Liver pathology in pregnancy.

Liver dysfunction occurs in up to 3% of pregnancies and can be due to pregnancy-associated liver injury, exacerbation of pre-existing liver disease, or co-incident with pregnancy. The most common form of pregnancy-associated liver injury is intrahepatic cholestasis of pregnancy (ICP). This condition is typically benign and self-limited, but is associated with fetal morbidity and mortality with high levels of serum bile acids. Acute fatty liver of pregnancy (AFLP) and the hypertensive disorders of pregnancy (including pre-eclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome) are more commonly associated with maternal and fetal complications and may necessitate expedient delivery. Histologically, ICP shows nonspecific features of cholestasis, while AFLP and the hypertensive disorders have more characteristic histologic findings. While not a true liver disease, hyperemesis gravidarum can cause elevated liver enzymes. Pregnant patients are at increased risk of developing severe hepatitis E and herpesvirus infections, Budd-Chiari syndrome, and gallstones, and they may also experience worsening of known chronic liver disease. Mass lesions in pregnancy including hemangiomas, focal nodular hyperplasia, and hepatocellular adenomas and carcinomas can present unique challenges for diagnosis and management. This review will explore the pathophysiology, presentation, histologic features, and management of these conditions.

GDF15: A Hormone Conveying Somatic Distress to the Brain.

GDF15 has recently gained scientific and translational prominence with the discovery that its receptor is a GFRAL-RET heterodimer of which GFRAL is expressed solely in the hindbrain. Activation of this receptor results in reduced food intake and loss of body weight and is perceived and recalled by animals as aversive. This information encourages a revised interpretation of the large body of previous research on the protein. GDF15 can be secreted by a wide variety of cell types in response to a broad range of stressors. We propose that central sensing of GDF15 via GFRAL-RET activation results in behaviors that facilitate the reduction of exposure to a noxious stimulus. The human trophoblast appears to have hijacked this signal, producing large amounts of GDF15 from early pregnancy. We speculate that this encourages avoidance of potential teratogens in pregnancy. Circulating GDF15 levels are elevated in a range of human disease states, including various forms of cachexia, and GDF15-GFRAL antagonism is emerging as a therapeutic strategy for anorexia/cachexia syndromes. Metformin elevates circulating GDF15 chronically in humans and the weight loss caused by this drug appears to be dependent on the rise in GDF15. This supports the concept that chronic activation of the GDF15-GFRAL axis has efficacy as an antiobesity agent. In this review, we examine the science of GDF15 since its identification in 1997 with our interpretation of this body of work now being assisted by a clear understanding of its highly selective central site of action.

Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3-2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10-8) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.

Direct analysis of hCGßcf glycosylation in normal and aberrant pregnancy by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

The analysis of human chorionic gonadotropin (hCG) in clinical chemistry laboratories by specific immunoassay is well established. However, changes in glycosylation are not as easily assayed and yet alterations in hCG glycosylation is associated with abnormal pregnancy. hCGß-core fragment (hCGßcf) was isolated from the urine of women, pregnant with normal, molar and hyperemesis gravidarum pregnancies. Each sample was subjected to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis following dithiothreitol (DTT) reduction and fingerprint spectra of peptide hCGß 6-40 were analyzed. Samples were variably glycosylated, where most structures were small, core and largely mono-antennary. Larger single bi-antennary and mixtures of larger mono-antennary and bi-antennary moieties were also observed in some samples. Larger glycoforms were more abundant in the abnormal pregnancies and tri-antennary carbohydrate moieties were only observed in the samples from molar and hyperemesis gravidarum pregnancies. Given that such spectral profiling differences may be characteristic, development of small sample preparation for mass spectral analysis of hCG may lead to a simpler and faster approach to glycostructural analysis and potentially a novel clinical diagnostic test.

Dietary antioxidant levels in hyperemesis gravidarum: a case control study.

OBJECTIVES: Dietary antioxidant intake decreases the risk of many diseases. Hyperemesis gravidarum (HG) is the most common eating disorder during pregnancy Therefore, the authors conducted this prospective and case control study to evaluate dietary antioxidant levels of women with HG and compare with healthy pregnant women. MATERIAL AND METHODS: This prospective case control study was conducted at a government hospital in the southeastern region of Turkey from February 2010 to May 2010. A total of 100 pregnant women were included into the study Dietary antioxidant levels (DAL) were measured according to the new 92-item antioxidant nutrient questionnaire developed by Satia et al. 50 women with HG and 50 healthy pregnant women were evaluated. Statistical analyses were carried out with statistical packages for SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS: There were no statistically significant differences between the groups regarding the age of the patients, gestational age, educational status, body height and weight (p > .05). Vitamin E, E equivalent, vitamin C, carotene and vitamin A levels were significantly lower in women with HG (p < .05). The results of logistic regression method for these variables including odds ratio (95 % CI) were as follows: 10.07 (1.52-66.51), 7.37 (2.66-20.41), 4.26 (2.66-20.41), 3.66 (2.38-5.63) and 2.75 (1.56-4.85), respectively CONCLUSION: According to this study, vitamin E, E equivalent, vitamin C, carotene and vitamin A levels of women may play a role in the pathogenesis of HG. Therefore, diet recommendations should be given by clinicians before pregnancy

Posttraumatic oxytocin dysregulation: is it a link among posttraumatic self disorders, posttraumatic stress disorder, and pelvic visceral dysregulation conditions in women?

This article explicates a theory that oxytocin, a sexually dimorphic neurotransmitter and paracrine hormone, is a plausible mechanism linking early relational trauma with posttraumatic self disorders (e.g., dissociation, somatization, and interpersonal sensitivity), posttraumatic stress disorder, and pelvic visceral dysregulation disorders (e.g., irritable bowel syndrome, chronic pelvic pain, interstitial cystitis, and hyperemesis gravidarum). This posttraumatic oxytocin dysregulation disorders theory is consistent with the historical and contemporary literature. It integrates attention to psychological and physical comorbidities and could account for the increased incidence of these disorders among females. Specific propositions are explored in data from studies of traumatic stress and women's health.

Hyperemesis gravidarum: is an ultrasound scan necessary?

BACKGROUND: Traditionally, in cases of hyperemesis gravidarum (HG), an ultrasound evaluation is recommended to confirm viability and to exclude multiple pregnancies and gestational trophoblastic disease (GTD). Our aim was to perform a case-control study to evaluate the incidence of these findings. METHODS: Each case of HG was matched for gestational age with the next ultrasound examination performed in an asymptomatic pregnancy. The findings were compared between the two groups. RESULTS: Two hundred and eighty-six cases of HG were matched with 286 asymptomatic women. The total number of viable pregnancies was higher in the HG group (280/286, 97.9%) than that in the control group (265/286, 92.6%; P = 0.006). The incidence of twins was 3.1% in each group (P > 0.999). The incidence of early pregnancy failure was 0.7% in women with HG compared to 7.0% in asymptomatic women (odds ratio 0.09, 95% CI 0.01-0.04, P < 0.0001). The one case of GTD was in the HG group; however, this case also presented with vaginal bleeding. CONCLUSIONS: Pregnancies complicated by HG had a similar risk of twin pregnancy, and a lower risk of early pregnancy failure compared to controls. In the absence of vaginal bleeding, there was no increase in GTD in women with HG. We conclude that an ultrasound scan is not clinically necessary in women presenting with HG, other than for maternal reassurance.

Relationship between adenosine and T-helper 1/T-helper 2 balance in hyperemesis gravidarum.

BACKGROUND: Adenosine modulates the T-helper (Th) 1/T-helper (Th) 2 balance. We evaluated the relationship between changes in plasma adenosine and the T-helper (Th) 1/T-helper (Th) 2 balance in hyperemesis gravidarum. METHODS: Plasma adenosine concentrations and the Th1/Th2 ratio were examined in the peripheral blood of 24 women with hyperemesis gravidarum and normal pregnancies. The proportion of CD4-positive cells that expressed intracellular cytokines (interferon gamma and interleukin 4) was analyzed by flow cytometry. The ratio of interferon-gamma-secreting cells to interleukin-4-secreting cells was taken as the Th1/Th2 ratio in vivo. The change induced by adenosine-receptor blocker 8-sulfophenyltheophylline was also measured in vitro to evaluate the possible role of adenosine in modifying the Th1/Th2 balance. RESULTS: In hyperemesis gravidarum, plasma adenosine and the proportion of interleukin-4-secreting cells were increased significantly, and the Th1/Th2 ratio was significantly lower than in normal pregnancy (p<0.05). The decrease in the proportion of IL-4-secreting cells after adenosine receptor blockade in hyperemesis gravidarum significantly exceeded that of normal pregnancy (p<0.05). CONCLUSIONS: Increased plasma adenosine may be involved in regulating the Th1/Th2 balance in hyperemesis gravidarum.

Hyperemesis gravidarum is associated with oxidative stress.

Hyperemesis gravidarum (HEG), associated with pregnancy, is a severe form of nausea and vomiting causing decrease in nutrient antioxidants. Hence, we hypothesize that oxidation injury may be involved in the pathogenesis of HEG. Plasma levels of the ubiquitous antioxidant, reduced glutathione (GSH) may serve as a sensitive measure for systemic oxidative stress. Women with pregnancies complicated by HEG (study group) were compared with pregnant women without HEG (pregnant control group) and with healthy nonpregnant women (nonpregnant control group). Plasma GSH levels were determined in the study group at the time of admission to hospital, and when the vomiting had ceased, it was compared with those of the two control groups. Plasma GSH levels were significantly higher in the pregnant control group than in nonpregnant controls (6.13 +/- 2.9 microM vs. 1.01 +/- 0.3 microM p <0.01). In contrast, values in the HEG women at the time of admission were significantly lower than the pregnant controls (3.12 +/- 1.6 microM, p <0.01). At the second sampling, when the women had ceased vomiting, plasma GSH values were higher than at the acute stage of the illness and were no longer significantly different from the pregnant control group (4.43 +/- 1.6 microM). Low values of plasma GSH in HEG patients suggest that oxidative stress is associated with this condition.