NAFLD refers to a group of diseases primarily characterized by macrovesicular steatosis of the liver that occurs in patients without excessive alcohol consumption (9). Currently, it is considered to be the most common CLDs worldwide, especially in the Western, with an incidence of nearly 25% (10). The actual prevalence of NAFLD may be higher because many remain asymptomatic in the early stages and there are no reliable non-invasive tests for screening. Its primary feature is fat deposition in hepatocytes, which can develop into fibrosis, cirrhosis, and even hepatocellular carcinoma. The incidence and mortality of hepatocellular carcinoma and cirrhosis brought on by NAFLD have kept increasing in recent years (11).

NAFLD has been regarded as the hepatic manifestation of systemic metabolic syndrome (12, 13). ED is a very important and common comorbidity of NAFLD, some patients even have abnormal semen parameters. The incidence of ED in patients with NAFLD ranges from 45 to 67% (14), which is much higher than the rate in the general population and 2.92 times higher than the rate in those without NAFLD. The degree of fat infiltration is closely related to ED. NAFLD is a significant independent factor associated with ED. The main reason may be that NAFLD and ED share common risk factors such as obesity, hypertension, and diabetes mellitus (15, 16). Numerous ED etiologies are present in 39.5% of NAFLD patients, and a significant portion of these patients have psychogenic ED. Therefore, careful evaluation of psychological status during diagnosis and treatment is important (14).

Cirrhosis is a chronic and progressive liver disease commonly seen in clinical, which is caused by long-term or repetitive impacts of one or more etiologies. It is often accompanied by ascites, hepatic encephalopathy, and varicose hemorrhage.

A high prevalence of ED is shown in alcoholic hepatitis, which is one of the major etiologies of cirrhosis. At present, some scholars consider that there is a correlation between cirrhosis and ED, which can be explained by haemodynamic alteration, hypogonadism, hypotestosteronemia, unhealthy lifestyle, and a lower quality of life. Through meta-analysis, Yoo et al. (17) found that the prevalence of ED in cirrhotic patients was 79.08%, and in decompensated cirrhotic patients was 88.4%. After controlling for other conditions such as diabetes, alcoholism, severe cardiac conditions, etc., Paternostro et al. (18) discovered that among male cirrhotic patients, 55% were categorized as mild-to-moderate ED and 8.3% as moderate-to-severe ED, and that with the decline of liver function, the severity of ED increased and the IIEF-5 score decreased significantly. In cirrhotic patients, the increase in absolute level of hepatic venous pressure gradient is an independent predictor of ED, suggesting that ED is correlated with portal hypertension, and this may be related to hemodynamic alternation in the splanchnic circulation, which can directly impair physiological penile erection. In men with alcoholic cirrhosis, ED may be related to the direct toxic effects of ethanol and acetaldehyde on the gonads.

However, previous studies had shown conflicting results regarding the impact of cirrhosis on the prevalence and severity of ED. Some scholars compared the incidence of ED among alcoholics with or without cirrhosis and diabetes, found that there was no difference between the groups (19). According to some studies, no difference was found in the prevalence of ED between patients with chronic viral hepatitis and patients with established cirrhosis (20), only age and hypoalbuminemia were found to be independent factors for ED (18). The reasons for these disparities could be that these studies used different IIEF-5 cut-offs or that these patients had higher expectations of erectile function.

Chronic viral hepatitis is a common disease worldwide. Despite the promotion of vaccination, the landscape is still far from satisfactory, with more than 300 million people suffering from various kinds of hepatitis. According to the World Health Organization, an estimated 257 million people are living with chronic hepatitis B, more than 70 million with hepatitis C, 80% of whom develop chronic disease, and 62 million with chronic hepatitis D. As for hepatitis A, 1.4 million new cases are reported globally each year (21–24).

The total prevalence of ED in patients with chronic viral hepatitis ranges from 14 to 78% (20, 25), even after adjustment based on IIEF-5 scores ≤ 17, 40% of patients with chronic viral hepatitis had ED (26). According to the IIEF cut-off, ED was confirmed in 76.4% of hepatitis B patients, with 60.3% classified as severe. Those with diabetes mellitus had the highest incidence of ED (92.6%), followed by those who progressed to cirrhosis (85.7%) (27). Patients with HBV-related liver cirrhosis exhibited a higher prevalence and severity of ED than chronic hepatitis B patients (4, 28). In comparison to patients with HBV infection, those with HCV seem to be more susceptible to ED. This may be due to the distinct biological properties of these two viruses. HCV infection is more likely to cause inflammation of the vascular endothelium, which is one of the pathogenesis of ED (29, 30). Cryoglobulinemia may play an important role in this process. HCV infection is one of the causes of cryoglobulinemia; cryoglobulins depositing in the vascular endothelium can result in systemic vasculitis, primarily involving the small and medium arteries. HCV patients with cryoglobulinemia have a higher incidence of ED than those without cryoglobulinemia (31).

Alcoholic liver diseases are caused by long-term alcohol abuse and usually manifest as fatty liver at the initial stage and may develop into alcoholic hepatitis, liver fibrosis, and cirrhosis. Long-term alcohol abuse is generally defined as a history of drinking alcohol for more than 5 years, which is equivalent to ethanol ≥ 40 g/d for men and 20 g/d ≥ for women, or a history of heavy alcohol consumption within 2 weeks, which is equivalent to ethanol > 80 g/d. There have been no specific reports retrieved on the association between alcoholic liver disorders and ED, and the points of view we discussed ut infra are all obtained from sporadic observations in other studies, and the available data are inadequately standardized and the cases are restricted.

Cornely et al. (19) observed that the prevalence and severity of ED were considerably higher in male cirrhotic patients with chronic alcohol abuse than in patients with more severe cirrhosis due to other etiologies. Another study found that the prevalence of sexual dysfunction (particularly ED and/or decreased libido) in alcohol-induced liver disease is comparable between cirrhotic and non-cirrhotic patients, leading to the conclusion that alcohol was the true cause of ED (32). However, the results from another study were completely different, Wang et al. (33) believed that the history of alcohol consumption had no effect on the prevalence of ED in patients with cirrhosis, but the levels of testosterone, estradiol, and PRL were different from those in the control group, suggesting that cirrhosis rather than alcohol was the real cause of sexual dysfunction.

The etiology and progression of liver disease contribute to the development of ED. Toda et al. (4) studied 117 subjects with viral hepatitis and idiopathic non-alcoholic liver disease, 53 of whom had cirrhosis (30 Child A, 17 Child B, and 6 Child C), and assessed their erectile function with the IIEF-5, finding that the incidence of ED increased as the Child-Pugh score worsened. However, in patients with Child-Turcotte-Pugh scores ≤ 10, their frequency and severity did not vary with the severity of liver disease.

Hepatitis viruses can directly damage the gonads and can also affect the occurrence of ED through a variety of complex mechanisms such as inflammation, oxidative stress, and apoptosis (25, 26). Chronic systemic inflammation with elevated C-reactive protein levels reduces the synthesis of NO in endothelial cells and ultimately leads to endothelial dysfunction, which may account for the relationship between ED and chronic hepatitis (49, 50). Compared with HBV, HCV infection had a more pronounced negative effect on erectile function; compared to the control group without infection, men with chronic HCV infection had significantly lower libido, erectile function, ejaculation, and overall satisfaction (51). Even after controlling for depression or other potentially confounding variables, the association between HCV and ED remains strong. This could be due to biological/virological factors or potential effects on the hypothalamic-pituitary-gonadal axis (52). The prevalence of ED in cirrhotic patients is higher than in chronic hepatitis patients. The mechanism remains unclear, but gonadal dysfunction, sex hormone imbalance, and low albumin levels may be the major causes (27). Kim M et al. (28) also found that the incidence of ED was significantly higher in patients with HBV-related cirrhosis than in chronic hepatitis patients without cirrhosis, and this difference remained significant even after four patients with Child-Pugh grade B cirrhosis were excluded. Physiological disturbances caused by protein malnutrition in patients with decompensated CLDs may be associated with ED. Edema, ascites, hypoalbuminemia, pleural effusion, and deteriorating physical function are usually present in advanced liver diseases and can also reduce libido and lead to ED. Branched-chain amino acids can improve serum albumin, muscle metabolism, and prognosis in patients with CLDs (53). In cirrhotic patients treated with branched-chain amino acids, an improvement in erectile function was observed (54), suggesting a correlation between physiological dysfunction and ED. Portal hypertension, as an independent risk factor for erectile dysfunction, can impair penile erectile function by altering the hemodynamic status of the visceral circulation (18). In a study of cirrhotic patients with a wider range of liver failure, Phylonenco et al. identified minimal hepatic encephalopathy as a possible risk factor for the progression of ED (55).

Minimal hepatic encephalopathy is considered to be associated with a poor quality of life as well as some behavioral abnormalities such as depression and anxiety. In their study, Nardelli et al. (56) found that the prevalence of ED was significantly higher in patients with abnormal neurocognitive tests than in normal subjects, and that, in the subgroup of patients with Child-Pugh A cirrhosis (n = 25), 100% of patients with minimal hepatic encephalopathy (n = 16) developed ED. However, in multivariate analysis, it was not identified as an independent risk factor for ED. This could be due to the sample size restrictions, which make it challenging to distinguish the effects of the two variables, liver dysfunction and cognitive impairment (57). Huyghe et al. (58) used a questionnaire to survey patients with end-stage liver disease who were candidates for liver transplantation, using the IIEF-5 score to assess erectile function and the patient-baseline Treatment-Satisfaction Scale score to assess sexual satisfaction. Of the 98 candidates who completed the questionnaire, 28 (29%) were sexually inactive, while 52 (74%) of the 70 sexually active patients had ED. Approximately 50% of patients felt that their erectile function had deteriorated in the previous 6 months.

In addition, some rare diseases can also cause liver dysfunction and ED. Hemochromatosis is a chronic iron overload caused by a high-iron diet, massive blood transfusions, or systemic disease. Excess iron stored in substantial cells such as the liver, heart, and pancreas can lead to degeneration and diffuse fibrosis, as well as metabolic and functional abnormalities. It can also cause hypothalamic-pituitary-gonadal axis dysfunction, direct testicular damage, diabetes, and other conditions that can lead to sexual dysfunction (59, 60). Autoimmune hepatitis is a chronic and progressive autoimmune-mediated inflammatory disease of the liver. Approximately 34% of patients have no symptoms but abnormal liver function at the initial visit. Thirty percent have cirrhosis, and 8% have decompensated cirrhosis symptoms such as hematemesis and/or melena. It may be connected to other autoimmune conditions like diabetes, which can result in hormonal imbalance and disruption of the hypothalamic-pituitary-gonad axis, ultimately impairing sexual function (61).

The liver is the largest metabolic organ in the human body, and it is also the primary site of sex hormone metabolism. It is well known that CLDs patients exhibit significant feminization, including gynecomastia, fat redistribution, loss of body hair, and other symptoms, as a result of hypogonadism and excessive estrogen production (8). Up to 90% of patients with cirrhosis have lower testosterone levels (62), which correlate with disease severity, and these patients tend to lose their circadian rhythm in testosterone levels. In the compensatory stage of liver disease, sex hormones may not change noticeably, but as liver function deteriorates to a decompensated stage, patients may present with testicular atrophy and interstitial fibrosis, which reduce the synthesis and secretion of testosterone.

The precise mechanisms underlying the associations between gonadal dysfunction and CLDs remain poorly understood. Testicular atrophy is present in more than 50% of male patients with cirrhosis. It may manifest histological abnormalities such as atrophy of the testis germ epithelium, thickening of the tubule basement membrane, and fibrosis of the leydig. In addition to testicular atrophy, CLDs may cause gonadal dysfunction via a variety of mechanisms. As is well known, as liver disease progresses, the liver's inactivation effect on estrogen weakens, and the transformation of testosterone and estrone into estradiol increases, leading to an increase in serum estradiol level, which inhibits pituitary gonadotropin release and reduces androgen secretion by testicular interstitial cells (62). In patients with NAFLD, the hypotestosteronemia can be explained by the hypogonadal-obesity-adipocytokine hypothesis (63). An increase in visceral adipose tissue raises the activity of the aromatase enzyme, which can convert testosterone to estrogen and decrease testosterone levels. Low testosterone levels then enhance the activity of the lipoprotein lipase enzyme, which promotes triglyceride uptake into adipocytes and further increases visceral adiposity, resulting in a vicious cycle (64). In addition, pro-inflammatory adipocytokines released from adipose tissue, including tumor necrosis factor-α, interleukin-1, and interleukin-6, have been shown to inhibit the pituitary axis, which in turn reduces testosterone levels (65). It had previously been demonstrated that ED caused by non-alcoholic steatohepatitis-induced testosterone deficiency was associated with increased TNF-α (66). The decreased activity of 17-β hydrogenase in the liver of CLDs patients reduces the conversion of androstenedione to testosterone, which is also one of the reasons for testosterone deficiency. However, what calls for special attention is that physiological decline should also be fully taken into account when analyzing testosterone levels in patients with CLDs, testosterone in men decays at a rate of 10% every decade after the age of 30 (67). ED may occur due to hormonal imbalances. Reduced testosterone levels can affect erectile function via multiple pathways, including increased apoptosis of smooth muscle cells and endothelial cells, resulting in decreased compliance and hemodynamic abnormalities of the corpus cavernosa; inhibition of the eNOS-No-cGMP pathway; and activation of the Rho A/Rho kinase pathway, resulting in decreased smooth muscle contraction and corpus cavernosum blood perfusion. In patients with cirrhosis, however, oral androgens may not increase serum testosterone levels but instead increase estrogen levels (8). Oral testosterone seemed to have no positive effect on sexual dysfunction in patients with cirrhosis, and androgen supplementation was only effective in cases of severe hypogonadism with testicular atrophy (51), implying that the main mechanism for ED may not be limited to total testosterone levels.

Although total testosterone levels are significantly lower in CLDs patients with ED, they were not significantly associated with the occurrence and severity of ED in multivariate analyses, raising the question of whether total or bioavailable testosterone is the more meaningful test method. Testosterone is mainly bound to albumin (50%), sex hormone-binding globulin (45%), and free testosterone (2%). Bioavailable testosterone includes albumin-bound testosterone and free testosterone. According to a meta-analysis, free testosterone levels were significantly lower in ED patients than in the non-ED group (17). Patients with hepatic insufficiency frequently have higher levels of estrogen and lower levels of testosterone, which can result in an increase in the production of sex hormone-binding globulin through a negative feedback loop. That then results in a higher binding between testosterone and sex hormone-binding globulin, further reducing bioactive free testosterone (62, 68). A hypothesis was proposed that low serum albumin could affect the ratio of free albumin to bound testosterone, thereby altering the testosterone response (51). In conclusion, free or bioactive testosterone may be a better marker of ED.

Drugs or medications can induce or aggravate ED in patients with CLDs.

IR is associated with hepatic fat deposition and is significantly increased in patients with NAFLD (79). The accumulation of lipid oxidation products in cells may interfere with the insulin signaling pathway via the phosphatidylinositol 32 kinase (PI32K), thereby affecting the transport function of glucose transporter 4, resulting in IR. IR can harm the vascular system through a variety of mechanisms, causing vascular dysfunction or structural destruction, such as atherosclerosis (80, 81), and eventually leading to ED (Figure 1). In the meantime, eNOS deficiency aggravates the early stage and accelerates the progression of NAFLD (82). This is a vicious circle, and it could be one of the mechanisms by which NAFLD leads to ED.

Anemia is common in patients with decompensated CLDs, and ED is also associated with lower hemoglobin levels. Low serum hemoglobin levels may indicate advanced liver disease and severe portal hypertension. Anemia can exacerbate the cirrhosis-related hyperdynamic circulation (34), which is characterized by visceral vasodilation and peripheral vasoconstriction. This might impair penile circulation and lead to ED (83). Furthermore, anemia reduces the supply of oxygen to tissues, including the corpus cavernosum, potentially impairing erectile function (84).

In addition to the aforementioned mechanisms, oxidative stress, inflammatory response, apoptosis, and other factors are also involved in the occurrence of CLDs-related ED (85, 86). Therefore, the mechanism of ED caused by CLDs is very complex and differs from that of the general population in some aspects. These distinct causes must be fully considered. Unfortunately, there are few studies on its concrete mechanisms, such as signaling pathways, that have been retrieved so far. More in-depth studies are needed to uncover the distinct mechanisms by which CLDs lead to ED.