Case Study 1

 

"Grand Rounds: A 32-Year-Old Woman With Fever and Flank Pain"
Ellen Sue Sossner Kaufman, RN, BSN, CCRN

[Clinician Reviews 7(9):204-208, 210-211, 1997. © 1997 Clinicians Publishing Group and Williams
& Wilkins.]

 

A 32-year-old white female was referred to a hepatologist for a liver biopsy following presentation to an emergency department (ED) where she had complained of fever and flank pain secondary to pyelonephritis from obstructive renal calculi. Past history was remarkable for a needle stick injury (the patient was a registered critical care nurse), sustained 10 years earlier in 1982 from a patient believed to be infected with non-A, non-B hepatitis. Six weeks subsequent to the needle stick, she became ill with a mild flu-like syndrome. She was not icteric and no laboratory tests were obtained. Routine physical exams following this exposure revealed sporadic elevations in liver function tests (LFTs). No further workup was obtained until her visit to the ED.

On physical exam in the ED, the patient was found to be well developed, well nourished, and in no acute distress. She was anicteric. Lymph nodes were negative, chest was clear to auscultation, and there was no hepatosplenomegaly.

No spider angioma or palmar erythema was present, and there was no edema of the extremities. The patient was very active and did not complain of fatigue or malaise. There was no evidence or history of decompensated liver disease or cirrhosis.

At the ED visit, laboratory values revealed a markedly elevated white blood cell count. Urinalysis was positive for blood, white blood cells, and bacteria.

Liver function tests were abnormal, with an aspartate aminotransferase (AST) of 48 U/L and an alanine aminotransferase (ALT) of 60 U/L. In light of these elevated LFTs, a complete hepatitis profile was obtained. The patient was found to be hepatitis C (HCV) antibody positive. She subsequently tested positive for HCV by polymerase chain reaction (PCR).

The patient was referred to a hepatologist who procured a percutaneous liver biopsy to establish baseline liver condition. Interferon alpha (IFN) therapy was initiated after careful consideration of side effects versus possible benefits. The patient began a drug regimen of 3 million international units (MIU) administered subcutaneously three times a week.

A decrease in LFTs was noted after 4 weeks of therapy. Liver function tests continued to decline and were normalized by week 8. The IFN was well tolerated except for complaints of fatigue and headache. After 26 weeks of drug therapy, the patient tested negative for the presence of serum HCV via PCR. At that time, the IFN dosage was reduced to 1.5 MIU three times per week. Liver function tests remained normal for eight more weeks, when they increased markedly. A new serum HCV test was positive, and the IFN dosage was increased to 3 MIU three times per week. Though LFTs returned to normal, side effects worsened, with hair thinning and mood swings compounding the chronic headache and fatigue. Drug therapy was discontinued at the patient's request because of the worsening side effects. Following discontinuation of IFN therapy, LFTs showed a rebound effect, reaching new highs (see Figure 1).

The patient remained off IFN therapy for 16 months. After reading about several new treatment modalities, the patient expressed interest in undergoing the IFN protocol in the Reichard study,[1] which documented a positive response from prolonged IFN therapy. With the guidance of a hepatologist, the patient began the new protocol of 3 MIU three times weekly for 52 weeks.

After 4 weeks of therapy LFTs normalized, and HCV was not detectable in the serum after 16 weeks of drug therapy (see Figure 2). Adverse reactions continued to be present but were better tolerated secondary to increased sleep, decreased stress, daily exercise, and a low-fat diet. Flu-like syndrome and hair thinning were the primary complaints.

Starting at week 60, the IFN dosage was weaned in increments of one-half million units every 4 weeks (ie, 2.5 MIU at week 60, 2.0 MIU at week 64, 1.5 MIU at week 68). At 1.5 MIU, the patient reverted to a seropositive state and all therapies were ceased as reevaluation was deemed necessary. Since the patient was asymptomatic with minimal liver damage, a decision was reached between the patient and her physician to discontinue any further IFN treatment. Liver function tests and HCV RNA by PCR continue to be monitored every 4 to 6 months to follow any progression or worsening of the disease. Currently the patient remains asymptomatic with no apparent worsening of her liver function. She leads an active life.

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Discussion

Infection with HCV poses a significant public health problem. This disease is a major cause of acute and chronic hepatitis and cirrhosis worldwide. It is estimated that an average of 150,000 people a year are diagnosed with HCV in the United States.[2] The prevalence is highly variable however, and the actual number of infected individuals is not known. Hepatitis C virus accounts for more than 90% of hepatitis cases attributable to percutaneous exposures,[2] thus the occupational risk for healthcare providers cannot be ignored. There is no vaccine currently available for HCV.

Hepatitis is a viral infection in which the hepatic cells necrose as a result of leukocytic-histiocytic reaction and infiltration.[3] The physical manifestations of viral hepatitis reflect liver cell damage resulting from the body's immune response to the virus, which in turn alters cellular function. The predominant mechanism for injury is thought to be direct hepatocytotoxicity,[4] though the exact mechanism by which this virus causes hepatitis is not known.

The pathogen itself is a positive, single-stranded RNA virus. It is enclosed in a lipid envelope containing approximately 10,000 nucleotides, which code for some 3,000 amino acids. The genomic organization of HCV is similar to that of the human flaviviruses known to cause yellow fever.[4] Like other RNA viruses, a DNA template is not required for replication.

Hepatitis C virus is spread via direct blood contact. Modes of transmission include needle-stick exposure, injecting-drug use, and transfusions. Other risk factors include body piercing, tattooing, and sharing razors, toothbrushes, and manicuring implements. There is, however, a population of HCV- positive individuals without any identifiable risk factors.

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Diagnosis

Clinically, the majority of hepatitis patients remain asymptomatic, evading detection until the disease becomes chronic. Many cases are detected incidentally through blood donation, blood tests ordered as part of routine physical examinations, employment physicals, or insurance examinations. Typically, the physical examination is unremarkable.

Laboratory analysis in the form of LFTs can confound efforts to diagnose HCV. Obesity and alcohol as well as certain pharmacologic agents can lead to elevated transaminases. The HCV infection can also produce wide fluctuations in LFTs, ranging from normal to three to four times the normal range. This yo-yo phenomenon is a distinguishing characteristic of HCV infection; therefore, the patient must undergo serial testing for monitoring three to four times yearly throughout his or her lifetime.[2]

Hepatitis C can manifest as an acute or chronic infection, though most cases are chronic. The chronic form is further subdivided into chronic persistent and chronic active hepatitis. Chronic persistent infection is characterized by the continued presence of the virus following infection and is capable of causing a recurrence of the disease.[5] It is the more benign form of the two and rarely progresses.

The chronic active form manifests as ongoing hepatocellular damage and is believed to progress to cirrhosis in 20% to 50% of documented cases.[6] Treatment Treatment modalities for HCV have been mostly empiric. Recently, IFN has been used successfully to treat chronic HCV infection. The decision to institute therapy remains controversial, however. Many practitioners prefer the wait-and-see approach given the low risk of mortality, the high proportion of asymptomatic patients, the frequent adverse reactions to IFN therapy, and the considerable cost of the treatment. Others believe the strong association between HCV and cirrhosis justifies treatment in most cases.[7]

The use of IFN as a nonspecific antiviral agent was discovered more than 35 years ago by Isaacs and Lindermann. They observed that fluids from virus-infected cell cultures contained a cell-specified protein that could react with cells to render them resistant to infection by many viruses.[5] It has since been discovered that IFN profoundly affects vital cellular and bodily functions, including cell metabolism and growth, immunity, and tumors. Interferon is not a selective drug and therefore inhibits proliferation of normal cells as well as infected cells.[7]

Currently, recombinant IFN is the only treatment approved for chronic hepatitis C. It is thought to act by directly inhibiting the replication of hepatocytopathic HCV through multiple mechanisms, including inhibiting viral attachment and uncoating, inducing intracellular proteins and ribonucleases that convey antiviral properties to the cell, and amplifying both specific and nonspecific immune responses to viral antigens.[4] Interferon does not have a selective affinity for hepatocytes.

Adverse reactions are common among patients undergoing IFN therapy, with primarily flu-like symptoms seen in approximately 50% of all recipients. Other frequent side effects include depression, alopecia, and gastrointestinal distress.[8] The high probability of side effects plays an important role in the risk-versus-benefit analysis. The treatment protocol, based on a 1989 study by Davis et al,[9] is 3 MIU IFN administered subcutaneously three times weekly for 6 months, after which the dosage is reduced to 1.5 MIU for three more months. This protocol, which has been widely accepted and used worldwide, is the only dosing regimen approved by the US Food and Drug Administration (FDA) for treatment of HCV. Approximately 50% of patients treated with IFN go into remission. Recurrence is common, affecting 70% to 80% of all patients within 6 to 12 months of discontinuing the conventional IFN-dosing regimen.[2] Response to the drug therapy is transient, and sustained remission is difficult to achieve.

The possibility of sustained remission occurring after a longer treatment regimen with IFN has been researched in two large-scale trials. In a Japanese study, more than 50% of 16 patients receiving 6 MIU for 52 weeks had a sustained response indicating that relapse was suppressed by prolonged IFN treatment. However, approximately 38% of the patients were resistant to prolonged IFN therapy.[10] A Scandinavian study by Reichard et al[1] of 30 patients treated for 60 weeks with 3 MIU three times weekly reported a sustained response in 60% of patients. Of those responding, 42% had a sustained response documented 24 weeks after treatment cessation. These studies support the conclusion that prolonged treatment with IFN induces a high percentage of sustained response, which coincides with cessation of viral replication.[1]

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Conclusion

Hepatitis C virus accounts for more than 90% of all hepatitis cases attributable to percutaneous exposure, putting physician assistants and nurse practitioners at increased occupational risk of acquiring the disease. The majority of infected persons remain asymptomatic until the disease becomes chronic; at that point hepatocellular damage can occur, and in some cases, the disease may progress to cirrhosis. Currently, there is no vaccine available for HCV, and the decision to initiate therapy remains controversial.

The only FDA-approved treatment for HCV is long-term administration of IFN. However, the high probability of side effects and treatment cost must be considered when weighing the risks and benefits of therapy. In addition, disease recurrence is common and remission is difficult to achieve. However, the results of two recent studies suggest that prolonged IFN therapy may halt viral replication and induce a high percentage of sustained response in patients.

 

About the Author

Ellen Sue Sossner Kaufman is a staff nurse in the open heart unit at Weustoff Hospital in Rockledge, Fla.