HURTS AND HELPS
| Drug Hepatotoxicity —Jeffrey S. Crippin, MD, Professor of Medicine and Medical Director, Liver Transplantation,
Washington University School of Medicine, St. Louis
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| Drug-induced liver injury (DILI): spectrum of presentation includes acute or chronic hepatitis, cholestasis, vascular
injury, granuloma, fatty liver, and condition resembling alcoholic liver disease; “signature injury” associated with
specific drug, eg, acute hepatitis, autoimmune-type hepatitis, mitochondrial injury, deposition of fat in liver, or
cholestasis; mechanisms—most drugs metabolized through cytochrome P450 system that involves oxidation, reduction,
hydrolysis, conjugation to protein, and production of water-soluble metabolite excreted in urine; DILI occurs
when metabolism forms toxic metabolite that covalently binds to cell, leading to mitochondrial injury and
cellular necrosis, or to oxidative stress that disrupts endoplasmic reticulum, or to immune response leading to apoptosis;
risk factors—patient >50 yr of age, female sex, genetics, alcohol abuse, dose and duration of treatment, and
nutritional status (starvation or obesity); incidence—acute liver failure 0.01% to 0.1%, overt liver disease 0.1% to
1.0%, and abnormal liver function tests (LFTs) 1% to 10%; signs—look for signature injury, jaundice, and transaminase
levels >3 times upper limit of normal (ULN); biopsy reveals extent, not cause, of injury; jaundice, acute
liver failure, ascites, confusion, and coma indicate serious injury; Maddrey grades serum alanine transaminase
(ALT) level >8 times ULN, or ALT >5 times ULN, or ALT >3 times ULN as intermediate injury; ALT level <3
times ULN sign of minor injury; diagnosis—usually based on circumstantial evidence; index of suspicion high if
patient became ill after starting drug or if withdrawal from drug resolves symptoms; do not rechallenge patient with
drug
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| Acetaminophen: usually metabolized through sulfation or glucuronidation; routine ingestion of large doses can lead
to increased activity of P450 system and apoptosis, or low levels of glutathione may prevent elimination of toxic
metabolite; dose <3 g/day safe, even in patient with abnormal LFTs; toxic at 10 to 15 g/day; most patients can take
3 to 9 g/day without harm (even patients with liver disease or abnormal LFTs); contraindicated in patients who
abuse alcohol (reports indicate liver failure can occur even in patients taking 2 g/day along with excessive alcohol
use)
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| Isoniazid: used in patients with positive purified protein derivative (PPD) test for tuberculosis; 10% to 20% of patients
taking isoniazid present with increased transaminase levels within first 2 mo of therapy; usually resolves
without cessation of therapy; severe DILI with jaundice occurs in 1% of patients overall and in 2% of older patients
(>50 yr of age); women at increased risk for severe DILI associated with this drug; check transaminase levels during
first 3 mo and over course of therapy; withdraw isoniazid if patient symptomatic (eg, fatigue, dark urine) with
elevated LFT
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| Diclofenac: common nonsteroidal anti-inflammatory drug (NSAID); 70% of patients present with acute hepatitis,
10% with elevated alkaline phosphatase (ALP); presentation within first 3 mo of therapy in 65% of cases and
within first year in ≈33%; consider obtaining LFTs in patient presenting at routine follow-up with symptomatic
complaints; small percentage of patients present with Stevens-Johnson–type syndrome (ie, fever, rash, eosinophilia);
mortality rate among patients with jaundice 1 in 10
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| Sulindac: elevated ALP in 70% of patients, hepatocellular injury in 30%; DILI presents within first 6 wk in 70% of
patients; thought to be idiosyncratic reaction
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| Amoxicillin–clavulanate (Augmentin): cholestasis occurs in 1 in 100,000 patients and can occur up to 6 wk after
cessation of therapy; DILI can take 1 to 4 mo to resolve
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| Amiodarone: associated with “alcohol-like” liver injury; causes phospholipidosis and mitochondrial injury; consider
risk-benefit to patient before withdrawal
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| Nitrofurantoin: can induce autoimmune hepatitis within 6 mo after starting therapy; keep suspicion high for DILI in
female patient with history of frequent urinary tract infection presenting with abnormal LFTs; cessation of therapy
resolves injury; consider trial of corticosteroids if cause of autoimmune hepatitis uncertain
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| 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins): recommend cessation of therapy
if ALT >3 times ULN (occurs in up to 3% of patients); documented cases of acute liver failure rare; accumulation
of HMG-CoA within liver results in elevation of ALT; can continue use despite abnormal ALT; no evidence
that monitoring LFTs in patients taking these drugs efficacious; study data—compared patients with high lipid
levels and abnormal LFTs and patients with high lipid levels and normal LFTs to patients with normal lipid levels
and abnormal LFTs; first 2 groups given statin drugs, third group not treated; ≈5% of treated patients with elevated
baseline ALT showed mild to moderate elevation of LFTs after treatment, but ≈6% of patients with elevated baseline
ALT who did not receive statin drug also had elevation of LFT; concluded HMG-CoA reductase inhibitors not
cause of elevation in LFT; patients with nonalcoholic steatohepatitis (NASH) can take statins
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| Update on Clinical Nutrition: Does it Make a Difference? —Robert G. Martindale, MD, Professor
of Surgery, Oregon Health and Science University, Portland
|
| Background: studies looking at issues in critical care provide information about clinical nutrition in intensive care
unit (ICU) and hospital patients; examples—daily dialysis allows better metabolic control; glucose control decreases
endogenous glucose production and preserves lean body mass, allowing better motility of gastrointestinal
(GI) tract; early resuscitation improves enteral tolerance, improves gut perfusion, decreases mucosal injury, and
maintains mucosal barrier; activated protein C enhances nutrient delivery and visceral uptake; changes in nutrition
delivery—in hospital patients, calories required decreased from 40 kilocalories (Cal)/kg of body weight per day to
20 Cal/kg per day (14-16 Cal in obese patient); protein required decreased from 2.2 to 2 g/kg of ideal body weight;
can achieve positive nitrogen balance in morbidly obese hospital patient
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| Glucose control: during normal immune response, macrophages migrate to infection site using chemotaxis; macrophages
kill bacteria through phagocytosis and oxidative burst or nitric oxide production; this immune response slows
down at blood glucose (BG) of 150 mg/dL; ability to kill bacteria decreases by 50% at BG of 200 mg/dL; chemotaxis
ceases at BG of 230 mg/dL; in postoperative period, hyperglycemia is hypermetabolic response that activates
overproduction of nuclear factor (NF)-kappaB and induces systemic inflammatory response syndrome (SIRS); study
data—Wolf et al found tight glucose control in ICU patients decreased polyneuropathy by 45%, dialysis rate by
50%, transfusion rate by 50%, and decreased prolonged ventilation, septicemia, and mortality; insulin stimulates
protein synthesis, decreases net protein breakdown, increases sodium diuresis, and enhances cardiac muscle (myotropic
effect on myocardium); study found intensive insulin therapy decreased catabolism for gluconeogenesis; glucose
control enhances insulin delivery and maintains lean body tissue by decreasing muscle loss during catabolic
illness
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| Lipids: intravenous (IV) lipids immunosuppressive and consist of pure ω-6 fatty acids; only IV solution available in
United States made from soybean oil (18-carbon ω-6 fatty acid); ω-6 fatty acids proinflammatory; 5 solutions
available in Europe and Asia (eg, IV olive oil rich in antioxidants; IV fish oil increases tissue microperfusion and
decreases arrhythmias in ventilator patients); study looking at effect of lipids on arrhythmias and myocardial function
shows infusion for 3 hr before myocardial insult lowers risk for cardiac arrhythmias by 50% to 70%; ω-3 fatty
acids being used in patients with ischemia before event stressful to myocardium to decrease potential for arrhythmia;
now looking at use of propofol in ω-3 fatty acid base, rather than current ω-6-based solution
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| Enteral vs parenteral nutrition: use parenteral nutrition only when necessary (immunosuppressive and associated
with multiple metabolic side effects); use GI tract when possible; enteral feeding reduces infection rate by ≈50%
(GI tract contains 70% of immune system); enteral formulas do not require Food and Drug Administration (FDA)
approval; special formulas usually not necessary; no data support efficacy of pulmonary formulas in patients on
ventilators; data support use of pulmonary formula in patients with acute respiratory distress syndrome (ARDS);
data support efficacy of formula that contains transforming growth factor- β (TGF- β) in patients with inflammatory
bowel disease (IBD) because it lowers inflammatory response within mucosa in small-bowel Crohn’s disease
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| Immune modulation: nutritional therapy used to enhance patient’s immune system and reduce risk for infection;
study found supplemental vitamins given to ICU patients on ventilators decreased organ failure and length of stay;
study found decreased ICU and ventilator days in patients with ARDS associated with use of formulas containing
ω-3 fatty acids; immune-modulating formulas found to decrease infection rate, especially in sickest ICU patients;
recommend use for ≥5 days to reach therapeutic levels
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| Tolerance: evidence-based protocol for early feeding associated with decreased mortality rate; avoid enteral feeding in patients
with hemodynamic instability (GI tract in inadequately resuscitated patient with inadequate blood volume cannot
vasodilate to accomodate increased metabolic demands of nutrients; can produce ischemic injury); 50% reduction of visceral
blood volume occurs after blood volume loss of 5%
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| Proximal vs distal feeding: stomach feeding indicated in most patients (elevate head of bed and watch for aspiration);
sicker patients require feeding into small bowel
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| Radiofrequency Ablation for Liver Tumors —Ronald Zagoria, MD, Professor of Radiology, Wake
Forest University School of Medicine, Winston-Salem, North Carolina
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| Radiofrequency ablation (RFA): electromagnetic energy similar to microwave; probe serves as antenna that emits
energy and causes cells around probe to vibrate rapidly, creating and dispersing frictional energy that becomes hot
enough to kill tumor cells; needle-like probes 15 to 17 gauge in diameter and come in different shapes and from
different manufacturers
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| Zone of ablation: single session takes 12 min; 3-pronged probe kills cells in 4-cm sphere around tip of probe; single
probe kills cells within 3-cm sphere around tip; heat sinks (eg, presence of blood, gallbladder, and aerated lung tissue)
can alter (eg, shrink) ablation zone; larger lesions require overlap of numerous ablation zones to try to destroy entire lesion
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| RFA procedure: guidance—can use ultrasonography (US), computed tomography (CT), magnetic resonance (MR),
and intraoperative guidance; ablation produces echogenic area that grows during 12-min session; can use CT guidance;
perform contrast-enhanced CT immediately after ablation to help identify untreated tumor areas and estimate
when lesion completely ablated; can be difficult to overlap ablation zones so every cancer cell killed in large tumors;
US not as helpful in identifying area of lesion in larger tumors because of obscuration, leading to overestimation
of kill area; sedation—procedure painful, particularly in liver (more nerve fibers, particularly around
capsule); can be done with conscious sedation, but use monitored general anesthesia without intubation in patient
with even minimally complicated lesion
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| Indications: hepatocellular carcinoma (HCC)—often untreatable because patients often have underlying liver disease
and have little liver reserves, or because of location or multiplicity of tumors; >15% of tumors resectable with modern
techniques; mortality rate very high if metastasis unresectable (not responsive to chemo- or radiotherapy); colorectal
metastases to liver—most common indication for RFA; often unresectable; mean survival without treatment 12 mo,
and median survival with chemotherapy 18 mo; long-term survival in patients with completely resectable tumors 20% to
40%
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| Hepatic RFA: study data—serious complication rate 3%, and mortality rate <1% ; complications include hemorrhage
(self-limited; seldom requires transfusion), pleural effusion, prolonged pain, abscess, and skin burns (usually
self-limited; treated conservatively); blood vessels—effective heat sinks; vessels ≥3 mm protected from thrombosis;
risk for puncture injuries; outcome—studies show risk for recurrence 2% to 48% (in larger tumors); study
showed new metastases developed in ≈57% of patients out to 3 yr; patient selection—for curative RFA, select patients
with up to 10 tumors ≤4 cm in size and no extrahepatic neoplasms, who have failed chemotherapy or had tumor
downsized by chemotherapy, and who are poor candidates for surgery; RFA for palliation—consider patients
with liver and lung metastases if lung metastases not overwhelming burden; patients who have controlled rectal recurrences
after rectal carcinoma; young patients; patients with breast cancer and liver-only disease, renal cell carcinoma,
ovarian cancer, or some other slow-growing metastases; patients with malignancies and only progressive
liver metastases; patients who require symptomatic relief of neuroendocrine tumors
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Educational Objectives
| The goal of this program is to educate the listener about hepatotoxicity of drugs, therapeutic use of nutritional support,
and radiofrequency ablation for liver tumors. After hearing and assimilating this program, the clinician will be
better able to:
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 | 1. Describe the mechanisms involved in drug-induced liver injury.
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| 2. Identify signs of drug-induced liver injury.
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| 3. Discuss how nutritional support can enhance the immune system of critically ill patients.
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| 4. Evaluate the efficacy of radiofrequency ablation for unresectable liver tumors.
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| 5. Identify patients who would benefit from hepatic radiofrequency ablation.
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Discussed on This Program
Acetaminophen (n-acetyl-p-aminophenol; APAP) [several trade names]
Amiodarone HCl [Cordarone, Pacerone]
Amoxicillin and potassium clavulanate (co-amoxiclav) [Augmentin, Augmentin ES-600, Augmentin XR]
Bromfenac 0.09% ophthalmic solution [Xibrom]
Diclofenac [Cataflam, Voltaren, Voltaren-XR]
Isoniazid (isonicotinic acid hydrazide; INH) [Nydrazid]
Nitrofurantoin [Furadantin]
Nitrofurantoin macrocrystals [Macrobid, Macrodantin]
Propofol [Diprivan]
Sulindac [Clinoril]
Tacrine HCl (tetrahydroacridinamine; THA) [Cognex]
Troglitazone [Rezulin] (withdrawn)
Trovafloxacin mesylate/alatrofloxacin mesylate [Trovan]
Suggested Reading
Blackburn AC et al: Deficiency of glutathione transferase zeta causes oxidative stress and activation of antioxidant
response pathways. Mol Pharmacol. 69:650, 2006; Clark HP et al: Staging and current treatment of hepatocellular
carcinoma. Radiographics. 25:S3, 2005; Crippin JS: Acetaminophen hepatotoxicity: potentiation by isoniazid. Am J
Gastroenterol. 88:590, 1994; Fontana RJ et al: Acute liver failure due to amoxicillin and amoxicillin/clavulanate.
Dig Dis Sci. 50:1785, 2005; Fountain FF et al: Isoniazid hepatotoxicity associated with treatment of latent tuberculosis
infection: a 7-year evaluation from a public health tuberculosis clinic. Chest. 128:116, 2005; Goldkind L et al: A
systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac
experience. Pharmacoepidemiol Drug Saf. Feb 3, 2006; Hawksworth J et al: Surgical and ablative treatment for metastatic
adenocarcinoma to the liver from unknown primary tumor. Am Surg. 70:512, 2004; Henn AR et al: Percutaneous
radiofrequency ablation of hepatic metastases for symptomatic relief of neuroendocrine syndromes. AJR Am J
Roentgenol. 181:1005, 2003; Kaplowitz N: Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov. 4:489, 2005;
Martindale RG et al: Preventing infectious complications with nutrition intervention. JPEN J Parenter Enteral Nutr.
29:S53, 2005; Martindale RG et al: The use of immune enhancing diet in head injury. JPEN J Parenter Enteral
Nutr. 25:S27, 2001; Martindale RG et al: Use of immune-enhancing diets in burns. JPEN J Parenter Enteral Nutr.
25:S24, 2001; Prandota J et al: Important role of proinflammatory cytokines/other endogenous substances in drug-
induced hepatotoxicity: depression of drug metabolism during infections/inflammation states, and genetic polymorphisms
of drug-metabolizing enzymes/cytokines may markedly contribute to this pathology. Am J Ther. 12:254,
2005; Puli SR et al: Hepatic cirrhosis caused by low-dose oral amiodarone therapy. Am J Med Sci. 330:257, 2005;
Turgeon DK et al: Acute hepatitis associated with alosetron (Lotronex). J Clin Gastroenterol. 39:641, 2005; Walgren
JL et al: Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol. 35:325, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Crippin reports research support and grants from Schering-Plough, Roche, and Otsuka and is on the Speaker’s
Bureau at Roche, Schering-Plough, and Gilead Sciences.
Dr. Crippin was recorded April 23, 2005, in St. Louis at Liver Diseases: Therapeutic Challenges, sponsored by
Washington University School of Medicine. Dr. Martindale addressed Medical and Surgical Approaches to GI Disorders,
sponsored by the Medical College of Georgia and held July 25-29, 2005, in Amelia Island, Florida. Dr. Zagoria
spoke October 8, 2005, in Winston Salem, North Carolina at Emerging Diagnostic and Therapeutic Options in GI
and Liver Disorders, sponsored by Wake Forest University. The Audio-Digest Foundation thanks the speakers and
the sponsors for their cooperation in the production of this program.
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