C A T H E D R A L A N D J O H N C O N N O N S C H O O L
M U M B A I , I N D I A
0 3 / 0 9 / 2 0 1 4
KARAN MODY CAID:12543300 This research study has been undertaken to see whether the Upper Normal Limit (UNL) of Alanine Aminotransferase (ALT) needs to be redefined in comparison to the current reporting levels for the Indian Population with healthy set parameters.
UPPER NORMAL LIMIT OF ALANINE AMINOTRANSFERASE FOR THE INDIAN POPULATION
1
INDEX
1. Foreword…………………………………………………………………... 2
2. Acknowledgments………………………………………………………… 3
3. Abstract…………………………………………………………………… 4
4. Introduction……………………………………………………………….. 5
5. Objectives…………………………………………………………………. 8
6. Methods…………………………………………………………………… 8
7. Results…………………………………………………………………….. 10
8. Discussion………………………………………………………………… 13
9. Conclusion……………………………………………………………….... 18
10. Glossary…………………………………………………………………… 20
11. References………………………………………………………………… 21
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2
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3
ACKNOWLEDGEMENTS
This research study to know whether the upper normal limits (UNL) of Alanine
Aminotransferase (ALT) needs to be redefined for Indian population would not have been
possible without the guidance of my mentors, Dr. Samir Shah, Head, Dept. of Hepatology,
Institute of Liver Diseases, HPB Surgery and Transplant, Global Hospitals, Mumbai, and Dr.
Shyam Kottilil, Scientific Director, NIH District of Columbia Program for AIDS Program,
National Institutes of Health/NIAID/LIR, Bethesda, MD, U.S.A., who have initialized this
research. The time they have taken out from their busy schedule to explain the concept and value
of this research is immensely appreciated. The mentorship and guidance right through this
research has been exemplary. The valuable feedback given by them during the preparation of this
research paper has made these analyses accurate and clinically relevant. Their support and
encouragement have made this research possible.
The data analysis required for this research would not have been possible without the
cooperation of the Metropolis Laboratory, Mumbai. Dr. Rina Shah, Head of Pathology, Global
Hospitals, Mumbai was instrumental in providing the required data. Dr. Gaurav Lillaney and the
staff of the IT department cannot be thanked enough for their patience and understanding in
retrieving meaningful data without which this research study would not have achieved its clinical
purpose.
4
ABSTRACT
Background:
Alanine Aminotransferase (ALT) is a liver enzyme that is found in blood. The Liver function test/Liver chemistry panel measures the level of ALT present in blood. When the liver is damaged, ALT is released into the bloodstream and levels increase. The farther from normal the test results are, the more likely you are to have significant liver disease. American Association for the Study of the Liver Diseases (AASLD) has redefined the Upper Normal Limit (UNL) of ALT at 30U/L in males and 19 U/L in females. For the Indian population the UNL of ALT is 45 U/L irrespective of sex.
Objectives:
To determine whether the current Upper Normal Limit (UNL) of ALT at 45 U/L for male and female in the Indian Population needs to be redefined in line or around AASLD Upper Normal Limit (UNL) of ALT at 30U/L in males and 19 U/L in females; whether there is modulation in UNL of ALT amongst apparently healthy and unhealthy study population with reference to set parameters; whether modulating Body Mass Index (BMI) has an influence on other set parameters of the study population; whether modulating BMI influences ALT levels in males and females of the study population; the percentage of males and females in the entire supplied population sample who lie between the current UNL of ALT and the redefined UNL of ALT who potentially require further follow-up and investigation for probable liver disease.
Method:
This retrospective study was completed on ALT data of 8034 patients of whom 1490 had readings of all set parameters available from the body profiles supplied by the Metropolis Laboratory and of these 215 males and 157 females formed the cohort having all normal readings of set parameters.
Results:
The 95% CI mean UNL of ALT was 33U/L for males and 21 U/L for females who had all normal set parameters. The 95% CI mean UNL of ALT was 40U/L for males and 26 U/L for females who had at least one abnormal set parameter. With BMI<25 kg/m2 73% of patients were normal and 27% (abnormal) suffered from at least one of high FBS, total cholesterol or blood pressure. When BMI≥25 kg/m2 the normal patients were 48% and abnormal were 52%. With BMI≤23 kg/m2 the normal patients were 80% and abnormal 20%, and when was set as BMI>23 kg/m2 48% were normal and 52% suffered one of the above ailments. Modulating BMI between 23 kg/m2 and 35 kg/m2 showed a constant rise in mean UNL of ALT for males and for females the rise was not constant. 23% of males and 39% of the females from the entire study population were between the current reporting UNL of ALT of 45U/L and new calculated UNL of ALT of 33 U/L and 21 U/L for males and females respectively.
Conclusion:
This study found the UNL of ALT for the normal cohort of males and females from the Indian population to be clearly lower than the current UNL of ALT; the UNL of ALT rose when patients were suffering from other ailments; modulating BMI had an impact on presence of other diseases; and a significant number of males and females were between the current and new UNL of ALT. These patients should be evaluated for liver damage in future studies.
5
INTRODUCTION
The liver is the largest glandular organ in the body weighing about three pounds and performs many vital
functions to keep the body pure of toxins and harmful substances. It is a vital organ that supports nearly
every organ in the body in some facet. Without a healthy liver, a person cannot survive (1).
The liver plays an active role in the process of digestion through the production of bile which is stored in
the gallbladder. Bile is the substance needed to digest fats and is a mixture of secretions containing water,
electrolytes and organic molecules like bile salts, cholesterol, and the pigment bilirubin. Bilirubin present
in bile is a product of the liver’s digestion of worn out red blood cells. The liver is responsible for
metabolizing carbohydrates, lipids, and proteins into biologically useful materials. The Kupffer cells of
the liver play an important role by capturing and digesting bacteria, fungi, parasites, worn-out blood cells,
and cellular debris (2).The liver also performs the following functions:
• Detoxifies the blood to rid it of harmful substances such as alcohol and drugs
• Stores some vitamins, iron and simple sugar glucose
• Converts stored sugar to usable sugar when the body’s sugar (glucose) levels fall below normal.
• Breaks down hemoglobin as well as insulin and other hormones
• Converts ammonia to urea, which is vital in metabolism
• Destroys old red blood cells
As the liver performs so many vital functions in digestion, metabolism, detoxification, storage, production
and immunity, it is prone to disease. Fortunately, the liver has an incredible capacity for regeneration of
dead and damaged tissues.
Common liver diseases include hepatitis infection, fatty liver disease, cancer as well as damage from
alcohol, the pain reliever acetaminophen, and some cancer drugs. Another common sign of liver problems
6
is jaundice, the yellowing of the skin and eyes due to the buildup of bilirubin, a waste product of normal
hemoglobin breakdown (1, 2).
Liver function tests (LFT)/ Liver chemistry panel are blood tests used to help diagnose and monitor liver
disease or damage. The tests measure the levels of certain enzymes and proteins in your blood.
Some of these tests measure how well the liver is performing its normal functions of producing protein
and clearing bilirubin. Other liver function tests measure enzymes that liver cells release in response to
damage or disease. Though, conditions other than liver disease or damage can lead to abnormal liver
function test results. Test results can be normal in people who have liver disease or damage.
Liver function tests can be used to:
• Screen for liver infections, for signs of inflammation seen with conditions such as hepatitis
• Monitor the progression of a disease, such as viral or alcoholic hepatitis, and determine how well
a treatment is working
• Measure the severity of a disease, particularly scarring of the liver (cirrhosis)
• Monitor possible side effects of medications
Liver function tests check the levels of certain enzymes and proteins in your blood. Levels that are higher
or lower than normal can indicate liver problems. Among other tests, LFT includes the determination of
the levels of Alanine aminotransferase (ALT); an enzyme found in the liver that helps your body
metabolize protein, and Aspartate aminotransferase (AST); an enzyme that helps metabolize alanine, an
amino acid. When the liver is damaged, ALT is released into the bloodstream and levels increase. The
farther from normal the test results are, the more likely you are to have significant liver disease (3).
Abnormal liver tests may be detected in the blood in a variety of liver conditions. Mild to moderate
elevations of the liver enzymes are common. They are often unexpectedly encountered on routine blood
screening tests in otherwise healthy individuals. One of the most common causes of mild to moderate
7
elevations of these liver tests is a condition referred to as fatty liver (hepatic steatosis). Fatty liver is most
often caused by alcohol abuse, diabetes and obesity. Chronic hepatitis B and hepatitis C infections are
other causes of chronic mild to moderate liver enzyme elevation. The other diseases that can cause liver
damage and corresponding abnormal liver enzymes are viral hepatitis A, autoimmune hepatitis, overdose
of acetaminophen, Wilson’s Disease, Crohn’s disease etc.(4,5)
Serum Alanine aminotransferase (ALT) is the most sensitive biochemical marker of hepatocellular
injury (6). Serum ALT is a valid and sensitive indicator of liver-cell damage. Serum ALT is an important
parameter for screening, diagnosis and follow-up of liver diseases (7, 8). Nowadays, Non-Alcoholic Fatty
Liver Disease (NAFLD) is the most common cause of asymptomatic serum ALT elevation in people (9).
Elevated liver enzymes discovered during routine medical care are associated with higher future
mortality(10).
American Association for the Study of the Liver Diseases (AASLD) has redefined the Upper Normal
Limit (UNL) of ALT at 30U/L in males and 19 U/L in females. This has now been internationally
accepted normal level for ALT. There have been numerous studies conducted around the world which
redefine the normal ALT threshold for a healthy population. But as ethnicity differences in ALT levels
have also been observed (11,12,13,14) it is imperative to see whether the old UNL of 45 U/L, irrespective of
sex, for the Indian Population needs to be redefined in line with the internationally accepted normal levels
of ALT. In India, currently used UNL for AST or ALT levels are mainly based upon western population
and those provided by manufacturer of kits (15). Currently defined UNL of ALT might underestimate
patients at risk of chronic liver disease (16).This retrospective research study has been conducted for
apparently healthy Indian Population with predetermined set parameters to primarily determine whether
the old UNL of ALT needs to be modified and brought in line or around the internationally accepted UNL
of ALT at 30U/L in males and 19 U/L in females, which apparently could be more sensitive for the
diagnosis of liver disease.
8
OBJECTIVES
The main objectives of this retrospective study of Indian Population are:
• To determine whether the current Upper Normal Limit (UNL) of ALT at 45 U/L for male and
female in the Indian Population needs to be redefined in line or around AASLD Upper Normal
Limit (UNL) of ALT at 30U/L in males and 19 U/L in females
• To determine whether there is modulation in UNL of ALT amongst apparently healthy and
unhealthy study population with reference to set parameters
• To determine whether modulating Body Mass Index (BMI) has an influence on other set
parameters of the study population
• To determine whether modulating BMI influences ALT levels in males and females of the study
population
• To determine the percentage of males and females in the entire supplied population sample who
lie between the current UNL of ALT and the redefined UNL of ALT who potentially require
further follow-up and investigation for probable liver disease
METHODS
Study Design
This is a retrospective study of patient blood and body profile data collected from Metropolis Laboratory,
Mumbai for the period January, 2012 to July, 2014.
Study Population, Cohort and Selection Criteria
The Metropolis Laboratory, Mumbai supplied ALT data for a total of 8034 patients in four tranches. This
data was supplied in Microsoft Excel Spreadsheets (MS Excel) with date, SID no., sex, age of the patients
and ALT values. A total of four spreadsheets were received having a patient count of 7238, 492, 142 and
9
162 respectively for whom ALT values were available. A separate body profile data of many patients in
Microsoft Word format (MS Word) was supplied, which had alcohol use, BMI, blood pressure and
impressions of Impaired Fasting Blood Sugar (FBS), Post Lunch Blood Sugar (PLBS), total cholesterol
etc. The Information Technology Department (IT) of the laboratory was explained to match test codes of
each separate test of ALT, FBS, total cholesterol, body checkup etc. The SID Nos. which contained all the
above test codes were then segregated and corresponding body profile data in MS Word was retrieved.
Few patient data in MS Excel had FBS and total cholesterol data along with the ALT readings but for a
significant remaining they had to be drawn out from the body profile impressions supplied in MS Word.
There were a number of body profiles for which the ALT data was missing and vice versa. Each SID No.
from the body profiles in MS Word had to be matched with the SID No. on the MS Excel containing the
ALT data. There were innumerable body profiles for which the corresponding ALT data was missing and
therefore, were not selected for the analysis. There were a number of body profiles which had only last
four digits of the SID No. and corresponding ALT data SID Nos. had multiple matching last four digits
but the initial series numbers were different. The body profiles were then matched by age, sex, BMI etc.
details on the ALT excel sheets and the unmatched were not selected for this study.
After matching the SID No. from the body profile in MS Word to the SID No. in four MS Excel
Spreadsheets containing ALT data as supplied by the IT department of the laboratory the corresponding
FBS, total cholesterol, blood pressure, BMI and alcohol use data/impression from MS Word was recorded
in columns of these four separate MS Excel Spreadsheets. Though, in all 8034 patient ALT data, 4973
males and 3085 females, was received in four MS Excel Spreadsheets only 1490 SID No. matched the
body profiles supplied.
These 1490 complete patient data formed the study population and was then put to test based on set
parameters of:
• BMI≤23 kg/m2(As per WHO the normal BMI for Asians≤23)(17)
• Normal blood pressure of 120/80, 130/80 mm Hg
10
• Total Cholesterol<200
• FBS≤100
• No regular or heavy use of alcohol
The cohort from the study population for this retrospective research came to a total of 372 apparently
healthy patients based on the above set parameters. The cohort included 215 males and 157 females.
Statistical Analysis
The entire statistical analysis, including the selection process based on the set parameters was completed
using MS Excel and McCallum Layton Confidence Interval Calculator. Using the ‘IF, AND, OR’
conditional formulae in MS Excel, separate “Normal”/“Abnormal” columns for each set parameter was
created in each of the four ALT MS Excel sheets. Then all the sheets were collated and final analysis was
done using mean, total count, standard deviation, median and percentile functions of MS Excel. The final
mean UNL at 95% CI was calculated using the McCallum Layton Confidence Interval Calculator.
RESULTS
On the basis of MS Excel ‘IF, AND, OR’ conditional formulae analysis a total of 215 males and 157
females were found to be apparently normal based on the set parameters. As per Table 1 below, for this
cohort of 215 males and 157 females the UNL of mean ALT was found to be 30.83 U/L and 19.06 U/L
respectively with BMI≤23 kg/m2. The standard deviation was 16.51 and 10.83 and median was 28 U/L
and 16U/L for males and females respectively. The corresponding 25, 75 and 95 percentiles were 18U/L,
40 U/L and 66.3 U/L for males and 11 U/L, 27 U/L and 36.40 U/L for females. The 95% Confidence
Interval (CI) for the mean ALT with study population having BMI≤23 was 28.62 to 33.04 for males and
17.37 to 20.75 for females with the CI at ±2.21 and ±1.69 respectively. The corresponding 95% CI for
mean ALT in study population of 274 males and 196 females having BMI<24 kg/m2was 29.51 to 33.25
11
and 17.71 to 20.89 and with study population of 360 males and 238 females having BMI<25kg/m2 the
corresponding 95% CI for mean ALT was 30.83 to 34.31 and 17.78 to 20.64.
Table 1: Calculation of mean ALT with 95% Confidence Interval of cohort at different BMI BMI≤23 BMI<24 BMI<25 FEMALES MALES FEMALES MALES FEMALES MALES TOTAL COUNT 157 215 196 274 238 360 MEAN 19.06 30.83 19.30 31.38 19.21 32.66 STD. DEV. 10.83 16.51 11.39 15.83 11.28 16.82 MEDIAN 16.00 28.00 16.00 29.00 16.00 29.00 PERCENTILE 25% 11.00 18.00 11.00 19.00 12.00 20.00 PERCENTILE 75% 27.00 40.00 26.25 40.00 26.00 42.00 PERCENTILE 95% 36.40 66.30 38.00 62.05 38.30 67.00 95% CI 17.37 to 20.75 28.62 to 33.04 17.71 to 20.89 29.51 to 33.25 17.78 to 20.64 30.83 to 34.31CI ±1.69 ±2.21 ±1.59 ±1.87 ±1.43 ±1.74
An analysis was conducted on the study population which was apparently unhealthy in terms of the set
parameters. If any one or more of the set parameters were found to be abnormal in patients from the study
population the ALT was separated onto a different MS Excel Spreadsheet. On this basis 721 males and
398 females as per Table 2 were identified to have at least one of the set parameters to be abnormal and
the sex wise 95% CI upper mean ALT was calculated for these patients at 40 U/L for males and 26 U/L
for females.
Table 2: Calculation of mean ALT with 95% CI for apparently unhealthy study population
A further analysis of the
study population was
conducted where BMI<25
kg/m2 and BMI≥25 kg/m2 as
well as BMI≤23 kg/m2 and
BMI>23kg/m2 were set as constants and apparent normalcy and abnormality of other set parameters (FBS,
total cholesterol and blood pressure) in relation to the BMI was calculated as seen in Table 3 and 4. Of the
total 1490 patient study population a total of 659 patients were found to have BMI≥25 kg/m2 of whom
315 (48%) apparently did not suffer either high sugar, high cholesterol or high blood pressure, and 52%
suffered from at least one of those ailments. Of the 831 patients with BMI<25 kg/m2 606 (73%) were
ABNORMAL MALES ABNORMAL FEMALESTOTAL COUNT 721 398MEAN 38.43 22.78STD. DEV. 24.83 28.09Median 32.00 18.00PERCENTILE 25% 22 13PERCENTILE 75% 45 26PERCENTILE 95% 83 4595% CI 36.62 to 40.24 20.02 to 25.54CI ±1.81 ±2.76
12
normal and 225 (27%) were apparently abnormal with respect to the above set parameters. On lowering
the BMI parameter to ≤23 kg/m2 and>23 kg/m2 it was found that 1022 patients were above 23 kg/m2 BMI
and 468 were below it.
Table 3: Comparison of apparently normal and abnormal patients with BMI – 25 kg/ m2
Out of the 1022 patients
having a BMI>23 kg/m2
546 (53%) were normal
and 476 (47%) were
apparently abnormal, while of the 468 patients with BMI≤ 23 kg/m2 375 or 80% were normal and 93 or
20% suffered from at least one ailment from the set parameters.
Table 4: Comparison of apparently normal and abnormal patients with BMI – 23 kg/ m2
In the next analysis
the BMI was
modulated in ranges
≤23 kg/m2, 23.01-
25kg/m2, 25.01-30 kg/m2 , 30.01-35 kg/m2 and >35 kg/m2 for males and females of the study population.
The corresponding 95%CI mean UNL of ALT for these ranges was calculated for both males and
females. Table 5 shows the calculated values of 95% CI upper mean of ALT at 34, 39, 43, 53 and 60 U/L
for males and 29, 21, 25, 25, 30 U/L for females in the different BMI ranges of ≤23 kg/m2, 23.01-
25kg/m2, 25.01-30 kg/m2 , 30.01-35 kg/m2 and >35 kg/m2 respectively.
TOTAL PATIENTS NORMAL PATIENTS ABNORMAL PATIENTS WITH ALL OR EITHER B.P.,
CHOLESTEROL, SUGAR
BMI≥25 NOS. 659 315 344 % 48% 52%
BMI<25 NOS. 831 606 225 % 73% 27%TOTAL PATIENTS 1490
TOTAL PATIENTS NORMAL PATIENTS ABNORMAL PATIENTS WITH ALL OR
EITHER B.P.,CHOLESTEROL, SUGAR
BMI>23 NOS. 1022 546 476 % 53% 47%
BMI≤23 NOS. 468 606 225 % 80% 20%TOTAL PATIENTS 1490
13
Table 5: Calculation of mean ALT for males and females with modulating BMI
ALT ALL MALES
ALT ALL FEMALES
ALT ALL MALES
ALT ALL FEMALES
ALT ALL MALES
ALT ALL FEMALES
ALT ALL MALES
ALT ALL FEMALES
ALT ALL MALES
ALT ALL FEMALES
BMI≤23 BMI≤23 BMI‐23.01‐25
BMI‐23.01‐25
BMI‐25.01‐30
BMI‐25.01‐30
BMI‐30.01‐35
BMI‐30.01‐35 BMI>35 BMI>35
MEAN
31.54 23.42 35.84 19.24 40.01 22.76 46.02 21.91 43.33 25.85 STD. DEV.
17.77 39.95 21.57 10.83 26.90 14.73 28.57 11.57 33.49 11.60 95% CI 29.45 to
33.63 17.74 to 29.1
33.23 to 38.45
17.37 to 21.11
37.03 to 42.99
20.38 to 25.14
39.13 to 52.91
19.08 to 24.74
26.38 to 60.28
21.39 to 30.31
CI
±2.09 ±5.68 ±2.61 ±1.87 ±2.98 ±2.38 ±6.89 ±2.83 ±16.95 ±4.46
Table 6 shows the last analysis done on entire available ALT data of 8034 patients. The valid ALT data of
4950 males was analyzed to find those having ALT>45 U/L and between 45 U/L and new UNL of ALT
at 33 U/L and also the percentage of men who were between the old and new UNL of ALT. 3084 female
ALT data was analyzed on the same basis but with a new UNL of ALT at 21 U/L. A total of 1380 males
had ALT>45 and 1127 were in the range 33<ALT≤45 and the percentage was calculated at 23% of total
males who were between the old UNL of ALT and new UNL of ALT. 336 females had ALT>45 and
1196 were in the range 21<ALT≤45. The percentage of females who were between the old and new UNL
of ALT was calculated at 39%.
Table 6: Calculation of number of males and females above old UNL of ALT and between old and new UNL of ALT in numbers and as a percentage
NOS. ALT>45 U/L
33<ALT≤45 U/L MALES
21<ALT≤45 U/L FEMALES
PERCENTAGE OF MALES AND FEMALES BETWEEN OLD AND NEW UNL OF ALT
TOTAL PATIENTS WITH SGPT AVAILABLE (MALE + FEMALE) 8034 1716
MALES 4950 1380 1127 22.77%
FEMALES 3084 336 1196 38.78%
TOTALS 8034 1716
DISCUSSION The upper normal limit (UNL) of ALT varies in different laboratories according to the commercial kit
used and the reference population chosen. For almost 50 years, it was accepted that UNL of ALT is about
40U/L (18). The UNL for the laboratory from which the entire data was accessed has a UNL of ALT
Fig 1: New
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14
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ulation
heavy
to set
d from
y. The
new UNL
abnormali
alcohol co
for a BM
compared
for males
the new B
apparently
21 U/L, a
in new U
redefining
accurate d
Fig 2: NUL
UNL of A
ALT leve
The corre
and no re
apparently
40 U/L in
SEX
UN
L of ALT fo
ities in the se
onsumption, w
MI≤23 (WHO
d to laboratory
and females
BMI has been
y healthy mal
and 34 U/L an
UNL of ALT
g the current l
diagnosis and
ALT in normal
ALT gains sig
ls even within
elation of the
egular or hea
y unhealthy m
n males and 2
Male
Female
NL ALT ModulatAbnor
Ab
or apparently
t parameters o
was calculate
BMI for Asi
y reference ra
respectively
n reproduced
les and femal
nd 21 U/L for
T in this hea
level of UNL
d follow up of
and abnormal p
gnificant forc
n current norm
set parameter
avy alcohol,
males and fem
26 U/L in fem
2
UNLALT U/
ion between Normal Patients
bnormal Norm
y healthy ma
of BMI, total
d for differen
ians) was cal
ange of 45 U/
as compared
d in Fig. 1. A
les of the stud
r males and f
althy study p
L of ALT for t
f liver disease
atients
ce in light of
mal range rela
rs of BMI≤23
with the UN
males in study
males when o
33
2126
L
ormal and
mal
15
ales and fema
l cholesterol, b
nt BMI modul
lculated at 33
/L for both se
to the curren
As the BMI w
dy population
females respe
population. T
the Indian Po
patients.
The
sign
aut
trea
elev
(19,2
several other
ated to co-mo
3, total choles
NL of ALT w
y population s
one or more
40
ales of the c
blood pressur
lations. The n
3 U/L for ma
exes. These le
nt reporting le
was modulate
n, the resultan
ectively not sh
The findings
opulation, wh
e redefining
nificant for
oimmune h
atment guidel
vated ALT
26,27,28). The n
r population s
orbidity and m
sterol<200, FB
was very sign
showed the 95
set parameter
cohort, who
re, FBS and n
new 95% CI m
ales and 21 U
evels were 25
evels. Illustrat
ed to BMI<24
nt UNL of AL
howing any s
of this stud
ich will ultim
of the UNL
chronic h
hepatitis pa
lines for thes
for the st
need for low
studies where
mortality (29,30
BS≤100, norm
nificant. The
5% CI mean o
rs were abno
did not have
no regular or h
mean UNL of
U/L for fema
5% and 50%
tively, the res
4 and BMI<2
LT was 33 U/
significant inc
dy clearly w
mately lead to
of ALT wou
hepatitis B
atients as
se diseases su
tart of trea
wering the cu
e slight increa
0).
mal blood pre
e UNL of AL
of ALT incre
ormal. The sa
e any
heavy
f ALT
les as
lower
sult of
25 for
L and
crease
arrant
more
uld be
and
most
uggest
atment
urrent
ase in
essure
LT of
ase to
ame is
illustrated
componen
Fig 3: Impa
percentag
to only 53
BMI≥25
apparent u
impact of
ailments l
BMI had m
Fig 4: Impa
for femal
kg/m2whe
20
40
60
80
100
120
Number
0
10
20
30
40
50
60
70
ALTU/L
d in Fig 2. It i
nts of the set p
ct of BMI modu
ge of normal p
3% and patien
the percentag
unhealthy pat
f modulating B
like high sug
more chances
ct of modulating
es the BMI m
ere the mean
0
00
00
00
00
00
00
BMI>=25 BMI<
Change in NorPopulati
<=23 23.01‐25
BMI and ALT R
is clear from
parameter.
ulation on ailmen
patients not h
nts having set
ge of normal
tients increase
BMI on other
gar, cholestero
s of suffering
g BMI on ALT
modulations
ALT jumped
<25 BMI>23 BMI
BMI kg/m2
rmal and Abnoron as BMI incre
25.01‐30 30.01‐35
BMI
Relation in Study Po
the finding th
nts in study popu
having any ail
t parameter ab
l patients in
ed to 52% fro
r ailments. A
ol and blood
from other d
in the study
d to 30 U/L f
<23
mal Study eases
TOTA
NORM
ABNO
>35
opulation
MA
FE
16
hat ALT doe
ulation
Whe
and >
>25
the s
from
param
when
lments set for
bnormality in
the study po
om 27%. Illu
clear finding
pressure on
diseases as set
The
was
in r
kg/m
95%
fema
right
did not have
from 25 U/L
AL
MAL
ORMAL
ALES
MALES
s modulate w
en BMI was
>23 kg/m2, an
kg/m2, the im
study populat
m any other a
meters was
n BMI mod
rth in the set
ncreased from
opulation dec
stration 3 num
of the study w
the study po
t out in the pa
study popula
analyzed for
ranges ≤23 k
m2 , 30.01-35
CI upper lim
ales. The 95%
t through the
e any consist
from the prev
with abnormal
modulated be
nd also betwe
mpact on ma
tion of 1490
ailment as me
studied. Illu
dulates from
parameters, r
m 20% to 46%
creased from
merically sho
was the impa
opulation. Peo
arameters.
ation ALT dat
the impact o
kg/m2, 23.01-2
5 kg/m2 and
mit mean of A
% CI mean fo
e BMI modu
ent impact ex
vious BMI ra
lity in one or
etween ≤23 k
een ≤25 kg/m
les and fema
patients suff
entioned in th
ustration 3 s
≤23 to >23
reduced from
%. For BMI<2
73% to 48%
ows this signi
ct of BMI on
ople having h
ta of 1490 pa
of modulating
25kg/m2, 25.
>35 kg/m2 o
ALT of male
or males incr
ulation ranges
xcept for BM
ange. Illustrat
more
kg/m2
m2 and
ales in
ffering
he set
shows
3 the
m 80%
25 and
% and
ificant
other
higher
atients
g BMI
01-30
on the
es and
reased
s. But
MI>35
tion 4
shows the
a dip and
showed a
establish i
The last a
of 8034 p
current U
females. I
Fig 5: Male p
Overall 1
males we
females w
were betw
used for
immense
tested nor
the preval
2458, 49%
Dis
e rising mean
rise back aga
definite relat
itself.
analysis was u
atients that w
UNL of ALT
Illustrations 5
population distribu
380 males an
ere between t
were between
ween the two
start of treat
significance
rmal under th
lence of chron
stribution of
ALT in male
ain to the BM
tion between
undertaken to
were above the
of 45 U/L an
5 and 6 show t
ution in ALT Rang
nd 336 femal
the current U
n the current U
mean ALT U
tment and gu
(19,26,27,28). In
he current UN
nic liver disea
1388, 28%
1127, 23%
f Males in A
es consistent w
MI ≤23 kg/m2 l
BMI and me
see the numb
e current UNL
nd new calcu
the number an
ges
les were abo
UNL of ALT
UNL of ALT
UNLs and 39%
uidelines for
this last anal
NL of ALT. T
ases (23). A fu
%
ALT Ranges
MALES ALT>45
MALES 33<ALT<
MALES ALT <=33
17
with rising BM
levels of mea
ean ALT in m
ber of males
L of ALT at 4
ulated UNL o
nd percentage
Fig 6:Fem
ve the curren
and the new
T of 45 U/L
% of females
many liver
lysis a total o
The current U
urther evaluat
<=45
3
1552, 50
D
MI ranges an
an ALT for fe
males but for f
and females i
45 U/L and th
of ALT at 33
e of males an
male population dis
nt UNL of m
w UNL of A
and new 21 U
were in simi
diseases a c
of 23% males
UNL of ALT
ion of these p
0%
Distribution o
nd relatively f
males. In con
females the r
in the entire a
he number tha
U/L for mal
nd females in b
stribution in ALT R
mean ALT of
ALT at 33U/L
U/L ALT me
ilar position.
orrect UNL
s and 39% fe
threshold m
patients shoul
337, 11%
1196, 39
of in Female A
flatter line sho
nclusion, this
elationship di
available ALT
at was betwee
les and 21 U/
both ranges.
Ranges
f 45 U/L and
L. A total of
ean. 23% of m
As ALT leve
for ALT ass
emales would
might underest
ld be carried
%
ALT Ranges
FEMALES ALT>45
FEMALES 21<ALT<
FEMALES ALT <=2
owing
study
id not
T data
en the
/L for
1127
1196
males
els are
sumes
d have
timate
out in
<=45
21
18
prospective studies to diagnose liver damage, if any, with the help of ultrasounds, liver biopsy etc. where
warranted.
There is a need to redefine the UNL of ALT for the Indian Population. In this retrospective study, the new
calculated UNL of ALT of 33 U/L for males and 21 U/L for females is significantly lower than the
current UNL of ALT at 45 U/L of the laboratory. UNL of ALT has been determined by kit and laboratory
manufacturers, which should have standardized values. Future studies on this aspect of standardization
should be carried out so that different laboratories around the world have similar or identical values.
This study had certain limitations such as there was no follow-up ALT reading of patients. It is also not
known whether the patients were fasting for the total cholesterol test. There were only a few records of
ultrasound, which could not be a fair assessment of presence of fatty liver disease for the Indian
population above the new UNL of ALT. There were no liver biopsy records to assess actual liver damage.
These could be part of future studies.
CONCLUSION
In summary, this retrospective study found the UNL of ALT for the normal cohort of males and females
from the Indian population to be clearly lower than the current UNL of ALT. The males and females of
the study population had a higher UNL of ALT when suffering from one or more of the ailments of the
set parameters as compared to the new UNL of ALT of apparently healthy cohort. In the study
population, modulating BMI had an impact on presence of other diseases of the set parameters. As the
BMI modulated in higher ranges the UNL of ALT rose in males but in females the correlation was not
very clear. There were a significant number of males and females, for whom the ALT data was available,
who fell between the current and new UNL of ALT. Many patients with high normal ALT (between the
new and old UNL) are likely to be unhealthy and require additional work up. These patients should be
evaluated for liver damage in future studies with aid of follow up ALT, ultrasound, liver biopsy etc.
19
where warranted. There should be a standardized protocol to be used by all laboratories which would
align the UNL of ALT at similar or identical values around the world. Hence, it is important to re-
evaluate consistent generalized reporting of ALT based on new UNL in Indian population.
20
GLOSSARY
Study Population: 1490 patients for whom ALT and set parameter data was available.
Cohort: A group of 215 males and 157 females who had BMI≤23 kg/m2 and all set parameters within normal range. These were considered to be apparently healthy for the purposes of final calculation of new UNL of mean ALT at 95% CI.
Set Parameters: The set parameters adopted for this study were: • BMI≤23 kg/m2 (As per WHO the normal BMI for Asians≤23) • Normal blood pressure of 120/80, 130/80 mm Hg • Total Cholesterol<200 • FBS≤100 • No regular or heavy use of alcohol
ALT: Alanine aminotransferase calculated in U/L BMI: Body Mass Index calculated in kg/m2
UNL: Upper Normal Limit
95% CI: Mean calculated at 95% Confidence Interval, with 95% certainty the mean would lie in the calculated range
FBS: Fasting Blood Sugar
21
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