بسم الله الرحمن الرحيم
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بسم الله الرحمن الرحيم. Noushin Afshar Moghaddam , M.D Associate Professor of Medicine Pathology Department Isfahan University of Medical Sciences. Fatty liver. Steatosis.

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بسم الله الرحمن الرحيم

NoushinAfsharMoghaddam, M.D

Associate Professor of Medicine

Pathology Department

Isfahan University of Medical Sciences



Steatosis
Steatosis

Steatosis (fatty liver, fatty change) corresponds to accumulation of triglycerides in the cytoplasm of hepatocytes. It is a frequent finding and represents a manifestation of reversible cell injury


Fatty liver
Fatty Liver

  • Any amount of fat in liver histology

    • Mirovesicular or macrovesicular

    • With or without inflammation

    • With or without fibrosis

    • Associated with other disease or not

    • Alcohol related or not

  • Alcoholic fatty liver / Non alcoholic fatty liver


  • Steatosis is a nonspecific lesion induced by a variety of causes.

  • The degree of lipid accumulation is variable, ranging from occasional fat droplets to diffuse deposition involving most parenchymal cells.

  • Minor amounts of steatosis are of uncertain significance, and occur more frequently in elderly people, possibly as part of the aging process.

  • More extensive steatosis is seen in a variety of primary hepatic diseases and ,in several systemic conditions.


Histologic preparation
Histologic preparation causes.

  • Histologically, in routinely fixed tissue, steatosis is represented by cytoplasmic vacuoles as the lipid is dissolved during processing. Very small droplet steatosis may be difficult to recognize.

  • Lipid can be demonstrated in frozen sections using oil red 0, or Sudan black, or in tissue that has been postfixed in osmium tetroxide.


Patterns and distribution
Patterns and distribution causes.

  • Macrovesicular and microvesicular steatosis.

  • Both may occur together to some extent in the same biopsy specimen, suggesting that large droplets form through coalescence of small lipid vacuoles.


Normal liver
Normal liver causes.

3

2

1


Normal liver1
Normal liver causes.


Normal liver2
Normal liver causes.


Acute fatty liver of causes. pregnancy. Detail of lobular parenchyma characterized by microvesicular steatosis and a small number of lymphocytes. (H&E)


Macrovesicular steatosis large droplet fatty change
Macrovesicular steatosis (large droplet fatty change) causes.

  • It is the most common pattern.

  • Uncomplicated macrovesicular steatosis used to be regarded as a benign and potentially fully reversible lesion, but this notion has been challenged

  • Its zonal distribution is variable.

  • It is most often centrolobular, :alcoholic liver disease, obesity, and diabetes.

  • In more severe degrees, the steatosis may become panlobular.

  • Steatosis in periportal zones is more commonly seen in cachexia and protein-energy malnutrition (kwashiorkor), in acquired immune deficiency syndrome (AIDS), after total parenteral nutrition, with phosphorus poisoning, and in steroid therapy.



What s the pathologist role
What’s the pathologist role? possible to define the etiology solely on the pattern of lipid distribution in the individual case.

  • The pathologist should provide information on severity by indicating the approximate amount of parenchyma involved (mild: less than one third; moderate: one third to two thirds; severe: more than two thirds).

  • Further useful information for the clinician is the finding of a mixed pattern of macro- and microvesicular steatosis because this may be of prognostic importance in relation to alcoholic liver disease.


Pathogenesis
Pathogenesis possible to define the etiology solely on the pattern of lipid distribution in the individual case.

  • The pathogenesis of steatosis is complex.

  • Alterations at many points of the complicated pathway of lipid metabolism can lead to accumulation of neutral fat within hepatocytes.


Microvesicular steatosis small droplet fatty change
Microvesicular steatosis (small droplet fatty change) possible to define the etiology solely on the pattern of lipid distribution in the individual case.

  • It is often more difficult to recognize, and its demonstration may require histochemistry.

  • It is generally a serious lesion associated with impairment of β-oxidation of lipids and frequently accompanied by disturbed liver function and coma.


Microvesicular steatosis small droplet fatty change1
Microvesicular steatosis (small droplet fatty change) possible to define the etiology solely on the pattern of lipid distribution in the individual case.

The causes are multiple.

  • Acute fatty liver of pregnancy

  • Reye's syndrome

  • Salicylates

  • Sodium valproate

  • Intravenous high dose tetracycline

  • Ethanol (in a small proportion of patients)

  • Inborn errors of mitochondrial fatty acid β-oxidation

  • Inherited urea cycle disorders


Classification of fatty liver disease
Classification of possible to define the etiology solely on the pattern of lipid distribution in the individual case.fatty liver disease

  • Alcoholic steatohepatitis or ASH

  • Non-alcoholic steatohepatitis or NASH


Ash vs nash
ASH vs. NASH possible to define the etiology solely on the pattern of lipid distribution in the individual case.

  • No qualitative histologic differences.

  • When large groups of patients compared: alcoholics tend to develop more severe disease.

  • NASH usually associated with:

    • more:

      • fat

      • nuclear glycogen

    • less:

      • hepatocellular damage

      • inflammation

      • fibrosis

      • Mallory bodies


Non alcoholic fatty liver disease nafld
Non-Alcoholic Fatty Liver Disease (NAFLD) possible to define the etiology solely on the pattern of lipid distribution in the individual case.

  • Defined as:

    • Deposition of fat droplets in hepatocytes

    • AND the absence of significant alcohol intake

      • Generally defined as less than ( 140gr ) ethanol per week

  • NAFLD is a range of conditions from near normal liver to cirrhosis


Other terms
Other Terms possible to define the etiology solely on the pattern of lipid distribution in the individual case.

  • Simple non-alcoholic fatty liver disease (NAFLD)

    • Only deposition of fat in liver

    • No inflammation or fibrosis

  • Non-Alcoholic Steatohepatitis (NASH)

    • NAFLD with inflammation(lobular or portal), hepatocyte ballooning, or fibrosis

    • Absence of serologic evidence of infection with hepatitis B or hepatitis C, …

    • Exclude viral hepatitis,autoimmune and metabolic diseases


Nafld spectrum of disease
NAFLD—Spectrum of Disease possible to define the etiology solely on the pattern of lipid distribution in the individual case.

NAFLD

Steatosis

Steatohepatitis (NASH)

NASH with Fibrosis

Cirrhosis


Nafld simple steatosis
NAFLD, simple steatosis possible to define the etiology solely on the pattern of lipid distribution in the individual case.

  • Fatty Liver

    • Only deposition of fat in liver

    • No inflammation

    • No fibrosis

    • Not believed to progress to cirrhosis

    • Up to 25 % of some populations!


Nafld steatosis
NAFLD—Steatosis possible to define the etiology solely on the pattern of lipid distribution in the individual case.


Histological section of a murine liver showing severe steatosis. The clear vacuoles would have contained lipid in the living cells, however the histological fixation caused it to be dissolved and hence only empty spaces remain


Deficiency of glucose-6-phosphatase results in accumulation of glycogen in hepatocytes. The liver is enlarged. The hepatocytes are swollen and a mosaic histological pattern with compression of the sinusoids is seen. Macro- and/or microvesicular steatosis can be present


Histological features considered necessary for the diagnosis of nash
Histological features considered necessary of glycogen in hepatocytes. The liver is enlarged. The hepatocytes are swollen and a mosaic histological pattern with compression of the sinusoids is seen. Macro- and/or microvesicular steatosis can be present for the diagnosis of NASH

  • Steatosis of varying morphology:

  • Predominantly macro vesicular

  • Mixed lobular inflammation

  • Hepatocellular ballooning generally in zone 3

  • Other findings:

  • Perisunuzoidal fibrosis

  • Mallory’s bodies,fatcysts,glycogented nuclei

  • Acidophil bodies in kuppfer cells

  • Megamitochondria

  • Lipogranuloma



macrovesicular hepatitissteatosis and ballooning



Mallory hepatitis

Body


Mallory hepatitisbodies:homogenouseosinophilicperinuclear

inclusions of variable size and shape. It composed of

hyperphosphorylated CK (7, 18, 19) together with

Ubiquitin heat shock protein.


Nafld nash without fibrosis
NAFLD—NASH (without fibrosis) hepatitis

Source: Ibdah 2003


  • glycogen hepatitis "in" hepatocyte nuclei



Lipogranuloma
Lipogranuloma vacuolation.


Lipogranuloma vacuolation.


periportal vacuolationhepatic steatosis, as may be seen due to steroid

use. Trichrome stain


Nafld nash with fibrosis
NAFLD—NASH (with fibrosis) vacuolation

Source: Ibdah 2003


Micrograph of inflamed fatty liver ( vacuolationsteatohepatitis)


Pericellular collagen and Mallory bodies (asterisks) in ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.


(zone 3) sinusoidal fibrosis, typical of alcoholic ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.


Steatohepatitis with cirrhosis. ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.


Cirrhosis
Cirrhosis ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.


Nafld histological spectrum
NAFLD—Histological Spectrum ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.

Cirrhosis

Time Progression

Fibrosis

Lobular Inflammation

Macrovesicular Steatosis


Grading and staging the ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain. histopathologic

Lesions of NASH


Grade 1 mild
Grade 1(Mild) ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.

  • Steatosis:predominantly macrovesicular,involves ‹33% up to 66% of the lobules

  • Ballooning: occasionally observed in zone 3

  • Lobular inflammation:scattered and mild acute (PMNs) inflammation and occasional chronic inflammation (mononuclear cells)

  • Portal inflammation:none or mild


Grade 2 moderate
Grade 2 (Moderate) ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.

  • Steatosis: any degree and usually mixed macrovesicular, and microvesicular

  • Ballooning: obvious and present in zone 3

  • Lobular inflammation: PMNs may be noted with ballooned hepatocytes and pericellular fibrosis; mild chronic inflammatory cells may be seen.

  • Portal inflammation: mild to moderate


Grade 3 severe
Grade 3 (Severe) ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.

  • Steatosis:>66%(panacinar);commonly mixed type

  • Ballooning: predominantly in zone 3;marked

  • Lobular inflammation: scattered acute and chronic inflammation;PMNs may appear concentrated in zone 3 areas of ballooning and perisinozoidal fibrosis.

  • Portal inflammation: mild to moderate


Staging Fibrosis in NASH ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.


Nash staging
NASH staging ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.

  • Stage 1:Zone 3 perivenularperisinozoidal/ pericellular fibrosis, focal or extensive

  • Stage 2:As above with focal or extensive periportal fibrosis

  • Stage 3:Bridging fibrosis,focal or extensive

  • Stage 4:Cirrhosis


Nash causes
NASH/causes ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.

  • jejunoileal bypass surgery, gastroplasty

  • rapid and profound weight loss in obese subjects

  • total parenteral nutrition

  • drugs' (amiodarone,perhexiline maleate, estrogens and estrogen receptor ligands, methotrexate)

  • occupational hepatotoxicity

  • disorders characterized by extreme insulin resistance

  • In most cases the etiopathogenesis of NASH appears multifactorial (obesity, type 2 diabetes,and hypertriglyceridemia)

  • the hepatic consequence of the metabolic syndrome or cardiovascular dysmetabolic syndrome or syndrome X


Risk factors for nafld in children
Risk Factors for NAFLD in Children ballooned hepatocytes are stained blue. Chromotrope Aniline Blue stain.

  • Presence of Insulin Resistance

  • Diabetes

  • Consumption of foods high in sugar and calories

    • Soft drinks /cola

    • Fast and junk food

  • High Fructose intake

  • Lack of exercise

    • Time spent on TV/video games


Ludwig et al proposed a subclassification to include etiopathogenesis
Ludwig(et.al) proposed a subclassification to include etiopathogenesis:

  • Primary NASH

    (related to obesity and insulin resistance)

  • Secondary NASH

    (post bypass surgery, drugs, and toxins)


Pathogenesis1
Pathogenesis etiopathogenesis:


Multiple hit theory
Multiple Hit Theory etiopathogenesis:

Normal Liver

Hit 1: ? Insulin resistance, endotoxins, …

 Fat accumulation

Fatty Liver

Hit 2: ? Oxidative stress, …

 Inflammation

Steatohepatitis

Hit 3: ? Oxidative stress, …

 Fibrosis

Cirrhosis

May loose fat


Nash diagnosis
NASH, Diagnosis etiopathogenesis:

  • Most patients are asymptomatic.

  • Hepatomegaly is the most common physical finding.

  • ALT / AST > 1, usually not so high

  • Ultrasound will demonstrate a fatty or “bright liver.”

  • In CT, the liver is darker than the spleen

  • Liver biopsy is required


Summary
Summary etiopathogenesis:

  • The prevalence of NASH (2-3%) is comparable to the prevalence of hepatitis B, and much larger than the prevalence of hepatitis C

  • Since hepatitis B is being vaccinated for, we will be seeing less of this disease in the future

  • But obesity is on the rise. (as is hepatitis C)

  • It can be concluded that in the near future, NASH and hepatitis C will be the major liver diseases we will be facing in Iran


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