HEREDITARY HEMOCHROMATOSIS Flashcards
Where is iron distributed in the body?
From diet and breakdown of erythrocytes
stored as Ferratin (in many organs)
GI is only way to get rid of iron
Hereditary hemochromatosis: due to what gene defect?
(HFE gene) on chromosome 6
What CYPs are involved in hereditary hemochromatosis?
- C282Y/C282Y –>accounts for 82-90% of cases
- C282Y/H63D = compound heterozygote and this combination
regulates the absorption of iron from the small intestine
HFE
When does HFE down-regulate transferrin?
when iron supplies are adequate
When needed, iron is absorbed and mobilized in
plasma compartment by_______
transferrin
A defective HFE gene fails to down-regulate transferrin
and iron continues to be absorbed from small intestine… this results in what?
Iron deposits in various organs and leads to development
of free radicals which can cause organ damage
What are two classes of secondary iron overload
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
What can cause Parenteral Iron Overload
Red cell transfusions
Iron-dextran injections
Long-term dialysis
Most common genetic disease in populations of
European ancestry, has both homo and heterozygous forms
Hemochromatosis;
C282Y; heterozygous in 10% caucasians
homozygous state in 0.5-.1%
C282Y/H63D = compound heterozygote in 3-5%
What are the more common symptoms for hemochromatosis:
- Liver function abnormalities 75%
- Weakness and lethargy 74%
- Skin hyperpigmentation 70%
All present at later age in women due to menstrual blood loss
What test do we order on patient we think has herditary hemochromatosis?
Fasting Transferrin Saturation
YOu suspect pt has herditary hemochromatosis and order a fasting transferring saturation test. The results are elevated, what do you do next?
Order genetic test
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?
Cell biopsy bc on 10% of these guys have hemotomochrossis; look for Prussian blue stain
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?
Biopsy if over 40 yo OR if elevated ALT/AST
Then do phlebotomy to get rid of overload iron
What does a hereditary hemochromatosis liver look like on biopsy?
Stains with Prussian blue
What is the goal serum ferritin for Hereditary hemochromatosis
** **• Goal serum ferritin < 50
• Initially weekly phlebotomy
• Once quarterly thereafter
PROGRESSIVE LENTICULAR DEGENERATION
Wilson Disease
Common sources of Copper in diet
• 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
How is Copper metabolized in the body
- Intestinal absorption–> Liver
- Liver has three options
a. Biliary excreation–> fecal excreation
b. Ceruloplasmin
c. Non-ceruloplasmin–> depositied extrahepatic + secreated in urine
What issues do we have with Copper metabolism in Wilsons Disease
Liver to biliary excreation is reduced
Ceruloplasmin is reduced
THUS we have Cu depositin in kidney, brain and cornea
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?
Unexplained liver disease
Acute liver failure
Cirrhosis
Neurological symptoms
Psychiatric symptoms
Neurological features of Wilson Disease
- Movement disorders
- Drooling, dysarthria
- Rigid dystonia
- Dysautonomia
- Migraine headaches
- Insomnia
- Seizures
- Depression
- Neurotic behavior
- Personality changes
- Psychosis
DIAGNOSIS OF WILSON DISEASE:
• 95% of homozygotes have level of Ceruloplasmin that is?
< 20mg/dL CERULOPLASMIN
* High CP levels occur in inflammation and may lead to false negatives
DIAGNOSIS OF WILSON DISEASE:
_______ EXCRETION OF COPPER
• Urine copper is derived from______ copper
• Rate of excretion in symptomatic patients
may exceed_______
URINARY
nonceruloplasmin
100 microgram/24hrs
What do you see in the cornea in the eye in wilson disease
Kayser-Fleischer Rings
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)
50 μg/g
> 250 μg/g dry weight
20-250
What are the three medications used for Wilson Disease?
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
• 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 ____
serpins
liver
electrophoretic mobility
Most common cause of genetic liver disease in children
• Most common genetic disease leading to liver transplantation in children
ALPHA-1 ANTITRYPSIN
DEFICIENCY
In adults can cause hepatitis, cirrhosis, liver cancer
• Most common cause of genetic emphysema in adults
A1AT deficiency
Pathogenesis of A1AT deficiency in lung
• Lung
Loss-of-function mechanism
The lack of A1AT allows uninhibited PMN medicated proteolytic damage to connective lung tissue
Pathogenesis of A1At deficiency in Liver
• Liver
Gain-of-function mechanism
Retention of inefficiently secreted A1AT Z
molecule in endoplasmic reticulum triggers a series of hepatotoxic events )
What A1AT deficiencys cause lung disease
- 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
What A1AT deficiency causes lung and liver issues?
• PiZZ, 10-15% activity, can cause both lung and liver disease
affects 1/1600-1800 live births
Pt has a 7 year pack history and has liver cirrhosis, what do we need to rule out?
A1AT defiency, most likely PiZZ bc smoking takes up to 20 yrs to devo emphysema, plus you have cirrhotic pt
How do you diagnose A1AT deficiency?
- Serum A1AT levels
- A1AT phenotypes
- Liver biopsy
What does A1AT look like histologically?
see that defective A1AT stain pink with PAS
Autoimmune hepatitis is _____ inflammation with wha tpresent in serum?
Hepatocyte inflammation with autoantiB in serum
Who gets autoimmne hepatitis?
- Insidious or acute onset; F/M 4:1
- 20-30 cases per million population
- 50% have other autoimmune disorders
What is elevated in Autoimmune hepatitis?
ALT, AST elevated >1000
Elevated gamma-globulin or IgG
Autoantibodies present
A pathologist describes a liver biopsy to you. States there is interface hepatitis (around portal triad) with plasma cell infliltration. What is your Dx?
Autoimmune hepatits
Autoimmune hepatitis is based on serological markers: What do we see in Type I (classic; 80-90% adults) for Organelle:
Markers:
Type I organelle: nucleus
ANA or ASMA
Autoimmune hepatitis is based on serological markers: What do we see in Type 2 (anti-LKM 1 hepatitis, children) for Organelle:
Markers:
Organelle: microsome
oAnti-liver-kidney microsomal antibody
What autoimmune dseaes are associated with AIH
- Thyroid disease
- Rheumatoid arthritis
- Diabetes
- Sjogren’s syndrome
- Polymyositis
- IgA deficiency
- Idiopathic thrombocytopenia
- Urticaria
- Vitiligo
- Addison’s disease
- Inflammatory Bowel Disease
What to you treat autoimmine hepatitis with?
Prednisone or Predinisone + Azathioprine (steroid sparring)
Your patient has AIH, what other factors would encourage you to put her on Prednisone only instead of adding azathioprine
cytopenia, thipurine methytransferase deficient, pregnancy, maligancy
When would you put patient with AIH on prednisone with Azathioprine?
Postmenopause, osteoporosis, Brittle diseaes, obese, acne, emotional lability, HTN
What is the goal when tx patietns with AIH?
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
- Chronic, progressive, cholestatic liver disease
- Destruction of intrahepatic bile ducts
- Probable autoimmune pathogenesis
Primary Biliary Cirrhosis
In PBC, you have destruction of:
intrahepatic bile ducts; the very small ones that don’t show up great on imaging
Who do we see PBC in?
- 90-95% women
- Predominantly Caucasian
- Mean age 52 at presentation, range 30-65
Rare
What is teh cause of Primary Biliary Cirrhosis?
• 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
How does AMA in primary biliary cirrhosis cause issues?
AMA targets pyruvate dehydrogenase complex PDC; PCD-E2 predominates and is located on the membrane of teh biliary epithelial cells or the Bile Duct
Pt comes in:
- Raised Alkaline Phosphatase
- AMA +
- Investigation for other autoimmune disease
Suspect Primary bilary cirrhosis
Main symptoms of PBC
can be asymptomatic; see pruitis and fatigue, hepatomegaly, splenomegaly and xanthomas, jaunice
Why do we have vitamin deficiencies associated with PBC?
- Decreased bile salt excretion, steatorrhea
- Correlates with duration and severity of liver disease
What are our fat soluble vitamins? What effect do we see when they are decreaesd from PBC?
KADE
vitamin D (8-23%): osteomalacia, fractures, regular bone densitometry
vitamin K (7-8%): prolonged PT
What are common autoimmune disorders associated with PBC?
Sjogrens, thyroiditis, RA, Scleroderma or CREST, Raynauds, Celiac
Labs in PBC:
- Alkaline Phosphatase:
- Bilirubin :
- Cholesterol :
3-4 x normal in >90%
bilirubin: usually rises late
cholesterol elevated in 85% *Not associated with heart disease
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?
Primary biliary cirrhosis
How do people with PBC do for survival?
Asypmtpomatic pts have much better outcomes
What medicaiton is used to tx PBC?
Ursodeoxycholic acid (UDCA) and helps with histology to decresase florid lesion, but need to take anti-histamine for itching
