Women with cirrhosis awaiting liver transplantation (LT) experience higher rates of waitlist mortality than men; it is unknown whether practices surrounding delisting for being "too sick" for LT contribute to this disparity beyond death alone. We conducted an analysis of patients listed for LT in the United Network for Organ Sharing/Organ Procurement and Transplantation Network not receiving exception points from May 1, 2007 to July 1, 2014 with a primary outcome of delisting with removal codes of "too sick" or "medically unsuitable." A total of 44 388 patients were included; 4458 were delisted for being "too sick" for LT. Delisting was more frequent in women (11% vs 9%, P < .001). Compared to delisted men, delisted women differed in age (58 vs 57), non-hepatitis C virus listing diagnoses (69% vs 56%), hepatic encephalopathy (36% vs 31%), height (161.9 vs 177.0 cm), private insurance (47% vs 52%), and Karnofsky performance status (60 vs 70) (P < .001 for all). There were no differences in Model for End-Stage Liver Disease including serum sodium and Child Pugh Scores. A competing risk analysis demonstrated that female sex was independently associated with a 10% (confidence interval 2%-18%) higher risk of delisting when accounting for rates of death and transplantation and adjusting for confounders. This study demonstrates a significant disparity in delisting practices by sex, highlighting the need for better assessments of sickness, particularly in women.

Purpose of review

In this review article we evaluate sex differences in the natural history of NAFLD and highlight distinct risk profiles of women with NAFLD, as well as unique treatment considerations and research gaps.

Summary of findings

Reproductive factors, such as menopausal status should be considered when evaluating NAFLD risk in women, as well as additional reproductive risk factors such as age at menarche, presence of polycystic ovary syndrome, and gestational diabetes. Women do appear to have lower risk for hepatocellular carcinoma from NASH, as well as lower mortality from NASH cirrhosis than men, although among women, NASH is now the leading indication for liver transplant. Data on sex differences in biomarker development and clinical trials are lacking, and researchers should be encouraged to evaluate biomarker performance by sex, and specifically report clinical trial endpoints in women.

A growing literature has highlighted important differences in transplant-related outcomes between men and women. In the United States there are fewer women than men on the liver transplant waitlist and women are two times less likely to receive a deceased or living-related liver transplant. Sex-based differences exist not only in waitlist but also in post-transplant outcomes, particularly in some specific liver diseases, such as hepatitis C. In the era of individualized medicine, recognition of these differences in the approach to pre and post-liver transplant care may impact short and long-term outcomes.

Background & aims

Infiltrative hepatocellular carcinoma (iHCC) is characterized by its indistinct borders and lack of a typical pattern of contrast enhancement. There are few published data on iHCC. We assessed outcomes, effects of treatment, and prognostic factors in a large cohort of patients with iHCC.

Methods

We analyzed data from 155 patients (median age, 60 years; 79% male; median level of α-fetoprotein, 347 ng/mL; median Model for End-Stage Liver Disease score, 13) with iHCC, on the basis of contrast-enhanced computed tomography or magnetic resonance imaging, from 2002-2010 at the University of California, San Francisco Medical Center. All imaging study results were independently reviewed by 2 investigators.

Results

Most of the patients had tumors of Barcelona Clinic Liver Cancer stage C (70%) or D (22%). The median maximum tumor diameter was 11.3 cm; 41% of lesions were hypovascular, 82% had macrovascular invasion, and 52% had extrahepatic metastases. Median survival was 4.0 months, and rates of survival at 6 and 12 months were 30% and 10%, respectively. On multivariate analysis, predictors of 6-month mortality were Child-Pugh class B or C cirrhosis; lack of tumor-directed therapy with chemoembolization (transarterial chemoembolization), radiofrequency ablation, or sorafenib; α-fetoprotein level >1000 ng/mL; female sex; Model for End-Stage Liver Disease score; and maximum tumor diameter. The percentages of patients surviving 6 and 12 months were 17% and 2% for those who received no therapy (n = 109), 73% and 36% for those who received sorafenib (n = 11), and 45% and 17% for those who received transarterial chemoembolization (n = 18) (all P values <.01).

Conclusions

Infiltrative HCC is a radiographically distinct and advanced form of hepatocellular carcinoma with a poor prognosis. Therapy with transarterial chemoembolization or sorafenib appears to prolong survival and requires further investigation.

UNLABELLED:  Introduction. Men have higher risk for hepatocellular carcinoma (HCC) than women. Pre liver transplant (LT) alpha fetoprotein (AFP) levels strongly predict post LT HCC recurrence. Though women with HCC have higher AFP, the contribution of AFP level by gender to post LT HCC recurrence is unknown. MATERIAL AND METHODS: In this UNOSbased, retrospective cohort study we investigate sex differences in HCC recurrence among LT recipients with MELD exception between 2006-2010. Covariates include race, disease etiology, co-morbidities, AFP at listing and LT, tumor burden, loco-regional therapy, and donor risk index. HCC recurrence was assessed by competing risks regression. RESULTS: Of the eligible cohort (n = 5,002) included 3,872 men and 1,130 women. HCC recurred in 258 men (7%) and 66 women (6%). Median listing AFP was higher in women than men (14 vs. 11 ng/dL, p < 0.001). While no sex difference in overall HCC recurrence was detected (HR 0.9, 95% CI 0.7-1.2, p = 0.38), there was a strong interaction between gender and AFP on recurrence risk (p = 0.02). HCC recurrence was nearly three times higher in women (HR 4.2, 95% CI 2.2-8.2, p < 0.001) than men (HR 1.5, 95% CI 1.1-2.1, p = 0.02) with AFP at LT between 101-500 ng/dL. CONCLUSION: This study reveals novel sex differences in post LT HCC recurrence, which was nearly three times higher in women than men with high AFP at LT. Pre-LT AFP levels appear to carry a different prognosis in women than men, and a subset of female LT recipients may benefit from more intensive HCC surveillance after LT.

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.

Patients with T1 hepatocellular carcinoma (HCC; 1 lesion < 2 cm) are currently not eligible for priority listing for liver transplantation (LT). A common practice is to wait without locoregional therapy (LRT) until tumor growth occurs from T1 to T2 (1 lesion 2-5 cm or 2-3 lesions ≤ 3 cm) to be eligible for listing with Model for End-Stage Liver Disease exception. We aimed to evaluate the intention to treat outcome of the "wait and not ablate" approach for nonresection candidates with T1 HCC until tumor growth to T2. The study included 114 patients with T1 HCC 1.0-1.9 cm followed by serial imaging every 3 months. Two investigators performed independent imaging reviews to confirm the diagnosis. Median increase in total tumor diameter was 0.14 cm/month. Probabilities of progression from T1 to directly beyond T2 without LT listing were 4.4% at 6 months and 9.0% at both 12 and 24 months. The 1- and 3-year survival was 94.5% and 75.5%. In multivariate analysis, predictors of rapid tumor progression, defined as a > 1 cm increase in total tumor diameter over 3 months, included alcoholic liver disease (odds ratio [OR], 6.52; P = 0.02) and Hispanic race (OR, 3.86; P = 0.047), whereas hepatitis B appeared to be protective (OR, 0.09; P = 0.04). By competing risks regression, predictors of exclusion from LT (with or without listing for LT under T2) were alpha-fetoprotein (AFP) ≥ 500 ng/mL (HR, 12.69; 95% confidence interval, 2.8-57.0; P = 0.001) and rapid tumor progression (HR, 5.68; P < 0.001). In conclusion, the "wait and not ablate" approach until tumor growth from T1 to T2 before LT listing is associated with a <10% risk of tumor progression to directly beyond T2 criteria. However, patients with AFP ≥ 500 ng/mL and rapid tumor progression are at high risk for wait-list dropout and should receive early LRT.

With rising prevalence of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease. One-third of obese or diabetic men have subnormal free and bioavailable testosterone concentrations.¹ Several studies have further shown low testosterone to be associated with imaging-confirmed NAFLD in men,² although it is unknown whether low testosterone confers increased risk of more clinically relevant manifestations of NAFLD, including nonalcoholic steatohepatitis (NASH) and NASH fibrosis. We therefore aimed to evaluate the association of testosterone with histologic features of NAFLD among a representative cohort of men from the multicenter NASH Clinical Research Network (NASH CRN).

The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA-positive donor organs are typically not given to patients who have cleared HCV. A 64-year-old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA <15 IU/mL by week 10. At week 18 of a planned 24-week treatment course, the patient underwent deceased-donor LT and received an organ from an anti-HCV-positive donor. Treatment was stopped at LT. At week 3 post LT, HCV RNA was detectable and revealed a genotype 3 HCV infection, compatible with transplantation of an organ with established infection. With retreatment with sofosbuvir, daclatasvir, and ribavirin for 12 weeks, the patient achieved a sustained virologic response. This report highlights how antiviral therapies can be used to optimize the outcomes of HCV-infected transplant patients.

While non-alcoholic steatohepatitis is a slowly progressive disease, patients may rarely present in acute liver failure. We describe six patients who developed severe hepatic dysfunction following rapid weight loss or malnutrition. Rapid weight loss (18 to 91 kg) occurred after Roux-en-Y gastric bypass in four patients and starvation-like dieting or hypoalbuminemia was noted in two patients. Four patients either died or received an urgent liver transplant. Pathologic findings were characterized by advanced alcoholic steatohepatitis-like features, including extensive/circumferential centrizonal pericellular fibrosis, central scar with perivenular sclerosis/veno-occlusion with superimposed hepatocellular dropout, abundant/prominent hepatocellular balloons, and numerous Mallory-Denk bodies, but there was no history of excess alcohol consumption. This study characterizes clinicopathologic features of aggressive non-alcoholic steatohepatitis following rapid weight loss or malnutrition, which should be included in the differential diagnosis with alcohol when a patient is considered for liver transplantation. The mechanism of liver injury in aggressive steatohepatitis is unknown, but rapid fat mobilization in obese patients may potentially cause oxidative stress to the liver and further study is needed to determine if there is a genetic predisposition to this form of injury and if antioxidants may protect the liver during rapid weight loss/malnutrition.