Alcoholic Metabolic Autoimmune Liver disease Flashcards
Child pt who presents with hypoglycemia, elevated liver enzymes, and nausea/vomiting.
-suspect what?
suspect Reye Syndrome!
What intermediate of alcohol metabolism damages liver?
- mechs (3)
- what enzyme is needed to metabolize this?
Acetaldehyde
- activates stellate cells to form collagen (fibrosis)
- Hepatocyte ballooning: microfilaments that maintain intracellular skeleton are sheared. Also, Mallory bodies are formed (bodies of intermediate filaments)
- kupffer cells produce TNF-A (Pentoxifylline inhibitis this)
Ethanol –> Acetaldehyde –> Acetic acid
Rxn 1. Alcohol DH and CYP2E1
Rxn 2. Aldehyde DH (50% asians have this mutated)
Wilson’s disease
- clinical presentation (3)
- typical population
- presentation at childhood
1. cirrhosis
2. neurologic (dementia, chorea, parkinsonian due to basal ganglia Cu deposition)
3. Kayser-Fleisher rings (requires opthalmologist to see)
Hepatic inflammation:
What happens histologically from stage 1 to 4?
inflammatory cells surround portal triad and expand outward
Primary Biliary Cirrhosis (PBC)
-clinical presentation
- Obstructive jaundice–symptoms include:
- pruritis
- xanthomas
- steatorrhea, malabsorption of DEAK
- often asymptomatic: incidental AMA+ finding from rheumatologist looking at other autoimmune disorders
Fulminant liver failure
Acute liver failure complicated by:
- coagulopathy
- encephalopathy
Wilson’s disease
- genetic allele
- inheritance pattern
- Auto rec
- ATP7B gene: ATP-mediated hepatocyte Cu transport protein
Hepatic fibrosis
- what cells mediate this
- what do they secrete
- where are they located
- Stellate cells, which secrete TGF-B to create fibrosis
- Space of Disse, beneath endothelial sinusoid cells
Hereditary hemochromatosis
-increased risk of what complication?
-hepatocellular carcinoma (b/c of free radial damage to DNA from Fe Fenton reaction)
Liver disease pt has high INR. How to tx immediately? (2)
- Use FFP (clotting factors)
- Vit K (only works for pts with cholestatic disease b/c malabsorption)
Autoimmune hepatitis
characteristic lab findings (3)
- ALT/AST >1000 (very high )
- elevated IgG
- autoantibodies
Type 1: (ANA–anti nuclear Ab)
(ASMA–Anti smooth m Ab)
Type 2: anti-liver kidney microsomal Ab
Hepatic Fibrosis:
what happens histologically from stage 1-4?
Fibrotic bands expand from portal triads to other portal triads.
- portal fibrosis
- periportal fibrosis
- bridging fibrosis
- cirrhosis (nodules created)
Metabolism of ethanol
-steps, enzymes, intermediates
75-80%:
Ethanol –> Acetaldehyde –> Acetic acid
Rxn 1. Alcohol DH and CYP2E1
Rxn 2. Aldehyde DH
20-25%:
-Ethanol is metab by MEOS (microsomal ethanol oxidizing system–P450)
Hepatic necrosis:
- what is this
- 2 most common causes
- Acute hepatocyte death (not fibrosis, which takes years)
- can lead to acute liver failure
most common causes:
- meds (acetaminophen)
- viral hepatitis
NAFL disease progression stages:
- Fatty Liver (NAFL)
- Steatohepatitis (NASH)
- NASH with fibrosis
- Cirrhosis
Hereditary hemochromatosis
- classic symptoms (3)
- other notable symptoms (3)
Classic triad:
- cirrhosis
- diabetes mellitus
- bronze skin
Other:
- dilated cardiomyopathy
- cardiac arrhythmias
- gonadal dysfunction (testicular atrophy)
What do AST and ALT require as cofactor?
What are AST/ALT alternate abbrev?
-PLP
AST: SGOT
ALT: SGPT
A1AT Deficiency
-Dx tests (3)
- serum A1AT levels
- phenotyping
- liver biopsy (A1AT globules stain red on PAS stain)
Autoimmune hepatitis
-histology finding
-Plasma cell infiltrate in liver
Hereditary hemochromatosis
- Labs: ferritin, TIBC, serum Fe, % sat
- Liver biopsy findings
high ferritin
low TIBC
high serum Fe
high % sat
- Fe accumulates in hepatocytes (brown pigment)
- distinguish from lipofuscin with Prussian blue stain (Fe is blue)
In Liver biopsy, you see brown pigment in hepatocytes. What could this be?
Fe or lipofuscin
-distinguish using Prussian blue stain (Fe is blue)
Hereditary hemochromatosis
- what lab finding value do you look for when you suspect Hereditary hemochromatosis?
- Tx
- What else to do if pt is >40 or has elevated ALT/AST?
-Fe/TIBC ratio >45%. (do genetic testing if you find this)
Tx: phlebotomy
-also do biopsy to look for possible cirrhosis
ALT/AST >500
Differential? (4)
- Autoimmune Hep
- Hep A/B
- Meds
- Ischemic disease
NASH
-drug tx (2)
- Pioglitazone (Actos)–oral hypoglycemic
- Vit E (antioxidant)
Note: Use Vit E in non-diabetic pts
Primary Biliary Cirrhosis (PBC)
-histological findings
“Florid Duct lesion”
-lymphocyte and monocyte proliferation around bile ducts (at portal triad)
What is most common cause of genetic liver disease in children, and also is the most common genetic disease leading to liver transplantation in children?
A1AT Deficiency
Wilson’s disease
-Tx (3)
Cu-chelating agents: (increase urinary excretion)
- D-Penicillamine
- Trientine
- Zinc (blocks intestinal absorption)
Alcoholic liver disease:
-what amount of alcohol intake do we start seeing problems
Daily intake of 4 or more drinks
(>60g/day)
Alcoholic liver disease
-progression of liver states
Fatty liver
/ \
Alcoholic hepatitis –> Cirrhosis
NAFL
-How much weight do you tell your obese patient to lose?
3-5% to improve steatosis, but
10% weight reduction needed to improve inflammation
-shoot for 10%, in 6 months
Mallory Bodies
inclusion bodies of intermediate filaments
-found in alcoholic hepatitis, among other liver diseases
How does ethanol intake affect metabolism cycles in the liver? (2)
Increased NADH:
- inhibits Krebs cycle, reduced gluconeogenesis (alcoholic hypoglycemia)
- reduced fatty acid oxidation
(fatty acids are trapped, causing steatosis)
Primary Biliary Cirrhosis (PBC)
-Tx (3)
autoimmune, but no steroid use!
- Ursodeoxycholic acid
- synthetic hydrophilic bile acid. bile duct damage is due to accum of hydrophobic bile acids, so try to reverse ratio.
Pruritis tx:
- Cholestyramine (during day)
- Diphenhydramine (during night)
Primary Biliary Cirrhosis (PBC)
- what is it
- classic population
- chronic autoimmune destruction of intrahepatic bile ducts
- white middle aged women
Non Alcoholic Fatty Liver disease:
risk factors (3)
- obese
- hypertriglyceridemia
- diabetes
Pts after completing gastric bypass surgery: what about their liver are you concerned about?
Rapid weight changes after gastric bypass surgery:
-can cause steatosis/steatohepatitis
Alcoholic Hepatitis:
drug tx (2)
Anti-inflammatory:
- steroids
- pentoxifylline (inhibits TNF-A)
- use this if steroids contraindicated
Hemochromatosis
-mech of tissue damage
Free radicals from Fenton reaction of Fe
Why is INR better indicator of liver function than Albumin?
when does Albumin become the better indicator?
Albumin can be affected by loss in urine/GI.
However, INR cannot be used in Warfarin tx. Must use albumin
Don’t give aspiring to child pt with viral disease. However, what child disease mimics viral disease and requires aspirin to tx?
Kawasaki’s disease
Primary Biliary Cirrhosis (PBC)
-what is target of AMA Ab?
-enzyme located on the membrane of biliary epithelial cells
(PDC-E2)–pyruvate DH complex
elevated Alkaline Phosphatase:
- what could it be? (3)
- how to distinguish
If elevated ALP is isolated, could be:
- Cholestatic disease
- pregnancy
- bone disease
- order GGT and 5’ nucleotidase
- if positive, then it’s liver
Alcoholic liver disease:
CDC definition of ‘excessive drinking?’
One or both of the following:
- Heavy drinking-
women: >1/day
men: >2/day - Binge drinking
women: >4 on single occasion
men: >5
Wilson’s disease
-lab findings for dx (3)
- high urinary Cu
- low serum ceruloplasmin (not reliable test b/c it’s elevated in inflammation)
- Liver biopsy (Cu deposits)
Wilson’s disease
-mech of genetic defect (2)
- genetic defect in ATP7B (Cu transport protein in liver)
1. Allows Cu to bind to ceruloplasmin
2. Transports Cu to Bile for excretion - Therefore, Cu deposits elsewhere in the body and is excrete in urine
What liver disease is autoimmune but is not tx with steroids?
Primary Biliary Cirrhosis (PBC)
(Use Urso, plus cholestyramine, benadryl)
NAFL vs NASH
Non alcoholic fatty liver:
- no inflammation
- pts die of heart disease
Non alcoholic steatohepatitis:
- inflammation with hepatocellular injury
- pts die of heart disease or liver failure
Reye syndrome
- what happens
- mech
- Fulminant liver failure and encephalopathy in children with viral illness given aspirin
- mitochondrial damage to hepatocytes
Wilson’s disease
-dx criteria
2 of 3:
- high urinary Cu
- low ceruloplasmin
- kayser fleisher rings
Which CYP is in alcohol metabolism?
-what else uses this?
CYP2E1.
-acetaminophen also uses
How can you tell a liver is fatty on ultrasound?
Fat is bright on US
A1AT Deficiency
- genetic alleles:
- inheritance pattern
- auto co-dom
- M: normal allele
- S: mutated, less severe
- Z: mutated, severe
M/M: normal
M/Z: asymptomatic
S/S: asymptomatic
Z/Z: lung and liver disease
null/null: lung disease but no liver disease b/c no abnormal protein in liver
Primary Biliary Cirrhosis (PBC)
- lab test values:
1. ALP
2. Bilirubin
3. Cholesterol
- elevated
- elevated, usu rises late
- Highly elevated, but so is protective HDL. primary care doctors don’t need to worry about heart disease
Hereditary hemochromatosis
- what gene (what does it do)
- what alleles
- inheritance pattern
- what populations, prevalence
- HFE gene, which regulates absorption of Fe from small intestine (down-regulates transferrin when body Fe is adequate)
- Auto rec
- 2 genotypes with symptoms:
1. C282Y/C282Y (most cases)
2. C282Y/H63D - N. european (0.5-1% are homozygotes!)
Primary Biliary Cirrhosis (PBC)
-these 2 are characteristically elevated in the blood:
- high AMA (anti mitochondrial Ab)
- elevated IgM
Wilson’s disease
-increased risk of what complication
-hepatocellular carcinoma
Autoimmune hepatitis
-Tx
Steroids, plus Azathioprine
-also use steroids in alcoholic steatohepatitis (only other liver disease for steroids)
How does Hereditary hemochromatosis differ from Secondary Fe overload? (histologically)
Hereditary hemochromatosis: Fe deposits in hepatocytes
Secondary Fe overload: Fe deposits in Kupffer cells. Usu no symptoms.
Alcoholic Hepatitis:
-how long does it take to see improvement in liver function after alcohol abstinence/nutritional support?
3 months. Lab values won’t change before 2-3 months.
