Influence of Age and Gender Before and After Liver Transplantation

Authors

  • Patrizia Burra,

    Corresponding author
    • Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
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    • This review is the report of the 3rd International Meeting of Women in Hepatology, Formigine, Italy, June 29-30, 2012.

  • Eleonora De Martin,

    1. Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
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  • Stefano Gitto,

    1. Department of Gastroenterology, University Teaching Hospital/University of Modena and Reggio Emilia, Modena, Italy
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  • Erica Villa

    Corresponding author
    • Department of Gastroenterology, University Teaching Hospital/University of Modena and Reggio Emilia, Modena, Italy
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    • This review is the report of the 3rd International Meeting of Women in Hepatology, Formigine, Italy, June 29-30, 2012.


  • These authors contributed equally to this work.

Address reprint requests to Patrizia Burra, M.D., Ph.D., Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 PD, Padua, Italy. Telephone: +39.049.8218726; FAX: +39.049.8218727; E-mail: burra@unipd.it; or Erica Villa, M.D., Department of Gastroenterology, University Teaching Hospital/University of Modena and Reggio Emilia, Via del Pozzo 1, 41124, Modena, Italy. Telephone: +39.059.4225308; FAX: +39.059.4224363; E-mail: erica.villa@unimore.it

Abstract

Women constitute a particular group among patients with chronic liver disease and in the post–liver transplantation (LT) setting: they are set apart not only by traditional differences with respect to men (ie, body mass index, different etiologies of liver disease, and accessibility to transplantation) but also by factors related to hormonal changes that characterize first the fertile age and subsequently the postmenopausal period (eg, disease course variability and responses to therapy). The aim of this review is, therefore, to evaluate the role of the interplay of factors such as age, gender, and hormones in influencing the natural history of chronic liver disease before and after LT and their importance in determining outcomes after LT. As the population requiring LT ages and the mean age at transplantation increases, older females are being considered for transplantation. Older patients are at greater risk for nonalcoholic steatohepatitis, osteoporosis, and a worse response to antiviral therapy. Female gender per se is associated with a greater risk for osteoporosis because of metabolic changes after menopause, the bodily structure of females, and, in the population of patients with chronic liver disease, the prevalence of cholestatic and autoimmune liver diseases. With menopause, the fall of protective estrogen levels can lead to increased fibrosis progression, and this represents a negative turning point for women with chronic liver disease and especially for patients with hepatitis C. Therefore, the notion of gender as a binary female/male factor is now giving way to the awareness of more complex disease processes within the female gender that follow hormonal, social, and age patterns and need to be addressed directly and specifically. Liver Transpl 19:122–134, 2013. © 2012 AASLD.

Abbreviations
AIH

autoimmune hepatitis

ALD

alcoholic liver disease

CI

confidence interval

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

HR

hazard ratio

LT

liver transplantation

MELD

Model for End-Stage Liver Disease

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

OR

odds ratio

PBC

primary biliary cirrhosis

SVR

sustained virological response.

Gender has scarcely been taken into account when indications, risk factors, and outcomes for liver transplantation (LT) have been evaluated. When gender has been considered, it has always been investigated as a binary male/female combination, and there has been a complete disregard of the fact that for females (and, to a lesser extent, for males), there is a profound difference between reproductive age and menopausal age. The onset of menopause represents a negative turning point for women with chronic liver disease in general and more so for those with a hepatitis C virus (HCV) infection. The aim of this review is, therefore, to evaluate the interplay of factors such as age, gender, and hormones in the natural history of chronic liver disease before and after LT and their importance in determining outcomes.

ROLE OF AGE AND GENDER IN THE PRETRANSPLANT SETTING

Western countries have seen an upward shift in the mean age of patients requiring LT. A reason for this shift is the high percentage of subjects with HCV or nonalcoholic fatty liver disease (NAFLD), which are 2 conditions known to affect patients.[1] This has led to an inadequate deceased donor/recipient ratio in many countries. Women represent approximately 30% of LT recipients, but the influence of their hormonal status has scarcely been considered so far.

It is well known that the liver plays a central role in sex hormone metabolism and detoxification. As a result, chronic liver disease is associated with relevant menstrual abnormalities. Parolin et al.[2] demonstrated that 59% of women with chronic liver disease had amenorrhea 1 year before transplantation. Mass et al.[3] reported regular menstrual cycles in 42%, irregular and unpredictable bleeding in 28%, and amenorrhea in 30% of female LT candidates 1 year before surgery. Usually within 1 year of LT, as a result of the normalization of sex hormone metabolism, most women of childbearing age return to their regular menstrual cycles, whereas perimenopausal women still display disorders in menstrual patterns in a high percentage of cases (69%).[4]

The progression of fibrosis in patients with chronic HCV is twice as rapid in men versus women.[5, 6] Experimentally, estrogens have been shown to exert a strong suppressive role on fibrosis in a rat model,[7, 8] and in the clinical setting, menopause has reportedly been associated with higher degrees of fibrosis.[9, 10]

A possible explanation for the protective role of estrogens in women with chronic liver disease resides in their role in keeping inflammation under control. With menopause, the fall of estrogen levels is accompanied by a rapid increase in the levels of proinflammatory and anti-inflammatory cytokines.[11] This leads to differential speeds of fibrosis development during fertile and menopausal ages, with women catching up with men in fibrosis progression after menopause.[12] A peculiar aspect of the hormonal status in the pre-LT setting is represented by the role played by estrogens in the ischemia/reperfusion phase. Experimental data indicate that female animals are more susceptible to hepatic reperfusion injury and have a higher sensitivity to reoxygenation damage after prolonged cold storage. This is difficult to reconcile with experimental data showing that estrogens can reduce ischemia/reperfusion injury and improve animal survival. Indeed, data about the role of estrogens in ischemia/reperfusion are discordant.[13-17]

NONALCOHOLIC STEATOHEPATITIS BEFORE LIVER TRANSPLANTATION

The incidence of metabolic syndrome in women substantially increases during perimenopause and early menopause. It is well known that postmenopausal women more frequently develop arterial hypertension, dyslipidemia, and diabetes and, consequently, are in worse cardiovascular condition than younger subjects. These negative metabolic effects of menopause are linked to weight gain, increases in abdominal adiposity, and decreased energy expenditures associated with menopausal hormonal modifications.[18]

Metabolic syndrome is often associated with NAFLD; this condition is characterized by hepatic triglyceride accumulation and can progress from steatosis to nonalcoholic steatohepatitis (NASH) and potentially to cirrhosis and hepatocellular carcinoma (HCC).[19] In the last 2 decades, NAFLD has been increasingly recognized as the most common liver disease in Western countries,[20] and its prevalence increases with age, diabetes mellitus, obesity, and hypertriglyceridemia,[21] with the genetic background modulating their effects.[22] NASH-related cirrhosis is an increasing indication for LT, and the prevalence of NASH is expected to continue to increase in the next years.[23]

NASH patients who are candidates for LT seem to be generally older, female, and Asian; are most often affected by diabetes, hypertension, obesity, and cardiac disease; and have a history of smoking.[24]

Although there are no definite data regarding this issue in the pre-LT setting, it is advisable to prevent pathological body weight gain or a worsening of metabolic syndrome. The association with cardiovascular risks and other causes of liver disease that can worsen the outcome after transplantation should at least be evaluated in these patients before surgery.

ALCOHOLIC LIVER DISEASE AS AN INDICATION FOR LIVER TRANSPLANTATION: DO GENDER AND AGE PLAY A ROLE?

End-stage alcoholic liver disease (ALD) represents a well-reported indication for LT. It is the second common cause of LT in the United States and Europe and accounts for approximately 20% of US LT procedures and approximately 40% of European LT procedures.[25, 26] A significant increase in ALD as an indication for LT has been reported in recent years, with the majority of recipients being male and older.[25]

Males and females present social and biological differences in terms of alcohol-related problems and liver disease. In general, men drink more and have more alcohol-related social problems than women,[27] and higher prevalences of heavy drinking and drinking-related problems have been reported in men.[28, 29] Notably, a US study has estimated the prevalence of alcohol use disorders to be 14.1% and 5.3% in men and women, respectively.[30]

Consequently, it is not surprising that men have a greater risk of alcohol dependency. In the United States, this is related to the difference in consumption patterns between genders and to different drinking habits: women drink more often but in lower amounts than men, who drink less frequently but consume larger quantities of alcohol.[31]

There are also clear biological differences between men and women with respect to metabolism and blood alcohol concentrations after the consumption of the same amount of alcohol. Women have a slower initial alcohol metabolism stage, which leads to superior alcohol blood absorption[31]; they have lower gastric alcohol dehydrogenase enzyme activity[32] and a lower body water content. The latter contributes in a relevant way to higher blood alcohol concentrations.[33, 34]

A heavy drinking pattern in women increases the risk of death to 60%, whereas the same pattern in men increases the risk to 40% in comparison with light drinkers.[28]

There are, moreover, differences in alcohol consumption patterns based on the ages of drinkers. Alcohol misuse in the elderly population is frequently underestimated and undetected. Heavy alcohol consumption, which is related to a variety of clinical presentations, was present in both genders in a study of 208 patients who were more than 60 years old.[22]

In the transplant setting, ALD patients have a long-term prognosis that is comparable to or even better than that of non-ALD patients; therefore, many authors have indicated that end-stage ALD is a good or excellent indication for LT.[25, 35-37]

HEPATITIS C VIRUS: RESPONSE TO ANTIVIRALS ACCORDING TO AGE AND GENDER

HCV infection is the main cause of liver cirrhosis and HCC worldwide. It is also the most common indication for LT in Europe (30%–40% of cases).[38]

Antiviral treatment in HCV-positive patients is aimed at decreasing the risk of disease progression and HCC development, with the achievement of a sustained virological response (SVR) being the main goal.[39] Successful pre-LT antiviral treatment is also the key factor able to prevent reinfection of the graft and, consequently, leads to a better prognosis.[40] Unfortunately, many patients do not respond to antiviral therapy or are not sufficiently fit to tolerate it before LT.[41]

Once more, in the treatment setting, age is a relevant issue, especially because it is evident from several epidemiological surveys that infected patients form an aging cohort with an increasing duration of infection and progressing disease.[42]

As for the role of gender, women have milder HCV disease than men during their reproductive years, although postmenopausal women lose this advantage and present with accelerated fibrosis progression[10] and more severe disease in comparison with groups of male patients of comparable ages.[12] This explains the high mean age of women with HCV who are listed for LT. Furthermore, the severity of fibrosis in patients with chronic HCV hepatitis is associated with metabolic syndrome, insulin resistance, diabetes, body mass index, and advanced steatosis (all conditions that increase with menopause).[9, 43]

There are conflicting data about SVR rates in women. Some studies have reported that response rates are not significantly different from those of men,[44] whereas other series have described female gender as an independent predictor of SVR.[45] We recently published a study of a large cohort of European women with chronic HCV and showed that menopausal status is related to a more marked inflammatory state, more rapid progression to fibrosis, and resistance to antiviral therapy in comparison with reproductive age. Indeed, we demonstrated that menopause is one of the key factors leading to a failure to achieve SVR, with age being only a surrogate predictor. Our results suggest that women with HCV should be treated early, and we should disregard the fact that liver disease is milder in women of reproductive age because this condition will last only as long as the estrogen-exposed period.[46] Because women in the transplant setting are mostly menopausal, this further compromises attempts to cure HCV with traditional drugs.

OSTEOPOROSIS IN FEMALE CANDIDATES FOR LIVER TRANSPLANTATION

Two conditions that are mostly found in women, autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), increase the risk of osteoporosis.[47, 48]

In the United States and Western Europe, AIH represents 20% of chronic hepatitis cases and predominantly affects women of potentially any age, but they are typically older than 40 years.[48, 49]

AIH in elderly patients appears to be characterized by distinct clinical features, a particular immunogenetic profile, favorable steroid response rates, and higher rates of cirrhosis at the time of diagnosis.[50] Interestingly, in a series of 20 patients who were more than 65 years old, the response rate to immunosuppression was comparable to the rate in younger patients.[51] AIH is a consolidated indication for LT, especially in its late phases, with the pretransplant evaluation being comparable to that for other acute and chronic liver diseases.[52]

In the pre-LT setting, one of the main clinical problems for elderly female patients with AIH is represented by osteoporosis,[53] which is a common complication in patients with chronic liver disease, particularly during the end stages and in the presence of chronic cholestasis.[54] In addition, the use of steroids as the standard of care for AIH may further increase osteoporosis. This suggests that postmenopausal women with AIH may be candidates for combination therapy with steroids and azathioprine.[50]

PBC is an autoimmune liver disease that primarily affects middle-aged women, and LT is an excellent option for subjects affected by end-stage liver disease.[52] PBC is associated with metabolic bone disease and may manifest itself at an age when female patients may already have developed osteoporosis.[47] It has been demonstrated that bone loss among patients with PBC is twice that among age- and gender-matched controls,[55] and the prevalence of osteoporosis is 14% to 52% according to the World Health Organization (http://www.who.int/). The mechanisms altering bone homeostasis in PBC are unknown, but osteoclast activity (increased in this condition) and hyperbilirubinemia, which impairs osteoblast function, seem to be the main accountable causal factors.[56]

Decreased bone mass is an important cause of morbidity in patients with PBC because of the increased risk of fractures, pain, and deformity.[57] A therapeutic approach is, therefore, paramount. Hormone replacement therapy has been used worldwide to treat symptoms of menopause and to prevent chronic conditions such as osteoporosis, but it is well known that hormone replacement therapy may be associated with an increased risk of serious adverse events. Indeed, defining optimal treatment regimens for osteoporosis in patients with PBC is very complex, especially because its pathogenesis remains poorly understood.[47] However, the management guidelines for postmenopausal osteoporosis can also be applied to female candidates for LT.

INCIDENCE OF HEPATOCELLULAR CARCINOMA IN AGED SUBJECTS: DO WOMEN CATCH UP WITH MEN?

HCC is a common cancer: it is the sixth most prevalent cancer and the third most frequent cause of cancer-related death.[58]

Generally, HCC accounts for approximately 6% of all human neoplasms. It is estimated that half a million cases occur every year worldwide, with HCC being the fifth most common malignancy in men and the ninth most common in women. HCC is rarely detected before 40 years of age except in areas hyperendemic for hepatitis B virus (HBV). Consequently, we can assume that the incidence of HCC increases with older age, with a peak at 50 to 60 years. Remarkably, HCC patients in areas with a high incidence of HCC (eg, China and sub-Saharan Africa) are, on average, 10 to 20 years younger than HCC patients in areas of lower incidence (eg, North America and Europe).[59]

As for the role of gender, men are 2 to 3 times more frequently affected by HCC in comparison with women, and the male-to-female ratio is more pronounced in areas with a high incidence of HCC. Obviously, this increased risk among men is at least partially explained by the higher frequency of viral hepatitis and alcoholic cirrhosis. Other authors have suggested a carcinogenic effect of testosterone. Very important reviews of the gender- and age-specific incidence of HCC in 23 populations from 21 registries have been conducted by Parkin et al.[60] and Muir et al.[61] Among men, the incidence of primary liver cancer has increased in Central Europe and North America as well as Oceania.[62] The rate changes in women are similar to the patterns found in men. The reasons underlying these trends are not well understood, but they may be associated with improvements in the screening, diagnosis, and management of HCC as well as the changes caused by anti-HBV vaccination in areas hyperendemic for HBV infections.[59]

The differences in the incidence of HCC between genders have been explained by the link between estrogens and inflammation-induced carcinogenesis.[63] In this direction, a recent experimental study in animals demonstrated that males had shorter survival times and larger tumor volumes than females because estrogens reduced tumor malignancies.[64] Along the same line, Wang et al.[65] reported that estrogen treatments of ovariectomized animals led to a relevant decrease in HCC progression in comparison with animals treated with ovariectomy alone.

SEXUAL DYSFUNCTION IN CIRRHOTIC PATIENTS

Sexual dysfunction and sex hormone disturbances are widely reported in men and women with chronic liver disease. They are mainly due to the abnormality of the physiology of the hypothalamic-pituitary-gonadal axis and to the etiology of liver disease.[66] In women with cirrhosis, chronic anovulation is a common problem, and it is manifested as secondary amenorrhea, oligomenorrhea, or irregular episodes of metrorrhagia.[3] As for the origin of liver disease, chronic alcohol abuse contributes to disturbances of hormonal status and to the reproductive performance of women.[67]

A cross-sectional study compared 54 women before LT and 45 women after LT.[68] Female patients with cirrhosis showed significantly lower levels of total testosterone and higher levels of prolactin and delta-4-androstenedione in comparison with transplant patients. Sexual dysfunction in female patients with cirrhosis correlated with older age.

QUALITY OF LIFE AND CHRONIC LIVER DISEASE: DO GENDER AND AGE MATTER?

The expectations that males and females have before LT are different. All domains of health-related quality of life except for pain are altered in patients with cirrhosis versus the general population. An Italian multicenter study showed that most areas of daily life were affected in patients with cirrhosis because of a perceived health problem: in men, the aspects more frequently affected were sex life and paid employment (especially for younger patients), whereas in women, home life and social life were more affected.[69] Recently, a study of 1103 patients with chronic liver disease (69% of whom had cirrhosis) revealed that age correlated weakly (r = 0.08–0.29) but significantly (P < 0.05) with every scale of Short Form 36.[70] After the researchers controlled for confounders (gender, presence of cirrhosis, and ethnicity), this inverse correlation between age and health-related quality of life remained significant for a large number of Short Form 36 scales. As for the impact of gender on health-related quality of life, the data suggested that female patients with chronic liver disease had more impairment of health-related quality of life than male patients on different scales of Short Form 36.

LIVER TRANSPLANTATION

Numerous studies have been reported on the role of female gender in the setting of LT; the main findings are summarized in Table 1.

Table 1. Main Findings for Women From Large LT Series
Analyzed VariablesStudyDesign, Country, and Center TypePatients (n)Females [n (%)]Main Findings
Females in the pre-MELD and MELD erasKlassen et al.[71] (1998)Retrospective cohort United States Multicenter74223429 (46)In the pre-MELD era, women were on the waiting list for a longer mean time than men (89 versus 68 days, P < 0.001) and had an increased mortality risk (P = 0.005).
Myers et al.[72] (2011)Retrospective cohort United States Multicenter40,39314,347 (36)In the MELD era, within 90 days of listing, women were less likely than men to undergo transplantation [HR = 0.8 (95% CI = 0.76–0.83)] and were more likely to die [HR = 1.09 (95% CI = 1.02–1.17)].
Moylan et al.[73] (2008)Retrospective cohort United States Multicenter21,895 before the MELD era; 23,793 in the MELD era8326 (38) before the MELD era; 7936 (33) in the MELD eraWomen were more likely than men to die or become too sick for LT in the MELD era [23.7% versus 21.4%, OR = 1.30 (95% CI = 1.08–1.47), P = 0.003] versus the pre-MELD era [22.4% versus 21.9%, OR = 1.08 (95% CI = 0.91–1.26), P = 0.37]. Women were less likely than men to undergo LT within 3 years during both the pre-MELD era [64.8% versus 67.6%, OR = 0.80 (95% CI = 0.70–0.92, P = 0.002] and the MELD era [39.9% versus 48.7%, OR = 0.70 (95% CI = 0.62–0.79), P < 0.001].
Female donors and donor gender mismatchMarino et al.[74] (1995)Retrospective cohort United States Single center462 grafts163 grafts (35) for female recipientsFemale donor gender was associated with graft failure [OR = 1.5 (95% CI = 0.97–2.32)]. Female donor/male recipient mismatch increased the risk of graft failure. Female donors were older than male donors.
Lai et al.[75] (2011)Retrospective cohort United States Multicenter28,2229226 (33)Female donor/male recipient mismatch increased the risk of graft failure [HR = 1.17 (95% CI = 1.11–1.23)]. Female donors were older than male donors (47 versus 39 years, P < 0.001).
Female recipientsDuffy et al.[76] (2010)Prospective cohort/cross-sectional United States Single center293169 (58)Female recipient gender was associated with better 20-year post-LT survival (P = 0.03).
HCV recurrenceBelli et al.[77] (2007)Retrospective cohort Italy/England Multicenter35493 (26)Female recipients had increased fibrosis progression with HCV recurrence [HR = 0.575 (95% CI = 0.36–0.98)].
Lai et al.[78] (2011)Retrospective cohort United States Multicenter1264304 (24)Female recipient gender was an independent risk factor for advanced disease due to HCV recurrence [HR = 1.31 (95% CI = 1.02–1.70)]. Female gender was an independent predictor of death [HR = 1.30 (95% CI = 1.01–1.67)] and graft loss [HR = 1.31 (95% CI = 1.02–1.67)].
Alcohol relapseKarim et al.[79] (2010)Retrospective cohort Canada Single center8020 (25)Female gender was a risk factor for alcohol recidivism in a multivariate analysis (OR = 18.80, P = 0.04).
Pfitzmann et al.[80] (2007)Retrospective cohort Germany Single center30081 (27)Females resumed alcohol consumption more frequently than men, although this difference did not reach statistical significance (25.9% versus 16.7%, P = 0.09). Gender was not an independent risk factor for alcohol relapse.
Bone mass lossBaccaro et al.[81] (2011)Prospective cohort/cross-sectional Brazil Single center2323 (100)Seven women (30.4%) were premenopausal, 3 (13%) were perimenopausal, and 13 (56.5%) were postmenopausal. The postmenopausal state was significantly associated with decreased bone mass [OR = 69.0 (95% CI = 2.89–1647.18), P < 0.001].
Sexual dysfunctionMass et al.[3] (1996)Retrospective cohort United States Single center6262 (100)After LT, 30 women (48%) experienced regular menses, 16 (26%) experienced irregular bleeding, and 16 (26%) experienced amenorrhea; 72% of the women were sexually active.
Ho et al.[82] (2006)Retrospective cohort Canada Single center15062 (41)Decreased libido was reported by 26% of females and 23% of males; difficulty in reaching an orgasm with intercourse was reported by 26% of females and 33% of males.
Burra et al.[68] (2010)Cross-sectional Italy Single center9954 (55)After LT, sexual dysfunction in females was greater among patients with depression (P = 0.003) and a reduced quality of life (P = 0.023).
PregnancyCoffin et al.[83] (2010)Retrospective cohort/case control United States Multicenter4266206 (4.8) after LTMaternal mortality was not greater in patients after LT versus controls (0% versus 0.02%, P = not significant), but LT patients had higher rates of fetal mortality (6.3% versus 2.0%, P < 0.001), antepartum hospital admission [OR = 2.27 (95% CI = 1.59–3.25)], maternal complications [OR = 2.63 (95% CI = 1.82–3.80)], fetal complications [OR = 2.49 (95% CI = 1.68–3.70)], gestational hypertension (30% versus 9%, P < 0.001), postpartum hemorrhaging (8% versus 3%, P % 0.009), infant prematurity (27% versus 11%, P < 0.0001), distress (10% versus 5%, P = 0.005), and intrauterine growth restriction (5 % versus 2%, P = 0.05).
Deshpande et al.[84] (2012)Meta-analysis United States Multicenter306306 (100)There were 450 pregnancies in 306 LT recipients. The rates of pre-eclampsia [OR = 21.9% (95% CI = 17.7%-26.4%)], cesarean section delivery [OR = 44.6% (95% CI = 39.2%–50.1%)], and preterm delivery [OR = 39.4% (95% CI = 33.1%–46.0%)] were higher than the rates in the general population (3.8%, 31.9%, and 12.5%, respectively).

In the era before the Model for End-Stage Liver Disease (MELD), a study from the Organ Procurement and Transplantation Network showed that female gender was significantly correlated with a longer stay on the LT waiting list and also with the risk of dying before LT; it also reported on critically ill patients and Asian Americans and African Americans.[71]

Creatinine, a component of the MELD score, is typically lower in females compared to males. The United Network for Organ Sharing database has shown that in comparison with men, women have, on average, lower median serum creatinine levels, estimated glomerular filtration rates, and mean MELD scores. After adjustments for relevant covariates (including creatinine and body weight), women were found to be less likely than men to undergo LT, and they had a greater 3-month mortality rate. The revision of MELD and MELD-sodium scores and the inclusion of estimated glomerular filtration rate did not improve discrimination for 3-month mortality.[72]

Even though race is no longer associated with a different probability of receiving a graft or dying on the waiting list, disparities based on gender still remain. A comparative study showed that women were more likely than men to die or become too sick for LT in the MELD era versus the pre-MELD era.[73]

Moreover, in the MELD era, the disparity in transplant rates for females has increased as waiting-list mortality risk has risen; this is particularly true for MELD scores ≥ 15.[85]

In another study, female gender with fulminant hepatic failure, primary nonfunction, blood group O, Child-Turcotte-Pugh score ≥ 11, and a MELD score ≥ 20 predicted waiting-list mortality.[86]

DONOR AND RECIPIENT AGE AND GENDER: IMPACT ON OUTCOMES OF LIVER TRANSPLANTATION

The different outcomes of female and male LT recipients can also be attributed to the different genders and ages of the donors. Donor/recipient gender mismatch and donor gender per se might predict outcomes after LT, although this is still controversial. Graft failure has been associated with donor age, particularly when the donor age is greater than 45 years. Interestingly, older donors (>60 years) are more likely to be female. Age and female donor gender seem to be at least additive in their impact on the graft survival rate.[74]

A recent study confirmed that recipients of gender-mismatched grafts had an 11% higher risk of graft loss.[75] In comparison with transplants matching male donors with male recipients, female-to-male mismatch was associated with a 17% increased risk of graft loss, whereas male-to-female mismatch was not.[75, 87] Interestingly, however, after adjustments for clinically relevant recipient-, donor-, and transplant-related factors, there was no longer an association between female-to-male mismatch and graft loss. Donor quality differed significantly between females and males: female donors were older and shorter and died more frequently of stroke. The donor risk index was significantly higher for female donors versus male donors. It seems that gender differences in donor quality, rather than gender mismatch, are predictive of graft loss.

Interestingly, in a study by Lai et al.,[75] female-to-female–matched transplants were associated with a decreased risk of graft failure in comparison with male-to-male–matched transplants, but this was true only for non–HCV-infected female recipients. This means that an HCV-positive status for a female recipient has an important effect that modifies the association between donor/recipient gender pairing and graft failure.

When what happens during LT has been mimicked with animal models, it has been observed that female rats develop a greater degree of hepatic tissue lactic acidosis during warm ischemia in comparison with males,[88] and this may provide a potential metabolic explanation for the worse outcomes of recipients with female donors. It suggests that female livers sustain a greater degree of injury from increased acidosis. Another experimental study illustrated that both female and male livers from rats given 17-beta-estradiol presented with a significant accumulation of lactates and H+, and this showed that the mechanisms for gender difference in the liver's metabolic response to ischemia are estrogen-mediated; this is observed even in the presence of male hormones.[89]

Female recipient gender has been associated with better 20-year overall survival,[76] but for ultraseptuagenarian recipients, no difference has been found between men and women.[90]

Data from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database have confirmed that women have better long-term survival after LT than men, but older age (>65 years) is associated with worse outcomes.[91]

Advanced age is a recipient risk factor for graft and patient survival. Once they are admitted to the intensive care unit, patients older than 60 years have a lower survival rate than younger recipients.[92] The lower survival rate of the elderly is not usually attributable to an increased severity of liver disease but rather is due to an increased incidence of malignancies.[93] As age increases, worse outcomes are reported, with a worse tendency for Child class C patients.[94]

Moreover, elderly patients have performed just as well as younger patients in different series,[95] and this supports the idea that age alone should not be considered a negative prognostic factor for survival in patients older than 70 years.

In a published study,[90] patients who were 70 years old or older and underwent LT were compared to recipients who were younger than 60 years. Their preoperative characteristics were similar, and the older patients were not at increased risk for medical or surgical complications, death, or graft loss (with the exception of cardiovascular complications).

Old patients may benefit from a senescent immune system[96] and have less need of immunosuppressive drugs and lower rates of acute and chronic allograft rejection.[97]

DISEASE RECURRENCE AFTER LIVER TRANSPLANTATION FROM AN AGE AND GENDER PERSPECTIVE

Disease recurrence after LT can be influenced by age and gender as we can see for NAFLD/NASH, alcoholic hepatitis, and HCV.

NASH recurs after LT in approximately 50% of patients,[98] and 5% to 10% progress to the cirrhosis stage.[99] Moreover, de novo NASH or NAFLD may develop after transplantation, and they have been reported in 20% and 10% of cases, respectively.[100]

Metabolic syndrome has been described in 48% to 58% of patients followed for more than 6 months after LT, and it is associated with a higher risk of cardiovascular and cerebrovascular events.[23] Interestingly, in a long-term observational study spanning 12 years,[101] metabolic syndrome was a significant risk factor for mortality in postmenopausal women versus men and premenopausal women.

The prevalence of diabetes rises from 15% before LT to 30% to 40% after LT.[102, 103] Many patients (20%–37%) remain diabetic after LT or may develop new-onset diabetes.[104, 105] Diabetes is also associated with older age but not menopausal status.[106]

Among LT recipients with dyslipidemia, 45% to 69% develop hyperlipidemia, which is a major risk factor for posttransplant cardiovascular-related disease.[107, 108]

Aging is characterized by the disruption of lipid homeostasis,[109] and menopause is associated with an impaired lipid metabolism characterized by increases in low-density lipoprotein and triglycerides and a reduction of high-density lipoprotein.[110-112] Similar results have recently been confirmed for ovariectomy among premenopausal subjects.[113] At least part of this increase is due to declining estrogen levels, which result in down-regulation of the hepatic low-density lipoprotein receptor.[114]

Obesity is frequently found after LT.[115] In particular, central adipose tissue, which typically manifests as increased abdominal girth, is a greater risk factor for metabolic syndrome and cardiovascular disease than peripheral adipose tissue.[116]

In Western societies, the population with the highest prevalence of overweight (body mass index = 25.0–29.9 kg/m2) and obesity (body mass index ≥ 30 kg/m2) generally ranges in age from 55 to 75 years.[103] Menopausal status is associated with weight gain, increased central fat mass, decreased physical activity, and circulating biomarkers such as adipokines.[18]

Alcohol relapse after transplantation has been variably reported (10%–50%).[38] Alcohol relapse remains a challenge, mainly because of the lack of predictive factors of heavy drinking patterns.[117, 118] Many demographic, familial, and social variables have been analyzed, and psychiatric comorbidities, female gender, and pretransplant abstinence of less than 6 months have been found to be significantly related to a higher risk of relapse of alcohol abuse. In a recent review,[80] females tended to resume alcohol consumption more frequently than men (25.9% versus 16.7%), although the difference was not statistically significant. Recurrent alcohol consumption was found more frequently among patients younger than 40 years, and the median age of relapsers was lower than the median age of abstainers. Nevertheless, neither gender nor age turned out to be independent risk factors for alcohol relapse in a multivariate analysis.

HCV recurrence after LT is universal, with associated liver disease developing in nearly two-thirds of patients.[119] Female gender has been described as a risk factor for severe HCV recurrence after LT and graft loss, and the risk increases with increasing donor age. Because women infected with HCV have a slower rate of fibrosis progression and a lower rate of cirrhosis than men, one interpretation is that women who need LT have genetic, virological, and immunological factors responsible for more severe HCV disease, which also progresses more rapidly after LT.[78] Another advocated hypothesis is that most LT women are in a postmenopausal state, and postmenopausal immunocompetent women with HCV chronic infections frequently have steatosis, which is an important cofactor for disease progression.[77]

The worse outcomes of HCV-infected women after transplantation were confirmed in a multicenter, retrospective Italian study.[120] All patients underwent combined antiviral therapy, and fibrosis progression on liver biopsy samples taken before and after antiviral therapy and 1, 3, and 5 years later was evaluated according to the Ishak score. Female recipients had a higher risk of fibrosis progression than men after antiviral therapy in a univariate analysis, and this tendency was confirmed at 3 years in both univariate and multivariate analyses. This risk was independent of SVR.

IMMUNOSUPPRESSION AND OSTEOPOROSIS

Immunosuppressive drugs are in part responsible for bone loss.[121, 122] Steroids are given at high doses immediately after LT, and doses are also increased in cases of rejection. The predominant effects of steroids are reduced bone formation due to decreasing osteoblast replication and differentiation and increased apoptosis.[123, 124]

Among calcineurin inhibitors, cyclosporine has adverse effects that increase bone turnover.[125] Apparently tacrolimus may cause less bone loss in humans than cyclosporine.[126, 127]

Postmenopausal women are at higher risk for developing osteoporosis than women with regular menses because of decreased serum estrogen levels.[128]

A prospective study evaluated 23 women who underwent LT: 13% were perimenopausal, and 56.5% were postmenopausal.[81] Among the perimenopausal and postmenopausal patients, decreased bone mass was found in 81.2%: 50% had low bone mass, and 31.2% had osteoporosis. Being postmenopausal was significantly associated with decreased bone mass (P < 0.001). The rate of low bone mass in climacteric women undergoing LT was similar to that reported in women awaiting LT (35%–50%)[129] and in a postmenopausal population with no liver disease.[128]

HORMONE LEVELS, SEXUAL FUNCTION, AND PREGNANCY: DOES LIVER TRANSPLANTATION PLAY A ROLE?

LT leads to partial improvements in both sex hormone levels and sexual function.[130] Women achieve normal menstruation and fertility a few months after transplantation; reportedly, 48% of women experience regular menses, 26% experience irregular bleeding, and 26% experience amenorrhea.[3]

At a median of 36 months after transplantation, 20 of 28 LT recipients (71.4%) were sexually active (70% with satisfaction).[2] On the other hand, another study found decreased libido and difficulty in reaching an orgasm with intercourse in 26% of females.[82] Although female transplant recipients do exhibit mild to moderate sexual dysfunction, they continue sexual activity at a high rate.[68, 131] Pregnancy outcomes are favorable after LT, although there is an increased risk of obstetric complications for both mothers and infants.[83, 132] Female LT recipients have higher rates of cesarean delivery and preterm labor than general obstetrical patients; nevertheless, no differences have been reported in the premature rupture of membranes or placenta previa or in the overall rate of fetal death.[84, 133] The optimal timing of conception is still a matter of debate, but waiting at least 1 year after LT is generally recommended.[134] As for immunosuppression, calcineurin inhibitors and steroids can safely be used, whereas azathioprine and mycophenolate mofetil are associated with increased toxic effects.[135]

CONCLUSIONS

The prevalence of old patients with chronic liver disease who require LT is increasing. Old women face major changes in their hormonal status, which are characterized by decreases in estrogen, a hormone that seems to play a protective role for the liver, particularly against HCV-related fibrosis progression and the development of HCC. Moreover, menopause is associated with metabolic syndrome and osteoporosis, which are marked in patients with cirrhosis and can be worse after LT because of the metabolic effects of immunosuppressive drugs. Although alcoholic cirrhosis is a good indication for LT, data about gender differences are lacking.

Both cirrhosis and menopause are associated with sexual dysfunction and poor quality of life, which partially improve after LT but may persist, especially in patients with a viral etiology.

LT can be safely proposed for older patients without comorbidities, but the dilemma of the optimal utilization of scarce organs with the greatest benefit is still present.

In menopausal women, it is always difficult to distinguish the effects of age, menopause, liver disease, and other confounding factors, as has been the case in the setting of LT. Therefore, personalized management strategies are mandatory, and hormonal replacement therapy should be considered.

ACKNOWLEDGMENT

The authors acknowledge all the members of the Women in Hepatology Group: Erica Villa, Modena, Italy (chair); Anna Alisi, Rome, Italy; Clara Balsano, Rome, Italy; Veronica Bernabucci, Modena, Italy; Annalisa Berselli, Modena, Italy; Annalisa Berzigotti, Barcelona, Spain/Bologna, Italy; Elena Bertolini, Modena, Italy; Maurizia Brunetto, Pisa, Italy; Elisabetta Bugianesi, Turin, Italy; Patrizia Burra, Padua, Italy; Vincenza Calvaruso, Palermo, Italy; Elisabetta Cariani, Modena, Italy; Alessia Ciancio, Turin, Italy; Barbara Coco, Pisa, Italy; Isabelle Colle, Brussels, Belgium; Eleonora De Martin, Padua, Italy; Mariagrazia Del Buono, Modena, Italy; Giovanna Fattovich, Verona, Italy; Annarosa Floreani, Padua, Italy; Guadalupe Garcia-Tsao, New Haven, CT; Chantal Housset, Paris, France; Aimilia Karampatou, Modena, Italy; Barbara Lei, Modena, Italy; Anna Licata, Palermo, Italy; Alessandra Mangia, San Giovanni Rotondo, Italy; Maria Luz Martinez-Chantar, Bilbao, Spain; Filomena Morisco, Naples, Italy; Paola Nasta, Brescia, Italy; Tomris Ozben, Antalya, Turkey; Teresa Pollicino, Messina, Italy; Maria Laura Ponti, Cagliari, Italy; Patrizia Pontisso, Padua, Italy; Helen Reeves, Newcastle, United Kingdom; Maria Rendina, Bari, Italy; Kryssia I Rodríguez-Castro, Padua, Italy; Caterina Sagnelli, Salerno, Italy; Teresa Santantonio, Foggia, Italy; Giada Sebastiani, Venice, Italy; Antonella Smedile, Turin, Italy; Gloria Taliani, Rome, Italy; Carmen Vandelli, Modena, Italy; Ranka Vukotic, Modena, Italy; and Anna Linda Zignego, Florence, Italy.

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