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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Summary

Background

Non-alcoholic fatty liver disease is prevalent in affluent countries and is strongly associated with metabolic syndrome.

Aim

To study the prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease.

Methods

73 consecutive patients with biopsy-proven non-alcoholic fatty liver disease and no history of diabetes underwent comprehensive metabolic screening. Diagnosis of diabetes and impaired glucose regulation was based on the 2006 American Diabetes Association criteria.

Results

The prevalence of undiagnosed diabetes and impaired glucose tolerance in non-alcoholic fatty liver disease patients was 33% and 29%, respectively. Among patients with 2-h plasma glucose above 7.8 mm, 47% had normal fasting glucose (below 5.6 mm). Impaired glucose tolerance was more common in patients with non-alcoholic steatohepatitis than those with simple hepatic steatosis (P = 0.036), and 2-h plasma glucose correlated with fibrosis stage (Spearman coefficient: 0.25, P = 0.046). In a binary logistic regression analysis, high fasting glucose and low high-density lipoprotein cholesterol were independent factors associated with diabetes. Nevertheless, if oral glucose tolerance test was only performed in non-alcoholic fatty liver disease patients with impaired fasting glucose, 20.8% of diabetes cases would be missed.

Conclusions

Isolated postchallenge hyperglycaemia is common among Chinese non-alcoholic fatty liver disease patients without history of diabetes. It is associated with histological severe disease, and cannot be accurately predicted by any fasting glucose cut-off.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease in developed countries. It is associated with cardiovascular morbidity,1, 2 and may progress to liver cirrhosis and hepatocellular carcinoma.3, 4 Owing to the westernized dietary habits in Asian countries, there may also be an epidemic of metabolic syndrome and NAFLD in the near future. In a recent population survey of 15 540 Chinese adults, 9.8% of men and 17.8% of women had metabolic syndrome, while around 30% were overweight.5 A screening of 3175 Chinese showed that 15% of the population had NAFLD diagnosed by ultrasonography.6 Among Chinese patients with biopsy-proven NAFLD, necroinflammation and fibrosis were found in 86% and 26%, respectively.7 According to various prospective studies, a quarter to half of these patients have progression in liver fibrosis with time.8–10

Non-alcoholic fatty liver disease is associated with components of the metabolic syndrome, including diabetes mellitus, hypertension, dyslipidaemia and central obesity.7, 11–13 According to the 2006 American Diabetes Association (ADA) criteria, the diagnosis of diabetes is made if the fasting glucose exceeds 7.0 mm. The cut-off was lowered from 7.8 mm in 1997 because the new value correlated better with postchallenge glucose levels. Alternatively, using the 75 g oral glucose tolerance test (OGTT), a 2-h plasma glucose above 11.1 mm also indicates diabetes. However, ADA discouraged clinicians to use OGTT because of the greater cost and inconvenience.14

Nevertheless, there have been suggestions that fasting and postchallenge glucose criteria might diagnose two different groups of diabetic patients. According to 11 population-based studies in Asia, only 37% of the diabetic patients fulfilled both the fasting and 2-h plasma glucose criteria.15 In a subsequent review of 13 European studies, 2-h plasma glucose increased with age, while fasting glucose did not.16 Moreover, NAFLD patients have hepatic insulin resistance together with peripheral insulin resistance.17 Whether this will affect postload glucose level is unknown. With this background, fasting glucose alone may not be adequate in the assessment of NAFLD patients.

In this study, we performed OGTT for Chinese patients with biopsy-proven NAFLD and determined the prevalence of undiagnosed diabetes and postchallenge hyperglycaemia. We also aimed to assess factors associated with diabetes in these individuals and define the role of OGTT among them.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Subjects

We prospectively recruited patients at the liver and general clinics of the Prince of Wales Hospital and Tseung Kwan O Hospital, Hong Kong. Liver biopsy was performed for Chinese patients aged 18–65 years with alanine aminotransferase (ALT) above 58 IU/L on two separate occasions at least 6 months apart. We excluded patients who consumed more than 20 g of alcohol per day. Patients with coexisting liver disease, namely chronic viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, α1-antitrypsin deficiency, biliary obstruction and drug-induced liver disease were excluded. Secondary causes (e.g. corticosteroid use, gastric bypass surgery) of liver steatosis were also excluded. As we aimed to study undiagnosed diabetes among NAFLD patients, those with known history of diabetes on diet or pharmacological treatment were also excluded from analysis. None of these patients was on lipid-lowering drugs.

To study the prevalence of undiagnosed diabetes among NAFLD subjects, we recruited gender- and age-matched community healthy controls at the proportion of 2 to 1. The control subjects had no history of diabetes mellitus, hypertension, dyslipidaemia or chronic liver disease.

Informed written consent was obtained from every patient. The study protocol was carried out in accordance with the principles of the Declaration of Helsinki as revised in 2000 and was approved by the Ethics Committee of the Chinese University of Hong Kong.

Clinical evaluation and laboratory tests

Comprehensive clinical assessment was performed. Comorbid illness and drug/herb intake was recorded with a standard questionnaire. Anthropometric tests included body weight, body height, hip and waist circumference measurements. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Waist-to-hip ratio (WHR) was defined as waist circumference (cm) divided by hip circumference (cm). Waist circumference was measured at a level midway between the lower rib margin and iliac crest with the tape all around the body in horizontal position.

For all patients at baseline (on the day of liver biopsy for patients with NAFLD), a fasting venous blood sample was taken for albumin, bilirubin, ALT, glucose, glycosylated haemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and insulin after fasting for 12 h. Insulin resistance was calculated by the homeostasis model (HOMA-IR), which was equal to fasting insulin (mU/L) × fasting glucose (mm)/22.5. Insulin level (Dako, Ely, UK) was measured by commercial ELISA kits.

The patients and controls underwent a 75 g OGTT after fasting for 12 h. Diabetes was diagnosed if the fasting glucose was at or above 7.0 mm or 2-h postglucose load plasma glucose was at or above 11.1 mm.14 Impaired fasting glucose (IFG) was defined as fasting glucose between 5.6 and 6.9 mm. Impaired glucose tolerance (IGT) was defined as 2-h postload plasma glucose between 7.8 and 11.0 mm. Isolated IGT was defined as patients with IGT but fasting glucose below 5.6 mm.

Histological assessment

Percutaneous liver biopsy was performed for patients with suspected NAFLD using the 16G Temno needle. Liver histology was assessed by a pathologist specialized in liver diseases (A.W.H.C.) who was blinded to the clinical data. A sample was considered adequate if it was longer than 1.5 cm and contained six portal tracts or more. Liver biopsy specimens were prepared with haematoxylin and eosin stain, Masson trichrome stain, Prussian blue stain, reticulin stain, orcein stain and periodic acid-Schiff stain. The histological grading and staging of NAFLD followed the Brunt's criteria.18 Macrovesicular steatosis was graded from 0 to 3, necroinflammatory activity was graded from 0 to 3 and fibrosis was staged from 0 to 4. Non-alcoholic steatohepatitis (NASH) was defined as necroinflammatory grade 2/3 and/or presence of liver fibrosis.7 Patients with at least grade 1 steatosis, grade 0 or 1 necroinflammation and absence of fibrosis were regarded as simple steatosis.

Statistical analysis

Statistical analysis was performed by Statistical Package for Social Science (spss) version 11.5 (Chicago, IL, USA). Continuous variables were expressed as mean ± s.d. or median (interquartile range). Continuous variables were compared using the Student's t-test. Categorical variables were compared using the chi-square test or Fisher exact test as appropriate. Correlation was assessed by the Pearson's test or Spearman's test as appropriate. To determine independent factors associated with diabetes among NAFLD patients, multivariate analysis was performed using binary logistic regression on variables with P-value below 0.1 in the univariate analysis. The sensitivities and specificities of fasting glucose cut-offs at 5.6 mm and 6.1 mm (definition of IFG according to the 2006 and 1997 ADA criteria, respectively)14, 19 to detect diabetes were calculated. All statistical tests were two-sided. Statistical significance was taken as P < 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

From January 2004 to December 2005, 124 ethnic Chinese had liver biopsy-confirmed NAFLD. Fifty-one patients had pre-existing diabetes on diet or pharmacological treatment. As expected, patients with pre-existing diabetes had higher fasting glucose and HbA1c (Table 1). However, their insulin resistance, as depicted by fasting insulin and HOMA-IR, was similar to patients without pre-existing diabetes. Patients with pre-existing diabetes had similar necroinflammatory grades to patients in the current cohort, but were more likely to have liver fibrosis (86% vs. 60%; P = 0.002).

Table 1.   Demographic, biochemical and histological data of NAFLD patients with and without pre-existing diabetes
CharacteristicsPatients with pre-existing diabetes (N = 51)Patients without pre-existing diabetes (N = 73)P-value
Age46 ± 1345 ± 80.51
Male gender, n (%)  23 (45)  52 (71)0.003
Body weight (kg)76 ± 1578 ± 140.36
Body mass index (kg/m2)29 ± 429 ± 50.84
Waist circumference (cm)95 ± 1096 ± 100.49
Hip circumference (cm)102 ± 9102 ± 90.66
Waist–hip ratio0.94 ± 0.070.94 ± 0.070.83
Systolic blood pressure (mmHg)137 ± 22134 ± 140.43
Diastolic blood pressure (mmHg)78 ± 1180 ± 110.46
ALT (IU/L)53 ± 3969 ± 580.088
Fasting glucose (mm)7.7 ± 3.25.8 ± 1.3<0.0001
HbA1c (%)7.5 ± 1.66.1 ± 1.0<0.0001
Total cholesterol (mm)5.5 ± 1.35.7 ± 1.10.39
HDL cholesterol (mm)1.22 ± 0.291.27 ± 0.360.40
LDL cholesterol (mm)3.0 ± 1.23.3 ± 1.10.14
Triglycerides (mm)2.64 ± 2.412.48 ± 1.900.70
Fasting insulin (pm)237 ± 245249 ± 3640.86
HOMA-IR (%)4.3 ± 4.03.3 ± 2.90.20
Brunt's score
  1. Continuous variables were expressed in mean ± s.d.

  2. ALT, alanine aminotransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HOMA-IR, homeostasis model for insulin resistance; NAFLD, non-alcoholic fatty liver disease.

 Steatosis grade
  119 (37%)32 (44%)0.55
  226 (51%)30 (41%)
  36 (12%)11 (15%)
 Necroinflammatory grade
  02 (4%)14 (19%)0.079
  135 (69%)43 (59%)
  212 (24%)15 (21%)
  32 (4%)1 (1%)
 Fibrosis stage
  07 (14%)29 (40%)0.015
  127 (53%)31 (43%)
  213 (26%)8 (11%)
  34 (8%)4 (6%)
  4 01 (1%)

Oral glucose tolerance test

Among 73 NAFLD patients without pre-existing diabetes, fasting glucose was 5.8 ± 1.3 mm. Nine (12%) patients had fasting glucose above 7.0 mm on two separate occasions, and were diagnosed to have diabetes. Sixty-four NAFLD patients with fasting glucose below 7.0 mm underwent OGTT. The 2-h plasma glucose of this cohort was 9.1 ± 2.9 mm (Table 2). Fifteen (21%) patients were diagnosed to have diabetes with postload plasma glucose above 11.1 mm, among them 10 also had IFG (fasting glucose between 5.6 and 6.9 mm). Twenty-one (29%) patients did not reach the criteria of diabetes but had IGT (2-h plasma glucose between 7.8 and 11.0 mm), among them nine also had IFG. Among the 36 patients with postload glucose above 7.8 mm, 17 (47%) had normal fasting glucose. On the other hand, only four (5%) patients had isolated IFG. Twenty-four (33%) patients had normal OGTT results.

Table 2.   Metabolic profile and oral glucose tolerance test results of NAFLD patients without pre-existing diabetes and controls
 NAFLD patients (N = 73) Controls (N = 146)P-value
  1. * Oral glucose tolerance test was performed in 64 NAFLD patients with fasting glucose <7.0 mm and all controls.

  2. HOMA-IR, homeostasis model for insulin resistance; NAFLD, non-alcoholic fatty liver disease.

Age45 ± 845 ± 80.90
Gender  52 (71%)104 (71%)1
Body weight (kg)78 ± 1465 ± 11<0.0001
Body mass index (kg/m2)29 ± 524 ± 3<0.0001
Waist circumference (cm)96 ± 1082 ± 8<0.0001
Hip circumference (cm)102 ± 994 ± 6<0.0001
Waist–hip ratio0.94 ± 0.070.86 ± 0.06<0.0001
Oral glucose tolerance test (mm)
 0-h plasma glucose5.8 ± 1.35.1 ± 0.7<0.0001
 1-h plasma glucose*10.8 ± 2.98.7 ± 2.90.001
 2-h plasma glucose*9.1 ± 2.96.6 ± 2.8<0.0001
0-h glucose (mm)
 ≥5.632 (44%)20 (14%)<0.0001
 ≥6.120 (27%) 9 (6%)<0.0001
 ≥7.0 9 (12%) 3 (2%)0.003
2-h glucose* (mm)
 ≥7.836 (49%)31 (21%)<0.0001
 ≥11.115 (21%)10 (7%)<0.0001
Fasting insulin (pm)249 ± 36453 ± 36<0.0001
HOMA-IR (%)3.3 ± 2.91.0 ± 0.7<0.0001

NAFLD and insulin resistance

Non-alcoholic fatty liver disease patients were more likely to have IGT (21 of 73 NAFLD patients vs. 21 of 146 controls had IGT, P < 0.0001) and diabetes (24 of 73 NAFLD patients vs. 10 of 146 controls had diabetes, P < 0.0001) than controls. In line with the higher prevalence of postchallenge hyperglycaemia, NAFLD patients also had higher insulin resistance. NAFLD patients had significantly higher fasting insulin level than controls (251 ± 377 pm vs. 57 ± 43 pm, respectively; mean difference: 194 pm; 95% confidence interval: 127–260 pm) and HOMA-IR (4.6 ± 2.9% vs. 1.1 ± 0.8%, respectively; mean difference: 3.5%; 95% CI: 3.0–4.0%).

Sixteen of 45 (36%) NASH patients and eight of 28 (29%) patients with simple steatosis had diabetes (P = 0.54). Among NAFLD patients not fulfilling the criteria of diabetes, NASH patients were more likely to have IGT than patients with simple steatosis (16 of 29 NASH patients vs. five of 20 patients with simple steatosis had IGT; P = 0.036). Moreover, 2-h plasma glucose had positive correlation with fibrosis stage (Spearman coefficient: 0.25, P = 0.046). While none of the patients with normal glucose regulation had stage 3 or 4 fibrosis, one patient with isolated IGT and four (17%) patients with diabetes had stage 3 or 4 fibrosis (Table 3). Similarly, grade 3 steatosis occurred in only one (4%) patient with normal glucose regulation but in five (20%) and five (21%) patients with IFG/IGT and diabetes, respectively. Among the three (23%) patients with IFG and grade 3 steatosis, two had coexisting IGT.

Table 3.   Histological severity of 73 NAFLD patients according to the pattern of impaired glucose regulation
Brunt's scoreNGR (N = 24)IFG/IGT (N = 25)Diabetic (N = 24)
  1. NGR, normal glucose regulation; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NAFLD, non-alcoholic fatty liver disease.

Steatosis grade
 113 (54%)8 (32%)11 (46%)
 210 (42%)12 (48%)8 (33%)
 31 (4%)5 (20%)5 (21%)
Necroinflammatory grade
 05 (21%)3 (12%)6 (25%)
 117 (71%)14 (56%)12 (50%)
 22 (8%)7 (28%)6 (25%)
 301 (4%)0
Fibrosis stage
 014 (58%)7 (28%)8 (33%)
 17 (29%)15 (60%)9 (38%)
 23 (13%)2 (8%)3 (13%)
 301 (4%)3 (13%)
 4001 (4%)

Predictors of undiagnosed diabetes among NAFLD patients

Non-alcoholic fatty liver disease patients with diabetes had higher fasting glucose than non-diabetic counterparts (Table 4). They also had lower HDL cholesterol level and higher serum triglycerides. There was also a trend that NAFLD patients with diabetes were older. In a binary logistic regression model (covariates included age, fasting glucose, HDL cholesterol and triglycerides), fasting glucose and HDL cholesterol remained as independent factors predicting the presence of diabetes (Table 4).

Table 4.   Factors associated with diabetes among NAFLD patients without pre-existing diabetes (univariate analysis)
FactorsDiabetes (N = 24)No diabetes (N = 49)P-value
Univariate analysis
 Age47 ± 744 ± 90.12
 Male gender18 (75%)34 (69%)0.62
 Body weight (kg)77 ± 1279 ± 150.48
 Body mass index (kg/m2)29 ± 429 ± 50.79
 Waist circumference (cm)97 ± 896 ± 100.72
 Hip circumference (cm)103 ± 9102 ± 100.89
 Waist–hip ratio0.95 ± 0.060.94 ± 0.080.56
 Systolic blood pressure (mmHg)136 ± 17132 ± 110.42
 Diastolic blood pressure (mmHg)82 ± 1279 ± 100.45
 ALT (IU/L)73 ± 5468 ± 600.72
 Fasting glucose (mm)6.9 ± 1.75.2 ± 0.6<0.0001
 HbA1c (%)6.5 ± 1.26.1 ± 0.70.14
 Total cholesterol (mm)5.6 ± 0.85.7 ± 1.20.52
 HDL cholesterol (mm)1.14 ± 0.271.33 ± 0.380.015
 LDL cholesterol (mm)3.2 ± 0.93.4 ± 1.10.56
 Triglycerides (mm)3.16 ± 2.872.15 ± 1.050.032
 Fasting insulin (pm)262 ± 323243 ± 2930.86
 HOMA-IR (%)3.6 ± 3.63.4 ± 1.90.67
 Presence of NASH16 (67%)29 (59%)0.54
FactorsAdjusted odds ratio95% confidence intervalP-value
  1. Covariates in the multivariate analysis include: age, fasting glucose, HDL cholesterol and triglycerides.

  2. ALT, alanine aminotransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HOMA-IR, homeostasis model for insulin resistance; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

Multivariate analysis
 Age (per year rise)1.00.9–1.10.82
 Fasting glucose (per mm rise)214–1150.001
 HDL cholesterol (per mm rise)0.0070–0.420.017
 Triglycerides (per mm rise)2.11.0–4.40.057

If OGTT was only performed in patients with IFG according to the 1997 ADA criteria (fasting glucose at or above 6.1 mm),19 nearly 40% of diabetes cases would be missed (Table 5). Even if the normal fasting glucose cut-off was lowered to 5.6 mm according to the 2006 ADA criteria,14 the sensitivity in detecting diabetes was only 79%.

Table 5.   Accuracy of different fasting glucose cut-offs in detecting undiagnosed diabetes in 73 NAFLD patients
 Fasting glucose (≥5.6 mm)Fasting glucose (≥6.1 mm)
  1. Diabetes was defined as fasting glucose at or above 7.0 mm and/or postload plasma glucose at or above 11.1 mm.

  2. Values in parentheses indicate 95% confidence intervals.

Sensitivity (%)79.2 (62.9–95.4)62.5 (43.1–81.9)
Specificity (%)73.5 (61.1–85.8)89.8 (81.3–98.3)
Positive predictive value (%)59.4 (42.4–76.4)75.0 (56.0–94.0)
Negative predictive value (%)87.8 (77.8–97.8)83.0 (72.9–93.1)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We set out to assess the prevalence of undiagnosed diabetes in Chinese NAFLD patients. The response to oral glucose challenge was abnormal in a significant proportion of this cohort. Thirty-three percentage of the patients had diabetes and another 29% had IGT. Notably, isolated postchallenge hyperglycaemia was common in this cohort. Twelve percentage of the patients had isolated IGT but normal fasting glucose, and 25% of the diabetic NAFLD patients had normal fasting glucose.

Abnormal glucose metabolism has been found in different NAFLD series. For example, among 19 Italian patients with biopsy-proven NAFLD, five had IGT and one had IFG.20 The higher prevalence of IGT than IFG echoed our findings. The overall prevalence of abnormal glucose metabolism is lower than that of our series probably because the Italian cohort contained patients with less severe disease (only three patients had grade 3 necroinflammation and no patient had stage 4 fibrosis). In 114 Turkish patients with elevated serum aminotransferase levels and bright liver on ultrasonography, 50 had IGT or diabetes according to the postload glucose level, suggesting the need to perform OGTT in NAFLD patients.21 However, the investigators combined IGT and diabetes in the analysis and did not take account of the fasting glucose level, making it difficult to assess the prevalence of isolated postchallenge hyperglycaemia. In another large population screening in Japan, the prevalence of ultrasonography-diagnosed NAFLD rose from 27% in people with normal fasting glucose, 43% in people with IFG, to 62% in people with newly diagnosed diabetes.22

Isolated postchallenge hyperglycaemia also exists but is much less common in the general population. Summarizing 13 European series, around 2–6% of people with fasting glucose below 7.0 mm had 2-h plasma glucose (11.1 mm).16 The corresponding percentage in the Asian series was 3%.15 As our series represent a group of patients with high risk of having metabolic syndrome, the prevalence of postchallenge hyperglycaemia was considerably higher. Our findings suggest strong insulin resistance among NAFLD patients. Using insulin clamp technique, it has been demonstrated that glucose disposal is reduced almost by half even among non-diabetic NAFLD patients.20, 23, 24 The defect is more severe among NASH patients than those with simple steatosis.25 On the other hand, hepatic glucose output is less suppressed after administration of insulin, indicating that hepatic sensitivity to insulin is reduced in NAFLD patients.23, 25

Although fasting glucose was an independent predictor of diabetes, using fasting glucose alone to screen NAFLD patients was limited by its low sensitivity. When normal fasting glucose was set at 5.6 mm according to the latest ADA criteria, the sensitivity in detecting diabetes was only 79%. Using 6.1 mm, the old definition of normal fasting glucose, the sensitivity for fasting glucose alone in detecting diabetes further decreases to 63%. In other words, OGTT can be considered a routine assessment for NAFLD patients in view of the high prevalence of postchallenge hyperglycaemia and poor sensitivity of fasting glucose alone. To the least, OGTT should be performed in NAFLD patients with IFG and/or low HDL cholesterol level, both of which being independent factors associated with diabetes in our cohort.

Does it matter to miss postchallenge hyperglycaemia? In our study, IGT and diabetes patients were more likely to have significant necroinflammation or liver fibrosis. While the majority of patients with normal glucose regulation had no or minimal liver fibrosis, stage 3 or 4 fibrosis was present in 5% and 17% of patients with IGT and diabetes, respectively. Similarly, 92% of patients with normal glucose regulation had no or minimal necroinflammation. By contrast, grade 2 necroinflammation was present in 33% and 25% of patients with IGT and diabetes, respectively. Besides having more severe NAFLD, patients with isolated postchallenge hyperglycaemia are also at risk of developing cardiovascular complications. Among 181 Swedish patients with acute myocardial infarction, previous undiagnosed IGT and diabetes occurred in 40% and 25%, respectively.26 Moreover, isolated postchallenge hyperglycaemia doubles the risk of cardiovascular events and mortality.27–29 In a prospective study on more than 2500 Japanese, IGT, but not IFG, increased the risk of dying from cardiovascular disease by 2.2-fold.30 These data suggest that isolated postchallenge hyperglycaemia not only is common in high-risk individuals, but also predicts poor outcome.

The association among dysglycaemia, cardiovascular disease and NASH probably reflects that the diseases are part of the metabolic syndrome and share common aetiologies. Diabetes is a chronic low-grade inflammatory state. For example, proinflammatory cytokines-like tumour necrosis factor-α, interleukin-6 and interleukin-18 are hypersecreted, whereas anti-inflammatory cytokines-like adiponectin are suppressed. In fact, some of these cytokines are also involved in the development of NASH. Among different populations, hypoadiponectinemia is associated with NAFLD and even NASH.31, 32 In addition, nuclear factor-κB activation and upregulation of tumour necrosis factor-α, interleukin-6 and intercellular adhesion molecule-1 are involved in animal models of steatohepatitis.33

Our study has several limitations. First, the number of patients is relatively small. However, our cohort has comprehensive metabolic profile and histological data. This is superior to radiological studies that are limited by their accuracy and inability to assess necroinflammation and fibrosis.34 Secondly, our patients were recruited from secondary and tertiary referral centres and our data may not reflect the true prevalence of IGT and diabetes among NAFLD patients in the community. Nevertheless, the metabolic profiles of NAFLD patients in our cohort are similar to those identified in the community by ultrasound screening.6, 35 As NAFLD is strongly associated with cardiovascular events, our data further support the need for comprehensive workup including OGTT in these patients.1, 2 Thirdly, our cohort contains Chinese patients only. These findings need to be confirmed in other ethnic groups. Fourthly, the control group in this study represents healthy individuals from the community. Although this provides data regarding the prevalence of postchallenge hyperglycaemia and diabetes in the general population in this age- and gender-group, our data cannot discern whether the high prevalence of dysglycaemia in the NAFLD patients was due to the liver disease or other metabolic factors. In particular, the control group was not matched for BMI with the NAFLD cases. Obesity per se is associated with a higher prevalence of dysglycaemia.

In conclusion, isolated postchallenge hyperglycaemia is common among Chinese NAFLD patients without history of diabetes. It is associated with histological severe disease, and cannot be accurately predicted by any fasting glucose cut-off.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was supported by the Hong Kong Society of Gastroenterology and Clinical Research Fellowship Scheme (A.Y.H.) jointly sponsored by Research Grants Council and The Chinese University of Hong Kong, Hong Kong. V.W. was supported by a fellowship scheme of the Hong Kong Association for the Study of Liver Diseases.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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