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Notable Cases
Non-alcoholic steatohepatitis in children and adolescents
Nicholas D Manton, Jill Lipsett, David J Moore, Geoffrey P Davidson
Anthony J Bourne and Richard T L Couper
MJA 2000; 173: 476-479
We describe 17 children with non-alcoholic steatohepatitis. All had
elevated levels of serum liver enzymes and 16 were morbidly obese.
Liver biopsy showed variable steatosis and fibrosis in nine
patients. At follow-up, 12 of 14 patients had persistent morbid
obesity and 11 had elevated liver enzyme levels.
Methods -
Clinical findings -
Discussion -
References -
Authors' details
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Non-alcoholic steatohepatitis (NASH) is well recognised in adults.
It occurs with obesity, insulin resistance or insufficiency and
associated metabolic abnormalities such as hyperlipidaemia and
hyperglycaemia. NASH also occurs in childhood, but, in this group, it
is not as well characterised. Obese, prepubertal children are at risk
of liver disease, with liver biopsies showing fatty change,
inflammation and fibrosis with progression to necrosis and
cirrhosis.1-4 We report here selected features of NASH in children presenting to a
tertiary care child and adolescent hospital. We aimed to
determine:
- the demographic details of these children;
- the presenting clinical signs and symptoms, and any associated
conditions;
- the biochemical and radiological findings;
- the range of histopathological findings with liver biopsy; and
- the clinical and biochemical outcomes.
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Patient identification | |
Patients were retrospectively identified by searching a
computerised database of histopathological specimens at the
Women's and Children's Hospital (formerly the Adelaide Children's
Hospital) for the years 1972-1999. All liver biopsies in this period
were reviewed, and cases selected if the liver biopsy showed
steatosis. Clinical details, investigations and disease course
were determined (retrospectively) from the hospital records. The
patients' weight/ideal body weight ratios were calculated using
charts from the National Centre for Health Statistics Growth Curves
for Children.5 |
Exclusion criteria | |
Patients were excluded when a known cause of steatosis was present.
These included inborn errors of metabolism, viral hepatitis,
autoimmune hepatitis, total parenteral nutrition, cystic fibrosis
or Wilson's disease.
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Liver biopsies | |
Fatty change was described as macrovesicular or microvesicular, and
the extent of steatosis was graded as mild, moderate or severe. The
presence of inflammation was graded as mild, moderate or severe.
Fibrosis was described (eg, portal tract fibrosis, perisinusoidal
fibrosis, septal fibrosis, bridging fibrosis, cirrhosis). In all
cases, tissue was submitted for electron microscopy.
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Seventeen patients were identified: 11 males and six females. Most
(14 of 17) were identified in the past five years. Mean age ± SD was 11.7 ±
1.7 years (range, 9-15 years). Persisting intermittent abdominal
pain (10 patients) was the commonest presenting symptom. Two
patients were identified after hepatomegaly on review for known
insulin dependent diabetes mellitus (IDDM) and, in two patients,
abnormal liver function tests (LFTs) were detected incidentally
during investigation for apparently unrelated problems (seizure
and diarrhoeal illness). One patient (Patient 17) was asymptomatic
and was investigated because his twin brother (Patient 13) was found
to have NASH. Five patients had relevant family history: one had
parents and brother with morbid obesity; one had a family history of
Gilbert disease, a disorder of bilirubin conjugation; one had a
father with cirrhosis; and two were twins with obesity and abnormal
liver function test results.
Box 1 summarises the clinical, biochemical and radiological
findings for our patients. Sixteen of the 17 patients were morbidly
obese (> 24% over ideal body weight [IBW]; mean, 53%; range, 25% to
118% over IBW). Eight patients had hepatomegaly either on clinical or
ultrasound examination. Alanine aminotransferase (ALT) was
elevated in all patients, gamma glutamyl transferase (GGT) was
elevated in eight, and alkaline phosphatase (ALP) was normal in all
patients. Five patients had elevated triglyceride levels and two had
elevated total serum cholesterol levels. Ultrasound examination in
11 patients showed increased echogenicity (suggestive of increased
liver fat) in 10.
The liver biopsy changes included both macro- and microvesicular
steatosis. Inflammation was present in eight patients and fibrosis
was present in nine patients. The degree of fibrosis ranged from mild
portal tract fibrosis to bridging fibrosis to probable cirrhosis (as
identified in a repeat biopsy in one of the patients). Increased
glycogen (intracellular and intranuclear) was seen in the two
patients with known IDDM and a third patient in whom a subsequent
diagnosis of IDDM was made. Mallory's hyalin was not seen in any of the
cases on immunohistochemical staining, a noteworthy finding given
that Mallory bodies are said to be seen more commonly in alcoholic
steatohepatitis than in NASH.5
Box 2 shows the follow-up data. Eleven patients had continued
elevation of liver enzyme levels, and persistent obesity despite
counselling. Two of the obese patients had normalisation of LFTs with
weight loss. None of the other obese patients lost weight, and in these
patients liver enzyme levels remained elevated. One of the patients
with diabetes (the only patient who was not morbidly obese) had
normalisation of LFTs with improved diabetes control. Seven of the
more recently identified patients were treated with
ursodeoxycholic acid; one had normalisation of LFTs with weight
loss.
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The association of abnormalities in liver function and
morphological changes on liver biopsy (steatosis, inflammation
and/or fibrosis) with obesity and insulin
resistance/insufficiency is well established in adults and
becoming increasingly recognised in children.
Most cases of NASH in the paediatric age group have been described in
older children and adolescents.1,2 Our series of 17 patients
shows that children may be asymptomatic or present with vague,
non-specific complaints, which conform to those described
previously.6 One of our patients had
marked acanthosis nigricans, a finding indicative of insulin
resistance and reported recently in another study.2 Most of our
patients were identified over the past 5-7 years, and we believe this
is largely due to the increased awareness of this condition and the
increasing prevalence of obesity in children in Australian
society.7 |
Clinical findings | |
In our series, all but one of the patients who had ultrasound of the
liver showed variable enlargement and increased echogenicity,
consistent with fatty change. In a study of 72 obese
children,4 increased echogenicity was
found in 53% of cases, and the authors proposed ultrasound as a useful
tool to determine liver involvement in obese children. Certainly,
our experience agrees with this. However, liver ultrasound will not
detect the more subtle histopathological features of more severe
liver damage, such as fibrosis. Only liver biopsy can demonstrate
such abnormalities.
Elevated ALT and GGT levels were the most common findings with LFTs.
This is consistent with another study,4 in which ALT was the most
elevated enzyme and the ALT/AST ratio was the reverse of that seen in
alcoholic steatohepatitis. We found no correlation between
presenting signs and symptoms, LFT abnormalities, and the
morphological changes at liver biopsy, unlike those reported in
adult patients with NASH.8 |
Liver histology | |
We found a wide variation in biopsy findings, from steatosis alone to
steatohepatitis and mild fibrosis to probable cirrhosis (with
documented progression on repeat biopsy). In the patients with known
glucose intolerance, increased glycogen within hepatocyte
cytoplasm and nuclei was noted. In addition, in Patient 1 (where
increased glycogen was noted), IDDM was subsequently diagnosed.
In adults, NASH follows a relatively benign clinical course compared
with alcoholic steatohepatitis.8,9 Although follow-up data
in the paediatric age group are limited, the finding of evolving
cirrhosis in one of our patients highlights the view that NASH may be a
progressive disease.10-12 Rashid and Roberts
have speculated that at least some patients with cryptogenic
cirrhosis occurring in adulthood may have had NASH since
childhood.2 A recent study13 found that
NASH is under-recognised in many adults with so-called cryptogenic
cirrhosis (with as many as 74% of such patients having a history of
obesity or diabetes mellitus). Septal fibrosis occurs frequently in
overweight adult patients with abnormal LFTs.14 |
Pathogenesis |
The pathogenesis of NASH is still being determined. A recent
study15 based on data from the
National Health and Nutrition Examination Survey concluded that
reduced serum levels of fat-soluble antioxidants are present in
obese children. Oxidant stress injury may be pivotal in the
pathogenesis of NASH,16 resulting in adipose
tissue synthesis of tumour necrosis factor (TNF). TNF antagonises
insulin receptors, leading to glucose intolerance,
hyperlipidaemia and steatosis. Another study17 suggests that
fatty livers are vulnerable to liver ATP depletion and necrosis,
indicating that altered hepatic energy homoeostasis may be
involved.
Increased lipid peroxidation may increase hepatic stellate cell
activation.18 Activated stellate cells
are matrix-producing myofibroblast-like cells which are thought to
be responsible for the laying down of fibrous tissue in hepatic
fibrosis.18 |
Intervention |
At this stage, therapy is limited to weight control and treatment of
insulin lack or resistance. Although weight loss in adult patients
has been effective in leading to regression of fatty
change,19 in all but two of our obese
patients weight control was not achieved and abnormalities of liver
function persisted.
Seven of our patients were treated with ursodeoxycholic acid, and one
showed normalisation of LFTs (with weight loss). Ursodeoxycholic
acid improves LFTs in patients with NASH.20 It is thought that this
agent is cytoprotective and, by preventing membrane injury, may
reduce liver injury in NASH.20 In our institution,
treatment of NASH with ursodeoxycholic acid is largely a matter of
individual preference for treating physicians, and guidelines have
not been established.
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Recommendations | |
Children presenting to paediatric outpatient units who are morbidly
obese should have their LFTs measured, and should be counselled
regarding weight loss. If the baseline LFTs are elevated, the
measurements should be repeated in 3-4 months. If the LFTs are still
abnormal, then other investigations (including hepatitis B and C
virus serology, autoimmune antibody screen, caeruloplasmin
levels, and serum triglyceride, cholesterol and blood sugar levels)
should be performed and liver biopsy considered. Liver biopsy and
other investigations might be performed earlier if the liver enzyme
levels are grossly elevated.
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- Baldridge AD, Perez-Atayde AR, Graeme-Cook F, et al. Idiopathic
steatohepatitis in childhood: a multicentre retrospective study.
J Pediatr 1995; 127: 700-704.
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Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children.
J Pediatr Gastroenterol Nutr 2000; 30: 48-53.
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Ludwig J, McGill DB, Lindor KD. Review: nonalcoholic
steatohepatitis. J Gastroenterol Hepatol 1997; 12:
398-403.
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Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese
children. Ultrasonography and liver enzyme levels at diagnosis and
during follow-up in an Italian population. Dig Dis Sci 1997;
42: 1428-1432.
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National Centre for Health Statistics Growth Curves for Children.
Adapted from Hamill PVV: NHCS Growth Curves for Children. DHEW
Publication (PHS) 78-1650.
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Neuschwander-Tetri B, Bacon B. Nonalcoholic steatohepatitis.
Med Clin N Am 1996; 80: 1147-1165.
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Lazarus R, Wake M, Hesketh K, Waters E. Change in body mass index in
Australian primary school children, 1985-1997. Int J Obes Relat
Metab Disord 2000; 24: 679-684.
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Lee R. Nonalcoholic steatohepatitis, a study of 49 patients.
Hum Pathol 1989; 20: 594-598.
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Mohd R, James O, Burt A, et al. The natural history of nonalcoholic
fatty liver: a follow-up study. Hepatology 1995; 22:
1714-1719.
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Bacon B, Farakvash M, Janney C, Neuschwander-Tetri B.
Nonalcoholic steatohepatitis: tightening the morphological
screws on a hepatic rambler. Hepatology 1995; 21: 1742-1743.
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Propst A, Propst T, Judmaier G, Vogel W. Prognosis in nonalcoholic
steatohepatitis [letter]. Gastroenterology 1995; 108:
1607.
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Kim W, Poterucha J, Porayko M, et al. Recurrence of nonalcoholic
steatohepatitis following liver transplantation.
Transplantation 1996; 62: 1802-1805.
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Caldwell S, Oelsner D, Iezzoni J, et al. Cryptogenic cirrhosis:
clinical characterisation and risk factors for underlying disease.
Hepatology 1999; 29: 664-669.
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Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight
patients. Gastroenterology 2000; 118: 1117-1123.
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Strauss R. Comparison of serum concentrations of α-tocopherol
and β-carotene in a cross-sectional sample of obese and nonobese
children (NHANES III). J Pediatr 1999; 134: 160-165.
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Lavine J. Relative antioxidant deficiency in obese children: a
weighty contributor to morbidity? [editorial]. J Pediatr
1999; 134: 132-133.
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Cortez-Pinto H, Chatham J, Chacko VP, et al. Alterations in liver
ATP homeostasis in human nonalcoholic steatohepatitis: a pilot
study. JAMA 1999; 282: 1659-1664.
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Reeves H, Burt A, Wood S, Day C. Hepatic stellate cell activation
occurs in the absence of hepatitis in alcoholic liver disease and
correlates with the severity of steatosis. J Hepatol 1996;
25: 677-683.
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Lieverse R, Jansen J, Masclee A, Lamers C. Gastrointestinal
disturbances with obesity. Scand J Gastroenterol 1993; 200:
S53-S58.
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Laurin J, Lindnor K, Crippin J, et al. Ursodeoxycholic acid or
clofibrate in the treatment of non-alcohol-induced
steatohepatitis: a pilot study. Hepatology 1996; 23:
1464-1467.
(Received 3 Apr, accepted 3 Aug, 2000)
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Women's and Children's Hospital, Adelaide, SA.
Nicholas D Manton, MB BS, Registrar, Department of
Histopathology;
Jill Lipsett, PhD, FRCPA,
Histopathologist, Department of Histopathology;
David J Moore,
MB BS, FRACP, Paediatric Gastroenterologist, Department of
Gastroenterology;
Geoffrey P Davidson, MD, FRACP,
Director, Department of Gastroenterology;
Anthony J Bourne,
MB BS, FRACPA, Director, Department of Histopathology;
Richard T L Couper, MB ChB, FRACP, Paediatric
Gastroenterologist, Department of Gastroenterology, and
University of Adelaide Department of Paediatrics.
Reprints will not be available from the authors.
Correspondence: Dr R
T L Couper, University of Adelaide Department of Paediatrics and
Department of Paediatric Gastroenterology, Women's and Children's
Hospital, 72 King William Road, North Adelaide, SA 5006.
rcouperATmedicine.adelaide.edu.au
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| 1: Clinical and investigation
findings |
| Patient |
Examination |
Biochemistry* |
Ultrasound |
Liver biopsy |
|
1
(M, 13) |
27% over IBW acanthosis nigricans |
ALT ratio 3.2
GGT ratio 4.4
AST ratio 1.9 |
Enlarged EL |
Severe macrovesicular steatosis with increased
glycogen |
2
(F, 13) |
27% over IBW short stature, hepatomegaly |
ALT 3.2
GGT 1.1
AST 3.0 |
Enlarged EL |
Moderate macro- and microvesicular steatosis
with increased glycogen and moderate inflammation |
3
(F, 11) |
118% over IBW |
ALT 1.3
GGT 5.5 |
Normal |
Severe macro- and microvesicular steatosis |
4
(F, 9) |
45% over IBW |
ALT 2.2 |
nd |
Severe macrovesicular steatosis, mild portal
tract inflammation, mild portal tract fibrosis |
5
(M, 12) |
10% over IBW tender hepatomegaly |
ALT 11.3
GGT 5.1 |
Enlarged EL |
Moderate macro- and microvesicular
steatosis, scattered glycogenated nuclei |
6
(M, 11) |
115% over IBW |
ALT 3.2
GGT 1.6
AST 1.6 |
Fatty change |
Severe mixed macro- and microvesicular steatosis
with bridging fibrosis and evolving cirrhosis |
7
(M, 13) |
81% over IBW hepatomegaly |
ALT 1.2 |
nd |
Moderate macrovesicular steatosis, mild portal
tract inflammation |
8
(M, 14) |
74% over IBW |
ALT 16.0
GGT 4.9 |
EL |
Severe macrovesicular steatosis, mild septal
fibrosis |
9
(M, 15) |
88% over IBW |
ALT 2.5
AST 1.5
TG 1.8 |
EL |
Severe macrovesicular steatosis, minimal perisinusoidal
fibrosis |
10
(F, 10) |
32% over IBW |
ALT 20.7
GGT 1.4
Cholesterol 1.2 |
nd |
Moderate macro- and microvesicular steatosis,
mild portal tract inflammation |
11
(M, 13) |
60% over IBW mild abdominal tenderness |
ALT 1.3
GGT 1.1
TG 1.5 |
nd |
Mild macrovesicular steatosis |
12
(M, 11) |
55% over IBW enlarged liver |
ALT 1.6
TG 1.7 |
EL |
Moderate macro- and microvesicular steatosis,
moderate portal tract inflammation, portal tract fibrosis with bridging
|
13
(M, 12) |
37% over IBW |
ALT 2.2 |
EL |
Moderate macro- and microvesicular steatosis,
mild perisinusoidal fibrosis |
14
(F, 9) |
44% over IBW palpable liver edge |
ALT 3.6 |
nd |
Moderate macrovesicular steatosis, focal hepatocyte
necrosis, mild portal tract inflammation, mild perisinusoidal fibrosis |
15
(F, 10) |
26% over IBW palpable liver edge |
ALT 2.8
Cholesterol 1.2 |
EL |
Mild macrovesicular steatosis, mild portal
tract inflammation |
16
(M, 11) |
25% over IBW palpable liver edge |
ALT 4.7
TG 1.1 |
EL |
Severe macro- and microvesicular steatosis,
mild portal tract inflammation, portal tract fibrosis with early bridging
|
17
(M, 12) |
37% over IBW |
ALT 4.8
TG 1.3 |
nd |
Severe macrovesicular steatosis, mild portal
tract fibrosis with early bridging |
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| *Biochemistry results are given
as a ratio of the measured value of serum liver enzyme, serum triglyeride,
or serum cholesterol levels over the normal maximum for the particular method
used. Sex and age at presentation. Twins. IBW=ideal body weight. ALT=alanine
aminotransferase. GGT=gamma glutamyl transferase. AST=aspartate aminotransferase.
TG=Serum triglycerides. EL=echogenic liver. nd=not done. |
| | Back to text | | |
| 2: Outcome data at latest
follow-up |
| Patient |
Follow-up period |
Percentage over
IBW |
Biochemistry* |
Remarks |
|
| 1 |
6 years |
45% |
ALT 1.9
GGT 5.8 |
Subsequently diagnosed with IDDM and Alstrom
syndrome |
| 2 |
Lost to follow-up |
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| 3 |
6 years |
25% |
|
Rapid weight loss with puberty, normalisation
of LFTs |
| 4 |
15 months |
36% |
ALT 3.4 |
|
| 5 |
2.5 years |
8% |
|
Normalisation of LFTs with improved diabetes
control |
| 6 |
2.5 years |
60% |
ALT 1.7 |
Persisting obesity with some improvement
in LFTs. Treated with ursodeoxycholic acid. Follow-up liver biopsy showed
probable cirrhosis |
| 7 |
Lost to follow-up |
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| 8 |
2 years |
78% |
ALT 4.1
GGT 1.9 |
Treated with ursodeoxycholic acid |
| 9 |
1 year |
51% |
ALT 4.0 |
|
| 10 |
4 months |
30% |
ALT 8.0
GGT 2.0 |
|
| 11 |
1 year |
56% |
ALT 2.3
GGT 1.4 |
|
| 12 |
1 year |
57% |
ALT 7.9
GGT 2.2 |
|
| 13 |
15 months |
36% |
ALT 3.0 |
Treated with ursodeoxycholic acid |
| 14 |
14 months |
36% |
ALT 3.8 |
Treated with ursodeoxycholic acid |
| 15 |
Not yet reviewed |
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| 16 |
1 year |
15% |
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Normalisation of LFTs with weight loss. Treated
with ursodeoxycholic acid |
| 17 |
1 year |
45% |
ALT 2.9 |
Treated with ursodeoxycholic acid |
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| *Biochemistry results are given
as ratio of the measured value of serum liver enzyme levels and the normal
maximum for the method used. Twins. LFT=liver function test. ALT=alanine
aminotransferase. GGT=gamma glutamyl transferase. |
| | Back to text |
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-carotene in a cross-sectional sample of obese and nonobese
children (NHANES III). J Pediatr 1999; 134: 160-165.