BASEM Flashcards
In hemolysis you will see increased. . .
. . .indirect (unconjugated) bilirubin. [hemolytic anemia]
In biliary obstruction you will see. . .
. . .direct (conjugated) bilirubin.
How is heme degraded?
To form bilirubin which is conjugated with glucuronic acid and excreted in the bile.
What is the B6 limitation with respect to Isoniazid and TB?
Isoniazid: Can cause B6 deficiency, resulting in peripheral neuropathy, CNS effects and anemia. Consider supplementation in patients in which neuropathy is common (e.g. diabetes, uremia, alcoholism, malnutrition, and HIB), pregnant women and persons with seizure disorder
What is the source of bile pigment?
Hemoglobin
What happens to RBCs at the end of their life?
(AFTER 120 DAYS)
-They are phagocytes by cells of the RES. Globin is cleaved to is constituent AAs and iron is returned to the body. Heme is oxidized and cleaved to produce carbon monoxide and biliveridin. Biliverdin is reduced to bilirubin which is transported to the liver complexed with serum albumin. IN the liver, bilirubin is converted to more water soluble compound reacting with UDP-glucoronate to form bilirubin monoglucuronide, which is converted to diglucuronide. Then excreted in bile, converted to urobilinogens by bacteria in intestine. Some goes to blood, some urine, some stool.
What is B6 deficiency associated with?
Microcytic, hypochromic anemia due to slowed heme production as delta-ALA synthase requires pyridoxal phosphate.
Where is bilirubin converted to a more water soluble compound (conjugation process in excretion) by reacting with UDP-glucuronate to form bilirubin monogluonide, which is converted to diglucuronide?
LIVER!!
Where is bilirubin conjugated?
IN THE LIVER
What could block direct (conjugated) bilirubin?
Biliary obstruction - tumor in bowel!
What is abdominal pain + CNS symptoms?
Acute porphyria (confusion, convulsions, muscle weakness, paralysis) - Almost all are autosomal dominant!
What is the #1 symptoms of acute porphyria?
1 abdominal pain - Vomiting, constipation, diarrhea, neurological symptoms
What is porphyria?
Inherited disorder that results in deficiencies in enzymes in pathway for heme biosynthesis
Acute intermittent Porphyria may cause long term what?
Long term increased risk of hepatocellular carcinoma!
What are the signs and symptoms of acute intermittent porphyria?
GI: pain, vomiting, constipation, on exam abdomen is tender, but not rigid, Hyponatremia in severe attacks, Neuropathy (2/3): motor, sensory, physchiatric - CV: increased BP, tachycardia, PHOTOSENSITIVITY NOT PRESENT
What do you want to give the patient with Acute porphyrias?
HEME!! (IV hematin, heme arginate, hematin)
What is the association between sporadic form of Hep C and porphyria cutanea tarda?
> 50% of patients with sporadic form are HCV positive - May be a precipitating factor
When do you need to do tests?
WHEN PATIENT IS SYMPTOMATIC
What is porphyria cutanea tarda?
Deficiency of hepatic uroporphyrinogen decarboxylase (URO-D) in heme synthesis pathway
-Autosomal Dominant inheritance, Most common porphyria
What are the precipitating factors of porphyria cutanea tarda?
- Increased iron stores (down regulation of hepcidin)
- Hepatitis C
- Estrogens
What are the symptoms of Porphyria Cutanea Tarda?
- Bullous dermatosis (blistering skin lesions)
- Scarring
- Hyperpigmentation
- Hypertrichosis
- See bullous lesion in sun exposed regions!!
How to treat PCT?
- Avoid precipitating factors (e.g. alcohol)
- Phlebotomy until in remission
- Iron chelation if phelebotomy not possible
When do you NEED to do tests for Porphyrias?
WHEN PATIENT IS SYMPTOMATIC
-They may have normal heme precursor levels during asymptomatic periods
What do you always see in symptomatic porphyria?
Increased heme precursors!!
In post-menopausal female or male, if they have iron deficiency with no obvious cause. . .
. . . you HAVE to look in the GI tract! Must send to colonoscopy and endoscopy and NOT miss a GI bleed.
What is the mechanism by which anemia of chronic disease works?
- There is too much hepcidin
- Bioavailability is the issue
What is ferritin?
Your storage iron!
What is the concept of heme iron and ferric iron in iron absorption (why vegetarians don’t absorb as well)?
Dietary iron is present in two forms in the diet:
(1) Heme iron (hemoglobin and myoglobin in beef, chicken, fish, etc.) = best absorbed [O2 binds Fe2+ better = ferrous]
(2) Non-heme iron/Fe3+ (cereal, vegetables) = taken up less avidly - greater than 1/3 of iron is from fortification of flour
What is a Hepatocyte?
(liver cell)
- Master regulator via its production of hepcidin.
- Hepcidin is the keystone regulator of systemic iron hemeostasis
What is Hepcidin?
Master regulator of systemic iron hemeostasis
- 25 AA polypeptide produced in response to inflammation (AOCD, IL6) and increased iron stores
- Binds to ferroportin and triggers its internalization and degradation to lysosomes
- Decresaes Fe release from macrophages, enterocytes, and hepatocytes
- Results in increased IC iron
What does Hepcidin deficiency cause?
Iron overload
What does excess hepcidin cause/what is it related to?
AOCD (anemia of chronic disease)
What happens in iron overload?
- When a lot of iron is around, transferrin saturation is high
- Hepcidin will then be generated
- Hepcidin will bind the enterocyte in liver. This doesn’t allow for the release of iron at the enterocyte.
- No adsorption occurs and no iron gets into the circulation!
What happens in the body when you have excess iron?
More hepcidin is produced!
-Hepcidin binds to duodenal enterocytes and triggers their degradation
When there is high iron, transferrin saturation is ___, when there is low iron, transferrin saturation is ____.
High, low
When transferrin saturation is low. . .
. . .the cell does not make hepcidin.
What is the primary therapy for hemochromatosis?
Hemachromatosis = too much iron and the number one way to get rid of it = REMOVING BLOOD FROM PATIENT
Increase in transferrin saturation signals to hepatocytes to increase hepcidin expression via. . .
a HFE and TfR2 dependent mannter
What is TIBC?
Total Iron Binding Capacity - Number of iron binding sites on transferin molecules. Serum transferrin concentration.
What iron indices are found in iron deficiency?
- Dec. serum iron
- Inc. TIBC
- Dec. Transferrin Saturation
- Dec. Ferritin
What iron indices are found in anemia of chronic disease?
- Dec. serum iron
- Dec. TIBC
- Dec. Transferrin Saturation
- Increased Ferritin (optional)
What iron indices are found in hemochromatosis?
- Inc. serum iron
- Dec. TIBC
- Inc. transferrin saturation
- Inc. ferratin
When you have low iron. . .
. . .body increases transferrin!
What is the mechanism by which anemia of chronic disease works?
Increased inflammatory cytokines (IL-6, IL-1B, etc.) induce hepcidin.
- There is too much hepcidin.
- Bioavailability is the issue
How do you diagnose anemia of chronic disease (AOCD)?
Chronic inflamm. process
- Increased ESR, CRP
- Look at other acute phase reactants (reduced albumin, transferrin)
What is the treatment for hemochromatosis?
Phlebotomy!
What is the mechanism for which HFE mutations cause hemochromatosis?
HFE is a transmembrane protein that regulates hepcidin expression. Mutation results in lack of interaction of HFE with TFR2 and reduced cell surface expression:
- Decreased hepcidin expression
- Increased FE absorption
- Increased serum iron and Tf saturation
- Decreased storage of iron in macrophages
What is hereditary hemochromatosis?
- HH, or primary iron overload is a collective label for a group of autosomal inherited iron overload disorders
- Hereditary condition affecting the hepcidin/ferroportin access.
What is type I hereditary hemochromatosis?
Classical HFE gene mutations resulting in cysteine-to-tyrosine subsitution at amino acid 282 (C282Y) or an aspartate-to-histidine substitution at amino acid 63 (H63D)
What is HFE?
A transmembrane protein belonging to MHC Class I and expressed at high levels in the liver.
What does hereditary hemachormatosis cause?
Severe symptoms not usually seen until decades of iron loading have passed!
- Classic triad: (1) DM (2) Hepatomegaly (3) Hyperpigmentation
- Usually death from cirrhosis, hepatocellular carcinoma, or CHF
- Goal is to make dx and tx in pre-symptomatic stage!
- Normal life expectancy if caught and phlebotomy started before DM or cirrhosis
What is the HFE genetic defect?
Penetrance C282Y/C282Y incomplete
-Elevated serum ferritin in
