Eur J Pediatr (1999) 158: 618±623

Ó Springer-Verlag 1999

ENDOCRINOLOGY

M. Salerno á S. Di Maio á N. Gasparini á M. Rizzo á P. Ferri á P. Vajro

Liver abnormalities in Turner syndrome

Received: 12 October 1998 and in revised form: 8 February 1999 / Accepted: 25 March 1999

Abstract We evaluated whether hepatic abnormalities represent a speci®c feature in girls with Turner syndrome (TS) or whether they are related to an increased susceptibility to hormonal therapies and/or other factors. Alanine aminotransferase, aspartate aminotransferase and c-glutamyl transferase were monitored in 70 patients with TS for a mean period of 7.6 ‹ 4.2 years. An increase in serum liver enzymes was observed in 14 out of 70 girls (20%) at a mean age of 12.7 years; it was present at entry before hormonal therapy in 3 girls and developed thereafter during the follow up in the other 11. The increase in serum liver enzymes was never observed before the age of 7 years. In the majority of cases (10/14) it was drug related: in 50% the liver abnormalities were transient and self-limiting, in the remaining cases they required interruption of hormonal therapy. Hepatotoxicity was more frequently observed in girls treated with oestrogens or oxandrolone than in those treated with growth hormone. In a small number of cases, liver disease was either auto-immunity-related (2/14), or cryptogenic (1/14) with a benign and self-limiting course. Obesity was a frequent ®nding, but it played a likely pivotal role only in one patient. Conclusion Hepatic abnormalities are relatively frequent in Turner syndrome and surveillance of liver function should be included in the management of these patients independent of initiation of hormonal treatment. Key words Alanine aminotransferase á Aspartate aminotransferase á c-Glutamyl transferase á Oestrogens á Turner syndrome Abbreviations GH growth hormone á IBW Ideal body weight á LFT liver function test á PE Ponderal excess á TS Turner syndrome Introduction

Turner syndrome (TS) represents one of the most frequent chromosome aberrations, with an incidence of about 1:2,000 live-born females. Since short stature and ovarian failure are the prominent features a€ecting girls with TS [25, 26], most of them require growth-promoting hormonal treatment to improve their ®nal height [3], and oestrogen therapy for feminization. Liver abnorP. Vajro (&) á M. Salerno á S. Di Maio á N. Gasparini M. Rizzo á P. Ferri Dipartimento di Pediatria, UniversitaÁ Federico II,

malities may ensue due to hepatotoxic e€ects of these drugs [5, 17, 19, 34]. However, several patients of a series of adults with TS [29] and a few anecdotal cases both in the paediatric and adult age groups [1, 4, 6± 8, 11, 13, 15, 28, 30] reported hepatic disease independent of drug treatment. The present study evaluates whether liver abnormalities are an additional speci®c feature of the multisystemic involvement of the syndrome, or whether it re¯ects

Via S. Pansini 5, I-80131 Napoli, Italy, e-mail: vajro @unina.it, Tel.: +39-081-746 2677 or 3504, Fax: +39-081-546 9811

619

an increased susceptibility of the liver to either hormonal therapies [34] or to other conditions, namely obesity [2, 23] and/or auto-immunity [14], which are frequently encountered in these patients. Patients and methods This retrospective study was carried out on 70 patients with TS (39 with XO karyotype and 31 with mosaicism or structural abnormalities of the X chromosome) followed up at our Department of Pediatrics during the last 15 years. Patients were followed up from a mean age of 7.0 ‹ 5.0 years to the age of 17.0 ‹ 6.0 years, for a mean period of 7.6 ‹ 4.2 years (range 1± 15 years). A total of 37 patients were on oestrogen replacement therapy of whom 32 had previously been treated with oxandrolone (0.12 mg/kg per day) or growth hormone (GH) (1U/ kg per week) or both before oestrogen therapy was started. A group of 24 patients, 6 of whom were previously treated with oxandrolone, were on GH treatment. Nine girls had not yet received hormonal treatments. During follow up, liver function tests (LFT) including serum levels of AST, ALT, GGT and muscle CK were evaluated before and at 6-monthly intervals during hormonal treatment. Normal values for liver enzymes in our laboratory are <35 U/L. Patients with persistent increase in serum liver enzymes were further evaluated with ultrasonography of the liver and appropriate laboratory investigations to rule out the most common causes of hypertransaminasaemia, including viral and auto-immune hepatitis, Wilson disease, coeliac disease, cystic ®brosis, a-1-antitripsin de®ciency, and muscular disease. None had previously been treated with potentially hepatotoxic drugs other than hormonal therapy, nor had any of them received either blood or blood products. None was taking herbal medicines, nor were any of them regular alcohol drinkers. Only three out of four patients with clinical signs of liver disease (i.e. hepatomegaly) and more severe abnormalities in liver enzymes underwent a needle liver biopsy. In all patients thyroid function was evaluated at 6±12 monthly intervals because of the high incidence of thyroiditis reported in patients with TS [22]. To evaluate the in¯uence of overweight on serum liver enzymes [2, 23, 32], the degree of adiposity was calculated in relation to ideal body weight (IBW) (percentage of the 50th percentile of weight for height age [20]). Ponderal excess (PE) was de®ned by weight greater than 120% of IBW. Values are expressed as mean ‹ standard deviation. Statistical di€erences between means were evaluated with the Student's t-test for a two group comparison. Fisher's exact test for 2 ´ 2 contingency tables was used to analyse binary data. Linear regression analysis was used to calculate correlation coecients for continuous variables.

Results

Table 1 summarises demographic, clinical and laboratory ®ndings in patients with increased serum liver enzymes compared to those without liver abnormalities. Eight patients with thyroiditis and abnormal thyroid hormones were on treatment with L-thyroxine. The number of obese patients and the degree of overweight in the group of 14 tended to be higher compared to patients without liver abnormalities (Table 1). However, changes in PE during the observation period did not correlate with variations in serum liver enzyme levels (r = 0.41, P = ns). An increase in serum liver enzymes was found in 14 out of 70 girls with TS (20%) (Table 1). Liver abnormalities were already present at entry in three girls and developed during follow up in 11 (Table 2). Increased serum levels of ALT, AST and GGT were observed in 100%, 78% and 36% of the 14 patients, respectively; a simultaneous increase of the three enzymes was observed in 36%. Other LFT were normal in all but one hypergammaglobulinaemic patient with auto-immune hepatitis who developed also severe coagulopathy. Hepatomegaly was present in 4 out of 14 patients. Following analysis of individual results (Table 2) the 14 patients were divided into four groups: group 1, early abnormality of LFTs after starting oestrogen replacement; group 2, late abnormality of LFTs after starting oxandrolone therapy; group 3, auto-immune liver disease; group 4, cryptogenic liver disease. In the ®ve patients of group 1 the increase in liver enzymes was observed 7.8 ‹ 8.3 months (range 2±22 months) after beginning oestrogen therapy. Four of them were overweight. A spontaneous normalisation occurred within a mean period of 11 ‹ 5 months without stopping the treatment and without correlation with PE variations. In the 5 girls of group 2, the increase in liver enzymes tended to occur later (19.8 ‹ 19.4 months; range 3±48 months) and to be higher than in group 1. This increase seemed secondary to treatment with oxandrolone: interruption of treatment coincided in all patients with

Table 1 Demographic and clinical ®nding of Turner syndrome (TS) patients with increased serum liver enzymes as compared to TS patients without abnormalities in liver function tests (LFTs)

Number of patients 45 XO karyotype Mosaicism or X abnormalities Age at diagnosis of TS (years) Thyroid antibodies Age at onset of abnormalities in LFTs (years) Number of obese patients IBW (%)

Patients with liver involvement

Patients without liver involvement

14 6/14 8/14 7.7 ‹ 4.7 6/14 12.7 ‹ 3.4 10/14 132 ‹ 24

56 33/56 23/56 7.0 ‹ 4.9 9/56 ± 24/56 125 ‹ 22*

P

ns (0.2) ns (0.2) ns (0.6) <0.03 ± 0.05 ns (0.3)

* Calculated at mean age (12.3 ‹ 2.3 years) comparable to that of the onset of abnormal LFTs in the group of patients with liver involvement

11.25

11.75

13

14

15.5

12

12.5

10

8.0

13.5

9

11

7.0

8

16.25

5

9.0

16.8

4

7

15.5

3

9.0

16.0

2

6

15.25

Age at diagnosis of liver disease (years)

1

Case

b

Normal values <35 U/l n.a. = not available c AH auto-immune hepatitis

a

4

3

2

1

Group

±

±

±

±

8.0

9.5

6.5

8.0

8.0

15.5

15.0

15.0

15.0

15.0

Age at beginning of treatment (years)

130

125

155

90

131

167

112

118

147

124

109

136

129

156

IBW %

175

292

324

63

114

205

106

70

168

99

53

45

52

71

ALTa (U/L)

89

89

166

45

90

43

45

34

98

56

30

41

37

48

ASTa (U/L)

33

38

233

10

34

23

14

13

70

50

28

72

19

26

GGTa (U/L)

Hepatomegaly

Hepatomegaly

Hepatomegaly

±

±

±

±

±

Hepatomegaly

±

±

±

±

±

Physical ®ndings

Steato®brosis

Steato®brosis

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

Steato®brosis

n.a.

n.a.

n.a.

Overweight

±

Overweight

Type Ia AHc Cryptogenic

Overweight

Coeliac disease

Overweight

±

Overweight/ GH ±

Overweight

±

Overweight

Overweight

Overweight

Possible cause

Overweight/ GH ±

Oxandrolone

Oxandrolone

Oxandrolone

Oxandrolone

Oxandrolone

Oestrogens

Oestrogens

Oestrogens

Oestrogens

Oestrogens

n.a.b n.a.

Most likely aetiology

Liver histology

Table 2 Demographic, clinical and laboratory ®ndings of 14 patients with TS at the time of onset of liver enzymes abnormalities and subsequent course

Spontaneous within 18 months Spontaneous within 6 months Spontaneous within 6 months Spontaneous within 12 months Spontaneous within 12 months 6 months after stopping oxandrolone 3 months after stopping oxandrolone 3 months after stopping oxandrolone 2 months after stopping oxandrolone 6 months after stopping oxandrolone 3 months after gluten-free diet 6 months after steroid therapy Spontaneous within 12 months 6 months after low-calorie diet

Normalization of LFTs

620

621

normalisation of liver enzymes and was followed by a further increase in two girls who had to resume treatment. Three girls from group 2 were overweight, however, PE did not change throughout the observation period and hormonal treatment. In one of the three (case 6) ultrasonography showed mild hepatomegaly and a bright liver; liver biopsy showed steato®brosis. Furthermore in cases 6 and 10, a further transient increase in ALT was observed when GH was added to oxandrolone. Liver function returned to normal when oxandrolone was stopped. In the two patients of group 3 the increase in serum liver enzymes was probably auto-immune in origin. The ®rst girl showed a modest increase in ALT and AST before any hormonal treatment, which persisted during treatment with GH. Laboratory and intestinal bioptic investigations revealed coeliac disease responsive to a gluten-free diet. The second patient was an obese girl with long-standing hypergammaglobulinaemia (ca. 2.2 g/l). Whilst in treatment with oestrogens, a sudden increase in serum liver enzymes and coagulopathy developed, together with the onset of auto-immune thyroiditis. Nonorgan speci®c auto-antibody determination revealed type Ia auto-immune hepatitis which required prompt steroid treatment. When LFTs improved, a liver biopsy was proposed but was refused by the parents. The remaining two patients (group 4) showed increased levels of serum liver enzymes before any treatment was started. Infectious or auto-immune hepatitis, coeliac disease, cystic ®brosis, a-1-antitripsin de®ciency and Wilson disease were ruled out. Sclerosing cholangitis was unlikely due to normal values of GGT, absence of anti neutrophil-cytoplasmic antibodies and to clinicallaboratory follow up: ultrasonography showed a mild hepatomegaly, liver biopsy revealed mild steato®brosis with fatty in®ltrate in both girls. In case 13, a spontaneous normalisation of LFTs occurred 1 year later. In case 14 liver damage seemed to be related to overweight (IBW 130%), since persistent normalisation of LFTs occurred only after weight reduction (IBW 118%). Among the remaining 56 TS patients, 3 girls with slightly increased serum AST levels (48.3 ‹ 0.6 U/L, range 48±49 U/L) and normal ALT and GGT showed increased levels of muscular enzymes (CK 675 ‹ 219; range 439±873 U/L; normal value <227 U/L). In one girl increased levels of CK occurred during GH therapy and returned to normal 4 months after treatment was stopped. In the second girl CK increased during oestrogen therapy but spontaneously normalised after 6 months. In the third patient the increase in CK was present at entry, before any treatment was started; she is now under evaluation to rule out primary muscular disease (data not shown). Discussion

Although multisystemic involvement characterizes TS [25, 27] liver abnormalities have not been reported to be

typical ®ndings of the syndrome. However, since 1966, several anecdotal cases of TS have suggested a possible linkage between X monosomy and liver involvement of varying severity including cirrhosis [1, 4, 6±8, 11± 13, 28, 30]. In our study population, increase in serum liver enzymes occurred in 20% of patients and was never observed before the age of 7 years. In the majority of cases (approx. 70%) it was drug-related and in 50% it was transient and self-limiting. In the remaining patients it required interruption of treatment, and in two cases a relapse occurred after resuming treatment. In a lower number of cases, liver disease was either auto-immunityrelated requiring steroid treatment or cryptogenic with a benign and self-limiting course. Although obesity was a frequent ®nding, it may have played an evident causal role in only one patient. Among the total number of patients treated with hormonal therapies, a consistent increase in serum liver enzymes was observed, particularly in girls treated with oestrogens (5/37, 13.5%) or oxandrolone (5/36, 13.8%), whereas an hepatotoxic e€ect was much lower in patients treated with GH (1/49, 2%). Wemme et al. [34] have recently shown that about 25% of patients with TS treated with oestrogens develop a considerable increase in hepatic enzymes, 3±6 months after the beginning of treatment, as opposed to 5% of normal women. Abnormalities in liver function secondary to oestrogens in our study were less frequent and normalised spontaneously without stopping treatment. Since oral oestrogen treatment has also been associated with more severe hepatic side-e€ects [24], low-dose transdermal 17-b-oestradiol [10] might be considered as an alternative treatment to prevent hepatotoxicity. Oxandrolone, an anabolic steroid, used alone or combined with GH in the treatment of short stature in TS, was occasionally found to increase serum liver enzymes in athletes [10]. Moreover Naera et al. [19] have reported a transient elevation of transaminases in 2 out of 32 (6%) TS girls treated with this hormone. In our study the rate of oxandrolone-related hepatic abnormalities was higher, although number and age of patients treated were comparable. Moreover the relationship between liver abnormalities and steroid hormone was con®rmed by normalisation of liver enzymes when the treatment was stopped, and by relapse in two girls who resumed therapy. Occurrence of other more severe hepatotoxic complications of anabolic hormone therapy was ruled out by normal ultrasonographic ®ndings, and by the benign clinical course and reversibility of the altered LFTs. A transient increase in transaminases and/or GGT has been reported in about 3% of children treated with GH [5], which is similar to our ®ndings in TS and also in a sample of 70 patients with GH de®ciency followed in our hospital (data not shown). This phenomenon is probably related to the e€ect of GH on cytochrome P450 or to possible hepatotoxic additives used in the preparation of the hormone [5]. In two of our

622

patients, GH possibly increased the hepatotoxic e€ect of oxandrolone. In some patients GH therapy may also be responsible for myositis [16, 35], however, serum CK levels were normal in all our 14 patients. By contrast, increased CK values were detected in 3 of the remaining 56 girls of our series of patients with TS, one of them being treated with GH and another still under evaluation for a primary myopathy [18, 21]. Patients with TS have higher incidence of autoimmune disorders than normal subjects [14]. In our study the increase in serum liver enzymes was related to coeliac disease in one girl, and to auto-immune hepatitis in another. In both, thyroid antibodies were also present. Coeliac disease today is well recognised as an auto-immune condition, often associated with other diseases having an auto-immune pathogenesis [31]. The association between coeliac disease, in¯ammatory colitis and primary cholangitis in a girl with TS [13] and a previous report of coeliac disease in another patient with TS [30] support the possibility that the liver involvement in this syndrome may also be related to an auto-immune disorder. An increased incidence of coeliac disease has been found in other chromosomal aberrations compared to the general population, indicating a possible predisposition to liver and intestinal disease in these patients [33]. Finally, obesity is a frequent ®nding in adolescent girls with TS [2, 23], and in our series was present in up to 50% of all patients. Although it has been recently recognised as a common cause (up to 25%) of liver abnormalities in normal children [32], obesity does not seem to represent a major single aetiological factor either in the TS literature or in our study population. Nevertheless, it may play a contributory or predisposing role since it was present in 70% of our patients with abnormalities of liver function. We found that the prevalence of liver abnormalities in paediatric and adolescent patients is much lower and more strictly related to hormonal treatment than in adults [29]. In most cases liver damage is frequently mild and apparently reversible. However, surveillance of liver function should be included in the management of girls with TS to detect and possibly treat other causes of liver damage. References 1. Andrade RJ, Alcantara R, Fraile JM, Lazo MD, Llamas A, Carmona C, Franquelo E (1995) Chronic asymptomatic intrahepatic cholestasis associated with Turner's syndrome. Gastroenterol Hepatol 18:375±378 2. Bernasconi S, Larizza D, Benso L, Volta C, Vannelli S, Milani S (1994) Turner's syndrome in Italy: familial characteristics, neonatal data, standards for birth weight and for height and weight from infancy to adulthood. Acta Paediatr 83:292±298 3. Carel JC, Mathivon L, Gendrel C, Chaussain JL (1997) Growth hormone therapy for Turner syndrome: evidence for bene®t. Horm Res 48 [Suppl 5]:31±34 4. Casais L, Pelaez JL, Ibarrola B, Calleja JL, Lopez Varela J, Perianes J (1966) Turner's syndrome with hepatic disease. Rev Clin Esp 101:134±136

5. Cesaretti G, Rossi A, Franchi G, Saggese G (1994) Hepatic side e€ects of growth hormone treatment. Riv Ital Pediatr (IJP) 20:537±540 6. Friedman E, Theodor E, Austein A, Sack J (1980) Cirrhosis in Turner's syndrome. Harefuah 98:210±211 7. Garavelli L, Donadio A, Banchini G, Fornaciari G, Plancher AC, Franchi F, Gardini G (1998) Liver abnormalities and portal hypertension in Ullrich-Turner syndrome. Am J Med Genet 80:180±182 8. Gardner LI (1974) Intrahepatic bile stasis in 45, X Turner's syndrome. N Engl J Med 290:406 9. Haupt HA, Rovere GD (1984) Anabolic steroids: a review of the literature. Am J Sports Med 12:469±484 10. Illig R, Decampo C, Lang-Mauritano MR, Prader A, Torresani T, Werder EA, Willi U, Schenkel L (1990) A physiological mode of puberty induction in hypogonadal girls by low dose transdermal 17-b-oestradiol. Eur J Pediatr 150:86±91 11. Ishiyama S, Makuuchi M, Ohta K, Yamazaki S, Hasegawa H, Watanabe S, Takayasu K, Moriyama N (1986) A case of cholangiocarcinoma and dysgerminoma associated with Turner's syndrome. Gan No Rinsho 32:433±439 12. Krivosheev AB (1990) Development of liver cirrhosis in female patients with Shereshevskii-Turner syndrome. Klin Med (Mosk) 68:95±96 13. Lacaille F, Canioni D, Bernard O, Fabre M, Brousse N, Schmitz J (1995) Celiac disease, in¯ammatory colitis and primary sclerosing cholangitis in a girl with Turner's syndrome. J Pediatr Gastroenterol Nutr 21:463±467 14. Larizza D, Martinetti Bianchi M, Lorini R, Maghnie M, Dugoujon JM, Cuccia Belvedere M, Severi F (1989) Autoimmunity, HLA, Gm and Km polymorphisms in Turner's syndrome. Autoimmunity 4:69±78 15. Ledinghen V de, Levillain P, Besson I, Palazzo L, Fabre M, Silvain C, Morichau-Beauchant M (1994) Nodular regenerative hyperplasia of the liver and Turner syndrome. Gastroenterol Clin Biol 18:898±899 16. Momoi T, Yamanaka C, Tanaka R, Yoshida A, Okumura M, Yamakura S, Takasaki Y, Sasaki H, Kawai M (1995) Elevation of serum creatinine phosphokinase during growth hormone treatment in patients with multiple pituitary hormone de®ciency. Eur J Pediatr 154:886±889 17. Moore B, Paterson M, Sturdee D (1987) E€ect of oral hormone replacement therapy on liver function tests. Maturitas 9:7±15 18. Morse RP, Rosman NP (1993) Diagnosis of occult muscular dystrophy: importance of the ``chance'' ®nding of elevated serum aminotransferase activities. J Pediatr 122:254±256 19. Naeraa RW, Nielsen J, Pedersen IL, Sorensen K (1990) E€ect of oxandrolone on growth and ®nal height in Turner's syndrome. Acta Pediatr Scand 79:784±789 20. National Center for Health Statistics NCHS Growth Charts (1976) Monthly vital statistics report, suppl (HRA) 25:76 21. Quan F, Janas J, Toth-Fejel S, Johonson DB, Wolford JK, Popovich BW (1997) Uniparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy. Am J Hum Genet 60:160±165 22. Radetti G, Mazzanti L, Paganini C, Bernasconi S, Russo G, Rigon F, Cacciari E (1995) Frequency, clinical and laboratory features of thyroiditis in girls with Turner's syndrome. Acta Pediatr Scand 84:909±912 23. Ranke MB, Subbe P, Majewski F, Bierich JR (1988) Spontaneous growth in Turner's syndrome. Acta Pediatr Scand [suppl] 323:22±30 24. Roberts EA (1994) Drug-induced liver disease in children. In: Suchy FJ (ed) Liver disease in children. Mosby St. Louis, pp 523±549 25. Saenger P (1996) Turner's syndrome. New Engl J Med 335:1749±1754 26. Salerno M, Job JC (1987) La taille dans le syndrome de Turner: correlations avec la taille des parents. Arch Fr Pediatr 44:863± 865 27. Staiano A, Salerno M, Di Maio S, Marsullo G, Marino A, Concolino D, Strisciuglio P (1996) Delayed gastric emptying: a

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32. Vajro P, Fontanella A, Perna C, Orso G, Tedesco M, De Vincenzo A (1994) Persistent hyperaminotransferasemia resolving after weight reduction in obese children. J Pediatr 125:239± 241 33. Vajro P, Cucchiara S, Vegnente A, Iorio R, Silva C de, Cipolletta L, Bianco MA (1998) Primary sclerosing cholangitis preceding Crohn's disease in a child with Down syndrome. Dig Dis Sci 43:166±169 34. Wemme H, Pohlenz J, Schonberger W (1995) E€ect of oestrogen/gestagen replacement therapy on liver enzymes in patients with Ullrich-Turner syndrome. Eur J Pediatr 154:807± 810 35. Yordam N, Kandemir N, Topaloglu H, Gogus S, Kucukali T (1994) Myositis associated with growth hormone therapy. J Pediatr 125:671

ANNOUNCEMENTS

9th International conference of the International Society for Research in Human Milk and Lactation (ISRHML) on ``Short and long term effects of breast feeding on child health''

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World Association for Infant Heath (WAIMH): 7th World Congress July 26±30, 2000 MontreÂal, Canada

7th Salzburg Weekend Seminar Oral Diseases in Children October 23±24, 1999

The World Association for Infant Mental Health (WAIMH) will hold its 7th World Congress in MontreÂal between July 26±30, 2000. The topic of the Congress will be Diversity: Challenges and Opportunities in Infancy. The theme will be discussed within the context of brain-behaviour, developmental psychopathology, culture, environmental health, caregiving and special babies/special caregivers. This Congress is relevant for all individuals working with preschool children

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Guest lecturer: Prof. Dr. C. Scully, Eastman Dental Institute, London

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