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
2
Q
What are the inflammation stages of the METAVIR score?
A
0 No activity 1 Minimal 2 Mild 3 Moderate 4 Severe
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
4
Q
What happens in stage 1 of the METAVIR system?
A
Portal fibrosis: area around the triad is affected, fibrosis often irreversible
5
Q
What happens in stage 2 of the METAVIR system?
A
Periportal fibrosis–extends beyond the triad
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
7
Q
What happens in stage 4 of the METAVIR system?
A
Nodules form, with scar tissue surrounding relatively normal tissue
Cirrhosis!
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
9
Q
What can can hepatic necrosis lead to?
A
Acute liver failure
10
Q
What is fulminant liver failure?
A
Acute liver failure with COAGULOPATHY and ENCEPHALOPATHY
11
Q
What are the two most common causes of acute and fulminant liver failure?
A
Medications--acetaminophen Viral hepatitis (NOT HCV)
12
Q
Alcohol content of beer, wine, and liquor?
A
5%
12%
40%
13
Q
Serving size of beer, wine, and liquor?
A
12 oz
4 oz
1.5 oz
14
Q
Amount of alcohol in beer, wine, and liquor?
A
- 8 gm
- 7 gm
- 4 gm
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
16
Q
What is heavy drinking for women? Men?
A
More than 1 drink/day on average
More than 2 drinks/day on average
17
Q
What is excessive drinking?
A
Heavy drinking or binge drinking or both
18
Q
What are the two methods by which ethanol is metabolized to acetaldehyde?
A
Alcohol dehydrogenase
CYP2E1
19
Q
How is acetaldehyde converted to acetic acid?
A
Aldehyde dehydrogenase
20
Q
What is the system that CYP2E1 is a part of?
A
Microsomal ethanol oxidizing system
21
Q
What else is metabolized by CYP2E1 aside from ethanol?
A
Acetaminophen
22
Q
Who is deficiency in aldehyde dehydrogenase?
A
Large percentage of Asian patients
**leads to flushing on consumption of ethanol
23
Q
What are the 2 key consequences of increased alcohol metabolism?
A
Increased NADH
Increased acetaldehyde
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
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
