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

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بسم الله الرحمن الرحيم

NoushinAfsharMoghaddam, M.D

Associate Professor of Medicine

Pathology Department

Isfahan University of Medical Sciences


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Fatty liver


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


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  • 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

  • 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

  • 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

3

2

1


Normal liver1

Normal liver


Normal liver2

Normal liver


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Acute fatty liver of 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)

  • 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.


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  • There are exceptions to the rule,however, and it is not possible to define the etiology solely on the pattern of lipid distribution in the individual case.

  • Identification of the cause requires close clinicopathologic correlation.


What s the pathologist role

What’s the pathologist role?

  • 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

  • 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)

  • 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)

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 fatty liver disease

  • Alcoholic steatohepatitis or ASH

  • Non-alcoholic steatohepatitis or NASH


Ash vs nash

ASH vs. NASH

  • 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)

  • 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

  • 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

NAFLD

Steatosis

Steatohepatitis (NASH)

NASH with Fibrosis

Cirrhosis


Nafld simple steatosis

NAFLD, simple steatosis

  • 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


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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


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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 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


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Alcoholic steatohepatitis with neutrophilic acute hepatitis


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macrovesicular steatosis and ballooning


Ballooning degeneration

Ballooning degeneration


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Mallory

Body


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Mallory bodies: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)

Source: Ibdah 2003


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  • glycogen "in" hepatocyte nuclei


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Steatohepatitis:Some hepatocyte nuclei show glycogen vacuolation


Lipogranuloma

Lipogranuloma.


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Lipogranuloma.


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periportalhepatic steatosis, as may be seen due to steroid

use. Trichrome stain


Nafld nash with fibrosis

NAFLD—NASH (with fibrosis)

Source: Ibdah 2003


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Micrograph of inflamed fatty liver (steatohepatitis)


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


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(zone 3) sinusoidal fibrosis, typical of alcoholic


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Steatohepatitis with cirrhosis.


Cirrhosis

Cirrhosis


Nafld histological spectrum

NAFLD—Histological Spectrum

Cirrhosis

Time Progression

Fibrosis

Lobular Inflammation

Macrovesicular Steatosis


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Grading and staging the histopathologic

Lesions of NASH


Grade 1 mild

Grade 1(Mild)

  • 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)

  • 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)

  • 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


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Staging Fibrosis in NASH


Nash staging

NASH staging

  • 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

  • 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

  • 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


Multiple hit theory

Multiple Hit Theory

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

  • 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

  • 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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