Liver Path 4

Question 1

Inherited Liver Diseases

Answer 1

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

Question 2

Regulation of Iron Homeostasis Mini-review

Answer 2

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

Question 3

Hepcidin

Answer 3

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)

Question 4

hepcidin-ferroportin complex

Answer 4

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).

Question 5

The Common Genetic Basis and Phenotypic Continuum of Haemochromatosis.

Answer 5

• 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

Question 6

Hemochromatosis

Answer 6

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.

Question 7

Classic Tetrad of Hemochromatosis

Answer 7

Hepatomegaly

Skin pigmentation

Destruction of pancreatic islets

Cardiomyopathy

Question 8

Hemochromatosis Diagnosis

Answer 8

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)

Question 9

Hemochromatosis Treatment

Answer 9

Phlebotomy to achieve mild iron deficiency
(mild microcytic/hypochromic anemia)

With treatment life expectancy is normal

Question 10

Secondary Hemochromatosis Iron Overload

Answer 10

Blood Transfusions for hereditary anemias
- Hemoglobinopathies

Blood Transfusions for acquired anemias

• Myelodysplastic syndromes
• Chronic kidney disease
• Leukemia

Iron supplements

Excess dietary iron

Question 11

Complications of hemochromatosis

Answer 11

** classic triad- skin pigmentation, cirrhosis, diabetes

hypopituitarism
cardiac failure
arthropathy
testicular atrophy

Question 12

bronze diabetes

Answer 12

hemochromatosis

pigmentation due to increased epidermal melanin

hemosiderin is also deposited in dermal macrophages and fibroblasts

Question 13

Wilson disease

Answer 13

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

Question 14

Copper Metabolism

Answer 14

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

Question 15

If Cu is not being secreted out of the cell into the bile,

Answer 15

then copper accumulates in the cell to toxic levels –>

Inflammation and Cell Death

Question 16

Laboratory Diagnosis of Wilson disease

Answer 16

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

Question 17

Wilson disease histology

Answer 17

Same histologic pattern as chronic active hepatitis from hepatitis virus

Steatosis can be seen in Wilson disease

Copper (rhodanine) stain

Question 18

Kayser–Fleischer ring

Answer 18

copper ring around the iris

disappears after copper-chelating treatment

Question 19

Alpha1-Antitrypsin Deficiency

Answer 19

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

Question 20

Alpha-1 Anti-trypsin Deficiency Clinical Features

Answer 20

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

Question 21

α1-Antitrypsin Deficiency histology

Answer 21

PASD staining shows the actual misfolded protein in the cytoplasm. This leads to apoptosis…inflammation…cirrhosis..

Question 22

Inherited Metabolic Liver Diseases- list from robbins

Answer 22

The inherited metabolic diseases in­clude hemochromatosis, Wilson disease, and α1-antitrypsin deficiency.

Question 23

robbins: Hereditary hemochromatosis

Answer 23

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

Question 24

robbins: Wilson disease

Answer 24

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.

Question 25

robbins: alpha 1 antitrypsin deficiency

Answer 25

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.

Question 26

Primary Biliary Cirrhosis

Answer 26

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

Question 27

primary biliary cirrhosis- clinical stuff

Answer 27

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

Question 28

Extrahepatic manifestations of autoimmunity

in primary biliary cirrhosis

Answer 28

Sjögren syndrome (dry eyes and mouth)
Systemic sclerosis,
Thyroiditis, 
Rheumatoid arthritis,
Raynaud phenomenon,
Celiac disease

Question 29

Primary Biliary Cirrhosis Histology

Answer 29

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.

Question 30

Primary Biliary Cirrhosis Diagnosis

Answer 30

Clinical features of cholestasis

Elevated serum alkaline phosphatase

Presence of anti-mitochondrial antibody

Biopsy with histologic findings of primary biliary cirrhosis

Question 31

Primary Sclerosing Cholangitis

Answer 31

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

Question 32

Primary Sclerosing Cholangitis clinical stuff

Answer 32

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

Question 33

Primary Sclerosing Cholangitis Diagnosis

Answer 33

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

Question 34

Primary Sclerosing Cholangitis: histology

Answer 34

characteristic “onion-skin” fibrosis affecting small ducts in the liver parenchyma

Question 35

Primary Sclerosing Cholangitis: ERCP shows

Answer 35

“beading” of bile ducts

Question 36

Primary biliary cirrhosis Key Concepts (Robbins)

Answer 36

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.

Question 37

Primary sclerosing cholangitis Key Concepts (Robbins)

Answer 37

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.

Question 38

Bone Marrow TransplantationHepatic Complications

Answer 38

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.

Question 39

Graft Versus Host Disease Histology

Answer 39

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.

Question 40

Vanishing Bile Duct Syndrome

Answer 40

associated with bone marrow transplants, chronic GVHD

Question 41

Liver Allograft Rejection

Answer 41

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