Transcript Liver Logic--50 ways to love your liver

50 ways to LOVE your LIVER…
Barb Bancroft, RN, MSN, PNP
[email protected]
www.barbbancroft.com
Just the facts…
• The adult liver is the size of a football and weighs
approximately 4 lbs.
• 2nd largest organ (skin is #1)
• At any given time approximately 10% of the blood
volume circulates in the liver; our entire blood supply
travels through the liver several times a day
• It is the second most transplanted organ—80% of all
liver transplant patients are alive after 5 years
Just the facts…
• We can function with only 10% of our liver,
provided that the remaining liver is intact and
undamaged
• More importantly we have the capacity to
regenerate the entire liver
• We’ve known this since the story of
Prometheus in the world of Greek Mythology
Zeus and Prometheus
• Prometheus, the creator of mankind in Greek
mythology, angered Zeus because Zeus
wanted Prometheus to destroy the whole race
of mortals. Prometheus politely declined and
gave the mortals the Flame of Olympus.
• Bad move for Prometheus.
Prometheus
• Zeus was so angry that he had
Prometheus chained naked to a pillar in
the Caucasian mountains and ordered a
giant vulture to dine on his liver every
day, year in and year out; and there was
no end to the pain because every night
his liver grew whole again
Moral of the Story?
• Don’t make Zeus angry…
• And, this ancient myth reflects the remarkable
capacity of the mature liver to regenerate lost
tissue.
• Normal turnover—every 300-500 days
• And in some of “us”, it occurs every Monday
morning…
ANATOMIC RELATIONSHIPS
• Located in the right upper quadrant, beneath
the diaphragm, and anterior to the gallbladder
• Two lobes—left lobe crosses the midline
• Dual blood supply-• ~70% via portal vein; 30% hepatic artery
• With this dual blood supply (primarily venous)
it’s almost impossible to infarct a liver
Hepatic artery
• ~30% of blood flow to the liver is arterial
• Tagamet (cimetidine), a common OTC H2
blocker, is a potent vasoconstrictor of the
hepatic artery; reduces blood flow to the liver
and delays the inactivation of certain drugs
• Results in increased toxicity
What drugs? A few examples…
• Propanolol (Inderal)—bradycardia
• Morphine --bradypnea
• And,
Viagra (sildenafil)—aka the “Pfizer
riser”
• Toxicity???
• “If you have had an erection for more
than 4 hours…”
• Priaprism (named appropriately after the
Latin god Priapus—the fertility god and
the “protector of the male genitalia”)
• Blue vision, commercial airline pilots
•
Let’s get back to liver anatomy—the liver is
located beneath the diaphragm
• How much embryology did you get in nursing
school?
The diaphragm and it’s origins…
• Diaphragm originates in the neck, supplied by
cervical cord segments C3 and C4
• Gill slits
• Arm buds, leg buds, and a tail
Referred pain
• C3,C4 supply the soma where the neck meets
the shoulder
• C3,C4 supply the visceral diaphragm
• Both sensory afferents meet at the same
cervical cord segments
• The brain interprets the pain or irritation as
the most “likely” area which would be the
shoulder
Causes of referred pain to the
shoulder
• Enlarged, inflamed liver? (right shoulder)
• Enlarged or ruptured spleen? (Kehr’s sign) (left
shoulder)
• Enlarged, inflamed gall bladder? Right shoulder)
• Ectopic pregnancy?
• Laparoscopy?
• Lower lobe pneumonia?
• Inferior (diaphragmatic) MI
Assessment of the patient with liver
disease
• Evidence-based physical assessment findings
predicting hepatocellular disease in patients
with jaundice
• LR is the likelihood ratio – higher the number
the more likely the disease or finding relates
to disease)
Physical Assessment
Findings predicting hepatocellular disease in patients
with jaundice
•
•
•
•
Spider angiomas (LR 4.7)*
Palmar erythema (LR 9.8)*
Hepatomegaly
Pruritis
Findings predicting hepatocellular disease in
patients with jaundice
• Dilated abdominal veins (LR 17.5)*
• Ascites (LR 4.4)*
• Ultrasound=100 ml
• 500 ml needed to palpate a fluid wave
(The development of ascites from any cause
heralds progressive deterioration and only
50% survival two years after onset)
Palpation of liver edge; auscultation
• Palpation for the liver edge at the right costal
margin—if you believe you are palpating the liver
edge below the right costal margin—you ARE (LR
233.7)
• Smooth with sharp edge?
• Rough? Nodular? Rock hard? Cobblestone feeling?
• Inflammation, venous congestion (CHF), tumor,
cirrhosis
• Auscultation for bruit
Ascites
• SAAG—serum ascites-albumin gradient;
• SAAG=albuminserum - albuminascites
• ratio greater than 1.1 is 97% predictive of
portal hypertension as the cause of ascites
• SAAG less than 1.1 is nonportal
hypertension—nephrotic syndrome, infection
(TB, fungal, CMV), pancreatic ascites,
peritoneal carcinomatosis (ovarian cancer)
More anatomy--the hepatic portal system
• A portal system consists of two
capillary beds connected by a large
vein
• The capillary system of the intestines
with the capillary system of the liver
via the portal vein
Portal hypertension
• Defined as: Increased resistance to portal blood flow-prehepatic, intrahepatic, and posthepatic
• Pre—obstructive thrombosis, narrowing of the portal vein,
massive splenomegaly with increased splenic blood flow
• Posthepatic—severe right-sided heart failure, constrictive
pericarditis, hepatic vein outflow obstruction
• Intrahepatic—cirrhosis (accounts for most cases of portal
hypertension)
Causes of cirrhosis of the liver
•
•
•
•
•
•
•
•
•
Hepatitis C (26%)
Alcoholism (21%)
Hepatitis B
Primary biliary cirrhosis
NASH (non-alcoholic steatohepatitis)
Hemochromatosis
Wilson’s disease
Parasitic flatworms (schistosomiasis)
Others…heavy metals, CR, syphilis, CHF
Portal hypertension and cirrhosis—sustained hepatic
-portal gradient pressures above 12 mmHg
• The four major clinical consequences of portal
hypertension are:
1) ascites
2) esophageal varices (esophagogastric junction),
varices of the vessels of the falciform ligament
(involving peripumbilical and abdominal wall
collaterals)
3) splenomegaly
4) hepatic encephalopathy
What causes the ascites?
• Increased pressure in the portal system
pushes fluid into the abdominal cavity
• Low serum albumin (decreased osmotic
pressure)
• Increased circulating aldosterone since the
liver cannot metabolize it—sodium and water
retention
Esophageal and gastric varices as a cause of
upper GI bleeding
• 90% of patients with cirrhosis will develop varices;
usually sicker patients with chronic liver
disease/cirrhosis; bleeding is more severe; associated
with coagulopathy (decreased clotting factors due to
liver dysfunction and thrombocytopenia)
• Mortality is increased without prompt endoscopic
therapy
• Risk of bleeding is increased with variceal size and
high pressures
Prevention and treatment of ruptured
esophageal varices—upper GI bleed
• Reduce portal pressure with beta blockers (“olols”, “alols”)—
propranolol (Inderal), nadolol (Corgard)
• Constrict splanchnic arteries supplying the portal system
during an acute bleed with vasopressin or somatostatin
(Octreotide) (watch out for the cardiac patient with the use of
vasopressin—use NTG)
• Emergency endoscopy with banding; thermocoagulation;
sclerotherapy (old treatment)
• TIPS (transjugular intrahepatic portosystemic shunt)—rescue
therapy when drugs and endoscopy fail—reduces
transhepatic venous pressure to less than 12 mmHg
Hepatic encephalopathy (HE)
• Occurs in 30-45% of patients with cirrhosis and
portends a poor prognosis; the probability of
transplant-free survival after the first episode is only
42% after 1 year and 23% after 3 years
• Disorder of neurotransmission in the CNS and
neuromuscular system
• Changes may progress over hours with acute liver
failure or insidiously with marginal hepatic function
in chronic liver disease
• Associated with elevated ammonia levels
Gut-flora and hepatic encephalopathy
• Gut flora, especially urease-containing species, such
as klebsiella and proteus species, are an important
source of ammonia in humans
• In patients with cirrhosis, the accumulation of
ammonia results from impaired hepatic clearance
due to hepatocellular failure and portosystemic
shunting.
• Other gut-derived toxins exacerbate neurochemical
changes
• Synergistic effect of inflammation
Neurological signs
• Manifested by a spectrum of disturbances in
consciousness, ranging from mild with subtle
behavior changes, to marked confusion and stupor,
to deep coma and death
• Mild hepatic encephalopathy can seriously impair a
patient’s daily functioning and quality of life
• Psychomotor slowing, deficits in attention, fine
motor performance is impaired
• Unable to drive and predicts the development of
overt hepatic encephalopathy
Overt hepatic encephalopathy
•
•
•
•
Marked confusion, stupor, coma
Rigidity
Hyper-reflexia
Asterixis (liver flap)--occurs when a group of
contracted muscles suddenly and temporarily goes
limp. For example, when the arms and hands are
outstretched, the hands suddenly drop, then resume
their original position. The movements are repetitive,
coarse, slow, and not rhythmic.
Prevention and Treatment
• The encephalopathy is preventable and/or reversible if the
underlying hepatic condition can be corrected
• Rifaximin (Xifaxan)—550 mg tablet to prevent hepatic
encephalopathy (HE)—it kills the bacteria in the gut that
produce ammonia and other toxins
• Adding rifamaxin to lactulose (20 to 40 grams daily) reduces
the risk of recurrent hepatic encephalopathy and
hospitalization by 50%
• One additional episode is prevented for every 4 patients
treated for 6 months
• Downside? Rifaximin costs $1200 per month; use when
lactulose alone is not enough to prevent recurrent HE
Functions of the LIVER
• It ONLY performs 500 functions per
day…zoweeee….
• Why do you think we haven’t been able to
make a “liver” machine?
• The heart and kidneys are wimps when
compared to the workhorse known as the
liver
• So what are some of the most important
functions?
Produces bile to help to absorb fats
• Before the small intestine can absorb fats—
including the fat-soluble vitamins A,D,E,K—the
fats must be emusified (suspended in fluids)
• The liver produces up to 27 ounces a day of
bile to do it
• Some bile goes directly to the small intestine
to meet the specific needs, and the rest is
stored in the gall bladder
Production of albumin (3.5-5.5 gm/dL)
• Functions:
1) hold water in the vascular space (not enough?
Consider fluid heading into the tissues and the
abdomen—especially the abdomen)
2) albumin and binding sites for drugs (proteinbound drug vs. free-bound)
• Let’s talk about the 1% rule in the world of geriatrics
• When do you reach your peak capacity in all tissues?
What age?
Binding drugs
• Reduced albumin synthesis with aging (or liver
disease) results in lower albumin levels
• Not uncommon for the geriatric patient to
have a level of 3.0 g/dL; less binding sites for
more drugs—greater toxicity
Let’s talk about warfarin/Coumadin
• INR and Coumadin—standard is to maintain
the INR between 2 and 3 for most indications
• Warfarin is highly protein-bound, but also
“loosely” bound
• Everybody wants to “knock” warfarin off its
albumin binding sites
Drugs that are highly “protein” or
albumin bound
• Sulfa drugs knock everyone off the binding
sites of albumin and can be especially
hazardous with Coumadin
• Older women with urinary tract infections
• TMP-SFX (Septra, Bactrilm)
• Older women and vaginal yeast infections
The antifungals--the “azoles” and
Coumadin
• Miconazole (Monistat)
• Fluconazole (Diflucan)
• Intraconazole
(Sporanox)
• Ketoconazole (Nizoral)
• Voriconazole (Vfend)
• Posaconazole (Noxafil)
• “You have a yeast
infection…”
Synthesis of clotting factors (the majority of
synthesizing is performed at night)
• Vitamin K dependent clotting factors are produced
by the liver
• II, VII, IX, X (highest in the a.m.)
• Make clotting factors at night? Release clotting
factors in the a.m.
• Combine the increased clotting factors in the
morning, with increased inflammatory mediators in
the morning, increased platelet aggregation due to
highest blood sugars (due to increased epinephrine
and cortisol to get you out of bed) and…you are a
heart attack waiting to happen!
Clotting factors
• Administration of vitamin K in a patient with
suspected liver failure
• If the PT fails to decrease after vitamin K
administration, acute liver failure is highly
suspect
• Warfarin (Coumadin) inhibits factor VII in 8-12
hours; takes 72 hours to inhibit all of the
others, so heparin is used until Coumadin
takes full effect
• Hemorrhage on warfarin? vitamin K is the
antidote
Wisconsin Alumni Research Fund
• Warfarin as rat poison
• Dwight David Eisenhower—first human
guinea pig
• Rats in Europe today
Lots and lots of drugs interact with
Coumadin
• The newest anti-coagulant is dabigatran
(Pradaxa) (approved for anti-coagulation in
patients with atrial fibrillation)
• No monitoring
• Few drug interactions
• No food interactions
• Too good to be true?
Aging and clotting factors
• Increased synthesis of fibrinogen and clotting
factors with aging
• Exception to the 1% rule (instead of
DECREASING the synthesis of clotting factors,
the liver increases them)
• Starting at age ?
• Who clots more? An 80 year old grandmother
or a 15 year old kid?
DIC and liver trauma
• Release of massive amounts of clotting factors with
liver trauma triggers disseminated intravascular
coagulation
• Utilization of all cl
• otting factors
• Triggers fibrinolytic system and the “splitting” of the
clots
• Fibrin Split Products or Fibrin Degradation Products
(D-Dimers) are potent anticoagulants
Causes of liver laceration
• Ruptured liver due to blunt abdominal trauma
• Steering wheel injury in car accident lacerated
liver
• Another cause: SUSPECT CHILD ABUSE if a
lacerated liver is accompanied by a ruptured
duodenum in a child that has NOT been in a
car accident
Production of Lipoproteins
• Another night shift job
• The liver enzyme HMG-Coenzyme A is
responsible for producing LDL cholesterol
• The “statin” sisters work in the liver to reduce
the production of LDL-cholesterol
• Best to give a statin drug before bedtime
(exception, Lipitor)
Who are the “statin sisters”?
• Lova (Mevacor), simva (Zocor), fluva
(Lescol), prava (Pravachol), atorva
(Lipitor), rosuva (Crestor),
pitavastatin (Livalo)
Can the statins be used in patients with
hepatitis?
• NOT at ALL in patients with active viral
hepatitis
• Can be used in healthy patients with normal
findings on LFTs who are carriers of HBV or
have stable compensated chronic HCV
• Not only are the statins safe and effective,
they may also improve liver chemistries and
decrease HCV replication
• (Ikeda; Lewis)
HDL production
• As far as cardioprotection is concerned, increasing
the HDL fraction is just as important as decreasing
the LDL fraction
• Drugs that increase HDLs include niacin (boost by
25%), rosuvastatin (more than other statins—12-14%
vs. ~6% for other statins), estrogen (endogenous and
exogenous) therapy
• Metformin (Glucophage) increases HDLs
• Pioglitazone (Actos) increases HDLs
• glucocorticoids, cyclosporine, tacrolimus
Another way to increase HDLs—ladies,
this is a tough one
• Decrease our carbohydrate intake
• Count your grams of carbs over 3 days
• Reduce by half (but not lower than 110 grams
per day)
• Boosts HDLs, decreases weight
So if HDLs are good for you, how can we
boost HDLs without drugs?
• Eat right— garlic (crush it, let it sit for 10
minutes, eat it raw or lightly sauteé it for less
than 6 minutes), beans, omega-3 fatty acids,
fiber, almonds (and other nuts), plant stanols
(Take Control, Benechol, Smart Balance,
Yoplait Yogurt, Minute Maid Heart Wise OJ)
• Decrease saturated and trans fats
The healthy liver inactivates hormones
produced by other organ systems
• Aldosterone
• Estrogen
Liver failure? Failure to inactivate of hormones
• Failure to inactivate aldosterone—higher circulating
aldosterone results in the retention of sodium and
H20 and ascites; (combine the excess aldosterone
with decreased albumin and increased portal
pressure and the ascites is significant)
• Treatment of ascites includes
aldactone(spironolactone) -- an aldosterone
antagonist; Lasix can also reduce sodium and water
via diuresis; sodium restriction
Estrogen
• Failure to inactivate estrogen—feminization in
the male—gynecomastia, testicular atrophy
(other causes of gynecomastia); spider
angiomas, palmar erythema; hypogonadism in
females, amenorrhea
Metabolism of alcohol (ETOH)
• Alcohol undergoes steroid biotransformation
in the liver to estradiol; in females this results
in decreased serum FSH and reduced
ovulation; in males it results in feminization
(gynecomastia)
• The liver doesn’t really differentiate from a
Budweiser or a Chardonnay or Gray Goose
vodka
Alcohol (ETHANOL)
• Boosts HDL production in the liver
• Increases endogenous tissue plasminogen
activator
• Anti-inflammatory
• Anti-oxidant
How much?
• 5 oz of wine of any color—This amount→
• Guys, you can have 2 glasses
Daily dose?
• How much of the hard stuff?
1-2 ounces for women
2-3 ounces for men
How about a daily brewski?
12 ounces for women
24 ounces for men
So, what’s my motto?
• Run a mile, drink a beer…
• Have a nice glass of wine with dinner
with my Mom…
• OR…
Women vs. men--alcoholism
• GAD (gastric alcohol dehydrogenase)—an enzyme
located in the stomach lining
• Reduced levels in women leads to a reduction in
metabolism
• More alcohol is absorbed into bloodstream quicker
without being metabolized to an inactive metabolite
• Hits the brain quicker (“cheap drunks”) and
• Hits the liver in higher concentrations -- earlier onset
of alcoholic hepatitis and cirrhosis by ~10 years
• 5-year survival rate for women with alcoholic
cirrhosis is 30% vs. men (70%)
Alcohol abuse
• Alcohol abuse—recurrent, harmful use of ETOH with
failure to fulfill work, school or home responsibilities
• Drinking and driving; recurrent legal problems,
continued drinking despite relationship problems
caused or worsened by drinking
• Problem drinking? More than 7 drinks per week for
women or more than 3 drinks/occasion; more than
14 drinks per week for men or more than 4
drinks/occasion
• Heaving drinking? 3-4 drinks per day for women,
more than 5-6 for men
The liver contains the primary enzyme system
for the metabolism of drugs
• CYP450 (cytochrome P 450) system inactivates the
majority of the 11,000 drugs on the market today
(plus OTC and other “alternative Rxs)
• This system is primarily located in the liver, but the
small intestine also has some of the same enzymes
that breakdown/inactivate drugs (referred to as
‘extra’ hepatic)
• The CYP450 system has numerous enzymes…named
CYP with a number, letter, and another number—
example: CYP3A4, CYP 2D6
CYP3A4
• The most abundant of all CYP enzymes
• Metabolizes ~60% of all drugs
• Located in the liver and in the small intestine
(extrahepatic)
• Initiates the drug metabolism in the small intestine
• Grapefruit can inhibit this enzyme in the small
intestine resulting in an increased bioavailability and
drug toxicity
Complex interactions with drugs and
the CYP enzymes
• The enzyme that metabolizes tamoxifen into a more POTENT
metabolite known as endoxifen
• The drugs, paroxetine (Paxil), fluoxetine (Prozac) and St. John’s
wort inhibit CYP2D6…what does this mean?
• It means that you can’t metabolize tamoxifen into endoxifen
as well, so the full benefits of tamoxifen are not realized in
breast cancer patients; can increase the risk of recurrence
• Choose escitalopram (Lexapro) or citalopram (Celexa) if an
antidepressant is necessary (both of these will also reduce hot
flashes in patients on tamoxifen)
Most of the enzymes inactive drugs,
however…
• A few drugs are metabolized to MORE active
metabolites
• Meperidine to normeperidine (Demerol)—retained
for longer periods of time
• Fluoxetine to norfluoxetine (Prozac)—half-life is 2 to
9 days
• Amitriptyline to nortriptyline (Elavil)—nortriptyline is
also a drug (Norpramin, Pamelor)
• Tamoxifen to endoxifen (100x more potent)
Smoking and the liver
• Smoking can accelerate the breakdown of
drugs in the liver by inducing the metabolism
of the drug
• Smoking can increase fibrinogen production in
the liver—increases clotting risk
• Smoking + estrogen can increase the clotting
risk even more (depending on age and dose of
estrogen)
The liver and acetaminophen
• Glutathione normally “detoxifies” a toxic
metabolite of acetaminophen (N-acetyl-pbenzoquinoneimine)
• Excess acetaminophen can deplete the stores
of glutathione and acetaminophen toxicity
occurs
• What factors can increase the risk of
acetaminophen toxicity?
Risk factors for acetaminophen toxicity
• Patients with liver disease
• Chronic alcohol abuse or sporadic binge
drinking with ingestion of therapeutic doses
• Starvation
• Drugs used with acetaminophen—
barbiturates, phenytoin, carbamazepine,
rifampin, INH, omeprazole, valproic acid
Acetaminophen toxicity—3250 mg/day is
ULN dose
• Most common cause of acute liver injury leading to
hepatic failure
1) suicide attempts
2) accidental overdoses
Acetaminophen overdose is the most frequent cause of
acute liver failure in the U.S. population, accounting
for 39% of cases (Ostapowicz)
• Minimum toxic single dose in healthy adults is
between 7.5 and 10 grams and ≥ 150 mg/kg in
children
• Individual variations --
Accidental overdoses
• In over 300 “itchy, sneezy, wheezy, snotty, achy,
breaky” over-the-counter products w/
acetaminophen —inadvertent overdoses (narrow
therapeutic index—toxic dose is not much higher
than therapeutic dose)
• Also in numerous prescription analgesics: Fioricet,
Lorcet, Percocet, Propacet, Roxicet, Ultracet (limit
“cets” to 325/mg per tab to reduce toxicity)
Theraflu for colds, Vicodin for pain, Excedrin for
headache or flu, Sinutab for allergies, Robitussin for
cough, Allerest for sleep…
Before you know it…
• The signs and symptoms of acute liver failure
are staring back at you in the mirror
Treatment
• Measure serum concentrations ≥ 4 hours after
ingestion; higher than 150 mcg/mL at 4 hours or 75
mcg/mL at 8 hours should be treated with Nacetylcysteine (Mucomyst {po}, Acetadote {IV})
• Mucomyst: Loading dose 140 mg/kg x1; Maint: 70
mg/kg q4 hours x 17 doses beginning immediately
after the loading dose
• (replenishes glutathione and detoxifies a highly
reactive metabolite of acetaminophen (NAPQI—Nacetyl-benzoquinoneimine)
Liver storage functions
• The liver stores 5,000-7000 mcg of B12; use only 1
mcg/day to maintain RBC production, CNS and PNS
myelin
• Takes 5-7 years to deplete B12 if you stopped eating
all B12 TODAY
• Foods that contain B12? Meat, meat and meat…no
fruits or green leafys
Who’s at risk for B12 deficiency?
• Vegetarians
• alcoholics
• previous gastric surgery such as partial gastrectomy,
bariatric surgery, malabsorption,
• autoimmune gastritis (pernicious anemia—
antibodies to intrinsic factor, can’t absorb B12))
• Over 55
• Drugs – PPIs, metformin (Glucophage)
What happens with a B12 deficiency?
• CNS changes—cognitive decline,
demyelination of certain spinal cord pathways
(#1 cause of nutritional dementia in the
elderly)
• PNS changes—peripheral neuropathy (one of
top 3 causes of PN in the elderly)
• Hematologic manifestations—megaloblastic
anemia (MCV greater than 120);
hypersegmented neutrophils
Treatment
• Replacing B12—the 4 S’s
• Injections (1000 mcg) for dementia and
neuropathy
• Oral/sublingual B12—1000 mcg/day
• Nasal B12—500 mcg/nostril twice a week
• Can you overdose on B12? NO
• The one dreaded side effect of excess B12
Liver storage functions
• Blood—backup from CHF; hepatomegaly
• Vitamin A and the liver—don’t overdose on Vitamin
A
• Iron
• Glycogen—stored glucose for acute needs and to
maintain blood sugar during fasting states—
nighttime for example
• Glycogenolysis—the breakdown of stored glycogen
for glucose needs—epinephrine, cortisol
• Predisone can do the same thing—increase the
blood sugar
Liver storage functions
• Metformin (Glucophage) works almost exclusively in
the liver to inhibit the catabolism of stored glycogen;
decreases blood sugar;
• Also decreases absorption of glucose in the GI tract,
too; more sugar to the bacteria located in the GI
tract = methane… ; nighttime dosing
• Metformin with Prednisone (inhibits glycogenolysis
caused by Prednisone)—prevents hyperglycemia
• **B12 deficiency with long-term metformin
Hemosiderosis vs. hemochromatosis
• Hemosiderosis is an acquired deposition of iron in some
tissues including the liver
• Causes—parenteral iron overload, transfusions, long-term
hemodialysis, sickle cell disease, leukemias, iron-dextran
injections, thalaseemia, sideroblastic anemia, increased oral
intake of iron, chronic liver disease, chronic alcoholic liver
disease
• Bantu siderosis—ingesting large quantities of alcoholic
beverages fermented in iron utensils in Africa
Hemochromatosis
• Hemochromatosis is homozygous-recessive inherited
disorder--1/200 – 1/300 in U.S. (HFE gene
chromosome #6)
• M/F(6:1); and earlier onset; why? physiological iron
loss (menstruation, pregnancy) delays iron
accumulation in women
• Total body iron pool ranges from 2 to 6 gr in normal
adults, 98% in hepatocytes
• In hematochromatosis the total iron accumulation
may exceed 50 gm; disease manifests after 20 gm of
stored iron
Hemochromatosis
• Lifelong accumulation, but the injury caused by
excessive iron is slow; hence symptoms usually
appear in the fifth to sixth decades of life
• Fully developed cases—micronodular cirrhosis
• Hepatocellular carcinoma is 200 x greater than
general population (Tx for iron overload does NOT
reduce risk)
• Diabetes in 75% to 80% of the cases
• Skin pigmentation in 75%-80% of cases
Hemochromatosis
• Serum ferritin and serum iron
• Rx: phlebotomy
• Rx: decreasing foods that contain iron won’t
make a big difference, but choose a dietary
multivitamin without iron (Centrum Silver or
Alphabet II Formula 644) (AARP)
• Drink black tea to decrease the absorption of
iron
Liver function tests
• Cellular integrity – AST (aspartate
transaminase), ALT (alanine transaminase)
• Bile formation and flow (bilirubin, GGT,
alkaline phosphatase)
• Protein synthesis (albumin, prothrombin time)
Hepatocellular enzymes
• AST is NON-specific…in other words, it is found in
many tissues and therefore not specific as a liver
enzyme
• ALT is found almost exclusively in liver cells and is
therefore highly specific for the liver
• If a “healthy” person demonstrates an elevated ALT, a
thorough history is warranted with special questions
such as hepatitis exposure, hepatotoxin exposure,
and drug effects
Hepatocellular enzymes
• If enzymes are not terribly elevated (less than
2x normal—(some hepatologists say up to 3x
normal), have the patient stop all drugs that
are NOT necessary and recheck the enzyme
levels in 2 weeks before doing a multi-million
dollar work-up
Hepatotoxin exposure and drug effects
• Chemicals (cleaning chemicals such as CCl4),
vinyl chloride
• Occupational hazards—dry cleaners, painters,
chemists
• Vitamin A toxicity
• Hundreds, if not thousands, of drugs can
elevate liver enzymes and cause druginduced-liver-injury
Drug induced liver injury (DILI)
• 14-40 per 100,000 patients; genetic variability
• Predictable vs. idiosyncratic
• Children are more prone to DILI w/ salicylates and valproic
acid
• Obesity increases the risk of liver injury due to halothane and
methotrexate (Rheumatrex dose pack, Trexall)
• Acetaminophen-induced liver injury is more likely in persons
who are fasting or malnourished, as well as those who
chronically abuse ETOH (more than 3 adult beverages per day)
Drug-induced liver injury—who’s at
risk?
• Women are more likely to experience DILI caused by
diclofenac (Voltaren), isoniazid, or nitrofurantoin,
while azathioprine (Azasan, Imuran) is a more likely
cause in men
• The incidence of liver injury varies among the NSAIDs
and appears to be the most common with diclofenac
(1-5 cases per 100,000) and sulindac (Clinoril)
• Oral contraceptives have also been implicated in
various types of drug-induced liver injury
What should be done?
• Discontinue the drug if all non-drug causes of
liver injury have been investigated and ruled
out
• What are the nondrug causes? Hepatitis A-E,
biliary disease, biliary obstruction, alcohol
abuse, autoimmune hepatitis or cholangitis,
bacterial infections that can mimic acute
hepatitis (Camplobacter, Salmonella, and
Listeria) and Wilson’s disease.
• But what if it’s the only drug that works for
that specific condition?
• Continue treatment with the drug if the ALT is
less than 5x the ULN, as long as the patient
remains asymptomatic and the serum
bilirubin remains within normal limits
Positive criteria that implicates a drug
• Drug levels elevated
• Allergic manifestations (peripheral eosinophilia,
rash, fever)—occur in about 23% of the patients
• Latency period of 1 month or less
• Rapid development of symptoms upon
rechallenge (not that you would do this to prove
your point…it would have to be an inadvertent
challenge)
• Liver biopsy—with eosinophilic infiltration,
granulomas
Drug-induced liver failure (acetaminophen
overdoses excluded)
• 70% female
• Median duration of drug exposure prior to
hospitalization was 2 months
• INH alone or in combination w/ other TB drugs
• Sulfa antibiotics
• Nitrofurantoin
• Phenytoin
• NSAIDS, statins, PTU, complementary and alternative
meds (KAVA) or illicit drugs)
Outcomes of drug-induced acute liver
failure
•
•
•
•
27% recovered spontaneously
42% had a liver transplant
13% died while awaiting transplant
18% not candidates for transplant because of
various contraindications and subsequently
died
(Reuben A et a. Drug-induced acute liver failure. Results of a U.S.
multicenter, prospective study. Hepatology 2010 December;
52:2065)
AST/ALT ratio
• AST 8-20 U/L (0.43-1.28 μKat/L—adult males;
11-26 U/L (0.19-0.44 μKat/L—adult females)
• ALT 10-40 U/L (0.17-0.68 μKat/L—adult males;
7-35 U/L (0.12-0.60)
• The normal AST/ALT ratio should be 1
If the AST/ALT ratio is greater than 1…
• Consider ETOH…
• AST is especially sensitive to alcohol
• If alcohol damages liver cells, the AST will
increase higher than the ALT
• Ratio in alcohol- induced hepatitis is usually
3:1 to 8:1*
*It is rare for the AST level to be more than 8
times the normal value in patients with
alcohol abuse
AST/ALT ratio of less than 1
• If less than 1 consider other causes of fatty
liver disease, viruses, autoimmune hepatitis,
hemochromatosis, Wilson’s disease, alpha-1
antitrypsin deficiency
• Always check the TSH—may see mild increase
in liver enzymes with hypothyroidism
• Eating lots of fast foods can also increase liver
enzymes
Extremely high levels of hepatocellular
enzymes
• Marked elevation of ALT and AST is typical of
severe acute viral hepatitis, toxic or drug-induced
hepatic necrosis, and shock or ischemia to the
liver
• The finding of extremely high levels (greater than
2000 to 3000 U/L) should always raise concern
for acetaminophen OD, use of excessive
therapeutic doses of acetaminophen by an
alcoholic patient, or shock and/or ischemia to the
liver
Alkaline Phosphatase (ALP, or AP)
• 35-105 U/L
• Think Biliary and Bone
• Any disturbance in the synthesis, secretion, or excretion of
bile leads to the accumulation of bile acids in the liver
increasing the synthesis of ALP
• Sensitive indicator of cholestasis—primary biliary cirrhosis,
primary sclerosing cholangitis
• Infiltrative processes such as liver metastasis
Bilirubin—direct (conjugated) and indirect
(unconjugated)
• Does bilirubin have any physiologic function?
• Waste product—excreted in urine (yellow) and
in stool (brown)
• The liver conjugates bilirubin
• Total bilirubin is 0.3-1.3 mg/dL
• Indirect = 1.0 mg/dL
• Direct = .3 mg/dL
Bilirubin
• RBC breakdown by splenic and liver
macrophages
• Bilirubin from RBC breakdown is referred to as
unconjugated, fat-soluble
• Takes 2 steps to find it in the lab, so it’s called
“IN-direct”
Bilirubin
• As it arrives at the liver, it is taken up by the liver cells and is
conjugated; this type only takes “one step” in the lab to
measure it, thus “DIRECT”
• It is now ready for secretion into the bile ducts and on to the
GI tract for excretion
• A small amount is sent to the kidneys
• A tiny amount is sent to the blood via the lymphatics (that’s
why the percentage of direct bilirubin is so low)
• Direct bilirubin = 0.3 mg vs indirect = 1 mg
Jaundice—becomes evident when the bilirubin
levels rise above 2.0-2.5
• Where do you turn yellow first?
• Two types of jaundice
• Hemolytic (increased breakdown of RBCs)—
greater than 80% of total bilirubin is indirect
• Obstructive (back-up in the biliary system)—
more than 50% of total bilirubin is direct
What does abdominal fat have to do with liver
disease…
• Abdominal fat = NEW ORGAN!
• Inflammatory mediators trigger hsCRP (inflammatory
protein) production by the liver
• Atherosclerosis and cardiovascular disease
• Hypertension
• Diabetes (increased incidence in teenagers)
• Colon cancer, Breast cancer, Uterine cancer
• Erectile dysfunction in men
• NAFLD and NASH (Non Alcoholic Steato-Hepatitis) and
chronic liver disease
NAFLD and NASH
• Nonalcoholic fatty liver disease (NAFLD) is a group of
conditions that have in common the presence of hepatic
steatosis (fatty liver) in the absence of heavy alcohol
consumption,(less than 20 gm/week);
• It has become the most common cause of chronic liver
disease in U.S and probably affects more than 30% of the
population
• Includes simple hepatic steatosis, steatosis with minor nonspecific inflammation, and non-alcoholis steatosis (NASH)
• The first two, simple steatosis and steatosis with minor nonspecific inflammation are stable conditions without significant
clinical problems
NAFLD and obesity
• Estimated that ~70% of obese individuals have some
form of NAFLD
• Strongly associated w/ obesity and the metabolic
syndrome
• It is the most common form of “cryptogenic”
cirrhosis, i.e. cirrhosis of “unknown” origin
• NAFLD contributes to the progression of other liver
diseases such as HCV infection and hepatocellular
carcinoma
NASH
• NASH (nonalcoholic steatohepatitis) is defined
as steatosis + significant liver inflammation is
characterized by presence of neutrophil (segs)
infiltrates leading to fibrosis and ~10-20%
progress to cirrhosis
• Elevated liver enzymes in 90% of the patients;
AST/ALT is less than 1, in contrast to alcoholic
steatohepatitis in which the ratio is above 2.02.5
• Usually asymptomatic or nonspecific sx such
as fatigue and RUQ discomfort
Causes of non-alcoholic fatty liver
disease
• Obesity
• Diabetes
• The above two have traditionally been the “only”
causes of NAFLD, but there are more…
• Males greater than females
• Drugs—prednisone, MTX, synthetic estrogens,
amiodarone (Cordarone, Pacerone), tamoxifen,
nifedipine, and diltiazem
• Heavy exposure to organic solvents
• Long-term IV feeding
• Rare genetic diseases
Treatment of NASH
• Can anything be done to reduce NASH?
• Drugs—pioglitazone (Actos) 30 mg/day with
34% improvement in the 4 major histological
features of NASH after 96 weeks
• Vit. E 800 IU/ day with 43% improvement
• How about weight loss? Yes, patients who lose
7% of their TBQ achieve significant histological
improvement (Promrat)
Hepatitis A—25% of hepatitis cases worldwide;
30,000 – 50,000 new cases in US/year
• Self limited disease, incubation period of 3-6
weeks;
• risk factors—endemic in countries with
substandard sanitation--fecal-oral transmission
• Infected workers in the food industry--Salad bars
can be particularly dangerous; oysters,mussels,
clams
The scallions at Chi-Chi’s in Pittsburgh (October
2003)
• Vaccine available
Hepatitis B—2 billion worldwide infected; 400
million with chronic infection
• 46,00 new infections in US per year; 5000 acute
symptomatic infections per year; ~1.2 million
Americans with hepatitis B
• Vertical transmission—90% of cases
• Day care—minor cuts
• Sexually transmitted
• IV drug use
• Very low risk of blood transfusion related --9 cases in
3.7 million donations (N Enlg J Med 2011 Jan 20;
364:236
Hepatitis B
• 12 years to make the vaccine
• Vaccine has been around for 40 years
• 1st “anti-cancer” vaccine; significant reduction in
chronic HBV infections which in turn significantly
reduced the # of hepatocellular carcinomas
• Virus—HBsAg, HBcAg, and HBeAg
• Treatment—interferon alfa and antiviral drugs
(adefovir/Hepsera; entacavir, lamivudine)
Hepatitis B
• Woodchucks, ducks, and squirrels with chronic
hepatitis B and hepatocellular carcinoma
Hepatitis B
• Prolonged incubation period—4 to 26 weeks
• Acute HBV in adults in US; 70% mild or no symptoms,
and non-icteric; 30% with jaundice—anorexia, fever,
URQ pain
• Hepatitis B antigens—HBsAg (surface); HBcAg (core);
HBeAg (important indicator of continued viral
replication, infectivity, and probably progression to
chronicity)
• Prevention via vaccination (40 years ago)
• Also prevents hepatocellular carcinoma
Hepatitis D (dependent on HBV for its
life-cycle)
How do you get D?
• Acute co-infection following exposure to serum
containing both HBV and HDV; the HBV must become
established first to provide the HBsAg necessary for
the development of the complete HDV virions
• Superinfection when a chronic carrier of HBV is
exposed to a new inoculum of HDV
(this may present as severe acute hepatitis and
progress to chronic w/ cirrhosis)
Hepatitis C--1989
• 4.1 million cases in U.S.
• Worldwide 170 million cases
• Most common chronic blood-borne infection and accounts for
almost half of all U.S. individuals with chronic liver disease
• New cases peaked in mid-1980s—over 230,000 new cases per
year; 19,000 new cases per year today
• Why? Decreased blood transfusions
• Progression to chronic disease occurs in the majority of HCVinfected individuals (85%) because the immune system is
unable to “clear” it
Hepatitis C virus
• Cirrhosis eventually occurs (5 to 20 years after acute
infection) in 20-30% of individuals with chronic HCV
infections
• Where’s the HCV vaccine? The virus has developed
multiple strategies to evade endogenous antiviral
immunity; also has genomic instability and antigenic
variability—a fancy way of saying it’s a moving target
and very difficult to make a vaccine against it
Hepatitis C virus—high risk groups
• IV drug user (even 1 time experimental
drug use)(54% of total cases)
• Needle stick injury (10%)
• Persons with conditions associated with
high prevalence of HCV—HIV (HCV is more
aggressive in the context of HIV coinfection)(25% of people living with HIV are
co-infected with hepatitis C)
Hepatitis C risk factors
• Blood transfusions prior to July1992 —or organ
transplant recipientss (the risk of blood transfusion
HCV in the U.S. is close to zero; risk of acquiring HCV
by needle stick is about 6x higher than that for HIV
(1.8 vs. 0.3%)
• Persons who have ever received hemodialysis
• Hemophiliacs who received clotting factor
concentrates prior to 1987
• Children born to HCV-infected moms (screen at age 1
or older)(6% transmission rate)
Hepatitis C high risk factors
• HCW after a mucosal exposure to HCV-positive blood
(1.5% of total cases)
• Current sexual partners of HCV-infected persons
(prevalence is low, but a negative test provides
reassurance)
• Persons with unexplained ALT elevations,
documented to be elevated for at least 6 months
(the 3 most common diagnoses for mildly elevated
ALT levels are chronic hepatitis C, alcoholic liver
disease, and nonalcoholic fatty liver disease)
Hepatitis C virus—secondary risk factors—the need
for screening is uncertain
• Sexual transmission with multiple partners—what does
multiple mean?
• Intranasal cocaine use
• Tattoos (prison applied?)
• Piercings
• Receipt of injection in a developing world
• Endoscopy clinics in Nevada (reuse of needles and syringes);
other outbreaks in U.S. due to reuse of medical devices
without proper sterilization)
•
(Parkinson E. What now? Responding to relapse in Hepatitis C. Advance for NPs
2007 (December);49-51)
Guys tattoos…
• Out there…
• Everywhere…
• Showin’ them off
• Gals are a bit more subtle…
• No vaccine available yet; drugs to treat
Las Vegas, NV (March 2008)
• Nevada health officials closed four private clinics after they
traced a hepatitis C outbreak to one of the facilities.
Authorities said that at least 40,000 patients of the Endoscopy
Center of Southern Nevada have been exposed to Hep C since
2004, when the clinic’s owners first instructed staff to reuse
hypodermic needles and medicine vials to save money. The
needles and vials weren’t adequately sterilized between uses,
leading to a hepatitis C outbreak that has hospitalized at least
6 people. The three other clinics owned by the doctors were
also closed as a precaution.
Treatment of chronic hepatitis C
• PEG Interferon alfa (q week) and Ribavirin (Rebetrol,
Virazole) qd
• Factors that influence response rate: baseline viral load,
HCV genotype, degree of fibrosis, race or ethnicity
• Anemia, depression, flu-like sx, alopecia, diarrhea
• Genotype 1b is the most resistant to therapy (48 weeks
Rx); genotypes 2 and 3 are most responsive to therapy
(24 weeks Rx); other types (48 weeks)
• Newer drugs on horizon (taribavirin—protease inhibitors)
Cure?
• Defined as a sustained viral response (SVR) of greater than 6
months
• Genotype 1? Less than 50% after 1year (unfortunately 75% of
the people in U.S. with HCV have genotype 1
• Genotypes 2 & 3? SVR of 70-80%after 24 weeks
• Treatment success rates are lower in HCV/HIV patients
• Numbers look better for all patients with the new protease
inhibitors being studied—telaprevir and boceprevir (added to
current therapies)
Autoimmune hepatitis
• Female predominance (78%)—especially in
young, and perimenopausal women
• Can occur concurrently with SLE, celiac
disease, thyroiditis, RA, UC, Sjogren syndrome
• Autoimmune genetic component
• Chronic, progressive of unknown etiology
Primary biliary cirrhosis (PBC)
• Autoimmune cholestatic liver disease in which the
epithelial cells lining the bile ducts are damaged by
the immune system
• Females: 30-65 years; 10/1 F/M
• ALP 2-10 x normal; anti-mitochondrial ab (95%)
• Usually have PBC x 20 years before dx; common in
siblings and 1st degree relatives
• Progressive injury assoc. w/ other autoimmune
diseases
• Sx: fatigue and pruritis
Treatment of pruritis
•
•
•
•
•
Bile-acid binding resin such as cholestyramine
Antihistamines
Rifampin 150 mg BID to TID PRN
2nd line—phenobarb
3rd line--Naloxone HCl for pruritis refractory to
other therapies
• Ursodiol (13-15 mg/kg/day) may help
Autoimmune hepatitis
• The injurious immune reaction may be triggered by
viral infections, drugs (minocycline, atorvastatin,
simvastatin, methyldopa, interferons, and herbal
products such as black cohosh
• Type 1 characterized by the presence of ANA
(antinuclear antibodies), SMA (anti-smooth muscle
antibodies), and AAA (anti-actin antibodies—most
common type and associated with HLA-DR3
Keep your liver healthy! Avoid liver
toxic drugs (If possible)
•
•
•
•
•
•
•
•
•
•
Acetaminophen
Estrogen (causes cholestasis in some women)
Anabolic steroids
Statins (not so bad on liver, more side effects w/ muscle aches
and pains)
NSAIDS
Amiodarone
Rheumatrex
Valproic acid (Depakote)
Copious amounts of alcohol
Various herbs that are liver toxic
Keep your liver healthy!
• Hydrate
• Herbs such as milk thistle to stimulate flow
• Drink coffee!! (tea doesn’t help) coffee improves
liver outcomes in HCV-infected pts w/ fibrosis
(Freedman ND)
Thank you.
• “After the White House, what is there to do
but drink? –Franklin Pierce, President of the
U.S., shortly before dying of cirrhosis of the
liver.
Barb Bancroft, RN, MSN, PNP
• [email protected]
• www.barbbancroft.com
Bibliography
• Argo CK et al. Systematic review of risk factors for fibrosis progression in
non-alcoholic steatohepatitis. J Hepatol 2009 Aug;51:371.
• Bakerman S. ABCs of Interpretive Laboratory Data 2002; Scottsdale, AZ
• Benhamon Y, et al. A phase III study of the safety and efficacy of
viramidine (taribavirin) versus ribavirin in treatment naïve patients with
chronic hepatitis C: ViSERI results. Hepatology 2009 Sep; 50:717.
• Bhatia AS, Mihas AA. Cholestatic liver disease. Postgrad Med 2006 (JuneJuly);119(1):67.
• Charles EC, et al. Evaluation of cases of severe statin-related transaminitis
with a large health maintenance organization. www.mdconsult.com
(accessed 4/30/07)
Bibliography
• Flora KD, Keeffe EB. Significance of mildly elevated liver tests
on screening biochemistry profiles. J Insur Med 1990:22:206210.
• Freedman ND et al. Coffee intake is associated with lower
rates of liver disease progression in chronic hepatitis C.
Hepatology 2009 Nov;50:1360.
• Ikeda M, et al. Different anti-HCV profiles of statins and their
potential for combination therapy with interferon. Hepatology
2006; 44:117-125.
• Learned J. Worth the wait: New, more effective therapies for
hepatitis C are on the way. Positively Aware. January/February
2011
Bibliography
• Lewis JH, et al. Efficacy and safety of high-dose pravastatin in
hypercholesterolemic patients with well compensated liver
disease. Hepatology 2007;46:1453-63.
• Ostapowicz G, et al. Results of a prospective study of acute
liver failure at 17 tertiary care centers in the US. Ann Intern
Med. 2002;137(12):947-954.
• Promrat K et al. Randomized controlled trial testing the effects
of weight loss on nonalcoholic steatohepatitis. Hepatology
2010 Jan;51:121.
• Reuben A et al. Drug-induced acute liver failure: Results of a
U.S. multicenter prospective study. Hepatology 2010
Dec;52:2065.
Bibliography
• Rordan SM, Williams R. Gut flora and hepatic
encephalopathy in patients with cirrhosis. N Engl J
Med 2010; 362 (12):1140-1141.
• The Medical Letter. Acetaminophen Safety—déjà vu.
Volume 51 (Issue 1316), July 13, 2009.
• Treatment Guidelines from the Medical Letter.
Treatment of Overdose. Volume 4 (Issue 49),
September 2006)
An interesting note on the embryology of the
liver and pancreas
• Human liver cells have the capacity to transform into
cells very similar to human beta cells of the pancreas
via reprogramming
• The dual ability arises from the role Pdx-1 gene plays
in the embryo where the liver and pancreatic tissue
develop from the same family of cells
• Pdx-1has a dual function in that deactivates liver
function genes and activates unexpressed pancreatic
beta cell genes
Rx for Type 1 diabetes from liver
cells?
• The technique works best in liver cells that are in the
process of regeneration; during cell division
chromosomes are exposed, making it easier for Pdx1 to alter their gene expression
(Ferber, Sarah. Sheba Medical Center, Tel Hashomer Israel. The
International Society of Stem Cell Research, July 2009,
Barcelona Spain)
Too much booze? Baaaaaaaad for
the liver…
• “If alcohol were to be invented today, and subjected
to the current safety-of-use assessments, it would
fail badly.”
• Ethanol, the active ingredient, is toxic itself—which is
why it is used to protect food from microbial
infections and to sterilize skin. An amount 3 x higher
than a common intoxicating dose can kill a naïve
drinker.
(Nutt D. Synthetic spirits: Can we use science to reduce the
harms of alcohol? The Scientist, January 2011)
Statin doses for LDL cholesterol
lowering
• Usually choose a statin drug that will reduce the LDL by 40 to
50%
• Pitavastatin (Livalo) 1-4 mg – 38 to 45% reduction
• Atorvastatin (Lipitor) 10 to 10 mg does the same as does
rosuvastatin (Crestor) 5 mg;
• Use Crestor and Lipitor for greater LDL-lowering
• Use Crestor and pravastatin (Pravachol) for decreased drug
interactions