Management of liver diseases in pregnancy
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Management of liver diseases in pregnancy
Management of liver diseases in pregnancyModerator-Prof. Anoop SarayaCandidate-Dr. Moka PraneethContentsPregnancy physiologic changesHepatitis-EHepatitis-BAcute liver failureCirrhosis & Portal hypertensionICPHGHELLP syndromeAFLP
Physiological changes in liver tests during normal pregnancyTestNormal RangeBilirubinUnchanged or slightly decreaseAminotransferasesUnchangedProthrombin timeUnchangedAlkaline phosphataseIncreases 2 to 4-foldFibrinogenIncreases 50%GlobulinIncreases in and globulins -fetoproteinModerate rise, esp. with twinsWBCIncreasesCeruloplasminIncreasesCholesterolIncreases 2-foldTriglyceridesIncreasesGlobulinDecreases in gamma-globulinHemoglobinDecrease in later pregnancyLiver diseases in pregnancyOnly in thesetting of pregnancycoincidental with pregnancyPreeclampsia-associatedChronic liver diseases e.g.: cholestatic liver disease,autoimmune hepatitis,Wilson disease,viral hepatitis, etcnot associated withpreeclampsiaThe preeclampsiaitselfHELLP-syndromeAFLPHyperemesisgravidarum Intrahepatic cholestasisof pregnancyStudyPatients (n)Prevalence of HEV infection (%)Prevalence of fulminant liver failure (%)Mortality rate (%)Jaiswal et al, 2001 (North India) 127585845Singh et al, 2003 (North India)60376464Khuroo et al, 2003 (North India) 76866955Beniwal et al, 2003 (North India)9747.47539.1Tsega et al, 1993 (Ethiopia)3259-42Kumar et al, North India 200465453273Patra et al 2007 North India220605541Stoszek et al 2006 (Egypt)242884.300Rasheeda et al (2008)115753.43.4Studies on Hepatitis E infection and Pregnancy5Hepatitis E virus infection and fulminant hepatic failure during pregnancy50 pregnant and 50 non-pregnant women with FHF and 150 pregnant healthy females withoutliverdisease as controls were recruited for the study.Serologically (38/50; 76%) as well as by RT-PCR (28/50; 56%), a significantly higher HEV positivity rate was found in pregnant FHF patients compared to non-pregnant women (serologically 15/50; 30%; RT-PCR 7/50; 14%). Jilani N et al. J Gastroenterol Hepatol. 2007 Hepatitis E virus infection and fulminant hepatic failure during pregnancyCD4 counts were lower (P < 0.05), while CD8 counts were higher (P < 0.05), and their ratio (CD4/CD8) in HEV positive pregnant FHF patients was significantly lower (P < 0.01) when compared to that of HEV negative pregnant FHF women or controls. Levels of estrogen, progesterone and beta-HCG were also found to be higher (P < 0.001) in HEV positive pregnant FHF patients when compared to HEV negative patients or controls. HEV infected pregnant FHF patients had a significantly higher mortality rate of 65.8% (25/38) compared to 23.5% (4/15) in HEV positive non-pregnant women (P < 0.001
7Immunological alterations in pregnant women with acute hepatitis E.Pregnant women with HEV had generalized immune suppression characterized by decrease in lymphocyte response to phytohemagglutinin (PHA) with a predominant Th2 bias as compared to non pregnant women with hepatitis E and normal healthy controls.Neither normal healthy pregnant women nor nonpregnant HEV infected women demonstrated decreased response to PHA. Pal R et al. J Gastroenterol Hepatol. 2005HEV by itself does not produce the immunological changes and needs a pregnancy as a physiological state to produce the above-mentioned changes.
8Pathogenesis of Hepatitis-E in pregnancy
Trophoblasts do not express MHC class proteins and hence resistant to T-cell mediated injury, which is a protective phenomenon to sustain the fetus. NK cells do not require MHC proteins and the trophoblasts are protected against the NK cells as they express a unique Human Leukocyte Antigen (HLA) molecule called HLA-G, which binds to NK receptors CD 16, and CD 56 and inactivates it. The placenta also expresses an enzyme called indoleamine 2, 3-dioxygenase which inactivates and depletes tryptophan, an amino acid essential to T-cell function and hence suppresses cell mediated immunity at the fetus-placental interface. Both the placenta and the trophoblasts secrete cytokines, including TGF-, IL-4, and IL-10, which inhibit cell-mediated immunity. cytokine production during pregnancy favors antibody production over cytotoxic T cell responses. T-cells are markedly reduced during early pregnancy up to the 20th week of gestation leading to reduced level of immunity. Progesterone > Estrogen causes thymic involution. hCG suppresses cell-mediated immunity.The activity of the p65 component of NF-B was diminished in both the peripheral blood mononuclear cells (PBMC) and post mortem liver biopsy specimens in pregnant patients with fulminant liver failure. There was a higher than normal level of p50 expression, but there was a near complete absence or a minimal expression of p65. Downregulation of NFkB sustains the fetus during pregnancy. 9Probable hypotheses for the variable pathogenesis of HEV
In North India, close to 60% of viral hepatitis in pregnant women was attributed to hepatitis E infection. Fulminant hepatic failure was more common among HEV-infected women (55%) who were 2.7 times at higher risk than non-HEV infected women (20%); maternal mortality was also higher secondary to fulminant hepatic failure in the HEV infected group (41%) vs. 7% in the non-HEV group. 10Termination of pregnancy in HEV-ALF?
Banait VS et al. Indian J Gastroenterol 2007All the studies have shown that pregnant women have the differential immune response which triggers fulminant liver failure. So the logical treatment should be to deliver the fetus as soon as possible. Therapeutic termination of pregnancy, which has been proved to be beneficial in pregnancyspecific disorders like HELLP syndrome and acute fatty liver of pregnancy have not been fully, explored in hepatitis E infection.Out of 156 pregnant women with liver disease, 45 had HEV-AVH, 42 had HEV-ALF, 6 had ALF non-HEV-related.Clinical and lab parameters of 42 pregnant women with HEV-ALF were retrospectively analysed. 2 patients were in 1st trimester, 14 in 2nd trimester, 26 in 3rd trimesterMedian age: 25.5 years, 12 (28.6%) were primigravidae22 women (4 in 2nd trimester, 18 in 3rd trimester labor started spontaneously in 13 women; in 9, it was induced because of IUFD- 14 out of 22 delivered a dead fetus) delivered whereas pregnancy continued in 20 women 14 died- out of 6 who survived, 5 delivered a normal baby at term and 1 delivered a preterm baby who died on 3rd day. Overall there were 29 (69%) fetal deaths and 23 (54%) maternal deaths. The maternal mortality in these 2 groups was similar. In patients with grades 1, 2 or 3 HE, delivery of fetus was associated with reduced mortality in those who delivered as against those who continued pregnancy. At present, although there is no consensus to treat patients with HEV infection in pregnancy, early delivery of the fetus if possible to prevent maternalmortality should be tried.
In 4 patients of HEV-ALF + IUFD, DIC was noted as early as 12 hours after fetal death. The increased fetal loss and improved survival in patients who delivered support the possibility that intrauterine transmission of HEV and intrauterine fetal hepatitis contribute to worsening of maternal condition. Whether delivery retards progression of DIC??
11Treatment algorithm for an HBV-infected woman who is already on antiviral therapy and presents with an unexpected pregnancy
Impact of pregnancy on chronic HBVNo worsening of liver disease in majorityOverall increase in HBV DNA levels during pregnancyMedian ALT levels decreased during pregnancyIncrease in ALT (3 x lowest ALT) within 6 months after deliveryCase reports of postpartum hepatic exacerbations
Terrault et al. Semin Liver Dis. 2007Soderstrom et al. Scand J Infect Dis 2003Borg et al. J viral Hep 2008Rasheed et al. Int J Gynaecol Obstet 2013HBV Infection in Women Considering Starting a Family: Which Drug?FDA classification: based on in vitro and animal studies Pregnancy class B: telbivudine and tenofovir DFPregnancy class C: interferon, adefovir, entecavir, and lamivudine Human data: Antiretroviral pregnancy registry: safety established for lamivudine and tenofovir, including exposure in first trimesterClinical studies of antiviral therapy to prevent perinatal transmission: safety established for lamivudine and telbivudine, mainly exposure in third trimester[2-5]1. Antiretroviral Pregnancy Registry. December 2012. 2. Xu WM, et al. J Viral Hepat. 2009;16:94-103. 3. Shi Z, et al. Obstet Gynecol. 2010;116:147-159. 4. Han GR, et al. J Hepatology. 2011;55:1215-1221. 5. Pan CQ, et al. Clin Gastroenterol Hepatol. 2012;10:520-526.FDA, US Food and Drug Administration; HBV, hepatitis B virus.
Certainly, these discussions would not be necessary if the available treatments were known to be safe when used in pregnancy. The US Food and Drug Administration (FDA) classifies medications regarding safety for use in pregnancy largely based on in vitro and animal studies. Class A agents are the safest, and class D includes drugs that are not to be used during pregnancy. Among the currently available hepatitis B drugs, telbivudine and tenofovir are considered to be class B, meaning there are no data from animal studies or in vitro studies to suggest teratogenicity. Others, including interferon, adefovir, entecavir, and lamivudine, are considered to be class C, meaning the available data suggest possible risks to the fetus.
There are, however, some human data on the safety of these drugs. The first comes from the Antiretroviral Pregnancy Registry, where safety has been established, including during the first trimester, for lamivudine and tenofovir, which are commonly used in HIV treatment. There are also clinical studies of antiviral therapy specifically to prevent perinatal transmission, and these studies provide safety data for lamivudine and telbivudine, although these drugs are mainly used