
 hepatitis c virus ( hcv ) infection is reported to have a prevalence of approximately 3% worldwide .
majority of patients with chronic hcv have a mild , asymptomatic elevation in serum transaminase levels with no significant clinical symptoms . around 25% of patients with chronic hcv have persistently normal alanine aminotransferase ( pnalt ) .
definition of normal alanine aminotransferase ( alt ) has changed over time and reference range for normal alt differs based on different laboratory cutoffs .
prati et al .   in 2002 suggested new cutoffs with 30  u / l ( international unit ) for men and 19  u / l for women compared to 40 
u / l and 30  u / l for men and women , respectively .
a 2009 american association for the study of liver disease ( aasld ) practice guideline suggested an alt value of 40  u / l on 2 - 3 different occasions separated by at least a month over a period of 6 months .
others have used 3 different alt levels equal to or below upper limit of normal ( uln ) separated by at least 1 month and sometimes over a period of 18 months .
it was generally thought that people with pnalt have a mild liver disease and the degree of liver fibrosis is minimal [ 614 ] . based on this ,
later on , it was realized that a considerable number of such patients developed significant inflammation and fibrosis over time .
more recently , treatment has been recommended along the same lines for patients with pnalt as patients with elevated alt .
although more data is becoming available about the relationship of liver enzymes and course of chronic hcv infection , data regarding hcv infection and pnalt is relatively scarce . because of variation in the definition of pnalt
, fewer studies have looked at the relationship of pnalt with chronic hcv infection using updated normal alt definitions .
department of hepatology at the university of illinois ( u of i ) medical center , chicago , had a database of over 1200 patients with chronic hcv infection .
medical records of these patients were reviewed in an effort to characterize patients with chronic hcv infection and pnalt .
histological and clinical parameters for patients with pnalt as well as elevated alt were analyzed .
database of patients with hcv infection presenting to u of i medical center , chicago , was reviewed .
patients with biopsy proven hcv infection and a detectable hcv ribonucleic acid ( rna ) in blood were chosen .
of these , patients with an alt at liver biopsy , at least one additional over the next 12 months , and liver biopsy slides available for review were identified .
most of the liver biopsy procedures were done at u of i medical center and in cases where biopsies were done at outside facility they were read again at u of i medical center .
two expert hepatologists , who were masked to clinical data , assigned knodell et al .  
intervals for alt measurement were chosen around the time of liver biopsy as well as 3 , 6 , and 12 months after biopsy .
patients with end - stage renal disease like those on dialysis and stage iv chronic kidney disease with creatinine clearance of 1529 , those who received organ transplant , those with co - infection with hiv , those who were positive for hepatitis b surface antigen ( hbsag ) , and those receiving antiviral therapy for chronic hcv were excluded .
pnalt was defined as alt  30  u / l on at least 2 different occasions over 12 months .
strict pnalt was defined as alt  30  u / l for males and 19 
u / l for females . demographic data including age at biopsy , gender , and race were recorded .
clinical data included body mass index ( bmi ) , alcohol use , tobacco use , and presence of diabetes mellitus ( dm ) .
hcv virus was further characterized by recording hcv rna levels , genotype , and duration of infection .
histological data included individual markers of inflammation like portal tract inflammation , piece meal necrosis , and lobular inflammation as well as fibrosis according to knodell et al . scoring system .
inflammatory score ( sum of portal tract inflammation , piece meal necrosis , and lobular inflammation ) and histologic activity index ( hai ) score ( sum of inflammatory score and fibrosis ) were calculated .
histologic data from pnalt was then compared with patients from elevated alt group . finally , clinical characteristics of pnalt with advanced fibrosis were compared with pnalt but with no advanced fibrosis .
independent sample t - test and chi - squared test were used to calculate p values where appropriate .
a total of 243 patients out of a database of 1200 patients with hcv satisfied the study criteria .
main reasons to exclude a large number of patients were a lack of detectable rna despite biopsy report , outside biopsy report but slides not available for review , single or no alt value , and patients undergoing treatments .
those analyzed were further divided into pnalt , strict pnalt , and elevated alt group .
32 ( 13% ) of these patients were identified as pnalt group and 211 ( 87% ) were identified as elevated alt group . only 13 ( 5% ) patients satisfied criterion for strict pnalt and this group was not analyzed further .
the range of alt values at different time intervals was specified ( table 1 ) .
24 ( 75% ) of pnalt patients were females while 85 ( 40% ) with elevated alt were females .
13 ( 41% ) with pnalt were african american ( aa ) compared to 87 ( 41% ) with elevated alt , 14 ( 44% ) were caucasian ( w ) compared to 79 ( 38% ) with elevated alt , and 5 ( 15% ) were hispanic ( h ) compared to 44 ( 21% ) with elevated alt .
there was no statistically significant difference in the racial distribution between pnalt and elevated alt group .
there was a higher frequency of women in the pnalt group compared to the elevated alt group ( p = 0.001 ) .
diabetes and alcohol use were more common among patients with elevated alt compared to pnalt ( p = 0.04 and 0.049 , resp . ) .
most notably , patients with pnalt had a higher rate of cirrhosis ( p = 0.007 ) .
there were no differences in age at biopsy , tobacco use , bmi , rna level , and duration of infection between pnalt and elevated alt groups ( table 2 ) .
further evaluation of liver histology showed no statistically significant difference in mean fibrosis score , mean portal tract inflammation score , mean piecemeal necrosis score ( pmn ) , mean lobular inflammation score , mean histologic activity index ( hai ) score , and mean inflammatory score between pnalt group and elevated alt group ( table 3 ) .
comparison of clinical characteristics of pnalt group with advanced fibrosis with pnalt group without advanced fibrosis showed that only platelet count was significantly different between the two groups ( table 4 ) .
tables 5 and 6 characterize the distribution of hcv genotypes based on pnalt and hai score , respectively .
the natural history of chronic hcv infection with pnalt is poorly understood [ 1820 ] .
we attempt to describe the characteristics of patients with pnalt , which constitutes almost 2530% of patients with chronic hcv infection .
firstly , a high proportion of patients with pnalt had advanced fibrosis , and degree of inflammation was not significantly different than chronic hcv infection with abnormal alt .
secondly , it was difficult to identify a substantially large set of patients with hcv infection and pnalt given that there is a significant fluctuation in the alt level over time [ 9 , 15 ] .
we chose duration of 12 months to observe the levels of alt instead of 6 months period .
it is becoming clear that 6 months is probably too short given that in some cases alt level may fluctuate after initial period of stability [ 7 , 2124 ] .
most patients with pnalt were females , which is consistent with earlier findings [ 79 ] .
similarly , age at biopsy , bmi , rna level , and duration of infection were not significantly different between the two groups .
hcv genotype distribution showed that a majority ( 81% ) of patients belonged to genotype 1 and it is a well - characterized fact .
there was no significant difference in terms of distribution of genotypes between the 2 groups ( table 5 ) .
also there was no significant difference in hai according to genotype distribution ( table 6 ) .
hcv genotyping was performed in 181/243 ( 75% ) patients and was missing in 62 ( 25% ) patients .
the likely reason was transition from paper to electronic records in 1990s and loss of some data .
within pnalt , those with advanced fibrosis differed from those without advanced fibrosis by platelet count only .
similarly , pnalt patients were divided based on low - normal alt ( < 19 ) and high - normal alt ( 2030 ) for comparing hai scores among them but no significance was seen ( table 7 ) .
studies to date have been mentioning a milder disease for pnalt in terms of fibrosis and necroinflammation [ 79 , 2628 ] .
some studies have pointed to this fact as well [ 14 , 29 , 30 ] .
this is an interesting finding given that despite significant inflammation ( comparable to abnormal alt ) the alt levels in some of these patients have been consistently low .
similarly , advanced fibrosis was more common in pnalt group as compared to the elevated alt group ( p = 0.007 ) .
it is thought that alt levels normalize in patients with advanced fibrosis   and that is why some authors will advocate doing liver biopsy in patients with hcv infection and normal alt levels .
it is interesting to note that the 6 patients with pnalt who had cirrhosis also had evidence of thrombocytopenia .
our results indicate that platelet count can be used as a marker to predict fibrosis in patients with pnalt .
for instance , almost all patients in the study group had an alt measured around biopsy but only slightly more than half had alt measured around 12 months .
second , sample size was relatively small and might not be a true representative of patients with pnalt .
this might in particular be valid for pnalt with advanced fibrosis as 8 ( 25% ) out of 32 patients with pnalt had f3-f4 while only 19 ( 9% ) out of 211 patients with elevated alt had f3-f4 ( p = 0.007 ) .
it is not clear if the outcome would have been the same if denominator for pnalt was high .
small sample size was caused mainly as described before as well as comorbid conditions like advanced kidney disease , hiv , hbsag positive , and being on antiviral treatment .
for example , 11 patients with pnalt were excluded as they had esrd ; alt levels are known to be lower in esrd [ 34 , 35 ] secondary to an impaired immune response in patients with esrd .
this raises concern that those with pnalt and severe liver fibrosis may have been in biochemical remission .
for example , of the 8 patients with severe liver fibrosis ( stages 3 and 4 ) and pnalt , only 2 patients had 4 alt measurements over 12 months ( over the period of 0 , 3 , 6 , and 12 months ) , while 3 patients had 3 alt measurements over 12 months , and the remaining 3 patients had only 2 alt measurements over the 12 months period .
thus , it is not possible to say with certainty that all patients with pnalt and severe liver damage had uniformly low alt all along .
in conclusion , histological changes observed in hcv patients with pnalt will argue that alt is not a reliable indicator of hepatic inflammation or fibrosis .
female gender , absence of dm , and abstinence from alcohol were associated with pnalt .
these findings indicate the need for more studies with higher number of pnalt patients to look at the relationship of pnalt with changes occurring at histological and molecular levels .
 patients with chronic hepatitis c virus ( hcv ) infection and persistently normal alanine aminotransferase ( pnalt ) are generally described to have mild liver disease . 
 the aim of this study was to compare clinical and histological features in hcv - infected patients with pnalt and elevated alt . 
 patients presenting to the university of illinois medical center , chicago , who had biopsy proven hcv , an alt measurement at the time of liver biopsy , at least one additional alt measurement over the next 12 months , and liver biopsy slides available for review were identified . 
 pnalt was defined as alt  30 on at least 2 different occasions over 12 months . 
 of 1200 patients with hcv , 243 met the study criteria . 
 13% ( 32/243 ) of patients had pnalt while 87% ( 211/243 ) had elevated alt . 
 significantly more patients with pnalt had advanced fibrosis ( f3 and f4 ) compared to those with elevated alt ( p = 0.007 ) . 
 there was no significant difference in the histology activity index score as well as mean inflammatory score between the two groups . in conclusion , in a well - characterized cohort of patients at a tertiary medical center , pnalt did not distinguish patients with mild liver disease . 