% of patients with this condition have liver dysfunction. Intrahepatic cholestasis of pregnancy is pruritus and elevated bile acids in the second half of pregnancy, accompanied by high levels of aminotransferases and mild jaundice. Maternal management is symptomatic with ursodeoxycholic acid; for the fetus, however, this is a high-risk pregnancy requiring close fetal monitoring and early delivery. Severe preeclampsia itself is the commonest cause of hepatic tenderness and liver dysfunction in pregnancy, and 2%-12% of cases are further complicated by hemolysis (H), elevated liver tests (EL), and low platelet count (LP)-the HELLP syndrome. Immediate delivery is the only definitive therapy, but many maternal complications can occur, including abruptio placentae, renal failure, subcapsular hematomas, and hepatic rupture. Acute fatty liver of pregnancy is a sudden catastrophic illness occurring almost exclusively in the third trimester; microvesicular fatty infiltration of hepatocytes causes acute liver failure with coagulopathy and encephalopathy. Early diagnosis and immediate delivery are essential for maternal and fetal survival. (HEPATOLOGY 2008;47:1067-1076.) M ost pregnant women are young and healthy, and physiological changes in pregnancy must not be mistaken for liver dysfunction (Table 1). Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes (Table 2). Although relatively uncommon, any liver disease can occur coincidentally in the pregnant patient and pregnancy may occur in a patient with underlying chronic liver disease. However, most liver dysfunction in pregnancy is pregnancy-related 1 and due to one of the 5 liver diseases unique to the pregnant state-hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia, the HELLP syndrome, and acute fatty liver of pregnancy (AFLP). These conditions are complications of pregnancy itself, and each has a characteristic timing in relation to the trimesters of pregnancy: HG in the first trimester, ICP in the second half of pregnancy, and the other 3 in the third trimes...

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Section: Intrahepatic Cholestasis Of Pregnancymentioning

confidence: 99%

Liver disease in pregnancy

2008

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“…The present study (1) identified three sulfated progesterone metabolites, 5a-pregnan-3a,-20a-diol-3,20-disulfate, 5b-pregnan-3a-20a-diol-3-sulfate, and 5b-pregnan-3a-20a-diol-3,20-disulfate, that were present in ICP patients in serum samples obtained even at [9][10][11][12][13][14][15] Abbreviations: ICP, intrahepatic cholestasis of pregnancy; PG, pruritus gravidarum.…”

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confidence: 58%

“…Patients with these characteristics have been identified in several studies, being usually labeled as having pruritus gravidarum (PG), an enigmatic entity that does not carry the fetal risks of a genuine ICP. (5,(9)(10)(11) Table 1 summarizes clinical and biochemical data previously reported in patients with ICP and in normal pregnancies, (7) comparing them with a concurrent unreported cohort of patients with PG in whom pruritus appeared at the same gestational age but was slightly less severe than in patients with ICP. In three of these patients with PG, pruritus diminished spontaneously 1 week prior to delivery; and in another patient, pruritus disappeared in the final week of pregnancy, a phenomenon that was not observed in patients with a genuine ICP.…”

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confidence: 99%

Sulfated progesterone metabolites in the pathogenesis of intrahepatic cholestasis of pregnancy: Another loop in the ascending spiral of medical knowledge

Reyes

2016

Hepatology

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P rogress in medical knowledge can be represented by an ascending spiral in which every loop stands over previous data, adds new findings that deepen our understanding of a disease, and helps to design further research and therapeutic strategies. New loops are frequently inspired by novel approaches to accepted hypotheses and usually supported by the use of more advanced technologies, as seems to be the case in the article by Abu-Hayyeh et al. (1) Intrahepatic cholestasis of pregnancy (ICP), a frequent liver disorder of pregnancy, implies an unpredictable risk of fetal distress, with premature deliveries and stillbirths. Its pathogenesis has been linked to effects of sex hormones during pregnancy, and in recent decades successive reports have revealed a role for progesterone derivatives.In this regard, the spiral started in 1970 when Sj€ ovall and Sj€ ovall reported increased sulfated metabolites of progesterone in serum and urine of Swedish patients with ICP, in contrast to normal pregnancies.(2) Furthermore, this biochemical peculiarity was identified in two patients during an early stage of pregnancy, before the onset of pruritus and abnormalities in serum liver tests, suggesting that it could have predicted the development of ICP.In 1979, Giusti et al. reported that an increase in sulfated progesterone metabolites in plasma from Italian patients with ICP did not occur in patients with viral hepatitis in pregnancy, giving further support to its specificity in ICP. In the 1990s, a series of reports centered in Sj€ ovall's laboratory, in Stockholm, Sweden, using now more sophisticated and precise techniques applied to serum and urine from Chilean patients with ICP and their controls, clarified that a distinctive biochemical feature in ICP was the switch of progesterone metabolism toward a four-fold to 10-fold increase in serum and urine concentration of sulfated metabolites, with an increased ratio of 3a-hydroxysteroid sulfates to 3b-hydroxysteroid sulfates, changes that were reversed after treatment with ursodeoxycholic acid. (4) Among other important steps in this research line, Glantz et al., in Sweden, reported similar changes in the pattern of progesterone metabolites in urine of ICP patients, with a reversal after ursodeoxycholic acid administration, correlating with an improvement in maternal pruritus (5) ; and Abu-Hayyeh et al. also reported increased levels of progesterone sulfates in ICP patients studied in the United Kingdom. (6) Therefore, this metabolic pattern has been detected in ICP patients from different geographic locations and ethnic origins.The present study (1) identified three sulfated progesterone metabolites, 5a-pregnan-3a,-20a-diol-3,20-disulfate, 5b-pregnan-3a-20a-diol-3-sulfate, and 5b-pregnan-3a-20a-diol-3,20-disulfate, that were present in ICP patients in serum samples obtained even at 9-15 Abbreviations: ICP, intrahepatic cholestasis of pregnancy; PG, pruritus gravidarum.

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“…Glutathione S-transferase-alpha (GSTA, a specific marker of hepatocellular integrity) is significantly elevated in women with ICP, when compared with healthy pregnancies. Also, it is helpful in differentiating between ICP and pruritus gravidarum, a benign condition with no elevation of fetal risk [110]. Serum gamma-glutamyl transpeptidase (GGT) and 5 0 -nucleotidase activity are normal or only mildly increased.…”

Section: Clinical Presentation and Diagnostic Evaluationmentioning

confidence: 98%

Pregnancy-Associated Liver Disorders

Hepburn

2008

Dig Dis Sci

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Liver disorders associated with pregnancy include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP), and acute fatty liver of pregnancy (AFLP). These conditions are relatively common and unique to pregnancy and are more likely to occur at certain terms of gestation specific to each condition. They can be associated with significant maternal and fetal morbidity and mortality. Although managing such patients may be very challenging, spontaneous resolution of the disease occurs shortly after termination of the pregnancy, usually without hepatic sequellae. Early diagnosis and timely treatment is a key to therapeutic success. This article explores the clinical features, pathophysiology, and management of these disorders.

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Glutathione S –Transferase and Liver Function in Intrahepatic Cholestasis of Pregnancy and Pruritus Gravidarum

Cited by 43 publications

References 36 publications

Liver disease in pregnancy

Liver disease in pregnancy

Sulfated progesterone metabolites in the pathogenesis of intrahepatic cholestasis of pregnancy: Another loop in the ascending spiral of medical knowledge

Pregnancy-Associated Liver Disorders

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