PathogenesisReview

September 17, 2012

Ashkan Afshin, MD, MPHScD Candidate, Department of Epidemiology

ScD Candidate, Department of Global Health & Population

Harvard School of Public Health

Kresge Building, Room 913

677 Huntington Avenue

Boston, Massachusetts 02115

Phone: (949) 235-6137

Email: aafshin@hsph.harvard.edu

Review Sessions

September 17, 2012 7:30-8:30pm Pathogenesis

September 24, 2012 7:30-8:30pm Neuropathophysiology

October 1, 2012 7:30-8:30pm Neuropathophysiology

Format:

• Brief review of the last lecture (20 min)• Discussing the questions received by email (10 min)• Q & A (30min)

Questions

Please send your questions or suggestions to:

Text Message:  (949) 235-6137 Email: aafshin@hsph.harvard.edu

Factors that Contribute to Disease

Intrinsic Factors Hereditary factors (Genetic Disorders) Immunologic factors (Immune Dysfunction, allergies,

autoimmune diseases, immunodeficiencies) Psychological factors (depression)

Extrinsic Factors Biological factors (Bacteria, Virus, Fungi, etc.) Nutritional factors (Iron deficiency Anemia) Physical factors (radiation, temperature, electricity, etc. ) Chemical factors (dugs, carbon monoxide, acids, etc.)

Mutation

A mutation is an error in the genetic code, causing you to make an incorrect form of the protein

Genetic diseases: cystic fibrosis, sickle cell anemia.

BRCA Genes BRCA1 is expressed in the cells of breast and other tissue.

Helps repair damaged DNA, or destroy cells if DNA cannot be repaired.

If BRCA1 is damaged, damaged DNA is not repaired properly and this increases risks for cancers

BRCA2 belongs to the tumor suppressor gene family. The protein encoded by BRCA2 is involved in the repair of

chromosomal damage with an important role in the error-free repair of DNA double strand breaks.

BRCA Genes BRCA1 and BRCA 2 are associated with increased risk of breast

cancer, and prostate cancer. BRCA2 increases the risk of pancreatic cancer.

Cancer Prevalence in

General Population Prevalence in

BRCA1 (+) or BRCA2 (+)

Breast 13.20% 36-85%

Ovarian 1.7%  16-60%

Gene-environment Interactions

Some genes promote disease, but only under certain environmental conditions.

Example?

Thrifty Gene Hypothesis

Thrifty Genes: Genes which enable individuals to efficiently collect and process food to deposit fat during periods of food abundance.

Thrifty Gene Hypothesis: populations whose ancestral environments were characterized by periods of feast and famine experienced positive selection for Thrifty Genes. Under modern conditions, populations with such thrifty metabolisms are expected to have high rates of diabetes and obesity. (e.g., Pima Indians) 

Pima Indians

Among Pima Indians living in the US 75% of Adult Pima Indians are obese 50% have type II diabetes

Among Pima Indians living a more traditional lifestyle in Mexico Most are not obese About 10% have diabetes

Epigenetics

Altered expression of genes based on environment during critical periods of development.

Can explain discrepancy between genotype and phenotype

Can be persist for generations May also explain why adult lifestyle and genetic

background alone fail to predict who is at greatest risk of heart disease and other conditions.

DNA Methylation One mechanism of Epigenetic change

https://www.hgu.mrc.ac.uk/Research/Meehan/images/4.jpg

Injury and Toxicity

Injury can be caused by trauma or by toxic exposure

The significance of an injury depends on how much extra capacity an organ has leftover.

Safety factor: How much beyond the expected maximal load a

structure is designed to handle Ratio of capacity to load

Biological Safety Factors(ratio of capacity to load)

Human Pancreas (enzyme secretion) About 10

Human Kidney (plasma filtration) About 4

Human Mammary Gland (milk production) About 3

Mammalian Lungs (aerobic capacity) About 1.25 - 2

From: Jared Diamond “Quantitative Evolutionary Design’ J. Physiol 2002, 542: 337-345

Inflammation

Signs Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain)

Biologic Mechanisms Increased blood flow to affected area Increased capillary permeability Movement of phagocytic cells into site of

injury

Is inflammation a good thing or a bad thing?

Good: Helps with defense against infection Helps with tissue repair

Bad: Causes pain Can damage healthy tissue Sometimes occurs inappropriately, eg: allergy,

autoimmune disease Chronic inflammation as been implicated in atherosclerosis,

which increases risk of heart attack and stroke

How do Cells and Tissues Respond to Stress?

Normal Cell

or Tissue

Adaptive Changes

Maladaptive Changes

(generally reversible)

Irreversible Damage

(Cell death)

Necrosis vs Apoptosis Necrosis

Generally a pathological process Promotes inflammation Often leads to loss of function

Apoptosis Often part of normal development Can minimize the “biological backfire”

associated with injury Minimizes loss of function