Case 1 -
Non-Alcoholic Fatty Liver Disease (Non-Alcoholic Steatohepatitis)
University of California, San Diego
San Diego, CA
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The patient is currently a 9 year old obese Hispanic boy who had initially been referred to hepatology
clinic at the age of 4 when hepatomegaly was discovered by his pediatrician during a well care visit. A
liver biopsy was performed and showed steatosis . Etiologies of liver disease other than steatosis were
excluded. No specific treatment was initiated except for dietary counseling and discussion of healthy
The patient continued to receive care from his pediatrician but recently returned to hepatology for
followup of his liver condition, because of excess weight and a concern for the development of diabetes.
Past Medical History: The patient was born at 8 months gestation after an uneventful prenatal
course. He weighed 5 lbs 4 oz at birth. Developmental milestones were met. When he was initially
referred to hepatology at the age of 4, he was noted to be "overweight". The patient has mild asthma.
His dietary intake is notable for 2-3 regular sodas per day, candy, fried cheese snacks and ice cream on
a daily basis, fast food meals twice a week large portion sizes and 4-5 hours of television viewing per
day. He does not regularly exercise.
Family history: The patient's father is morbidly obese and has hypertension and type 2 diabetes. The
patient's mother is in good health. Maternal and paternal relatives have diabetes, hypertension, high
Medications: Inhaled albuterol PRN
Review of Systems: Non contributory
Physical Exam: At the time of his return to Heptology Clinic at the age of 9, the patient weighed
55.7 kg and measured 135 cm in height. BMI was 30.56. The remainder of the physical exam was normal
except for the presence of severe acanthosis nigricans around the neck and in the axilla bilaterally.
LABS: Significant laboratory abnormalities include ALT 383, AST 257, GGT 171. Fasting glucose was
A second liver biopsy was performed. On the basis of the results, the patient was eligible for and
consented to be part of an NIH sponsored treatment trial and is currently enrolled in the trial.
Both liver biopsies are included for review.
Non-alcoholic Fatty Liver Disease (Non-alcoholic Steatohepatitis)
Non Alcoholic Fatty Liver Disease in Children
Fatty liver associated with obesity and diabetes (Nonalcoholic Fatty Liver Disease (NAFLD)) has been
increasingly recognized in children as the prevalence of childhood obesity climbs. NAFLD is considered
the most common liver disease in children. As in adults, NAFLD in children is the hepatic manifestation
of the metabolic syndrome or syndrome X. Also similar to adult NAFLD, the disease encompasses a spectrum
of pathology from simple steatosis to steatohepatitis and in some, cirrhosis and end stage liver disease.
The earliest reports of fatty liver in children consisted of case series which identified obesity as a
common clinical denominator in children with fatty infiltration of hepatocytes but no other cause for
liver disease . Larger series demonstrate fatty liver occurring as early as 2-3 years of age but
increasing with age and more common in boys. NAFLD is highly prevalent in obese children of Hispanic
ethnicity . In children with fatty liver who are not obese, insulin resistance or diabetes is a
defining clinical feature.
The prevalence of fatty liver in the general pediatric population is difficult to estimate. Most
studies describing NAFLD in children are based on elevation of serum transaminases or imaging studies
rather than biopsy. It is estimated that up to 15% of children in the United States are currently
obese. Elevated ALT levels are found in approximately one quarter of obese children and ultrasound
findings of fatty liver in half to three quarters of obese children
. In an autopsy study in which
fatty liver prevalence was determine by liver histology in 954 children and adolescents fatty liver was
present in 13%. An additional 17% had minimal steatosis defined as fat droplets in less than 5 % of
hepatocytes. Of the total population of children, 16% were overweight and 23% obese. One third of the
obese children had fatty liver. This study also documented an increased prevalence in Hispanic, Native
American and Asian populations as compared to Caucasian and Black ethnicities .
Because relatively fewer liver biopsies are performed in children as compared to adults, less is know
about the pathologic features of fatty liver disease in children. A study in 1995 by Baldridge et al
described biopsy findings in 14 children with idiopathic steatohepatitis. Described were a range of fat
accumulation from mild to severe, rare lipogranulomas, rare lobular inflammatory foci and rare Mallory
hyaline (in 1/14). Common to all biopsies were portal inflammation and portal fibrosis. All the
biopsies also had additional fibrosis described as "portal-portal bridging, portal central bridging,
centrilobular sclerosis, or perisinusoidal…centrilobular" collagen. Ballooning degeneration was not
noted . These findings contrast in some ways with the classically described findings in adult NASH:
zone 3 accumulation of fat, ballooning hepatocytes and perisinusoidal zone 3 fibrosis with a relative
absence of portal based pathology
The portal based pattern with relative lack of ballooning degeneration as reported in the
children described by Baldridge has been noted in some adult populations as well . To date, it
constitutes one of several histologic patterns of NAFLD which have been described. In children as in
adults, the simplest histologic form of the disease is steatosis, which can be diffusely distributed or
have a marked zonal distribution. Farther along the spectrum, some children have liver biopsy findings
similar to classically described adult NASH, specifically, a zone 3 predominant pattern of fat
accumulation with liver injury manifest by lobular inflammation, ballooning degeneration and in some
pericentral, perisinusoidal fibrosis. This pattern appears to represent a minority of children and
adolescents with fatty liver .
A second histologic pattern predominates in the pediatric age group. This pattern is characterized by
more severe steatosis overall (at least moderate to severe), relative sparing of the central vein and
perivenular hepatocytes and more significant portal based inflammation and fibrosis. Ballooned
hepatocytes and the usually accompanying Mallory hyaline are less frequent.
When the ethnic and gender attributes of children with the different NAFLD/NASH histologic patterns
were analyzed, children of black race were more likely to have simple steatosis, while Asian, Hispanic
and Native American ethnicities more frequently demonstrated a Pediatric, portal based or Type 2 NASH
histologic pattern. A majority of children of white race showed a classic or adult type histologic
Difficulties in the interpretation of liver biopsies from children suspected to have NAFLD include
relative lack of awareness of alternate histologic patterns of NASH as well as diagnostic difficulties
inherent in the histologic pattern itself. Specifically, pediatric or Type II NASH is described by a
relative lack of identifiable histologic findings such as ballooned liver cells and perisinusoidal
fibrosis. Furthermore, there is less agreement between pathologists on presence, absence or degree of
histologic features in pediatric biopsies as compared to adult biopsies. This may be due to the relative
rarity of many of the individual pathologic findings. Given these problems, it is more difficult to
achieve a "NASH" diagnosis in biopsies showing the pediatric, Type II pattern. In a study from the NIH
NASH CRN Pathology Committee, the only pediatric biopsy which all 9 pathologists agreed was NASH was one
which showed classic adult Type I ballooning degeneration with lobular inflammation and Mallory Haline!
If one considers NASH as an advancing form of NAFLD with liver injury, then the presence
of fibrosis, even if only portal based, seems a reasonable indicator that injury in the presence of
steatosis has occurred. Remaining are the problems of diagnosing NASH with a relative paucity of
histologic indicators for liver injury in the absence of fibrosis. The NASH Activity Score as proposed
for use in the NASH CRN assigns a value for steatosis (0-3), Lobular inflammation (0-3) and ballooning
(0-2) in which cases with marked steatosis but little inflammation or little or no ballooning fall in the
the "indefinite for steatohepatitis" category . While individual histologic features correlate with
some clinical aspects of NAFLD, the outcome and ultimate significance of the histologic findings in the
progression of the disease remains to be determined. A number of reported cases of histologic
progression have been noted, with development of cirrhosis, so NAFLD/NASH in children is not an innocuous
A diagnosis of NAFLD/NASH is one in which infectious, drug, autoimmune and metabolic diseases
including Wilsons Disease are excluded. In the adolescent, alcohol use must also be considered in the
differential diagnosis. In adults, steatosis or steatohepatitis has been shown to have a detrimental
effect on the progression of various other types of liver disease including Hepatitis C and can exist
concurrently with other chronic liver diseases.
Treatment studies of fatty liver in children are few and include trials with Vitamin E and metformin
. Weight loss can help however is a difficult process for many patients.
In summary, NAFLD in children and adolescents is a spectrum of disease ranging from simple steatosis
to cirrhosis and end stage liver disease. The histologic features of NASH in children may be different
than in adults and constitute a portal based pathologic process with moderate to severe steatosis. This
pattern may also be present in some adults with NAFLD. Recognition of the pediatric type pattern of NASH
will aid in diagnosis, staging and appropriate treatment for children with the disease.
- Baldridge, A.D., et al., Idiopathic steatohepatitis in childhood: a multicenter retrospective study. J Pediatr, 1995. 127(5): p. 700-4.
- Schwimmer, J.B., et al., Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr, 2003. 143(4): p. 500-5.
- Chan, D.F., et al., Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord, 2004. 28(10): p. 1257-63.
- Franzese, 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(7): p. 1428-32.
- Schwimmer, J., Kahen, T, Lavine J, Stanley C,Behling C., Prevalence of Fatty Liver in Children. Submitted, 2005.
- Brunt, E.M. and D.G. Tiniakos, Pathological features of NASH. Front Biosci, 2005. 10: p. 1475-84.
- Brunt, E.M., Pathology of nonalcoholic steatohepatitis. Hepatol Res, 2005.
- Brunt, E.M., Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis, 2001. 21(1): p. 3-16.
- Abrams, G.A., et al., Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease. Hepatology, 2004. 40(2): p. 475-83.
- Schwimmer, J.B., et al., Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology, 2005. 42(3): p. 641-9.
- Kleiner, D.E., et al., Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology, 2005. 41(6): p. 1313-21.
- Molleston, J.P., et al., Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol, 2002. 97(9): p. 2460-2.
- Lavine, J.E., Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr, 2000. 136(6): p. 734-8.
- Schwimmer, J.B., et al., A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther, 2005. 21(7): p. 871-9.