1. 50 ways to LOVE your LIVER…
Barb Bancroft, RN, MSN, PNP

2. 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

3. 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

4. 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.

5. 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
His brother, by the way, was Atlas. Atlas defied Zeus by fighting on the side of Cronus—Zeus zapped his brother Menoetius, and spared Atlas—whom he condemned to support Heaven on his shoulders for all eternity—Hence, the vertebrae—the Atlas

6. 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 days
And in some of “us”, it occurs every Monday morning…

7. 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

8. 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

9. What drugs? A few examples…
Propanolol (Inderal)—bradycardia
Morphine --bradypnea
And,

10. 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
Fertility god, protector of livestock, fruit plants and gardenes, and right along with your fruit plants and gardens, the protector of the male genitalia…best noted for his large, permanent erection, giving rise to the medical term priapism. Also the patron god of sailors and fishermen

11. Let’s get back to liver anatomy—the liver is located beneath the diaphragm
How much embryology did you get in nursing school?

12. 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

13. 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

14. 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

15. 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)

16. Physical Assessment Findings predicting hepatocellular disease in patients with jaundice
Spider angiomas (LR 4.7)*
Palmar erythema (LR 9.8)*
Hepatomegaly
Pruritis

17. 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)

18. 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

19. 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)

20. 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

21. 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)

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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.

31. 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

32. 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?

33. 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

34. 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 (protein- bound 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?

35. 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

36. 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

37. 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

38. The antifungals--the “azoles” and Coumadin
Miconazole (Monistat)
Fluconazole (Diflucan)
Intraconazole (Sporanox)
Ketoconazole (Nizoral)
Voriconazole (Vfend)
Posaconazole (Noxafil)
“You have a yeast infection…”

39. 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!

40. 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

41. Wisconsin Alumni Research Fund
Warfarin as rat poison
Dwight David Eisenhower—first human guinea pig
Rats in Europe today

42. 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?

43. 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?

44. 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

45. 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

46. 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)

47. Who are the “statin sisters”?
Lova (Mevacor), simva (Zocor), fluva (Lescol), prava (Pravachol), atorva (Lipitor), rosuva (Crestor), pitavastatin (Livalo)

48. 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)

49. HDL production glucocorticoids, cyclosporine, tacrolimus
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

50. 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

51. 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

52. The healthy liver inactivates hormones produced by other organ systems
Aldosterone
Estrogen

53. 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

54. Estrogen
Failure to inactivate estrogen—feminization in the male—gynecomastia, testicular atrophy (other causes of gynecomastia); spider angiomas, palmar erythema; hypogonadism in females, amenorrhea

55. 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

56. Alcohol (ETHANOL) Boosts HDL production in the liver
Increases endogenous tissue plasminogen activator
Anti-inflammatory
Anti-oxidant

57. How much? 5 oz of wine of any color—This amount→
Guys, you can have 2 glasses

58. Daily dose? How much of the hard stuff? 1-2 ounces for women
2-3 ounces for men

59. How about a daily brewski?
12 ounces for women
24 ounces for men

60. So, what’s my motto? Run a mile, drink a beer…
Have a nice glass of wine with dinner with my Mom…
OR…

61. 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%)

62. 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

63. 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

64. 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

65. 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)

66. 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)

67. 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)

68. The liver and acetaminophen
Glutathione normally “detoxifies” a toxic metabolite of acetaminophen (N-acetyl-p-benzoquinoneimine)
Excess acetaminophen can deplete the stores of glutathione and acetaminophen toxicity occurs
What factors can increase the risk of acetaminophen toxicity?

69. 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

70. 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 --

71. 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…

72. Before you know it…
The signs and symptoms of acute liver failure are staring back at you in the mirror

73. 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 N-acetylcysteine (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—N-acetyl-benzoquinoneimine)

74. Liver storage functions
The liver stores 5, 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

75. 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)

76. 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

77. 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

78. 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

79. 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

80. 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

81. 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

82. 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

83. 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

84. Liver function tests
Cellular integrity – AST (aspartate transaminase), ALT (alanine transaminase)
Bile formation and flow (bilirubin, GGT, alkaline phosphatase)
Protein synthesis (albumin, prothrombin time)

85. 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

86. 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

87. 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 drug-induced-liver-injury

88. 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)

89. 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

90. 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.

91. 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

92. 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

93. 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)

94. 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)

95. AST/ALT ratio
AST 8-20 U/L ( μKat/L—adult males; U/L ( μKat/L—adult females)
ALT U/L ( μKat/L—adult males; 7-35 U/L ( )
The normal AST/ALT ratio should be 1

96. 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

97. 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

98. 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

99. Alkaline Phosphatase (ALP, or AP)
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

100. 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 mg/dL
Indirect = 1.0 mg/dL
Direct = .3 mg/dL

101. 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”

102. 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

103. 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

104. 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

105. 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 non-specific inflammation, and non-alcoholis steatosis (NASH)
The first two, simple steatosis and steatosis with minor non-specific inflammation are stable conditions without significant clinical problems

106. 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

107. 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
Usually asymptomatic or nonspecific sx such as fatigue and RUQ discomfort

108. 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

109. 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)

110. 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

111. 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

112. 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)

113. Hepatitis B
Woodchucks, ducks, and squirrels with chronic hepatitis B and hepatocellular carcinoma

114. 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

115. 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)

116. 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 HCV-infected individuals (85%) because the immune system is unable to “clear” it

117. 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

118. 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 co-infection)(25% of people living with HIV are co-infected with hepatitis C)

119. 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)

120. 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)

121. 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)

122. Guys tattoos… Out there… Everywhere… Showin’ them off
Gals are a bit more subtle…
No vaccine available yet; drugs to treat

123. 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.

124. 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)

125. 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)

126. 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

127. Primary biliary cirrhosis (PBC)
Autoimmune cholestatic liver disease in which the epithelial cells lining the bile ducts are damaged by the immune system
Females: 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

128. 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

129. 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

130. 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

131. 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)

132. 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

133. 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 (June-July);119(1):67.
Charles EC, et al. Evaluation of cases of severe statin-related transaminitis with a large health maintenance organization. (accessed 4/30/07)

134. Bibliography
Flora KD, Keeffe EB. Significance of mildly elevated liver tests on screening biochemistry profiles. J Insur Med 1990:22:
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:
Learned J. Worth the wait: New, more effective therapies for hepatitis C are on the way. Positively Aware. January/February 2011

135. Bibliography
Lewis JH, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well compensated liver disease. Hepatology 2007;46:
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):
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.

136. Bibliography
Rordan SM, Williams R. Gut flora and hepatic encephalopathy in patients with cirrhosis. N Engl J Med 2010; 362 (12):
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)

137. 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

138. 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 Pdx-1 to alter their gene expression
(Ferber, Sarah. Sheba Medical Center, Tel Hashomer Israel. The International Society of Stem Cell Research, July 2009, Barcelona Spain)

139. 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)

140. 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