Contraception in patients with liver disease and liver transplant.

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Antimullerian Hormone, a Marker of Ovarian Reserve, Is Protective Against Presence and Severity of NASH in Premenopausal Women.

BACKGROUND & AIMS: Antimüllerian hormone (AMH) is a marker of ovarian reserve with emerging data linking lower levels to some metabolic and inflammatory diseases in women. Whether AMH levels influence nonalcoholic fatty liver disease (NAFLD) is unknown. METHODS: Leveraging the NASH Clinical Research Network we determined the association of AMH levels within 6 months of liver biopsy with presence and severity of histologic measures of NAFLD in premenopausal women. Outcomes included presence of nonalcoholic steatohepatitis (NASH), presence and severity of fibrosis, and NAFLD Activity Score and its components. Logistic and ordinal logistic regression models were adjusted for age, race/ethnicity, homeostatic model assessment for insulin resistance, body mass index, dyslipidemia, polycystic ovary syndrome, estrogen-progestin use, and menstrual cyclicity. RESULTS: Median cohort age was 35 years; 73% were white and 24% Hispanic. Thirty-three percent had diabetes, 81% had obesity, and 95% had dyslipidemia. On biopsy 71% had NASH, 68% had any fibrosis, and 15% had advanced fibrosis. On adjusted analysis (n = 205), higher AMH quartiles were inversely associated with NAFLD histology including prevalent NASH (adjusted odds ratio [AOR], 0.64; 95% confidence interval [CI], 0.41-1.00), NAFLD Activity Score ≥5 (AOR, 0.52; 95% CI, 0.35-0.77), Mallory hyaline (AOR, 0.54; 95% CI, 0.35-0.82), and higher fibrosis stage (AOR, 0.70; 95% CI, 0.51-0.98). The protective effects of AMH were more pronounced among women without polycystic ovary syndrome (n = 164), including lower odds of NASH (AOR, 0.53; 95% CI, 0.32-0.90) and any NASH fibrosis (AOR, 0.54; 95% CI, 0.32-0.93). CONCLUSIONS: AMH may reflect a unique biomarker of NASH in premenopausal women and findings suggest a novel link between reproductive aging and histologic severity of NAFLD in women.

Sex differences in chronic liver disease and benign liver lesions.

The epidemiology, natural history, and therapeutic responses of chronic liver diseases and liver lesions often vary by sex. In this review, we summarize available clinical and translational data on these aspects of the most common liver conditions encountered in clinical practice, including the potential contributions of sex hormones to the underlying pathophysiology of observed differences. We also highlight areas of notable knowledge gaps and discuss sex disparities in access to liver transplant and potential strategies to address these barriers. Given established sex differences in immune response, drug metabolism, and response to liver-related therapies, emerging clinical trials and epidemiological studies should prioritize dedicated analyses by sex to inform sex-specific approaches to liver-related care.

Parental leave, childcare policies, and workplace bias for hepatology professionals: A national survey.

BACKGROUND: The presence of workplace bias around child-rearing and inadequate parental leave may negatively impact childbearing decisions and sex equity in hepatology. This study aimed to understand the influence of parental leave and child-rearing on career advancement in hepatology. METHODS: A cross-sectional survey of physician members of the American Association for the Study of Liver Diseases (AASLD) was distributed through email listserv in January 2021. The 33-item survey included demographic questions, questions about bias, altering training, career plans, family planning, parental leave, and work accommodations. RESULTS: Among 199 US physician respondents, 65.3% were women, and 83.4% (n = 166) were attendings. Sex and racial differences were reported in several domains, including paid leave, perceptions of bias, and child-rearing. Most women (79.3%) took fewer than the recommended 12 paid weeks of parental leave for their first child (average paid leave 7.5 wk for women and 1.7 for men). A majority (75.2%) of women reported workplace discrimination, including 83.3% of Black and 62.5% of Hispanic women. Twenty percent of women were asked about their/their partners' pregnancy intentions or child-rearing plans during interviews for training. Women were more likely to alter career plans due to child-rearing (30.0% vs. 15.9%, p = 0.030). Women were also more likely to delay having children than men (69.5% vs.35.9%). CONCLUSIONS: Women reported sex and maternity bias in the workplace and during training interviews, which was more frequently experienced by Black and Hispanic women. As two-thirds of women had children during training, it is a particularly influential time to reevaluate programmatic support to address long-term gender disparities in career advancement.

Prevalence of nonalcoholic fatty liver disease increased with type 2 diabetes mellitus in overweight/obese youth with polycystic ovary syndrome.

OBJECTIVES: Polycystic ovary syndrome (PCOS) increases non-alcoholic fatty liver disease (NAFLD) risk and severity in adults, but data in adolescents with diverse backgrounds are limited. We evaluated NAFLD prevalence and characterized NAFLD risk factors in overweight/obese adolescents by PCOS status. METHODS: Retrospective study of overweight (n=52)/obese (n=271) female adolescents (12-18 years old), evaluated clinically 2012-2020, was conducted comparing PCOS patients to age-matched non-PCOS controls. NAFLD was defined as ALT≥44U/L x2 and/or ≥80U/L x1, hepatic steatosis on imaging, or NAFLD on biopsy, in absence of other liver disease. Metabolic comorbidities were captured. Log-binomial regression models estimated prevalence risk ratios (PR). RESULTS: NAFLD prevalence was 19.1 % in adolescents with PCOS (n=161), similar to those without (n=162) (16.8 %, p=0.6). Adolescents with PCOS were more likely to have insulin resistance, hypercholesterolemia, and higher triglycerides (p<0.05). Those with PCOS and concomitant type 2 diabetes (T2DM) did have increased NAFLD risk (PR 2.5, p=0.04), but those with PCOS without T2DM did not (PR 0.9, p=0.8). Adolescents with PCOS and NAFLD, compared to those with PCOS without NAFLD, had a higher prevalence of metabolic comorbidities including hypercholesterolemia (77 vs. 48 %), T2DM (29 vs. 8 %), and hypertriglyceridemia (65 vs. 37 %) (p<0.01). CONCLUSIONS: Almost 1 in 5 overweight/obese female adolescents had NAFLD, but PCOS did not increase NAFLD risk in this diverse cohort. Among young women with PCOS, concomitant T2DM did increase the risk for NAFLD. Closer monitoring of obesity comorbidities in adolescents with PCOS is essential for optimizing health and merits updating current guidelines.

Influence of progestin-only hormonal use on hepatocellular adenomas: A retrospective cohort study.

OBJECTIVES: Exogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients. STUDY DESIGN: In this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures. RESULTS: A total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only). CONCLUSIONS: During discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception. IMPLICATIONS: In this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.

Polycystic ovary syndrome is associated with nonalcoholic steatohepatitis in women of reproductive age.

Polycystic ovary syndrome (PCOS) occurs in approximately 10% of all reproductive-age women, with over 50% of these patients having imaging-confirmed nonalcoholic fatty liver disease (NAFLD). Whether PCOS increases the risk for more clinically relevant disease, such as nonalcoholic steatohepatitis (NASH), is unclear. Such findings are relevant to prognosticating risk of progressive liver disease in the growing population of young adults with NAFLD. Using weighted discharge data from the United States National Inpatient Sample from 2016 to 2018, we evaluated the association of PCOS with the presence of NASH among reproductive-age women with NAFLD. The association of PCOS with NASH was assessed by logistic regression, adjusting for demographic and comprehensive metabolic comorbidities. Other causes of hepatic steatosis and chronic liver diseases were excluded. Our analysis included 189,440 reproductive-age women with NAFLD, 9415 of whom had PCOS. Of those with PCOS, 1390 (15%) had a distinct code for NASH. Women with PCOS were younger (median age, 33 vs. 40 years; p < 0.001) and more likely to have diabetes (37.0% vs. 34.0%), obesity (83.0% vs. 58.0%), dyslipidemia (26.0% vs. 21.0%), and hypertension (38.0% vs. 35.0%) (all p ≤ 0.01). On adjusted analysis accounting for these metabolic comorbidities, PCOS remained independently associated with an increased prevalence of NASH (adjusted odds ratio, 1.22; 95% confidence interval, 1.05-1.42; p = 0.008). Conclusions: Among reproductive-age women with NAFLD, metabolic risk factors were more common in those with PCOS. Despite adjustment for these metabolic comorbidities, PCOS remained associated with a 22% higher odds of having NASH. These findings support efforts to increase NAFLD screening in young women with PCOS and highlight the potential "head start" in progressive liver disease among young women with PCOS.

Pregnancy Is Not Associated with an Increased Risk of Decompensation, Transplant, or Death in Compensated Cirrhosis.

Background and Aims: Childbirth in women with cirrhosis is increasing and associated with a higher risk of perinatal outcomes compared to the general population. Whether pregnancy influences the risk of liver-related events compared to nonpregnant women with cirrhosis is unclear. This study evaluates the association between pregnancy and liver-related outcomes in women with compensated cirrhosis. Approach and Results. Population-based retrospective matched cohort study in Ontario, Canada, using routinely collected healthcare data. Pregnant women with compensated cirrhosis and without prior history of decompensation between 2000 and 2016 were identified and matched to nonpregnant women with compensated cirrhosis on age, etiology of cirrhosis, and socioeconomic status in a 1 : 2 ratio. The association between pregnancy and the composite outcome of nonmalignant decompensation, liver transplant (LT), and death up to two years after cohort entry was estimated using the multivariate Cox proportional hazard regression adjusting for potential confounders. Overall, 5,403 women with compensated cirrhosis were included (1,801 pregnant; 3,602 nonpregnant; median age 31 years (IQR 27-34); 60% nonalcoholic fatty liver disease, 34% viral hepatitis). After two years of follow-up, only 19 (1.1%) pregnant women had a liver-related event compared to 319 (8.9%) nonpregnant women. Pregnant women with compensated cirrhosis had a lower hazard of a liver-related event compared to nonpregnant women (aHR 0.14, 95% CI 0.09-0.22, P < .001). Conclusions: Pregnancy in women with compensated cirrhosis is not associated with increased liver-related events compared to nonpregnant women. These results can facilitate counselling women with cirrhosis of child-bearing age and suggests that pregnancy may not accelerate liver disease progression.

Awarding additional MELD points to the shortest waitlist candidates improves sex disparity in access to liver transplant in the United States.

Since the introduction of the MELD-based allocation system, women are now 30% less likely than men to undergo liver transplant (LT) and have 20% higher waitlist mortality. These disparities are in large part due to height differences in men and women though no national policies have been implemented to reduce sex disparities. Patients were identified using the Scientific Registry of Transplant Recipients (SRTR) from 2014 to 2019. Patients were categorized into five groups by first dividing into thirds by height then dividing the shortest third into three groups to capture more granular differences in the most disadvantaged patients (<166 cm). We then used LSAM to model waitlist outcomes in five versions of awarding additional MELD points to shorter candidates compared to current policy. We identified two proposed policy changes LSAM scenarios that resulted in improvement in LT and death percentage for the shortest candidates with the least negative impact on taller candidates. In conclusion, awarding an additional 1-2 MELD points to the shortest 8% of LT candidates would improve waitlist outcomes for women. This strategy should be considered in national policy allocation to address sex-based disparities in LT.

Associations of NAFLD with circulating ceramides and impaired glycemia.

AIM: Determine the association of circulating ceramides with NAFLD and glycemic impairment. METHODS: Sample: 669 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort aged 40-84 years without cardiovascular disease, cirrhosis, or significant alcohol intake. CLINICAL MEASURES: Computed tomography scans at baseline for hepatic attenuation. Fasting serum specimens at baseline and after 5 years. Lipidomics: LC-MS-based analysis of 19 known ceramide signals. STATISTICAL ANALYSIS: Linear and logistic regression models of log-transformed ceramides, hepatic attenuation and glucose adjusted for age, sex, calories, study site, BMI, exercise, diet quality, alcohol, saturated fat, lipid-lowering medications and fasting glucose. RESULTS: Average age was 55 years, 44% were women, mean BMI was 25.9 kg/m2, and 8% had NAFLD. In adjusted models, Cer(d16:1/20:0) and Cer(d18:1/18:0) were associated with lower mean hepatic attenuation (increased liver fat) (ß -4.29; 95% CI [-5.98, -2.59]) and (ß -3.40; 95% CI [-5.11, -1.70]), and LacCer(d18:1/16:0) with higher attenuation (ß 4.44; 95% CI [2.15, 6.73]). All three ceramides partially mediated the relationship between hepatic attenuation and fasting glucose by 16%, 11% and 5%, respectively, after 5-years. CONCLUSIONS: Three circulating ceramides were strongly associated with NAFLD and fasting glucose after 5 years, and partially mediated this association.

Outcomes of pregnancy in autoimmune hepatitis: A population-based study.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) disproportionately affects young women, which may have implications in pregnancy. However, data on pregnancy outcomes in women with AIH are limited. APPROACH AND RESULTS: Using weighted discharge data from the United States National Inpatient Sample from 2012 to 2016, we evaluated pregnancies after 20 weeks gestation and compared outcomes in AIH to other chronic liver diseases (CLD) or no CLD in pregnancy. The association of AIH with maternal and perinatal outcomes was assessed by logistic regression. Among 18,595,345 pregnancies, 935 (<0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Temporal trends in pregnancies with AIH remained stable from 2008 to 2016 with 1.4-6.8/100,000 pregnancies per year (p = 0.25). On adjusted analysis, the odds of gestational diabetes (GDM) and hypertensive complications (pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2, 95% CI: 1.5-3.9, p < 0.001; hypertensive complications: OR: 1.8, 95% CI: 1.0-3.2, p = 0.05) and also compared to no CLD in pregnancy (GDM: OR: 2.4, 95% CI: 1.6-3.6, p < 0.001; hypertensive complications: OR: 2.4, 95% CI: 1.3-4.1, p = 0.003). AIH was also associated with preterm births when compared with women without CLD (OR: 2.0, 95% CI: 1.2-3.5, p = 0.01). AIH was not associated with postpartum hemorrhage, maternal, or perinatal death. CONCLUSIONS: Rates of pregnancy in women with AIH have remained stable in recent years, although AIH is associated with notable maternal and perinatal risks, such as GDM, hypertensive complications, and preterm birth. Whether these risks are influenced by steroid use and/or AIH disease activity warrants evaluation. These data support a low risk of postpartum hemorrhage and favorable survival of mothers and infants.

Proteomic analysis of TGFß-induced A549 secretome identifies putative regulators of epithelial-mesenchymal transition.

Imparting epithelial to mesenchymal transition (EMT) during cellular transformation, a major driving force behind tumor progression, is one of the notorious oncogenic activities of transforming growth factor ß (TGFß); however, the secretary factors released during TGFß-induced EMT that may have role in potentiating EMT and tumor progression are poorly known. This study was undertaken to identify such secreted protein factors from TGFß-induced A549 cells cultured in serum-free chemically defined medium (FreestyleTM ) using Matrix Assisted Laser Desorption Ionization-Time of flight/Time of flight (MALDI-TOF/TOF) mass spectrometry. We identified some of the potential factors such as ESR, ANXA2, ALDH1A, TGFß-induced protein ig-h3, and PAI-1 that were not only secreted but some were also elevated in TGFß-induced A549 cells. Interestingly, these factors are widely reported to play crucial role in EMT induction and progression, which not only validates our findings but also opens avenues for further investigation, if upon secretion they act exogenously through certain receptors to potentiate cellular signaling involved in EMT induction and tumor progression.