Metabolic Diseases and NASH

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Metabolic Diseases and NASH

• Ankur Gupta
• Be Phan
• Steve Lee
• Trinh Kazmierski

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INTRODUCTION

• Metabolism the process your body uses to get or
  make energy from the food you eat
• Metabolic disorder occurs when one or more steps
  in the metabolic pathway are disrupted

HOW ARE METABOLIC DISORDERS RELATED TO
NASH? Metabolic disorders are a major risk factor
leading the development of NASH.
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NASH DISEASE

• NAFLD Non-Alcoholic Fatty Liver Disease
• NAFLD fat accumulation in the liver exceeding
  5-10 by weight
• Those diagnosed with NAFLD may progress to NASH
• NASH Non-Alcoholic SteatoHepatitis
• NASH resembles alcoholic liver disease, but
  occurs in those who drink little or no alcohol
• May progress to cirrhosis
• Cirrhosis irreversible scarring of the liver
  resulting in impairment of blood flow through the
  liver and impairment of liver function

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THE LIVER
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RISK FACTORS

• Obesity (gt70)
• Diabetes mellitus (up to 75)
• Hyperlipidemia
• Insulin resistance
• Metabolic factors (malnutrition dieting)
• Abdominal surgery
• Drugs toxins
• Other medical conditions

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SIGNS SYMPTOMS

• Silent liver disease
• NASH progression results in following symptoms
• Fatigue
• Unexplained weight loss
• General weakness
• Aching in upper stomach area
• Cirrhosis of the liver
• Fluid build up in legs and abdomen
• Yellowing of skin
• Nosebleeds
• Blood in stool

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DIAGNOSIS

• Medical history
• Blood tests to rule out other liver diseases
• Liver Function Tests (LFT)- alanine amino
  transferase OR aspartate amino transferase
  elevated in 90 of cases, but not conclusive
• Imaging tests- reveal fat accumulation in the
  liver, but difficult to distinguish from other
  liver diseases
• Liver biopsy (most conclusive)

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Proposed Progression of NASH Disease
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BIOCHEMICAL BACKGROUND

• NASH is a multi-faceted disease with many
  biological factors associated with the
  progression from bland steatosis to NASH
  including
• Insulin resistance
• Cytokine imbalance favouring inflammation
• Susceptibility to oxidative stress
• Genetic predisposition
• Others

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BIOCHEMICAL PATHWAYS INSULIN RESISTANCE
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INSULIN RESISTANCE

• Insulin a peptide hormone that promotes the
  synthesis of energy storage molecules, such as
  the synthesis of triglycerides from fatty acids
• Insulin resistance impairment in
  insulin-stimulated glucose uptake to promote
  glucose storage Insulin resistance results in
  increase lipolysis causing the breakdown of fats
• Lipolysis results in increase of free fatty acids
  (FFAs) released into circulation
• Influx of FFAs to the liver increases FFA
  oxidation
• FFA oxidation increase creates high levels of
  reactive oxygen species (ROS) resulting in liver
  damage

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BIOCHEMICAL PATHWAY CYTOKINE IMBALANCE
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CYTOKINE IMBALANCE

• Damage is caused by fat accumulation and
  resulting lipotoxicity leads to activation of
  intracellular signaling pathways, leading to
  expression of several cytokines that are
  responsible for recruitment of inflammatory cells
• Events lead to a vicious circle that causes
  worsening of liver damage, further inflammation,
  maintenance of steatosis, disease progression,
  and insulin resistance.

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TREATMENT

• No specific drug treatments for NASH exist
• In some cases, disease progression can stop and
  even reverse on its own without treatment
• In other cases, disease can slowly get worse,
  leading to cirrhosis
• NASH progresses to advanced liver disease in
  about 15-20 of cases

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ROLE OF THE PHARMACIST

• Pharmacists can help patients manage the
  underlying conditions that contribute to liver
  damage by educating patients on
• Reducing cholesterol levels
• Losing weight
• Controlling diabetes
• Reducing alcohol consumption
• Stopping the use of medicines that may be
  exacerbating symptoms

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TREATMENT
Remember to Keep Fit and Have Fun!!
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SUMMARY SLIDE

• Proposed causes
• Insulin resistance 2.
  Release of toxic inflammatory proteins by
• 
  fat cells (cytokines)

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REFERENCES

• BCHealth Guide Program. (2007). Non-alcoholic
  steatohepatitis (NASH). Retrieved February 19,
  2008, from http//www.bchealthguide.org/kbase/topi
  c/special/ut1396spec/sec1.htm.
• Marra, F. et al. (2008). Molecular basis and
  mechanisms of progression of non-alcoholic
  steatohepatitis. Electronic versions. Trends in
  Molecular Medicine, 14 (2), 72-81.
• National Digestive Diseases Information
  Clearinghouse (NDDIC). (2003) Cirrhosis of the
  Liver. Retrieved February 19, 2008, from
  http//digestive.niddk.nih.gov/ddiseases/pubs/cirr
  hosis.
• Smith, C. (2005). Basic Medical Biochemistry (2nd
  ed.). Baltimore Lippincott Williams Wilkins
• Stanfield, C.L. Germann, W.J. (2008).
  Principles of Human Physiology (3rd ed.). San
  Francisco Pearson.
• U.S. National Library of Medicine the National
  Institutes of Health. (2008) Metabolic Disorders.
  Retrieved February 19, 2008, from
  http//www.nlm.nih.gov/medlineplus/metabolicdisord
  ers.html.
• Yoneda, M. et al. (2007). Life Style-Related
  Diseases of the Digestive System Gene Expression
  in Nonalcoholic Steatohepatitis Patients and
  Treatment Strategies. Electronic version.
  Journal of Pharmacological Sciences, 105,
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