introduction to nonalcoholic fatty liver disease

Nonalcoholic Fatty Liver Disease (NAFLD) Is A Burgeoning Health Problem That Affects One-Third Of Adults And An Increasing Number Of Children In Developed Countries. The Disease Begins With The Aberrant Accumulation Of Triglyceride In The Liver, Which In Some Individuals Elicits An Inflammatory Response That Can Progress To Cirrhosis And Liver Cancer. Although NAFLD Is Strongly Associated With Obesity And Insulin Resistance, Its Pathogenesis Remains Poorly Understood, And Therapeutic Options Are Limited. Here, We Discuss Recent Mechanistic Insights Into NAFLD, Focusing Primarily On Those That Have Emerged From Human Genetic And Metabolic Studies.

The Liver Biopsy Remains The Gold Standard For The Definitive Diagnosis Of NASH.

Biochemical Tests Are None Reliable Biomarkers Associated Wit Severe Increases Of Liver Enzymes.

The Ultrasound Is Most Often Used And Provides A Qualitative Assessment Of Hepatic Fat Content.CT, MRI, MR Spectrometry Offer Greater Sensitivity For Detecting Lesser Degree Of Steatosis.

Histopathologic Features Of NAFLD And NASH Are: Steatosis (From 5% Of Hepatocytes) And Additional Changes Such As Lobular Inflammation, Hepatocellular Ballooning And Necrosis, The Presence Of Mallory-Denk Bodies And Pericellular Fibrosis.

PRECLINICAL ANIMAL MODELS

There Is An Urgent Need Of Preclinical Models In Order To Understand The Disease Pathogenesis And To Assess Efficacy Of Potential Drug Candidates/ The Available Animal Models Are Not Considered Fully Adequate.

The Ideal Animal Model Represents The Model Which Is Representative Of The Human Disease. The Disease Is Not Requiring Gene Mutations And often Correlates With The Diet And Obesity. The Disease Is Part Of a Metabolic Syndrome And Demonstrates a Systemic Inflammatory State Extending Into The Visceral Adipose Tissue. From A Pathogenesis point of View There Is Activation Of Cellular Signaling Pathways.

The Histopathology Of The Disease In Animals Should Show Concordance With The Human Disease And Progression To Fibrosis And Hepatocellular Cancer.

Non-alcoholic fatty liver and steatotic hepatitis are one of the most common complex Progressive Hepatitis diseases of this century which are not related to Alcohol neither viral infections.It is strongly associated With a metabolic syndrome, including obesity, insulin resistance/type 2 diabetes and dyslipidemia. Overall, it is a leading cause of chronic liver disease affecting 30% of the general population in US and Western Europe.

SCORING SYSTEMS OF PRECLINCAL MODELS

Clinical Samples are Limited To Very Small Needle Biopsies And So, The Scoring Systems In Human Pathology Have Been Built With This Limitations.

the Animal Model must Accurately Reproduce The Nature And Dynamic Of Human Features Of NASH. often Animal models show limitations and so, The full translatability Of The human scoring System To Current Animal Models is often Difficult. Histopathological Features Such As Ballooning or Degeneration are Rarely Seen In Rodents And Appear To Be Over Diagnosed In Model Publications. Balloon Degeneration Is An Extreme Case Of Hydropic Degeneration And Is Often Mistaken For Micro-Vacuolation. A well trained Toxicological - veterinary pathologist can make the difference and provide you reliable data.

FREQUENTLY ASKED QUESTIONS FROM RESEARCHERS

  1. Is Target Expression And Localisation Comparable Between Animal Model And Diseased Man Liver ? YES: Animal Model Translatability Can Be Assessed By Careful Molecular Localisation. Integrin-Beta 6 In Translation Can Be Assessed By Careful Molecular Localisation In Animal Models.

  2. Does Bile Duct Play A Role In The Hepatic Fibrinogenesis ? YES: Ductular Reaction Refers To Proliferation Of Ductular Type Epithelium Believed To Represent Activation And Proliferation Of Hepatic Progenitor Cells. It Correlates Closely With The Severity Of Fibrosis Across A Range Of Human Liver Diseases Including Hepatitis C, Alcoholic And Nonalcoholic Steato-Hepatitis And Hemochromotosis. Although, The Role Of Ductular Reaction In Hepatic Fibrinogenesis Is Not Clearly Established.

  3. Is Quantification Possible In NASH ? YES, Quantitative Image Analysis Is Usually Used To Normalise The Readouts Assuming That The Treatment Has No Effect On Area/Volume Of The Liver. The Total Area Of The Liver Can Not Be Used As A Denominator Of The Ratio Because Of The Total Area Of The Liver. Subtraction Of The Fat Area Improved The Accuracy Of The Evaluation. Other Possible Methods Are Assuming Weight = Volume And Apply The Principles Of Stereology To Calculate The Absolute Area

  4. What Are The Most Common Diagnosis Used The NASH Animal Models For Scoring Systems The Scoring Systems May Vary As No Ideal Scoring System Exists. The Main Features Are Steatosis, Inflammation, Fibrosis & Hepatic Ballooning. All histopathological evaluations should Follow the best practice guidelines For the society of toxicological pathologists.