35. Metabolic/Storage Dz of Liver Flashcards
What are the 3 Metabolic diseases that we covered?
Alpha1-antitrypsin deficiency (A1AT)
Hereditary Hemochromatosis (HH)
Wilson’s Disease
Why is it important to ask about childhood diseases/health history when investigating these metabolic diseases?
Clinical features can manifest in childhood, then disappear during development, then reappear in adulthood.
What are a few ways in which metabolic liver disease causes harm?
_Increased storage in the liver: _
- accumulation of metabolic products like fat
- Hepatomegaly, splenomegaly
- inflammation –> fibrosis
- susceptability to infection
Metabolic failure:
hypoglycemia, hyperammonia, developmental delays
Given that there is such a huge range of clinical presentation of these diseases, what symptoms should we focus on?
-Growth failure, seizures, developmental delays
But there are a ton of signs: hepatomegaly, splenomegaly, cardiac issues, ascites, jaundice..)
Screening tests for metabolic liver diseases?
- Serum tests for electrolytes, ammonia, glucose, amino acids….
- Urine tests
- Liver biopsy (not required but may be used to exclude other conditions)
- Genetic testing
NASH: inherited or acquired? what are the systemic clinical features?
Acquired
Clinical features: obesity, metabolic syndrome
NASH: what is the pathophysiology?
Increased FFAs, steatosis, increased oxidation, increased inflammation, increaesed apoptosis
NASH: diagnostic tests and questions?
US/CT
Look for steatosis
Exclude other liver diseases
Exclude EtOH history
NASH: liver histology?
- Steatosis
- Lobular inflammation
- Hepatocyte ballooning
- Mallory bodies
- Fibrosis
HH: what is the inheritance pattern? gene, protein?
Auto recessive
HFE gene
- 80% C282Y/C282Y
- 6% C282Y/H63D
- Others unknown
HH: pathophysiology?
- Decr hepcidin activity
- macrophages and enterocytes release iron into serum
- Fe deposition in organs
HH: diagnostic tests?
Transferrin sat > 45%
High ferritin levels
Elevated liver enzymes
Genotype: C282Y, H63D
LIver biopsy to exclude other dz
HH: liver histology?
incr hepatic iron concentration
Wilson’s disease: inheritance pattern? gene? what does the gene do?
Auto recessive
gene ATP78
encodes Cu-transporting P-type ATPase
Wilson’s: pathophysiology?
Less ATPase activity
Less Cu excreted in bile, and bound to ceruloplasmin
Cu deposits in organs
Wilson’s Dz: how does it present in children?
How does it present in adults?
Children: liver disease, acute liver failure
Adults: liver disease, possible neuropsych issues
Wilson’s Dz: diagnostic tests?
Low ceruloplasmin levels
Increased UCu (urinary copper?)
KF rings in eyes (sunflower effect)
Increased Cu with acute liver injury
Wilson’s Dz: liver histology?
- Hepatic Cu content (>250ng/g)
- Chronic Liver Disease
alpha 1 anti trypsin deficiency: interitance pattern? gene? what alleles are pathologic/normal?
- Auto Recessive
- Mutation in A1AT protein coded by SERPINA1 gene
- ZZ is homozyg mutant (A1AT activity is 15% of normal)
- MM is normal
A1AT: pathophysiology?
mutated A1AT accumulates in the liver
Less circulating A1AT
Destruction of pulm CT matrix
A1AT: presentation in children? presentation in adults?
-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
A1AT: diagnostic testing?
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)
A1AT: liver histology?
- Di-PAS- positive globules
- Other atypical features such as steatosis
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
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.
What are the Lung effects of A1AT deficiency?
Inability to inhibit neutrophil elastase leads to destruction of lung parenchyma –> lung disease and COPD
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.
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.
What’s this?
A1AT liver biopsy
the A1AT is the magenta droplets trapped in hepatocytes.
A1AT: treatment for liver disease?
- Smoking cessation
- Treat other concomitant diseases (obesity, alcohol, metabolic risk factors)
-Liver transplant is curative
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.
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)
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
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.
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
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
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
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
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.
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
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)
What are the stages in the progression of HH?
- Genetic predisposition
- Iron overload, but asymptomatic
- Iron overload with early symptoms (lethargy, arthropathy)
4. Iron overload with organ damage: cirrhosis, HCC, cardiomyopathy, diabetes
What are the most common causes of death in HH?
HCC (28%)
Cirrhosis (20%)
Cardiomyopathy (7%)
Diabetes (6%)
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
HH: treatment?
Phlebotomy!
weekly or biweekly
Aim for ferritin levels of 50-100 lg/L
This is what?
Hereditary Hemochromatosis liver.
Blue = iron deposition
Disease?
HH. blue = iron
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
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
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
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.
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
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.
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)
What disease? (special stain)
Special stain for copper –> Wilson’s Disease
Wilson’s Disease: treatment?
D-penicillamine (copper chelator)
Trientine (for neuro symptoms)
Zinc
Liver transplant
Genetic screen other family members
Non-hemolytic anemia should make me think what?
Wilson’s Dz
Does replacing A1AT treat liver disease in A1AT deficiency?
Nope. But if
