hepatic diseases Flashcards
hepatic blood flow
inferior of superior mesenteric vein - portal vein - liver - sinusoidal spaces (space of Disse) - hepatocytes filter blood and blood moved back in the hepatic vein - inferior vena cava
normal liver function
digestive functions endocrine functions clotting functions plasma proteins organic metabolism cholesterol metabolism excretory/degradative functions
drug metabolism
phase I - non-synthetic reactions, REDOX* and hydrolysis, may detoxify a substance or make it toxic, typically involves CYP enzymes, may involve alcohol and aldehyde dehydrogenase
phase II - conjugation reactions, typically render a substance non-toxic
hematological fxns
receives around 25% of cardiac output
removes old or damaged RBCs
synthesizes plasma proteins, transport nutrients and clotting factors
AST
aspartate aminotransferase
normal values*: 0-50 IU/L
found in: liver, heart, skeletal muscle, kidney, brain, spleen, pancreas and lungs
elevated in: any disease that causes injury/damage to above tissues
ALT
alanine aminotransferase normal values*: 5-60 IU/L found in liver, heart, muscle and kidney more specific for liver injury than AST elevated in: cirrhosis, obstructive jaundice and hepatitis
Alk Phos
Alkaline Phosphatase
normal values*: 35-130 IU/L
found in: bone, liver and placenta (cells that line bile duct)
elevates in: obstructive jaundice, liver lesions, cirrhosis, paget’s disease, metastatic bone disease
GGT
gamma glutamyl transferase
normal values*: 0-85 IU/L (men have higher levels due to prostate)
found in: liver, kidney, prostate and spleen
elevated in: cirrhosis, cholelithiasis, biliary obstruction, chronic alcohol use
bilirubin
normal value: 0-1.4 mg/dL
direct/conjugated normal value: 0-0.3 mg/dL
both conjugated and unconjugated will elevate in hepatitis and cirrhosis
direct/conjugated - associated with RBC destruction
unconjugated - associated with liver blockage/destruction
LDH
lactate dehydrogenase
normal range: 90-200 IU/L
found in: liver, kidney, heart, lungs
not specific for liver dysfunction, only tissue breakdown
serum albumin
normal level: 3.6-5 g/dL
low in liver disease
coagulation
INR, PT and aPPT
elevated in cirrhosis
ammonia
NH3
normal values: 15-50 micromol/L
produced from intestinal bacteria
converted to urea in liver
BUN
blood urea nitrogen
normal values: 10-20 mg/dL
low in cirrhosis
cholesterol
may be low
LFT vs LIT
LFT = liver function test -albumin -bilirubin -cholesterol -BUN -INR LIT = liver injury test -AST -ALT -Alk Phos -GGT
hepatocellular test magnitude
AST/ALT
over 10x normal - hepatitis, drugs, ischemia
under 10x normal - broad diagnosis
components of liver disease
drugs* chronic alcohol consumption* chronic viral hepatitis* metabolic liver disease immunologic diseases vascular disease
hepatitis A
acute viral infection
typically self-limiting
transmission - fecal-oral
commonly associated with: poor sanitation and hygiene, overcrowded areas, travel
supportive care, does not lead to chronic infection
vaccination - 2 inactivated vaccines
hep A vaccines and doses
havrix:
- 1-18: 720 units, 2 doses, 0 and 6-12 mo
- 19+: 1440 units, 2 doses, 1 and 6-12 mo
vaqta:
- 1-18: 25 units, 2 doses, 0 and 6-18 mo
- 19+: 50 units, 2 doses, 0 and 6-18 mo
twinrix (also includes HBV): 18+, 720 units, 3 doses, 0, 1 and 6 mo
CDC recommendations for hep A vaccination
**all children at 1 year of age
**travelers to countries that have risk of infection
**anticipating close contact with an international adoptee from a country of high endemicity
age 2-18 in communities with high disease incidence, men who have sex with men, illegal drug users, persons with occupational risk for infection, persons who have clotting factor disorders, persons with chronic liver disease
hepatitis B
not self-limiting - will need treatment
transmission: sexually, parenterally, perinatally
complications: cirrhosis, hepatocellular carcinoma
chronic HBV: detectable serum levels or past 6 months
HBV vaccinations
engerix-B
- 0-19: 10 mcg at 0, 1 and 6 mo
- 20+: 20 mcg at 0, 1 and 6 mo
-dialysis: 40 mcg at 0, 1, 2 and 6 mo
recombivax HB
- 0-19: 5 mcg at 0, 1 and 6 mo
- 20+: 10 mcg at 0, 1 and 6 mo
-dialysis: 40 mcg at 0, 1, and 6 mo
comvax (+HIB): 6 wk-15 mo, 5 mcg at 2, 4, 12-15 mo
pediarix (+DTaP, IPV): 6 kw-6 yr, 10 mcg at 2, 4 and 6 mo
twinrix (+Hep A): 18+, 20 mcg at 0, 1 and 6 mo
HBV vacc. recommendations
**infants
**those with a h/o STDs and persons with a h/o multiple sex partners (over 1 partner/6 months)
**healthcare/public safety workers with exposure to blood in the workplace
**chronic dialysis/ESRD patients including predialysis, peritoneal dialysis and home dialysis patients
previously unvaccinated children under 19, adults at risk, adults seeking vaccination, MWHSWM, current or recent inj-drug users, household contracts/partners of persons with HBV infection, clients/staff of institutions for the developmentalyl disabled, international travelers to regions with 2+% prevalence of HBV infection, recipients of clotting factor concentrates, STD clinic patients, HIV patient/HIV testing patient, drug abuse treatment and prevention clinic patients, correctional facilities inmates, persons with chronic liver disease
Hep C
most common BBP, transmission: parenteral, sequelae: chronic hepatitis, cirrhosis, hepatocellular cancer
single largest risk factor is injection-drug use
screening for Hep C
**anyone born between 1945 and 1965
**current or past use of injection drugs
**patients who have ever been on hemodialysis
coinfection with HIV, received blood transfusions or organ transplantations before 1992, received clotting factors before 1987, patients with unexplained elevated ALT levels or evidence of liver disease, healthcare and public safety workers after a needle-stick or mucosal exposure to HCV-positive blood, children born to HCV positive mothers, sexual partners of HCV positive patients
drug induced liver disease
Many drugs are associated with adverse reactions involving the liver
Rare, potentially fatal, largely unpredictable outcome of drug treatment
No specific diagnostic tests for drug-induced liver disease - Important to know the patterns of drug-related pathology
Normal metabolic outcome = decrease the reactivity - However - many causes of drug induced liver disease are a result of bioactivation
hepatocellular injury
centrilobular necrosis, steatohepatitis, phospholipidosis, generalized hepatocellular necrosis
significant elevations in the serum aminotransferase
usually precede elevations in total bilibrubin and alkaline phosphatase
most injuries occur within 1 year of initiation
further subdivided based on histology/presentation
centrilobular necrosis
AKA direct or metabolite-related hepatotoxicity
damage spreads outward from the middle of a lobe of the liver
mild/early diagnosis - small amount of liver tissue, asymptomatic elevations in aminotransferases, minimal cirrhosis/recovery likely
severe/delayed diagnosis - large amount of tissue affected, NV, upper abdominal pain and jaundice
**EXAMPLE MEDICATION: ACETAMINOPHEN
acetaminophen
in overdose, bioactivated to N-Acetyl-p-benzoquinone imine (NAPQI)
NAPQI is very reactive, with a high affinity for sulfhydryl groups
glutathione provides source of available sulfhydrl groups within hepatocyte to detoxify NAPQI
when glutathione stores depleted, reacts directly with hepatocyte
administration of N-acetylcystine early after ingestion of the OD halts this process
nonalcoholic steatohepatitis (NASH)
accumulation of fatty acids in the hepatocyte (“supersize me”) - can see without drug induced cause in DM and poor diet
Engorgement with fatty acids, eventually disrupts hepatocyte homeostasis
Production of free fatty acids from excess circulating carbs, accelerates this process
May present with abdominal fullness or pain as only complaint
More severe cases: nausea, vomiting, steatorrhea, pruritus, and fatigue.
**EXAMPLE MEDICATIONS: TETRACYCLINE, VALPROATE
phospholipidosis
Accumulation of phospholipids instead of fatty acids
Amiodarone is associated with this reaction
Amiodarone and its major metabolite remain in the liver for several months after therapy is stopped
Usually develops in patients treated for more than 1 year
The patient can present with either elevated aminotransferases or hepatomegaly; jaundice is rare
generalized hepatocellular necrosis
Mimics the changes associated with viral hepatitis
Drugs causing this reaction generally do so via induction of the innate immune response
Subject to genetic polymorphism.
Wide variation in the sensitivity of the population to hepatic damage
**Example Medication: ISONIAZID
isoniazid
Slow acetylators* of the N-acetyltransferase2 (NAT2) genotype are at greater risk
Isoniazid is acetylated to acetylisoniazid, which, in turn, is hydrolyzed to acetylhydrazine.
Acetylhydrazine is toxic to the cellular proteins in the hepatocyte
Rapid acetylators detoxify acetylhydrazine rapidly, converting it to diacetylhydrazine
other presentation of drug induced liver injury
toxic cirrhosis
cholestatic injury
liver vascular disorders
toxic cirrhosis
Scarring effect of hepatitis leads to the development of cirrhosis
Some drugs tend to cause such a mild case of hepatitis that it may not be detected
Mild hepatitis can be easily mistaken for a more routine generalized viral infection.
If the offending drug or agent is not discontinued, this damage will continue to progress.
**Example Medications: METHOTREXATE (psoriasis and arthritis), VITAMIN A (causes fibrosis when taken for long periods in high doses, accelerated by ethanol)
cholestatic injury
Disturbances prevent the movement of bile through the canalicular system
More common in elderly and males
Some may have genetic predisposition
Accumulation of toxic bile acids and excretion products
**EXAMPLE MEDICATIONS: CHLORPROMAZINE, AMOXICILLIN-CLAVULANIC ACID, and CARBAMAZEPINE
liver vascular disorders
Peliosis hepatitis is a rare type of hepatic vascular lesion
Development of large, blood-filled lacunae (space or cavity)
Rupture can lead to severe peritoneal hemorrhage
**EXAMPLE MEDS: androgens, estrogens, tamoxifen, azathioprine.
assessment of drug-induced liver disease
patient history is best and most important technique assess: -environmental/occupational exposures -herbals -meds (Rx and OTC) -nutritional status -recreational drugs -vitamins/supplements potential drug reactions should be judges as to the: -timing of the reaction -pharmacokinetic considerations -information from the literature -inclusion of alternative nondrug causes -close clinical observation once drug is stopped
laboratory assessment of liver injury
no good clinical test available to determine exact type of liver damage - liver biopsy common specific patterns of enzyme elevation that have been identified and can be helpful necrotic: alkphos: x1 GGT: x1 AST: x3 ALT: x3 LDH: x3 cholestatic: alkphos: x3 GGT: x3 AST: x1 ALT: x1 LDH: x1 chronic: alkphos: x1 GGT: x2 AST: x2 ALT: x2 LDH: x1
alcoholic liver disease
most common cause of cirrhosis responsible for around 44% of cirrhotic deaths 3 main histological phases: -steatosis/fatty liver -acute alcoholic hepatitis -cirrhosis
pathophysiology - alcohol
alcohol dehydrogenase (ADH) converts EtOH to acetaldehyde
-acetaldehyde has direct toxic effects - damage to hepatocytes, induce fibrosis, couples to proteins
ethanol oxidation increases liver metabolic processes to reduction - increased reactive oxygen species, fatty liver, acidemia, hypertriglyceridemia
risk factors for ALD**
women, cumulative EtOH consumption, beer and spirits consumption, binge drinking, drinking between meals, drinking multiple different EtOH beverages
fatty liver disease
occurs in around 90-100% of EtOH abuse cases
occurs due to presence of triglycerides in hepatocytes
liver function typically stays normal
reversible with ETOH abstinence
acute EtOH hepatitis (AAH)
clinical syndrome of jaundice and liver failure
occurs after decades of heavy drinking
more common in men
typical age presentation 40-60 years old
AAH assessment: CAGE
do you feel you should Cut down on your alcohol consumption?
have people every Annoyed you by critisizing your drinking?
have you felt Guilty about your drinking?
have you ever had a drink first thing in the morning to steady your nerves (Eye-opener)>
clinical pres: rapid onset of jaundice, RUQ pain, encephalopathy
AAH assessment labs
AST: 2-3x higher than ALT ALT: elevated, but not much higher than 100 IU/L INR/PT: elevated total bili: elevated albumin: low
Maddrey’s score
***(4.6 x (prothrombin time-control prothrombin time)) + serum bilirubin in mg/dL score over 32: -poor prognosis -threshold for starting CSs -threshold for starting pentoxifylline
pentoxifylline
MOA: phosphodiesterase inhibitor that also modulates TNF-a
dose: 400 mg TID
showed decreased mortality in hospitalized patients with EtOH hepatitis
decreases the risk of hepato-renal syndrome
EtOH withdrawal
signs:
-initial: HA, tremors, sweating, NV, irritability, anorexia,
-worsen between 24-48 hours after EACH cessation
symptom appearance: within a few hours
symptom duration: around 48 hours
