Weeks 3 & 4: Liver Function Flashcards
metabolic function of liver
detoxification/breakdown: toxins, hormones, drugs
synthesis: bile - for emulsification of fats in the lumen of the GI tract
protein: production - including amino acids, clotting factors, vitamins, albumin and various other hormones. Activation.
carbohydrate: including glyconeogenesis.
lipid: including cholesterol and triglyceride production
red blood cells: normal in the fetus but pathological in adults
storage: nutrients - glucose. vitamins & minerals: Vitamin A/D/B12, iron & copper
Immunological: kupffer cells lining sinusoids acts as antigen presenting cells
liver (hepatocyte) function and revelation after resection
removing metabolic waste production, hormones, drugs & toxins
producing bile to aid in digestion
processing nutrients absorbed from the digestive tract
storing glycogen, certain vitamins and minerals
Maintaining normal blood sugar
Synthesizing plasma proteins, albumin, and clotting factors
Producing immune factors & removing bacteria
Removing senescent red blood cells from the circulation
Excreting bilirubin
common lab liver tests
Bilirubin AST ALT GGTP Alkaline phosphate LDH PT
what has recently happened to normal values
ALT
AST, normal range
<40
ALT normal range
19-35 for women, 29-33 for men
GGT normal range
< 60
alkaline phosphate normal range
< 112
what are the liver enzymes
ast, alt, ggt, alkaline phosphate
what are liver function tests?
bilirubin, albumin, prothrombin time
normal range for bilirubin
< 1.2
albumin normal range
3.5-4.5
prothrombin time normal range
< 14 seconds
WBC normal?
4000-11000
hematocrit normal?
> 40
platelet normal
> 150000
what should you say instead of liver function tests?
liver tests b/c more tests aren’t a function of liver function
what does ALT (alanine transaminase) do?
Produce in hepatocytes
Very specific marker of hepatocellular injury
Relatively low concentrations in other tissues so more specific than AST
Levels fluctuate during the day
Rise may occur with the use of certain drugs or during periods of strenuous exercise
what does AST aspartate transaminase do?
Occurs in two isoenzymes, indistinguishable on standard AST assays
The mitochondrial isoenzyme is produced in hepatocytes and reacts to membrane stresses in a similar way to ALT
The cytosolic isoenzyme is present in skeletal muscle, heart muscle and kidney tissue
Caution must be exercise in its use to evaluate hepatocellular damage
Usually rises in conjunction with ALT to indicate hepatocellular injury: a hepatitis picture
what does alkaline phosphatase (ALP) do
A group of isoenzymes that act to dephosphorylate a variety of molecules throughout the body
Produced in the membranes of cells lining bile ducts and canaliculi
Released in response to the accumulation of bile sales or cholestasis
Non-hepatic production in the kidney, intestine, leukocytes, placenta & bone
Physiological rise in pregnancy or in growing children
Pathologic rise in Paget’s disease, renal disease, and with bone metastases
what does GGT do (gamma glutamyl transferase)?
Present in liver, kidney, pancreas & intestine
It is found in the microsomes of hepatocytes and biliary epithelial cells
Elevation of GGT in association with a rise in ALP is highly suggestive of a biliary tract obstruction and is known as a cholestatic picture
Subject to rise with hepatic enzyme induction d/t chronic alcohol use or drugs such as rifampicin and phenytoin
what test is liver specific?
GGTP - an isolate elevation of just one of the other test values should raise suspicion that a source other than the liver is the cause, when several liver test results are simultaneously out of normal range consideration of non-hepatic sources becomes irrelevant
GGTP level is too sensitive, frequently elevated when no liver disease is apparent. A GGTP is useful in only two instances
- it confers liver specificity to an elevated alkaline phosphate level
- in aminotransferase level elevations with AST/ALT ratio > 2, elevation of GGTP further supports alcoholic liver disease
in addition it can be used to monitor abstinence from alcohol
an isolated elevation of the GGTP level does not need to be further evaluated unless there are additional clinical risk factors for liver disease
differential diagnosis of increased AST
primary liver disease acute myocardial infarction muscle trauma/diseases pancreatitis intestinal surgery burns renal infarction pulmonary embolism
differential diagnosis of increased ALT
primary liver disease biliary obstruction pancreatitits ALT>AST viral hepatitis AST>ALT alcoholic liver disease
differential diagnosis of increased ALP
biliary obstruction primary liver disease (changes parallel GGT) infiltrative liver disease bone diseases hyperparathyroidism
differential diagnosis of increased GGT
biliary obstruction
primary liver disease (changes parallel ALP)
alcohol consumption
pancreatitis
differential diagnosis of increase bilirubin
biliary obstruction
primary liver disease
hemolytic anemias
hypothyroidism
medications & liver
may cause increases in one or more liver chemistry tests because of direct hepatotoxicity or cholestasis
ALT & AST?
are abundant liver enzymes
AST is also present in heart & muslce
where is ALP present?
in nearly all tissues, primarily bone & liver.
where is GGT?
abundant in liver, kidney, pancreas & intestine
do ALT & AST vary on lab?
yes, generally < 40
mild ALT & AST elevations?
- less than 5 times upper normal limit - they should be rechecked prior to extensive workup
possible causes: chronic hepatitis C or B, acute viral hepatitis, NAFLD, hemachromatosis, autoimmune hepatitis, medicaitons, alcohol-related liver injury, Wilson’s disease
moderately elevated ALT & AST?
- 5-15 times upper normal limit.
should be investigated w/o waiting to confirm the persistence of abnormal ALT,
possible causes - entire spectrum of liver diseases
severe ALT & AST elevations
> 15 times ULN
suggest severe acute liver cell injury
acute viral hepatits, ischemic hepatitis, or other vascular disorder, toxin mediated hepatitis, acute autoimmune hepatitis
what is bilirubin?
heme degradation product excreted in the bile, it requires conjugation in the liver before it is secreted
what should you do about hyperbilirubinemia?
investigate cause by direct (conjugated) or indirect (unconjugated) fraction of bilirubin
pre-hepatic causes (increased production, decreased liver uptake)
cause increase of indirect
intra-hepatic/post-hepatic causes
decreased hepatic excretion, increase of direct
increased production causes of hyperbiliirubinemia
hemolysis
decreased liver uptake causes of hyperbilirubinemia
Gilbert syndrome (5% of populatin - benign)
decreased hepatic excretion causes of hyperbilirubinemia
bile duct obstruction, primary biliar cirrhosis, primary sclerosing cholangitis, benign recurrent cholestasis, hepatitis, cirrhosis, medications, sepsis, total parenteral nutrition, Dublin-Johnson Syndrom,
what causes increased GGT?
alcohol consumption
what causes increased ALP & GGT
bile duct obstruction, primary biliary cirrhosis, primary sclerosing cholangitis, benign recurrent cholestasis, infiltrative disease of the liver (sarcoidosis, lymphoma, metastatasic disease)
causes of isolated elevated ALP (extra hepatic disease)
bone disease, pregnancy, chronic renal failure, lymphoma, congestive heart failure
causes of abnormal PT and albumin levels
indicate severe hepatic synthetic dysfunction & indicates progression to cirrhosis or impending hepatic failure
what is nonalcoholic fatty liver disease?
fatty infiltration (steatosis) of the liver, exceeding 5% of liver weight
requires exclusion of alcohol as potential cause. acceptable levels of alcohol consumption are controversial but in general < 20 grams/ day (2 drinks) in men & < 10 grams/day (1 drink) in women
what is primary NAFLD?
common term for typical NAFLD associated w/ central obesity and/or DM2 or insulin resistance w/o another specific etiology
what is secondary NAFLD?
used to defined as NAFLD in the absence of insulin resistance and associated w/ other causes such as :
polycystic ovary syndrome
hypothyroidism
hypogonadism
hypopituitarism
medicaiton use (glucocorticoids, tamoxifen, amiodarone, HAART, diltiazem)
disorders of lipid metabolism (abetalipoproteinemia, lipodystrophy, Weber-CHristian syndrome, Andersen’s disease)
total parenteral nutrition and jejunoileal bypass surgery
many cases of secondary NAFLD likley represent an exacerbation of often unrecognized “primary” NAFLD
what is non alcoholic steatohepatitis (NASH)?
the more seer form of NAFLD characterized by inflammation, hepatocyte injury (ballooned hepatocytes) with or without fibrosis. it can progress to cirrhosis & possibly liver cancer
what is NASH cirrhosis
the presence of cirrhosis w/ current or previous evidence of steatosis or NASH
what is cryptogenic cirrhosis
a term used to define the presence of cirrhosis w/ no obvious etiology, frequently there is a history of DM & obesity.
do DM2 have > or < risk for cirrhosis
DM2 higher risk for cirrhosis compared to the general population, possibly d/t NAFLD
also at higher risk of hepatocellular carcinoma compared to the general population, possibly d/t NAFLD
race groups at higher risk for NAFLD?
non hispanic whites and hispanics at higher risk
what are predictors of more severe disease of NAFLD?
age > 40-50 years female severe obesity hypertension DM hypertriglyceridemia elevated ALT, AST, GGT, AST/ALT ratio > 1
genetic predisposition for NAFLD?
single variant in an allele is strongly associated w/ liver fat & liver inflammation. allele is more common among Hispanics.
diagnosis of NAFLD requires?
presence of steatosis (by imaging or liver biopsy)
absence of significant alcohol consumption
competing cause of chronic liver disease
what are tests to rule out co-existing treatable conditions for NAFLD?
viral hepatitis C
autoantibodies
hemachromatosis
imaging methods to distinguish fatty liver and steatohepatitis?
no imaging methods to distinguish fatty liver & steatohepatitis
but imaging can help exclude biliary tract or focal liver disease
how to detect the presence of liver fat?
US is more sensitive than CT scan, less expensive & no radiation risk…
MRI primarily used in research settings to quantify the amount of fat in the liver
how to detect liver fibrosis
US based transient elastography measures tissue elasticity non invasively and correlates well w/ liver fibrosis in liver biopsy in patients with viral hepatitis. this method has been approved by FDA.
what is gold standard for NAFLD diagnosis
liver biopsy
staging (extent of injury)
& grading (degree of activity) of NAFLD
what is NAFLD activity score?
range from 0-8, composite score based on findings of steatosis, inflammation and hepatocyte injury
a higher NAS indicates greater damage
fibrosis is scored separately
how is fibrosis scored?
0-4; 0-2 minimal, 3-4 bridging fibrosis & cirrhosis
limitations of liver biopsy
patient inconvenience
potential for complications
sampling error
what are non-invasive markers of fibrosis?
proprietary algorithm panel based fibrosis scores based on a combination of biochemical serum assays & routine lab tests and can reliably identify those with either minimal or advanced disease
however
substantial gray zone precluding accurate fibrosis diagnosis & staging
some are commercially available
limited dated are available of their utility in NAFLD
what is the new word for liver function tests?
liver chemistries (ALT, AST, alkaline phosphate & bilirubin) are markers of liver injury (not liver function)
should be referred to as liver chemistries/liver tests
what are markers of hepatocellular function that can be influenced by extrahepatic factors?
albumin, bilirubin, prothrombin time
what tests require assessment & potential evaluation?
elevations of AST and/or ALT, alkaline phosphate & bilirbuin suggest hepatocelluar injury and are the abnormal liver chemistries that require assessment & potential evaluation
which is more specific, ALT or AST
ALT more specific marker of hepatic injury
how do you confirm an elevated alkaline phosphate level of hepatic origin?
by elevation of the GGT or fractionation of alkaline phosphate
Signs/symptoms of NAFLD
most common: asymptomatic, fatigue, right upper quadrant pain
palmar erythema, spider angiomas in cirrhosis
clinical findings associated w/ metabolic syndrome commonly seen
hepatomegaly, acanthosis nigricans in children
lipoatrophy/lipodystrophy
is mildly elevated serum ferritin common in patients w/ NAFLD?
mildly elevated serum ferritin is common in patients with NAFLD
if serum ferritin & transferrin saturation are both elevated then this is suggestive of hemochromatosis & genetic testing is justified
non-pharmacologic treatment of NAFLD
diet & exervise are cornerstones of therapy. weight lostt 5-6% effetively improves steatosis & other histological features of NAFLD and reduces risk of progression
notes for weight loss on NAFLD treatment
avoid rapid weight loss, can cause histological exacerbation
what about exercise w/o weight loss for NAFLD treatment?
evidence suggests it may help, encourage increased physical activity level even in the absence of weight loss
diet composition for NAFLD treatment?
effects of specific diets on NAFLD are not known
recommended balanced diet such as that endorsed by ADA or AHA
pharmacologic treatment for NAFLD
obeticholic acid, improved histological features of NAFLD. adverse effects: increase in LDL & pruritits
thizolidinediones for treatment of NAFLD
pioglitazone significantly improves histological outcomes & b/c of other benefits in treatment in DM2, can be considered drug of choice for NAFLD in those w/ DM2
biguanides for NAFLD?
metformin usually only used in research data.
antioxidants in NAFLD?
pilot data suggest improvement w/ vitamin E
cytoprotective agents:
large RCT showed use of ursodeoxycholic acid shows no histologic benefits
gold standard for NAFLD?
biopsy, used to diagnose, stage and grade NAFLD, not routinely performed
common initial approach to NAFLD?
lab tests to rule out other potential causes of liver disease are most common initial approach
what is a cornerstone to initial management
lifestyle changes
is there FDA approved medication therapy?
no FDA-approved medication therapy
although thiazolidinediones may be preferred in patients with both NAFLD
and T2DM
non hepatic source of abnormal bilirubin?
red blood cells (hemolysis, intra-abdominal bleed, hematoma)
non hepatic source of abnormal AST
skeletal muscle, cardiac muscle, red blood cells
non hepatic source of abnormal alt
skeletal muscle, cardiac muscle, kidneys
non hepatic source of abnormal ldh
heart, red blood cells (hemolysis)
non hepatic source of abnormal alkaline phosphate
bone, first trimester placenta, kidneys, intestines
aminotransferases (AST & ALT) abnormal in?
hepatocellular injury: ethanol, hepatitis, ischemic injury, NAFLD, acute biliary obustruction
Rare: hyperthyroidism, celiac disease, skeletal muscle disease
alkaline phosphate abnormal in
cholestasis, canalicular injury, children during bone growth, bone disease, pregnancy (placenta origin)
GGT abnormal in ….
cholestasis, medications, ethanol, rarely anorexia nervosa, hyperthyroidism, myotonic dystrophy
bilirubin abnormal in…
any acute or chronic liver disease, congenital disorders of bilirubin metabolism
what is hepatitis?
inflammation of the liver
many causes:
toxic agents (drugs, ETOH, mushrooms, organic solvents, dietary supplements)
infectious A-E, CMV, HSV, EBV
mechanical - injury, obstruction, thrombus, Budd-Chiarai
autoimmune
common drugs that induce hepatitis
acetaminophen & methotrexate
what is fibrosis?
scarring, possibly reversible
what is cirrhosis?
scarred non-functional tissue - will not regenerate
can compensate with cirrhosis
what is liver failure?
the organ is non-functional or severely impaired, also called decompensated.
acute liver failure?
also called fulminant - liver failure that develops in days to weeks
hyperacute 2-7 days,
sub acute up to 6 months
chronic liver failure?
progressive fibrosis over time with continued exposure to provocatory agent
often can live for a while without transplant (just using medication)
causes of acute liver failure
usually drugs
drugs: tyelnol, herbal supplements, NSAIDs, hepatitis a, b, e cancer Budd-Chiari (venous malformation) toxins auto-immune metabolic
causes of chronic liver failure
alcohol hepatitis C NASH/NAFLD primary biliary cirhhosis primary sclerosing cholangitis medications/toxins: methotrexate, tylenol, supplements metabolic
day to day exposure over long periods of time
signs & symptoms of liver failure
jaundice, ascites, edema, dark urine, pale stools, palmar erythema, odor - fector hepatic, caput medusae, encephalopathy, day/night reversal, hepatomegaly, splenomegaly, umbilical hernia, pruritus, nausea/malaise
labs for liver failure
hyperbilirubinemia, hypoalbunemia, hyponatremia, hypoglycemia, transaminitis, thrombocytopenia, increased creatinine, azotemia, coagulopathy, increased serum ammonia.
should I measure serum ammonia?
no, doesn’t really do anything to trend ammonia
give lactulose if high
you would send an ammonia if they are somnolent
CV sequellae liver failure
hypotension, pulmonary hypertension, arrhythmias
respiratory sequellae of liver failure
dyspnea, hepatic hydrothorax, aspiration from encephalopathy
infection sequellae of liver failure
SBP, cholangitis, sepsis
GI sequellae of liver failure
anorexia, constipation, GI bleeds, varies
renal sequellae of liver failure
hepato-renal syndrome, hyponatremia
if someone has 2 weeks of kidney issues list them for a kidney/liver transplant
heme sequellae of liver failure
anemia, coagulopathy
ONC sequellae of liver failure
hepatocellular carcinoma
endocrine sequellae of liver failure
hypoglycemia
neuro sequellae of liver failure
encephalopathy, RUQ pain
derm sequellae of liver failure
pruritus
initial lab results for liver failure
WBC normal to low
UA - proteinura common, bilirubinemia before jaundice
significantly elevated ALT & AST > 500 (marker of inflammation & insult of parnchymea)
elevated bilirubin & alkaline phosphate (obstruction of biliary tree) elevated after ALT/AST normalize
where is alkaline phosephate also?
in bones, so you want to send fractioned alk phose to tell if bone or liver.
GGT or GTT to tell if actively drinking
prognosis with acute hepatitis
remove offending agent and you recover
acute hepatitis turns into acute liver failure and you need liver tx
you get better but go on to chronic liver failure which may necessitate a liver transplant
what is MELD?
model for end stage liver disease
supportive care for liver failure
monitor INR, CBC, bilirubin, and LFTs
Encephalopathy - limit po protein & give lactulose
Hypoglycemia – 10 % glucose infusion
Coagulopathy – Vitamin K, FFP
Hyponatremia – free water restrict
• Ascites – low Na diet, diuretics prn,
– careful paracentesis (significant loss albumin, 6-8 gm of albumin per kilo of fluid removed)
what are the ‘real lfts’
hypoglycemia, hypoalbminemia, elevated INR
why low salt diet?
Na would leak into the tissues and water will follow the Na
why low protein diet?
breakdown protein - get ammonia - liver can’t handle the ammonia
what kind of diet for liver failure
high carb diet, low Na, & fluid restriction. page 14
why do paracentesis for liver failure?
remove fluid
why do thoracentesis for liver failure
remove fluid - hepatic hydrothorax
what other interventions are there for liver failure?
TIPS: transjugular intrahepatic protosystemic shunt, improves ascites but decreases LOC, makes encephalopathy worse b/c it doesn’t clear ammonia
ERCP/EGD
biopsy - gold standard for disease process figuring out
transplant
medications used to manage liver failure
lactulose: encephalopathy - give lactulose until brain is OK
rifaximin: abx changes gut flora & helps to keep those that will keep ammonia
spironolactone/furosemide: diuretic
midodrine: increase NP
cipro or daily abx: bactrim to prevent spontanesou bacterial pertinotis
propranolol: assist w/ portal HTN, keep pressure low in portal varices
octreotide
pantoprazole
how do you determine the mode of transmission of Hep A-E?
if it’s a vowel - fecal / oral route
if its a consonant: blood/mucosal transmission
prodromal phase
malaise, myalgia, arthralgia & fatigue
anorexia, nausea & vomiting common
diarrhea or constipation
rash, arthritis or serum sickness in early HBV
fevers <104F
mild constant RUQ or epigastric abdominal pain, increased w/ exertion
icteric phase
dark urine & clay colored stool
jaundice at onset or within 10 days
intensified prodromal symptoms BUT some patients are asymptomatic
tender helaptomegaly
splenomegaly
posterior cervical lyphadenopathy rare but some patients have normal exam
chronic liver failure
reduce metabolic function
impaired bile formation and flow
produces multisystem organ failure, encephalopathy, increased incidence of infection: spontaneous bacterial peritonitis (E. coli, klebsiella, strep)
hepatitis A
caused by HAV
fecal / oral transmission
incubation period 15-50 days, average 28 days
diagnosis by blood test - positive HAV IgM
not a common cause of liver failure
new infections for hep A 2015
2800
new infections hep B 2015
21900
living with Hep C
3.5 million
what helped decline of hep a virus?
hep a vaccine, declined 95% since 1995
hep a sign/symptoms
young children often asymptomatic
abrupt onset: fever, fatigue, anorexia, N/V, abd pain, dark urine, clay colored stools, joint pain, jaundice
-symptoms last < 2 months
-HAV can live outside the body for months
-chlorinated water kills it
-can’t get reinfected
what can offer short term protection for HAV?
IG, must be given within 2 weeks after exposure
is hep E more or less common if have another hepatitis?
more common if have another hepatitis
HEV
- fecal oral route
- symptoms: fever, fatigue, anorexia, N/V, abd pain, jaundice, dark urine, clay stools, joint pain
- treatment: supportive, avoid ETOH
- clinical course: self limited - acute illness.
- no FDA approved test for HEV
hep b transmission
- blood mucous
- must have mucosal/percutaneous contact with infectious blood/body fluid
- not spread through food, water, casual contact, sharing utensils, breastfeeding
hep B symptoms
same as all other hep: fever, fatigue, anorexia, N/V, and pain, jaundice, dark urine, clay colored stools, joint pain
tend to be sicker at beginning and into icteric phase faster
who’s at risk for hep b
-infants born to infected mothers
-sex partners of infected persons
-MSM
IVDA
-household contact of those infected
occupational
HD patients
travelers to countries w/ intermediate/high prevalence of HBV infection
unprotected sex, > 1 sex partner in previous 6 months, non-monogamous relationship
incubation period for HBV
60-160 days, average 90 days
clinical illness (jaundice for HBV)?
> 5 years, 30-50%
acute case fatality rate for HBV
0.5-1%
chronic infection rate for hbv
infants >90%, >5y/o 25-50%
premature mortality from chronic liver disease 15-25%
hep b surface antigen
person is infected
hep b surface antibody
indicates recovery or immunity from infection/indicates seroconversion from vaccination
hep b core antibody
appears at the onset of symptoms in acute Hep b, persists for life
IgM antibody to anti-Hbc
recent infection (<6 months), acute infection
IgM - smoking gun = you’re infected
Hep B e antigen
active viral replication
Hep B DNA
quantitative, viral load
