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Non-alcoholic steatohepatitis in children and adolescents

Nicholas D Manton, Jill Lipsett, David J Moore, Geoffrey P Davidson and Anthony J Bourne
Med J Aust 2000; 173 (9): 476-479.
Published online: 6 November 2000

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

- - More articles on Gastroenterology


  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.


Methods

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.

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.



Clinical findings

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.


Discussion

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.

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.


References

  1. Baldridge AD, Perez-Atayde AR, Graeme-Cook F, et al. Idiopathic steatohepatitis in childhood: a multicentre retrospective study. J Pediatr 1995; 127: 700-704.
  2. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000; 30: 48-53.
  3. Ludwig J, McGill DB, Lindor KD. Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol 1997; 12: 398-403.
  4. 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.
  5. National Centre for Health Statistics Growth Curves for Children. Adapted from Hamill PVV: NHCS Growth Curves for Children. DHEW Publication (PHS) 78-1650.
  6. Neuschwander-Tetri B, Bacon B. Nonalcoholic steatohepatitis. Med Clin N Am 1996; 80: 1147-1165.
  7. 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.
  8. Lee R. Nonalcoholic steatohepatitis, a study of 49 patients. Hum Pathol 1989; 20: 594-598.
  9. Mohd R, James O, Burt A, et al. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1714-1719.
  10. Bacon B, Farakvash M, Janney C, Neuschwander-Tetri B. Nonalcoholic steatohepatitis: tightening the morphological screws on a hepatic rambler. Hepatology 1995; 21: 1742-1743.
  11. Propst A, Propst T, Judmaier G, Vogel W. Prognosis in nonalcoholic steatohepatitis [letter]. Gastroenterology 1995; 108: 1607.
  12. Kim W, Poterucha J, Porayko M, et al. Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation 1996; 62: 1802-1805.
  13. Caldwell S, Oelsner D, Iezzoni J, et al. Cryptogenic cirrhosis: clinical characterisation and risk factors for underlying disease. Hepatology 1999; 29: 664-669.
  14. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118: 1117-1123.
  15. 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.
  16. Lavine J. Relative antioxidant deficiency in obese children: a weighty contributor to morbidity? [editorial]. J Pediatr 1999; 134: 132-133.
  17. 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.
  18. 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.
  19. Lieverse R, Jansen J, Masclee A, Lamers C. Gastrointestinal disturbances with obesity. Scand J Gastroenterol 1993; 200: S53-S58.
  20. 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)



Authors' details

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

*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.
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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
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
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
16 1 year 15% Normalisation of LFTs with weight loss. Treated with ursodeoxycholic acid
17† 1 year 45% ALT 2.9 Treated with ursodeoxycholic acid

*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.
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  • Nicholas D Manton
  • Jill Lipsett
  • David J Moore
  • Geoffrey P Davidson
  • Anthony J Bourne


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