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GI Final - MSI Spring > Disorders Affecting the GI System > Flashcards

Disorders Affecting the GI System Flashcards

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1
Q

What is the neurocristopathology of hirschprung disease?

A

aberration in neural growth, migration and differentiation during embryological development

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2
Q

What are the two forms of hirschprung disease?

A

short-segment and long-segment form

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3
Q

describe the short-segment form of Hirschprung disease

A

Aprroximately 80% of cases

Aganglionic segment does not extend beyond the upper sigmoid

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4
Q

Describe the long-segment form of Hirschprung disease

A

L-HSCR
aganglionosis extends proximal to the sigmoid
can also be called total colonic aganglionosis or total intestinal HSCR

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5
Q

There is a congenital absence of what cells in Hirschprung disease?

A

Congenital absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the GI tract

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6
Q

Which enteric plexus forms first?

A

The outer myenteric plexus

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7
Q

What are the clinical presentations of Hirschprung disease?

A

intestinal obstruction
colon distention from lack of peristalsis
Most of time is isolated disease (70%)
more common in males and Asians

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8
Q

What syndromes can Hirschprung disease be associated with?

A

12% down syndrome - most frequent chromosomal abnormality in associated
2% bardet-biedl syndrom
9% cartilage-hair hypoplasia syndrome

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9
Q

What gene is most associated with Hirschprung disease?

A

RET: tyrosine kinase receptor

Autosomal dominant

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10
Q

What are proto-oncogenes?

A

genes that code for proteins that help regulate cell growth

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11
Q

Where is the RET gene expressed?

A

in neural crest cells

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12
Q

A loss-of-function mutation of the RET gene causes what disease?

A

Hirschprung

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13
Q

A gain-of-function mutation of the RET gene causes what disease?

A

MEN - multiple endocrine neoplasia syndrome

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14
Q

What does the RET gene provide instructions for?

A

producing a protein that is involved in signaling withing cells, including nerves in the intestine

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15
Q

What deficiency can lead to emphysema, jaundice, and cirrhosis?

A

Alpha antitrypsin ATT

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16
Q

What is iron bound to and transported in the body by?

What is it stored in?

A

Transferrin

Ferritin molecules in liver and heart

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17
Q

What are the only physiolgical mechanisms for excretion of excess iron from the body?

A

blood loss, pregnancy, menstruation

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18
Q

What happens to iron if there is too much?

A

deposited in liver, heart, and some endocrine tissues
damages tissues
fibrosis

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19
Q

What happens if there are too many erythrocytes destroyed?

A

accumulates in reticuloendothelial macrophages first
tissue parenchyma after macrophages
Iron deposited in bone marrow, spleen

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20
Q

iron is only lost through….

A

enterocyte shedding: GI cells sloughed

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21
Q

What is HFE responsible for?

A

the most common form of iron-overload: hemochrmatosis

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22
Q

What is the HJV gene responsible for?

A

Most cases of juvenile hemochromatosis; rare but has severe iron overload

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23
Q

What is the TFR2 gene responsible for?

A

Less common but with similar clinical presentation to HFE mutations; transferrin receptor-2

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24
Q

What is the HAMP gene translated to?

A

hepcidin: an iron-regulating hormone critical for absorption

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25
What are factors that increase iron absorption? (your body wants to take in iron)
``` inadequate diet impaired absorption Celiac disease GI bleeding Anemias, decreased erythropoiesis Hypoxia ```
26
What are factors that decrease iron absorption? | your body does not want more iron
regular blood transfusions high iron diet iron loading vitamins
27
What is the HFE protein?
human hemochromatosis protein | functions to regulate circulating iron uptake by regulating the interaction of TFR1/2 with transferrin
28
What is hepcidin?
protein that is a key regulator of the entry of iron into circulation. inhibits ferroportin
29
What is transferrin?
iron-binding blood plasma glycoprotein that controls the level of free iron in biological fluids
30
What is the TFR1 protein?
Protein required for iron import from transferrin into cells by endocytosis
31
What is the TFR2 protein?
Protein involved in the uptake of transferrin-bound iron into cells by endocytosis, although its role is minor compared to TFR1
32
What is the ferroportin protein?
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
33
What is hepcidin secretion from the liver regulated by?
HFE protein, HJV and the TFR2 signaling pathways
34
What happens in states of iron deficiency?
hepcidin levels low | Ferroportin allows entry of iron from duodenal enterocytes into blood and recirculation of iron from Mo into plasma
35
What happens in states of iron excess?
Hepcidin levels increase Promotes internalization and degradation of ferroportin decreased iron absorption from gut decreased release from Mo
36
What results in low hepcidin levels despite high iron levels and inappropriate continued transport of iron into the plasma
mutations of HFE, HJV, or TFR2
37
What regulation of iron happens during normal levels of iron?
Fe2+ transported by transferrin Transferrin binds 2 molecules Transferrin and HFE complete for binding sites at TFR1 receptor on hepatocytes and other cells Transferrin binds better Unbound HFE is then elevated on cell surface which stimulates hepcidin expression so that healthy levels of iron absorption is maintained
38
What is the mechanism of iron regulation when there is too much iron?
More TFR2 is produced than TFR1 Transferrins bind more TFR2 than TFR1 TFR2 binding stimulates hepcidin expression Hepcidin down regulates transport of Fe 2+ out of enterocytes Also HFE is free and stimulates hepcidin expression
39
What are the characteristics of hemochromatosis?
Late onset non-specific early symptoms (Fatigue, arthralgia, ED, darker) Then hepatosplenomegaly next liver fibrosis and cirrhosis carcinoma endocrinopathies increased incidence of infection with decreased hepcidin
40
What are the endocrinopathies of hemochromatosis?
diabetes(decreased insulin), hypopituitarism, hypogonadism, hypoparathryoidism all the above are iron deposition
41
What is the ONLY sign or symptom specific to hemochrmatosis?
The iron fist pain in knuckles of the pointer and middle finger however, not everyone with HHC experiences the iron fist
42
What does intracellular iron lead to?
incrased free radical production and peroxidation of phospholipids of organelles such as mitochondria, lysosomes, microsomes
43
Free radicals in cells can lead to what?
cell degeneration - increased enzymes Cell death - increased liver enzymes increased collagen synthesis leading to fibrosis and cirrhosis
44
What tests are used to determine hemochromatosis?
Serum iron serum ferritin Total iron binding capacity: how well body can bind to iron
45
What test is more reliable when testing for hemochromatosis?
Serum ferritin: measures amount of iron contained or stored in the body
46
Why can TIBC test not be helpful in determining hemochromatosis?
Serum iron/TIBC = TS% | because there are other types of iron overload where TS% is normal
47
What are the treatments for hemochromatosis?
Therapeutic phlebotomy: bring blood ferritin levels to ideal range Maintenance therapy once 'normal'
48
What point mutation occurs in hereditary hemochromatosis?
C282Y - 90% of HH Cys to Tyr mutation at residue 282 H63D: His to Asp at residue 63
49
Describe the genetics of hemochromatosis?
HH may occur as homozygous condition or compound heterozygous condition Incomplete penetrance Incidence: northern european ancestry 1:250
50
Copper is a cofactor for what enzymes?
``` lysyl oxidase superoxide dismutase chytochrome-c oxidase tyrosinase monoamine oxidase dopamine beta-hydroxylase ```
51
What enzyme is involved in CT formation and has copper as a cofactor?
Lysyl oxidase
52
What enzyme is involved for free radical scavenging and copper is its cofactor?
Superoxide dismutase
53
What enzymes are involved in electron transfer and has copper as its cofactor?
cytochrome-c oxidase and tyrosinase
54
What enzyme is involved in neurotransmitter formation and has copper as its cofactor?
monoamine oxidase
55
What enzyme is involved with conversion of dopamine to noradrenalin and has copper as its cofactor?
dopamine beta hydroxylase
56
Where is copper absorbed?
in stomach and duodenum
57
What is copper bound to and transported to the liver?
albumin
58
What is ATP7A expressed in?
most cells
59
what is ATP7B expressed in?
liver, brain, kidney and placenta
60
What does ATP7B facilitate?
incorporation of copper into apoceruloplasmin to yield ceruloplasmin
61
What is ceruloplasmin ?
major copper-carrying protein in the blood, and in addition plays a role in iron metabolism Iron:oxidoreductase important in iron absorption (Fe2+ to Fe3+) Each ceruloplasmin carries 6 copper atoms levels increased during inflammation, infection, and trauma Promotes iron (Fe2+) loading onto transferrin
62
What is 90% of copper bound to?
ceruloplasmin | other 10% to albumin
63
What two proteins are at the brush border of intestinal cells on basolateral and apical surfaces of enterocytes? what are their roles?
DMT1 CRT1 Cu can enter from blood and intestine In enterocyte, Cu binds to proteins with a high affinity for copper
64
What is the normal function of ATP7A? what happens if its impaired?
move Cu from intestinal mucosa into blood | Menkes syndrome: Uptake is imapired, Cu deficiency, all enzymes that use it as cofactors are inefficient
65
What are the clinical presentations of menkes disease?
infant: 2-3 months Loss of developmental milestones, hypotonia, seizures, failure to thrive Temperature instability hypoglycemia Hair: scalp and eyebrow hair short, sparse, coarse, twisted, lightly pigmented Vascular tortuosity Laxity of skin occipital horns: calcifications at trapezius and SCM mm insertion
66
What are two ways to excrete copper?
Excess Cu induces metallothionein production enterocytes MT binds Cu-enterocytes shed Ceruloplasmin binds excess Cu in liver: excreted with bile
67
What mutation prevents Cu release from hepatocytes ?
ATP7B - wilson disease Apoceruloplasmin is degraded ceruloplasmin levels decrease Fe2/Fe3 levels affected
68
What are the clinical presentations of wilson's disease?
progressive lenticular degeneration bilateral softening of the lenticular nucelus liver cirrhosis Neurologic symptoms: movement disorders, rigid dystonia Psychiatric symptoms: depression, neurotic behaviors, disorganization of personality Kayser-fleischer rings - Cu dposition in descemet's membrane of cornea
69
What disease has a defect in intestinal absorption of Cu. Decreased serum Cu, decreased liver Cu, increased intestinal/kidney Cu? what is the Tx?
Menkes syndrom | Daily copper/histidine injections
70
What disease has a defect in billiary excretion of Cu, decreased serum Cu, increased liver Cu and increased urinary Cu? what is the Tx?
Wilson disease | Cu chelation
71
What is primary hemochromatosis?
A hereditary defect that causes the body to absorb too much iron Source: NIH
72
What is secondary hemochromatosis?
Usually the result of another disease or condition that causes iron overload Anemia, chronic liver disease, alcoholism, Hep C, and blood transfusions
73
What happens when HFE is mutated and too little is produced?
Decreased TFR2 Decreased HAMP No hepcidin Increase of Fe 2+ transfer out of enterocytes into blood

GI Final - MSI Spring (11 decks)

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