Disorders Affecting the GI System Flashcards
What is the neurocristopathology of hirschprung disease?
aberration in neural growth, migration and differentiation during embryological development
What are the two forms of hirschprung disease?
short-segment and long-segment form
describe the short-segment form of Hirschprung disease
Aprroximately 80% of cases
Aganglionic segment does not extend beyond the upper sigmoid
Describe the long-segment form of Hirschprung disease
L-HSCR
aganglionosis extends proximal to the sigmoid
can also be called total colonic aganglionosis or total intestinal HSCR
There is a congenital absence of what cells in Hirschprung disease?
Congenital absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the GI tract
Which enteric plexus forms first?
The outer myenteric plexus
What are the clinical presentations of Hirschprung disease?
intestinal obstruction
colon distention from lack of peristalsis
Most of time is isolated disease (70%)
more common in males and Asians
What syndromes can Hirschprung disease be associated with?
12% down syndrome - most frequent chromosomal abnormality in associated
2% bardet-biedl syndrom
9% cartilage-hair hypoplasia syndrome
What gene is most associated with Hirschprung disease?
RET: tyrosine kinase receptor
Autosomal dominant
What are proto-oncogenes?
genes that code for proteins that help regulate cell growth
Where is the RET gene expressed?
in neural crest cells
A loss-of-function mutation of the RET gene causes what disease?
Hirschprung
A gain-of-function mutation of the RET gene causes what disease?
MEN - multiple endocrine neoplasia syndrome
What does the RET gene provide instructions for?
producing a protein that is involved in signaling withing cells, including nerves in the intestine
What deficiency can lead to emphysema, jaundice, and cirrhosis?
Alpha antitrypsin ATT
What is iron bound to and transported in the body by?
What is it stored in?
Transferrin
Ferritin molecules in liver and heart
What are the only physiolgical mechanisms for excretion of excess iron from the body?
blood loss, pregnancy, menstruation
What happens to iron if there is too much?
deposited in liver, heart, and some endocrine tissues
damages tissues
fibrosis
What happens if there are too many erythrocytes destroyed?
accumulates in reticuloendothelial macrophages first
tissue parenchyma after macrophages
Iron deposited in bone marrow, spleen
iron is only lost through….
enterocyte shedding: GI cells sloughed
What is HFE responsible for?
the most common form of iron-overload: hemochrmatosis
What is the HJV gene responsible for?
Most cases of juvenile hemochromatosis; rare but has severe iron overload
What is the TFR2 gene responsible for?
Less common but with similar clinical presentation to HFE mutations; transferrin receptor-2
What is the HAMP gene translated to?
hepcidin: an iron-regulating hormone critical for absorption
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
What are factors that decrease iron absorption?
your body does not want more iron
regular blood transfusions
high iron diet
iron loading vitamins
What is the HFE protein?
human hemochromatosis protein
functions to regulate circulating iron uptake by regulating the interaction of TFR1/2 with transferrin
What is hepcidin?
protein that is a key regulator of the entry of iron into circulation. inhibits ferroportin
What is transferrin?
iron-binding blood plasma glycoprotein that controls the level of free iron in biological fluids
What is the TFR1 protein?
Protein required for iron import from transferrin into cells by endocytosis
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
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
What is hepcidin secretion from the liver regulated by?
HFE protein, HJV and the TFR2 signaling pathways
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
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
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
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
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
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
What are the endocrinopathies of hemochromatosis?
diabetes(decreased insulin),
hypopituitarism, hypogonadism, hypoparathryoidism
all the above are iron deposition
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
What does intracellular iron lead to?
incrased free radical production and peroxidation of phospholipids of organelles such as mitochondria, lysosomes, microsomes
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
What tests are used to determine hemochromatosis?
Serum iron
serum ferritin
Total iron binding capacity: how well body can bind to iron
What test is more reliable when testing for hemochromatosis?
Serum ferritin: measures amount of iron contained or stored in the body
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
What are the treatments for hemochromatosis?
Therapeutic phlebotomy: bring blood ferritin levels to ideal range
Maintenance therapy once ‘normal’
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
Describe the genetics of hemochromatosis?
HH may occur as homozygous condition or compound heterozygous condition
Incomplete penetrance
Incidence: northern european ancestry 1:250
Copper is a cofactor for what enzymes?
lysyl oxidase superoxide dismutase chytochrome-c oxidase tyrosinase monoamine oxidase dopamine beta-hydroxylase
What enzyme is involved in CT formation and has copper as a cofactor?
Lysyl oxidase
What enzyme is involved for free radical scavenging and copper is its cofactor?
Superoxide dismutase
What enzymes are involved in electron transfer and has copper as its cofactor?
cytochrome-c oxidase and tyrosinase
What enzyme is involved in neurotransmitter formation and has copper as its cofactor?
monoamine oxidase
What enzyme is involved with conversion of dopamine to noradrenalin and has copper as its cofactor?
dopamine beta hydroxylase
Where is copper absorbed?
in stomach and duodenum
What is copper bound to and transported to the liver?
albumin
What is ATP7A expressed in?
most cells
what is ATP7B expressed in?
liver, brain, kidney and placenta
What does ATP7B facilitate?
incorporation of copper into apoceruloplasmin to yield ceruloplasmin
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
What is 90% of copper bound to?
ceruloplasmin
other 10% to albumin
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
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
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
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
What mutation prevents Cu release from hepatocytes ?
ATP7B - wilson disease
Apoceruloplasmin is degraded
ceruloplasmin levels decrease
Fe2/Fe3 levels affected
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
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
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
What is primary hemochromatosis?
A hereditary defect that causes the body to absorb too much iron
Source: NIH
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
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
