Liver involvement in Turner syndrome patients is most often asymptomatic, detected during systematic blood testing. In general, the diagnosis of Turner syndrome precedes that of liver involvement, although abnormal liver tests may sometime be the first symptom, which leads to the subsequent diagnosis of the syndrome.
The pattern of hepatic histological changes reported in Turner syndrome patients is quite variable, from minimal abnormalities , to steatosis , steatohepatitis , biliary involvement [14-17], cirrhosis [8-10] and nodular regenerative hyperplasia [7, 11, 18, 19]. The mechanisms and prognosis of liver disease had not been investigated in most early studies, although few reports mentioned that the consequences of the hepatic involvement could sometime be severe . Accordingly, a five-fold increased risk of ‘cirrhosis’ was reported in Turner syndrome patients, compared to control patients . In the cohort study mentioned above, where liver biopsy was performed in most patients, three principal types of lesions were identified (illustrated in Fig. 1). Among them, steatosis was the most common finding, followed by liver nodular architectural changes and biliary lesions. Although the pathophysiological mechanisms of steatosis are becoming more and more clear, those responsible for the other anatomical changes remain hypothetical and will be discussed in this review (Fig. 2).
Steatosis and non-alcoholic fatty liver disease (NAFLD)
Histopathological features of non-alcoholic fatty liver disease have been found in a relatively important proportion of Turner syndrome patients. NAFLD corresponds to a spectrum of liver injuries mimicking alcohol-induced liver disease in patients who are not heavy drinkers. NAFLD includes both steatosis, which has a benign course, and steatohepatitis, which may eventually lead to fibrosis and subsequent progression to cirrhosis. Overweight and insulin resistance syndrome have recently been recognized as a common cause of non-alcoholic fatty liver disease [21, 22]. As overweight, defined by a body mass index (BMI) value above 25 kg/m2, impaired insulin secretion and diabetes are frequent in Turner syndrome patients [20, 23-25], it is likely that this type of hepatic lesions reflects the same pathophysiological mechanisms as in overweight patients without Turner syndrome . In a 5-year follow-up study in Sweden, body weight, BMI, total cholesterol, triglycerides and apolipoproteins A and B were higher in Turner syndrome women with elevated liver enzymes than in Turner syndrome women with normal levels . Multivariate analysis showed that gamma glutamyl transferase was correlated with total cholesterol independently of other factors.
Liver architectural changes, nodular formation and vascular lesions
Marked liver architectural changes can be observed in some Turner syndrome patients. They include cirrhosis, nodular regenerative hyperplasia (NRH) and multiple focal nodular hyperplasia (FNH). NRH is defined as the presence of multiple small liver parenchymal nodules without annular fibrosis and with conserved portal tracts. FNH corresponds to the presence of a large nodule with or without intranodular fibrosis, alternating with fibrotic areas containing numerous abnormal arteries and ductules. Changes in the intrahepatic portal veins, including thrombosis, intimal thickening, or complete obstruction and replacement by a fibrous scar containing numerous vessels, are frequently associated with liver architectural changes; they are considered as features of obliterative portal venopathy .
Several findings suggest that the architectural changes described above are the consequence of a primary vascular involvement. Indeed, NRH is currently thought to represent a form of adaptation to microcirculatory disturbances causing heterogeneous distribution of intrahepatic blood flow [28-30]. According to this hypothesis, NRH combines hepatocyte atrophy in areas of decreased perfusion, with hepatocyte hyperplasia in areas of normal perfusion. FNH is also considered as a focal hyperplastic hepatocellular response caused by focal deprivation of portal perfusion and enhanced arterial perfusion in the corresponding area . Finally, cirrhosis with no evidence for a known cause of chronic liver disease in Turner syndrome patients may correspond to the final stage of a vascular disorder. Extra-hepatic vascular malformations, including aortic coarctation, aortic bicuspidia, cerebral vessel aneurysm and gastrointestinal telangiectasia, are common in Turner syndrome [32-36] and aortic anomalies were found more frequently in patients with marked architectural changes of the liver .
Aortic valve abnormalities and aortic coarctation are not the only arterial problems observed in Turner syndrome patients. Recently, investigations in asymptomatic patients revealed far more complex and extensive cardiovascular phenotype [37, 38]. A study combining echocardiography and magnetic resonance imaging reported that nearly 75% of adult women with Turner syndrome display generalized dilatation of the ascending aorta [39, 40], which may be associated with generalized dilatation of major vessels, such as brachial and carotid arteries. In women with Turner syndrome, thickness of carotid intima-media and artery diameters are larger than in normal controls. It was proposed that oestrogen deficiency might contribute to arterial intimal thickening . Consistent with this hypothesis, increasing doses of hormonal replacement therapy resulted in a reduction in intima-media thickness in young hypogonadal women with Turner syndrome . Finally, women with Turner syndrome, have an increased cardiovascular mortality rate from both structural and ischemic heart disease, especially aortic dissection, which is a leading cause of premature mortality in these patients. Recently, prospective data on the aortopathy were obtained in adult Turner patients using highly sensitive 3D cardiovascular magnetic resonance. Accelerated ascending aortopathy was present, with significant growth rate of the aorta diameter during the 2.4 years of follow-up . If a similar rapidly progressing dilatation would also take place in other vascular beds over time, one could speculate than the liver might also be progressively affected, explaining why liver involvement is increasing with age in Turner syndrome patients.
Venous malformations, such as agenesia or hypoplasia of the portal venous system, may occur in Turner syndrome women [42, 43]. A case of presinusoidal portal hypertension caused by congenital hypoplasia of the intrahepatic portal system, known as the Cruveilhier–Baumgarten disease, was reported. The examination of the explanted liver showed no cirrhosis but, instead, a severe parenchymal atrophy causative of the liver dysfunction .
Thromboembolic complications occur more frequently in Turner syndrome patients, probably explained by frequent high levels of von Willebrand factor, factor VIII, fibrinogen and C-reactive protein and increased occurrence of the Leiden factor mutation [45, 46]. These disorders might contribute to the obliterative portal venopathy observed in the liver of some Turner syndrome patients  and to increased risk of deep venous and portal vein thrombosis in Turner syndrome patients .
In conclusion, vascular hepatic involvement in Turner syndrome patients could be part of a more general vascular disorder, likely of congenital origin, involving vessels of different sizes, types and locations.
Several types of biliary involvement have been reported in the context of Turner syndrome, including sclerosing cholangitis, primary biliary cirrhosis, bile duct paucity and biliary atresia.
Non-inflammatory, concentric fibrosis of small intrahepatic bile ducts, resembling primary sclerosing cholangitis, has frequently been found in adult Turner syndrome patients. Although Turner syndrome women have a higher than expected incidence of inflammatory bowel disease , a condition that is frequently associated with primary sclerosing cholangitis, sclerosing cholangitis mostly involves extrahepatic bile ducts, whereas only intrahepatic bile ducts are involved in Turner syndrome patients. In addition, in case reports of Turner syndrome patients with biliary lesions, associated inflammatory bowel disease is generally not mentioned. These findings indicate that the ductal fibrosis in Turner syndrome patients is caused by a different pathophysiological mechanism than primary sclerosing cholangitis.
Bile duct fibrosis frequently occurs in patients with damaged arterioles in proximity of bile ducts . Thus, the concentric biliary fibrosis might well be related to an altered blood supply. If this hypothesis is correct, biliary lesions found in patients without marked architectural alterations could correspond to one end of the spectrum of vascular-related abnormalities, with the marked architectural changes described above being at the other end.
Cholangitis and ductopaenia, described in patients with Turner syndrome , are commonly observed in patients with primary biliary cirrhosis (PBC). The frequency or prevalence of PBC in Turner syndrome has not been studied, although biliary involvement of Turner syndrome and PBC share similarities , and that cases of PBC have been reported in patients with Turner syndrome [51-53]. In both diseases, the frequency of cholestasis is increasing with age, and both diseases are strongly associated with autoimmune disorders. Autoimmunity is more frequent in Turner syndrome patients than in normal females  with, in particular, increased risk of developing autoimmune thyroid disease . A recent study reported a significantly more frequent X chromosome monosomy in women with primary biliary cirrhosis than in controls matched for age . It was proposed that the X chromosome contains genes involved in immune tolerance, the functional loss of which would predispose the patients to a self-tolerance breakdown and subsequent development of autoimmune diseases [57, 58]. So far, however, only one homebox-containing gene has been identified, with clear implication in Turner syndrome phenotype. This short stature homebox gene SHOX, is localized in the pseudoautosomal region (PAR1) of X chromosomes [59, 60], and is involved in the short stature phenotype of Turner syndrome patients. Additional studies are necessary to determine its potential association with autoimmune or liver dysfunction.
Intrahepatic biliary atresia was reported in children with Turner syndrome . One hypothesis is that abnormal angiogenesis could be implicated in the paucity of bile ducts. In the Alagille syndrome, a dominantly inherited multisystem disorder, both vascular abnormalities and bile ducts paucity are present. The vasculopathy is probably the primary abnormality causative of the bile duct paucity, as the development of intrahepatic bile ducts is dependent on the intrahepatic arterial branch formation .
Role of oestrogen therapy
Oestrogen-induced hepatotoxicity was proposed for long time as the main cause of liver test abnormalities in Turner syndrome patients receiving hormone replacement therapy [62, 63]. However, the causative role of oestrogens has never clearly been established in these studies. Moreover, both alterations of liver tests and liver architectural changes were reported whether Turner syndrome patients were treated with estrogens or not . In addition, abnormal liver tests were not improved by cessation of replacement therapy [2, 6, 7]. Therefore, it is now well accepted, that the discontinuation of replacement therapy is not necessary in Turner syndrome patients with elevated liver enzymes. Discontinuation could instead be deleterious, as several studies reported a beneficial effect of natural oestrogens on liver function of Turner syndrome patients [5, 64-66]. In addition, one study reported that higher doses than those normally used for replacement therapy (up to 4mg of oestradiol) had beneficial effects on markers of cardiovascular risk in Turner patients . A similar improvement could potentially be obtained for liver involvement as suggested by a dose–response study of 14 women with Turner syndrome who received 1, 2 and 4 mg oestradiol daily in a cyclical formulation .