Liver Pathology 4 - SRS Flashcards
What are the inherited diseases of the liver we covered?
- Hemochromatosis
- Wilson disease
- Alpha-1-antitrypsin deficiency
What are the two types of hemochromatosis?
Hereditary
Secondary
What is the inheritance pattern for wilson disease?
What does it result in?
Autosomal recessive
Impaired copper excretion and failure to incorporate copper into ceruloplasmin
Iron homeostasis depends on what?
Hepcidin regulating ion transport across membranes and intracellular storage.
What is the most common mutation that leads to decreased hepcidin synthesis?
Mutation in the HFE protein
In the HFE mutation, when does the onset of the symptoms usually arise?
Late onset (graphic appears to show late 40’s and 50’s)
If a patient experiences early life onset iron overload, what are the two likely mutations?
HAMP
HJV
Hereditary hemochromatosis is one of the most common genetic disorders in humans.The adult form of hemochromatosis is almost always caused by mutations of HFE which regulates the production of hepcidin.
What are the typical causes of death in patients with hemochromatosis?
Cirrhosis
Cardiac disease
What is the classic tetrad of hemochromatosis?
- Hepatomegaly
- Skin pigmentation
- Destruction of pancreatic islets
- Cardiomyopathy
What is the screening test for hemochromatosis?
Transferrin saturation - will be High if positive
After a positive screening test, what should be done to dx hemochromatosis?
–MRI of liver to get idea of iron content
–Iron biopsy (iron content; fibrosis) Not as useful
–HFE mutation (genotype)
What is the treatment for hemochromatosis? Outcome?
Phlebotomy to achieve mild iron deficiency - goal is mild microcytic/hypochromic anemia
Life expectancy with treatment is normal
What are three causes of secondary hemochromatosis?
Blood transfusions
Iron supplements
Excess dietary iron
Blood transfusions for what conditions specifically are associated with secondary hemochromatosis?
–Myelodysplastic syndromes
–Chronic kidney disease
–Leukemia
–Hemoglobinopathies
What is the keyword associated with the diabetes from hemochromatosis?
What causes this to develop?
Bronze diabetes
Pigment is d/t increased epidermal melanin
What do you see here?
What caused it?
Liver and pancreas are both brown from hemochromatosis derived iron overload
What is shown here?
Hemochromatosis
What is shown here?
Cirrhosis secondary to hemochromatosis
What is the inheritance pattern for wilson disease?
Where do the toxic levels of copper tend to accumulate?
Autosomal recessive
Accumulations in the:
Liver
Brain
Eye
At what ages and with what conditions do patients with Wilson disease typically present?
Liver disease age 5 - 15
or
neuropsychiatric in their 20’s
What is the treatment for Wilson disease?
Chelation
Penicillamine
Liver transplant if cirrhosis
Where is copper absorbed?
What happens to it in the liver?
- Dietary copper is absorbed in duodenum
- In the liver, copper is incorporated into apoceruloplasmin to produce ceruloplasmin
What is a hallmark lab finding in Wilsons disease?
Decreased cerulloplasmin
What percent of plasma copper is bound to ceruloplasmin?
90-95%
What mediates the excretion of ingested copper in bile and production of ceruloplasmin?
Copper transporting atpase
As mentioned earlier, screening testing for Wilsons is done with serum ceruloplasmin. What are the specific and sensitive tests?
- Increased urine copper (specific)
- Increase liver copper content by biopsy (most sensitive, highest positive predictive value)
Your patient had a low serum ceruloplasmin level so you took a biopsy. What did you stain the tissue with here and what did it reveal?
Stain with rhodanine (copper stain)
Shows copper accumulation indicative of Wilson disease
This 18-year-old woman presented intermittent tremor of the hands since the age of 15 years. What is the finding shown at left? What condition is this seen in?
Kayser-Fleischer ring
Wilsons disease
Where does the copper deposition in the brain d/t wilsons disease typically end up?
Basal Ganglia
What is the inheritance pattern of Alpha1-Antitrypsin Deficiency?
What is defective?
•Autosomal recessive disorder of protein folding marked by very low levels of circulating α1-Antitrypsin (α1AT)
What is the major function of α1-Antitrypsin (α1AT)?
What is the most common clinically significany mutation and what are the circulating levels of α1-Antitrypsin (α1AT)?
•
•
- Major function of this protein is the inhibition of proteases
- The most common clinically significant mutation is PiZ
–α1AT levels are only 10% of normal
Alpha-1 Anti-trypsin deficiency can present in the neonate, how?
•Neonatal hepatitis with cholestatic jaundice appears in 10% to 20% of newborns with the deficiency
What are two possible consequences of alpha-1-antitrypsin deficiency?
- Hepatocellular carcinoma develops in 2% to 3% of PiZZ adults
- Panlobular emphysema
What does the PASD stain show here?
What does this lead to?
Pooled accumulation of misfolded alpha-1-antitrypsin
Leads to apoptosis, inflammation, cirrhosis
This liver was removed from a 6 year old. What likely caused this?
α1-AT deficiency
In Primary Biliary Cirrhosis, Autoimmune cholangiopathy, a disease of unknown etiology, selectively affects What?
Small intrahepatic bile ducts
What does the damage in primary biliary cirrhosis progress to?
•progressive bile duct damage, chronic cholestasis, biliary fibrosis/cirrhosis leading to hepatic failure
What population is most often affected by primary biliary cirrhosis?
Middle age women with a peak incidence in the 40 - 50 age group
60% of patients with primary biliary cirrhosis are asymptomatic, and it affects women 9 times more often than men. What antibodies are the most characteristic laboratory finding?
Anti-mitochondrial antibodies (AMA)
What are the alkaline phosphatase levels like in primary biliary cirrhosis?
Elevated, 3-5x normal
In addition to AMA, what other antibodies can be seen in primary biliary cirrhosis? In what patients is this more common?
ANA - mostly in male patients with the condition
The Initial injury in primary biliary cirrhosis affects the small interlobular bile ducts within portal tracts leading to progressive duct loss. What are characteristically seen associated with damaged bile ducts in the early stages?
Epitheliod granulomas and lymphocytic reaction
Do all patients with primary biliary cirrhosis progress to cirrhosis?>
Nope
What do you see in this sample taken from a patient with primary biliary cirrhosis?
Portal tract markedly expanded by infiltrate of lymphocytes and plasma cells. The granulomatous reaction involves a bile duct undergoing destruction (florid duct lesion)
What happened to this liver?
Bile stained d/t end stage biliary cirrhosis
Primary Sclerosing Cholangitis is a progressive disease of liver characterized by cholestasis with obliterative fibrosis of?
intra- and extrahepatic bile ducts with dilation of preserved segments
What is coexistant in up to 70% of primary sclerosing cholangitis cases?
Inflammatory bowel disease
(90% Ulcerative colitis, 10% Crohn disease)
Primary Sclerosing Cholangitis is a mostly male disease (2:1), presenting at age 40 years with symptoms of chronic liver disease and typically live 10-15 years. The prognosis is variable with patients having what two possible outcomes?
Recurrent cholangitis
biliary cirrhosis
What is the pathogenesis of PSC?
Pathogenesis is unknown but features suggest an immunologic process involving T cells
What are the treatment options for PSC?
No cure
Cholestyramine for pruritus
liver transplant for liver failure
PSC is diagnosed with both pathologic and radiologic findings. What lab values might we find in this condition?
- Elevate alkaline phosphatase (90% of patients)
- Perinuclear antineutrophilic cytoplasmic antibody (pANCA) (90% of patients) (non-specific finding)
On imaging what will you see in PSC?
Large duct disease with strictures, beading and dilation
What does a liver biopsy of a PCS patient reveal? 4
- obliterative cholangitis with inflammation
- characteristic periductular onion ring fibrosis,
- ductopenia
- secondary biliary cirrhosis
What is shown here?
PCS
- left: a histologic specimen demonstrating fibrosis and inflammation surrounding the bile duct.
- The gross specimen demonstrates the thickening of the wall of the bile duct (arrow) causing many strictures.
What is this finding typical of?
Primary Sclerosing Cholangitis: characteristic “onion-skin” fibrosis affecting small ducts in the liver parenchyma
What does this Endoscopic Retrograde Cholangiopancreatogram (ERCP)indicate our patient has?
PSC - note the strictures and dilations of the ducts
How often does GVHD develop in hematopoietic stem cell transplantaion?
up to 70% of patients
What is the most characteristic histological feature of graft versus host disease impact on the liver?
Bile duct damage
This specimen demonstrates a characteristic feature of chronic GVHD, can you spot it?
Probably not, since it’s vanishing bile duct syndrome… and just like that… it’s gone.
