8/19/2019 CBP Articol

1/4

Pediatric-Onset Primary Biliary Cirrhosis

YASER DAHLAN,* LESLIE SMITH,‡

DOUG SIMMONDS,§

LARRY DOUGLAS JEWELL,

IAN WANLESS,¶

E. JENNY HEATHCOTE, and VINCENT GORDON BAIN**Division of Gastroenterology, Department of Medicine,  ‡Department of Pediatrics, and  Department of Pathology, University of Alberta,

Edmonton, Alberta;  ¶ Toronto Western Hospital, University of Toronto, Toronto, Ontario; and  §Red Deer Regional Hospital, Red Deer, Canada

Unlike other autoimmune liver diseases, primary biliary

cirrhosis (PBC) has not been reported in childhood. We

report 2 cases of PBC diagnosed at 16 and 15 years of

age, respectively. The first girl was noted to have in-

creased liver enzyme levels at 16 years of age. Antimi-

tochondrial antibody (AMA) was strongly positive, and

serum quantitative immunoglobulin M level was 8.26g/L (normal, 0.6–3 g/L). A liver biopsy specimen

showed stage II PBC. Despite treatment with ursodeoxy-

cholic acid, she developed progressive cholestasis, in-

tractable pruritus, and a significant sensory neuropathy

and weight loss eventually requiring liver transplanta-

tion. Her mother had PBC/autoimmune overlap syn-

drome and underwent successful liver transplantation at

34 years of age. The second girl had persistently ele-

vated liver enzyme levels following cholecystectomy at

15 years of age for symptomatic cholelithiasis. Endo-

scopic retrograde cholangiopancreatography showed no

abnormalities. AMA was positive at 1:160, and serum

quantitative immunoglobulin was 6.96 g/L. A liver bi-

opsy specimen showed stage II PBC, and her liver en-

zyme levels almost normalized after starting treatment

with ursodeoxycholic acid. In conclusion, we present 2

liver biopsy–confirmed cases of pediatric-onset AMA-

positive PBC. With increased awareness of early-onset

PBC, further pediatric cases may be discovered.

Primary biliary cirrhosis (PBC) is a liver disease char-acterized by destruction of the intralobular bileducts that may eventually lead to cirrhosis and liver

failure. In contrast to other types of liver disease, 95% of patients with PBC are women.1,2

Fatigue and pruritus are the most common presenting

symptoms of PBC; however, as many as 50% of patients

diagnosed are asymptomatic and are discovered inciden-

tally to have elevated liver enzyme levels in a cholestatic

pattern.3,4 Rarely, patients present with advanced disease

manifested by esophageal variceal hemorrhage, ascites, or

hepatic encephalopathy.

The prevalence and possibly the incidence of PBC are

increasing. In a population-based study performed in the

United Kingdom, it was estimated that the incidenceincreased from 23 cases per 1 million in 1987 to 32 cases

per 1 million in 1994.5 It is possible that these increases

are related to better detection and increased awareness

rather than a true increase in disease incidence. The

diagnosis of PBC is usually made between 30 and 50

years of age, but the disease has been reported in women

as young as 22 years and as old as 93 years. To our

knowledge, it has not been reported in childhood.1–3 Wereport 2 cases of well-documented PBC newly diagnosed

in girls aged 16 and 15 years, respectively.

Case Report

Case 1

The first patient came to medical attention in

1992 when she was 11 years old because of abdominal

pain. Her liver enzyme levels were as follows: total

bilirubin, 16   mol/L (normal,  21   mol/L); alkaline

phosphatase, 272 U/L (normal, 100–500 U/L for chil-dren); serum aspartate aminotransferase, 48 U/L (normal,

7–40 U/L); and serum alanine aminotransferase, 30 U/L

(normal,  50 U/L). Serum   -glutamyltransferase level

was not measured. In 1995, at 15 years of age, she

continued to have abdominal pain. Repeat testing

showed only an increased  -glutamyltransferase level of 

107 U/L (normal, 10–65 U/L). Ultrasonography of the

abdomen showed increased liver echotexture but was

otherwise normal. Antimitochondrial antibody (AMA)

was strongly positive at a titer of 1:800; serum quanti-

tative immunoglobulins (Ig) showed IgM to be 8.26 g/L(normal, 0.6 –3 g/L), IgG was normal at 13.54 g/L

(normal, 6.94–16.18 g/L), and IgA was normal at 1.85

g/L (normal, 0.70 –7.00 g/L). Antinuclear antibody,

smooth muscle antibody, and liver/kidney microsomal

antibody were all negative. Serum  1-antitrypsin, cop-

per, and ceruloplasmin levels were normal. Serology for

hepatitis A, B, and C was negative. A liver biopsy

 Abbreviations used in this paper:  AMA, antimitochondrial antibody;

PBC, primary biliary cirrhosis.

©  2003 by the American Gastroenterological Association

0016-5085/03/$30.00doi:10.1053/S0016-5085(03)01358-1

GASTROENTEROLOGY 2003;125:1476 –1479

8/19/2019 CBP Articol

2/4

specimen when the patient was 16 years old showed stageII PBC (Figure 1). Her mother had PBC/autoimmune

overlap syndrome diagnosed at 30 years of age and

subsequently underwent liver transplantation at 34 years

of age. Her maternal grandmother and great-grand-

mother died from liver cirrhosis of unknown cause. The

patient was started on ursodeoxycholic acid 1250 mg/day

in 1996; however, her liver enzyme levels increased

progressively. By 1999, at age 18 years, her liver enzyme

levels were as follows: alkaline phosphatase, 660 U/L;

serum alanine aminotransferase, 105 U/L; serum  -glu-

tamyltransferase, 372 U/L; and total bilirubin, 24

mol/L. She had developed progressive fatigue, pruritus,

and weight loss of 100 lb from 250 lb despite a normal

appetite and no evidence of an eating disorder. She had

peripheral neuropathy characterized by a sensation of 

numbness in the upper and lower extremities in a glove-

and-stocking distribution. She had   fine motor control

impairment manifested by dif ficulty with handwriting.

Furthermore, she fell frequently and reported clumsiness.

She had not experienced any pain. There was no history

of exposure to drugs or toxic agents.

Initial examination did not show jaundice or xantho-

mata or other skin changes except excoriations frompruritus. Her liver and spleen were not palpable. She had

gross impairment of proprioception sense at the toes,

ankles, knees,   fingers, and wrists, accompanied by re-

duced vibration sense distal to the hips and elbows and

a positive Romberg’s sign. Perception of temperature

and pinprick were normal. Deep tendon reflexes were

absent.

Laboratory values were as follows: hemoglobin, 110

g/L; mean corpuscular volume, 73 fL; iron, 7   mol/L

(normal, 6 –28   mol/L); ferritin, 150   g/L (normal,

12–300  g/L); 25-OH vitamin D, 12 nmol/L (normal,25–200 nmol/L); vitamin A, 1.2  mol/L (normal, 1.5–

3.5  mol/L); and albumin, 32 g/L (normal, 37–51 g/L).

However, she had a normal international normalized

prothrombin ratio and normal levels of vitamin E, vita-

min B12, folate, thyroid-stimulating hormone, calcium,

and urine trace elements. A fasting lipid profile showed

the following: cholesterol, 7.33 mmol/L (desirable,

4.60 mmol/L); serum triglycerides, 0.74 mmol/L (de-

sirable, 2.30 mmol/L), low-density lipoprotein choles-

terol, 6.09 mmol/L (desirable,   3.00 mmol/L); and

high-density lipoprotein cholesterol, 0.90 mmol/L (de-

sirable,   0.90 mmol/L). Total plasma homocysteine

level was normal. Electrophysiology studies showed nor-

mal motor function but either absent or markedly di-

minished amplitude and velocity of sensory neural re-

sponses. A sural nerve biopsy specimen showed

moderately severe chronic axonal neuropathy selective for

large-diameter   fibers with moderate to marked loss of myelinated fibers without xanthomata. Additional inves-

tigations performed in view of the patient’s weight loss

showed a negative endomysial antibody and normal gas-

troscopy, small bowel biopsy, colonoscopy (including

terminal ileal examination and biopsy), and 72-hour fecal

fat collection. A test for human immunodeficiency virus

was negative. Bone mineral density was normal. Repeat

abdominal ultrasonography for persistent right upper

quadrant pain showed cholelithiasis with no signs of 

acute cholecystitis and a normal biliary tree. She under-

went laparoscopic cholecystectomy in 2001 at the age of 

20 years with improvement of her abdominal pain. For

her neuropathy, she was started on vitamin E 200 IU

twice daily and then intravenous immunoglobulin with

no significant improvement. Despite treatment with ur-

sodeoxycholic acid, her liver enzyme levels increased

progressively with a peak alkaline phosphatase level of 

1328 U/L in 2001; however, she did not display clinical

features of portal hypertension. Magnetic resonance

Figure 2.   Portal tract showing a partially necrotic duct surrounded by 

granulomatous inflammation. The   arrow    indicates a point of ductrupture. Masson’s trichrome stain.

Figure 1.   The biopsy specimen shows a damaged segmental bile

duct with a portal and periportal lymphoid infiltrate and bile ductular

reduplication consistent with stage II PBC. H&E stain.

November 2003 PEDIATRIC–ONSET PBC 1477

8/19/2019 CBP Articol

3/4

cholangiopancreaticography showed no dilatation or ir-

regularity of the intrahepatic or extrahepatic biliary sys-

tem, hepatic or splenic enlargement, or any focal liver

mass.

She had intractable pruritus and she continued to lose

weight despite a good appetite. Her peripheral neurop-

athy slowly progressed. She sustained frequent falls. In

April 2002, she underwent successful liver transplanta-

tion with no complications and was discharged home on

tacrolimus 3 mg twice daily and mycophenolate mofetil

1000 mg twice daily. She has done well postoperatively

and has normal liver enzyme levels 1 year after trans-

plantation. She has continued to improve with a 20-kg

weight gain and no further pruritus. Her peripheral

neuropathy is progressively improving, and there have

been no further falls. There has also been steady improve-

ment in her fine motor movements, but her electrophysi-ologic studies are unchanged. Histologic examination of 

the explanted liver showed typical features of stage IV

PBC.

Case 2

The second patient presented with gallstones

causing biliary-type pain at 15 years of age. She under-

went a laparoscopic cholecystectomy but had postchole-

cystectomy abdominal pain and underwent endoscopic

retrograde cholangiopancreatography, which showed no

abnormalities. Liver enzyme levels 1 year later (in 1999)when she was 16 years old were as follows: alkaline

phosphatase, 204 U/L; serum aspartate aminotransferase,

163 U/L; and serum bilirubin, normal. The levels were

still elevated 2 months later. She developed Raynaud’s

phenomenon, mild sicca symptoms including dry eyes

and dry mouth, and symptoms of gastroesophageal reflux

but no other symptoms of the CREST syndrome. She had

a normal barium swallow and esophageal motility studies

but a markedly positive Bernstein test. She gives no

history of pruritus or weight loss and remains energetic.

There was no family history of liver disease or autoim-mune disease. Examination showed an overweight young

woman at 210 lb. She was anicteric, and there were no

stigmata of chronic liver disease or lymphadenopathy.

There was no palpable hepatosplenomegaly.

Additional investigations showed the patient to be

AMA positive in a titer of 1:160, serum IgM level of 

6.96 g/L (normal, 0.6 –3 g/L), and normal serum IgG and

IgA levels; antinuclear antibody was positive at 1:320

titer. Smooth muscle antibody, anti–liver/kidney micro-

somal antibody, and serology for hepatitis A, B, and C

were all negative. Serum levels of 1-antitrypsin, copper,and ceruloplasmin were normal, as was her thyroid-

stimulating hormone level. In July 2000, at 17 years of age,

a liver biopsy specimen showed stage II PBC (Figure 2).

She was started on ursodeoxycholic acid 2 g/day, and

her liver enzyme levels almost normalized as follows:

total bilirubin, 8.0   mol/L; alkaline phosphatase, 109

U/L; serum aspartate aminotransferase, 57 U/L; serum

alanine aminotransferase, 58 U/L; and  -glutamyltrans-

ferase, 74 U/L. Omeprazole was given for gastroesopha-

geal reflux, and her symptoms markedly improved.

Discussion

We present 2 cases of PBC with diagnoses at the

ages of 15 and 16 years. The diagnoses were based on

increased liver enzyme levels with a pattern typical of 

anicteric cholestasis, positive AMA, and typical hepatic

histologic   findings. Other causes of chronic cholestasiswere considered, but the positive AMA in high titer,

high IgM level, negative smooth muscle antibody and

anti–liver/kidney microsomal antibody, and liver biopsy

findings in both cases strongly supported the diagnosis of 

PBC. Both patients were overweight, raising the possi-

bility of nonalcoholic fatty liver disease, which has been

described in obese children6,7; however, this was not

supported by liver biopsy   findings in either case. Both

patients had early-onset cholelithiasis; however, the prev-

alence of cholelithiasis has been reported to be high in

PBC.8 Biliary ductal stones were excluded in both cases.

The  first patient had a family history of PBC, which

prompted early diagnosis by measurement of AMA when

just the  -glutamyltransferase level was elevated. In ad-

dition to young age at presentation, the unusual features

of this case include sensory neuropathy and profound

weight loss. Extensive investigations, including nerve

biopsy, did not show an etiology. Although her serum

vitamin E levels were normal, she was treated with

high-dose oral supplementation because of the reported

association between vitamin E deficiency and neuropathy

in PBC9–11; however, no objective response was observed.

She lost weight despite a good appetite and in theabsence of any eating or overt metabolic disorder.

PBC has not been previously reported in childhood;

however, other diseases considered autoimmune in etiol-

ogy such as autoimmune hepatitis and primary sclerosing

cholangitis are well recognized as causes of chronic liver

disease in childhood. The reason for early presentation in

these 2 cases is unknown, but there is a strong genetic

predisposition in the  first case.

In summary, we have presented 2 well-documented

cases of pediatric-onset PBC with follow-up of 7 and 4

years since diagnosis, respectively. However, the long-term natural history and prognosis remains unknown.

1478 DAHLAN ET AL. GASTROENTEROLOGY Vol. 125, No. 5

8/19/2019 CBP Articol

4/4

With increased awareness of early-onset PBC, further

pediatric cases may be discovered.

References

1. Sherlock S, Scheuer PJ. The presentation and diagnosis of 100patients with primary biliary cirrhosis. N Engl J Med 1973;289:

674– 678.

2. Kaplan MM. Primary biliary cirrhosis. N Engl J Med 1996;335:

1570 –1580.

3. Balasubramaniam K, Grambsch PM, Wiesner RH, Lindor LD,

Dickson ER. Diminished survival in asymptomatic primary biliary 

cirrhosis. A prospective study. Gastroenterology 1990;98:1567–

1571.

4. Tornay AS Jr. Primary biliary cirrhosis: natural history. Am J Gas-

troenterol 1980;73:223–226.

5. James OFW, Bhopal R, Howel D, Gray J, Burt AD, Metcalf JV.

Primary biliary cirrhosis once rare, now common in the United

Kingdom? Hepatology 1999;30:390 –394.

6. Kinugasa A, Tsunamoto K, Furukawa N, Sawada T, Kusunoki T,

Shimada N. Fatty liver and its   fibrous changes found in simpleobesity of children. J Pediatr Gastroenterol Nutr 1984;3:408–

414.

7. Manton ND, Lipsett J, Moore DJ, Davidson GP, Bourne AJ, Couper

RT. Non-alcoholic steatohepatitis in children and adolescents.

Med J Aust 2000;173:476 – 479.

8. Conte D, Barisani D, Amio GP, Fraquelli M, Bianchi PA. Choleli-

thiasis in cirrhosis: analysis of 500 cases. Am J Gastroenterol

1991;86:1629–1632.

9. Charron L, Peyronnard JM, Marchand L. Sensory neuropathy as-sociated with primary biliary cirrhosis. Histologic and morphomet-

ric studies. Arch Neurol 1980;37:84– 87.

10. Knight RE, Bourne AJ, Newton M, Black A, Wilson P, Lawson MJ.

Neurologic syndrome associated with low levels of vitamin E in

primary biliary cirrhosis. Gastroenterology 1986;91:209–211.

11. Jeffrey GP, Muller DP, Burroughs AK, Matthews S, Kemp C,

Epstein-Metcalfe TA, Southam E, Tazir-Melboucy M, Thomas PK,

et al. Vitamin E deficiency and its clinical significant in adults with

primary biliary cirrhosis and other forms of chronic liver disease.

J Hepatol 1987;4:307–317.

Received May 27, 2003. Accepted August 14, 2003.

Address requests for reprints to: Vincent Gordon Bain, M.D., Univer-

sity of Alberta, 205, College Plaza, 8215-112 Street, Edmonton, Al-berta, Canada T6G 2C7. e-mail: vince.bain@ualberta.ca; fax: (780)

492-8130.

November 2003 PEDIATRIC–ONSET PBC 1479