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M2 GI > 35. Metabolic/Storage Dz of Liver > Flashcards

35. Metabolic/Storage Dz of Liver Flashcards

1
Q

What are the 3 Metabolic diseases that we covered?

A
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2
Q

Alpha1-antitrypsin deficiency (A1AT)

Hereditary Hemochromatosis (HH)

Wilson’s Disease

A
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3
Q

Why is it important to ask about childhood diseases/health history when investigating these metabolic diseases?

A

Clinical features can manifest in childhood, then disappear during development, then reappear in adulthood.

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4
Q

What are a few ways in which metabolic liver disease causes harm?

A

_Increased storage in the liver: _

  • accumulation of metabolic products like fat
  • Hepatomegaly, splenomegaly
  • inflammation –> fibrosis
  • susceptability to infection

Metabolic failure:

hypoglycemia, hyperammonia, developmental delays

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5
Q

Given that there is such a huge range of clinical presentation of these diseases, what symptoms should we focus on?

A

-Growth failure, seizures, developmental delays

But there are a ton of signs: hepatomegaly, splenomegaly, cardiac issues, ascites, jaundice..)

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6
Q

Screening tests for metabolic liver diseases?

A
  • Serum tests for electrolytes, ammonia, glucose, amino acids….
  • Urine tests
  • Liver biopsy (not required but may be used to exclude other conditions)
  • Genetic testing
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7
Q

NASH: inherited or acquired? what are the systemic clinical features?

A

Acquired

Clinical features: obesity, metabolic syndrome

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8
Q

NASH: what is the pathophysiology?

A

Increased FFAs, steatosis, increased oxidation, increased inflammation, increaesed apoptosis

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9
Q

NASH: diagnostic tests and questions?

A

US/CT

Look for steatosis

Exclude other liver diseases

Exclude EtOH history

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10
Q

NASH: liver histology?

A
  • Steatosis
  • Lobular inflammation
  • Hepatocyte ballooning
  • Mallory bodies
  • Fibrosis
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11
Q

HH: what is the inheritance pattern? gene, protein?

A

Auto recessive

HFE gene

  • 80% C282Y/C282Y
  • 6% C282Y/H63D
  • Others unknown
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12
Q

HH: pathophysiology?

A
  • Decr hepcidin activity
  • macrophages and enterocytes release iron into serum
  • Fe deposition in organs
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13
Q

HH: diagnostic tests?

A

Transferrin sat > 45%

High ferritin levels

Elevated liver enzymes

Genotype: C282Y, H63D

LIver biopsy to exclude other dz

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14
Q

HH: liver histology?

A

incr hepatic iron concentration

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15
Q

Wilson’s disease: inheritance pattern? gene? what does the gene do?

A

Auto recessive

gene ATP78

encodes Cu-transporting P-type ATPase

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16
Q

Wilson’s: pathophysiology?

A

Less ATPase activity

Less Cu excreted in bile, and bound to ceruloplasmin

Cu deposits in organs

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17
Q

Wilson’s Dz: how does it present in children?

How does it present in adults?

A

Children: liver disease, acute liver failure

Adults: liver disease, possible neuropsych issues

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18
Q

Wilson’s Dz: diagnostic tests?

A

Low ceruloplasmin levels

Increased UCu (urinary copper?)

KF rings in eyes (sunflower effect)

Increased Cu with acute liver injury

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19
Q

Wilson’s Dz: liver histology?

A
  • Hepatic Cu content (>250ng/g)
  • Chronic Liver Disease
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20
Q

alpha 1 anti trypsin deficiency: interitance pattern? gene? what alleles are pathologic/normal?

A
  • Auto Recessive
  • Mutation in A1AT protein coded by SERPINA1 gene
  • ZZ is homozyg mutant (A1AT activity is 15% of normal)
  • MM is normal
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21
Q

A1AT: pathophysiology?

A

mutated A1AT accumulates in the liver

Less circulating A1AT

Destruction of pulm CT matrix

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22
Q

A1AT: presentation in children? presentation in adults?

A

-Children: liver dz > lung dz. most common hereditary liver disease in children! –> jaundice, hepatomegaly, failure to thrive, acute liver failure.

-Adults: lung dz > liver dz

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23
Q

A1AT: diagnostic testing?

A

Low A1AT levels

Can phenotype the protein

Can genotype the patient for alleles

Liver biopsy not required (may use to rule out other causes of liver dz)

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24
Q

A1AT: liver histology?

A
  • Di-PAS- positive globules
  • Other atypical features such as steatosis
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25
A1AT: highest prevalance in what race? What % of patients with ZZ alleles have clinical disease? It is recommended to screen for A1AT if a patient has what other disease?
- Highest prev in Northern Europeans - 15% of pts with ZZ alleles present with disease - If pts have COPD, recommended to screen for A1AT
26
A1AT: what is the role of the normal protein? What organs are affected when it is mutated?
- normally inhibits proteases, especially neutrophil elastase, which is released during inflammation. Protective effect against inflammation. - 2 organs involved: Lung and Liver Picture: reactive loop (yellow) normally interacts with enzymes, but if mis-folded the individual proteins will polymerize and accumulate.
27
What are the Lung effects of A1AT deficiency?
Inability to inhibit neutrophil elastase leads to destruction of lung parenchyma --\> lung disease and COPD
28
What are the Liver effects of A1AT deficiency?
**Accumulation** of aberrantly folded A1AT protein in the Endo Reticulum --\> apoptosis, mitochondrial injury, hepatic cell necrosis --\> fibrosis and cirrhosis.
29
Adults with ZZ alleles for A1AT are at higher risks for developing what other liver conditions? What is a behavior that makes things worse?
ZZ allele patients are at higher risk for cirrhosis (x8) and HCC (x2) Smoking makes it worse. Duh.
30
What's this?
A1AT liver biopsy the A1AT is the magenta droplets trapped in hepatocytes.
31
A1AT: treatment for liver disease?
- Smoking cessation - Treat other concomitant diseases (obesity, alcohol, metabolic risk factors) **-Liver transplant is curative**
32
A1AT: treatment for lung disease?
Lung replacement therapy to increase anti-neutrophil elastase activity in bronchoalveolar lavage fluid. Basically, give them the A1AT protein that they are lacking.
33
Iron distribution in our body?
- Absorbed from diet via **duodenum** - moved through plasma via **transferrin** (2 seater Smart car) - Found in RBCs as **Hgb** - Stored in macrophages and hepatocytes in **ferritin** - Loss is minimal (some lost w menstruation)
34
Hepcidin. Where is it produced? What does it respond to? What does it do?
- Produced in liver. - Responds to iron levels in the blood - Stimulates iron transportation into cells (macrophages, enterocytes, hepatocytes) - by regulating ferroportin. Acute phase reactant: it is elevated in inflammation
35
Ferroportin: where is it found? what does it do? What regulates its activity?
Found on enterocytes, hepatocytes, macrophages. Main iron export protein from cytoplasm -\> circulation Regulated by hepcidin binding. Pic: ferroportin is the "Basolateral Transporter" at the bottom of the cell.
36
What were her main points from this super-crappy picture?
Part of Iron Regulation: Ferroportin is in green at the basolateral membrane of the enterocyte. Iron passes through the **ferroportin**, binds to apotransferrin to form **transferrin** (2 seat Smart car). **Transferrin** is sensed by hepatocytes which then decide what to do with their **ferroportin** transporters
37
what is Hepcidin? Where is it expressed? What does it do?
Hepcidin= key regulator of iron Expressed in hepatocytes, excreted into circulation Binds to ferroportin (on macrophages, enterocytes) Results in internalization and degradation of ferroportin **--\> decreases iron export from enterocytes and macrophages**
38
What's going on in this pic?
The receptor at the top of the pic senses plasma Transferrin (with 2 iron molecules attached). (note HFE is part of this complex) It then releases Hepcidin, which acts on both macrophages and enterocytes, and causes them to internalize or destroy their Ferroportin transporters. Effect: less iron absorbed from the diet/duodenum, less iron released from hepatocytes to circulation
39
A mutation in HFE will lead to what systemic effect?
Leads to decreased hepcidin expression, increased iron absorption - Increased hepcidin level --\> decr ferroportin, decr serum iron - Decreased hepcidin -\> incr ferroportin, incr serum iron
40
There are a lot of types of iron overload: how can you tell if it is HFE-related?
- Can test for mutation of HFE or other related genes - If HFE-related, will show impaired synthesis or function of **hepcidin**. - Will have elevated transferrin saturation - Progressive iron deposition in many organs - Normal erythropoiesis - Responsive to phlebotomy.
41
How can you tell if iron overload is NOT related to HFE?
**-Not associated with hepcidin function** **-Transferrin saturation** will be slightly elevated or low -Iron will accumualted in rhe RES and other cells (Kuppfer cells) Not responsive to phlebotomy
42
Hereditary Hemochromatosis: full picture.... mutation in what? causes what protein change? increases body levels of what? deposits in what?
**•Mutation in HFE** --Decreased expression of hepcidin –Increased iron absorption despite adequate iron levels –Increased iron levels –Increased transferrin saturation –Deposition in the liver, heart, spleen and endocrine organs (possibly also skin --\> bronze skin tone)
43
What are the stages in the progression of HH?
1. Genetic predisposition 2. Iron overload, but asymptomatic 3. Iron overload with early symptoms (lethargy, arthropathy) **4. Iron overload with organ damage: cirrhosis, HCC, cardiomyopathy, diabetes**
44
What are the most common causes of death in HH?
**HCC** (28%) **Cirrhosis** (20%) **Cardiomyopathy** (7%) **Diabetes** (6%)
45
what genetic variant puts HH patients at worst risk for developing HCC?
**C282Y homozygosity** = "bad combination" These patients are at 120x incr risk for HCC
46
HH: treatment?
**Phlebotomy!** weekly or biweekly Aim for ferritin levels of 50-100 lg/L
47
This is what?
Hereditary Hemochromatosis liver. Blue = iron deposition
48
Disease?
HH. blue = iron
49
Wilson's disease: problem in regulation of what? How is homeostasis of this element maintained normally?
Problem in regulation of **copper**. Homeostasis is maintained by **biliary excretion of Cu**
50
Wilson's Disease: big picture, what is the problem?
**•Defective biliary excretion of copper** leading to **accumulation** in various organs –Liver, brain, cornea and kidneys
51
Wilson's Disease: what is the gene that is mutated? The resulting protein does what? What is the main transporter of Copper?
Gene: **ATP7B gene** Protein transports Cu from intracellular proteins into secretory pathways (excretes into bile) **Main transporter of Cu = ceruloplasmin**
52
This super-crappy picture shows what?
Copper processing within the hepatocytes. The ATP7B protein is on the Golgi Apparatus. Brings Cu from cytoplasm, places it on apocerulopoasmin to form ceruloplasmin. The Ceruloplasmin (incl copper) is then excreted into plasma or into bile.
53
Wilson's Disease: clinical presentation?
Variable: but involves Liver, Eye, CNS May be speech or developmental delays due to deposition of Cu in parts of the brain (globus pallidus) Also: non-hemolytic anemia
54
What is this? what disease?
**Kayser-Fleischer Ring**. Often seen in **Wilson's** (though non-specific) Deposition of Cu in cornea. Present in 95% of patients with neuropsych symptoms MUST do a slit-lamp eye exam on Wilson's Dz pts for this reason.
55
Wilson's Dz: Liver histology?
–Steatosis –Glycogenated nuclei in hepatocytes, **Mallory hyline bodies** –Focal necrosis –Cirrhosis- usually **macronodular**, but also micronodular –Copper staining in hepatocytes (cirrhosis can be found in Kupffer cells) –Mitochondrial abnormalities (Dense bodies in the mitochondria)
56
What disease? (special stain)
Special stain for copper --\> Wilson's Disease
57
Wilson's Disease: treatment?
D-penicillamine (copper chelator) Trientine (for neuro symptoms) Zinc Liver transplant Genetic screen other family members
58
Non-hemolytic anemia should make me think what?
Wilson's Dz
59
Does replacing A1AT treat **liver** disease in A1AT deficiency?
Nope. But if
60

M2 GI (41 decks)

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