Clinicopathology of Hereditary liver disease Flashcards

1
Q

Hereditary hemochromatosis presentation

A
  • very tanned (tan in wintertime)
  • abnormal LFTs
  • increased ferritin levels
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2
Q

primary iron overload

A

Hereditary hemochromatosis

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3
Q

secondary iron overload

A

alcohol or NAFLD/NASH, transfusion related

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4
Q

Hemochromatosis

A

disorder of iron metabolism that leads to iron overload

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5
Q

Hereditary hemochromatosis mechansism

A

body absorbs too much iron from the diet, excess iron stored in the liver, skin, heart, pancreas, testes and joints, severe tissue damage

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6
Q

where is iron deposited in HH

A

liver, skin, heart, pancreas, testes and joints

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7
Q

histology of HH

A

iron overload, fibrosis, cirrhosis

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8
Q

total body iron stores by age in HH

A

men present earlier than women

women have menstrual cycle which naturally decreases iron stores - will present about 15 years later

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9
Q

how do we detect iron overload?

A

can see on MRI

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10
Q

which organ does not acculumate iron?

A

spleen - therefore color can be used as a reference on MRI imaging

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11
Q

hepatocytes with Fe overload

A

yellowish brown, refractive granules

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12
Q

what stain tests for iron?

A

Prussian blue

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13
Q

HH histology

A

low power: areas of brownish discoloration over the liver

high power: portal area in the central portion of the field, periportal hepatocytes with refeactile yellow brown pigment

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14
Q

where does iron deposition in the liver start?

A

periportal areas - zone 1!!!! other disease are zone 3 due to lack of blood flow, but zone 1 here because liver thinks it wants the iron

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15
Q

untreated HH can lead to

A

cirrhosis

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16
Q

which cancer can arise from hemochromatosis with cirrhosis?

A

hepatocellular carcinoma - common because iron is toxic, so it can cause mutations

pathology can show larger nodules with no accumulation of iron, with cellular atypic and thicker cell plates

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17
Q

do hepatocellular carcinomas accumulate iron?

A

no because cirrhotic regenerative nodule has not had time to accumulate iron

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18
Q

non-genetic mechanism for iron overload

A

secondary

transfusion associated iron overload, or patients on chronic transfusion regiments (sickle cell, hemolytic anemias, etc)

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19
Q

difference between primary iron deposits and secondary iron deposits

A

primary includes iron deposits in the liver cell hepatocytes

secondary has iron in the kupferr cell macrophages, trying to clear it out, and then progresses to hepatocytes as overload increases

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20
Q

difference between primary iron deposits and secondary iron deposits

A

primary includes iron deposits in the liver cell hepatocytes

secondary has iron in the kupferr cell macrophages, trying to clear it out, and then progresses to hepatocytes as overload increases

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21
Q

what is the hepatic iron index

A

it normalizes to a patients age to determine if there is a hereditary cause or not

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22
Q

how can you tell if patient has hemolytic anemia on liver biopsy?

A

abnormal shaped cells in sinusoidal spaces (sickle cell)

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23
Q

hemochromatosis treatment

A

phlebotomy - removal of iron to deplete stores

unless patient is anemia or has a blood disorder - chelating agents

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24
Q

prime protein of iron absorption

A

hepcidin

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25
Q

dietary iron is taken up by the ____ and stored within the cell as ____

A

enterocytes

ferritin

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26
Q

ferroportin

A

iron can be absorbed through the basolateral membrane by ferroportin

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27
Q

hepcidin is made where

A

liver

28
Q

HFE protein makes

A

hepcidin, hemojuveline, and transferrin receptor 2 (TFR2)

29
Q

hepcidin causes ____ iron release from cells when it binds to _____

A

decreased

ferroportin

30
Q

HFE mutation

A

leads to downregulation of hepcidin and therefore uncontrolled release of iron from enterocyte and macrophages

31
Q

hepcidin binds ____ to prevent ____ release into blood stream

A

ferroportin

iron

32
Q

_____ hepcidin levels leads to decreased serum iron

A

increased

33
Q

how does iron cause damage to tissues?

A

iron causes injury and inflammation by reactive O2 species

34
Q

what organs can iron overload deposit? what conditions are then caused?

A

liver - cirrhosis - high risk for HCC

heart - cardiac dysfunction/restrictive cardiomyopathy, HFPEF

pituitary - hypergonadotropism, infertility

pancreas - diabetes mellitus

joints - arthropathy

skin - increased pigmentation

35
Q

inheritance pattern of HH

A

autosomal recessive disorder, HFE gene mutation on chromosome 6

36
Q

principal missense mutations in hereditary hemochromatosis

A

major mutation C282Y

minor mutation H63D

37
Q

phenotypes associated with HH

A

C282y/C282y homozygous (primary driver for HH)

compound heterozygote - C282Y/H63FD - will not result in full-blown disease and may not lead to cirrhosis `

38
Q

what is bronze diabetes

A

skin pigmentation, liver cirrhosis, diabetes

39
Q

how does HH cause diabetes?

A

pancreatic iron deposition damages islet cells

leads to increased insulin resistance

40
Q

are organ Fe deposits reversible?

A

cardiac is reversible with treatment

41
Q

goal ferritin level

A

< 50 ng/ml or hemoglobin <11

42
Q

iron chelators

A

desferoxamine, deferasirox, oral deferiprone

43
Q

Wilson’s disease

A
  • genetic disorder of copper metabolism

- failure of hepatocytes to excrete excess dietary copper into biliary canaliculi

44
Q

Wilson’s disease histology

A

accumulation of copper starting in periportal hepatocytes

45
Q

effects of Wilsons disease on liver

A

acute liver failure, chronic hepatitis, fibrosis, cirrhosis

46
Q

how is excess copper normally excreted?

A

through bile from the liver

47
Q

where will copper accumulate?

A

liver, kidneys, brain, joints, cornea with damage to these organs

48
Q

how does Wilson’s disease present?

A

usually with neuropsychiatric or liver symptoms

49
Q

which zone is affected by Wilsons disease?

A

zone 2

50
Q

genetics of Wilson’s disease

A

mutation of ATP7B - encodes copper transporting ATPase

51
Q

organ systems affected and how

A

liver - chronic hepatitis, cirrhosis or fulminant hepatic failure by age 30-40

heme - hemolytic anemia (esp if fulminant)

neuro - psychosis, seizures, ataxia, tremors, behavior changes if Cu deposits in brain

renal - proximal rental tubular acidosis, nephrolitiasis

52
Q

Kayser-Fleishcer rings

A

golden brown pigment deposits around periphery of pupil (Wilsons)

53
Q

lab results in Wilson’s disease

A
  • high serum copper > 10 mcg/dL
  • high urine copper >100 mcg/24 hrs (can’t be excreted from bile so urinated out)
  • low serum ceruloplasmin
  • relatively low alk phos in setting of high total bilirubin (ALP: TBili <4)
54
Q

ceruloplasmin

A

protein that binds free copper, if overload - low levels since excess copper is binding it all up

55
Q

Wilson’s disease treatment

A

copper chelation

liver transplantation for fulminant hepatic failure or decompensated cirrhosis

56
Q

copper chelating agents

A

d-penicillamine, Tridentine, zinc (competitively binds for intestinal absorption of copper)

57
Q

alpha 1 antitrypsin deficiency

A
  • genetic metabolic disorder, predisposes to chronic pulmonary and liver disease
58
Q

A1AT deficiency imaging

A

consistent with cirrhosis and portal hypertension,

hyperinflation of lungs

59
Q

gene mutation in A1AT deficiency

A

SERPINA1 gene encodes A1AT protein

  • serine protease inhibitor, creates altered structure that prevents export from hepatocytes
60
Q

histology of A1AT Deficiency

A

variably sized eosinophilic, PAS positive granules within the cytoplasm of periportal hepatocytes

non specific inflammatory changes, including fibrosis leading to cirrhosis

polymerized aggregates of A1AT visible in hepatocyte cytoplasm as variably sized eosinophilic globules

61
Q

what stain do we use in A1AT deficiency?

A

PAS because its cheaper than the actual AIAT stain

62
Q

most common mutation to gene that regulates A1AT deficiency

A

SERPINA gene most common mutation is PiZZ

63
Q

treatment for A1AT deficiency

A

liver transplantation

enzyme replacement can help pulmonary disease but not liver dysfunction

64
Q

inheritance pattern of A1AT deficiency

A

autosomal co-dominant

65
Q

normal phenotype of A1AT

A

PiMM

so abnormal is S, Z, or null

66
Q

no A1AT protein made at all and disease implications

A

Pi-null/null - all will get emphysema but none will get cirrhosis!