Delayed puberty in girls having biliary atresia

Delayed Puberty in Girls Having Biliary Atresia By Miwako Nakano, Morihiro Saeki, and Kazuhiko Hagane Tokyo, Japan Q Biliary atresia patients have several problems even after undergoing successful Kasai operation. Fourteen female patients have been followed for over 12 years after successful Kasai original portoenterostomy procedures. The oldest patient is 21 years of age. All patients are jaundice-free, but 10 patients have a history of esophageal varices and/or hypersplenism, Five patients complain of menstrual disorders. The average age of menarche was delayed 1 year, 9 months, compared with Japanese controls. Two cases of 11 (18.2%) presented primary amenorrhea after 14 years, 6 months, which is mean + 2SD of Japanese controls. Four cases of 11 136.4%l showed secondary amenorrhea. Unestablished menstrual cycles after 2 years of menarche w e r e observed in two patients of nine (22.2%). Four cases had regular menstruation. Five patients showed delay in the development of pubic hair and breasts. Six patients showed atypical body height velocity pattern that showed no peaking, and one patient showed no growth spurt. All the patients with amenorrhea had portal hypertension. In hormonal evaluation, the patients with menstruation showed normal or slightly good reaction of luteinizing hormone and follicle stimulating hormone in the luteinizing hormone-releasing hormone test, having normal to high estradiol levels. The patients with menstrual abnormality showed overreaction of LH, having normal estradiol levels. 9 1990 by W.B. Saunders Company. INDEX WORDS: Biliary atresia; delayed puberty; amenorrhea.

FTER KASAI hepatoportoenterostomy, many biliary atresia patients can be expected to survive. The number of surviving cases is increasing with sophisticated operative technique and better postoperative management. Portal hypertension that may develop afterward in jaundice-free cases can also be managed successfully by both surgical or noninvasive methods. However, because we know little about long-term follow-up because of the small number of patients, several problems have been observed unexpectedly. One of them is delayed puberty or hypogonadism observed in female patients. We reported the case of one patient having secondary amenorrhea in 1986.1

A

After this case, we have noticed five patients with menstrual abnormalities. This is what prompted us to investigate the menstrual condition of these patients in order to improve their social condition and our knowledge of the postoperative evolution of these patients. MATERIALS AND METHODS Twenty-five patients have been followed over 12 years after successful surgery for biliary atresia. All underwent the Kasai original Roux-en-Y portoenterostomy. Of this group, 14 were females, of ages ranging from 12 to 21 years. There were no deaths after 12 years of age. All the patients have a normal social life. Three patients are working as office clerks. Two work full-time and one works parttime. Eleven patients are studying: two go to college, three go to high school, five go to junior high school, and one is an elementary school student. Eight patients have not been hospitalized except for regular examination after 12 years of age. Others have histories of admissions on account of planned treatment or emergency episodes due to liver abnormalities. In everyday life, 11 patients have no limitations. Two patients, including one with percutaneous transhepatic cholangiography (PTC) drainage tube and one with bronchial asthma, avoid gymnastics classes. One patient who is working avoids full exercise. Two patients complain of easy fatigability. Retrospective clinical evaluation was performed in these 14 patients over 12 years of age regarding age of menarche, menstruaI condition, development of breasts and pubic hair, and growth of body height. Liver condition was evaluated. Hormonal evaluation was also performed (luteinizing hormone [LH]-reteasing hormone [RH] test in 10 cases, estrogen level in 1 l cases).

RESULTS

Menarche and M e n s t r u a l Condition

From the Department of Surgery, National Children's Hospital, Tokyo, Japan. Presented at the 22nd Annual Meeting of the Pacific Association of Pediatric Surgeons, Portland and Sun River, Oregon, May 22-26, 1989. Address reprint requests to Miwako Nakano, MD, Department of Surgery, National Children's Hospital, 3-35-31, Taishido, SetagayaKu, Tokyo 154, Japan. 9 1990 by W.B. Saunders Company. 0022-3468/90/2507-0027503.00/0

Menstrual conditions at present are studied (Table 1). Three patients have not yet had their first menstruation. As the age of first menstruation (mean + 2SD) of Japanese controls is 14 years 6 months by the data from Hibi, 2 the number of cases thought to have primary amenorrhea is two of 11 cases (18.2%). Four patients had secondary amenorrhea, three of them had a few menstrual cycles after menarche following years of amenorrhea, and one had a period of irregular menstrual cycles. The rate of secondary amenorrhea was 36.4% (4/11). Three patients present irregular menstrual cycles that show delays in interval and sometimes skip l month. One of these patients is within 1 year of menarche. Therefore, two of nine patients who had menarche 2 years ago present irregular menstruation defined as unestablished menstrual cycle after 2 years of menarche. The rate is 22.2% (2/9). Four patients have almost regular menstrual cycles including one patient whose menarche started several months ago.

808

Journal of Pediatric Surgery, Vol 25, No 7 (July), 1990: pp 808-811

DELAYED PUBERTY IN GIRLS WITH BA

809

T e b l e 1. Menstrual Conditions of the Girls With BA Over 12 Years Old Menstrual

No. of

Cycles

Cases

12

1

No menarche

3

Secondary amenorrhes

4

Irregular cycles Regular cycles

3 4

Age (years) 13

14

15

1

1

16

17

18

1

1

1 1

19

20

21

1

1

1*

1

1

1

1

* Just started.

Menarche is delayed in biliary atresia patients evaluated by percentage of postmenarcheal girls (Fig 1). This method is useful to evaluate the groups constituted by various ages in puberty. The control curve are quoted from the survey of 298 school girls at Tokyo in 1967. 2 The pattern of the curve of the biliary atresia group is mildly flattened, which represents the abnormalities of this group. The age of 50% of postmenarcheal girls, which corresponds to the mean age of menarche, is 14 years 3 months in the biliary atresia group and 12 years 6 months in the control group. There is a 1 year 9 months delay period in the biliary atresia group. Because the survey of the controls was performed about 20 years ago, the control curve must shift toward the left side at present due to improved nutritional and social conditions. Therefore, this delay in the biliary atresia group is thought to be underestimated.

Body Height Growth Velocity The longitudinal height growth chart was examined, then a height velocity was estimated by the "eye-fit method" in each patient. Normal Japanese control data published in 1988 s show growth spurt from 9.41 years and sharp peaking at 11.19 years. Growth rate at the peak is 8.74 cm per year. Four patients, one with regular menstruation, two with irregular menstruation, and one with secondary amenorrhea, showed almost normal growth pattern. Six cases, two of them with regular menstruation, three with secondary amenorrhea, and one with no menarche, showed atypical oJ r-

S/"

Pubic Hair

Breast and Pubic Hair Development Breast and pubic hair development is also delayed in some patients with amenorrhea (Fig 2). 3 Because we do not have appropriate control data for Japanese girls, the data from Marshall and Tanner, 4 reported in 1969, have been used as controls. Two patients with primary amenorrhea and two with secondary amenorrhea showed apparent delay of both breast and pubic hair 100-

development. One patient with secondary amenorrhea showed delay in pubic hair development only.

C:

Mean

5

N

4

~

3

C

c

F--

2

1

1'1

I'3

1'2

6 ~--

. . . . . . . . . . . . . . . . . . . . . . . .

Mean+2SD

Age

(3.) tO

B Feast

r'9

-

9 s/o 7

Mean .o

.

,0 o"

if)

50-

J o

.........

Q. O

,~ .~,'-. . . . . . . . . . .

13

t;ir,

~

4-

~

3

~

2

S S

ll

j/"

fi

f2

13

i'4

T5

10

lz

age(yrs.)

1

...o m,,

f

p

i'0

9

, ,g

_

~,~'~

Mean+2SD

d

fl

S

9

cr

12 f3 14 15

17 18

Age Fig 1.

Percent of postmenarchal girls by age. Normal controls

( H . n = 2981 were surveyed in 1967 at Ota-ku, Tokyo. The number of patients is given for each circles of the biliary atresia patients c u r v e (O---O}. T o t a l n u m b e r is 15, because one patient

who underwent surgery in another hospital and was referred for follow-up is included.

Fig 2. The age-related boundaries of normal pubic hair and b r e a s t development and pubertal stages of bUiary atresia patients. [J, Regular cycles; m, irregular cycles; ~ , secondary amenorrhea; &, no menarche; O----O, normal pubic hair d e v e l o p m e n t ; O n - O , normal breast d e v e l o p m e n t ,

810

NAKANO, SAEKI, AND HAGANE

velocity pattern, which showed no peaking, so in this group the peak age could not be determined. The body height itself is ranged from the line of - 2 S D to over + 2SD. One patient with primary amenorrhea had no growth spurt at all from childhood, which indicates a definite delay of puberty in this patient and her height was also under - 2SD.

Three patients had episodes of jaundice, defined as serum total bilirubin level over 4.0 mg/dL, after 10 years of age. All of them showed primary or secondary amenorrhea. One patient had an episode of ascending cholangitis due to a bile lake, which developed into liver abscess and was treated by PTC drainage. She presented with primary amenorrhea. Esophageal varices were found in nine cases. Six of them were treated by esophageal transection or endoscopic sclerotherapy. Three cases showed spontaneous regression. Ten patients showed hypersplenism, defined as platelet count lower than 100 x 103. Five of them underwent splenectomy, one underwent partial splenic embolization, and two were treated conservatively. All the patient with no menarche or secondary amenorrhea showed esophageal varices and/or hypersplenism (Table 2). Two of three patients with irregular menstrual cycles had portal hypertension. Serum bile acid levels, one of the most sensitive indicators of bilirubin metabolism, were evaluated (Table 2). Four patients with regular menstrual cycles showed relatively low bile acid levels. Ten patients with menstrual abnormalities showed a variety of bile acid levels ranging from I0 to 187 ~mol/L. L H R H Test and Estrogen Levels

The patients with regular menstrual cycles showed an almost normal to slightly overreaction of LH and a normal pattern of follicle stimulating hormone (FSH) (Fig 3). 6 The patients with menstrual abnormalities showed high levels of LH and overreaction of LHRH. FSH showed almost normal to mild over-reaction, except for one case that showed high levels. Serum estradiol level with menstrual cycles were ranged from 61 pg/mL to 318 pg/mL. Normal value Table 2. Menstrual Disorder in BA Girls; Serum Bile Acid Levels

Cycles

Regular Irregular cycles Secondary amenorrhea No menarche

Serum Bile Acid Levels (p,mol/L) <50 51-100 >101 4 2

1

1 1

No. of Cases

With Portal Hypertension(%)

1

1 (25) 2 (77)

3 1

4 (100) 3 (100)

W i t h Menstruation(follicular phase)

60mlU/m~

80

FSH

"1 LH-RH

60

40

40 1 ~'

20

Liver Function and Menstrual Conditions

Menstrual

mlU/ms

.............. 0

30

60

....

.....................

201 90

120

0

30

60

90

(rain.)

300

mlU/m~

120 (rain.)

Amenorrhea group //

1,

/

250 mlU/m~ , - - ~n i

200

"'.

xt

,'

1

150 100 50 0

30

60

90

120 (rain,)

0

30

60

90 !20 (rain.)

Fig 3. The results of the LHRH test. Shadowed area shows the normal range of Japanese controlsfl

of estradiol in Japanese women is 31 +_ 18 pg/mL in the follicular phase and 150 to 400 pg/mL in the ovulatory phase. 7 The high estradiol levels in these patients did not correlate always with the ovulatory day by other data. Therefore, estradiol in these patients was thought to be rather high. Estradiol levels of the patients with amenorrhea ranged from 23.8 to 90.6 pg/mL. Estrogen levels ranged from 5.0 to 109 pg/mL in patients with menstrual cycles and 12.3 to 90.0 pg/mL in patients with amenorrhea. The normal value in Japanese women ranges from 5 to 81 pg/mL, s DISCUSSION

Delayed puberty was observed in the biliary atresia patients of this series. Not much is known about the prognosis of biliary atresia because of the small number of surviving cases. Kasai reported long-term survivors of biliary atresia over 10 years old. In his report, 10 girls experienced menstruation and seven had regular cycles. 9 We also could not find any good report concerning the onset of puberty in patients with chronic liver disease such as metabolic liver disease. With regard to hormonal metabolism, it is said that liver diseases are associated with increased production of estrogen from circulating androgens in both men and women leading to gynecomastia in men. i~ Therefore, precocious puberty might be expected in biliary atresia patients with liver chirrhosis showing high

DELAYED PUBERTY IN GIRLS WITH BA

811

estrogen level. On the contrary, in this series, biliary atresia patients show delayed menarche, menstrual abnormalities, delayed development of breasts and pubic hair, and atypical height velocity pattern, which suggests delayed puberty, or hypogonadism. According to other reports, patients with cirrhosis fail to produce elevated level of L H and have abnormally poor release of L H a n d F S H in r e s p o n s e to clomiphene. ~1 However, in the L H R H test, L H levels of these bitiary atresia patients were rather high and showed good reactions, and F S H showed almost normal to mild overreaction. This type of reaction was similar to a pattern associated with polycystic ovary syndrome. One case showed high levels of both L H and FSH, which is compatible with ovarian resistance syndrome or ovarian failure. Others presenting good reactions by L H R H were also thought to have the similar situation of mild degree of gonadotropinresistant ovary because polycystic ovary syndrome was excluded clinically. In these conditions of hypergo-

nadotropic hypogonadism, estrogen levels must be low. However in this series, serum estrogen levels were normal to high, which is compatible with the high estrogen levels in liver disease. Patients with menstruation showed normal reaction in the L H R H test and normal to high estrogen levels. On the other hand, patients with amenorrhea showed overreaction in the L H R H test and normal to mild increase of estrogen levels. It is suggested that the amenorrhea group needs more estrogen to start or maintain menstruation. In fact, one patient with secondary amenorrhea had an episode of menstruation after progesterone treatment. Although we do not know much about this pathological condition of delayed puberty, it is suggested that the estrogen of biliary atresia patients is an inactive form because of liver d a m a g e a n d / o r target organs of estrogen become refractory after long exposure to relatively high estrogen levels. Further examination and clinical evaluation are needed to explain this phenomenon in female patients with biliary atresia.

REFERENCES

1. Saeki M, Ogata T, Nakano M: Problems in long-term survivors of biliary atresia, in Ohi R (ed): Biliary Atresia. Tokyo, Japan, Professional Postgraduate Services, 1987, pp 287-293 2. Hibi I: Survey on the obese school children. A report at Ota-ku, Tokyo, supported by the Board of Education, 1968, pp 20-21 3. Soules MR: Adolescent amenorrhea. Pediatr Clin North Am 34:1083-1103, 1987 4. Marshall WA, Tanner JM: Variation in pattern of pubertal changes in girls. Arch Dis Child 44:291-303, 1969 5. Tanaka T, Suwa S, et al: Longitudinal standards for growth rate for children. Clin Endocrinol (Tokyo) 17:621-624, 1988 6. Aono T, Minamigawa J, Miyake A, et al: LH-RH test. Jpn J Clin Med 38:984-993, 1980

7. Furuhashi N, Takahashi T, Kohno H: Estradiol (E2). Jpn J Clin Med 43:943-945, 1985 8. Furuhashi N, Takahashi T, Kohno H: Estrone (E 0. Jpn J Clin Med 43:940-942, 1985 9. Kasai M, Ohi R, Chiba T: Long-term survivors after surgery for biliary atresia, in Ohi R (ed): Biliary Atresia. Tokyo, Japan, Professional Postgraduate Services, 1987, pp 277-280 10. Hsueh A: Ovarian hormone synthesis, circulation, and mechanism of action, in DeGroot LJ (ed): Endocrinology. Philadelphia, PA, Saunders, 1989, pp 1929-1939 11. Grand R J, Ulshen MH: Clinical and physiologiealabnormalities on hepatic function. Pediatr Clin North Am 22:897-928, 1975