Clinical Impact of Sexual Dimorphism in Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)

Patrizia Burra; Debora Bizzaro; Anna Gonta; Sarah Shalaby; Martina Gambato; Maria Cristina Morelli; Silvia Trapani; Annarosa Floreani; Fabio Marra; Maurizia Rossana Brunetto; Gloria Taliani; Erica Villa


Liver International. 2021;41(8):1713-173. 

In This Article

NASH as Indication for Liver Transplantation

NASH has become the leading indication for LT in the US[117] and NASH/HCC is the most rapidly growing in the waiting list for LT.[118] NASH was the second cause for LT globally in the last years, the leading cause for LT for women, the second leading cause for men and the leading cause by 2016 among Asian, Hispanic and non-Hispanic white females.[119] In Nordic countries, NAFLD was the second most rapidly increasing indication for LT between 1994 and 2015, going from 2% in 1994–1995 to 6.2% in 2011–2015.[120] A recent Italian monocentric study highlighted that the proportion of NASH patients listed for LT significantly increased from 5% to 9.5% after the introduction of direct-acting antiviral agents for HCV, also showing a significant increase of those listed for HCC (from 2% to 5.9%).[121]

Pre-transplant Workup – Assessment of Operative Risk

The selection process among patients with NASH can be particularly challenging among all LT candidates, as they are most likely to carry risk factors for cardiovascular disease. Cirrhotic female patients have been found to have decreased levels of oestrogen, progesterone and luteinizing hormone, frequently becoming amenorrhoeic. It would, therefore, seem possible that the potential protective effect of oestrogens may be reversed in the context of end-stage liver disease, failing to protect them against potential cardiovascular complications during and after LT. Moreover, women with NASH present a significantly high incidence of non-liver cancers, especially breast cancer, which may be related to its known association with diabetes, obesity and MS.[122] Therefore, even though women have lower MELD scores than men as a result of lower median creatinine levels with the same degree of renal impairment, the higher number of women listed, together with the fact that NASH is becoming the first indication for LT, could theoretically outweigh the disadvantage previously posed for women to LT access for other indications. Nevertheless, in a recent ELTR analysis, the overall number of LT performed in Europe constantly increased until 2007; however, the percentage of male patients significantly increased over time, whereas female recipients significantly decreased.[123] Thus, NASH women remain longer on the waiting list for transplant, are more likely to be removed, have a higher risk of death and are less likely to receive LT compared to men with NASH, even when adjusting for potential confounding covariates. As a matter of facts, when the authors compared NASH patients to HCV patients, the magnitude of sex discrepancy resulted higher in NASH patients,[124] meaning that other unknown or unintentional biases exist in organ allocation.

Renal Dysfunction in Patients Transplanted for NASH

NASH has been recognized as an independent factor of stage 3 chronic kidney disease (CKD) after LT; the reason for this independent association seems to be related to the chronic inflammatory state associated with a high level of circulating inflammatory cytokines.[125] In contrast to general population,[5] female sex is a risk factor for a faster decline in kidney function after solid organ transplants.[126]

A multicentre observational study published on LT recipients showed that female sex was an independent prediction factor of CKD stage 3 at 1 and 5 years and female patients had a faster decline in eGFR than men,[127] confirming the sex difference already showed in renal transplant recipients.[128] Women may have a higher susceptibility to calcineurin inhibitors mediated kidney injury, but the reason for the discrepancy between transplant recipients and the general population has not been completely identified. These data suggest the need for sex-based personalized approaches to identify the best strategies to prevent the decline of kidney function after LT.

Long-term Post-transplant Complications

De novo MS is a frequent complication in LT recipients overall, showing a progressive increase overtime. Non-modifiable risk factors for allograft steatosis and/or NASH include age, genetics, sex and pre-existing cardiovascular diseases. Female sex is a possible risk factor for steatosis after transplant but features of MS were found to be more frequent in males in an Italian cohort of LT recipients.[129] Furthermore, male patients presented a significantly lower survival rate when transplanted for metabolic disease compared with female patients in a European study;[123] however, this results still need to be confirmed in other cohorts before an accurate interpretation can be drawn. Besides sex differences, a recent meta-analysis examining 17 studies, representing 2,378 post-LT patients, found the 5-year incidence rates for recurrent NAFLD to be 82% and the rate of cirrhosis from 1% to 11%.[130] Sepsis accounted for a mortality of 4%-16% in recipients with NASH and 1% to 8% in recipients without NASH.[118] Infection and cardio/cerebrovascular complications were the commonest causes of death in NASH patients without HCC in a European study. Moreover, female sex, extreme low or high recipient BMI and age >60 years and low or high recipient BMI independently predicted death in those patients.[131] Thus, careful assessment and selection of patients will be critical to maintain acceptable survival in those transplanted for NASH, which should be better defined considering sex differences.