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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
Pigments:
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
Hepatomegaly
pale, yellow color
greasy appearance
FATTY CHANGE
– 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
Definition
Prelevance
Risk Factors
Pathogenesis
Natural History
Clinical Features
Diagnosis
Treatment
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
Steatosis
Steatohepatitis (NASH)
NASH with Fibrosis
Cirrhosis
NAFLD—importance?
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
NAFLD—Pathogenesis
NAFLD—Pathogenesis
TRIGLYCERIDE ACCUMULATION
INSULIN RESISTANCE
Lipid Peroxidation and Hepatic Lipotoxicity
Cytokine Activation and Fibrosis
Adiponectin and Leptin (Adipocytokines)
Abnormal Lipoprotein Metabolism
TRIGLYCERIDE ACCUMULATION
The normal liver contains less than 5% lipid by weight
Excessive importation of FFA
Obesity
Rapid weight loss,excessive
conversion of carbohydrates and proteins to triglycerides
Impaired VLDL synthesis and secretion
Abetalipoproteinemia,
Protein malnutrition,
Choline deficiency
Impaired beta-oxidation of FFA to ATP
Vitamin B5 deficiency,
Coenzyme A deficiency
INSULIN RESISTANCE
Increased
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)
Adoponectin
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
Leptin
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
Hypertension
Diabetes or insulin resistance
Hypertriglyceridemia
Elevated ALT,AST, γ-GT level
AST:ALT transaminase ratio >1
Elevated immunoglobulin A level
NAFLD—Symptoms
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
NAFLD—Imaging
Ultrasound
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
Fatty Change | howMed Lectures
This movie requires Flash Player 9
Want a clearer concept, also see
Article on Fatty Change
Images on Fatty Change
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
Pigments:
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
Hepatomegaly
pale, yellow color
greasy appearance
FATTY CHANGE
– 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
Definition
Prelevance
Risk Factors
Pathogenesis
Natural History
Clinical Features
Diagnosis
Treatment
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
Steatosis
Steatohepatitis (NASH)
NASH with Fibrosis
Cirrhosis
NAFLD—importance?
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
NAFLD—Pathogenesis
NAFLD—Pathogenesis
TRIGLYCERIDE ACCUMULATION
INSULIN RESISTANCE
Lipid Peroxidation and Hepatic Lipotoxicity
Cytokine Activation and Fibrosis
Adiponectin and Leptin (Adipocytokines)
Abnormal Lipoprotein Metabolism
TRIGLYCERIDE ACCUMULATION
The normal liver contains less than 5% lipid by weight
Excessive importation of FFA
Obesity
Rapid weight loss,excessive
conversion of carbohydrates and proteins to triglycerides
Impaired VLDL synthesis and secretion
Abetalipoproteinemia,
Protein malnutrition,
Choline deficiency
Impaired beta-oxidation of FFA to ATP
Vitamin B5 deficiency,
Coenzyme A deficiency
INSULIN RESISTANCE
Increased
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)
Adoponectin
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
Leptin
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
Hypertension
Diabetes or insulin resistance
Hypertriglyceridemia
Elevated ALT,AST, γ-GT level
AST:ALT transaminase ratio >1
Elevated immunoglobulin A level
NAFLD—Symptoms
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
NAFLD—Imaging
Ultrasound
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