11. Alcoholic, Metabolic, and Autoimmune Liver Disease Flashcards Preview

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

Flashcards in 11. Alcoholic, Metabolic, and Autoimmune Liver Disease Deck (131):
1

What is METAVIR?

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

2

What are the inflammation stages of the METAVIR score?

0 No activity
1 Minimal
2 Mild
3 Moderate
4 Severe

3

What are the fibrosis stages of the METAVIR system?

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

4

What happens in stage 1 of the METAVIR system?

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

5

What happens in stage 2 of the METAVIR system?

Periportal fibrosis--extends beyond the triad

6

What happens in stage 3 of the METAVIR system?

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

7

What happens in stage 4 of the METAVIR system?

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

8

What is hepatic necrosis?

Injury causing lysis of hepatocytes, acute cell death
Happens much more quickly than fibrosis, which may take years

9

What can can hepatic necrosis lead to?

Acute liver failure

10

What is fulminant liver failure?

Acute liver failure with COAGULOPATHY and ENCEPHALOPATHY

11

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

Medications--acetaminophen
Viral hepatitis (NOT HCV)

12

Alcohol content of beer, wine, and liquor?

5%
12%
40%

13

Serving size of beer, wine, and liquor?

12 oz
4 oz
1.5 oz

14

Amount of alcohol in beer, wine, and liquor?

13.8 gm
10.7 gm
13.4 gm

15

What is binge drinking for women? men?

4 or more drinks in a single occasion
5 or more drinks in a single occasion

16

What is heavy drinking for women? Men?

More than 1 drink/day on average
More than 2 drinks/day on average

17

What is excessive drinking?

Heavy drinking or binge drinking or both

18

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

Alcohol dehydrogenase
CYP2E1

19

How is acetaldehyde converted to acetic acid?

Aldehyde dehydrogenase

20

What is the system that CYP2E1 is a part of?

Microsomal ethanol oxidizing system

21

What else is metabolized by CYP2E1 aside from ethanol?

Acetaminophen

22

Who is deficiency in aldehyde dehydrogenase?

Large percentage of Asian patients
**leads to flushing on consumption of ethanol

23

What are the 2 key consequences of increased alcohol metabolism?

Increased NADH
Increased acetaldehyde

24

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

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

25

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

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

26

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

Loss of fenestration
Dense ECM
Activated Kupffer cells
Activated stellate cells
Los of

27

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

Fatty liver

28

What do ALD patients with fatty liver develop?

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

29

How are inflammatory cells recruited in conversion to alcoholic hepatitis?

IL-8 and TNF from Kuppfer cells

30

What are 5 risk factors for ALD?

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

31

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

2
<300

32

What are three hematological characteristics seen in ALD?

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

33

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

1. Abstinence and lifestyle modification -- nutritional support
2. Anti-inflammatory drugs -- glucocorticoids and penoxyifylline

34

How does pentoxifylline work?

Inhibits TNF alpha

35

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

Discriminant function:
4.6 (PT - PT control) + total bilirubin
**patients with values over 32 have a 1 mo mortality from 30-50%

36

What are two drugs that improve survival in alcoholic hepatitis?

Glucocorticoids
Pentoxifylline

37

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

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

38

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

Obese female with diabetes mellitus

39

What are the two histological categories of NAFLD?

Non-alcoholic fatty liver (NAFL)
Non-alcoholic steatohepatitis (NASH)

40

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

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

41

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

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

42

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

Non-alcoholic fatty liver disease

43

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

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

44

What are the most common risk factors for NAFLD?

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

45

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

Prevalence increases
Severity (including advanced fibrosis/cirrhosis) increases

46

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

Non-alcoholic fatty liver (20% of americans)
NASH is the second most common

47

What is the gender preference for NAFLD? Race?

Males>females
Hispanics>caucasians>African Americans

48

What is obesity defined as?

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

49

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

NAFLD
**present in 18% children

50

What type of hyperlipidemia increased the risk for NAFLD?

Hypertriglyceridemia rather than hypercholesteremia
**3 fold greater risk with TGs>200

51

Three key causes of steatosis and steatohepatitis

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

52

How will a fatty liver appear on CT?

Darker (compare to spleen)
Nodular if NASH is present

53

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

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

54

Loss of __% body weight will improve steatosis
Loss of __% is needed to improve inflammation

3-5%
10% **this is the magic # for reversing NASH

55

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

Reduce transaminases
Reduce inflammation
*neither reduce fibrosis

56

What is the drawback of using pioglitazone for NASH?

Weight gain

57

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

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

58

What gene is implicated in hereditary hemochromatosis?

HFE gene on chromosome 6

59

People with hereditary hemochromatosis have one of two mutations:

C282Y/C282Y (80-90% of cases)
C282Y/H63D

60

What does the HFE gene regulate?

Absorption of iron from the small intestine
Downregulates transferrin when iron supplies are adequate

61

What happens when there is a defective HFE gene?

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

What are causes of secondary iron overload?

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

63

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

Hemochromatosis

64

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

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

65

What are the key components of the presentation of hemochromatosis?

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

66

Why does hemochromatosis present later in women?

Due to menstrual blood loss

67

What is the first step of evaluating possible hereditary hemochromatosis?

Fasting transferring saturation
45% is abnormal

68

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

Proceed with genetic testing--
C282Y/H63D
C282Y/C282Y

69

Why is biopsy recommended if hereditary hemochromatosis is found?

Higher risk of developing cancer

70

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

Biopsy if >40yo or if elevated ALT/AST
Phlebotomy

71

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

Prussian blue stain

72

What is the tx for hemochromatosis? Goal serum ferritin?

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

73

Inheritance of hemochromatosis?

Autosomal recessive

74

What are the dietary sources of copper?

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

75

What are the two problems in Wilson's disease?

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

What age group is often diagnosed with WD?

Younger--3 to 40 yo

77

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

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

78

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

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

79

What is decreased in pateitns with WD?

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

80

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

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

81

Urine copper is derived from:
Rate of excretion in patients with WD (symptomatic) may exceed:

Non-ceruloplasmin
100 microgram/24hr

82

What is the best test for WD?

High urinary copper

83

What is seen in the eyes of patients with WD?

Kayser-Fleischer Rings

84

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

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

85

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

Rhodanine stain (red granules)

86

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

D-penicillamine
Trientine (BETTER SAFETY PROFILE)

87

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

Zinc

88

What is A1AT?

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

89

Where is A1AT predominantly made?

Liver

90

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

Zinc
Trientine

91

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

Liver disease in children
Emphysema in adults

92

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

Hepatitis
Cirrhosis
Liver cancer

93

What are the three inherited genes for A1AT?

M (main)
S
Z (most common mutant)

94

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

PiMM (protease inhibitor MM)

95

Pathogenesis of lung disease in A1AT deficiency

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

96

Pathogenesis of liver disease in A1AT deficiency

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

97

PiMM results in ___% activity
Disease?

100%
No liver or lung disease

98

PiMS results in ___% activity
Disease?

80%
No liver or lung disease

99

PiMZ results in ___% activity
Disease?

60%
No liver or lung disease

100

PiSS results in __% activity
Disease?

50-60%
No liver or lung disease

101

PiSZ results in ___% activity
Disease?

30-40%
Lung disease only

102

Pi null-null activity causes ___% activity
Disease?

0%
Lung disease only (no liver accumulation)

103

PiZZ causes ___% activity
Disease?

10-15%
Liver and lung disease

104

Three things that should be evaluated for A1AT deficiency?

Serum A1AT levels
A1AT phenotypes
Liver biopsy

105

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

Abnormal A1AT accumulations

106

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

Autoimmune hepatitis

107

Gender preference of AI hepatitis

Female:male 4:1

108

What will be found on labs with AI hepatitis?

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

109

What histologic features are characteristic of AI hepatitis?

Interface hepatitis: infiltration around portal tract
Portal plasma cell infiltration

110

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

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

111

What antibodies are found in type 1/classic AIH?

ANA (anti-nuclear antibody)
ASMA (anti-smooth muscle antibody)

112

What antibody is found in type 2 AIH?

Anti-liver-kidney microsomal antibody

113

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

Thyroid disease
**also RA, diabetes, Sjoren's syndrome, polymyositis, vitiligo, psoriasis, IBD, Addison's

114

What two drugs are used for the tx of AIH?

Prednisone--sometimes used by itself
Azathioprine (steroid sparing agent)

115

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

Postmenomausal/osteoporosis
Brittle diabetes
Obesity
Acne
Emotional lability
Hypertension

116

What is the tx endpoint for AIH?

Normal ALT/AST
Normal IgG
Resolution of inflammation on biopsy

117

20 yr survival of AIH patients who were treated
Untreated patients in 3 yo, 10 yr

80%
50% dead in 3 yr, 90% in 10 yr

118

What is primary biliary cirrhosis?

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

119

Who gets PBC?

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

120

Pathogenesis of PBC?

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

121

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

Multi-enzyme complex--pyruvate dehydrogenase complex (PDC)

122

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

PDC-E2
Membrane of the biliary epithelial cells

123

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

Increased ALP
AMA +

124

What are the two key symptoms of PBC?

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

125

What are lipid deposits seen with cholestatic liver disease?

Xanthelasma (tuberous)

126

What causes the steatorrhea in PBC?

Decreased bile salt excretion

127

What vitamins are not absorbed in PBC?

Fat soluble vitamins--A, D, E, K

128

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

Osteomalacia, fractures
Prolonged QT interval with hypokalemia

129

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

Sjogren's syndrome (>50%)
**less commonly thyroiditis, RZ, raynauds, scleroderma

130

What biochemistries are abnormal in PBC? (3)

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

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

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