Liver involvement in Turner syndrome

Authors


Correspondence

Dominique Roulot, Unité d'Hépatologie, Hôpital Avicenne, 125 route de Stalingrad, 93009 Bobigny, France

Tel:  00 331 48 95 54 30

Fax:  00 331 48 95 54 50

e-mail: dominique.roulot@avc.aphp.fr

Abstract

Liver test abnormalities are frequent in adult patients with Turner syndrome, corresponding to various pathophysiological mechanisms. Steatosis, steatofibrosis and steatohepatitis are the most frequently reported lesions, caused by metabolic disorders, which are commonly related to overweight. Marked architectural changes, including nodular regenerative hyperplasia, multiple focal nodular hyperplasia and cirrhosis, found in some patients, are associated with a risk of severe liver-related complications. Architectural changes are often observed and are associated with vascular disorders caused by congenitally abnormal vessels. Finally, small bile duct alterations resembling sclerosing cholangitis occur in several patients. Oestrogen replacement therapy does not cause liver toxicity in patients with Turner syndrome and is not contraindicated in case of elevated liver enzymes. Moreover, in recent studies, oestrogen therapy was reported to improve liver function tests. Because of the wide spectrum of potential liver injuries that may occur in Turner syndrome patients, a regular screening of liver enzymes is recommended for early detection and treatment.

Turner syndrome is one of the most frequent inherited diseases, with a prevalence of 1/2500 female live birth. It results from the total or partial loss of the X chromosome. Clinically, this syndrome is characterized by short stature, gonadal dysgenesia, dysmorphic features, congenital heart and renal malformations and predisposition to autoimmune diseases [1].

Liver involvement is frequent in adolescent and adult patients with Turner syndrome. The prevalence of liver test abnormalities, such as the elevation of aminotransferases, gamma glutamyl transferase and alkaline phosphatase, ranges from 20 to 80%, depending on the patient's age, the highest values being observed in the oldest patients [2-5]. In a large cohort of adult Turner syndrome women with a 5-year follow-up, the prevalence of pathological liver enzymes was 36% at 33 years, with an annual increased incidence of 3.4% over the 5 years [6].

Multiple causes may produce liver test abnormalities in Turner syndrome patients, including all common causes of liver involvement, such as viral hepatitis or chronic alcoholism, which must be ruled out at first. However, compared to the general population, their prevalence is not increased in Turner syndrome. Excess weight and oestrogen replacement therapy have both been proposed to cause the elevation of liver enzymes [3, 4]. Although oestrogen therapy has definitely been proven not to cause liver toxicity in women with Turner syndrome [2, 7], excess weight is one of the most frequent causes of liver tests abnormalities in this particular population.

For long time, comprehensive studies of liver involvement in Turner syndrome patients have been missing, contrasting with the relatively high number of epidemiological studies and case reports [7-11]. A cohort study with systematic histopathological examination analysed the histological features, causes and prognosis of liver involvement in Turner syndrome patients [12]. One important finding of this study was the confirmation that severe liver complications, such as portal hypertension, are possible albeit rare in Turner syndrome patients. Consequently, a systematic screening for liver involvement should be included in the follow-up of women with Turner syndrome, preceding a more accurate investigation in case of liver test changes.

Hepatic lesions and mechanisms of liver involvement

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 [13], to steatosis [14], steatohepatitis [4], 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 [13]. Accordingly, a five-fold increased risk of ‘cirrhosis’ was reported in Turner syndrome patients, compared to control patients [20]. 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).

Figure 1.

The three principal hepatic lesions observed in Turner syndrome. (a) Steatohepatitis, associating macrovacuolar steatosis (arrow) and portal inflammatory infiltrate. (b) Architectural changes with nodular regenerative hyperplasia. The limits of two nodules are indicated by the arrows. (c) Biliary lesions with concentric periductal fibrosis indicated by the arrows.

Figure 2.

The different mechanisms of liver lesions in Turner syndrome. Dotted lines indicated hypothetical mechanisms. NAFLD, non-alcoholic fatty liver disease; BMI, body mass index; NRH, nodular regenerative hyperplasia; FNH, focal nodular hyperplasia.

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 [26]. 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 [6]. 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 [27].

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 [31]. 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 [12].

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 [34]. 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 [41]. 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 [38]. 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 [44].

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 [12] and to increased risk of deep venous and portal vein thrombosis in Turner syndrome patients [47].

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.

Biliary lesions

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 [48], 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 [49]. 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 [12], 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 [50], 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 [54] with, in particular, increased risk of developing autoimmune thyroid disease [55]. A recent study reported a significantly more frequent X chromosome monosomy in women with primary biliary cirrhosis than in controls matched for age [56]. 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 [16]. 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 [61].

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 [12]. 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 [41]. 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 [67].

Liver involvement outcome

Natural history of liver involvement in Turner syndrome patients

To date, only one cohort study reported long-term follow-up of Turner syndrome patients with liver involvement. In this study, patients referred to liver departments for abnormal liver tests were followed up for an average of 9 years [12]. In most cases, liver involvement did not progress to overt hepatic disease. Major complications were observed in three patients who all displayed marked liver architectural changes. One patient died of uncontrolled refractory ascites with pleural effusion and cardiac failure. The second patient experienced uncontrolled bleeding from oesophageal varices and intractable cholestasis, requiring orthotopic liver transplantation 6 years after the diagnosis of liver involvement. The third patient underwent surgery for portocaval shunting to treat recurrent variceal bleeding. In conclusion, major liver complications remain uncommon in Turner syndrome patients and are only observed in case of marked architectural changes.

A case of hepatocellular carcinoma (HCC) was reported more recently in a child with congenital absence of the portal vein, receiving growth hormone therapy for Turner syndrome [43]. This patient developed FNH and adenomatous changes in the liver before the HCC occurrence. Two coincidental factors, namely vascular abnormalities and growth hormone therapy, may have predisposed this patient to develop HCC. The prolonged use of growth hormone therapy might have contributed to transform the focal hyperplasic adenomatous response caused by the local deprivation of portal perfusion. A previous case of hepatocellular adenoma in a Turner syndrome patient receiving recombinant growth hormone therapy [68] and reported examples of hormone-induced adenomatous changes evolving to HCC [69] support this hypothesis.

Outcome under ursodeoxycholic acid treatment

Ursodeoxycholic acid is commonly recommended in biliary disease, mainly in patients with PBC [70]. As biliary involvement occurs in about two-third of Turner syndrome patients with elevated liver enzymes, particularly, in case of cholestatic profile, ursodeoxycholic acid treatment has often been prescribed. This treatment proved to be effective at least on biological tests. In one study, serum aminotransferase and alkaline phosphatase levels returned to normal after a few weeks of treatment in most patients receiving ursodeoxycholic acid, although the gamma glutamyl transferase remained slightly increased [12]. Ursodeoxycholic acid treatment had no beneficial effect on biological tests in patients with liver architectural changes. Although a beneficial effect of ursodeoxycholic acid on anatomical lesions has not been documented so far, in the absence of a case–control study, it cannot be ruled out that the progression of biliary lesions might be also delayed by this treatment. In conclusion, ursodeoxycholic acid therapy probably provides some beneficial effect in Turner syndrome patients with biliary lesions and no alteration of liver architecture.

Managing of Turner syndrome patients with persistent elevated liver enzymes

Initial evaluation

The initial evaluation of Turner syndrome patient with abnormal liver tests documented for more than 6 months should include two non-invasive procedures: liver stiffness measurement (LSM) using transient elastography (TE) and abdominal ultrasound examination with assessment of blood flow using Doppler effect.

Liver stiffness measurement by TE is a non-invasive method reflecting the quantity of liver fibrosis [71]. LSM values are strongly correlated with liver enzymes levels in patients with Turner syndrome [72]. TE might thus be a useful tool to identify, among Turner syndrome patients with elevated liver enzymes or metabolic risk factors, those who necessitate more invasive diagnostic procedures (liver biopsy) for the optimal classification of the liver damage.

Abdominal ultrasound examination with assessment of blood flow using Doppler effect can detect hepatic nodules, portal hypertension and/or liver steatosis. In case of isolated cholestatic syndrome with normal ultrasound examination, ursodeoxycholic acid should be proposed at first. In case of ultrasonographic signs of hepatic steatosis, the treatment of the metabolic syndrome, based primarily on weight loss, is required to avoid complications of non-alcoholic fatty liver disease. When ultrasonographic signs of portal hypertension are present, the histological examination of the liver should be performed. If liver architectural changes are present, upper gastrointestinal endoscopy will establish the presence or absence of oesophageal varices, which require either long-term ß-blocker treatment or variceal ligation.

Subsequent monitoring

Liver blood tests and blood cell counts are recommended twice a year for all patients with Turner syndrome and abnormal liver enzymes. For patients who did not undergo liver biopsy at the initial evaluation with persistently elevated liver enzymes for more than 6–12 months, despite the correction of the metabolic syndrome and/or ursodeoxycholic acid treatment, liver biopsy should be considered. In case of liver architectural changes, abdominal ultrasound examination should be performed once a year, associated with upper gastrointestinal endoscopy every 3 years to detect signs of portal hypertension.

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