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151 Cards in this Set
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- Back
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HEREDITARY HEMOCHROMATOSIS
- according to Von Recklinghausen, HH is an Assuming Blood disorder that causes an increased what? |
- Skin pigmentation
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HEREDITARY HEMOCHROMATOSIS
- according to Sheldon, HH is an inborn error of what metabolism? - according to Sheldon, All pathologic Manifests of Dz is secondary to? |
- Iron
- Iron deposition in affected organs |
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HEREDITARY HEMOCHROMATOSIS
- inheritance pattern? - common or not? - HH is the MC what? |
- AR
- one of the most common - MC AR / single gene Dz in Caucasians |
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HEREDITARY HEMOCHROMATOSIS
- name of the gene involved in HH? - location on which chromosome? |
- HFE gene
- Chromosome 6 |
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HEREDITARY HEMOCHROMATOSIS
- what are the 2 major mutations involved in HH? |
- C2 82Y
- H6 3D |
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HEREDITARY HEMOCHROMATOSIS
- which mutational type is very common in White North Euro populations? - how common is it? |
C2 82Y homozygous
1:250 |
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HEREDITARY HEMOCHROMATOSIS
- in HH, what causes the excess tissue Iron Deposition? |
- increased Intestinal Iron Absorption
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HEREDITARY HEMOCHROMATOSIS
- Hemochromatosis (not HH) is defined as what? - MC form of Hemochromatosis? |
- several disorders of Iron Homeostasis
- HFE-related Hereditary Hemochromatosis (HH) |
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HEREDITARY HEMOCHROMATOSIS
- what are the 3 mutational forms of HH? |
- C2 82Y : C2 82Y Homozygote
- C2 82Y : H63D Heterozygote - other HFE gene mutations |
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HEREDITARY HEMOCHROMATOSIS
- what are the 5 non-HFE related HH? |
(HH FAT)
- Hemojuvelin (HJV) mutation - Hepcidin (HAMP) mutation - Ferroportin 1 (SLC 40 A1) mut. - African Iron Overload - Transferrin Receptor 2 (TfR2) mut. |
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HEREDITARY HEMOCHROMATOSIS
- HH can be secondary to? - give 4 examples |
- Iron overload
- Iron Overload Anemia (Beta-Thalessemia maj., Chronic Hemolytic Anemia, & Sideroblastic anemia) - Parenteral Iron overload (RBC transfusions, IV iron) - Dietary Iron Overload - Chronic Liver Dz |
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HEREDITARY HEMOCHROMATOSIS
- Pathophysiology of HH x3 |
- Altered function of HFE gene product
- Max. or Unrestricted intestinal absorption of dietary iron - Iron-induced Tissue Injury & Fibrosis |
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HEREDITARY HEMOCHROMATOSIS
- in HH, describe the Iron uptake mechanism that exists |
- NO important physiologic mechanism to regulate iron loss.
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HEREDITARY HEMOCHROMATOSIS
- Iron homeostasis depends on what? x2 |
Tight linkage btw body's
- Iron Requirements & - Iron Absorption |
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HEREDITARY HEMOCHROMATOSIS
- Dietary Iron is absorbed where in the GI? |
- Duodenum
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HEREDITARY HEMOCHROMATOSIS
- Duodenal Iron Absorption tied to Iron Requirements by at least what 2 defined regulators? |
- Erythropoietic regulator
- Stores Regulator |
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HEREDITARY HEMOCHROMATOSIS
- in HH, how does the Stores Regulator function? |
- at a Higher Set Point
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HEREDITARY HEMOCHROMATOSIS
- Hepcidin produced where? - Hepcidin excreted into where? - Hepcidin normal function? - How does Hepcidin get affected in HH? |
- Liver
- Plasma - Negative regulator of dietary Iron Absorption - Decreased/Faulty hepatic synthesis |
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HEREDITARY HEMOCHROMATOSIS
- Decreased/Faulty Liver synthesis of Hepcidin leads to? - which leads to? |
- Decreased plasma levels of Hepcidin
- Faulty regulation of dietary iron absorption |
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HEREDITARY HEMOCHROMATOSIS
- in HH, there is an Uncontrolled release of iron from what 2 cells? |
- Macrophages
- Duodenal enterocytes |
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HEREDITARY HEMOCHROMATOSIS
- the C282Y:C282Y Homozygote genotype presents what clinical phenotype expression? |
- Most clinically Significant Dz
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HEREDITARY HEMOCHROMATOSIS
- the C282Y:H63D Heterozygote genotype presents what clinical phenotype expression? |
- Variable expression
- Variable clinical significance |
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HEREDITARY HEMOCHROMATOSIS
- the H63D:H63D Homozygote genotype presents what clinical phenotype expression? |
- little or no clinical significance
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HEREDITARY HEMOCHROMATOSIS
- organ damage is usually related to? - symptoms of HH is usually related to? |
- EXTENT of Iron Overload
- EXTENT of Iron Overload |
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HEREDITARY HEMOCHROMATOSIS
- most common HH symptoms? x5 |
- Weakness
- Lethargy - Arthralgia - Abdominal Pain - Sexual dysfunction (males) |
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HEREDITARY HEMOCHROMATOSIS
- prevalence of liver disease in HH? |
> 95% of clinically significant HH patients
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HEREDITARY HEMOCHROMATOSIS
- HH effect on liver enzymes? - HH complications? x2 |
- elevated liver enzymes
- Liver Failure - Cirrhosis |
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HEREDITARY HEMOCHROMATOSIS
- MCC of death due to HH is? |
- Cirrhosis
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HEREDITARY HEMOCHROMATOSIS
- in HH patients that develop cirrhosis, there is a marked increase in what risk? |
HCC
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HEREDITARY HEMOCHROMATOSIS
- in HH patients with Liver disease, which patients have a poorer prognosis? |
- patients with Liver Transplants
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HEREDITARY HEMOCHROMATOSIS
- HH is associated with what systemic involvement? x5 |
(LACES)
- Liver Dz - Arthropathy - Cardiac disorder - Endocrine - Skin pigmentation |
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HEREDITARY HEMOCHROMATOSIS
- in HH, cardiac dz is the leading cause of what complication? |
- Sudden Death
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HEREDITARY HEMOCHROMATOSIS
- list the Cardiac Dz's found to be in association with HH. x3 |
(DMD)
- Dilated cardiomyopathy - Mixed-Dilated-Restrictive pattern - Dysrhythmias (conduction disturbance) |
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HEREDITARY HEMOCHROMATOSIS
- list 3 Endocrine disorders of HH |
(DHS)
- DM - Hypogonadism - Secondary Hypothyroidism |
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HEREDITARY HEMOCHROMATOSIS
- in HH patients with Arthropathy, what joints are classically involved? - in HH patients with Arthropathy, the joint changes resemble what other disorder on X-ray? |
- 2nd & 3rd MCP
- 2nd & 3rd PIP - Pseudogout (aka CPPD) |
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HEREDITARY HEMOCHROMATOSIS
- describe the hyperpigmentation involved in HH |
- Metallic or Slate-Gray hue ("bronzing")
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HEREDITARY HEMOCHROMATOSIS
- what causes the Metallic or Slate-Gray hue ("bronzing") x2 - above occurs in which skin layer? |
- Melanin increase
- Direct Iron deposit - Dermis |
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HEREDITARY HEMOCHROMATOSIS
- besides the Metallic or Slate-Gray hue ("bronzing"), what other skin manifests are associated with HH? |
(BAN)
- Body Hair loss - Atrophy of skin - Nail flattening |
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HEREDITARY HEMOCHROMATOSIS
- for HH, what are the Reversible conditions? x3 |
(HCC)
- Hepatomegaly - Cardiomyopathy - Cardiac conduction abnormalities |
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HEREDITARY HEMOCHROMATOSIS
- for HH, what are the Irreversible conditions? x5 |
(DATCH)
- DM - Arthropathy - Thyroid dysfunction - Cirrhosis - Hypogonadotropic Hypogonadism |
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HEREDITARY HEMOCHROMATOSIS
- Diagnosis is based on ? - what lab tests would support the clinical suspicion of HH? x2 |
- clinical suspicion
- Elevated Liver Enzymes - Abnormal Iron Studies |
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HEREDITARY HEMOCHROMATOSIS
- what clinical suspicion associated with age of onset? - what clinical suspicion associated with race? - what clinical suspicion associated with gender? |
- 40s to 50's
- North Euro ancestry - Women develop later in life (due to menses, childbirth) |
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HEREDITARY HEMOCHROMATOSIS
- Iron studies have what requirement? - Iron studies measure what 3 things? - Thus, Iron studies provide what important value? |
- FASTING!!!!!
(FIT) - Ferritin - Iron - TIBC - Transferrin saturation |
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HEREDITARY HEMOCHROMATOSIS
- what is the equation for Transferrin Saturation? |
= (Iron / TIBC) x 100
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HEREDITARY HEMOCHROMATOSIS
- what is the EARLIEST phenotype expression of HH? |
- Transferrin saturation > 45%
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HEREDITARY HEMOCHROMATOSIS
- can you Dx HH with a Transferrin Saturation > 45%? - what test confirms Diagnosis? |
- NO!!!!
(you needs da) - HFE gene mutational analysis |
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HEREDITARY HEMOCHROMATOSIS
- Ferritin is usually elevated under what condition of HH? x2 - above conditions would show Ferritin values to be what? |
- Clinically significant HH
- Iron Overload HH - Greater than 1000 mcg/L |
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HEREDITARY HEMOCHROMATOSIS
- does a Ferritin level > 1000 mcg/L become a diagnostic for HH? - why or why not? |
- No!
- May be elevated for other reasons (acute phase reactant, chronic liver dz) |
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HEREDITARY HEMOCHROMATOSIS
- Ferritin may be normal in which patients with HH? - why? |
- Young patients with HH
- not yet developed iron overload |
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HEREDITARY HEMOCHROMATOSIS
- what are the conditions to NOT get a liver biopsy? x4 |
- Homozygote C282Y or Comp. Heterozygote
- NO Hepatomegaly - Ferritin < 1000 - LFTs are normal |
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HEREDITARY HEMOCHROMATOSIS
- what are the conditions to DO a Liver Biopsy? x4 |
- C282Y Homozygote or Comp. Hetero
- Hepatomegaly - Ferritin > 1000 - LFTs abnormal |
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HEREDITARY HEMOCHROMATOSIS
T/F : Liver Biopsy is used for HH diagnosis |
- False
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HEREDITARY HEMOCHROMATOSIS
- Liver biopsy for HH is performed SOLELY for? |
- Assessing Damage (if any)
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HEREDITARY HEMOCHROMATOSIS
- Liver biopsy would assess what 2 types of liver damage? - Liver Biopsy would also show what in regards to Hepatocytes? |
- Fibrosis
- Cirrhosis - Hemosiderin deposits in hepatocytes |
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HEREDITARY HEMOCHROMATOSIS
- what is the stain used for Liver biopsy - above stain serves what purpose? |
- Perls Prussion Blue
- Determination & Localization of Iron Stores |
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HEREDITARY HEMOCHROMATOSIS
- liver biopsy can show that in INITIAL HH, iron stores are found where? - with increasing iron concentration, Iron stores can be LATER found where? |
- Periportal Hepatocytes
- Kupffer cells - Bile Duct cells |
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HEREDITARY HEMOCHROMATOSIS
- Liver biopsy can not only localize, but also Determine Iron Stores by obtaining what value? |
- HIC
(Hepatic Iron Concentration) |
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HEREDITARY HEMOCHROMATOSIS
- normal liver biopsy will show what HIC values? - abnormal liver biopsy associated with Fibrosis/Cirrhosis will show what HIC values? |
< 1,500 mcg/g
> 20,000 mcg/g |
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HEREDITARY HEMOCHROMATOSIS
- Primary Tx for HH? - describe the above Tx in the initial stages - above Tx applied until when? |
- Phlebotomy
- Remove 1 unit (500 mL) of blood per week (until) - Hematocrit (Hct) < 37% |
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HEREDITARY HEMOCHROMATOSIS
- during the Tx of HH with Phlebotomy, you must also do frequent monitoring of what 2 levels? |
- Hematocrit (Hct)
- Ferritin |
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HEREDITARY HEMOCHROMATOSIS
- Maintenance Tx with Phlebotomy with HH is? |
- remove 1 unit of blood every 3 to 4 months
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HEREDITARY HEMOCHROMATOSIS
- Phlebotomy goals in HH treatment for Hematocrit levels? - Serum Ferritin levels? - Transferrin saturation levels? |
< 37%
< 50 mEq/L (or ng/dL) < 50% |
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HEREDITARY HEMOCHROMATOSIS
- currently what is the American Red Cross policy on blood donation from HH patients? |
- does NOT accept HH pt blood
(however, pilot program recently completed and is being evaluated for implementation) |
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HEREDITARY HEMOCHROMATOSIS
- besides Phlebotomy, what other Tx METHOD is possible? - above method done with what Meds? |
- Chelation
- Deferoxamine |
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HEREDITARY HEMOCHROMATOSIS
- what are the advantages or disadvantages associated with Deferoxamine chelation Tx in HH compared to Phlebotomy? x3 |
Disadvantages of Chelation (Deforaxamine)
- Less effective - Painful infection - $$$$$$$$ |
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HEREDITARY HEMOCHROMATOSIS
- in positively Dx'd HH patients, what additional steps should be taken? |
- Genetic Testing of Family members
(siblings & children) |
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HEREDITARY HEMOCHROMATOSIS
- Genetic testing of family members of HH patients have what problems associated? - above problem is mostly associated with what aspect of healthcare? |
- Genetic discrimination / stigmatization
- Insurance (disability, health, life) |
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HEREDITARY HEMOCHROMATOSIS
- Genetic testing should be done BY or in cooperation WITH? |
- Genetic counselor
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WILSON'S DISEASE
- inheritance pattern - frequency compared to HH - Prevalence? |
- AR
- Wilson's is Rare - HH is more common - 1:30,000 |
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WILSON'S DISEASE
- Wilson's Dz is a disorder of? - associated gene - gene on what chromosome? - describe the mutations of above gene |
- Copper metabolism/overload
(dietary amount exceeds TRACE amt) - ATP 7B gene - Chromosome 13 - MULTIPLE mutations |
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WILSON'S DISEASE
- involved gene? - normal gene product? |
- ATP 7B
- Copper Dependent ATPase |
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WILSON'S DISEASE
- what is the normal function of the ATP7B product Cu2+ dependent-ATPase? x2 |
Transport of Copper across
1.) Canalicular Membrane ==> Biliary system ==> Excretion 2.) Trans-Golgi Network |
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WILSON'S DISEASE
- ATP7B product Copper Dependent ATPase allows for Copper to be transported thru the Trans-Golgi network. What happens next? |
- Copper incorporated into Ceruloplasmin
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WILSON'S DISEASE
- what is Ceruloplasmin? |
- Copper binding protein
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WILSON'S DISEASE
- normally, Ceruoplasmin binds what % of copper in plasma? |
- greater than 90%
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WILSON'S DISEASE
- Defective gene product ATPB7 leads to what event for copper? - where does the above happen? - what are 3 consequences to the above? |
- Copper accumulation
- inside Hepatic Lysosomes 1.) Non-excretion into Bile 2.) Accumulation of Hepatocellular Cu2+ 3.) Destabilized Ceruloplasmin with markedly diminished halflife |
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WILSON'S DISEASE
- Wilson's Dz causes excess copper deposition in what 3 important places? |
- Brain
- Eyes - Liver (also Endocrine organs, Skeletal muscle, Pancreas, Heart, Joints) |
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WILSON'S DISEASE
- Wilson's Dz is generally a Dz of what population group? - usually presents when? |
- Young persons Dz
- 2nd and 3rd decade (uncommon after 40) |
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WILSON'S DISEASE
- Classic Presentation by symptoms in what 3 areas? |
(Wilson LPN)
- Liver - Psychiatric - Neuro |
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WILSON'S DISEASE
- Hepatic presentation more common in what population group? - describe the hepatic symptomatic presentation |
- Children/Adolescents
- Variable (Vague Sx, Self-limiting Acute Hep) |
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WILSON'S DISEASE
- complications? x3 |
- Fulminant Acute Liver Failure RARE
- Chronic, Advanced Liver Dz - Cirrhosis |
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WILSON'S DISEASE
- Neurologic presentation more commo in what population group? - Most Neuro presentation have what kind of hepatic involvement? |
- 2nd to 3rd decade
- UNDIAGNOSED hepatic involvement |
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WILSON'S DISEASE
- what are the 2 forms of Neuro presentation? |
- Movement disorders
- Rigid dystonia |
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WILSON'S DISEASE
- which form of Neuro presentation occurs first? |
- Movement disorders
(Rigid Dystonia follows later) |
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WILSON'S DISEASE
- Neuro form of Movement Disorders show what symptoms? x3 - Neuro form of Rigid Dystonia shows what symptoms? x7 |
(FTP)
- Fine motor control loss - Tremors - Poor coordination (MR G DDD) - Mask like facies - Rigidity - Gait disturbance - Drooling - Dysarthria - Dysphagia |
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WILSON'S DISEASE
- Early clues to Rigid Dystonia. x3 |
(CHD)
- Clumsiness - Handwriting deterioration - Dysphonia (soft, whispery voice) |
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WILSON'S DISEASE
- by the time Neuro presentation has advanced to Rigid dystonia, describe its effect on Intellect |
- NOT impaired
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WILSON'S DISEASE
- what % of Wilson's patients present with purely Psychiatric Sx? - what are the Psychiatric Sx? x4 |
- 20%
- Compulsive behavior - Aggressive/antisocial behavior - Phobias - Depression |
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WILSON'S DISEASE
- Wilson's may present with what 2 ocular signs? |
- Kayser-Fleischer rings
- Sunflower cataracts |
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WILSON'S DISEASE
- etiology of Kayser-Fleischer rings - etiology of Sunflower cataracts |
- Cu deposition in Decemet's membrane of CORNEA
- Cu deposition in the LENS |
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WILSON'S DISEASE
- Kayser-Fleischer rings can be seen with what exam? - Sunflower cataracts seen in what exam? |
- Slit Lamp exam
- Slit Lamp exam |
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WILSON'S DISEASE
T/F : Kayser-Fleischer rings are pathognomonic to Wilson's Dz T/F : Sunflower cataracts interferes with vision |
- False
(absent in 15 to 50% of preSx or exclusively hepatic involvement) - False |
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WILSON'S DISEASE
- Kayser-Fleischer rings are present in 95% of what wilson's patients? |
- those with Neuro-Psych Dz
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WILSON'S DISEASE
- Kayser Fleischer rings will disappear with what therapy? - Sunflower cataracts will disappear with what therapy |
- chelation
- chelation |
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WILSON'S DISEASE
- list other Dz features of Wilson's Dz x8 |
- HEMOLYTIC Anemia
(sudden release of Cu into blood) - Fanconi syndrome (renal) - Pancreatitis (CLERK) - Cardiomyopathy & arryhthmias - Large joint arthritis - Endocrine disorders - Rhabdomyolysis - Kidney stones |
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WILSON'S DISEASE
- Diagnosis requires clinical suspicion. Give example of such patient. |
- Young patient with appropriate Liver and/or NeuroPsych S&Sx
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WILSON'S DISEASE
- Initial Screening Test for Wilson's Dz - values for above screening test |
- Serum Ceruloplasmin
- Low serum levels < 30 mg/dL) |
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WILSON'S DISEASE
- what is the Primary Problem with the initial screening test of Serum Ceruloplasmin levels? - list other problems associated with using Ceruloplasmin serum levels to screen for Wilson's. x3 |
- Ceruloplasmin is an Acute Phase Reactant
(can be elevated by nonspecific inflamm) - Affected by different lab methods - May be Normal in HEPATIC Dz - Low levels NOT unique to Wilson's |
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WILSON'S DISEASE
- besides serum Ceruloplasmin levels, what other test can be used for further confirmation? |
- 24 hour urine copper
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WILSON'S DISEASE
- what conditions would merit further investigation from the 24 urine copper test? |
- elevations, even BORDERLINE elevations
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WILSON'S DISEASE
- 24 copper urine tests may be elevated in? |
- Presymptomatic patients
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WILSON'S DISEASE
- describe the protocol for 24 urine test |
- 3 separate 24 hour collections
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WILSON'S DISEASE
- Provocative Test using what? |
- Penicillamine
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WILSON'S DISEASE
- when applying Penicillamine for the Provocative test, patients with Wilson's Dz will ? |
- INCREASE urinary Copper excretion moreso than normal patient
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WILSON'S DISEASE
- Provocative test, with Penicillamine, will have to provide what value for confirming Wilson's Dz? |
> 250 mcg per 24 hours
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WILSON'S DISEASE
T/F : Liver biopsy is diagnostic for Wilson's Dz |
True
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WILSON'S DISEASE
- Liver biopsy to quantify what? - Liver biopsy to assess? |
- Hepatic Copper Concentration
- Liver damage (fibrosis/cirrhosis) |
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WILSON'S DISEASE
- how many reported mutations are there for ATP7B gene? - thus what is the challenge? |
- over 260
- whether a detected mutation is dz causing and not a rare normal variant |
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WILSON'S DISEASE
- if a mutation is identified in a patient by genetic testing, then ? |
- analysis can be carried out in patient
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WILSON'S DISEASE
- Treatment goals x2 |
- Mobilize Accumulated Tissue Copper
- Prevent further copper absorption from GI |
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WILSON'S DISEASE
- what Tx method can meet the goal of mobilizing Accumulated Tissue Copper? - give example of meds for above |
- Chelation
- Penicillamine |
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WILSON'S DISEASE
- what is the classic 1st line Tx? - what is the 2nd line Tx? |
- Penicillamine
- Trientene |
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WILSON'S DISEASE
- what additional Tx can meet the goal of further copper absorption? - what is the NEW TX for Neuro Wilson's Dz? |
- Zinc
- Tetra-Thio-Molybdate |
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WILSON'S DISEASE
- what INITIAL side effect is associated with 50% of patients taking Penicillamine chelator? - prognosis of side effect? |
- Initial Worsening of Neuro Sx
- most recover |
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WILSON'S DISEASE
- Penicillamine is limited by many side effects such as? x5 |
- Multiple Skin reactions
- Chronic depletion of other trace metals - Severe Cytopenias - Nephrotic syndrome - Lupus-like reaction |
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WILSON'S DISEASE
- 2nd line of Tx is? - MOA? - Adverse SE? x2 |
- Trientene (2-2-2-tetramine)
- Copper chelator - GI upset - Iron deficiency (chelates dietary iron) |
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WILSON'S DISEASE
- which patients gets Trientene? - advantages of Trientene over Penicillamine x2 - disadvantages of Triemtene over Penicillamine |
- pts intolerant to Penicillamine
- rare Neuro worsening - extremely rare Bone Marrow suppression - Less potent chelator BUT NOT clinically significant |
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WILSON'S DISEASE
- Zinc will prevent what? - MOA? |
- further copper absorption
(its NOT a chelator tho) - Interferes with Cu absorption in GI |
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WILSON'S DISEASE
- Zinc side effects? - Conditions for combining with chelator - if combo Zinc with chelator, what precaution? - why? |
- Gastritis / GI upset
- in severe dz - Temporarily separated during Day - Drugs may neutralize each other |
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WILSON'S DISEASE
- Tetrothiomolybdate is a new treatment for? - MOA x2 |
- Wilson's NEURO deterioration
- Interferes with GI absorption of Cu2+ - Binds Plasma Cu with High affinity |
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WILSON'S DISEASE
- Tetrathiomolybdate is used in combo with? - why? |
- chelating agent
- increase amount of Free copper (with which to bind) |
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WILSON'S DISEASE
- Side effects with Tetrathiomolybdate |
- Bone marrow suppression possible
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WILSON'S DISEASE
- Pts with Wilson's Dz must also avoid what in their diet? x5 - what additional dietary precaution? |
AVOID (CNS MD)
- Cu containing supplements - Nuts - Shellfish - Mushrooms - Dried fruit - Analysis of home drinking water supply is necessary |
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WILSON'S DISEASE
- if a Wilson's Dz patient becomes pregnant, do you continue or discontinue treatment? - which meds MUST be discontinued b/c of its teratogenic effect? - then switch to which meds? |
- Continue you must
- Penicillamine is teratogenic - Trientene &/or Zinc |
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WILSON'S DISEASE
- which meds are Teratogenic? - what associated condition is also Teratogenic? |
- Penicillamine
- Copper Deficiency also teratogenic |
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WILSON'S DISEASE
- since copper deficiency is also teratogenic, what option do you have to consider? |
- decrease Trientene by 25%
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WILSON'S DISEASE
- Wilson's leading to Hepatic Failure or End Stage Liver Dz will thus indicate the need for? |
- Liver transplant
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WILSON'S DISEASE
- prognosis of Wilson's Dz with transplanted liver? - recent reports indicate what prognostic effect post-transplant? |
- Wilson's does NOT recur in transplanted liver
- Significant improvement in Neuro-deficits |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- inheritance pattern? - common or not? - MC? |
- AR
- one of the most common genetic disorders - MC METABOLIC Dz affecting Liver |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- Clinical picture x2 |
- Premature Emphysema
- Liver Dz |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- normally, A1AT is what? - normally A1AT inhibits what? - normal A1AT function is to Protect against? |
- Protease Inhibitor of Lung
- Inhibits Neutrophil Elastase - Protects against uninhibited destruction of CT by NEUTROPHIL ELASTASE |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- Pathophysiology of Premature emphysema? - what exacerbates premature emphysema |
- A1AT loss of activity
(leads to premature emphysema) - smoking |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- in the Liver, A1AT is synthesized where? - after synthesis, where does it go before secretion? |
- Rough ER of Hepatocytes
- Golgi ==> Secretion |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- mutant A1AT protein undergoes what modifications? x2 - above modifications due to mutant protein causes what event? |
- Misfolding
- Polymerization - Aberrent Retention in ER |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what is the Pathophysiology leading to Liver Dz in A1AT deficiency? |
- mechanism unknown
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what is the classic A1AT deficient allele? - what phenotype causes clinically significant Dz? |
- PiZZ phenotype
- PiZZ phenotype |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what is the "Pi" mean in PiZZ? - list the 4 types of A1AT proteins |
- Protease Inhibitor
- ZZ - MM - SS - SZ |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- PiZZ is representative of what genetic setup? |
- Homozygote
(b/c ZZ) |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- Liver Dz in A1AT Deficiency seen in what population group? - A1AT Deficiency Liver Dz can manifest as? x2 |
- Younger patients less than 50
- Neonatal Hepatitis - Childhood Liver Dz (RARE) |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- in younger patients (< 50 yo), Liver Dz from A1AT Deficiency causes what Signs and Symptoms? x4 |
- Abnormal "Liver Function Tests"
(transaminases, bilirubin) - Hepatomegaly - UNDiagnosed Chronic Liver Dz - Cirrhosis |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- Liver Dz in A1AT Deficiency carries an increased risk of what liver condition? - above risk is especially seen in? |
- HCC
- Males over 50 years old |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- give example of patient whom you suspect clinically with A1AT deficiency - big clue in clinical suspicion is? |
Younger patient ( < 50 yo)
with Abnml Liver Chemistries &/or Chronic Liver Dz &/or Hepatomegaly Early emphysema in NON-smoker |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what lab values will give clues to Dz? - what is the problem with above values? |
- Low levels of A1AT in serum
- A1AT is an Acute Phase Reactant (elevated in inflamm, CA, preg., or other stressors) |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- since serum A1AT is an Acute Phase Reactant, what must be held true diagnostically? |
- Never base DX on A1AT levels alonew
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- if you have clinical suspicion, what tests should you order? x2 |
- A1AT levels
AND!!! - Phenotype analysis (genetic testing) |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what test is the basis for DX |
- Phenotype analysis
(genetic testing) |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- are Liver Biopsies necessary? - what would a Liver Biopsy do to help? x2 |
- no
- confirm DX - Assess damage (fibrosis/cirrhosis) |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what is the classic homozygote in A1AT deficiency? |
PiZZ
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what is the specific therapy for A1AT associated Liver Dz? - what is the specific therapy for A1AT associated Lung Dz? |
- no current therapies exist
- Replacement Therapy IV with Purified A1AT |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what can be done for Liver Dz in A1AT deficiency? - what are the benefits of above? x3 |
- Liver Transplant
(PCR) - Prevents further progression of Liver AND Lung Dz - Corrects metabolic defect - Replaces damaged organ |
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ALPHA 1 ANTITRYPSIN DEFICIENCY
- what is the specific therapy METHOD for A1AT associated Lung Dz? - Therapy utilizing what? - administered how? - what benefits does this allow? |
- Replacement Therapy
- Purified A1AT - IV infusion - Slower Decline in Lung Function |
