Hepatic Inflammation and Fibrosis Flashcards
What are the 5 stage of fibrosis?
0 - No fibrosis 1 - Portal fibrosis 2 - Periportal fibrosis 3 - Septal fibrosis 4 - Cirrhosis
Acute liver failure complicated by coagulopathy and encephalopathy
Fulminant liver failure
What is the most common cause of acute and fulminant liver failure?
Medications (acetaminophen)
Viral hepatitis
What constitutes heavy drinking for women and men?
Women = more than 1 drink per day on average Men = more than 2 drinks per day on average
What enzyme takes ethanol to acetaldehyde? How much is metabolized by this?
Alcohol dehydrogenase – 75-80%
What is another mechanism by which ethanol is metabolized?
Microsomal Ethanol Oxidizing System (MEOS) – 20-25%
What is the enzyme that many asians have a mutation in?
Aldehyde dehydrogenase
What are some consequences of alcohol metabolism?
Increased NADH – inhibits TCA cycle, reduces gluconeogenesis; reduced fatty acid oxidation
Increased acetaldehyde – activates stellate cells to form collagen, microfilaments are sheared, Kupffer cells produce TNFa
What does the histology of alcoholic hepatitis look like?
Fat cells and inflammatory cells
What are some risk factors for ALD?
Quantity of alcohol (>30g/day in men or >20g/day in women)
Drinking on an empty stomach
Binge drinking
Hep C
What lab abnormalities can be found with ALD?
AST/ALT ration >2-3 ALT usually <300 Rarely raised alk phase Low albumin Prolonged INR (advanced) Macrocytosis/anemia Thrombocytopenia (advanced)
Treatments for alcoholic hepatitis
Abstinence and lifestyle modifications
Anti-inflammatory drugs = Glucocorticoids, Pentoxifylline–inhibits TNFa
What is the equation to determine when to treat alcoholic hepatitis?
4.6 (PT - PT control) + T BILI
If >32 have 1 month mortality from 30-50%
Why is pentoxifylline preferred in a patient that has an active infection?
Steroids will make it worse!
Most common cause of elevated transaminases in the US.
Non-alcoholic fatty liver disease
What are the two histological classes of NAFLD?
- Non-alcoholic fatty liver (NAFL) = presence of hepatic steatosis without inflammation or hepatocellular injury
- Non-alcoholic steatohepatitis (NASH) = presence of hepatic steatosis and inflammation with hepatocellular injury with or without fibrosis
What are the stages in progression of NAFLD?
Fatty liver (Hepatosteatosis) –> Steatohepatitis (NASH) –> Steatohepatitis with fibrosis –> Cirrhosis
What is NAFL associated with?
Metabolic syndrome
- Obesity
- Diabetes
- Hypertriglyceridemia - 3 fold greater risk with triglycerides > 200
Who is particular susceptible to NAFLD?
Increased age
Males > Females
Hispanics > Caucasians > African Americans
What is the most common liver disease in children in the US?
NAFLD
Some common causes of steatosis and steatohepatitis to be aware of.
Alcohol
Medications = amiodarone, steroids, HAART, tamoxifen, diltizem
Nutritional: TPN, weight changes - gastric bypass
How can a fatty liver be diagnosed on ultrasound?
Fat comes out bright and if nodules are observed = NASH
What are some treatments for NAFLD?
Diet/exercise
Gastric band
Orlistat
How much of your body weight must you lost to improve steatosis? How much to improve inflammation?
3-5% to improve steatosis
10% to improve inflammation
What are some treatment options for non-diabetic NAFLD?
Vitamin E
Pioglitazone
What is the genetic alteration that accounts for 82-90% of cases of hemochromatosis?
HFE gene on chromosome 6
C282Y/C282Y
What is the compound heterozygote in hemochromatosis?
C282Y/H63D
What is the role of the HFE gene?
HFE regulates the absorption of iron from the small intestine. When we need iron, it is absorbed and mobilized by transferrin. HFE will down regulate transferrin when iron supplies are adequate. With mutation, iron continues to be absorbed from the small intestine.
What might be some causes of secondary iron overload?
Anemia caused by ineffective erythropoiesis
Liver Disease
Parenteral Iron Overload
Where does Fe deposit in primary vs secondary hemochromatosis?
Primary = hepatocytes Secondary = Kupffer cells
How does hereditary hemochromatosis present?
Liver function abnormalities Weakness and lethargy Skin hyper pigmentation (bronze diabetes) Diabetes Arthralgia Impotence in males EKG abnormalities
What test is used as a work up for hereditary hemochromatosis?
Fasting transferrin saturation If elevated (>45%) then check with genetic testing
When do you biopsy for hereditary hemochromatosis?
You consider it is genetic testing shows C282/H63D
If C282Y/C282Y you biopsy if the patient is over 40 or if they have an elevated ALT/AST
Then do phlebotomy for treatment
What is the goal serum ferritin in hemochromatosis?
<50
Initially do weekly phlebotomy, then once quarterly after
What are some dietary sources of copper?
Seafood Organ meats Nuts and nut butters Legumes Chocolate Enriched cereals Fruits and veggies
What parts of copper metabolism are reduced Wilson’s Disease?
Excretion in the bile
Binding to ceruloplasmin
Where does Cu start to deposit in Wilson’s Disease?
Extrahepatic in kidney, brain and cornea
How is Wilson’s Disease diagnosed?
No one single finding is adequate - combination of clinical biochemical and pathological analysis
Consider the diagnosis in patients 3-40 years old with unexplained liver disease, acute liver failure, cirrhosis, near symptoms, psychiatric symptoms
How is Wilson’s Disease characterized?
Autosomal recessive
Defect in ATP7B gene
How does ceruloplasmin contribute to a diagnosis of Wilson’s disease?
95% of homozygotes have level <20mg/dL
But high CP can occur in inflammation so there may be some false negatives
What might the urinary excretion of copper be in a patient with symptomatic Wilson’s Disease?
May exceed 100 micrograms/24 hours
What are some treatments for Wilson’s Disease?
D-penicillimine (lots of SE)
Trientine
Zinc
Where is alpha-1 antitrypsin made?
In the liver
How does alpha-1 antitrypsin deficiency differ between children and adults?
It is the most common genetic liver disease in children, leading to liver transplant
In adults it can cause hepatitis, cirrhosis, liver cancer; most common cause of emphysema in adults
What are the possible inherited genes in alpha-1 antitrypsin deficiency?
M (main)
S
Z (most common mutant)
*Most healthy individuals with normal A1-AT are PiMM
What is the pathogenesis of lung and liver disease in A1-AT deficiency?
Lung = loss of function mechanism, lack of A1AT allows uninhibited PMN mediated damage to CT of lung
Liver = gain of function mechanism, retention of inefficiently secreted A1AT Z molecule in ER triggers serious of hepatotoxic events
Which A1-AT deficiencies lead to disease?
PiSZ - 30-40% activity, causes lung disease only
Pi null-null - 0% activity, causes lung disease only
PiZZ - 10-15% activity, can cause both lung and liver disease
What do the labs of someone with autoimmune hepatitis look like?
ALT, AST elevation, occ. > 1000
Elevated gamma-globulin or elevated IgG
Autoantibodies
What are some differentials to think of with really high AST, ALT?
Hepatitis B
Autoimmune Hepatitis
Medications
Ischemic Liver Disease
What is visible on histology of an individual with autoimmune hepatitis?
Interface hepatitis
Plasma cell infiltrate
What are the two subclassifications of AIH?
Type 1 = Classic (80-90%), adults; in nucleus, ANA, ASMA
Type 2 = anti-LKM 1 hepatitis, children; in microsome, anti-liver-kidney microsomal antibody
What is present in approximately 50% of AIH cases?
Other associated autoimmune conditions
What is the treatment for AIH?
Prednisone only
Prednison + Azathioprine
When do you stop treatment for AIH?
With normal ALT, AST, IgG, gamma-globulin, and resolution of inflammation on biopsy
Chronic, progressive, cholestatic liver disease
Destruction of intrahepetatic bile ducts
Primary biliary cirrhosis
What is the probably pathogenesis for PBC?
Autoimmune
90-95% women, caucasian, mean age of 52 at presentation (range 30-65)
High prevalence of serum autoantibodies (Antimitochondiral antibodies, AMA)
Elevated IgM
Increased familial incidence of disease
What is the major target antigen in PBC?
PDC-E2 on the membrane of biliary epithelial cells
How do patients with PBC present?
Elevated alk phos (3-4x normal)
AMA +
Investigation for other autoimmune diseases
Bilirubin usually rises
Cholesterol elevated – but not associated with heart disease
Fatigue and Itching!
What is a common complication with PBC?
Fat soluble vitamin deficiency
Vitamin D deficiency –> osteomalacia, fractures, regular bone densitometry
Vitamin K deficiency –> prolonged PT
What is the most common autoimmune disorder associated with PBC?
Sjogren’s/Sicca syndrome
What is a histological finding of PBC?
Florid-duct lesion = lymphocytes and mononuclear cells causing inflammatory changes around bile ducts
Treatment for PBC.
Ursodeoxycholic acid (UDCA) -- decreases inflammation around bile ducts to lead to less fibrosis For itching -- cholestyramine or benedryl at night
