Hepatitis C Infection With Normal Liver Chemistry Tests

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Hepatitis C Infection With Normal Liver Chemistry Tests

Clinical Gatrsoenterology and Hepatology, May 2008

Fried, University of North Carolina at Chapel Hill, Chapel

Hill, North, Carolina

Article Outline

• Clinical Scenario

• The Dilemma

• Defining Normal Serum Alanine Aminotransferase Activity

• Natural History of Chronic Hepatitis C With Persistently Normal

Alanine Aminotransferase

• Response to Antiviral Therapy

• Current Treatment Recommendations for Hepatitis C With Persistently

Normal Alanine Aminotransferase

• Recommendations

• Suggested Reading

Clinical Scenario

A 50-year-old man was recently diagnosed with chronic hepatitis C

after a life insurance physical. He was very surprised by the

diagnosis because he led an active lifestyle, exercised regularly,

and did not smoke or drink any alcohol except a glass of wine once or

twice per month. He had experimented with injecting drugs during his

freshman year at college. During the last 5 years, he had undergone

regular physicals and never was told of any " liver problems. " In

reviewing laboratory data from his referring provider, liver enzymes

had been checked on 2 previous annual physicals, with serum ALT

activities of 44 and 41 U/L. Physical examination shows a healthy

man, body mass index, 24 kg/m2, without any stigmata of chronic liver

disease. Currently, serum ALT activity is 44 U/L, and HCV RNA is

>700,000 IU/mL with genotype 1. Platelet count is 244,000 cells/mm3.

The Dilemma

This patient is a generally healthy man who was likely infected with

chronic hepatitis C more than 30 years before the consultation.

Despite the prolonged duration of infection, he had no signs or

symptoms of hepatitis C or advanced liver disease. There is

historical evidence that his serum ALT activities have been

persistently within the normal range. When confronted with such an

individual, clinicians might speculate that aggressive treatment of

hepatitis C in this vigorous patient is unwarranted. However, further

evaluation and management can be planned only after considering the

natural history of chronic hepatitis C infection with persistently

normal ALT levels and the outcome of therapy in these patients.

Defining Normal Serum Alanine Aminotransferase Activity

Elevations of serum ALT and AST activity serve as important markers

for liver injury. The finding of an abnormal ALT in a patient, even

in the absence of clinical signs or symptoms, should prompt further

evaluation for occult liver disease. Hereditary hemochromatosis,

chronic viral hepatitis, and nonalcoholic steatohepatitis are

frequently overlooked causes of asymptomatic ALT abnormalities that

could have serious consequences over time. To define " abnormal ALT "

that would prompt clinical investigation, healthcare providers must

be confident in the definition of " normal " ALT, a value below which

they can be secure that liver disease is unlikely. However, despite

the importance of these definitions to general medical care and the

seemingly simple dichotomy that should be represented by a laboratory

test above or below a specific threshold, significant controversy

exists as to the absolute value for a normal ALT.

Reference ranges for serum ALT activity vary widely across

laboratories. An informal search of Web resources indicate that the

upper limit of normal ALT is generally between 40 and 50 U/L for

males and slightly lower for females, although a normal ALT value as

high as 72 U/L was noted. How can the variability be explained, and

what are the clinical consequences of applying different thresholds

for normality?

Reference ranges for serum ALT activity are often developed from the

variance in results derived from a local " healthy " population. Thus,

including subjects with occult liver disease in this reference group

could spuriously raise the threshold for what is considered normal

ALT activity. This possibility was examined in an important study

from Italy. Prati et al evaluated more than 6000 first-time blood

donors and examined the associations between clinical and laboratory

factors and serum ALT levels. Serum ALT activity was associated with

several risk factors for fatty liver disease including body mass

index, blood glucose levels, and hypertriglyceridemia among others.

When only subjects with the lowest risk for liver disease were

analyzed, the study suggested that the updated upper limit of normal

ALT should be 30 U/L for males and 19 U/L for females.

The new reference range recommended by this study improved the

sensitivity for identifying patients with liver disease but decreased

the specificity. Adoption of these thresholds as normal could lead to

a dramatic increase in the diagnosis of patients with occult liver

disease, most as a result of nonalcoholic fatty liver disease, the

impact of which is beyond the scope of this article. Nevertheless,

the new reference range as suggested in this study does have clinical

correlates in patients with chronic hepatitis C. As discussed below,

patients with persistently normal ALT activity (PNALT) defined by

local laboratories often have significant liver disease. Furthermore,

when sustained virologic response (SVR) is achieved in these

patients, the level of ALT activity often decreases to levels below

30 U/L, suggesting that necroinflammatory activity was indeed present

before treatment.

Natural History of Chronic Hepatitis C With Persistently Normal

Alanine Aminotransferase

Approximately 25% of patients with chronic hepatitis C have PNALT,

defined as serum ALT repeatedly within the normal range for a

specified prolonged period of observation. Guidelines from the

American Association for the Study of Liver Disease suggest that at

least 2 ALT measurements within the normal range taken during a

period of at least 6 months can define those with PNALT. However, it

has long been recognized that serum ALT levels fluctuate in patients

with chronic hepatitis C, and flares of disease activity might occur

at irregular intervals.

The absence of a gold standard for PNALT makes comparisons across

studies difficult. Nevertheless, it is generally accepted that

individuals with PNALT have more mild hepatic histology when compared

with patients with persistently abnormal ALT. In a retrospective

study, the necroinflammatory activity was negligible and the stage of

fibrosis in 480 patients with PNALT was significantly lower compared

with a large cohort of patients with abnormal ALT (Table 1). It

should be noted that 10% of the PNALT cohort had stage 3 bridging

fibrosis on liver biopsy. Other cross-sectional studies have shown

that cirrhosis was present in 0%–11% of patients with PNALT.

Several studies have attempted to evaluate the long-term outcome in

patients with PNALT, and all suggest that they have a slower rate of

fibrosis progression (fibrosis score over estimated duration of

infection) compared with patients with abnormal ALT activity. In a

study of 24 patients with PNALT who underwent serial liver biopsies

during a 10-year follow-up period, fibrosis stage remained stable. In

aggregate, these data support the favorable natural history of HCV

with PNALT, but the potential still exists for progression to

advanced liver disease.

Response to Antiviral Therapy

Initial concerns that PNALT patients should be treated differently

developed from early trials of standard interferon that demonstrated

PNALT patients could have a flare of ALT during therapy or after

treatment cessation, particularly in nonresponders to treatment. The

low overall chance of response with interferon monotherapy coupled

with the potential for increasing disease activity discouraged the

use of this agent in those with PNALT. Indeed, early registration

trials for interferon and ribavirin combination therapy and peg-

interferon therapies all excluded patients with normal ALT at the

time of screening, which hampered our understanding of the treatment

response in this patient population. Subsequently, small studies of

interferon in combination with ribavirin showed more favorable

results with SVR rates as high as 50% in patients with normal serum

ALT activity, similar to those reported in patients with abnormal ALT.

The largest randomized trial of patients with PNALT treated with peg-

interferon and ribavirin was reported by Zeuzem et al. More than 400

patients with PNALT (3 measurements of ALT within the normal range

during the 18 months before enrollment) were randomized (3:3:1) to

receive peg-interferon alfa-2a 180 ìg/week and ribavirin 800 mg/day

for 24 or 48 weeks or observation only. No patient in the observation

arm achieved spontaneous viral clearance. The overall SVR was 30% for

patients treated for only 24 weeks and 52% for patients treated for

48 weeks. As with all interferon-based studies, genotype had a major

impact on treatment response. Genotype 1 patients had SVR rates of

13% and 40% in the 24- and 48-week arms, respectively, whereas

genotype 2 and 3 had response rates of 72% and 78%, respectively.

These results are consistent with studies that included only subjects

with abnormal ALT levels, although in the present study the lower

dose of ribavirin than is currently recommended for genotype 1

patients (1000–1200 mg/day) likely compromised these results to some

extent.

The evolution of serum ALT levels in this study of patients with

purportedly PNALT is particularly instructive and further undermines

the current accepted thresholds for normal ALT. The median baseline

ALT value in this cohort was approximately 25 IU/L, well within the

normal range. In those achieving SVR, serum ALT activity further

decreased and remained between 10 and 15 IU/L. In addition, 52% of

patients with well-documented PNALT in the untreated arm had

transient elevations of ALT above the upper limit of normal during

the observation period.

Current Treatment Recommendations for Hepatitis C With Persistently

Normal Alanine Aminotransferase

Numerous evidence-based guidelines have been published by various

governmental agencies and professional societies regarding management

of patients with chronic hepatitis C, and all of them have included

comments about patients with PNALT activities. They generally

recognize the difficulty in defining normal ALT for an individual

patient, that the natural history in this subset of patients with

chronic hepatitis C might be more benign, and that antiviral response

is generally similar regardless of ALT levels. The most recent

National Institutes of Health Consensus Statement in 2002

acknowledged that " all patients with chronic hepatitis C are

potential candidates for antiviral therapy. " Qualifying statements

for patients with normal ALT included that expert opinions differed

on the need for biopsy and treatment for these patients and suggested

that " numerous factors must be considered in recommending treatment,

including favorable genotype, presence of hepatic fibrosis, patient

motivation, symptoms, severity of comorbid illness, and the patient's

age. "

Excerpts from guidelines from the American Association for the Study

of Liver Diseases recommend that " Regardless of the serum

aminotransferases levels, the decision to initiate therapy with

interferon and ribavirin should be individualized based on the

severity of liver disease by liver biopsy, the potential of serious

side effects, the likelihood of response, and the presence of

comorbid conditions. "

Recently published guidelines by the American Gastroenterological

Association suggest that " Patients with normal ALT activity are

candidates for antiviral therapy or for monitoring without

intervention as determined on an individual basis and as influenced

by patient factors such as motivation, genotype, histologic activity,

and fibrosis. "

Recommendations

Patients with chronic hepatitis C and PNALT should be evaluated in a

similar manner to patients with chronically abnormal ALT levels, such

as screening for other chronic liver diseases including

hemochromatosis. During the initial consultation, I would provide

reassurance about the natural history of chronic hepatitis C in those

with PNALT. However, I would also stress the uncertainties of this

information and our limited ability to predict outcome over the

ensuing decades. I would evaluate this patient's candidacy for

antiviral therapy and probe whether there were any contraindications

to peg-interferon and ribavirin treatment. During a discussion about

the probabilities of SVR versus the potential side effects associated

with combination antiviral therapy, I would assess the patient's

level of enthusiasm for undergoing treatment. For black patients, the

likelihood of SVR is significantly lower than for white patients, and

this must be factored into the discussion as well.

I would also suggest a liver biopsy in this patient to assess grade

and stage to provide prognostic information that might be helpful as

he contemplates antiviral therapy. For patients with genotype 2 or 3,

liver biopsy is more likely to be deferred in light of the higher

likelihood of SVR, although alcohol use and the potential for hepatic

steatosis or advanced fibrosis, among other factors, might lead to

biopsy in individual cases. Liver biopsy before therapy is not

mandatory, particularly for individuals who are certain that they

would like to begin treatment.

The results of liver biopsy must be interpreted cautiously as a

result of the well-documented potential for sampling error.

Noninvasive serum panels of hepatic fibrosis might provide

supplementary evidence regarding stage of liver disease but also

suffer from significant limitations. Thus, providers must use all

available clinical information as they counsel the patient about

disease severity and potential for progression.

During a follow-up visit after the patient has had the opportunity to

reflect on our initial discussion, we would review biopsy results and

again discuss therapeutic options. For patients with moderate to

severe hepatic histology (>stage 2), antiviral therapy should be

encouraged. For milder liver disease (stage 0–1), patients might

choose to defer treatment, although follow-up biopsy in 3–5 years

should be considered to verify stable disease.1 My general

recommendation is that good treatment candidates (without

contraindications) undergo antiviral therapy with peg-interferon and

ribavirin, regardless of hepatic histology, if they are sufficiently

motivated. The probability of SVR usually outweighs the manageable

risks associated with treatment.