treatment status and abnormal liver enzymes



Only recently has liver disease been recognized as a major complication of type 2 diabetes. In the population-based Verona Diabetes Study, liver disease is an important cause of death in type 2 diabetes1. Cirrhosis was the fourth leading cause of death and accounted for 4.4% of diabetes-related deaths. The standardized mortality ratio (SMR), i.e., the relative rate of an event compared with the background rate, for cirrhosis was 2.52 compared with 1.34 for cardiovascular disease (CVD). In another prospective cohort study2, cirrhosis accounted for 12.5% of deaths in patients with diabetes. Cryptogenic cirrhosis, of which diabetes is, by far, the most common cause, has become the third leading indication for liver transplantation in the U.S.3,4. In another paper from Cleveland of 132 patients with NAFLD, 33% had type 2 diabetes, of whom 25% had cirrhosis compared with only 10% of non-diabetic NAFLD patients.

Virtually the entire spectrum of liver disease is seen in patients with type 2 diabetes. This includes abnormal liver enzymes, nonalcoholic fatty liver disease (NAFLD), from steatosis (bland fatty infiltration of hepatocytes) to nonalcoholic steatohepatitis (steatosis plus inflammation, necrosis or fibrosis) to cirrhosis and, in some patients, to end-stage liver disease and hepatocellular carcinoma. The prevalence of NAFLD is as high as 50% in patients with type 2 diabetes and 100% in patients with diabetes and obesity. Of these affected patients, 50% have steatohepatitis and 19% have cirrhosis.6,7 Among 101 patients with NAFLD by liver biopsy, diabetes was found to be the only factor independently associated with an increased risk of advanced fibrosis (bridging fibrosis or cirrhosis) by multivariate analysis (RR:2.3, P<.01).9 There is also an unexplained association of diabetes with hepatitis C and a higher incidence of acute liver failure. Finally, the prevalence of diabetes in cirrhosis is 12.3-57%. 8 Thus, patients with diabetes have a high prevalence of liver disease and patients with liver disease have a high prevalence of diabetes.

NAFLD and NASH are diagnosed in clinical settings using detailed techniques, such as liver biopsy and ultrasound imaging, which are not easily applied in epidemiological studies 9,10. However, patients with NAFLD and NASH are commonly characterized by elevated circulating concentrations of markers of liver injury, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and {gamma}-glutamyltransferase (GGT). 10,11 In fact, NAFLD and NASH have been reported to be the most common causes of chronically elevated transaminase levels 12. These observations indicate that AST, ALT, and other markers of liver injury may be useful surrogate measures of NAFLD and related conditions for large studies.

Liver function tests are commonly used in clinical practice to screen for liver disease. The most common LFTs include the serum aminotransferases, alkaline phosphatase, bilirubin, albumin, and prothrombin time. Aminotransferases, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), measure the concentration of intracellular hepatic enzymes that have leaked into the circulation and serve as a marker of hepatocyte injury. Alkaline phosphatase (ALP), g-glutamyl transpeptidase (GGT), and bilirubin act as markers of biliary function and cholestasis. Albumin and prothrombin reflect liver synthetic function. Individuals with type 2 diabetes have a higher incidence of liver function test abnormalities than individuals who do not have diabetes. Mild chronic elevations of transaminases often reflect insulin resistance. 10 Transaminases are usually, but not always elevated, with the AST:ALT ratio < 1. Patients with an AST:ALT > 1 have more fibrosis and more progressive disease. Gamma glutamyl transferase is usually abnormal (> 35 U/L) and alkaline phosphatase may be up to twice normal (upper limit of normal =125 U/L), sometimes giving rise to a cholestatic variant. 13


This study is set to describe the prevalence of abnormal liver function tests among Filipino type 2 diabetics and whether this is associated with treatment status.


At present, the presence of diabetes has little implication for the specific treatment of liver disease. Given the fact that at least 50% of patients with type 2 diabetes have NAFLD, evaluation of their risk must be done routinely to avoid the drastic complication of liver disease. However, the suspected diagnosis of NAFLD or NASH in any patient with type 2 diabetes is not yet a part of the protocol for diabetes management.

If high prevalence of abnormal liver function tests (ALFT) is revealed, requesting for these tests may justify screening at initial evaluation and may serve as basis for further work-up of existing liver disease.

The study may help define the profile of diabetic patients with abnormal liver function tests in terms of treatment status and other control variables (age, glucose control, duration of diabetes, obesity and dyslipidemia).

The potential importance of DM treatment in preventing or ameliorating liver disease may be established.


Antidiabetic agents have generally been shown to decrease ALT levels as tighter blood glucose levels are achieved. 14 From the Mexico City Diabetes Study, after controlling for gender, age, BMI, waist-to-hip ratio (WHR), and alcohol intake - higher ALT and GGT values were significantly associated with both IGT and diabetes, whereas AST values were associated with IGT only. 15 Erbey reported that those who were overweight (BMI 25-30 kg/m2) and obese (BMI >30 kg/m2) were more likely to have elevated ALT. 22 In another study, outpatients who were overweight, showed poor diabetes control during a short duration of diabetes controlled by treatment with diet or oral agents, and had a mature age at onset of diabetes displayed the most significant clinical explanatory variables associated with abnormal ALT. 20 The presence of fatty liver in type 2 diabetes potentially increases atherogenesis by increasing triglycerides, reducing HDL levels, and increasing small, dense LDL.16


There is an association between treatment status and abnormal liver function test. Patients who are untreated have a higher likelihood of having abnormal liver function test results, while controlling for age, glucose control, duration of diabetes, obesity and dyslipidemia.


1. To estimate the prevalence of abnormal liver function tests (ALFT) among Filipino type 2 diabetics among patients consulting at UERMMC ISDF.

2. (This was the original objective: To determine if there is an association between treatment status and abnormal liver function tests (ALFT) among type 2 diabetics while controlling for age, duration of diabetes, glucose control, dyslipidemia and obesity.) CHANGE TO: TO DETERMINE THE PROPORTION OF PATIENTS WITH ABNORMAL ALT AMONG TREATED AND UNTREATED TYPE 2 DM PATIENTS.

(They advised me to compute the means and standard deviation using Independent T test)


Age - current age of patient in years categorized into 10-year age bands:

20 - 29 y.o , 30 - 39 y.o , 40 - 49 y.o., 50 - 59 y.o., 60 - 69 y.o., > 70 y.o.

Duration of DM - Duration of diabetes was calculated for established diabetics as current age minus the reported age at the time of diagnosis. Duration will then further categorized into quartiles:

Newly diagnosed diabetics - <0.1 year

Glycemic Control - was be measured using HbA1c categorized into tertiles based on the American Diabetes Association guidelines:

Dyslipidemia - diagnosis is based on National Cholesterol Education Program Adult

Treatment Panel III (NCEP ATP III) guidelines for patients with coronary heart disease equivalents to include diabetes.

Treatment Status -

Treated: Subjects with anti-diabetic therapy for >3 months.

Untreated: Newly diagnosed with type 2 diabetes without medications or previously treated but stopped their medications for more than three months immediately prior to the study .



Filipino patients consulting at UERMMC ISDF Out Patient Clinic.

Type 2 DM patients with available data on the necessary variables, including results of laboratory exams.


This is a cross-sectional design and it is hard to establish the temporal ambiguity on order of onset of diabetes and liver disorder. Since this is a chart review, only the secondary data is obtained, therefore, we cannot control the way the data was originally collected.

Liver enzymes had been used as surrogate markers of liver disease but it has its limitations. Individuals with mild fatty liver infiltrations may present with normal transaminases. Liver ultrasound could have been useful to identify patients with steatosis, however, this data is absent in this study.


Many reports document an increase in liver disease occurring in type 2 diabetic patients. The prevalence increases in subjects with diabetes and with severe obesity and has been reported to range from 25 to 75% or even higher 18. An analysis of the Hispanic Health and Nutrition Examination Survey reported that abnormal alanine aminotransferase levels were significantly more common in Mexican Americans with diabetes as compared with their diabetic counterparts. The odds of having an elevated alanine aminotransferase level were approximately threefold greater for those with diabetes.19

Salmela et al. 20 noted that 22.9% of 118 outpatients with type 2 diabetes had an elevated ALT value during random evaluation. GGT was also elevated in 23.7% of patients. These abnormalities were rarely more than two times the upper limit of the reference range. Thirty three patients used insulin in addition to diet and oral hypoglycemic drugs including sulfonylurea and metformin. None of the patients had known chronic liver disease, and none had clinically significant diabetic nephropathy. Hemoglobin A1c averaged 11.2 ± 2.4%. In multivariate analysis, outpatients who were overweight, showed poor diabetes control during a short duration of diabetes controlled by treatment with diet or oral agents, and had a mature age at onset of diabetes displayed the most significant clinical explanatory variables associated with abnormal ALT and GGT.

To investigate the reliability of LFT's in assessing the histological changes, Salmella et al. looked at 63 type 2 diabetes patients with abnormal liver histology. Forty-eight had fatty liver or steatosis with nonspecific inflammatory changes, whereas 14 had evidence of fibrosis. GGT and ALT were most commonly elevated. As histology worsened (steatosis to inflammation to fibrosis), there was no significant difference in mean values of ALT and GGT. Therefore, although abnormal LFT results are common in diabetes, especially in overweight type 2 diabetic patients, they are not reliable in predicting histological changes in the liver.

Jick et al. 21, in a recent epidemiologic study of 44,406 patients with type 2 diabetes, found that during follow-up, 605 patients developed liver disease (incidence rate 0.53 per 100 person-years), ranging from hepatitis to gallbladder disease to hepatosteatosis to carcinoma involving the liver or biliary ducts.

Erbey et al. analyzed 18,825 noninstitutionalized patients within the United States with an oversampling of African Americans and Mexican Americans. Of the total sample, 4.1% had elevated ALT, and 6.7% had type 2 diabetes. Of those with type 2 diabetes, the prevalence of elevated ALT was 7.8%, compared to a 3.8% prevalence in those without diabetes. The prevalence of ALT elevation greater than three times normal was not significantly different between the nondiabetic and diabetic patients (0.4 vs. 0.7%). Those who were overweight (BMI 25-30 kg/m2) and obese (BMI >30 kg/m2) were more likely to have elevated ALT. There was a 10.6% prevalence in obese diabetic patients versus a 6.6% prevalence in obese nondiabetic patients.22

Approximately 5% of patients with type 2 diabetes mellitus may have mildly elevated serum alanine aminotransferase (ALT) values. In 83% of these patients, ALT levels usually decrease during antidiabetic therapy.23

In a study done among Filipinos with type 2 diabetes seen at St. Lukes Medical Center, elevated ALT was seen in 16%, elevated AST in 14%, and 13% had ALT/AST >1.24

Due to the recent epidemic of childhood obesity, and increasing awareness, NASH is now being diagnosed more frequently. The prevalence of abnormal aminotransferases twas described in thirty-nine children ages 9-18 years with type 2 diabetes (negative GAD, ICA-512, Insulin antibodies) who were seen at Children's Hospital San Diego from 2000-2002. ALT or AST were raised (>40 U/L) in 49%, >80 U/L (>2X normal) in 23%, and >120 U/L (>3X normal) in 8% and the clinical phenotype of those with NASH. 25 In four clinical trials involving 3,701 patients with type 2 diabetes, between 2 and 24% of screened patients had liver enzyme tests above the upper limit of normal (ULN) 26. In these studies, investigators noted that ~5% of the patients had concomitant liver disease at baseline. In another report involving 13 clinical trials and 5,003 patients with type 2 diabetes, in which patients with serum ALT, aspartate aminotransferase (AST), or alkaline phosphatase >2.5 times ULN were excluded, 5.6% had serum ALT values between 1 and 2.5 times ULN.10 (At baseline entry into the studies, when the mean HbA1c levels were between 8.5 and 9.0%, 381 of 6,822 patients (5.6%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range.) Evaluation of asymptomatic individuals with mild elevations of ALT and AST reveals that 98% have liver disease-most commonly, fatty liver disease and chronic hepatitis.27 The most common cause of a mild elevation of serum ALT is NAFLD, 28 the most prevalent liver disease in type 2 diabetes.

Serum transaminases could be useful as surrogates in screening therapies for NASH. A longitudinal cohort study of 102 subjects who had both baseline and 2-yr biopsy and multiple measurements of serum aminotransferases found out that the rate of aminotransferase change correlated with changes in inflammation and fibrosis, but not steatosis. 29



Analytical Cross Sectional Design


The patients in this study are regularly attending several out-patient diabetes clinic in Metro Manila from the period of June 2005 to May 2007.

Inclusion Criteria:

  • Subjects with a clinical diagnosis of type 2 diabetes according to the guidelines set forth by the American Diabetes Association (ADA).
  • Subjects with antidiabetic therapy for more than three months prior to the liver function test .
  • Subjects who are drug naïve defined as:
  • newly diagnosed with type 2 diabetes without medications or
  • previously treated but stopped their medications for more than twelve months.
  • Liver function test and lipid profile were done simultaneously during the study period.
  • Anthropometric measurements (height and weight; waist and hip circumference optional) were taken during the time liver function test was done.

Exclusion Criteria

  • Current or past excessive alcohol drinking as defined by an average daily consumption of alcohol more than 20 g.
  • Subjects known to be Hepatitis B surface antigen or Hepatitis C antibody positive.
  • Subjects who have findings consistent with cirrhosis and other chronic liver diseases.
  • Subjects taking amiodarone and other drugs known to promote fatty liver disease.
  • Subjects taking statins, thiazolidinediones, and other drugs that may alter the liver enzyme levels.
  • Treatment < or = 3 months


Epi Info Version 6 was used to calculate the sample size using a power of 80^% and 5% level of significance. Based on previous studies 16,20, the prevalence of abnormal liver function tests is 5% for the type 2 diabetics with treatment and 15% for those untreated. The sample size calculated was 159 per group or 318 in all.


We calculated the prevalence and significance of associations between the treatment status and the rest of the variables using the Chi-square tests. To assess the risk factors for elevated ALFT, we used logistic regression modeling and multinomial logistic, including factors and all covariates. We used logistic stepwise regression to determine what variables contribute significantly to the ALTF. We also checked the goodness of fit of the data to the model and also determined the effect of the contribution accounted for or explained by the variables to the forms of ALTF. Further correlations among different variables were also checked. All analyses used SPSS Version 11.5.



The baseline clinical characteristics of the subjects grouped by treatment status are reported in Table 1. A total of 317 subjects were included in this study. Forty eight percent (n=151) were in the untreated group and 52% (n=166) in the treated group. Most of the subjects were 40 to 60 years old for both the treated and untreated subjects. There were more male subjects for both groups. More than a half of the subjects were diagnosed diabetics for one to three years, and almost half are obese I. The glucose control was almost equally distributed across the three tertiles. Eighty percent (n=255) had elevated LDL and sixty percent (n=188) had low HDL. Abnormal total cholesterol (57.7%, n=183) and triglycerides (42.9%, n=136) were found in half of the subjects. Forty percent (n=127) of the subjects had abnormal ALT and they are almost equally distributed to both the treated and untreated subjects. AST, GGT and AP were also abnormal in sixty to ninety percent of the subjects.

When the association of the different variables to treatment status was tested using the Chi- square tests, only the duration of diabetes, HbA1c and GGT revealed highly significant association. AST has some significant association as well.

In the logistic regression, (Table 2), liver enzyme levels were associated with some variables, especially abnormal GGT vs TRIGLY (p-value=0.011, odds ratio=2.3), normal GGT vs. treatment status (p-value=0.003, odds ratio=0.355). Interestingly, in the multinomial logistic regression, abnormal ALT among males was associated with age of 20-30 years old (p-value=.032, odds ratio=11.299) and with normal BMI (p=0.000, odds ratio=4.467). Using stepwise logistic regression analysis, more associations were seen with abnormal AST vs. BMI (p=0.000), vs. A1c >6.5 (p=0.017, odds ratio 0.438), vs. females (p=0.000, odds ratio 3.020). ). By logistic regression, there was a significant association with abnormal alkaline phosphatase (AP) vs. A1C (p-value 0.05, odds ratio=0.431), vs. LDL (p-value 0.04, odds ratio=10.689).

In the correlation analysis, elevated ALT, AST, AP were most strongly associated with female gender and HDL while total cholesterol and triglycerides, treatment status and duration were weakly associated with elevated AST.


In this present study, the prevalence of abnormal liver enzymes among Filipino diabetics ranged from 40 to 90%. These values are far higher from the previous reports of 14 to 23% prevalence of abnormal enzymes among diabetics. 20,24 This could be explained by the stringent values set by the American College of Physicians on the normal ALT and other liver function tests.

Among the lipid parameters, elevated LDL was shown to be the most frequent abnormality in this group of Filipino diabetics. Elevated LDL was seen in 80% of the subjects in this study while low HDL and elevated triglycerides were only seen in 50 to 60%. These results are different from the usual lipid abnormalities (low HDL and elevated TRIGLY) expected among diabetics. It should be noted that the subjects were not taking any lipid-lowering agents. There were also more obese subjects with BMI >25 kg/m2 (65%) in this study.

Duration of diabetes, HbA1c, GGT and to some extent, AST were the only variables shown to affect treatment status using the chi-square test. HbA1c definitely improves with treatment. But among the liver enzymes, only GGT and AST may show improvement with treatment. This was further elucidated in the logistic regression analysis that treated patients have the odds of having normal GGT three times more than those untreated. Our findings have also shown a strong association between abnormal GGT and elevated triglycerides. This finding was also reported in another study done among Mexicans where there was a very strong independent association of serum triglycerides and GGT. 14 This suggests that GGT and hypertriglyceridemia may be biochemical markers for a fatty liver with the attendant increased export of triglyceride-rich lipoproteins.

GGT is gaining ground of interest in the field of diabetes. An attractive hypothesis is that GGT may relate to diabetes because it is a marker of oxidative stress. GGT has a pivotal role in the maintenance of intracellular defenses through its mediation of extracellular glutathione transport into most types of cells 30. Increases in GGT activity in response to oxidative stress may serve to facilitate transport of glutathione into cells. In addition, although GGT has been regarded as a marker of liver disease, it shows a high activity in the kidney and in several other organs 31. Thus, increased serum GGT concentrations may identify subjects with a generalized increase in oxidative stress 32. Currently, the mechanisms underlying the association of GGT with insulin resistance, the Metabolic Syndrome, and diabetes incidence have not been elucidated, but there are at least two potential mechanisms: GGT as a marker of hepatic steatosis or visceral obesity 33,34 and GGT as a marker of oxidative status, especially of glutathione homeostasis

An interesting finding in this study showed that there was a strong association of abnormal ALT among younger diabetic males (p-value=.032, odds ratio=11.299) with normal BMI (p=0.000, odds ratio=4.467). This is contrary to previous reports that ALT is commonly seen among overweight diabetics. 22 ALT is popularly used as the surrogate marker in NAFLD patients who have the features of metabolic syndrome. A recently reported study by Targher 35 provided further evidence that a normal serum ALT level provides little diagnostic or prognostic value when assessing patients for NAFLD, because more than four-fifths (86%) of their patients with NAFLD had normal ALT levels. Even when more stringent criteria were used (i.e., ALT >30 units/l in men and >19 units/l in women), most patients with NAFLD (63%) had normal ALT levels. Therefore, serum ALT levels appear to be insensitive markers for NAFLD.

In conclusion, this study further strengthens the suggestion of a previously reported study 14 that GGT and hypertriglyceridemia may be better biochemical markers for a fatty liver, and serum ALT levels appear to be insensitive markers for NAFLD.35


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