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Fatty Change

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Outline of Lecture

Fatty Change

Intracellular accumulations of endogenous or exogenous substances

Lipids:  fat may accumulate in the liver as fatty change

Proteins:  abnormal protein accumulation is often irreversible.

Glycogen:  glycogen storage diseases

Complex Lipids:  sphingolipidoses and other lipid accumulations

Intracellular accumulations of endogenous or exogenous substances

Complex carbohydrates:  mucopolysaccharidoses and other complex carbohydrate diseases.

Minerals: iron, as hemosiderin, or carbon, as anthracotic pigment


lipofuscin is a benign brown pigment of lipid origin that may accumulate with age, or

melanin from melanomas, or

bilirubin as in jaundice

Fatty Change

Hepatic lipid accumulation is characterized by intracellular accumulation of triglycerides, and due to the failure of metabolic removal.


Defects in fat metabolism are often induced by alcohol consumption, and also associated with diabetes, obesity, and toxins.


Fatty change is most often seen in the liver (and heart), and is generally reversible.

FATTY CHANGE – Gross features


pale, yellow color

greasy appearance

– Microscopic features

Fat vacuoles coalesce and displace the nucleus to the periphery of the cell

vacuoles appear clear, with well-defined edges

lipid accumulations must be distinguished from accumulations of water or glycogen, using special preparation and stain – Oil Red-O.


Nonalcoholic Fatty Liver Disease (NAFLD)

NAFLD—Presentation Outline



Risk Factors


Natural History

Clinical Features



Defining NAFLD

A liver biopsy showing moderate to gross macrovesicular fatty change with or without inflammation (lobular or portal), Mallory bodies, fibrosis, or cirrhosis.

Negligible alcohol consumption (less than 40 g of ethanol per week)

History obtained by three physicians independently.

Random blood assays for ethanol should be negative.

If performed, desialylated transferrin in serum should also be negative.

Absence of serologic evidence of hepatitis B or hepatitis C.

NAFLD—Spectrum of Disease




Steatohepatitis (NASH)


NASH with Fibrosis





Prevalence of NAFLD 13-18% and that of NASH specifically 2-3% (1.2-9%)


Is the leading cause of cryptogenic cirrhosis


Is a disease of all sexes, ethnicities, and age groups (peak 40-59)


Occurs more frequently in females (65 to 83%)

NASH—Risk Factors

NAFLD—Risk Factors







Lipid Peroxidation and Hepatic Lipotoxicity


Cytokine Activation and Fibrosis


Adiponectin and Leptin (Adipocytokines)


Abnormal Lipoprotein Metabolism


The normal liver contains less than 5% lipid by weight

Excessive importation of FFA


Rapid weight loss,excessive

conversion of carbohydrates and proteins to triglycerides

Impaired VLDL synthesis and secretion


Protein malnutrition,

Choline deficiency

Impaired beta-oxidation of FFA to ATP

Vitamin B5 deficiency,

Coenzyme A deficiency



Peripheral lipolysis


Triglyceride synthesis


Hepatic uptake of fatty acids

Insulin Resistance

In peripheral tissues, muscle and adipose, decreased uptake of glucose

In liver, failure of insulin to stimulate glycogen synthesis and suppress gluconeogenesisè failure of insulin to downregulate hepatic glucose production

Peripheral Insulin Resistance and failure of humoral mediator

Resulting in steatosis and NASH

Increased fatty acid uptake and synthesis (lipogenesis), suppression of mitochondrial B-oxidation, and impaired TG seretion as VLDL

Alternatively, steatosis and NASH coud be attributable to the combined effect of severe peripheral IR and relative failure of humoral (adipokine) mediators that combat the effects of high insulin levels and fasting hyperglycemia on hepatic lipid turnover.

Lipid Peroxidation & Hepatic Lipotoxicity

Free radicals initiate the process derived from fat metabolism, in the setting of preexisting defects in mitochondrial oxidative phosphorylation.


Free radical attack on unsaturated fatty acids

The products of the reaction are another free radical and a lipid hydroperoxide, forms a second free radical and, amplifies the process.


Imbalance between pro- and antioxidant substances (oxidative stress)

Cytokine Activation and Fibrosis

Lipoperoxide induce expression of inflammatory cytokines


Cytokine level elevation, especially TNF-α has been well described in NAFLD.

Adiponectin and Leptin (Adipocytokines)


A hormone secreted by adipose tissue

Enhance both lipid clearance from plasma and beta-oxidation of fatty acids in muscle.

Direct anti-inflammatory effects,

Suppressing TNF-alpha production in the liver


Coded for by the obesity gene & govern satiety through action at the hypothalamus

Elevated levels in NASH were attributed to factors involved in production.

No difference in leptin level was seen between patients with worsening injury or those without

Adiponectin and Leptin (Adipocytokines)

Adoponectin is a hormone secreted by adipose tissue

Enhance both lipid clearance from plasma and beta-oxidation of fatty acids in muscle.

It has also has direct anti-inflammatory effects, suppressing TNF-alpha production in the liver

Leptin is a circulating protein coded for by the obesity gene and produced primarily in white adipose tissue

Its level is increased in cirrhosis .

Its primary role is to govern satiety through action at the hypothalamus

Human obesity is usually associated with elevated leptin levels .

Elevated leptin levels in progressive NASH were attributed to factors involved in production; no difference in leptin was seen between patients with worsening injury or those without on serial biopsy

Resistance to leptin in the CNS rather than the liver may be important in the pathogenesis of NASH.

NAFLD—Natural History

Steatosis generally follows a benign course

Steatosis can progress to NASH ±  fibrosis

NASH with fibrosis has increased liver-related morbidity and mortality


A study of 103 patients who underwent serial liver biopsies (mean interval between biopsies of 3.2 years) found:

Fibrosis stage progressed in 37 percent

Remained stable in 34 percent

Regressed in 29 percent

Independent predictors of fibrosis progression


Diabetes mellitus,

Low initial fibrosis stage

Higher body mass index.

Elevated liver enzymes

Predictors of More Severe Histology in NASH

Age >40–50 y

Female gender

Degree of obesity or steatosis


Diabetes or insulin resistance


Elevated ALT,AST, γ-GT level

AST:ALT transaminase ratio >1

Elevated immunoglobulin A level


NAFLD—Exam Findings

NAFLD—Laboratory Findings

The AST/ALT ratio is usually less than 1(90%)

Antinuclear antibody positive in ~30%

Increased  IgA

Abnormal iron indices in 20% to 60%

Elevated PT and low albumin with cirrhosis

Alkaline phosphatase is less frequently elevated

Hyperbilirubinemia is uncommon


Normal labs do not rule out NAFLD



Difficulty in differentiating fibrosis from fatty infiltration

Misinterpretation of focal fatty sparing as a hypoechoic mass

Poor detection if the degree of steatosis is less than 20%  to 30%

As initial testing in a suspected case and for large population screening, it is a reliable and economical


Computed Tomography

Sensitivity and specificity of detecting fatty liver (with spleen-minus-liver attenuation of 10 Hounsfield units) were 0.84 and 0.99

M R Spectroscopy

Correlation between liver fat concentration and 1H-spectroscopy was 0.9

Demonstrates a heterogeneous-appearing echotexture “bright liver”
B.  Relatively hypodense liver compared to the spleen (liver-to-spleen ratio <1)

NAFLD—Histological Spectrum


NASH (without fibrosis)

Liver biopsy in NASH, Indications

Peripheral stigmata of chronic liver disease






Abnormal iron studies


Diabetes and/or significant obesity in an individual over the age of 45

Management Summary

There is no proven effective therapy for NASH.


Gradual, sustained weight loss is hallmark therapy


Attempts should be made to modify potential risk factors (obesity, hyperlipidemia, and poor diabetic control).


Rapid weight loss potentially worsening of liver disease


Gemfibrozil, & insulin sensitizers require further study


Clofibrate ,UDCA & Vitamin E is not useful in NASH.

Fatty change in heart cells

When cardiac muscle suffer hypoxia they burn glucose instead of fat by protein HIF-1.

HIF-1 activates genes that cause cardiac cells to produce & store fat.

Fatty myocardial cells can undergo necrosis.

Tigered effect myocardium pattern in prolonged hypoxia

Diffuse pattern in diphtheria toxin.

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