Disorders Affecting the Gastrointestinal System Flashcards
Hirschsprung Disease
- MEGACOLON
- NEUROCRISTOPATHOLOGY: Aberration in Neural Growth, Migration, and differentiation during embryological development
Two Forms:
1) SHORT SEGMENT FORM:
- Approximately 80% of Cases
- AGANGLIONIC Segment DOES NOT Extend beyond the Upper Sigmoid
2) LONG SEGMENT FORM
- L- HSCR
- AGAGLIONOSIS Extends PROXIMAL to the SIGMOID
- Can also be called TOTAL COLONIC AGANGLIONOSIS or Total HSCR!!!
Hirschsprung Disease Cont
- Congenital absence of INTRINSIC GANGLION CELLS in the MYENTERIC (Auerbach) and SUBMUCOSAL (Myenteric) Plexuses of the Gastrointestinal Tract
- Enteric Neurons are organized in Ganglia, found within TWO MAIN PLEXI. An outer Myenteric Plexus develops FIRST and occupies a position between the LONGITUDINAL and CIRCULAR MUSCLE LAYERS. An Inner Submucosal Plexus forms alter in Gestation and resides within the SUBMUCOSA
Clinical Presentation of Hirschsprung Disease
- Intestinal Obstruction
- Colon DISTENTION form a LACK OF PERISTALSIS
- Variability depends on Region affected
- Isolated Disease (70% of Cases)
SYNDROME ASSOCIATED:
a) 12% DOWN SYNDROME: Most Frequent Chromosomal Abnormality in association!!!!!!!!!
b) 2% BARDET-BIEDL Syndrome
c) 9% Cartilage-Hair Hypoplasia Syndrome
INCIDENCE VARIES (5000 Live Births)
a) Whites = 0.75
b) Blacks = 1.05
c) Asians = 1.4
d) Male: Female = 4:1!!!!!!!!
Genetics
RET
MOI:
- AD
Location:
Chr 10q11.2
Protein Function:
- Tyrosine Kinase Receptor
Frequency:
- 70 to 80%
- 50% Familial
- 15 to 20% Sporadic
RET Gene
- PROTO-ONCOGENE: Genes that code for Protein that help Regulate Cell Growth
- Expressed in NEURAL CREST CELLS
- Responsible for MEN (Multiple Endocrine Neoplasia) Syndromes:
- ***GAIN OF FUNCTION MUTATIONS: A Type of Mutation in which the Altered Gene product possesses a New Molecular Function or a New Pattern of Gene Expression
- HIRSCHPRUNG DISEASE:
- ** LOSS OF FUNCTION MUTATIONS result in REDUCED or ABOLISHED Protein Function
RET Gene Cont
- The RET Gene provides instruction for producing a Protein that is involved in signaling WITHIN Cells, including Nerves in the Intestine
- Mutations in the RET Gene that cause Hirschsprung Disease result in a NONFUNCTIONAL Version of the RET protein that CANNOT transmit signals within cells
- Without RET protein Signaling, Enteric Nerves DO NOT Develop Properly
Liver Disorders
1) Alpha Antitrypsin (AAT) Deficiency:
- Jaundice, Cirrhosis
2) Hereditary Hemochromatosis!!!!!
- Secondary Hemochromatosis
3) Wilson Disease and Menkes Syndrome!!!!!!
Iron is Controlled by the Need for Hemoglobin
- Male: 1 to 2 mg/day
- Female: 2 to 3 Menstruating, Pregnant 6 to 7 mg/day
- Iron lost ONLY through Enterocyte Shedding
- Iron is bound and transported in the body via TRANSFERRIN and stored in FERRITIN Molecules (Liver and Heart)
- Most recycled in formation of Erythrocytes
- No Physiological Mechanism for Excretion of Excess IRON from the Body other than Blood Loss, Pregnancy, Menstruation or other Bleeding
Iron Overload
1) TOO MUCH is ABSORBED
- Iron in Excess of Transferrin Binding Capacity
- Deposited in Liver, Heart, and some Endocrine Tissues
- Can lead to Tissue Damage and Fibrosis
2) TOO MANY ERYTHROCYTES ARE DESTROYED
- Accumulates in RETICULOENDOTHELIAL MACROPHAGES FIRST!!!!!!!!
- Tissue PARENCHYMA after Macrophages
Secondary Hemochromatosis a Build-up of Iron due to Anemia, Chronic Liver Diseases, often a result of Hepatitis C infection or Alcoholism. Frequency Blood Transfusions*
Important Genes in Iron Absorption Regualtion
1) HFE:
- Protein: HFE
* ** Responsible for MOST COMMON Form of Iron Overload: HEMOCHROMATOSIS
2) HJV:
- Protein: Hemujuvelin
* ** Responsible for Most Cases of JUVENILE HEMOCHROMATOSIS; Rare but have SEVERE IRON OVERLOAD
3) TFR2:
- Protein: Transferrin Receptor 2
* ** Less Common but with Similar Clinical Presentation to HFE Mutation
4) HAMP:
- Protein: HEPCIDIN!!!!!!!
* ** Hepcidin a Irone-Regualting Hormone Critical for Absorption
Factors Increasing Iron Absorption
- Inadequate Diet
- Impaired Absorption
- Celiac Disease
- GI Bleeding
- Anemias, Decreased Erythropoiesis
- Hypoxia
Factors Decreasing Iron Absorption
- Regular Blood Transfusions
- High Iron Diet
- Iron Loading Vitamins
Iron Regulation
- Human Hemochromatosis Protein: HFE, Functions to REGULATE CIRCULATION Iron Uptake by regulating the interaction of TFR1/2 with TRANSFERRIN
1) HEPCIDIN: A Key regulator of the Entry of Iron into the Circulation
2) TRANSFERRIN:Iron Binding Blood Plasma Glycoprotein txt Controls the Level of Free Iron in Biological Fluids
3) TFR1: Protien required for Iron Import from TRANSFERRIN into Cells by Endocytosis
4) TFR2: Protien involved in the Uptake of Transferrin-bound Iron into Cells by Endocytosis, although its Role is MINOR Compared to TFR1
5) FERROPORTIN: Transmembrane Protein that Transports Iron from the INSIDE of a cell to the OUTSIDE of the Cell. INHIBITED by HEPCIDIN, results in the RETENTION of IRON
Example of Iron Regulation
- Hepcidin Secretion from the Liver is REGULATED by HFE PROTIEN, HJV, and the TFR2 Signaling Pathways
1) In states of IRON DEFICIENCY, Hepcidin levels are LOW and the Iron Transport Protein FERROPORTIN allows Entry of Iron from DUODENAL Enterocytes into the blood and the Recircualtion of Iron from Macrophages into the Plasma
2) In states of IRON EXCESS, Hepcidin levels INCREASE and this promotes the Internalization and Degradation of the Ferroportin and results in DECREASED IRON ABROPTION from the Gut and DECREASED Release from Macrophages - Mutation in HFE, HJV, or TFR2 result in LOW HEPCIDIN Levels despite HIGH IRON Levels and Inappropriate continued Transport of Iron into the Plasma
Iron Regulation
1) Fe2+ Transported by TRANSFERRIN
- Bind 2 Molecules
- Transferrin and HFE Compete for Binding Sites at TFR1 Receptor
- Hepatocyte and other Cells
- Transferrin binds TFR1 BETTER THAN HFE
- Unbound HFE is then ELEVATED on Cell Surface which STIMULATES HEPCIDIN EXPRESSION
2) Too much Fe2+ causes more TFR2 to be produced than TFR1
- Transferrins bind more TFR2 than TFR1 because more is expressed
- TFR2 binding stimulates HEPCIDIN Expression —————————-> Hepcidin DOWN REGULATES Transport of F22+ out of Enterocytes
Hepcidin Regulates Fe2+ Intake
- When Fe2+ is ELEVATED, Hepcidin ELEVATED!!!!!!
- *** More TFR2 is Produced and Binding Transferrin and more HFE is Free. Both Stimulate HEPCIDIN Expression!!!
- Hepcidin acts on FERROPORTIN
- FERROPORTIN Internalizes and DEGRADES ——————————————–> Decreases Fe2+ Transfer to Body!!!!!!!!!!
