hemoglobin a1c ( hba1c ) is the gold standard for the measurement of long - range glycemic control in patients with diabetes mellitus .
many studies have reported diabetes mellitus to be a risk factor in patients with alcoholic liver disease and nonalcoholic fatty liver disease ( nafld ) for the development of fibrosis and fibrosis progression [ 13 ] . in the united states , 2% of adult americans ( 5.3 million )
are infected with hepatitis b or c   and an estimated 31% or more with nafld [ 5 , 6 ] .
glucose intolerance is seen in up to 80% of patients with cld , and frank diabetes is present in 3060% [ 7 , 8 ] .
depending on its etiology , cld has a significant impact on hepatic glucose metabolism . among patients with cld ,
these factors can contribute to longer or shorter red blood cell ( rbc ) survival   and can lead to alteration of the hba1c .
factors such as nutritional anemia can lead to increased rbc survival and falsely elevated hba1c levels , whereas bleeding and hemolysis can lower rbc survival time and falsely lower hba1c values .
very few studies are dedicated to systematically evaluating the accuracy of hba1c in cld patients . in a screening of 20,000 measurements of hba1c ,
of nine abnormally low results , six were the result of cirrhosis , two resulted from hematological neoplasms with anemia , and one was due to hemoglobin f . in a small case series ( 15 patients with compensated cirrhosis and 20 patients with chronic hepatitis ) , 40% of cirrhotic patients with diabetes had hba1c levels below reference range for patients without diabetes .
methodist university hospital transplant institute has been systematically screening its liver transplantation candidates for diabetes with hba1c levels .
measuring hba1c is the gold standard for monitoring blood glucose control in diabetes and can now also be used to diagnose diabetes when its results are 6.5% .
the study objective is to look at glucose and hba1c levels in cirrhotic patients and determine if hba1c levels are a reliable predictor of glycemic control in patients who are presented for liver transplantation at methodist university hospital transplant institute between january 1 , 2006 , and january 1 , 2014 .
the study population included 200 electronic medical records ( emr ) of patients who were evaluated for liver transplantation at the methodist university hospital transplant institute in memphis , tennessee , from july 7 , 2010 , through september 22 , 2011 .
patients who did not have hba1c levels in the emr were excluded from the study .
patients were referred for liver transplantation after they were evaluated by a primary care physician or gastroenterologist ; the referral was indicated for them based on their clinical presentation and results of laboratory and diagnostic tests such as computed tomography ( ct ) scans or magnetic resonance imaging ( mri ) or model of end stage liver disease ( meld ) scores .
we reviewed comprehensive history and physical examination at time of referral to the transplant institute .
the collected data included patients ' demographics , cigarette smoking and alcohol history , past medical history , whether or not they were transplanted , meld at time of time transplant , liver alone or simultaneous liver - kidney transplant , etiology of liver disease , hba1c level reported from laboratory , and three glucose levels at time of transplant referral .
 hba1c ( ma1c ) were averaged , logged , and input into an hba1c calculator from the american diabetes association website ( http://professional.diabetes.org/diapro/glucose_calc ) to determine the  calculated 
the difference between ma1c and ca1c levels was computed and the patients were divided into three groups : group 1 , difference of < 0.5 ; group 2 , 0.511.5 ; and group 3 , > 1.5 .
variables between the three groups were analyzed by one - way anova and chi - square tests for ordinal and categorical variables .
t - test was used for continuous variables and z test for comparison of proportions .
the medical records of patients who were evaluated for liver transplantation and had hba1c levels collected at the methodist university hospital transplant institute in memphis , tennessee , from july 7 , 2010 , through september 22 , 2011 , were reviewed , yielding a total of 200 cases .
the mean age for this cohort was 54 years with a male predominance : 67% were male .
forty - four percent and 39% of patients had a history of alcohol abuse and smoking history , respectively .
sixty - two patients ( 31% ) in this study were diabetics . of those 62 diabetic patients , 26 ( 42% ) were on insulin .
of the 200 patients included in this study , 55.5% ( 111 ) underwent liver transplant and of those 111 patients who underwent liver transplant , 10% ( 11 ) underwent simultaneous liver and kidney transplant .
most common etiology of liver disease in our cohort was hepatitis c virus at 41% ( 82 ) , followed by hepatocellular carcinoma ( hcc ) 23% ( 46 ) , alcohol 22% ( 44 ) , nonalcoholic steatohepatitis ( nash ) 16% ( 32 ) , primary sclerosing cholangitis 6% ( 12 ) , primary biliary cholangitis 4.5% ( 9 ) , and hepatitis b virus 4.5% ( 9 ) .
the remaining 14% ( 28 ) of patients in this cohort referred to transplant institute included patients with cryptogenic cirrhosis , autoimmune hepatitis , alpha-1-antitrypsin deficiency , wilson 's disease , hemochromatosis , polycystic liver disease , cholangiocarcinoma , and neuroendocrine tumor .
the distribution of ma1c and the average glucose levels are depicted in figure 1 ( all patients ) , figure 2 ( patients without diabetes ) , and figure 3 ( patients with diabetes ) .
the expected glucose levels for each range of ma1c ( x - axis ) values were obtained from the following website : http://www.diabeteschart.org/bgc1.html .
one can infer from the figure that the ma1c values tend to group towards the lower values and actual average glucose values tend to group towards the higher values .
for example , among diabetic patients , 58% of patients had ma1c < 6 , while 77% of patients had actual average glucose levels of more than 140  mg / dl .
similarly 88% of nondiabetic patients had hba1c < 5.5 , but 38% had actual average glucose levels of more than 110  mg / dl .
ninety - seven ( 49% ) patients had hba1c of less than 5 followed by 72 ( 36% ) patients with hemoglobin a1c of 5 - 6 and 21 patients ( 11% ) with hemoglobin of more than 7 .
the discordance between ca1c and ma1c was further categorized into three groups : group 1 , the difference between ca1c and ma1c < 0.5 ( n = 106 ) ; group 2 , the difference between ca1c and ma1c 0.51.5 ( n = 70 ) ; and group 3 , the difference between ca1c and ma1c > 1.5 ( n = 24 ) .
patients with high discordance were more anemic and had higher incidence of diabetes ( table 1 ) . in a multivariate model including those with high discordance versus those with no discordance , hemoglobin levels were the only independent predictor ( odds ratio 0.77 95% ci 0.600.99 ; p value 0.04 ) . among the 200 patients included in the study , 46 patients had hcc.(29 in nondiabetics ( 29% ) and 17 in diabetics ( 27% ) ) .
as expected , hcc was most commonly seen in patients with hepatitis c and nash .
the clinical features of patients with hcc and without hcc are highlighted in table 2 . in the multivariate model
independent predictors of hcc were measured by hba1c ( or 2.69 955 , ci 1.385.43 , and p value 0.008 ) and age ( or 1.07 955 , ci 1.021.13 , and p value 0.004 ) .
female gender was a negative predictor for hcc ( or 0.24 95% , ci 0.940.637 , and p value 0.004 ) .
presence of diabetes was not predictor for hcc . to further study the relationship between hba1c and hcc we studied the 62 patients with diabetes .
, hba1c is an independent predictor of hcc ( or 2.14 95% , ci 1.233.70 , and p value 0.007 ) .
lowest incidence of hcc , 13.4% , is seen in patients with hba1c being less than 5 , followed by 28% for hba1c levels of 5 - 6 , 38% for patients with hba1c levels of 6 - 7 , and 50% for patients with hba1c greater than 7 ( p value 0.0001 ) .
cirrhosis and advanced liver disease have been associated with an increased risk for hyperglycemia and diabetes mellitus . the diagnostic yield of common tests used to define diabetes in the general population differs from those with liver disease .
hba1c is a reliable test to assess chronic glycemia and recommended both for the diagnosis and monitoring of diabetes mellitus ; however , hba1c is neither accurate nor reliable in patients with cirrhosis .
liver cirrhosis promotes glucose intolerance and diabetes through various mechanisms including insulin resistance and impaired insulin secretion .
sixty to 80% of patients with liver disease have glucose intolerance and 1015% eventually develop overt diabetes .
patients with cirrhosis are frequently anemic and therefore hba1c measurements may not provide accurate measure of glycemic control as shown in our analysis .
most common causes of anemia in patients with liver disease are chronic gastrointestinal ( gi ) blood loss from portal hypertension [ 1517 ] and aplastic anemia secondary to viral hepatitis [ 1821 ] . in addition , antiviral therapy , especially ribavirin , for hepatitis c [ 2224 ] or immunosuppressive agents used to treat autoimmune liver diseases can lead to anemia . in patients with alcoholic liver disease , several factors such as nutritional deficiency , malabsorption , and direct toxic effect of alcohol on bone marrow can cause anemia [ 2527 ] .
hypersplenism secondary to portal hypertension is another important mechanism of anemia in patients with chronic liver disease .
any condition that shortens erythrocyte survival or decreases mean erythrocyte age ( e.g. , recovery from acute blood loss , hemolytic anemia ) will falsely lower hba1c test results .
hba1c results must be interpreted with caution given the pathological processes , including anemia , increased red cell turnover , and transfusion requirements , that adversely impact hba1c as a marker of long - term glycemic control .
the etiology of anemia is most likely related to hypersplenism or hemolysis associated end stage liver disease or chronic gi blood loss from portal hypertensive gastropathy .
since etiology of anemia in patients with decompensated cirrhosis is multifactorial , our retrospective study could not analyze the effects of different types of anemia on hba1c levels in these patients .
cirrhosis and advanced liver disease have been associated with an increased risk for hyperglycemia and type 2 diabetes mellitus ( t2 dm ) .
the diagnostic yield of common tests used to define diabetes and insulin resistance in the general population differs significantly from the one observed in patients with liver disease .
hba1c is a reliable test to assess chronic glycemia and recommended both for the diagnosis and monitoring of t2 dm ; however , hba1c is neither accurate nor reliable in patients with cirrhosis .
a validation study has not been performed to define its true usefulness in the setting of cirrhosis .
the results of our analysis suggest there is discordance in hba1c measurements in patients with decompensated cirrhosis .
this study indicates that hba1c levels are not a reliable predictor of glycemic control in patients with decompensated cirrhosis , especially in those with severe anemia . to date there are limited numbers of studies dedicated to systematically evaluating the accuracy of hba1c levels in cirrhotic patients .
it is critical for providers and patients to have evidence - based data to guide their management strategies to optimize individualized care .
therefore , we conducted a comprehensive review of 200 unique patients referred to the methodist university hospital transplant institute with at least one hba1c level to help provide insight and help guide physicians decision - making in this uncertain area . although diabetes is a major public health problem and the fifth leading cause of death in the united states   it is less known to be associated with increased risks of developing hcc [ 3133 ] .
although such an association could be related to the underlying chronic liver diseases that preceded the development of hcc [ 3437 ] , there are several lines of evidence suggesting that diabetes is in fact an independent risk factor for hcc development [ 3739 ] .
there is also evidence reporting that findings of hcc recurrence after liver resection and transplantation are seen among patients with diabetes [ 40 , 41 ] .
it is interesting that in our data set diabetes was not independent predictor of hcc , while hba1c was a strong independent predictor for risk of hcc .
our findings could be extrapolated to indicate that glycemic control could lead to a lower risk of hcc in patients with diabetes .
people with established diabetes have an increased risk of developing certain types of cancers over the general population [ 4247 ] .
previous publications have reported the association of hcc with other comorbidities , such as diabetes mellitus . in our study
, table 2 provides evidence that diabetes can increase the risk of hcc in patients with chronic liver disease .
evidence that diabetes can increase the risk of hcc was also seen in a publication written by li et al . in 2015 .
hyperinsulinemia , insulin resistance , and cytokine production have been shown to cause fat accumulation in the hepatocytes leading to oxidative stress and progressive liver injury and fibrosis [ 5052 ] .
there has also been evidence published showing a relationship between hba1c levels , elevated liver enzymes , and hepatic steatosis .
recent advances in understanding of nash and hcc have revealed that hcc to be the leading cause of obesity - related cancer deaths in middle aged men .
we conclude that hba1c levels should only be evaluated in context with all liver function parameters as well as a red blood count in patients with liver disease .
although the pathophysiologic reasons have still not been confirmed , our data demonstrate that hba1c levels are not a reliable predictor of glycemic control in patients with decompensated cirrhosis , especially in those with severe anemia
. this interference may be due to alterations in erythrocyte lifespan and altered protein metabolism , but further investigations are needed to elucidate the exact cause of the interference in patients with liver disease .
 
 introduction . aim of this study is to determine if hba1c levels are a reliable predictor of glycemic control in patients with decompensated cirrhosis . methods . 200 unique patients referred for liver transplantation at university of tennessee / methodist university transplant institute with a hba1c result were included . 
 three glucose levels prior to the  measured  a1c ( ma1c ) were input into an hba1c calculator from the american diabetes association website to determine the  calculated  a1c ( ca1c ) . 
 the differences between ma1c and ca1c levels were computed . 
 patients were divided into three groups : group a , difference of < 0.5 ; group b , 0.511.5 ; and group c , > 1.5 . 
 results . 
 97 ( 49% ) patients had hemoglobin a1c of less than 5% . 
 discordance between calculated and measured hba1c of > 0.5% was seen in 47% ( n = 94 ) . 
 higher level of discordance of greater than > 1.5 was in 12% of patients ( n = 24 ) . 
 hemoglobin was an independent predictor for higher discordance ( odds ratio 0.77 95% , ci 0.600.99 , and p value 0.04 ) . 
 hba1c was an independent predictor of occurrence of hcc ( or 2.69 955 , ci 1.385.43 , and p value 0.008 ) . 
 conclusion . 
 hba1c is not a reliable predictor of glycemic control in patients with decompensated cirrhosis , especially in those with severe anemia . 
1. Introduction
2. Methods
3. Results
4. Discussion