LIVER LOGIC
Barb Bancroft, RN, MSN, PNP
BBancr9271@aol.com
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
• 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 (within 30 days)
• 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…
Location and blood supply
• Major portion of the liver is located in the right
upper quadrant, beneath the diaphragm, and
anterior to the gallbladder
• 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 (increased
bioavailability of certain drugs)
What drugs? A few examples…
• Propranolol (Inderal)—bradycardia
• Morphine --bradypnea
• And,
the “Pfizer riser”-- Viagra (sildenafil)—
• Toxicity???
• “If you have had an erection for more than 4
hours…”
• Priaprism (named appropriately after the Latin
god Priapus, best known for his large,
permanent erection, was the fertility god and
the “protector of the male genitalia”)
• Blue vision, commercial airline pilots
• GERD
Let’s get back to liver anatomy—the liver is
located beneath the diaphragm
• How much embryology did you get in nursing
school?
• Sperm meets the egg
The diaphragm and it’s origins…
• Diaphragm originates in the neck, supplied by
cervical cord segment C3
• Gill slits
• Arm buds, leg buds, and a tail
Referred pain
• C3 supplies the soma where the neck meets
the shoulder
• C3 supplies the visceral diaphragm (via the
phrenic nerve)
• The somatic (skin) and visceral (diaphragm)
sensory afferents meet at the same cervical
cord segment
• The brain interprets the pain or irritation as
the most “likely” area—which would be the
shoulder
Causes of referred pain to the
shoulder—GI causes
• Enlarged liver? inflamed liver? (right shoulder); liver
laceration; liver biopsy
• Enlarged or ruptured spleen? (Kehr’s sign) (left
shoulder)
• Enlarged, inflamed gall bladder? Right shoulder)
Physical assessment of the patient
with liver disease
• Evidence-based physical assessment findings
predicting hepatocellular disease in patients
with jaundice (McGee, 2012)
• LR is the likelihood ratio – higher the number
the more likely the finding relates to the
specific disease (baseline is 1)
Findings predicting hepatocellular disease in
patients with jaundice
• Dilated abdominal veins (LR 17.5) (secondary to
portal hypertension)
• Palmar erythema (LR 9.8)*
• Spider angiomas (LR 4.7)*
• *both of these findings are due to the inability of the
liver to metabolize estrogen—higher circulating
estrogen levels result in palmar erythema and spider
angiomas
Findings predicting hepatocellular disease in
patients with jaundice--ascites
• 80% of ascites is caused by decompensated
chronic hepatocellular disease
• Ascites (LR 4.4)—why is this LR so low? Because
there are many other causes of ascites
(peritoneal carcinomatosis is the #1 cause
unrelated to cirrhosis – ovarian cancer)
• an ultrasound can pick up as little as 100 ml of
fluid—ultrasound also documents parenchymal
liver disease, splenomegaly, and an enlarged
portal vein
Determining the causes of ascites via
paracentesis
• SAAG ratio—Serum Ascites-Albumin Gradient
• SAAG=albuminserum / albuminascites
• ratio greater than 1.1 g/dL is 97% predictive of
portal hypertension (PH) as the cause of ascites—
cirrhosis is the most common cause of PH;
• SAAG less than 1.1 g/dL is normal portal pressure
—peritoneal carcinomatosis (ovarian cancer),
Chronic Heart Failure (CHF), nephrotic syndrome,
infection (TB, fungal, CMV), pancreatic ascites
Palpation of liver edge
• 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
Cirrhosis
• Liver biopsy specimens represent 1/50,000 of
the liver.
• They can lead to either an underestimation or
an overestimation of the degree of hepatic
fibrosis.
Causes of cirrhosis of the liver
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Hepatitis C
Chronic alcoholism
Hepatitis B
Primary biliary cirrhosis; primary sclerosing cholangitis
NASH (non-alcoholic steatohepatitis)
Hemochromatosis—hereditary iron storage disease
Wilson’s disease
Parasitic flatworms (schistosomiasis)—not common in US 
Autoimmune hepatitis
Drug-induced cirrhosis—methotrexate, amiodarone
Sarcoidosis
Polycystic liver disease
Causes of acute liver failure
(fulminant)
• A: acetaminophen, autoimmune hepatitis, amanita
mushroom toxin
• B: hepatitis B
• C: cryptogenic (clueless)
• D: drugs (acetaminophen, isoniazid, disulfiram)
• E: Esoterica (Wilson disease, Budd-Chiari – occlusion of the
hepatic veins that drain the liver—1) thrombosis (PV,
pregnancy, postpartum, COC, lupus, herbal products—
Comfrey, Germander, Chaparral, heliotrope—sunflower
seeds), 2) compression of hepatic vein via tumor)
• F: Fatty infiltration (Reye syndrome, acute fatty liver disease
of pregnancy)
Acute liver failure
• DEFINITION: Acute hepatitis complicated by
encephalopathy occurring within 8 weeks of disease onset
in the absence of preexisting liver disease.
• Patients typically present with progressive lethargy and
jaundice over several days. Most common causes in North
America are: acetaminophen )(~46%),
indeterminate/cryptogenic (15%), drug-induced (12%),
hepatitis B (7%), hepatitis A (3%)
• RX: liver transplant—can progress from mild
encephalopathy to coma in hours; without transplantation
most patients with ALF will die; most common causes of
death are cerebral edema and infection
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
connected to 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 of the portal vein,
narrowing of the portal vein, massive splenomegaly
with increased portal blood flow
• Posthepatic—severe right-sided heart failure
(pulmonary arterial hypertension), constrictive
pericarditis, hepatic vein outflow obstruction
• *Intrahepatic—cirrhosis (accounts for most cases of
portal hypertension)
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? (3 reasons)
1. Increased (hydrostatic) pressure in the portal
system pushes fluid into the abdominal cavity
2. Low serum albumin due to decreased
production from liver failure(decreased
osmotic pressure)
3. Increased circulating hormone, aldosterone;
non-functioning liver is unable to metabolize
it—excess aldosterone results in excess
sodium and water retention
Portal hypertension and 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
Prevention and treatment of ruptured
esophageal varices—upper GI bleed
• Reduce portal pressure with beta blockers
(“olols”, “alols”)—propranolol (Inderal),
nadolol (Corgard), carvedilol (Coreg)
• Constrict splanchnic arteries supplying the
portal system during an acute bleed with
somatostatin (Octreotide)
Prevention and treatment of ruptured
esophageal varices—upper GI bleed
• Emergency endoscopy with rubber band
ligation/clipping is the preferred method;
sclerosing agents (alcohol, ethanolamine, etc can
be injected into the bleeding sites in some cases);
less rebleeding with banding, fewer
complications, decreased mortality with banding
• TIPS (transjugular intrahepatic portosystemic
shunt)—shunt from the portal vein to the hepatic
vein, bypassing liver) 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;
• 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,
especially urease-containing species, such as klebsiella
and proteus species, are an important source of
ammonia in humans; the accumulation of ammonia
results from impaired hepatic clearance due to
hepatocellular failure and portosystemic shunting.
Neurological signs of hepatic
encephalopathy
• 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
Overt hepatic encephalopathy
• Marked confusion, stupor, coma
• 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
• Rifaximin (Xifaxan)—550 mg tablet to prevent
hepatic encephalopathy (HE)— kills the bacteria in
the gut that produce ammonia and other toxins
• Adding rifaximin to lactulose* (an osmotic laxative—
20 to 40 grams daily) reduces the risk of recurrent
hepatic encephalopathy and hospitalization by 50%
• *side effects—increased gas, abdominal distention,
diarrhea
Probiotics for Cirrhosis
• The probiotic, VSL#3, taken daily x 6 months,
significantly improves liver function and reduces the
risk of hospitalization in patients with cirrhosis.
• Also reduces the risk of hepatic encephalopathy
• 19.7 percent of patients treated with the probiotic
were hospitalized vs. 42.2% in the control group; only
24.2 percent were hospitalized for complications of
cirrhosis vs. 45.3 percent of controls
• No negative side effects
• Clinical Gastroenterology and Hepatology , December
2104
Model for End-Stage Liver Disease
• Scoring system for assessing the severity
of chronic liver disease;
• Used by the United Network for Organ Sharing
(UNOS) and Eurotransplant for prioritizing
allocation of liver transplants instead of the
older Child-Pugh Score
Model for End-Stage Liver Disease
• Based on the risk or probability of death
within 3 months if the patient does not
receive a transplant.
• calculated based only on laboratory data using
3 lab tests:
• creatinine, bilirubin, and the INR.
• MELD score ranges from 6 to 40.
Model for End-Stage Liver Disease
• In interpreting the MELD Score in hospitalized
patients, the 3 month mortality is:
• Score of ≥40— 71.3% mortality
30–39 — 52.6% mortality
20–29 — 19.6% mortality
10–19 — 6.0% mortality
<9 — 1.9% mortality
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?
• 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 emulsify the fats
• 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)
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
• Warfarin is highly protein-bound, but also
“loosely” bound; 97% bound, 3% free
• INR and Coumadin—standard is to maintain
the INR between 2 and 3 for most indications
• Stronger binding drugs “knock” warfarin off
its albumin binding sites—increasing the
“free” drug and increasing drug toxicity
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—
Monistat and the INR
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!
• How to prevent a heart attack??
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 (for 3 days) until Coumadin
takes full effect
• Hemorrhage on warfarin? vitamin K is the
antidote
• K Centra—4-factor prothrombin complex
concentrate to treat hemorrhage from warfarin
DIC and liver laceration
• The release of massive amounts of clotting factors
with liver trauma triggers disseminated intravascular
coagulation
• Utilization of all clotting factors
• Triggers fibrinolytic system and the “splitting” of the
clots
• D-Dimers (old names:Fibrin Split Products or Fibrin
Degradation Products) are potent anticoagulants
Causes of liver laceration
• Ruptured liver due to blunt abdominal trauma
• Steering wheel injury in car accident w/
lacerated liver
Production of Lipoproteins
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Lipoproteins—HDL, LDL, triglycerides (TGs)
Clinically, the most important is LDL
Another night shift job for the liver
The liver enzyme HMG-Coenzyme A reductase
is responsible for producing LDL cholesterol
• The “statins” work in the liver to inhibit HMGcoenzyme A reductase and reduce the
production of LDL-cholesterol; also reduce the
production of triglycerides
Who are the “statin sisters”?
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Lova (Mevacor),
fluva (Lescol),
prava (Pravachol),
simva (Zocor),
atorva (Lipitor),
rosuva (Crestor),
Pitava (Livalo)
Best time to give a statin drug is in the evening
(exceptions Lipitor/atorvastatin)(Crestor/rosuvastatin can also be given
any time due to long half-lives)
The healthy liver inactivates hormones
produced by other organs
• Aldosterone produced by the adrenal gland
• Estrogen produced by the ovaries, testes, fat tissue
Liver failure? Failure to inactivate of hormones
• Failure to inactivate aldosterone—higher circulating
aldosterone results in the retention of sodium and
H20 and ascites; (as mentioned earlier, combining
excess aldosterone with decreased albumin and
increased portal pressure and the ascites is
significant)
Liver failure? Failure to inactivate of hormones
• Treatment of ascites includes:
…aldactone(spironolactone)(100 mg/day) -- an
aldosterone antagonist (increases water loss more
than sodium loss, decreases K+ secretion—may
cause hyperkalemia);
…Lasix (40 mg/day) can also reduce sodium and
water via diuresis (watch out for low K+);
…sodium restriction
Metabolism of alcohol (ETOH)
• Alcohol undergoes steroid
biotransformation in the liver to
estradiol;
• The liver doesn’t really differentiate from
a Budweiser or a Chardonnay or Gray
Goose vodka
Estrogen
• Failure to inactivate estrogen—feminization in
the male—gynecomastia, testicular atrophy;
hypogonadism in females, amenorrhea
• Other signs of estrogen excess: spider
angiomas, palmar erythema;
How much alcohol over the years does
it take to develop cirrhosis of the liver?
• Clinically evident alcoholic liver disease is
unlikely until the individual has imbibed
excessively for at least 6-10 years
• A conservative threshold amount for this level
of disease in men is 70-80 grams of alcohol
per day (about 6 ounces of 86-proof* liquor, a
six-pack of beer, or a 750 ml bottle of wine)
• For women? 35-40 grams daily
Why less in women?
• GAD (gastric alcohol dehydrogenase)—an enzyme
located in the stomach lining that metabolizes ETOH
• 30% less in women leads to a reduction in
metabolism
• More alcohol is absorbed into bloodstream quicker
without being metabolized to an inactive metabolite
• Wine is first choice in women (50%), spirits (24%),
beer (21%)
• 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%)
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
The liver and acetaminophen
• Acetaminophen overdose is the most frequent
cause of acute liver failure
• Glutathione in the liver normally “detoxifies” a
toxic metabolite of acetaminophen (N-acetyl-pbenzoquinoneimine—NAPQ1)
• Excess acetaminophen can deplete the stores of
glutathione resulting in the build-up of NAPQ1
and acetaminophen toxicity occurs
• What factors can increase the risk of
acetaminophen toxicity?
Risk factors for acetaminophen toxicity
• Patients with chronic liver disease
• Chronic alcohol abuse or sporadic binge
drinking with ingestion of therapeutic doses of
acetaminophen
• Starvation
• Drugs used with acetaminophen—
barbiturates, phenytoin, carbamazepine,
rifampin, INH, omeprazole, valproic acid
Acetaminophen toxicity
• Most common cause of acute liver injury
leading to hepatic failure
1) suicide attempts
2) accidental overdoses
• Minimum toxic single dose in healthy adults is
between 7.5 and 10 grams and ≥ 150 mg/kg in
children
Accidental overdoses
• Over 300 “itchy, sneezy, wheezy, snotty, achy,
breaky” over-the-counter products w/
acetaminophen —inadvertent overdoses (narrow
therapeutic index—i.e., the toxic dose is not much
higher than therapeutic dose)
• Also in numerous prescription analgesics: Fioricet,
Lorcet, Percocet, Propacet, Roxicet, Ultracet—
limiting the amount of acetaminophen to 325 mg
per tablet or capsule (used to have
325/500/650/750 depending on the formulation)
• Theraflu for colds, oxycodone for pain, Excedrin for
headache or flu, Sinutab for allergies, Robitussin for
cough, Allerest/Nyquil 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})
• replenishes glutathione and detoxifies a highly
reactive metabolite of acetaminophen (NAPQI—Nacetyl-benzoquinoneimine
Liver storage functions
• The liver stores of B12
• 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
and animal products (milk, eggs) (+fortified
foods)…no fruits or green leafys
Who’s at risk for B12 deficiency?
• Vegetarians, vegans
• alcoholics
• previous gastric surgery such as partial gastrectomy,
bariatric surgery, malabsorption syndromes including
Crohn’s disease
• autoimmune gastritis (pernicious anemia—
antibodies to intrinsic factor, can’t absorb B12))
• Age over 55
• Drugs – PPIs, metformin (Glucophage)
What happens with a B12 deficiency?
• You’re anemic and demented with a
peripheral neuropathy
Treatment
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Replacing B12
Oral/sublingual B12—1000 mcg/day
Nasal B12 gel—500 mcg/nostril twice a week
Injections (1000 mcg) for dementia and
neuropathy
• The 4 S’s
• Can you overdose on B12? NO
• The one dreaded side effect of excess B12
(greater than 3,000 mcg/day)?
Liver storage functions
• Blood—backup from CHF (“nutmeg” congestion);
hepatomegaly
• Iron—iron storage disease--hemochromatosis
• Vitamin A and the liver—don’t overdose on Vitamin
A; excess vitamin A is TOXIC to the liver
• How much vitamin A do you get from eating liver?
Liver ingestion and vitamin A
• The recommended daily amount of vitamin A
for humans is:
• 2310 IU/day for women
• 3000 IU/day for men
• 3 oz of liver = 100 grams
• 3 oz chicken liver? 12,000 IU of vitamin A
• 3 oz of calf liver? 14,378 IU of vitamin A
Polar bear liver and vitamin A toxicity
• 3 oz of polar bear liver? 2.4 to 3.5 million IU
• Long known to the Inuits that polar bear liver
shouldn’t be eaten
• Why? You die.
Liver storage functions
• Glycogen—stored glucose for acute needs and
to maintain blood sugar during fasting
states—nighttime and between meals
• Glycogenolysis—the breakdown of stored
glycogen for glucose needs—epinephrine,
cortisol, glucagon
• Predisone (and other glucocorticoids) can do
the same thing—increasing the blood sugar
Liver storage functions--glycogen
• Metformin (Glucophage) works almost exclusively in
the liver to inhibit the catabolism (breakdown) of
stored glycogen; decreases blood sugar
• Also decreases absorption of glucose in the GI tract
(osmotic diarrhea), too; more sugar to the bacteria
located in the GI tract = methane… ; nighttime
dosing (use long-acting metformin)
• Metformin given with Prednisone (inhibits
glycogenolysis caused by Prednisone)—prevents
hyperglycemia
Hemochromatosis
• Hemochromatosis is homozygous-recessive inherited
disorder--1/200 – 1/300 in U.S. (HFE gene {C282Y} is
located on chromosome #6) – causing an excess
absorption of iron and accumulation
• M/F(6:1); and earlier onset(40-60); why? Physiological
iron loss (menstruation, pregnancy) delays iron
accumulation in women (usually postmenopausal sx)
• Total body iron pool ranges from 2 to 6 grams 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
• Fully developed cases—micronodular cirrhosis
• Hepatocellular carcinoma is 200 x greater than
general population (Tx for iron overload does NOT
reduce risk)
• Also accumulates in the skin and pancreas
• Diabetes in 75% to 80% of the cases
• Skin pigmentation in 75%-80% of cases “BRONZE
diabetes”
Hemochromatosis
• 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
• Liver tests can be relatively normal in patients with serious
liver disease and abnormal with diseases that don’t affect the
liver. Up to 6% of healthy, asymptomatic people have
abnormal liver enzyme levels, although only 1% of the general
population has liver disease.
• NEED TO TAKE A CAREFUL HISTORY and do a complete
physical exam
• 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
3x normal)—have the patient stop all drugs
that are NOT necessary (including alcohol,
NSAIDs, drugs that contain acetaminophen)
and recheck the enzyme levels in 2 weeks
before doing a multi-million dollar work-up
Hepatotoxins
• Dry cleaning – tetrachloroethylene
• Paint thinner—toluene, turpentine
• Nail polish removers – acetone, methyl and
ethyl acetate
• Spot removers (hexane)
• Detergents (citrus terpenes)
• Occupational hazards—dry cleaners, painters,
chemists, nail salon workers
Hepatotoxin exposure and drug effects
• Vitamin A toxicity
• Hundreds, if not thousands, of drugs can
elevate liver enzymes and cause druginduced-liver-injury (DILI)
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 (Depakote, Depakene, sodium valproate)
• Obesity increases the risk of liver injury caused by
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
(Voltaren) (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 if a drug is
suspected?
• 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.
AST/ALT ratio
• AST -- 8-20 U/L —adult males; 11-26 U/L) —
adult females)
• ALT -- 10-40 U/L —adult males; adult females
-- 7-35 U/L
• 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—fatty liver!
Extremely high levels of hepatocellular
enzymes
• The finding of extremely high levels (greater
than 50-100 x normal) 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)
• 36-92 U/L
• 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 --0.3-1.2 mg/dL
• Direct (conjugated)-- 0- 0.3 mg/dL
• Indirect (unconjugated) (total minus direct)
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—brown stools
• A small amount is sent to the kidneys – yellow urine
• A tiny amount is sent to the blood via the lymphatics (that’s
why the percentage of direct bilirubin is so low)
The “Yella” Jaundice
• 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
Skin
• Bilirubin level for jaundice—serum bilirubin >
2.5-3 mg/dL
• (unconjugated bilirubin is taken up by tissues
more than conjugated…)
What does abdominal fat have to do with liver
disease…
• Abdominal fat = NEW ORGAN!
• 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 is the most common form of “cryptogenic”
cirrhosis, i.e. cirrhosis of “unknown” origin
• Includes simple hepatic steatosis, steatosis with
minor non-specific inflammation, and the most
significant type: non-alcoholic steatohepatitis
(NASH)
NASH
• The clinical course of NASH is variable but, as
a group, natural history studies suggest that
1/3 of patients show disease progression, 1/3
of patients have disease regression, and 1/3
have stable disease over a 5-10 year period
(McNally PR)
Causes of non-alcoholic fatty liver
disease
• Obesity
• Diabetes
• The above two (“diabesity”) have traditionally been the “only”
causes of NAFLD, but there are more…
• Males greater than females
• Drugs—prednisone and other glucocorticoids, MTX, synthetic
estrogens, amiodarone (Cordarone, Pacerone), tamoxifen and other
estrogen antagonists, nifedipine, diltiazem, chemotherapy
(irinotecan and oxaliplatin), valproic acid, ibuprofen, ASA,
• Jejunal-ileal bypass, extensive bowel resection, bilopancreatic
diversion
• Long-term IV feeding (TPN)
• Hepatitis C
Treatment of NAFLD/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
3%, 5%, and especially 10% of their TBQ
achieve significant histological improvement
• (Chalasani )
• *Bariatric surgery improves NAFLD but it’s not
recommended at this time specifically for this indication
Treatment of NAFLD/NASH
• Reduce caloric intake by 500 calories/day
• Diets higher in MUFA/PUFA and lower in
processed foods and simple carbohydrates
and saturated fatty acids
• Exercise 4x per week; burn 400 calories each
time
Aramchol for fatty liver disease (NAFLD
and NASH)
• A drug initially developed to treat gall stones has
been shown to significantly reduce the fat found
in the liver in patients who are obese and who
also have glucose intolerance
• Reduction in fat content improved metabolic
parameters including blood glucose and liver
function tests
• On the fast track for FDA approval
• Clinical Gastroenterology and Hepatology,
December 2014
Hepatitis A—25% of hepatitis cases worldwide;
• Self limited disease, incubation period of 3-6
weeks;
• risk factors—endemic in countries with
substandard sanitation--fecal-oral
transmission
• Vaccine available
Hepatitis B—2 billion worldwide infected; 400
million with chronic infection
• Large proportion of immigrants from areas of
the world where HBV is highly prevalent
(China/Hong Kong #1, Phillipines, SE Asia,
Middle East, Africa)
Hepatitis B—2 billion worldwide infected; 400
million with chronic infection
• Vertical transmission—90% of cases (if mom is
+ in last trimester)
• Day care—minor cuts
• Sexually transmitted
• IV drug use
• Very low risk of blood transfusion related --9
cases in 3.7 million donations (N Engl J Med
2011 Jan 20; 364:236
Hepatitis B
• Vaccine has been around for 40 years
• significant reduction in chronic HBV infections which in
turn significantly reduces the # of hepatocellular
carcinomas
• Treatment of HBV—interferon alfa and antiviral drugs
(adefovir/Hepsera; entacavir, lamivudine)
• Tenofovir (Viread)—long-term suppression of HBV
replication with improved liver histology; 96 patients w/
cirrhosis pretherapy; 74% no longer cirrhotic after 5
years (Marcelli, et al. Lancet 2012 December 10)
U.S. Hepatitis C cases—scope of the
problem
• HCV is the most common chronic blood-borne infection in the
world (170 million with 300,000 deaths per year); 3-4 million
new cases diagnosed every year
• Accounts for almost half of all U.S. individuals with chronic
liver disease
• New cases peaked in the U.S. in mid-1980s—over 230,000
new cases per year; 19,000 new cases per year today
• Why? Decreased blood transfusions and widespread testing
of blood available in 1992
• **BABY BOOMERS (1945-1965)—3%
Hepatitis C infection
• 6 different genotypes—HCV 1 through 6; subtypes 1a, 1b, 2a,
etc.
• Genotypes exhibit geographic variability—U.S. genotype 1
(70%); the different genotypes respond differently to anti-HCV
drugs
• 60-70% are asymptomatic during the acute infection
• If symptomatic—fatigue, fever, dark urine, clay-colored stools,
abdominal pain, anorexia, nausea, vomiting, joint pain,
“Yellow” jaundice
Hepatitis C virus
• Progression to chronic disease occurs in the majority
of HCV-infected individuals (55-85%) because the
immune system is unable to “clear” it
• Cirrhosis eventually occurs (5 to 20++ years after
acute infection) in 20-30% of individuals with chronic
active HCV infections
• Hepatocellular carcinoma occurs in about 3% of the
population infected with hepatitis C
HCV can be transmitted through:
• The use of needles and equipment that have
been used by someone else for preparing,
injecting, inhaling or snorting a drug (cocaine,
meth, heroin)
• Transfusions and organ transplants prior to
1992 in U.S. and Canada
• Receiving a blood transfusion in another
country where screening procedures are not
effective or routine
HCV can be transmitted through:
LESS COMMON ROUTES OF TRANSMISSION
• Sharing personal items with an infected person (e.g.
razors, shavers, toothbrushes, nail clipper)
• Reuse of medical equipment that has not been
properly sterilized
• Reuse of tattooing, body piercing, and acupuncture
equipment that has not been properly sterilized
• High-risk sexual activity (no condoms, blood involved—
menstruation, rough anal sex)
• Clotting factors prior to 1987
• Occupational exposures for HCPs—needle stick injury
Mom-to-baby—vertical transmission
• Mother-to-infant contact (2% for infants of
anti-HCV, seropositive women; when a
pregnant woman is HCV-RNA positive at
delivery, the risk increases to 4-7%)
Guys tattoos…
• Out there…
• Everywhere…
• Showin’ them off
• Gals are a bit more subtle…
Groups strongly recommended for
testing
• IV drug user (even 1 time experimental drug
use)(54% of total cases)
• Needle stick injury (10%)--FYI: risk of acquiring
HCV by needle stick is about 6x higher than
that for HIV (1.8 vs. 0.3%)
• 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 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) (How about multiple partners? How
many?)
• 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)
• Receipt of an injection in a developing world
Updated U.S. guidelines (CDC)—
testing for HCV infections
• More than 75% of patients with HCV are baby
boomers—born between 1945 and 1965
• This group accounts for 73% of HCV mortality,
and 35% of undiagnosed “baby boomers”
have already progressed to advanced stages of
liver disease
• A one-time test for HCV is recommended
without prior ascertainment of risk
RX: Game Changer
Major game-changer—the new oral
drugs for HCV
• 4-drug antiviral combination
– Viekira Pak -- 4 tablets per
day x 12 weeks…$83,320
• Harvoni (2 drugs combined;
sofosbuvir and ledipasvir) –
1 tablet per day x 12 weeks
… $94,500—CURE at least
94% of the patients with
genotype 1 (the main type
in U.S.)
• $900 in Egypt…
Keep your liver healthy! Avoid liver
toxic drugs (If possible)
•
•
•
•
•
•
•
•
Acetaminophen
Anabolic steroids
NSAIDS—especially diclofenac
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)
• Chlorogenic acid—every two
cups of coffee decreases risk of
hepatocellular carcinoma by
43% (Environmental Nutrition,
March 2009)
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
• bbancr9271@aol.com
• www.barbbancroft.com
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non-alcoholic steatohepatitis. J Hepatol 2009 Aug;51:371.
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• 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.
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• (Chalasani N et al. The diagnosis and management of NAFLD: Practice
guidelines by the American Association for the Study of Liver Diseases, Am
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• Charles EC, et al. Evaluation of cases of severe statin-related transaminitis
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(accessed 4/30/07)
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