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GI > 11. Alcoholic, Metabolic, and Autoimmune Liver Disease > Flashcards

11. Alcoholic, Metabolic, and Autoimmune Liver Disease Flashcards

1
Q

What is METAVIR?

A

Scoring system for liver biopsies that takes the inflammation (grade) and fibrosis (stage) into account

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2
Q

What are the inflammation stages of the METAVIR score?

A 
0 No activity
1 Minimal
2 Mild
3 Moderate
4 Severe
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3
Q

What are the fibrosis stages of the METAVIR system?

A 
0 No fibrosis
1 Portal fibrosis
2 Periportal fibrosis
3 Septal fibrosis
4 Cirrhosis
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4
Q

What happens in stage 1 of the METAVIR system?

A

Portal fibrosis: area around the triad is affected, fibrosis often irreversible

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5
Q

What happens in stage 2 of the METAVIR system?

A

Periportal fibrosis–extends beyond the triad

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6
Q

What happens in stage 3 of the METAVIR system?

A

Septal fibrosis–bridging fibrosis occurs between triads, and some laying down of collagen/CT towards the portal vein

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7
Q

What happens in stage 4 of the METAVIR system?

A

Nodules form, with scar tissue surrounding relatively normal tissue
Cirrhosis!

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8
Q

What is hepatic necrosis?

A

Injury causing lysis of hepatocytes, acute cell death

Happens much more quickly than fibrosis, which may take years

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9
Q

What can can hepatic necrosis lead to?

A

Acute liver failure

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10
Q

What is fulminant liver failure?

A

Acute liver failure with COAGULOPATHY and ENCEPHALOPATHY

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11
Q

What are the two most common causes of acute and fulminant liver failure?

A 
Medications--acetaminophen
Viral hepatitis (NOT HCV)
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12
Q

Alcohol content of beer, wine, and liquor?

A

5%
12%
40%

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13
Q

Serving size of beer, wine, and liquor?

A

12 oz
4 oz
1.5 oz

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14
Q

Amount of alcohol in beer, wine, and liquor?

A
  1. 8 gm
  2. 7 gm
  3. 4 gm
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15
Q

What is binge drinking for women? men?

A

4 or more drinks in a single occasion

5 or more drinks in a single occasion

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16
Q

What is heavy drinking for women? Men?

A

More than 1 drink/day on average

More than 2 drinks/day on average

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17
Q

What is excessive drinking?

A

Heavy drinking or binge drinking or both

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18
Q

What are the two methods by which ethanol is metabolized to acetaldehyde?

A

Alcohol dehydrogenase

CYP2E1

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19
Q

How is acetaldehyde converted to acetic acid?

A

Aldehyde dehydrogenase

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20
Q

What is the system that CYP2E1 is a part of?

A

Microsomal ethanol oxidizing system

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21
Q

What else is metabolized by CYP2E1 aside from ethanol?

A

Acetaminophen

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22
Q

Who is deficiency in aldehyde dehydrogenase?

A

Large percentage of Asian patients

**leads to flushing on consumption of ethanol

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23
Q

What are the 2 key consequences of increased alcohol metabolism?

A

Increased NADH

Increased acetaldehyde

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24
Q

What are the adverse effects of increased NADH from alcohol metabolism?

A

Inhibition of the TCA cycle resulting in reduced gluconeogenesis
Reduced fatty acid oxidation

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25
Q

What are the adverse effects of increased acetaldehyde from alcohol metabolism?

A

Activation of stellate cells to form collagen
Shearing of microfilaments that maintain intracellular skeleton
Kuppfer cells produce TNF alpha and IL-8

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26
Q

What are 5 aspects of the pathogenesis of alcohol at the sinusoids

A 
Loss of fenestration
Dense ECM
Activated Kupffer cells 
Activated stellate cells 
Los of
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27
Q

What is the first change that is seen in alcoholic liver disease (ALD)?

A

Fatty liver

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28
Q

What do ALD patients with fatty liver develop?

A

Alcoholic hepatitis 10-35%
Cirrhosis 8-20%
**40% of patients with alcoholic hepatitis may convert to cirrhosis

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29
Q

How are inflammatory cells recruited in conversion to alcoholic hepatitis?

A

IL-8 and TNF from Kuppfer cells

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30
Q

What are 5 risk factors for ALD?

A
  1. Quantity of alcohol (>30 g/day in men and 20 g/day in women)
  2. Alcohol outside of meals (slow emptying slow absorption)
  3. Binge drinking
  4. Gender (risk higher for women)
  5. Hepatitis C
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31
Q

What is the AST/ALT ratio in ALD? What is ALT usually below?

A

2

<300

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32
Q

What are three hematological characteristics seen in ALD?

A
  1. Prolonged INR (in advanced disease)
  2. Macrocytic anemia
  3. Thrombocytopenia (in advanced disease)
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33
Q

What are the two main components of treatment of alcoholic hepatitis?

A
  1. Abstinence and lifestyle modification – nutritional support
  2. Anti-inflammatory drugs – glucocorticoids and penoxyifylline
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34
Q

How does pentoxifylline work?

A

Inhibits TNF alpha

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35
Q

How do you determine who should be treated for viral hepatitis?

A

Discriminant function:

  1. 6 (PT - PT control) + total bilirubin
    * *patients with values over 32 have a 1 mo mortality from 30-50%
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36
Q

What are two drugs that improve survival in alcoholic hepatitis?

A

Glucocorticoids

Pentoxifylline

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37
Q

What is the scoring system for determining how sick a patient with cirrhosis is?

A

Child-Turcotte-Pugh score
5-7 Mild
8-10 Moderate
11-15 Severe

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38
Q

What is the classic patient with non-alcoholic fatty liver disease (NAFLD)

A

Obese female with diabetes mellitus

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39
Q

What are the two histological categories of NAFLD?

A

Non-alcoholic fatty liver (NAFL)

Non-alcoholic steatohepatitis (NASH)

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40
Q

What is the histological category of non-alcoholic fatty liver defined as?

A

Presence of hepatic steatosis without inflammation of hepatocellular injury (ballooning of hepatocytes)

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41
Q

What is the histologic category of NASH (non-alcoholic steatohepatitis) defined as?

A

Presence of hepatic steatosis WITH inflammation and hepatocellular injury (ballooing of hepatocytes) with or without fibrosis

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42
Q

What is the most common cause of elevated transaminases in the US?

A

Non-alcoholic fatty liver disease

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43
Q

What is the progression of non-alcoholic fatty liver disease?

A

Fatty liver (hepatosteatosis)
Steatohepatitis (NASH, 10%)
Steatohepatitis with fibrosis (35% of NASH)
Cirrhosis (15% of NASH)

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44
Q

What are the most common risk factors for NAFLD?

A
  1. Abdominal obesity
  2. High fasting glucose
  3. Hypertriglyceridemia (more so than cholest)
    * *also low HDL and high BP
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45
Q

How does the prevalence and severity of NAFLD change with age?

A

Prevalence increases

Severity (including advanced fibrosis/cirrhosis) increases

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46
Q

What is them ost common chronic liver disease in the US?

A

Non-alcoholic fatty liver (20% of americans)

NASH is the second most common

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47
Q

What is the gender preference for NAFLD? Race?

A

Males>females

Hispanics>caucasians>African Americans

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48
Q

What is obesity defined as?

A

BMI over 30 or 30 lb overweight for a 5’4 person

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49
Q

What is the most common liver disease in children in the US?

A

NAFLD

**present in 18% children

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50
Q

What type of hyperlipidemia increased the risk for NAFLD?

A

Hypertriglyceridemia rather than hypercholesteremia

**3 fold greater risk with TGs>200

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51
Q

Three key causes of steatosis and steatohepatitis

A
  1. Alcohol
  2. Medications–amiodarone, steroids, HAART, tamoxifen, diltiazem
  3. Nutrition–total parenteral nutrition
    * *also insulin resistance, abetalipoproteinemia, weight cancers
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52
Q

How will a fatty liver appear on CT?

A

Darker (compare to spleen)

Nodular if NASH is present

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53
Q

What are the three things to target for therapeutic strategies for NAFLD?

A
  1. Progression to obesity, HTN, hyperlipidemia
  2. Insulin resistance
  3. Oxidative stress
54
Q

Loss of __% body weight will improve steatosis

Loss of __% is needed to improve inflammation

A

3-5%

10% **this is the magic # for reversing NASH

55
Q

What are the effects of pioglitazone and vitamin E on patients with NASH?

A

Reduce transaminases
Reduce inflammation
*neither reduce fibrosis

56
Q

What is the drawback of using pioglitazone for NASH?

A

Weight gain

57
Q

What improves liver histology in non-diabetic patients with NASH and should be first line therapy?

A

Vitamin E

**not recommended for patients with diabetes, NAFLD w/o liver biopsy, or NASH cirrhosis/cryptogenic cirrhosis

58
Q

What gene is implicated in hereditary hemochromatosis?

A

HFE gene on chromosome 6

59
Q

People with hereditary hemochromatosis have one of two mutations:

A

C282Y/C282Y (80-90% of cases)

C282Y/H63D

60
Q

What does the HFE gene regulate?

A

Absorption of iron from the small intestine

Downregulates transferrin when iron supplies are adequate

61
Q

What happens when there is a defective HFE gene?

A

Failure to limit absorption from the small intestine and to down-regulate transferrin
**iron deposits in various organs leads to free-radical development, organ damage

62
Q

What are causes of secondary iron overload?

A

Anemia caused by ineffective erythropoiesis–thal major, sideroblastic anemia, etc
Liver disease–ALD, HBV, HCV, nonalcoholic steatohepatitis (NASH)
Parenteral iron overload–transfusions, dialysis

63
Q

What is the most common genetic disorder in populations of European ancestry?

A

Hemochromatosis

64
Q

__% of caucasians are heterozygous (C282Y/WT)
___% are homozygous C282Y/C282Y
___% are compound heterozygote C282Y/H63D

A

10%
0.5-1% (of this group, 50% will develop disease)
3-5%

65
Q

What are the key components of the presentation of hemochromatosis?

A 
Liver function abnormalities 75%
Weakness and lethargy 74%
Skin hyperpigmentation 70%
Diabetes mellitus 48%
Arthralgia 44%
Impotence in males 45%
EKG abnormalities 31%
66
Q

Why does hemochromatosis present later in women?

A

Due to menstrual blood loss

67
Q

What is the first step of evaluating possible hereditary hemochromatosis?

A

Fasting transferring saturation

45% is abnormal

68
Q

What should be done if fasting transferring saturation is over 45% in testing for hereditary hemochromatosis?

A

Proceed with genetic testing–
C282Y/H63D
C282Y/C282Y

69
Q

Why is biopsy recommended if hereditary hemochromatosis is found?

A

Higher risk of developing cancer

70
Q

Recommended tx if person is found to be C282Y/C282Y +?

A

Biopsy if >40yo or if elevated ALT/AST

Phlebotomy

71
Q

What kind of stain will show iron on a liver biopsy?

A

Prussian blue stain

72
Q

What is the tx for hemochromatosis? Goal serum ferritin?

A

Phelabotomy
<50
**initially weekly phelb, once quarterly therafter

73
Q

Inheritance of hemochromatosis?

A

Autosomal recessive

74
Q

What are the dietary sources of copper?

A 
Seafood
Organ meats 
Nuts/nut butters
Legumes
Chocolate
Enriched cereals
Fruits and vegetables
75
Q

What are the two problems in Wilson’s disease?

A
  1. Reduced ability to get copper from the liver into the biliary tree
  2. Reduced ceruloplasmin, which typically binds copper in the blood to make it non-toxic
76
Q

What age group is often diagnosed with WD?

A

Younger–3 to 40 yo

77
Q

What are some sx that should lead you to consider dx of Wilson’s Disease?

A 
Acute liver failure **
Unexplained liver disease
Cirrhosis
Neurological sx (due to deposits in the brain)
Psychiatric sx
78
Q

What are the neurological features seen in Wilson’s Disease?

A 
Movement disorders
Drooling/dysarthria
Rigid dystonia
Dysautonomia
Migrane headaches
Insomnia
Seizures 
Depression
Neurotic behavior 
Personality changes 
Psychosis
79
Q

What is decreased in pateitns with WD?

A

Ceruloplasmia–95% of homozygotes have a level <20mg/dl

80
Q

Why are there often false negatives when looking at ceruloplasmin to diagnose Wilson Disease?

A

High CP levels occur in inflammation (acute phase protein) and may lead to false negatives (cancel out the decrease in ceruloplasmin usually seen)

81
Q

Urine copper is derived from:

Rate of excretion in patients with WD (symptomatic) may exceed:

A

Non-ceruloplasmin

100 microgram/24hr

82
Q

What is the best test for WD?

A

High urinary copper

83
Q

What is seen in the eyes of patients with WD?

A

Kayser-Fleischer Rings

84
Q

What is the normal hepatic copper content?
Content in homozygous WD patients?
Content in heterozygous WD patients?

A

50 ug/g dry weight
>250 ug/g dry weight
20-250 ug/g dry weight

85
Q

What stain can be used to find accumulations of copper on liver biopsies?

A

Rhodanine stain (red granules)

86
Q

What are the two drugs that can be used in WD to bind copper and increase the urinary excretion?

A

D-penicillamine

Trientine (BETTER SAFETY PROFILE)

87
Q

What is the drug that can be used in WD to prevent copper form being absorbed in the GI tract?

A

Zinc

88
Q

What is A1AT?

A

Inhibitor of elastase, part of family of structurally unique protease inhibitors called serpins

89
Q

Where is A1AT predominantly made?

A

Liver

90
Q

In WD, what is the first line drug for increasing fecal Cu excretion? Increasing urine Cu excretion?

A

Zinc

Trientine

91
Q

A1AT deficiency is the most common cause of genetic___ disease in children
MCC of genetic ____ in adults

A

Liver disease in children

Emphysema in adults

92
Q

In adults, A1AT deficiency can cause ___, ____, and ____

A

Hepatitis
Cirrhosis
Liver cancer

93
Q

What are the three inherited genes for A1AT?

A

M (main)
S
Z (most common mutant)

94
Q

Healthy individuals with normal A1AT levels have the genotype ____, present in over 90% Caucasians in the US

A

PiMM (protease inhibitor MM)

95
Q

Pathogenesis of lung disease in A1AT deficiency

A

Loss of function mechanism

Lack of A1AT allows uninhibited PMN mediated proteolytic damage to connective tissue

96
Q

Pathogenesis of liver disease in A1AT deficiency

A

Gain of function mechanism

Retention of inefficiently secreted A1AT Z molecule in the ER triggers hepatotoxic events

97
Q

PiMM results in ___% activity

Disease?

A

100%

No liver or lung disease

98
Q

PiMS results in ___% activity

Disease?

A

80%

No liver or lung disease

99
Q

PiMZ results in ___% activity

Disease?

A

60%

No liver or lung disease

100
Q

PiSS results in __% activity

Disease?

A

50-60%

No liver or lung disease

101
Q

PiSZ results in ___% activity

Disease?

A

30-40%

Lung disease only

102
Q

Pi null-null activity causes ___% activity

Disease?

A

0%

Lung disease only (no liver accumulation)

103
Q

PiZZ causes ___% activity

Disease?

A

10-15%

Liver and lung disease

104
Q

Three things that should be evaluated for A1AT deficiency?

A

Serum A1AT levels
A1AT phenotypes
Liver biopsy

105
Q

What will be seen on liver biopsy with A1AT def with PAS stain?

A

Abnormal A1AT accumulations

106
Q

What will cause elevated ALT and AST along with autoantibodies in the serum?

A

Autoimmune hepatitis

107
Q

Gender preference of AI hepatitis

A

Female:male 4:1

108
Q

What will be found on labs with AI hepatitis?

A

ALT/AST over 1000
Elevated gamma globulin or elevated IgG
Autoantibodies

109
Q

What histologic features are characteristic of AI hepatitis?

A

Interface hepatitis: infiltration around portal tract

Portal plasma cell infiltration

110
Q

What are the two subclasses of AI hepatitis based on serological markers?

A 
Type 1 (Classic): 80-90%, adults)
Type 2 (anti-LKM 1 hepatitis, children)
111
Q

What antibodies are found in type 1/classic AIH?

A

ANA (anti-nuclear antibody)

ASMA (anti-smooth muscle antibody)

112
Q

What antibody is found in type 2 AIH?

A

Anti-liver-kidney microsomal antibody

113
Q

What is the AI disease that is most commonly associated with AIH?

A

Thyroid disease

**also RA, diabetes, Sjoren’s syndrome, polymyositis, vitiligo, psoriasis, IBD, Addison’s

114
Q

What two drugs are used for the tx of AIH?

A

Prednisone–sometimes used by itself

Azathioprine (steroid sparing agent)

115
Q

When might you use a combination of predinsone and azathioprine for tx of AIH?

A 
Postmenomausal/osteoporosis 
Brittle diabetes 
Obesity
Acne
Emotional lability
Hypertension
116
Q

What is the tx endpoint for AIH?

A

Normal ALT/AST
Normal IgG
Resolution of inflammation on biopsy

117
Q

20 yr survival of AIH patients who were treated

Untreated patients in 3 yo, 10 yr

A

80%

50% dead in 3 yr, 90% in 10 yr

118
Q

What is primary biliary cirrhosis?

A

Chronic, progressive, cholestatic liver disease
Destruction of intrahepatic bile ducts
Probable AI pathogenesis

119
Q

Who gets PBC?

A

90-95% cases are women
Mostly caucasian
Mean age 52, range from 30-65

120
Q

Pathogenesis of PBC?

A

High serum autoantibodies–antimitochondrial antibodies (AMA)
Elevated IgM
**associated with other autoimmune diseases

121
Q

What is the major target of the antimitochondrial anitbodies in PBC?

A

Multi-enzyme complex–pyruvate dehydrogenase complex (PDC)

122
Q

What antigen that is the target of AMAs predominates in PBC? Where is it located?

A

PDC-E2

Membrane of the biliary epithelial cells

123
Q

What are the two components of presentation of PBC in asymptomatic patients (25% cases)

A

Increased ALP

AMA +

124
Q

What are the two key symptoms of PBC?

A

Fatigue 65%
Pruritus 55% – due to bile acid/salt deposition
**also hepatomegaly, splenomegaly, jaundice, xanthelasma

125
Q

What are lipid deposits seen with cholestatic liver disease?

A

Xanthelasma (tuberous)

126
Q

What causes the steatorrhea in PBC?

A

Decreased bile salt excretion

127
Q

What vitamins are not absorbed in PBC?

A

Fat soluble vitamins–A, D, E, K

128
Q

What are the adverse effects of vitamin D deficiency seen in PBC? Vitamin K

A

Osteomalacia, fractures

Prolonged QT interval with hypokalemia

129
Q

What is the AI disorder that is most commonly assoicated with PBC?

A

Sjogren’s syndrome (>50%)

**less commonly thyroiditis, RZ, raynauds, scleroderma

130
Q

What biochemistries are abnormal in PBC? (3)

A
  1. ALP is 3-4 x normal in over 90%
  2. Bilirubin rises late
  3. Cholesterol is elevated in 85%: NOT ASSOCIATED WITH HEART DISEASE
131
Q

What is the only drug that can be used for PBC?

A

Ursodeoxycholic acid: hydrophilic, synthetic bile acid. Improves the balance of hydrophobic to hydrophilic bile acids

GI (28 decks)

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