Digestive Pathology Lecture 6 Reproduction Prohibited This file contains original text and images as well as materials adapted from copyrighted sources For use only as a temporary educational aid Partially or completely copying or distributing the contents of this file may constitute an infringement of the fair use exception for teaching faculty of the U.S. Copyright Law LSUHSC-New Orleans, 2015 Last updated on September 30, 2015 --
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Digestive Pathology Lecture 6 - School of Medicine · –Hemochromatosis 12. Intrahepatic biliary tract diseases 13. Circulatory disorders 14. Hepatic disease in pregnancy 15. ...
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Digestive Pathology Lecture 6
Reproduction Prohibited
This file contains original text and images as well as materials adapted from copyrighted sources
For use only as a temporary educational aid
Partially or completely copying or distributing the contents of this file may constitute an infringement of the fair use exception
D. Huster. Wilson disease. Research Clinical Gastroenterology Volume 24, Issue 5 2010 531 - 539
Kayser-Fleischer ring, slit lamp
Wilson disease
In hepatocytes copper is:
– Transported into the golgi apparatus where it is incorporated into apo-ceruloplasmin to form ceruloplasmin which is SECRETED into circulation (90-95% of plasma copper)
– Transported into bile (canaliculi) to be EXCRETED
ATP7B gene codes for a copper-transporting ATPase required for both functions
Defect in the ATP7B gene interferes with both secretion and excretion
ATP7B-mediated copper export in the hepatocyte
Copper entrance: copper transporter CTR1. Copper is delivered to ATP7B in the golgi apparatus by the copper chaperone ATOX1. In the golgi apparatus copper is incorporated in various cuproenzymes including ceruloplasmin. When copper levels rise, ATP7B redistributes to a vesicular compartment and participates in copper excretion in the bile via an unknown mechanism that probably involves COMMD1
Wilson disease
Diagnosis– LOW serum ceruloplasmin
– HIGH non-ceruloplasmin serum copper
– HIGH urinary copper
– HIGH hepatic copper
– Ophthalmologic evaluation
– Genetic testing is now available• Sequencing of the ATP7B gene, more than 500
different mutations identified
Alpha1-antitrypsin deficiency
Autosomal recessive disorder with codominant expression
The most common genetic cause of liver disease in children
The most common genetic cause of emphysema in adults
Alpha1-antitrypsin deficiency A1AT is a serine protease inhibitor (Pi, SERPINA1)
– Inhibition of neutrophil elastase and other proteases
SERPINA1 gene, has more than 100 allelic variants
Each gene allele provides half of the enzyme level
The normal gene product is PiM
Most common deficiency alleles are:
– PiS (50-60% enzyme levels)
– PiZ (10-20% enzyme levels)
Most common carrier genotypes: PiMS, PiMZ
Most common deficiency genotypes: PiSS, PiSZ, PiZZ
Alpha-1-antitrypsin deficiency
A single amino acid substitution
Alpha-1 antitrypsin abnormally folded
Cannot move from ER
Form large aggregates that resist normal degradation including autophagy
Appear as PAS-positive cytoplasmic globes
Alpha1-antitrypsin deficiency, biopsy, PAS stain
Alpha-1-antitrypsin deficiency
Defective degradation of the misfolded protein appears to induce apoptosis, inflammation
Only 10% of PiZZ individuals develop clinical disease
Other genetic/environmental factors must play a role
Alpha-1-antitrypsin deficiency
Liver manifestations
– Neonatal (giant cell) hepatitis
– Chronic hepatitis (adolescents)
– Cirrhosis (adults)
– Hepatocellular carcinoma
Lung manifestations:
– Emphysema
Alpha-1-antitrypsin deficiency
Diagnosis
– Serum levels of A1AT, used for screening
– Protein electrophoresis (phenotype)
– DNA analysis (genotype)
– Liver biopsy
Underdiagnosed
– PiZZ, present in 1/1800 live births
Hemochromatosis
Iron metabolism Absorbed in duodenum and proximal jejunum
No natural mechanism of excretion
Amount absorbed must balance out losses: epithelial exfoliation, minor hemorrhages, menstruation
Ferroportin, an iron channel, controls the release of iron into the circulation from: enterocytes, macrophages, hepatocytes
Hepcidin, produced in the liver, binds ferroportin which is then internalized and degraded preventing the release of iron
Hepcidin, ferroportin
Low iron, low hepcidin: ferroportin exports iron into the circulation
High iron, high hepcidin: hepcidin binds to ferroportin inducing its internalization and degradation; iron remains in the cells
Iron transport and storage Iron is transported in blood by TRANSFERRIN
Iron is stored as:– FERRITIN (circulation, readily available)
Other manifestations:– Joint pain (arthropathy), the most common presenting
complaint, may precipitate pseudogout
– Cardiomyopathy: arrhythmia, heart failure
– Thyroid and adrenal insufficiency
– Hypogonadism: impotence, amenorrhea, early menopause
Hemochromatosis, bronze skin pigmentation
Hemochromatosis, liver, pancreas, lymph nodes
HemochromatosisA, Hereditary hemochromatosis, iron accumulates in hepatocytes before spilling over to Kupffer cells. Accumulation in periportal hepatocytes in early stages of the disease, becomes panlobular later on. B, Prussian blue stain. C,Secondary hemochromatosis, heavy iron deposition may be seen in Kupffer cells (arrow). Gastrointestinal and liver pathology. C. Iacobuzio-Donahue
Focal nodular hyperplasiaHyperplastic nodule with central stellate scar
Focal nodular hyperplasiaFibrous scar with misshaped vessels and bile ducts, hyperplastic lobular parenchyma
Robbins, Cotran
Focal nodular hyperplasia
Hyperplastic response to focal increased blood flood (vascular malformations)
More common in females
Questionable association with oral contraceptives
Nodular regenerative hyperplasiaRegenerative nodules, absence of fibrosis
Nodular regenerative hyperplasia, reticulumNodules surrounded by rims of compressed cords
Nodular regenerative hyperplasia
May be subclinical, no liver dysfunction
Presents with portal hypertension
Uncertain etiology
Associated with : toxic/drug vascular injury, autoimmune, infectious, hematologic/thrombotic conditions.
Obstructive vasculopathy with global decrease of the (low-pressure) venous portal blood supply and compensatory increase of the (high pressure) arterial blood supply
The liver III11. Inborn errors of metabolism
12. Intrahepatic biliary tract diseases
13. Circulatory disorders
14. Liver disease in pregnancy
15. Nodular hyperplasias
16. Benign neoplasms
– Hemangiomas
– Adenomas17. Malignant neoplasms
Cavernous hemangiomas
The most common liver neoplasm
Red-blue soft nodules
Usually less than 2 cm
Often directly beneath the capsule
Significance:
– Mistaken for metastatic tumors
– Percutaneous biopsies may cause profuse bleeding
Cavernous hemangiomas
Hepatic adenoma Well-demarcated proliferation of hepatocytes
– No bile ducts
Often subcapsular
Young women
Related to the use of oral contraceptives and anabolic steroids
May regress on discontinuance
Significance:– Mistaken for hepatocellular carcinoma
– Rupture, bleeding
– May undergo malignant transformation
Hepatic adenoma
Adenoma subtypes
HNF1α mutation, fatty, almost no malignant transformation
β-catenin mutation, cytologic atypia, highest-risk for malignant transformation
Inflammatory, associated with non-alcoholic fatty liver disease, small risk of malignant transformation
The liver III11. Inborn errors of metabolism
12. Intrahepatic biliary tract diseases
13. Circulatory disorders
14. Liver disease in pregnancy
15. Nodular hyperplasias
16. Benign neoplasms
17. Malignant neoplasms
– Hepatoblastoma
– Angiosarcoma
– Hepatocellular carcinoma
– Cholangiocarcinoma
– Metastases
Hepatoblastoma
Infants
More common in boys
Immature hepatocytes
Some have mesenchymal elements (cartilage, bone, striated muscle)
Survival has improved
Only chance for cure: total resection
Hepatoblastoma, fetal-like or embryonic-like hepatocytes
Odze & Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas
Hepatoblastoma, bone (osteoid) and undifferentiated mesenchyme
Odze & Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas
Angiosarcoma
Exposure to
– Poly-vinyl chloride (PVC) industry
– Arsenic
– Thorotrast
The latency period several decades
Highly aggressive, metastasize widely
Angiosarcoma
Liver carcinomas, mayor types
Hepatocellular carcinoma (hepatoma)
– 90% of all primary cancers
Cholangiocarcinoma
Mixed forms
Liver and intrahepatic bile duct cancer incidence rates
Hepatocellular carcinoma
Uncommon in the US
Cirrhosis present in > 85%
Male predominance 3:1
Rare before age 60
Hepatocellular carcinoma
HBV endemic regions
20-40% of all cancers
Vertical transmission (200-fold risk)
Cirrhosis may not be present
Male predominance 8:1
Younger age (20-40 years)
Risk factors
Cirrhosis
HBV
HCV
Alcohol, NASH
Primary hemochromatosis, A1AT deficiency, Wilson disease