Flashcards in 11. Alcoholic, Metabolic, and Autoimmune Liver Disease Deck (131):
What is METAVIR?
Scoring system for liver biopsies that takes the inflammation (grade) and fibrosis (stage) into account
What are the inflammation stages of the METAVIR score?
0 No activity
What are the fibrosis stages of the METAVIR system?
0 No fibrosis
1 Portal fibrosis
2 Periportal fibrosis
3 Septal fibrosis
What happens in stage 1 of the METAVIR system?
Portal fibrosis: area around the triad is affected, fibrosis often irreversible
What happens in stage 2 of the METAVIR system?
Periportal fibrosis--extends beyond the triad
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
What happens in stage 4 of the METAVIR system?
Nodules form, with scar tissue surrounding relatively normal tissue
What is hepatic necrosis?
Injury causing lysis of hepatocytes, acute cell death
Happens much more quickly than fibrosis, which may take years
What can can hepatic necrosis lead to?
Acute liver failure
What is fulminant liver failure?
Acute liver failure with COAGULOPATHY and ENCEPHALOPATHY
What are the two most common causes of acute and fulminant liver failure?
Viral hepatitis (NOT HCV)
Alcohol content of beer, wine, and liquor?
Serving size of beer, wine, and liquor?
Amount of alcohol in beer, wine, and liquor?
What is binge drinking for women? men?
4 or more drinks in a single occasion
5 or more drinks in a single occasion
What is heavy drinking for women? Men?
More than 1 drink/day on average
More than 2 drinks/day on average
What is excessive drinking?
Heavy drinking or binge drinking or both
What are the two methods by which ethanol is metabolized to acetaldehyde?
How is acetaldehyde converted to acetic acid?
What is the system that CYP2E1 is a part of?
Microsomal ethanol oxidizing system
What else is metabolized by CYP2E1 aside from ethanol?
Who is deficiency in aldehyde dehydrogenase?
Large percentage of Asian patients
**leads to flushing on consumption of ethanol
What are the 2 key consequences of increased alcohol metabolism?
What are the adverse effects of increased NADH from alcohol metabolism?
Inhibition of the TCA cycle resulting in reduced gluconeogenesis
Reduced fatty acid oxidation
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
What are 5 aspects of the pathogenesis of alcohol at the sinusoids
Loss of fenestration
Activated Kupffer cells
Activated stellate cells
What is the first change that is seen in alcoholic liver disease (ALD)?
What do ALD patients with fatty liver develop?
Alcoholic hepatitis 10-35%
**40% of patients with alcoholic hepatitis may convert to cirrhosis
How are inflammatory cells recruited in conversion to alcoholic hepatitis?
IL-8 and TNF from Kuppfer cells
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
What is the AST/ALT ratio in ALD? What is ALT usually below?
What are three hematological characteristics seen in ALD?
1. Prolonged INR (in advanced disease)
2. Macrocytic anemia
3. Thrombocytopenia (in advanced disease)
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
How does pentoxifylline work?
Inhibits TNF alpha
How do you determine who should be treated for viral hepatitis?
4.6 (PT - PT control) + total bilirubin
**patients with values over 32 have a 1 mo mortality from 30-50%
What are two drugs that improve survival in alcoholic hepatitis?
What is the scoring system for determining how sick a patient with cirrhosis is?
What is the classic patient with non-alcoholic fatty liver disease (NAFLD)
Obese female with diabetes mellitus
What are the two histological categories of NAFLD?
Non-alcoholic fatty liver (NAFL)
Non-alcoholic steatohepatitis (NASH)
What is the histological category of non-alcoholic fatty liver defined as?
Presence of hepatic steatosis without inflammation of hepatocellular injury (ballooning of hepatocytes)
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
What is the most common cause of elevated transaminases in the US?
Non-alcoholic fatty liver disease
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)
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
How does the prevalence and severity of NAFLD change with age?
Severity (including advanced fibrosis/cirrhosis) increases
What is them ost common chronic liver disease in the US?
Non-alcoholic fatty liver (20% of americans)
NASH is the second most common
What is the gender preference for NAFLD? Race?
What is obesity defined as?
BMI over 30 or 30 lb overweight for a 5'4 person
What is the most common liver disease in children in the US?
**present in 18% children
What type of hyperlipidemia increased the risk for NAFLD?
Hypertriglyceridemia rather than hypercholesteremia
**3 fold greater risk with TGs>200
Three key causes of steatosis and steatohepatitis
2. Medications--amiodarone, steroids, HAART, tamoxifen, diltiazem
3. Nutrition--total parenteral nutrition
**also insulin resistance, abetalipoproteinemia, weight cancers
How will a fatty liver appear on CT?
Darker (compare to spleen)
Nodular if NASH is present
What are the three things to target for therapeutic strategies for NAFLD?
1. Progression to obesity, HTN, hyperlipidemia
2. Insulin resistance
3. Oxidative stress
Loss of __% body weight will improve steatosis
Loss of __% is needed to improve inflammation
10% **this is the magic # for reversing NASH
What are the effects of pioglitazone and vitamin E on patients with NASH?
*neither reduce fibrosis
What is the drawback of using pioglitazone for NASH?
What improves liver histology in non-diabetic patients with NASH and should be first line therapy?
**not recommended for patients with diabetes, NAFLD w/o liver biopsy, or NASH cirrhosis/cryptogenic cirrhosis
What gene is implicated in hereditary hemochromatosis?
HFE gene on chromosome 6
People with hereditary hemochromatosis have one of two mutations:
C282Y/C282Y (80-90% of cases)
What does the HFE gene regulate?
Absorption of iron from the small intestine
Downregulates transferrin when iron supplies are adequate
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
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
What is the most common genetic disorder in populations of European ancestry?
__% of caucasians are heterozygous (C282Y/WT)
___% are homozygous C282Y/C282Y
___% are compound heterozygote C282Y/H63D
0.5-1% (of this group, 50% will develop disease)
What are the key components of the presentation of hemochromatosis?
Liver function abnormalities 75%
Weakness and lethargy 74%
Skin hyperpigmentation 70%
Diabetes mellitus 48%
Impotence in males 45%
EKG abnormalities 31%
Why does hemochromatosis present later in women?
Due to menstrual blood loss
What is the first step of evaluating possible hereditary hemochromatosis?
Fasting transferring saturation
45% is abnormal
What should be done if fasting transferring saturation is over 45% in testing for hereditary hemochromatosis?
Proceed with genetic testing--
Why is biopsy recommended if hereditary hemochromatosis is found?
Higher risk of developing cancer
Recommended tx if person is found to be C282Y/C282Y +?
Biopsy if >40yo or if elevated ALT/AST
What kind of stain will show iron on a liver biopsy?
Prussian blue stain
What is the tx for hemochromatosis? Goal serum ferritin?
**initially weekly phelb, once quarterly therafter
Inheritance of hemochromatosis?
What are the dietary sources of copper?
Fruits and vegetables
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
What age group is often diagnosed with WD?
Younger--3 to 40 yo
What are some sx that should lead you to consider dx of Wilson's Disease?
Acute liver failure **
Unexplained liver disease
Neurological sx (due to deposits in the brain)
What are the neurological features seen in Wilson's Disease?
What is decreased in pateitns with WD?
Ceruloplasmia--95% of homozygotes have a level <20mg/dl
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)
Urine copper is derived from:
Rate of excretion in patients with WD (symptomatic) may exceed:
What is the best test for WD?
High urinary copper
What is seen in the eyes of patients with WD?
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
What stain can be used to find accumulations of copper on liver biopsies?
Rhodanine stain (red granules)
What are the two drugs that can be used in WD to bind copper and increase the urinary excretion?
Trientine (BETTER SAFETY PROFILE)
What is the drug that can be used in WD to prevent copper form being absorbed in the GI tract?
What is A1AT?
Inhibitor of elastase, part of family of structurally unique protease inhibitors called serpins
Where is A1AT predominantly made?
In WD, what is the first line drug for increasing fecal Cu excretion? Increasing urine Cu excretion?
A1AT deficiency is the most common cause of genetic___ disease in children
MCC of genetic ____ in adults
Liver disease in children
Emphysema in adults
In adults, A1AT deficiency can cause ___, ____, and ____
What are the three inherited genes for A1AT?
Z (most common mutant)
Healthy individuals with normal A1AT levels have the genotype ____, present in over 90% Caucasians in the US
PiMM (protease inhibitor MM)
Pathogenesis of lung disease in A1AT deficiency
Loss of function mechanism
Lack of A1AT allows uninhibited PMN mediated proteolytic damage to connective tissue
Pathogenesis of liver disease in A1AT deficiency
Gain of function mechanism
Retention of inefficiently secreted A1AT Z molecule in the ER triggers hepatotoxic events
PiMM results in ___% activity
No liver or lung disease
PiMS results in ___% activity
No liver or lung disease
PiMZ results in ___% activity
No liver or lung disease
PiSS results in __% activity
No liver or lung disease
PiSZ results in ___% activity
Lung disease only
Pi null-null activity causes ___% activity
Lung disease only (no liver accumulation)
PiZZ causes ___% activity
Liver and lung disease
Three things that should be evaluated for A1AT deficiency?
Serum A1AT levels
What will be seen on liver biopsy with A1AT def with PAS stain?
Abnormal A1AT accumulations
What will cause elevated ALT and AST along with autoantibodies in the serum?
Gender preference of AI hepatitis
What will be found on labs with AI hepatitis?
ALT/AST over 1000
Elevated gamma globulin or elevated IgG
What histologic features are characteristic of AI hepatitis?
Interface hepatitis: infiltration around portal tract
Portal plasma cell infiltration
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)
What antibodies are found in type 1/classic AIH?
ANA (anti-nuclear antibody)
ASMA (anti-smooth muscle antibody)
What antibody is found in type 2 AIH?
Anti-liver-kidney microsomal antibody
What is the AI disease that is most commonly associated with AIH?
**also RA, diabetes, Sjoren's syndrome, polymyositis, vitiligo, psoriasis, IBD, Addison's
What two drugs are used for the tx of AIH?
Prednisone--sometimes used by itself
Azathioprine (steroid sparing agent)
When might you use a combination of predinsone and azathioprine for tx of AIH?
What is the tx endpoint for AIH?
Resolution of inflammation on biopsy
20 yr survival of AIH patients who were treated
Untreated patients in 3 yo, 10 yr
50% dead in 3 yr, 90% in 10 yr
What is primary biliary cirrhosis?
Chronic, progressive, cholestatic liver disease
Destruction of intrahepatic bile ducts
Probable AI pathogenesis
Who gets PBC?
90-95% cases are women
Mean age 52, range from 30-65
Pathogenesis of PBC?
High serum autoantibodies--antimitochondrial antibodies (AMA)
**associated with other autoimmune diseases
What is the major target of the antimitochondrial anitbodies in PBC?
Multi-enzyme complex--pyruvate dehydrogenase complex (PDC)
What antigen that is the target of AMAs predominates in PBC? Where is it located?
Membrane of the biliary epithelial cells
What are the two components of presentation of PBC in asymptomatic patients (25% cases)
What are the two key symptoms of PBC?
Pruritus 55% -- due to bile acid/salt deposition
**also hepatomegaly, splenomegaly, jaundice, xanthelasma
What are lipid deposits seen with cholestatic liver disease?
What causes the steatorrhea in PBC?
Decreased bile salt excretion
What vitamins are not absorbed in PBC?
Fat soluble vitamins--A, D, E, K
What are the adverse effects of vitamin D deficiency seen in PBC? Vitamin K
Prolonged QT interval with hypokalemia
What is the AI disorder that is most commonly assoicated with PBC?
Sjogren's syndrome (>50%)
**less commonly thyroiditis, RZ, raynauds, scleroderma
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