Disorders Affecting the Gastrointestinal System Flashcards Preview

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Flashcards in Disorders Affecting the Gastrointestinal System Deck (41):
1

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!!!

2

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

3

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!!!!!!!!

4

Genetics

RET

MOI:
- AD

Location:
Chr 10q11.2

Protein Function:
- Tyrosine Kinase Receptor

Frequency:
- 70 to 80%
- 50% Familial
- 15 to 20% Sporadic

5

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

6

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

7

Liver Disorders

1) Alpha Antitrypsin (AAT) Deficiency:
- Jaundice, Cirrhosis

2) Hereditary Hemochromatosis!!!!!
- Secondary Hemochromatosis

3) Wilson Disease and Menkes Syndrome!!!!!!

8

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

9

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****

10

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

11

Factors Increasing Iron Absorption

- Inadequate Diet
- Impaired Absorption
- Celiac Disease
- GI Bleeding
- Anemias, Decreased Erythropoiesis
- Hypoxia

12

Factors Decreasing Iron Absorption

- Regular Blood Transfusions
- High Iron Diet
- Iron Loading Vitamins

13

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

14

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

15

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

16

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!!!!!!!!!!

17

Too Little HFE

- Decreased UNBOUND HFE (Increased Bound HFE) leads to DECREASED TFR2 ------------------------------->

- Resulting in DECREASED HAMP Expression ------------------------------------------- (Hepcidin) ------>

- Leading to INCREASED Fe2+ Transfer out of Enterocytes

18

Characteristics of Hemochromatosis

- Late ONSET Generally: 40 to 50s in Males
- Later onset in Females

- Nonspecific Early Symptoms:
a) Fatigue
b) Arthralgia
c) Erectiel Disfunction
d) Increased Pigmentation


- Progresses to HEPATOSPLENOMEGALY

- Liver Fibrosis and Cirrhosis

- Increased Liver Damage LEADING to Carcinoma

- ENDOCRINOPATHIES
a) Diabetes
b) Hypopituitarism
c) Hypogonadism
d) Hypoparathyroidism
****All of these are IROND DEPOSITION*****


- Increased Incidence of Infection with Decreased Hepcidin!!!!

19

Iron deposition in Organs for all Except Melanin Depositor and Arthritis

1) Increased Melanin Production (BRONZE SKIN)

2) Calcium Pyrophosphate Crystal Deposition (ARTHRITIS)

3) Initially 2nd/ 3rd Metatarsal then other joints (ARTHRITIS)

4) Cell Damage (ELEVATED LIVER ENZYMES)

5) Scarring (CIRRHOSIS)

6) Decreased Insulin leading to Decreased GLUT 2 (DIABETES MELLITUS)

7) Hypogonadism from Deposition in Pituitary and hypothalamus (TESTICULAR ATROPHY, Decreased FSH/ LH Secretion)

20

Symptoms of Hemochromatosis

- Pain in Knuckles of the Pointer and Middle Finger, collectively called "The Iron Fist" is the ONLY SIGN or Symptom SPECIFIC to Hemochromatosis

- However, Not everyone with HHC experiences the Iron Fist

21

Intracellular Iron

- Leads to INCREASED Free Radical produciotn and Peroxidation of Phospholipids of Organelles
a) Mitochondria
b) Lysosomes
c) Microsomes

- Events lead to:
a) Cell Degeneration: Increased Enzymes
b) Cell Death: Increased Liver Enzymes
c) Increased Collagen Synthesis leading to Fibrosis and Cirrhosis

22

What tests are Needed to Obtain a Diagnosis?

1) SERUM IRON (SI)

2) SERUM FERRITIN (SF) which measure the amount of Iron contained or stored in the Body. Serum Ferritin references ranges are different for Adults and Children. For Adults, the Ideal Range is 50 to 150 ng/mL

3) TOTAL IRON BINDING CAPACITY (TIBC). This test tells how well your body can bind to Iron. Serum Iron divided by TIBC x 100% gives you important Information about the TRANSFERRIN-IRON SATURATION PERCENTAGE (TS%)

4) TS% is usually 25 to 35%; in some people with IRON OVERLOAD, the TS% is VERY HIGH. There are Other types of Iron Overload where the TS% is Normal.

23

Treatment

- It is very important to get IRON LEVELS DOWN TO NORMAL. Therapeutic BLOOD REMOVAL, or PHLEBOTOMY, is the most common means of Iron Reduction. Therapeutic Phlebotomy (TP) is the same as regular Blood Donation but TP requires a Doctor's Order (Prescription)

- Regular Blood Donation can be done every 8 weeks. A Person with Severe Iron Overload may need to give Blood as much as 8 times in a Single Month! The Goal is to Bring Blood FERRITIN Levels to an Ideal Range of 50 to 150 ng/ mL. Depending on the amount of Iron Overload at the time of Diagnosis, reaching Normal levels can require several Phlebotomies

- Once Iron levels reach Normal, a person can begin MAINTENANCE THRAPY, which involves making a Blood Donation every 2 to 4 months FOR LIFE. Some people may need to give Blood more or Less depending on what they eat and how quickly their body absorbs Iron

24

Treatment Cont

- The TS% and Serum Ferritin tests can be don periodically to help determine how often Blood Should be removed

- When Hemochromatosis is Diagnosed early and treated before organs are damaged, a person can live a Normal Life Expectancy. For people who have the disease at the time of Diagnosis, Life Expectancy may be shortened depending upon the Disease. If a person is Diagnosed and treated before Serum FERRITIN is above 1,000 ng/mL the risk of Cirrhosis or Liver Cancer is Less than 1%

25

Hereditary Hemochromatosis Genetics

1) C282Y: 90% of HH (Mutation of HFE)!!!!!!!!!!!!!!
- Cys to TYR MUTATION at residue 282!!!!!!!!!!!!!!!

2) H63D
- HIS to ASP Mutation at Residue 63


- HH may occur as a Homozygous Condition or as a Compound heterozygous Condition

- INCOMPLETE PENTRANCE

- Incidence:
a) Northern European Ancestry= 1:250 !!!!!!!!!!!!!!!!!!!!!!!!
b) Blacks = 1:6000

26

Wilsons Disease and Menkes Syndrome Introduction

- Copper is a COFACTOR

- Absorbed in the STOMACH and DUODENUM

- Bound to Albumin and transported to Liver

27

Wilsons Disease and Menkes Syndrome

- Two genes are involved in Copper Homeostasis
1) ATP7A:
- Expressed in MOST CELLS



2) ATP7B:!!!!!!!!!!!!!!!!!!!
- Expressed in Liver, Brain, Kidney, and Placenta

- Facilitates Incorporation into APOCERULOPLASMIN to yield CERULOPLASMIN (Copper is the Rate Limiting Step!!!!!!!!!!)

- CERULOPASMIN is the Major Copper Carrying Protein in the Blood, and in addition plays a role in Iron Metabolism

28

Cerulopasmin

- 90% of Copper is bound to Ceruloplasmin

- 10% of Copper is bound to Albumin

- Cerulopasmin is an IRON: OXIDOREDUCTASE important in Iron Absorption (Fe2+ to Fe3+)

- Each Cerulopasmin carries 6 Copper Atoms

- Increased levels during Inflammation, Infection, and Trauma Required

29

Regulation of Iron Absorption

- CERULOPLASMIN promotes Iron loading onto TRANSFERRIN which only Binds Fe2+ -------------------------------------->

- Reduced Cu2+ leads to REDUCED Fe2+ TRANSPORT that leads to an INCREASED attempt to INCREASE Fe2+ Absorption!!!!

30

ATP7A and ATP7B

- Important with Two Proteins at BRUSH BORDER of Intestinal Cells

1) DMT1: Divalent Metal Transporter 1

2) CRT1: Copper Transporter 1, aka SLC31A1
- Located on BASOLATERAL and APICAL Surfaces of Enterocyte- Cu2+ can enter from Blood and Intestine
- In Enterocyte Cu2+ binds to Proteins with a HIGH AFFINITY for Copper

31

Menk-es Syndrome ATP7A

Normal Function:
- Move Cu2+ from Intestinal mucosa into Blood

If ATP7A is MUTATED:
- Uptake is Impaired
- Cu2+ Deficiency occurs
- Co factor Deficiency and Inefficient reactions

32

Clinical Presentation of Menkes Syndrome

Infant:
- Healthy until age 2 or 3 months
- Loss of Developmental Milestones, hypotonia, Seizures, and Failure to Thrive occur


- Diagnosis is usually Suspected when Infants EXHIBIT Typical Neurologic Changes and Concomitant Characteristics CHANGES OF THE HAIR (Short, Sparse, Coarse, Twisted, often Lightly Pigmented)

- Temperature instability and hypoglycemia may be present in the NEONATAL PERIOD. Death usually occurs by THREE YEARS of Age!!!!!!!

33

Menkes Hair

Hair Changes:
- Scalp and (Usually) Eyebrow hair is SHORT, Sparse, Coarse, Twisted (Pili Torti), and often Lightly Pigmented (White, Silver, or Gray)

- Shorter and Thinner on the Sides and back of the Head. The hair can be reminiscent of Steel Wool cleaning pads!!!!!

34

Vascular Tortuosity

- Three dimensional MR Angiography shows Markedly TORTUOUS INTRACRANIAL and EXTRACRANIAL Vessels, which are Characteristics of MENKES DISEASE!!!!

35

Laxity of Skin

OCCIPITAL HORNS: Distinctive Wedge-shaped Calcifications at the sires of Attachment of TRAPEZIUS MUSCLE and the STERNOCLEIDOMASTOID MUSCLE to the Occipital bone. Occipital Horns may be Clinically Palpable or Observed on Skull Radiographs

36

Wilson Disease ATP7B

- Two ways to Excrete Copper
1) EXCESS Cu2+ induces METALLOTHIONEIN (MT) PRODUCTION ERYTHROCYTES:
- MT Binds Cu2+: ENTEROCYTES SHED!!!!!!

2) CERULOPASMIN BINDS EXCESS Cu2+ in LIVER:
- EXCRETED WITH BILE!!!!!!!



- ATP7B Mutations prevent Cu2+ release from Hepatocytes
a) Apoceruloplasmin is Degraded
b) Cerulopasmin levels DECREASE
c) Fe2+/ Fe3+ levels affected

37

Clinical Presentation of Wilsons Disease

***** PROGRESSIVE LENTICULAR DEGENRATION
- Bilateral softening of the Lenticular Nucleus
- Liver Cirrhosis

38

Clinical Presentation of Wilsons Disease Cont

1) NEUROLOGIC SYMPTOMS:
- MOVEMENT DISORDERS (Tremors, Poor Coordination, Loss of Fine Motor Control, Chorea, Choreathetosis)

- RIGID DYSTONIA (Mask-like facies, Rigidity, Gait Disturbance, Pseudobulbar Involvement)


2) PSYCHIATRIC SYMPTOMS
- Depression, Neurotic Behaviors, Disorganization of Personality, and occasionally, Intellectual Deterioration

3) KAYSER-FLEICHER RINGS:
- Copper DEPOSITION in DESCEMET'S Membrane of the CORNEA!!!!!
- Reflect a HIGH DEGREE of Copper Storage in the Body

39

Menkes Syndrome

GENE:
- ATP7A

DEFECT:
- Intestinal ABSORPTION of Copper

LABORATORY FINDINGS:
- Decreased Serum Copper
- DECREASED Liver Copper
- Increased Intestinal/Kidney Copper

TREATMENT:
- Daily Copper/ Histidine Injections

40

Wilson Disease

GENE:
- ATP7B

DEFECT:
- Biliary EXCRETION of Copper

LABORATORY FINDINGS:
- Decreased Serum Copper
- INCREASED Liver Copper
- Increased Urinary Copper

TREATMENT:
- Copper Chelation

41

Alpha Antitrypsin (AAT) Deficiency

- Emphysema

- Lung: has LOW ALVEOLAR CONCENTRATIONS, NO PROTECTION against Proteases such as Neutrophil ELASTASE

- Jaundice, Cirrhosis (Liver)