HealthWise: Hepatitis Seeing Lucinda Porter, RN No organ is more important than any other, but try to convince us of that when it comes to our eyes.  This point was demonstrated recently when a patient I was working with developed vision problems.  Six months earlier he had completed hepatitis C (HCV) treatment.  Naturally he wondered if there was a correlation between his eye condition and the treatment. His liver specialist and other experts in the field did not believe there was a correlation in this particular case.  Eye diseases are common, particularly as we age.  According to the National Eye Institute (NEI), in the 2000 U.S. census there were more than 119 million adults over age 40 with age-related eye diseases.  This number is expected to double in the next three decades.  Some eye conditions are associated with HCV.  The most common of these is dry eye syndrome.  HCV treatment may cause or worsen some eye problems.  Corneal ulcers are associated with HCV and its treatment.  Prescription information for peginterferon-alpha with ribavirin warns of ophthalmologic (eye) disorders such as decreased, blurred or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema.  Let’s discuss these and other terms. Courtesy of the National Eye Institute – www.nei.nih.gov The outer most layer of the eye is the cornea.  Ulcerations on the cornea may be caused by a variety of factors, HCV being one of them.  One example, Mooren’s ulcer is discussed in the HCV Advocate’s Medical Writers’ Circle’s Extrahepatic Manifestations of Chronic Hepatitis C, by Remoroza and Bonkovsky. Retinopathy refers to retina problems.  The retina is a nerve-rich area in the back of the eye.  It receives light and transmits images to the brain.  Many factors cause retinopathy.  People with high blood pressure or diabetes have a higher risk for retinal problems.  White puffy spots on the retina are called cotton wool spots and may indicate nerve damage.  A retinal thrombosis is a blockage in one of the retinal vessels.  A retinal hemorrhage is a bleeding vessel.  Treatment-related retinopathy usually ceases after medication is stopped. The macula lies near the center of the retina.  It is responsible for clarity of sight.  Macular edema means that there is swelling caused by fluid accumulation. Optic neuritis is swelling of the optic nerve.  This nerve transmits information from the retina to the brain.  The head of the optic nerve is the optic disc.  If the disc swells due to an increase in pressure from the brain or spinal fluid, the result is known as papilledema. When undergoing HCV treatment, report eye problems immediately.  Many of these problems turn out to be minor, often caused by dry eyes or even fatigue.  However, since some eye problems can contribute to permanent vision impairment, let your doctor evaluate the situation. Dry eye syndrome or keratoconjunctivitis sicca is common, more so in people with HCV.  It can be caused by insufficient or improper tear production or when tears evaporate too quickly.  Inflammation may accompany dry eyes.  This condition may be uncomfortable or painful.  Ulcers, scars, and even vision loss may occur if dry eye syndrome is not treated. Certain factors may intensify dryness, such as air travel, dry climates, menopause, and some medications.  Antihistamines, decongestants, antidepressants, tranquilizers, estrogen and interferon may cause eye dryness.  Some people develop dry eyes after vision surgery, such as the Lasik procedure. Eye dryness is associated with other diseases, particularly autoimmune disorders.  Those with HCV have an increased risk of autoimmune disease, so your medical provider may want to rule out other causes before assuming that dry eyes are related solely to HCV. Treatment of dry eyes begins with understanding the cause of the problem.  Over-the-counter tear replacement drops or ointment may be suggested.  Choose preservative-free artificial tears if you use them more than 4 times daily.  Avoid sun and glare.  Use sunglasses that wrap around your head and block out UVA and UVB rays.  Your specialist may suggest a dietary supplement, such as omega-3 fatty acids.  Since too much or too little of certain vitamins may contribute to dryness or other problems, do not take a supplement without first discussing it with your medical provider.  Your eye specialist may prescribe medication or recommend plugging your eyes’ tear drainage holes. Your HCV medical provider may know something about eye diseases, but you should see an eye specialist to manage these.  Unless you have a severe problem or need surgery, you will likely see a doctor of optometry (O.D.). Optometrists have 4 years of advanced training in their field.  Although they are not physicians, optometrists can prescribe medication and handle most eye problems except surgery.  If the problem is more complicated, you may be referred to an ophthalmologist (M.D.).  This specialist has attended medical school and can perform surgery.  If you need glasses, you may see an optician.  This professional dispenses glasses and in some states, contact lenses, but does not treat eye diseases. Patients should have a baseline eye exam prior to beginning HCV treatment.  Those with diabetes or hypertension should consult with an ophthalmologist before treatment.  Patients with multiple health conditions, such as HIV and diabetes, need close monitoring during HCV treatment. HCV patients who need a liver transplant are at risk for post-operative eye infections that may occur in all post-transplant situations.  Post-transplant patients with vision or eye problems are encouraged to report these immediately. Eye problems are a concern for those living with HCV, but can occur in anyone.  In spite of the numbers, many of us are tempted to blame every ache and pain on hepatitis C.  It is a natural response to living with a chronic disease.  Others operate in the opposite extreme and deny having any aches or pains of any cause.  Learning to live somewhere in between is sensible.  It takes knowledge and practice to navigate illness.  While you are practicing, keep your eyes wide open. http://www.hcvadvocate.org/news/newsLetter/2008/advocate0708.html#4   Retinal Toxicity During Pegylated Alfa Interferon Therapy for Chronic Hepatitis C By Ronald Baker, PhD There have been documented and anecdotal reports of ocular side effects during therapy with pegylated interferon and ribavirin. The aim of the current study was to evaluate the effect of therapy with pegylated interferon and ribavirin on the eyes of patients with chronic hepatitis C. In this small study, 10 patients receiving peginterferon alfa-2a (Pegasys) and ribavirin and 10 healthy volunteers underwent full ophthalmic investigations and multifocal electroretinogram testing at baseline, and at regular intervals during treatment and post-treatment. The multifocal electroretinogram maps retinal function. Responses were compared with sequential recordings from healthy volunteers. Results All patients had normal clinical ophthalmic investigations at baseline. During therapy a single patient experienced central visual disturbance lasting 24 h with no prolonged ill effect. No other patient was aware of any change in vision. Fundal abnormalities [relating to the retinal area] appeared in five patients during treatment. The multifocal electroretinogram showed reductions in retinal function in five patients. Nine of 10 patients exhibited abnormalities on at least one multifocal electroretinogram or fundoscopic investigation. The authors conclude, "Subclinical retinal toxicity during anti-viral therapy with pegylated alpha-interferon and ribavirin was frequent in this study and it suggests that patients should be warned of this risk and monitored during therapy." Department of Clinical Physics and Bioengineering, Gartnavel General Hospital, Glasgow, UK. See also Is Screening for Peginterferon-related Retinopathy in Hepatitis C Justified? and Treatment with Pegylated Interferon May Cause Eye Complications in Patients with Chronic Hepatitis C Commentary Serious ocular disorders do not appear to occur frequently among patients using standard interferon or the peginterferons plus ribavirin. However, such problems can occur. If vision problems develop, patients should immediately call their physician and set up an appointment to see an ophthalmologist for a complete eye examination. The product information on the pegylated interferons contains a warning about potential ophthalmologic disorders. The following text is excerpted from the WARNINGS section of the Pegasys Product Information (9). There is a similar WARNING on potential ocular disorders associated with peginterferon alfa-2b in the Peg-Intron/Rebetol product information: “Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and papilledema are induced or aggregated by treatment with PEGASYS or other alpha interferons. “All patients should receive an eye examination at baseline. Patients with preexisting opthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic opthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. “Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.” [emphasis added] Selected Excerpts from the Literature on Retinal Toxicity Related to Therapy with Standard Interferon and/or Pegylated Interferon: “The incidence of serious ocular pathology associated with anti-HCV therapy may be very high and is probably associated with peg-IFN alpha-2b. Increased monitoring of patients treated with peg-IFN alpha-2b for retinal and visual changes is warranted.” C Farel et al (3). “Although ocular toxicity is uncommon, it should be emphasized that it can occur any time after the start of interferon therapy, and physicians now treating chronic hepatitis C patients with pegylated interferon must be aware of this potentially serious adverse event.” RA Willson (8). The multifocal electroretinogram can detect retinal dysfunction in chloroquine retinopathy even when the full-field electroretinogram is normal and retinal alterations are subtle. Kellner et al (5). “This case report underlines the necessity of an EOG on patients with INF-alpha therapy. Until now, the pathogenesis of this retinal toxicity has been poorly understood. These results show that the retinal pigmented epithelium is probably implicated at an early stage in this retinal toxicity.” M Crochet et al (2) “Subclinical retinal toxicity during anti-viral therapy with pegylated alpha-interferon and ribavirin was frequent in this study and it suggests that patients should be warned of this risk and monitored during therapy.” Chisolm et al (1) ‘Subclinical neurovisual impairment is a frequent, largely unrecognized complication of low-dose IFN therapy, and patients with chronic hepatitis B and older age appear to be most susceptible. This apparently innocuous complication is long lasting, possibly irreversible in some patients, with yet undetermined consequences on visual function.” Manesis et al (6) “8/19 patients, while on treatment, developed an asymptomatic retinopathy. Among these 3/8 were relapsers and 5/9 were non-responders to interferon monotherapy. All retinal changes faded, often while the patients continued the therapy. There was no significant association in occurrence of retinopathy with haematological and/or biochemical changes.” Jain et al (4) “Although ocular toxicity is uncommon, it should be emphasized that it can occur any time after the start of interferon therapy, and physicians now treating chronic hepatitis C patients with pegylated interferon must be aware of this potentially serious adverse event.” Willson (8) 04/06/05   Citations (1) J A Chisholm and others. Retinal toxicity during pegylated alpha-interferon therapy for chronic hepatitis C: a multifocal electroretinogram investigation. Alimentary Pharmacology & Therapeutics. 21(6): 23-32. March 15, 2005. (2) M Crochet and others. Retinopathy caused by interferon alpha associated with ribavirin therapy and the importance of the electro-oculogram: a case report. Journal of French Ophthalmolology 27(3):257-262. March 2004. (3) C Farel and others. Serious ophthalmic pathology compromising vision in HCV/HIV co-infected patients treated with peginterferon alpha-2b and ribavirin. AIDS 18(13):1805-9. September 3, 2004. (4). K Jain and others. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. British Journal of Ophthalmology 85(10):1171-3. October 2001. (5). U Kellner, Kraus H, Foerster MH.. Multifocal ERG in chloroquine retinopathy: regional variance of retinal dysfunction. Graefe's Archive for Clinical and Experimental Ophthalmology 238(1): 94-97. January 2000. (6). E K Manesis and others. Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis. Hepatology 27(5):1421-7. May 1998. (7). A Tsolakos and N Zalatimo. Hepatitis C: a review of diagnosis, management, and ocular complications from treatment. Optometry 74(8): 517-23. August 2003. (8). R A Willson. Visual side effects of pegylated interferon during therapy for chronic hepatitis C infection. Journal of Clinical Gastroenterology 38(8): 717-722. September 2004. (9). Hoffman-La Roche. WARNINGS: Ophthalmologic Disorders. Pegasys Product Information. Page 10. January 2004.   Ophthalmological Side Effects of Hepatitis C Treatment are Related to Vascular Endothelial Growth Factor Levels Ophthalmological side effects, including vision problems, are sometimes reported by patients receiving interferon-based therapy for chronic hepatitis C. To determine the incidence and cause of these adverse events, researchers prospectively screened interferon-treated patients for vascular ophthalmological side effects, and looked for evidence of activation of angiogenesis (proliferation of new blood vessels). The study included 34 chronic hepatitis C patients; 18 were treated with 180 micrograms/week of pegylated interferon alfa-2a (Pegasys) plus 800 mg/day of ribavirin, while 16 received 1.5 micrograms/kg/week of pegylated interferon alfa-2b (Peg-Intron) plus 800-1200 mg/day of ribavirin. Complete ophthalmological evaluation and serum levels of vascular endothelial growth factor (VEGF) -- a cytokine that promotes blood vessel proliferation -- were assessed before and at the end of therapy. Results 13 patients (38.2%) developed vascular ophthalmological side effects during interferon therapy; 8 patients (23.5%) developed subconjunctival hemorrhage, and 5 (14.7%) had evidence of retinopathy. In 3 of the 13 patients, visual acuity was affected, and 2 had residual lesions during post-treatment follow-up. These side effects were not associated with age, sex, HCV genotype, antiviral schedule, type of interferon, or response to therapy. At the end of treatment, the group with vascular ophthalmological side effects had significantly higher serum VEGF levels than the group without detectable ophthalmological side effects (281 vs 117 pg/mL; P = 0.05). These differences increased when VEGF values were adjusted for platelet count. In the ophthalmological side effects group, baseline VEGF (164 vs 64 pg/mL, P = 0.046) and VEGF/platelet values (0.920 vs 0.320 pg/106 platelets, P = 0.024) were also significantly higher. In a multivariate model, VEGF/platelet values at the end of treatment and hepatic fibrosis stage were the only predictors of vascular ophthalmological side effects. Conclusion The authors concluded that in this exploratory study, antiviral therapy for chronic hepatitis C "frequently induces vascular ophthalmological side effects, apparently through an activation of angiogenesis." 7/21/06 Reference R J Andrade, F J Gonzalez, L Vazquez, and others. Vascular ophthalmological side effects associated with antiviral therapy for chronic hepatitis C are related to vascular endothelial growth factor levels. Antiviral Therapy 11(4): 491-498. 2006.     OPHTHALMOLOGIC EFFECTS A variety of visual changes can occur among patients treated with interferon-based therapy, including retinal hemorrhage, vision changes, and vision loss.1 Ophthalmologic toxicity of interferon is usually reversible, but consideration should be given to treatment discontinuation when it occurs. Any patient with ophthalmologic symptoms should be sent for an ophthalmology consult. PATHOPHYSIOLOGY The underlying pathogenesis of retinopathy associated with interferon is not clear and is probably multifactorial. Lohmann et al2 reports that although the mechanism of interferon-associated anterior ischemic optic neuropathy is unclear, it is most likely to be linked to an immunologic process. It has been postulated that interferon alfa is able to produce autoantibodies, and subsequently causes deposition of immune complexes in the small retinal or optic nerve arteries. Interferon is also an immunomodulator that stimulates other cytokines, such as various interleukins, and upregulates histocompatibility complex class II proteins. These interleukins can cause an inflammatory reaction of the blood vessels and lead to ischemia. Unfortunately, such ischemia and vision loss may be permanent. The incidence of ophthalmologic complications does not seem to be influenced by the type or dose of interferon. However, there is a reported higher incidence of complications in patients with certain clinical entities, specifically diabetes, hypertension, retinal arterial sclerosis, and anemia.3 High levels of low-dose lipoprotein cholesterol and atherosclerotic index may also influence the likelihood of the development of retinopathy.3 There may be a physiologic relationship between the presence of retinal complications and levels of plasma-activated complement 5 (C5a), which is a known potent intravascular aggregator of granulocytes.4,5 In specific clinical studies, when retinal hemorrhage occurred, C5a levels were significantly increased. A high C5a level may be an important step in the pathogenesis of retinal capillary infarction, microvascular emboli, hemorrhage, and cotton wool spot formation. The time of onset after administration is nonspecific, though there are reports of patients with HCV infection who have experienced retinal hemorrhage and/or cotton wool spots early in the course of therapy (ie, within the first 8 weeks).3 There seems to be no relationship between the incidence of retinopathy and the levels of liver enzymes, but increased incidence is reported in patients after the WBC and the platelet count have reached a nadir. Sudden bilateral visual loss with disc-related field defects and segmental optic disc edema has been reported but is rare. Permanent loss of vision is thought to be a result of closure of the retinal capillaries. In a Japanese study,6 50 patients treated with interferon for chronic HCV, HBV, or renal cell carcinoma were examined for retinal complications. Retinal hemorrhages or cotton Side Effects Management Handbook • X. Neurologic/Ophthalmologic • p. 15 wool spots were observed in 23 patients (46%). Hemorrhage without cotton wool spots was found in 14 patients, cotton wool spots without hemorrhage in 5 patients, and both conditions in 4 patients. These findings were potentially reversible. There was one case of branch retinal artery occlusion and one case with micro-aneurysm. RBC decreased significantly in patients with retinopathy compared with those without retinopathy (P <.05%). In another study,7 cotton wool spots disappeared after interferon treatment was stopped and they did not return unless interferon therapy was restarted. However, in three cases, the cotton wool spots disappeared despite continued therapy. These cases emphasize the need for careful retinal surveillance of patients treated with interferon to diagnose this potentially reversible retinal ischemia. Special note: Patients with chronic HCV are known to have circulating immune complexes, and patients with hypertension and/or diabetes have been shown to have damage to endothelial cells, retinal ischemia, and capillary nonperfusion.8 It may be in this population of patients, in whom this combination of factors exists, that the most severe problems are more likely to be seen. BASELINE TESTS RECOMMENDED9 · Ocular examination, including: · Photographic documentation · Recording of visual evoked responses (VERs) · Electroretinograms · Visual acuity · Visual fields All healthcare providers should be aware of potential risk to patients treated with interferons. Patients without conditions predisposing to vascular nonperfusion should be followed closely and visual complaints investigated thoroughly.8 Delayed clinical diagnosis or delays in follow-up of subjective complaints are likely to be associated with poor visual outcomes. COMMON SUBJECTIVE SYMPTOMS* FREQUENTLY NOTED CLINICAL FINDINGS1-3,7,8,10-12 · Abnormal vision · Latency in VERs · Blurred vision · Subconjunctival hemorrhage · Diplopia · Cotton wool spot formation · Dry eyes · Retinopathy · Eye pain · “Splinter hemorrhages” · Nystagmus · Macular edema · Photophobia · Optic tract neuropathy · Vision loss · Capillary nonperfusion · Coinfected patients: vision changes, loss · Anterior ischemic optic neuropathy · Rule out CMV retinitis *Patients may be asymptomatic early in treatment. Side Effects Management Handbook • X. Neurologic/Ophthalmologic • p. 16 TREATMENT STRATEGIES2,11,13 1. Discontinue interferon-based therapy. After discontinuation, treatment-associated neurovisual abnormalities may resolve. There are reports of persistent complications, so careful monitoring of patients is required. If the physician elects to resume interferon therapy; advise him/her to obtain a letter of clearance from an ophthalmologist. 2. Obtain a CBC with differential. 3. Consider aspirin and prednisone for anterior ischemic optic neuropathy. 4. Recommend, for local symptomatic relief: a. Artificial tears/lubricants b. Cool cloths over eyes c. Reduced exposure to light: close blinds/drapes, dim lights, use sunglasses 5. Recognize that patients with a history of CMV retinitis will commonly relapse during antiviral therapy. Special Note: 1. Postliver transplantation symptomatic complications can occur.14 2. Ocular complications have been reported in 2% of patients with 65% of these being opportunistic infections such as14: a. Herpes viral retinitis b. Fungal chorioretinitis c. Central retinal vein occlusion d. Herpes zoster ophthalmicus e. Herpetic keratitis f. Cyclosporine retinopathy 3. There are reported clinical trials of interferon alfa-2a for the treatment of choroid neovascularization membranes.10 REFERENCES 1. Kadayifcilar S, Boyacioglu S, Kart H, Gursoy M, Aydin P. Ocular complications with highdose interferon alpha in chronic active hepatitis. Eye. 1999;13:241-246. 2. Lohmann CP, Kroher G, Bogenrieder T, Spiegel D, Preuner J. Severe loss of vision during adjuvant interferon alfa-2b treatment for malignant melanoma. Lancet. 1999;353:1326. 3. Kawano T, Shigehira M, Uto H, et al. Retinal complications during interferon therapy for chronic hepatitis C. Am J Gastroenterol. 1996;91:309-313. 4. Sugano S, Suzuki T, Ishii K, et al. Elevated plasma C5a levels as a possible risk factor of retinal bleeding during interferon-alfa therapy for chronic hepatitis C. Hepatology. 1996;24 (4 part 2):277. 5. Sugano S, Suzuki T, Watanabe M, Ohe K, Ishii K, Okajima T. Retinal complications and plasma C5a levels during interferon alpha therapy for chronic hepatitis C. Am J Gastroenterol. 1998;93:2441-2444. 6. Chuman T, Nao-i N, Sawada A, Kawano T, Shigehira M. Interferon-induced retinal changes. Journal of Japanese Ophthalmology. 1994;98:616-621. 7. Guyer DR, Tiedeman J, Yannuzzi LA, et al. Interferon-associated retinopathy. Arch Ophthalmol. 1993;111:350-356. 8. Chambers RB, Downie A, Foote B, Davidorf FH. Interferon alfa-associated retinopathy. J Am Osteopath Assoc. 1997;97:43-45. Side Effects Management Handbook • X. Neurologic/Ophthalmologic • p. 17 9. Manesis EK, Moschos M, Brouzas D, et al. Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis. Hepatology. 1998;27:1421-1427. 10. Thoelen A, Menozzi M, Huber C, Messmer E. Treatment of choroidal neovascularization in age-related macular degeneration with interferon alpha-2a: a short term, nonrandomized pilot study. Geriatric Journal of Ophthalmology. 1995;4:137-143. 11. Purvin VA. Anterior ischemic optic neuropathy secondary to interferon alfa. Arch Ophthalmol. 1995;113:1041-1044. 12. Shahidullah AB, Cerulli MA, Berman DH. Interferon may cause retinopathy during hepatitis therapy. Am J Gastroenterol. 1995;90:1543. 13. Woodruff R. Symptom Control in Advanced Cancer. Melbourne, Australia: Asperula Pty Ltd; 1997:90-91. 14. Ng P, McClusky P, McCaughan G, Glanville A, MacDonald P, Keogh A. Ocular complications of heart, lung, and liver transplantation. Br J Ophthalmol. 1998;82:423-428.   Here are a few messages from others who have had problems with their eyes while on treatment. You can read these by entering our Chat Room and Message Boards     From:  RADMAN11    Apr-28 12:28 pm       (2 of 3)    7385.2 in reply to 7385.1  I was on my 9th week of peginton/ribavarin therapy whe I started getting "blurry"vision.I didn't think any thing of it that day.The next day it was still there so I figured I'd call my gastroenterologist+let him know.He referred me the following day to an opthomaligist,at which time my vision was NOTICEABLY worse. The Doc didn't see anything ,but sent me for an MRI 2 days later.At that point my vision was really getting bad,Fast!After nothing showed on the MRI,I was sent for a spinal tap,to see if there was excess spinal fluid pressure.It,too,showed nothing.This was at 7 days after the start of symptoms,at which time I could not see well enough to drive or work.Next day I was sent to a nuero-opthamologist who saw hemorrhaging in both eyes+swelling of the optic nerve(pappiledema).He recommended immediately stopping pegintron/ribavarin.At this point I had about a 1/4 inch round area of vision in my left eye+60% loss in the right(9 days after start of symptoms).That was in nov.'02Iwas finally able to see well enough to return to work in early Feb'03.I now(4-28-03) have about 40% vision in my left eye+80% in the right.The nuero-op doc informed that as probably as good as it was going to get+that after talking to other docs,this is being diagnosed more+more!Some days the vision is'ok"+other days it is not good at all.So.BEWARE! this is a fairly common side effect of this therapy.I am unable to undergo any further treatment,but blood work (done this past week) shows all liver levels normal.GOOD LUCK,

Elevated ALT/AST

ELEVATED ALT/AST

WARNING:

Hepatotoxicity, including fatality, has been observed in interferon-treated patients. Any

patient developing liver function abnormalities during treatment should be monitored

closely, and if appropriate, treatment should be discontinued. When hepatotoxicity

occurs, it is usually seen in the first 5 to 6 weeks of treatment.

Interferon-based therapy is contraindicated in patients with decompensated liver disease.

There are reports of worsening liver disease, including jaundice, hepatic encephalopathy,

hepatic failure, and death following interferon therapy in such patients. Therapy should

be discontinued for any patient developing signs and symptoms of liver failure. Patients

with a documented rise in aminotransferase levels during interferon therapy should be

further evaluated for AIH and drug toxicities.

ALT/AST ELEVATIONS AND LIVER DISEASE

Liver diseases themselves may be associated with mild, moderate, or marked elevation of

ALT and/or AST levels.1 Although moderate aminotransferase elevations are nonspecific,

certain liver diseases tend to be associated with either mild or marked ALT elevation.

LIVER CONDITIONS ASSOCIATED WITH MILD, ASYMPTOMATIC ELEVATION OF

ALT/AST1

Common Uncommon

· Fatty liver and NASH (40%–60% of cases) · Drug-induced liver disease

· Chronic HCV (20%–40% of cases) · Autoimmune hepatitis

· Chronic HBV · Alpha1-antitrypsin deficiency

· Alcoholic liver disease · Wilson’s disease

· Hemochromatosis · Miscellaneous conditions

DEFINITION OF MILD/MARKED AMINOTRANSFERASES IN LIVER DISEASE1

Test Mild* Moderate Marked

ALT or AST <2–3 2–3 to 20 >20

Alkaline phosphatase <1.5–2 1.5–2 to 5 >5

*Numbers in table refer to multiples of the upper limits of normal for the individual enzyme.

Side Effects Management Handbook • IX. Hematologic • p. 8

LIVER CONDITIONS ASSOCIATED WITH MARKED INCREASE OF ALT/AST

· Acute viral hepatitis

· Drug-induced hepatitis, especially acetaminophen (Tylenol®)/alcohol and antiretroviral therapy

· Hepatic ischemia due to shock or severe right heart failure

· Acute biliary obstruction

· Budd-Chiari syndrome

MANAGEMENT STRATEGIES

1. Monitor liver enzyme levels in accordance with package inserts.

2. If aminotransferase levels flare, reassess for other causes and consider dose reduction

or discontinuation of therapy.

REFERENCE

1. American Digestive Health Foundation/American Liver Foundation. Viral Hepatitis Facts:

Approach to Elevated Liver Enzymes. HBV087R0.

Fatigue

FATIGUE

Fatigue is a common symptom of hepatitis, and it can become worse while treating.

1. Get plenty of rest. Sleep more at night and take naps during the day if you can. Try to schedule regular rest periods each day.
2. Limit your activities: Do only the things that are most important to you.
3. Delegate tasks. Don’t be afraid to get help when you need it. Ask family and friends to pitch in with things like child care, shopping, housework, or driving.
4. Eat well, and be sure to include plenty of healthy foods.
5. When sitting or lying down, get up slowly. This will help prevent dizziness.
6. Don’t stand when you can sit.
7. Plan your activities and assemble everything before you start.
8. Reschedule daily tasks so you do some only 3 or 4 times a week so you have time to rest each day.
9. Use a cart, wagon or basket to carry things from one part of the house to the other to eliminate retracing your steps.
10. Sit on a stool in the bathroom while shaving or applying makeup. Prop elbows up on counter if you can.
11. Use warm, not hot water for baths or showers. Hot water increases muscle fatigue.
12. If your fatigue is severe, think about asking your doctor for a handicap sticker for your car.
13. Shop when you are at your peak energy.
14. When shopping alone, ask a grocery clerk to carry out groceries.
15. If you arrive home from grocery shopping tired, put away only the perishables. A family member of friend can do the rest.
16. Shop by phone whenever possible.
17. Avoid peak shopping/traffic hours.

FATIGUE

Fatigue is a multidimensional condition with several theoretic foundations: physiologic,

pathologic, and psychological.1,2 Fatigue may be a subjective feeling of tiredness,

weariness, diminished energy, or temporary loss of physical and emotional energy

preventing response to sensory or motor stimuli.3,4 Moreover, fatigue is often a primary

dose-limiting factor that prevents completion of therapy.5 Fatigue is closely correlated

with other conditions, such as sleep disorders, anxiety, agitation, stress, and depression,

and continued, unmanaged fatigue can lead to deterioration of physical and mental

activities.2

Fatigue is the principal side effect of interferon and ribavirin therapy in each trial listed in Table 1. This is partly a direct side effect of interferon-alpha, with its stimulation of the immune response giving the release of cytokines and other factors that cause fatigue, and is partly related to the anemia caused by ribavirin. Ribavirin is directly toxic to red blood cells, causing them to break down, giving a median decline in hemoglobin of approximately 3 g/dL,(3,4) which will cause most patients to feel fatigued. Fatigue also can clearly be multifactorial, with insomnia, dehydration, and anorexia contributing in individual patients. Management Encourage patients to get plenty of sleep, keep well-hydrated, and eat well-balanced meals to maintain their weight if possible. Acetaminophen (Tylenol) <2 gm per day orally in divided doses, also can be very helpful in combating fatigue, particularly with 325-1,000 mg as a premedication prior to an interferon dose if the fatigue is worse 1-2 days after an interferon injection.

PATHOPHYSIOLOGY

Interferon

Two different types of fatigue are associated with interferon: (1) physical fatigue or

weakness that occurs from activation of the interferon cascade and subsequent flulike

syndrome6; and (2) neuroendocrine system fatigue that is associated with

neuropsychological fatigue (mental or depressive), that may be accompanied by cognitive

(CNS) slowing or decreased performance status that occurs as an effect of these agents.7

Fatigue accompanying interferon administration is frequently a dose-limiting or

treatment-limiting toxicity and may lead to dose reduction in 10% to 49% of all patients.7

Ribavirin

Ribavirin may cause an acute decrease in Hgb during the first 1 to 2 weeks of

administration (a mean Hgb drop of 2.7 g/dL) that can quickly cause a patient to

experience acute fatigue. However, this initial fatigue may often progress slowly to

chronic fatigue from the same mechanisms stated above. Ribavirin also causes

intermittent fatigue when administered to patients infected with HCV.8

Side Effects Management Handbook • VII. Flulike Syndrome • p. 5

CONTRIBUTING RISK FACTORS FOR FATIGUE3

Physiologic Psychologic/Psychosocial Treatment/Situational

· Anemia (impaired aerobic

energy metabolism)

· Metabolic disease

· Cancer

· Poor nutritional status

· Hypermetabolic state (active

tumor growth, infection,

fever, or surgery)

· Cardiovascular disease

· Chronic obstructive

pulmonary disease

· HIV/HCV co infection

· Thyroid or hepatic

dysfunction

· Weakness

· Chronic pain

· Diagnostic tests

(psychologic or physical)

· Anticipatory

nausea/vomiting

· Ethyl alcohol, excess

caffeine, nicotine, other

addictive substances

including illicit drugs

· Sleep disturbances

· Lack of exercise

· Anxiety

· Depression

· Grief, loss

· Social factors/psychosocial stress

–Divorce

–Work difficulties

–Economic status

–Lack of social support

· Stress

· Environmental influence

· Interferon or other bio- or

chemotherapy

· Surgery

· Radiation therapy

· Transplantation

· Dose/timing of

administration: interferon

· Other medications, eg:

–Antibiotics

–Ribavirin

–Analgesics, sedating

antihistamines

–Antihypertensives

–Anxiolytics

–Antidepressants

–Sleep agents (long-

acting)

TYPES OF FATIGUE1,4

Acute: Normal or expected tiredness characterized by localized, intermittent, or sporadic

symptoms; rapid onset; and short duration (days or weeks) that are usually relieved by

rest. Chronic: Abnormal or excessive generalized tiredness that is constant or recurrent

for at least 1 month and an insidious gradual onset with cumulative effect. Chronic

fatigue is not relieved by sleep or rest, and while its cause is unknown, it has a major

impact on quality of life (QOL) and ability to maintain compliance with a drug regimen.

Fatigue arises following the initial flulike syndrome (FLS) accompanying interferon

treatment, but unlike FLS, develops more slowly and may continue to increase with

continued therapy.

Side Effects Management Handbook • VII. Flulike Syndrome • p. 6

ASSESSMENT

1. Assess subjective and objective data that may influence fatigue.

2. Elicit patient information about patterns of fatigue: onset, duration, intensity,

alleviating or aggravating factors, sleep patterns, impact on QOL, and signs and

symptoms.1

3. Assess objective and subjective symptoms of fatigue, including general appearance,

description, attitude, speech, activity, and concentration.3

4. Consider testing extent of fatigue with Pearson-Byars Scale, Fatigue Symptom

Checklist, Symptom Distress Scales, Profile of Mood States, Rhoten Fatigue Scale, or

other fatigue scales.1,3,7

5. Review medications: Replace sedating antihistamines and other sedating drugs if

possible. Address other drug side effects that cause fatigue or flulike symptoms

(nausea/vomiting, anorexia, depression, anemia, diarrhea).

6. Obtain CBC with differential; rule out treatment-induced anemia.

7. Assess laboratory data (TSH, glucose and hormone levels, including electrolytes,

alanine aminotransferase/aspartate transaminase [ALT/AST], SMA; serum albumin;

and extrahepatic diseases).9

8. Determine if pain (or arthralgias and myalgias) awaken patient or if medications are

required to prevent awakening.

9. Assess thyroid function.4

10. Assess for presence of other risk factors (see Risk Factor table above).

11. Assess timing and extent of exercise schedule. Assess for complaints of dyspnea on

exertion or chest pain while exercising.

12. Assess food and fluid intake.

PREVENTIVE STRATEGIES

1. Instruct patient about need for adequate diet, hydration, rest, and exercise and energy

conservation; develop patient self-report form.

2. Encourage light exercise program, especially aerobic exercises (eg, walking), to build

strength and endurance and to increase patient tolerance and improve pre-existing

activity level.

3. Consider education regarding patient-initiated interventions or energy-conservation

techniques: resting, “catnapping” (no longer than 20 minutes), alteration of activities;

limit standing.

4. Help patients improve sleep/wake patterns.

5. Provide strategies to improve nutritional, environmental, or social situation.

6. Suggest reading or engaging in other distracting/relaxing activities.

7. Educate family members; bolster support systems.

TREATMENT STRATEGIES

1. Consider altering timing of administration (eg, give peginterferon in the afternoon or

evening).

2. Consider use of psychostimulants for profound fatigue (eg, methylphenidate

[Concerta™, Metadate®, Methylin®, Ritalin®], 20 mg PO SR Q AM; rarely, BID).

Side Effects Management Handbook • VII. Flulike Syndrome • p. 7

3. Consider administration of an antidepressant to increase energy levels; bupropion

(Wellbutrin XL®) 100 to 400 mg QD in divided doses; and mirtazapine (Remeron®)

15 to 30 mg QHS.

4. For fatigue from emotional stress, counsel regarding possibility of chronic fatigue;

offer feedback and encouragement in defining limitations/abilities; supply emotional

support by verbal and nonverbal responses; help patient develop effective coping

patterns with adequate support systems; prevent or resolve a crisis by utilizing crisis

intervention techniques; and/or make appropriate referrals to mental health worker,

social worker, or chaplain.

5. Encourage relaxation strategies: music, visual imagery, yoga, visualization, walking,

etc.

6. Consider addition of amantadine (Symmetrel®) 100 mg QHS to reduce neuromuscular

fatigue.10

7. Consider recommending omega 3 120–180 mg PO QD, vitamin E 800 IU/d,

vitamin C 1000 mg/d, and multivitamins.

By Jillian L. Lokere, MS

October 31, 2004 — The serotonin antagonist ondansetron significantly reduces the fatigue and depression associated with chronic hepatitis C virus (HCV) infection, according to a study by Thierry Piche, MD, and colleagues presented at the 55th annual meeting of the American Association for the Study of Liver Diseases held in Boston, Massachusetts.

Chronic HCV infection commonly causes fatigue, for which there is little effective therapy. Ondansetron, a 5-hydroxytryptamine receptor type 3 (5-HT3) antagonist, has shown efficacy in the treatment of chronic fatigue syndrome. Therefore, Dr. Piche and colleagues conducted a placebo-controlled, double-blind trial to test its effects on the fatigue associated with chronic HCV infection.

Thirty-six patients with chronic HCV whose main symptom was fatigue (scored higher than 4 on a visual analogue scale) were randomized to receive either ondansetron (4 mg twice daily) or placebo for 30 days. Fatigue and depression were measured at Days 0, 15, 30, and 60 using the Fatigue Impact Scale and the Beck Depression Inventory, both of which are self-report questionnaires.

Ondansetron significantly improved patient fatigue scores after 15 days of treatment; and this improvement was sustained through the final endpoint at 60 days. At baseline, the mean fatigue score was 85.4 in the ondansetron group and 98.2 in the placebo group, a nonsignificant difference. On Day 15, the ondansetron group reported a 30% improvement from baseline, with a mean score of 57.1. This improvement was maintained at Day 30 and Day 60, with mean scores of 54.5 and 60.8, respectively. No significant improvements in fatigue were seen in the placebo group at any time point.

Similar improvements were seen in the depression scores of patients receiving ondansetron, with a 50% reduction in depression by Day 15 that was maintained throughout the study. Again, no improvements were seen in the placebo group.

The investigators suggest that the positive impact of ondansetron on chronic HCV-related fatigue supports the idea that the fatigue experienced by these patients involves serotoninergic pathways, which might also be the case for other chronic liver diseases. 5-HT3 antagonists could therefore be useful in these cases, although the cost of treatment is a concern.

Reference

Piche T, Vanbiervliet G, Renou C, et al A. Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomized double blind placebo controlled study. Program and abstracts of the 55th Annual Meeting of the American Association for the Study of Liver Diseases; October 29 - November 2, 2004; Boston, Massachusetts. Abstract 354.

http://clinicaloptions.com/hep/news/news_AASLD2004_354.asp

Fever is principally a side effect of treatment, and tends to be worse with the first few injections. Fever >101° F (38.5° C) for more than 24-48 hours, or not following an  injection, should prompt a medical evaluation for an infectious source of the fever.

Flulike Syndrome

FEVER, CHILLS, AND RIGORS

PATHOPHYSIOLOGY

Fever is a commonplace response to most biologic agents and is strongly dependent on

dosage. As part of the FLS associated with interferon, initial fevers of 104°F are not

uncommon.1 The patient’s overall condition, including general health, age, CV status,

and potential for infection should be assessed before administering antipyretics.1 Severity

of fever, chills, and rigors abates somewhat as treatment continues and as tachyphylactic

response occurs.2 Flulike symptoms that appeared upon initial administration, first with

chills and rigors, followed by fever about an hour later, may recur if dosage is increased.3

Fever has come to be viewed as an adaptive mechanism that facilitates body defenses.

Many of the cytokines, including the interferons, interleukins, and TNF-a, are

endogenous mediators of fever (endogenous pyrogens), although TNF may also be an

endogenous antipyretic.4 These and other mediators of immunity initiate a pathway that

raises the thermoregulatory set point of about 98.6°F (37°C) to raise body temperature—a

neuro-immunomodulatory reaction.5,6 The cytokines within the hypothalamus may

initiate fever, but the signals may originate from peripheral nerves within the brain.4 High

fevers (over 104°F) may be induced by the initial dose of interferon, other biologic

response modifiers, biologic agents, disease, malignancy, and many other causes. The

fever process may be induced via a multipathway mechanism that may have therapeutic

value. Thus, controversy still exists as to the wisdom of administering antipyretics to

reduce a mild fever.1

Interferon alfa modulates fever by changing the body’s release of hypothalamic

prostaglandin E2, which may stimulate a neurotransmitterlike substance to raise the

temperature set point.7 Fever is a multiphasic process that is a series of physiologic

responses (eg, peripheral vasoconstriction and shivering) and compensatory behavioral

responses (eg, adding clothing or changing body position).4 The stages of fever include:

· Stage I: Chill or Cold5

As the body is working to raise the temperature set point, vasoconstriction and

shivering (during which the patient feels cold) may occur, which may lead to

increased oxygen consumption and tissue catabolism. Other responses include thirst

and chills.

· Stage II: Hot or Plateau5

The body temperature achieves or exceeds the new set point. Skin is flushed and

warm, basal metabolic rate and oxygen demand are elevated, and tachycardia and

tachypnea will be experienced. Thirst is common, as are headaches and myalgias.

The cause for the fever may be determined and treated, or antipyretics may be

administered at this point.

Side Effects Management Handbook • VII. Flulike Syndrome • p. 9

· Stage III: Wet (Defervescence)5

Responses include vasodilation, flushing, and diaphoresis (especially above 38°C),

and dehydration.

ASSESSMENT STRATEGIES

1. Educate patients regarding appropriate way to take temperature (eg, avoid taking

temperature immediately after drinking coffee or smoking; keep thermometer in place

for adequate time).

2. Investigate infectious causes for development of high fever or fever persisting for

more than 48 hours after administration of peginterferon.

PATIENT EDUCATION

Patients should be informed that:

1. Flulike symptoms often accompany biologic therapy and severity may vary.

2. Adaptation or tachyphylaxis usually develops to fever and chills in about 2 to

3 weeks.

3. To ensure adequate hydration, they should drink the equivalent, in fluid ounces per

day, of one half their body weight (in lb). For example, a 160-lb person should

consume 80 fl oz water/d.

4. Relaxation and guided imagery techniques can minimize discomfort and anxiety.

5. A diary can be used to record fever patterns and other symptoms.

6. They should report to medical personnel any fevers uncontrolled by antipyretics or

unrelated to treatment.

7. They should notify medical personnel of “red flags” such as fever >104°F, prolonged

rigors, altered mental state, or cyanosis.

TREATMENT STRATEGIES

1. Evening administration (but earlier than at bedtime) of interferon may be helpful in

reducing the patient’s awareness of fever and other flulike symptoms, although the

patient may experience loss of sleep.2 Depending on the timing of symptoms, patients

may need to try even earlier administration.

2. Comfort measures (warm blankets, extremity wraps, ice packs) can be helpful.

3. Promote adequate hydration and give IV hydration if needed.

4. Antipyretics may be administered to reduce temperature >101°F and as analgesia,

but controversy exists as to their overall effect.1 Some providers recommend

premedicating with these agents and others inform patients to take them as soon as

flulike symptoms begin to develop.

a. Acetaminophen (Tylenol®) 325 to 650 mg Q6H PRN, not to exceed 2 to 3 g/d.

b. Ibuprofen (Motrin®, Advil®) 200 to 800 mg TID, not to exceed 2400 mg/d, with

food.

5. Prednisone is known to limit therapeutic effect and should not be used.8

6. Diphenhydramine (Benadryl®) 35 to 50 mg PO is infrequently used in resistant cases

as premedication and Q6H PRN.

7. Anti-HCV treatment can be dose reduced or discontinued should fever and other side

effects become unmanageable, but patients should be advised that the biologic effects

Side Effects Management Handbook • VII. Flulike Syndrome • p. 10

may be compromised by dose reduction and that the fever may contribute to the

therapeutic response.2

REFERENCES

1. Sandstrom SK. Nursing management of patients receiving biological therapy. Semin Oncol

Nurs. 1996;12:152-162.

2. Borden EC, Parkinson D. A perspective on the clinical effectiveness and tolerance of

interferon-a. Semin Oncol. 1998;25(suppl 1):3-8.

3. Kiley KE, Gale DM. Nursing management of patients with malignant melanoma receiving

adjuvant alpha interferon-2b. Clin J Oncol Nurs. 1998;2:11-16.

4. Kluger MJ, Kozak W, Leon LR, Soszynski D, Conn CA. Cytokines and fever.

Neuroimmunomodulation. 1995;2:216-223.

5. Haeuber D. The flu-like syndrome. In: Rieger PT, ed. Biotherapy: A Comprehensive

Overview. Boston, Mass: Jones and Barlett; 1995:243-258.

6. Mackowiak PA. Concepts of fever. Arch Intern Med. 1998;158:1870-1881.

7. Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis. 1999;(suppl 2):

S294-S304.

8. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Saf. 1994:10:115-150.

Side Effects Management Handbook • VII. Flulike Syndrome • p. 11