Liver Path 4 Flashcards
Inherited Liver Diseases
Hemochromatosis is caused by excessive iron absorption
- hereditary hemochromatosis
- secondary hemochromatosis
Wilson disease is an autosomal recessive disorder resulting in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin
Alpha 1 Antitrypsin deficiency
Regulation of Iron Homeostasis Mini-review
There is no physiological pathway for iron excretion
Iron homeostasis depends on *hepcidin to regulate iron transportation across membranes and intracellular storage
Decreased *hepcidin synthesis caused by mutations in HFE protein, central role in the pathogenesis of hemochromatosis
Hepcidin
Hepcidin is a peptide hormone produced primarily by the liver and secreted into the circulation
Synthesis increases in response to iron and inflammation (IL-6) and decreases in response to erythropoiesis
Regulates systemic iron metabolism by interacting with its receptor ferroportin, a transmembrane iron-export protein
Negative regulator of iron absorption and recycling.
Hepcidin is regulated by several molecules including high iron gene *(HFE), hemojuvelin *(HJV), and transferrin receptor *(TfR2)
*(These interact with each other to regulate hepcidin)
hepcidin-ferroportin complex
Hepicidin regulates the transmembrane transport of iron.
Binds to Ferroprotein, forms hepicidin-ferroportin complex, which is degraded in the lysosomes and iron is locked inside the cells (mainly enterocytes, hepatocytes and macrophages).
The Common Genetic Basis and Phenotypic Continuum of Haemochromatosis.
- Dominant role in hepcidin synthesis (e.g.HAMPorHJV), circulatory iron overload occurs rapidly
If Haemochromatosis gene is * less critical for hepcidin synthesis (e.g. HFE), a milder late-onset phenotype will arise
Hemochromatosis
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
Death may result from cirrhosis or cardiac disease.
Classic Tetrad of Hemochromatosis
Hepatomegaly
Skin pigmentation
Destruction of pancreatic islets
Cardiomyopathy
Hemochromatosis Diagnosis
Screening test: transferrin saturation
(Serum Iron/TIBC ) normal >16%
MRI of liver to get idea of iron content
Iron biopsy (iron content; fibrosis) Not as useful
- HFE mutation )C282Y)
Hemochromatosis Treatment
Phlebotomy to achieve mild iron deficiency
(mild microcytic/hypochromic anemia)
With treatment life expectancy is normal
Secondary Hemochromatosis Iron Overload
Blood Transfusions for hereditary anemias
- Hemoglobinopathies
Blood Transfusions for acquired anemias
- Myelodysplastic syndromes
- Chronic kidney disease
- Leukemia
Iron supplements
Excess dietary iron
Complications of hemochromatosis
** classic triad- skin pigmentation, cirrhosis, diabetes
hypopituitarism
cardiac failure
arthropathy
testicular atrophy
bronze diabetes
hemochromatosis
pigmentation due to increased epidermal melanin
hemosiderin is also deposited in dermal macrophages and fibroblasts
Wilson disease
Autosomal recessive disorder caused by mutation in copper transporting ATPase
Toxic levels of copper accumulate in organs especially liver, brain and eye
Typically present with liver disease age 5-15 years, or neuropsychiatric in 20’s
Treatment: chelation, (Penicillamine), liver transplant for cirrhosis
Copper Metabolism
Dietary copper is absorbed in duodenum
In the liver, copper is incorporated into apoceruloplasmin to produce ceruloplasmin
90-95% of plasma copper is bound to cerulloplasmin
Copper transporting ATPase mediates the excretion of ingested copper in bile and the production of ceruloplasmin
If Cu is not being secreted out of the cell into the bile,
then copper accumulates in the cell to toxic levels –>
Inflammation and Cell Death
Laboratory Diagnosis of Wilson disease
Low serum ceruloplasmin (screening)
Increased urine copper (specific)
Increase liver copper content by biopsy (most sensitive, highest positive predictive value)
Serum copper is highly variable as it depends on ceruloplasmin level
Wilson disease histology
Same histologic pattern as chronic active hepatitis from hepatitis virus
Steatosis can be seen in Wilson disease
Copper (rhodanine) stain
Kayser–Fleischer ring
copper ring around the iris
disappears after copper-chelating treatment
Alpha1-Antitrypsin Deficiency
Autosomal recessive disorder of protein folding marked by very low levels of circulating 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 Clinical Features
Neonatal hepatitis with cholestatic jaundice appears in 10% to 20% of newborns with the deficiency
Hepatocellular carcinoma develops in 2% to 3% of PiZZ adults
Other than globules the histopathologic findings remain nonspecific and include fibrosis and variable portal inflammation
Panlobular emphysema
α1-Antitrypsin Deficiency histology
PASD staining shows the actual misfolded protein in the cytoplasm. This leads to apoptosis…inflammation…cirrhosis..
Inherited Metabolic Liver Diseases- list from robbins
The inherited metabolic diseases include hemochromatosis, Wilson disease, and α1-antitrypsin deficiency.
robbins: Hereditary hemochromatosis
is caused by a mutation in theHFEgene, whose product is involved in intestinal iron uptake by its effect on hepcidin levels. It is characterized by accumulation of iron in liver and pancreas
robbins: Wilson disease
is caused by a mutation in the metal ion transporterATP7B,which results in accumulation of copper in the liver, brain (particularly basal ganglia), and eyes (“Kayser-Fleisher rings”).
Wilson disease effects on the liver are protean, presenting as acute massive hepatic necrosis, fatty liver disease, or chronic hepatitis and cirrhosis.
robbins: alpha 1 antitrypsin deficiency
is a disease of protein misfolding that results in impaired secretion of α1Antitrypsin into the serum.
The Z variant of α1-Antitrypsin is the most likely to impair secretion by hepatocytes and cause disease, particularly when homozygous, that is, thePiZZgenotype; the main consequences are pulmonary emphysema caused by increased elastase activity and liver injury caused by the accumulation of abnormal α1-Antitrypsin.
Primary Biliary Cirrhosis
Autoimmune cholangiopathy disease of unknown etiology which selectively affects the small intrahepatic bile ducts with progressive bile duct damage, chronic cholestasis, biliary fibrosis/cirrhosis leading to hepatic failure
Usually affects middle-aged women with a peak incidence in the 40–50 age group
primary biliary cirrhosis- clinical stuff
60% are asymptomatic
Female preponderance of 9 to 1
Anti-mitochondrial antibodies (AMA) are the most characteristic laboratory finding (95%)
Disproportionate elevation of serum alkaline phosphatase to levels three to five times normal
Extrahepatic manifestations of autoimmunity
in primary biliary cirrhosis
Sjögren syndrome (dry eyes and mouth) Systemic sclerosis, Thyroiditis, Rheumatoid arthritis, Raynaud phenomenon, Celiac disease
Primary Biliary Cirrhosis Histology
Initial injury affects the small interlobular bile ducts within portal tracts leading to progressive duct loss
Epitheliod granulomas and lymphocytic reaction are characteristically seen associated with damaged bile ducts in the early stages
Necroinflammatory and cholestatic process accompanied by fibrosis extends along the terminal distribution of the portal tracts leading to portal–portal bridging septa.
Primary Biliary Cirrhosis Diagnosis
Clinical features of cholestasis
Elevated serum alkaline phosphatase
Presence of anti-mitochondrial antibody
Biopsy with histologic findings of primary biliary cirrhosis
Primary Sclerosing Cholangitis
A progressive disease of liver characterized by cholestasis with obliterative fibrosis of intra- and extrahepatic bile ducts with dilation of preserved segments
Inflammatory Bowel Disease coexists in approximately 70% of individuals with PSC
90% Ulcerative Colitis; 10% Crohn disease
~4% of patients with UC get PSC
Primary Sclerosing Cholangitis clinical stuff
Mostly male disease (2:1), present at age 40 years with symptoms of chronic liver disease and live 10-15 years
Variable prognosis with some patients having severe recurrent cholangitis while other patients progressed to biliary cirrhosis
Pathogenesis is unknown but features suggest an immunologic process involving T cells
No cure, cholestyramine for pruritus, liver transplant for liver failure
Primary Sclerosing Cholangitis Diagnosis
Diagnosis is based on pathologic and radiologic findings
Elevate alkaline phosphatase (90% of patients)
Perinuclear antineutrophilic cytoplasmic antibody (pANCA) (90% of patients) [non-specific finding]
Asymptomatic patients with persistent elevation of serum alkaline phosphatase
Large duct disease with strictures, beading and dilation
Liver biopsy shows obliterative cholangitis with inflammation and characteristic periductular onion ring fibrosis, ductopenia and secondary biliary cirrhosis
Primary Sclerosing Cholangitis: histology
characteristic “onion-skin” fibrosis affecting small ducts in the liver parenchyma
Primary Sclerosing Cholangitis: ERCP shows
“beading” of bile ducts
Primary biliary cirrhosis Key Concepts (Robbins)
an autoimmune disease with progressive, inflammatory, often granulomatous, destruction of small to medium sized intrahepatic bile ducts.
Primary biliary cirrhosis occurs most often in middle aged women, is associated with autoantibodies (particularly AMA), and with other autoimmune diseases such as Sjögren syndrome and Hashimoto thyroiditis.
Primary sclerosing cholangitis Key Concepts (Robbins)
an autoimmune disease with progressive inflammatory and sclerosing destruction of bile ducts of all sizes, intrahepatic and extrahepatic; diagnosis is made not by biopsy, but by radiologic imaging of the biliary tree. It occurs most often in younger men and has strong associations with inflammatory bowel disease, particularly ulcerative colitis.
Bone Marrow TransplantationHepatic Complications
Graft versus host disease (GVHD) develops in up to 70% of patients undergoing hemopoietic stem cell transplantation (HSCT)
- Characterized by jaundice and cholestatic liver biochemistry
- Elevations in serum transaminase levels are typically mild.
Graft Versus Host Disease Histology
Predominantly modest mononuclear portal inflammatory infiltrate
Lymphocytic infiltration of bile duct epithelium
Bile duct damage is the most characteristic histological feature
Chronic GVHD biliary pattern of cirrhosis.
Vanishing Bile Duct Syndrome
associated with bone marrow transplants, chronic GVHD
Liver Allograft Rejection
Humoral rejection (preformed antibody) *** Endothelial cells in the graft are the main targets for humoral mediated damage
Cellular Rejection
- Diagnostic triad - portal inflammation, bile duct damage and venular endothelial inflammation
Chronic–> irreversible injury to the bile ducts, arteries and veins–> bile duct loss and vascular obliteration–> ischemic liver damage and fibrosis
