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GI 2 > HEREDITARY HEMOCHROMATOSIS > Flashcards

HEREDITARY HEMOCHROMATOSIS Flashcards

1
Q

Where is iron distributed in the body?

A

From diet and breakdown of erythrocytes

stored as Ferratin (in many organs)

GI is only way to get rid of iron

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2
Q

Hereditary hemochromatosis: due to what gene defect?

A

(HFE gene) on chromosome 6

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3
Q

What CYPs are involved in hereditary hemochromatosis?

A
  • C282Y/C282Y –>accounts for 82-90% of cases
  • C282Y/H63D = compound heterozygote and this combination
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4
Q

regulates the absorption of iron from the small intestine

A

HFE

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5
Q

When does HFE down-regulate transferrin?

A

when iron supplies are adequate

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6
Q

When needed, iron is absorbed and mobilized in
plasma compartment by_______

A

transferrin

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7
Q

A defective HFE gene fails to down-regulate transferrin
and iron continues to be absorbed from small intestine… this results in what?

A

 Iron deposits in various organs and leads to development
of free radicals which can cause organ damage

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8
Q

What are two classes of secondary iron overload

A

 Anemia caused by ineffective erythropoiesis
o Thalassemia major
o Sideroblastic anemia
o Congential dyserythropoietic anemia
o Congential atransferrinemia
o Acerulopasminemia

Liver disease
o Alcoholic liver disease
o HBV, HCV
o Nonalcoholic steatohepatitis

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9
Q

What can cause Parenteral Iron Overload

A

 Red cell transfusions
 Iron-dextran injections
 Long-term dialysis

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10
Q

Most common genetic disease in populations of
European ancestry, has both homo and heterozygous forms

A

Hemochromatosis;

C282Y; heterozygous in 10% caucasians

homozygous state in 0.5-.1%

C282Y/H63D = compound heterozygote in 3-5%

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11
Q

What are the more common symptoms for hemochromatosis:

A
  • Liver function abnormalities 75%
  • Weakness and lethargy 74%
  • Skin hyperpigmentation 70%

 All present at later age in women due to menstrual blood loss

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12
Q

What test do we order on patient we think has herditary hemochromatosis?

A

Fasting Transferrin Saturation

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13
Q

YOu suspect pt has herditary hemochromatosis and order a fasting transferring saturation test. The results are elevated, what do you do next?

A

Order genetic test

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14
Q
A
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15
Q

Ou suspect pt has herditary hemochromatosis and order a fasting transferring saturation test. It’s elevated and you order a genetic test, your patient is C282Y/H63D. What do you do next?

A

Cell biopsy bc on 10% of these guys have hemotomochrossis; look for Prussian blue stain

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16
Q

Ou suspect pt has herditary hemochromatosis and order a fasting transferring saturation test and its elevated. YOu do a genetic test and your patient is C282Y/C282Y. What do you do next?

A

Biopsy if over 40 yo OR if elevated ALT/AST

Then do phlebotomy to get rid of overload iron

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17
Q

What does a hereditary hemochromatosis liver look like on biopsy?

A

Stains with Prussian blue

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18
Q

What is the goal serum ferritin for Hereditary hemochromatosis

A

** **• Goal serum ferritin < 50
• Initially weekly phlebotomy
• Once quarterly thereafter

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19
Q

PROGRESSIVE LENTICULAR DEGENERATION

A

Wilson Disease

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20
Q

Common sources of Copper in diet

A

• Seafood:
 oysters, squid, lobster, mussels, crab, and clams
• Organ meats:
 beef liver, kidneys, and heart
• Nuts and nut butters:
 such as cashews, filberts, macadamia nuts, pecans, almonds,
and pistachios
• Legumes:
– soybeans, lentils, navy beans, and peanuts
• Chocolate:
 unsweetened or semisweet baker’s chocolate and cocoa
• Enriched cereals:
 bran flakes, shredded wheat, and raisin bran
• Fruits and vegetables:
 dried fruits, mushrooms, tomatoes, potatoes, sweet potatoes,
bananas, grapes, and avocado
• Black pepper

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21
Q

How is Copper metabolized in the body

A
  1. Intestinal absorption–> Liver
  2. Liver has three options
    a. Biliary excreation–> fecal excreation
    b. Ceruloplasmin
    c. Non-ceruloplasmin–> depositied extrahepatic + secreated in urine
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22
Q
A
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23
Q

What issues do we have with Copper metabolism in Wilsons Disease

A

Liver to biliary excreation is reduced

Ceruloplasmin is reduced

THUS we have Cu depositin in kidney, brain and cornea

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24
Q

Wilson Disease is combination of clinical, biochemical and pathological analysis, not very common, and NO ONE SINGLE FINDING is adequate for diagnosis thus must be considered for unexplained liver disease in pts 3-40 with what symtpoms?

A

 Unexplained liver disease
 Acute liver failure
 Cirrhosis
 Neurological symptoms
 Psychiatric symptoms

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25
Q

Neurological features of Wilson Disease

A
  • Movement disorders
  • Drooling, dysarthria
  • Rigid dystonia
  • Dysautonomia
  • Migraine headaches
  • Insomnia
  • Seizures
  • Depression
  • Neurotic behavior
  • Personality changes
  • Psychosis
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26
Q

DIAGNOSIS OF WILSON DISEASE:
• 95% of homozygotes have level of Ceruloplasmin that is?

A

< 20mg/dL CERULOPLASMIN

* High CP levels occur in inflammation and may lead to false negatives

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27
Q

DIAGNOSIS OF WILSON DISEASE:
_______ EXCRETION OF COPPER
• Urine copper is derived from______ copper
• Rate of excretion in symptomatic patients
may exceed_______

A

URINARY

nonceruloplasmin

100 microgram/24hrs

28
Q

What do you see in the cornea in the eye in wilson disease

A

Kayser-Fleischer Rings

29
Q
A
30
Q

Diagnosis of Wilson Disease; based on concentration

  • Normal hepatic copper content ______dry weight
  • Homozygous WD is:
  • Heterozygous WD ____μg/g dry weight
  • Obtain liver biopsy see accumulation of red granules (accumulation of copper–> rhodanine stain)
A

50 μg/g

> 250 μg/g dry weight

20-250

31
Q

What are the three medications used for Wilson Disease?

A

D-Penicillamine; binds free Cu; helps excreation in urine

Tientine: binds unbound copper and you will urinate it out with less side effects then D-Penicillamine

Zinc: inhibits absorption of copper in intestines

32
Q

• A1AT is an inhibitor of the proteolytic enzyme elastase.
• It is part of a larger family of structurally
unique protease inhibitors, referred to as ______.
• Predominantly made in the_____
• At least 100 alleles of A1AT have been identified and given a letter code based upon ____

A

serpins

liver

electrophoretic mobility

33
Q

Most common cause of genetic liver disease in children
• Most common genetic disease leading to liver transplantation in children

A

ALPHA-1 ANTITRYPSIN
DEFICIENCY

34
Q

In adults can cause hepatitis, cirrhosis, liver cancer
• Most common cause of genetic emphysema in adults

A

A1AT deficiency

35
Q

Pathogenesis of A1AT deficiency in lung

A

• Lung
 Loss-of-function mechanism
 The lack of A1AT allows uninhibited PMN medicated proteolytic damage to connective lung tissue

36
Q

Pathogenesis of A1At deficiency in Liver

A

• Liver
 Gain-of-function mechanism
 Retention of inefficiently secreted A1AT Z
molecule in endoplasmic reticulum triggers a series of hepatotoxic events )

37
Q

What A1AT deficiencys cause lung disease

A
  • PiSZ, 30-40% activity, causes lung disease only
  • Pi null-null, 0% activity, causes lung disease only
  • PiZZ, 10-15% activity, can cause both lung and liver disease
38
Q

What A1AT deficiency causes lung and liver issues?

A

• PiZZ, 10-15% activity, can cause both lung and liver disease
 affects 1/1600-1800 live births

39
Q

Pt has a 7 year pack history and has liver cirrhosis, what do we need to rule out?

A

A1AT defiency, most likely PiZZ bc smoking takes up to 20 yrs to devo emphysema, plus you have cirrhotic pt

40
Q

How do you diagnose A1AT deficiency?

A
  • Serum A1AT levels
  • A1AT phenotypes
  • Liver biopsy
41
Q
A
42
Q

What does A1AT look like histologically?

A

see that defective A1AT stain pink with PAS

43
Q

Autoimmune hepatitis is _____ inflammation with wha tpresent in serum?

A

Hepatocyte inflammation with autoantiB in serum

44
Q

Who gets autoimmne hepatitis?

A
  • Insidious or acute onset; F/M 4:1
  • 20-30 cases per million population
  • 50% have other autoimmune disorders
45
Q

What is elevated in Autoimmune hepatitis?

A

ALT, AST elevated >1000

Elevated gamma-globulin or IgG

Autoantibodies present

46
Q

A pathologist describes a liver biopsy to you. States there is interface hepatitis (around portal triad) with plasma cell infliltration. What is your Dx?

A

Autoimmune hepatits

47
Q

Autoimmune hepatitis is based on serological markers: What do we see in Type I (classic; 80-90% adults) for Organelle:

Markers:

A

Type I organelle: nucleus

ANA or ASMA

48
Q

Autoimmune hepatitis is based on serological markers: What do we see in Type 2 (anti-LKM 1 hepatitis, children) for Organelle:

Markers:

A

 Organelle: microsome
oAnti-liver-kidney microsomal antibody

49
Q

What autoimmune dseaes are associated with AIH

A
  • Thyroid disease
  • Rheumatoid arthritis
  • Diabetes
  • Sjogren’s syndrome
  • Polymyositis
  • IgA deficiency
  • Idiopathic thrombocytopenia
  • Urticaria
  • Vitiligo
  • Addison’s disease
  • Inflammatory Bowel Disease
50
Q

What to you treat autoimmine hepatitis with?

A

Prednisone or Predinisone + Azathioprine (steroid sparring)

51
Q

Your patient has AIH, what other factors would encourage you to put her on Prednisone only instead of adding azathioprine

A

cytopenia, thipurine methytransferase deficient, pregnancy, maligancy

52
Q

When would you put patient with AIH on prednisone with Azathioprine?

A

Postmenopause, osteoporosis, Brittle diseaes, obese, acne, emotional lability, HTN

53
Q

What is the goal when tx patietns with AIH?

A

normal ALT, AST, IgG,
gamma-globulin, resolution of inflammation on biopsy

Tx pts 65% respond w/in 18 months and 80% w/in 3 yrs

most die within 10 yrs if untreated

54
Q
  • Chronic, progressive, cholestatic liver disease
  • Destruction of intrahepatic bile ducts
  • Probable autoimmune pathogenesis
A

Primary Biliary Cirrhosis

55
Q

In PBC, you have destruction of:

A

intrahepatic bile ducts; the very small ones that don’t show up great on imaging

56
Q

Who do we see PBC in?

A
  • 90-95% women
  • Predominantly Caucasian
  • Mean age 52 at presentation, range 30-65

Rare

57
Q

What is teh cause of Primary Biliary Cirrhosis?

A

• High prevalence of serum autoantibodies
(antimitochondrial antibodies, **AMA; ** present in 95%
• Elevated IgM
• Association with other autoimmune diseases
• Increased familial incidence of disease
 6% family history of PBC

58
Q

How does AMA in primary biliary cirrhosis cause issues?

A

AMA targets pyruvate dehydrogenase complex PDC; PCD-E2 predominates and is located on the membrane of teh biliary epithelial cells or the Bile Duct

59
Q

Pt comes in:

  • Raised Alkaline Phosphatase
  • AMA +
  • Investigation for other autoimmune disease
A

Suspect Primary bilary cirrhosis

60
Q

Main symptoms of PBC

A

can be asymptomatic; see pruitis and fatigue, hepatomegaly, splenomegaly and xanthomas, jaunice

61
Q

Why do we have vitamin deficiencies associated with PBC?

A
  • Decreased bile salt excretion, steatorrhea
  • Correlates with duration and severity of liver disease
62
Q

What are our fat soluble vitamins? What effect do we see when they are decreaesd from PBC?

A

KADE

 vitamin D (8-23%): osteomalacia, fractures, regular bone densitometry
 vitamin K (7-8%): prolonged PT

63
Q

What are common autoimmune disorders associated with PBC?

A

Sjogrens, thyroiditis, RA, Scleroderma or CREST, Raynauds, Celiac

64
Q

Labs in PBC:

  • Alkaline Phosphatase:
  • Bilirubin :
  • Cholesterol :
A

3-4 x normal in >90%

bilirubin: usually rises late

cholesterol elevated in 85% *Not associated with heart disease

65
Q

Pathologist describes medium sized bile ducts infiltrated with inflammatory cells; lymphocyts and mononuclear cells; causes changes around the bile duct. Called Florid duct inflammtion and elevated AMA+, what is your Dx?

A

Primary biliary cirrhosis

66
Q

How do people with PBC do for survival?

A

Asypmtpomatic pts have much better outcomes

67
Q

What medicaiton is used to tx PBC?

A

Ursodeoxycholic acid (UDCA) and helps with histology to decresase florid lesion, but need to take anti-histamine for itching

GI 2 (12 decks)

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