Risk Factors for NASH
• Type د 2دDiabetes د د
• Obesity د
The pathogenesis of NAFLD NASH
• The دpathogenesis دof دNAFLD د دNASH د
remain دpoorly دdefined. دCurrent دconcept د
suggest دthe دdevelopment دof دNASH دis دa د
Two دhit دprocess د
* First hit.
• Involve accumulation of Fat in hepatocytes.
* Second hit.
• Oxidative دstress دis دthought دto دbe دa دkey دrole د
in دthe د 2دnd دhit د
Diagnosis of NASH
* Clinical diagnosis:
• Clinical experience with pediatric NASH is
limited, while there are no characteristic
• Children may complain of abdominal pain
although they are often asymptomatic
• Hepatomegaly can often detected on
examination, however this physical finding may
be missed in clinical practice.
• Acanthosis nigricans, a black pigmentation found
in skin fold and axilla associated with
• Malaise or tiredness, history of drug ingestion
may be elicited at time of presentation.
Pointers to NAFLD/
NASH in clinical
• Unexplained elevation of ALT and GGT,
typically minor, in a person with metabolic
• ‘Rubbery’ hepatomegaly
• Recent weight gain and expanding waistline
• Lifestyle or medication changes favouring
• Family history of type 2 diabetes, NAFLD,
vascular disorders or hyperlipidaemia
• Raised serum ferritin not attributable to iron storage
disorder or alcohol
• Abnormalities of hepatic imagingadiffuse echogenicity
on ultrasonogram (‘bright liver’), radiolucency on CT
• Patient with chronic HCV infection and diabetes and/or
obesity, ‘rubbery’ hepatomegaly or steatosis with HCV
• Patient with chronic HBV infection, raised ALT but nondetectable HBV DNA in presence of metabolic risk
• ALT, alanine aminotransferase; CT, computerized
tomography; GGT, gamma-glutamyl transpeptidase;
HBV DNA, hepatitis B
• Imaging studies.
Fibroscan (Transient elastography).
• Non invasive biomarkers:
NASH fibro SURE.
New generation of biomarker as FT, ST and NT.
Auto immune marker.
• Serum ALT was found to be reliable as
screening tool for fatty liver.
– Aminotramsferase: the ratio of
AST/ALT is usually 1
– in NASH often 2
– Alkaline phosphatase: increase or may
• GGT can be mildely elevated
• NASH fibrosure is non invasive assessment of
liver status for patient with NAFLD.
• Quantitative results of to biochemical
• α 2Macroglobulin.
• Apolipoprotein A.
γ glutamyl transpeptides (GGT).
Alanine aminotransferase (ALT).
Asparatate aminotransferase (AST)
NASH fibro SURE should only be used for
patient with suspected NAFLD, it is not
recommended for patient with other liver
• Steatosis marker: has been studied in a
variability of patient types including
hepatitis C, alcoholic liver disease and
Provide quantitative marker for hepatic
• steatosis score 0.5 had sensitivity of
71% and specificity of 72% for
identification of significant steatosis
• Biomarker to predict steatosis
(Steatotest) fibrosis (fibrotest) among
patient – NAFD, the diagnostic
accuracy of all biomarker used to
identify liver fibrosis seldom exceed
75-80%. These serum markers not
available in all lab., may be expensive
can't substitute liver biopsy
• Both microsomal and mitochondrial
function are disturbed in NASH,
• MBT for liver microsomal function
• KBT for liver mitochondrial function.
Liver breath test predirect higher state
Autoimmune Ab: (Auto immune
• In a pediatric study, seven of 14 children
with NAFLD were found to be +ve for ANA
or SMA in six and GPC in one, 4 of 6
children were be +ve for Ab.
Several NASH-specific biomarkers
• Several NASH-specific biomarkers have
recently been developed. The CK-18, a
biomarker of apoptosis, was developed
and tested in patients with NAFLD.
Another non-invasive biomarker (NASH
Diagnostics) is a simple panel that
includes Cleaved CK-18, a product of the
subtraction of Cleaved CK-18 level from
intact CK-18, serum adiponectin
Liver biopsy is considered to be
the gold standard for diagnosis
Known to be nonprogressive
Steatosis plus lobular
Probably benign (not
regarded as NASH
NASH without fibrosis
may progress to
degeneration and Mallory
NASH with fibrosis
may progress to
cirrhosis and liver
—Natural history of nonalcoholic fatty liver disease. Small proportion of
patients with fatty liver develop nonalcoholic steatohepatitis. Less than
10% of nonalcoholic steatohepatitis patients develop cirrhosis. Current
research is aimed at detecting early stages of fibrosis that are potentially
reversible. aProbable percentage of patients with hepatic steatosis
progressing to nonalcoholic steatohepatitis. bDisease progression (%) of
all nonalcoholic steatohepatitis patients.
Differential diagnosis of NASH
In contrast to adults, with whom the major differential
diagnosis is with alcoholic liver disease. In children
the main considerations are metabolic or
inflammatory disease that cause fatty liver in
• Relatively common:–
Hereditary fructose intolerance.
Glycogen storage disease.
Differential diagnosis of NASH
• Less common:
Lipid storage disease.
Cholesterol ester storage disease.
Hereditary tryrosinaemia type 1.
A beta or hypo beta lipoprotienaemia.
Weber ehristian disease.
Porphyria cutanea tarda .
Diseases Associated with NASH
Obstructive steep apnea
Treatment of NASH in children
The current best treatment of any form of
NAFLD in children is life style
modification in contrast to adult NAFLD.
This is not centered around weight
reduction programs, but directed towards
increased physical activity promotion of
healthy balanced diet to support normal
growth and development. The success of
this approach is variable and additional
drug intervention might be needed.
Therapeutic option available for patient
Change in habit: diet physical exercise.
Drugs that improve insulin sensitivity.
Lipid lowering agent.
Antibiotics: lactobacillus prevent gut derived endotoxaemia.
Anti TNF antibodies, TNF- receptor antagonist.
Nutritional supplementation: Carnitine, choline.
The main goal therapy for NAFLD should be to prevent progression
of NAFLD to cirrhosis, un fortunately although a variety of treatment
modalities have been proposed, none has proven efficacy in
changing this end point
Role of nutrition in treatment of
• Nutritional recommendation for NASH focus on
the underlying disease (Metabolic syndrome
other secondary causes)
• Diet composition:
Dietary composition has an important
consideration. There is some evidence that
carbohydrate loading may be problematic, thus
the food with high amount of corn syrup, product
of high sugar content, high starch food may be
particularly dangerous. It may not be just the
total calorie intake that lead to NASH, but the
types of calorie.
• Polyunsaturated fatty acid especially formulation
rich in omega-3 are widely accepted in medical
community for their beneficial affect on
• Recent studies ameliorate hepatic steatosis in
human animal models of NASH by reducing
hepatic fat content. One year course of omega-3
fatty acid (3gm/day) will produce improvement in
NASH histological injury
Fiber in diet
• Children require help with appetite control. Food
make individual feel full without delivering high
amount of calories, in this regard fruits
vegetables come to forfront of good selection.
The most satisfying component of vegetable is
dietary fiber in particular soluble fiber.
• The most interesting of all soluble fiber is
delivered from oats. Oat contain unique type of
fiber hydrocolloid or oat-beta glycan it is
proposed as fat substitute in foods
• This soluble fiber has an ability to
smooth out blood sugar concentration
following meals. This is called second
meal effect of low glycaemic index
• So soluble fiber is valuable in ↓
weight, ↓ IR control blood sugar
• High fiber diet may tend to ↓
• Diet will therefore need to be tailored
to individual needs. The inclusion of n-3
fatty acid, high MUFA foods, fruits,
vegetables, low GI, high fiber foods
reduced intake of saturated fat, simple
carbohydrate sweetened drink may be
universally recommended to NAFLD
Drug therapy of NASH
• Although diet and exercise is the
mainstay of treatment, medication
might be warranted if an appropriate
diet and regular physical activity don't
improve biochemical markers and
• Most attention of pediatric NAFLD is given
to either vitamin E as antioxidant or to anti
diabetic drugs, Metformin as an agent that
• Antioxidant: the use of antioxidants for
the treatment of NAFLD to protect cellular
structures against damage from oxygen
free radicals and from reactive products of
Antioxidant against oxidative stress
• Natural antioxidants (vitamin E, ubiquinone)
• Synthetic antioxidants (including
dihydroquinoline-type – only used
• Ursodeoxycholic acid
• Oral vitamin E 400-1200 IU daily improves
hepatic enzymes in patients with NAFLD
• It might improve NASH by modulating
cytokines and inhibiting the expression of
intrahepatic TGF-ß, which is involved in
Lipid Lowering Drugs
• As hypertriglyceridaemia and low HDL
cholesterol levels are a manifestation of
insulin resistance and common among
subjects with NAFLD, several
investigators have used lipid lowering
drugs to treat NAFLD The use of statin
drugs is currently contraindicated in the
presence of active liver disease or
persistent unexplained increases of
Drug that protect hepatocyte
• Several drugs believed to be
hepatoprotective have been used in
patient with NASH .these include
UDCA, betain, vitamin E, lecithin, βcarotin ,and selenium and taurine
• Dietary supplement of antioxidant as
vitamin E ,selenium and restriction of iron
intake may be beneficial for prevention of
advanced disease, further regulation of
bacterial flora in the gut using probiotic is
promising for prevention and treatment of
• Silymarin this is the active ingredient in the
milk thistle herb. It has a history of improving
liver health. Many studies have shown that milk
Increase the speed of liver cell regeneration
Restrain liver fibrosis
Protect the liver from injury
Decrease cholesterol absorption
It is believed that it increase production of anti
oxidant enzyme that help liver breakdown toxin,
• Selenium is a powerful anti oxidant that works
synergistically to asses protection against further
damage in liver injury. Selenium is a mineral that
functions as a component of glutathione
peroxidase, an essential antioxidant system. It is
involved in metabolism of vitamin E.
• Recommended daily intake in childhood (110 years): 40-50µg.
• Selenium dietary source: Organ
meat,fish,mashroom and selfish are generally
• Many studies reported that zinc protected
induced liver injury,not only reduction of
oxidative stress in hepatocyte ,but also by
prevention of intestinal permeability
Recommended intake in children: 10mg
• Zinc dietary source: zinc is found
abundantly in shelfish,red meat,legumes
Prognosis and Prevention
• Prognosis of NASH :Prognosis is
dependant not only on the severity of the
disease and number of risk factors, but
also on the degree of histological damage.
The presence of NASH Vs NAFLD and the
stage of fibrosis provide a gradient for
Can NAFLD /NASH be prevented or
• Because liver failure doesn't occur in NAFLD/
NASH unless cirrhosis has developed,
reducing or reversing fibrotic progression
must be of ultimate objective of treatment.
• There is now compelling evidence that type 2
diabetes can be prevented or at least delayed
in onset by life style intervention. NASH, a
consequence of IR should also be prevented
by change in diet physical activity
• Nonalcoholic fatty liver disease (NAFLD), a
condition associated with obesity and
diabetes, is increasingly being recognized in
the western population.
• Simple fatty liver is the most common form of
NAFLD and seems to be a benign condition.
In contrast, nonalcoholic steatohepatitis may
progress to advanced fibrosis and cirrhosis.
• The diagnosis is often made after incidentally
finding elevated liver enzyme levels or by clinical
suspicion in patients with obesity or diabetes.
Laboratory results or imaging examinations may
confirm the diagnosis. However, at present, only a
liver biopsy can differentiate simple steatosis from
• There is no clear consensus on the effectiveness
of the pharmacologic treatment of NAFLD. Several
therapies, including insulin-sensitizing, antioxidant
agents, and hepatoprotective medications, have
been studied. Lifestyle modifications, particularly
weight loss, have been shown to be particularly
• NAFLD affects a substantial portion of the
general population and is associated with
the metabolic syndrome, which includes
obesity, insulin resistance, hyperlipidemia,
and hypertension. Patients with NAFLD
not only suffer from the metabolic sequlae
of insulin resistance but have increased
• Although simple fatty liver seems to be a
benign condition, some patients may
progress to NASH and ultimately to
cirrhosis. Because of the consequences of
the disease, we emphasize the
importance of the detection of NAFLD in
high-risk groups, including obese patients,
as well as those with evidence of insulin
resistance or other components of the
• Screening and surveillance methods
should be applied more uniformly from
center to center, and reliable non invasive
techniques are needed for the diagnosis
of NAFLD and the detection of progressive
liver disease. The diagnosis of NAFLD
should prompt management of the
metabolic risk factors.
• . Weight loss regimens are believed to be
helpful, and numerous drugs have been
investigated in small studies. Large,
randomized, clinical trials are necessary to
determine the real benefit of these agents.
Finally, studies on the pathogenesis of NAFLD
may not only improve our understanding of the
mechanisms involved in NAFLD progression, but
may lead to potentially novel therapeutic
strategies to treat this condition.
• We should screen all children at risk for
development of NASH (obese diabetic
children) by U/S laboratory investigation.
• We should encourage our children to avoid
unhealthy food which lead to obesity.
• Encourage mother for exclusive breast
feeding at 1st 6 month of life which proved to
prevent obesity at childhood period