Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis

Authors


  • Potential conflict of interest: Nothing to report.

  • The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health. As per the policy of the network, the manuscript for this article was reviewed by the NIDDK before publication. The authors take complete responsibility of the data analyses and credibility of findings.

Abstract

Previous studies have shown familial aggregation of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Therefore, we aimed to examine whether family history of diabetes mellitus (DM) is associated with nonalcoholic steatohepatitis (NASH) and fibrosis in patients with NAFLD. This was a cross-sectional analysis in participants of the NAFLD Database study and PIVENS trial who had available data on family history of DM. One thousand and sixty-nine patients (63% women), with mean age of 49.6 (± 11.8) years and body mass index (BMI) of 34.2 (± 6.4) kg/m2, were included. Thirty percent had DM, and 56% had a family history of DM. Both personal history of DM and family history of DM were significantly associated with NASH, with an odds ratio (OR) of 1.93 (95% confidence interval [CI]: 1.37-2.73; P <0.001) and 1.48 (95% CI: 1.11-1.97; P = 0.01) and any fibrosis with an OR of 3.31 (95% CI: 2.26-4.85; P < 0.001) and 1.66 (95% CI: 1.25-2.20; P < 0.001), respectively. When the models were adjusted for age, sex, BMI, ethnicity, and metabolic traits, the association between diabetes and family history of DM with NASH showed an increased adjusted OR of 1.76 (95% CI: 1.13-2.72; P < 0.001) and 1.34 (95% CI: 0.99-1.81; P = 0.06), respectively, and with any fibrosis with a significant adjusted OR of 2.57 (95% CI: 1.61-4.11; P < 0.0001) and 1.38 (95% CI: 1.02-1.87; P = 0.04), respectively. After excluding patients with personal history of diabetes, family history of DM was significantly associated with the presence of NASH and any fibrosis with an adjusted OR of 1.51 (95% CI: 1.01-2.25; P = 0.04) and 1.49 (95% CI: 1.01-2.20; P = 0.04), respectively. Conclusions: Diabetes is strongly associated with risk of NASH, fibrosis, and advanced fibrosis. Family history of diabetes, especially among nondiabetics, is associated with NASH and fibrosis in NAFLD. (HEPATOLOGY 2012;56:943–951)

Nonalcoholic fatty liver disease (NAFLD) is the most-common cause of elevated serum alanine aminotransferase in the United States.1 Approximately 1 in every 3 Americans is estimated to have NAFLD.2 Although it is a highly prevalent disease, not all patients with NAFLD develop progressive liver disease. Based upon the current understanding of the natural history of NAFLD, it is well accepted that only a subset of patients with histologic features of nonalcoholic steatohepatitis (NASH) progress to advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).3 Therefore, improved understanding of risk factors that predict increased risk of presence of NASH and fibrosis on liver histology could help in the risk stratification of patients with NAFLD.4

Previous studies have shown that metabolic traits, such as diabetes, hypertension, dyslipidemia, and obesity, are associated with increased risk of NASH and advanced fibrosis among patients with NAFLD.5, 6 Metabolic traits are known to have both genetic and environmental influences, suggesting a key role of familial risk factors in metabolic diseases,7 including NAFLD and NASH.8, 9 Previous studies have now shown familial clustering of serum gamma-glutamyl transpeptidase (a marker of fatty liver), NAFLD, NASH, and advanced fibrosis.7, 10-13 Recent studies have shown that parental obesity is associated with increased odds of suspected NAFLD, and there is strong familial clustering of NAFLD, especially in the setting of coexisting insulin resistance (IR).11, 14 Family history is part of routine medical evaluation.15 However, there are limited data on whether family history of diabetes increases the risk of NASH and fibrosis among patients with NAFLD.

We conducted a cross-sectional analysis derived from a prospective, multicenter study of patients with biopsy-proven NAFLD to test the hypothesis that family history of diabetes is associated with increased risk of NASH and fibrosis, after adjusting for multiple metabolic traits as well as personal history of diabetes, in patients with NAFLD who are enrolled in the NASH Clinical Research Network (CRN) studies.

Abbreviations

ALT, alanine aminotransferase; BMI, body mass index; BP, blood pressure; CI, confidence interval; CRN, NASH Clinical Research Network; DM, diabetes mellitus; HbA1c, glycated hemoglobin; HCC, hepatocellular carcinoma; HDL, high-density lipoprotein; IR, insulin resistance; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio; PNPLA3, patatin-like phospholipase domain-containing protein 3; SD, standard deviation; Tg, triglyceride.

Materials and Methods

Study Design and Participants.

This was a cross-sectional study utilizing prospectively collected data from the participants of the multicenter NAFLD Database study and PIVENS trial derived from the NASH CRN studies at the baseline visit.5, 16 The details of the inclusion and exclusion criteria and study designs have been previously published.5, 16, 17 The NASH CRN studies are sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and all patients provided written informed consent before enrolling into these studies.

Derivation of the Cohort and Family History Data.

Information on demographic characteristics, anthropomorphic measurements, alcohol consumption, medical history, medication use, clinical tests, and liver biopsy results were collected at the baseline visit, as previously described.5 There were 1,069 participants 18 years or older enrolled in the above-mentioned NASH CRN studies between October 2004 and February 2008 who had available liver biopsies and data on the family history of diabetes in their first-degree relatives (i.e., parents or children or siblings). Family history of diabetes was based upon patient report during the baseline medical history interview with the clinical coordinator. The exact wording of the question was as follows: “Do any of the patient's first degree relatives (parent, brother, sister, child) have diabetes (Type 1 or Type 2): Yes, No, Don't know.” A mix of interview data and data obtained by a comprehensive chart review was utilized to collect family history data. In addition, family history questions on the baseline form could be answered by interview with the patient, parent, or both and in consultation with the patient's partner, if available. Thus, we utilized all sources to get the most-accurate information pertaining to family history. The clinical coordinator and study physician both reviewed and performed a chart review to obtain the most-accurate information. All forms were cosigned by the clinical coordinators and the study physician, confirming the authenticity of the family history data obtained.

NAFLD Diagnosis.

Participants had to meet specific criteria regarding the diagnoses of NAFLD to be enrolled in the observational database study and the PIVENS trial. Patients with alcohol consumption of >140 g/week (>70 g/week if female) in the 2 years preceding screening or with suspected alcohol-related liver injury were excluded. In addition, other etiologies of chronic liver disease were carefully excluded. For the purposes of enrollment into the observational database study, the diagnosis of NAFLD was based on the histological diagnosis of NAFLD or cryptogenic cirrhosis, as described above, or on imaging studies consistent with these.5 However, for this study, only subjects with available liver biopsy were included.

For the purposes of this study, NAFLD was defined based on the following criteria: (1) histologic diagnosis of NAFLD or histologic diagnosis of cryptogenic cirrhosis; (2) alcohol use history consistent with NAFLD, as defined above; and (3) exclusion of liver disease of other etiologies, including viral or autoimmune hepatitis, drug-induced liver disease, and cholestatic or metabolic liver disease. These other potential etiologies were carefully investigated based on database study specific criteria at screening, as previously published.5, 17

Other Variables.

All data used in these analyses were obtained within 6 months of liver biopsy. The following variables were analyzed: demographic features (e.g., age at enrollment [years], gender, race [white or other], and ethnicity [Hispanic/Latino]); family history, clinical data (e.g., waist circumference, body mass index [BMI] (kg/m2), diastolic blood pressure [BP], and systolic BP); laboratory measures (e.g., triglyceride [Tg], high-density lipoprotein [HDL], and fasting serum glucose levels); and presence of diabetes.

Diabetes status was based upon previous history of diabetes according to patient/physician report (and/or use of medications to treat diabetes and/or fasting plasma glucose >125 mg/dL or a 2-hour glucose >200 mg/dL during an oral glucose tolerance test during the baseline visit). To determine whether the association between family history of diabetes and advanced histology in NAFLD is mediated by prediabetes, the cohort was further classified into prediabetic and normoglycemic participants. Prediabetes was defined as fasting glucose between 100 and 125 mg/dL or glycated hemoglobin (hemoglobin A1c; HbA1c) between 5.7% and 6.4%; normoglycemia was defined as fasting glucose <100 mg/dL and HbA1c <5.7%. Patients with discordant results (e.g., glucose <100 mg/dL and HbA1c >6.4% or patients without diagnosis of diabetes, but with discordant one-time laboratory values) were set to missing (N = 22).

Family history of a condition or disease was self-reported to be present in a first-degree relative (i.e., parent, sibling, or child). The presence of patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 G allele was determined for each patient, as previously described,18 and included in the analysis.

Outcomes.

NASH and fibrosis

Liver biopsy slides stained with hematoxylin and eosin and Masson's trichrome were reviewed and scored centrally by the NASH CRN pathology committee, as previously reported.19 Central pathology committee pathologists reviewed biopsies without any knowledge of the local pathology readings or clinical or laboratory values of patients in the study.19, 20

Fibrosis was graded based on Brunt's modified classification: 0 = no fibrosis; 1a = mild, zone 3 perisinusoidal fibrosis (requires trichrome); 1b = moderate, zone 3 perisinusoidal fibrosis (does not require trichrome); 1c = portal/periportal fibrosis; 2 = zone 3 perisinusoidal or periportal fibrosis or both; 3 = bridging fibrosis; and 4 = cirrhosis.19-22 Advanced fibrosis was defined as stages 3 and 4 and compared with mild or no fibrosis (stages 0-2). Any fibrosis was defined as stages 1-4 and compared with no fibrosis (stage 0). Diagnosis of NASH was classified as either definite NASH or suspicious for NASH (i.e., borderline NASH) based upon central pathology reading, as previously defined,19, 20 and compared with no NASH. These categories were defined before conducting statistical analyses.

Statistical Analyses.

All data were reported as means and standard deviations (SDs), numbers and percentages, or odds ratios (ORs) and 95% confidence intervals (CIs). We first evaluated the baseline characteristics of patients for familial trait using chi-square and Wilcoxon's rank-sum tests. Based on these results, we assessed the effect of family history of diabetes on two separate outcome measures: NASH and fibrosis (i.e., any fibrosis, and then advanced fibrosis, in separate models). Three multiple logistic regression models were run for each of the following outcomes: NASH (definite/borderline versus none), any fibrosis (grades 1-4 versus 0), and advanced fibrosis (grades 3 and 4 versus 0-2). All models included both family history of diabetes and personal history of diabetes as covariates and the following covariates for adjustment: age at enrollment (years); gender (female versus male); BMI (kg/m2); ethnicity (Hispanic versus non-Hispanic); waist circumference (cm); Tg level (mg/dL); HDL level (mg/dL); systolic BP (mmHg); diastolic BP (mmHg); and blood glucose level (mg/dL).

We then conducted sensitivity analyses by excluding patients with personal history of diabetes and examined the association between family history of diabetes and presence of NASH and fibrosis on liver histology using the above-mentioned logistic regression models. We then utilized Wald's test for interaction to assess whether there was a significant interaction between personal history of diabetes and family history of diabetes for these histological traits.

Finally, joint effects of personal history of diabetes and family history of diabetes was examined using three separate logistic regression models to analyze the individual effects of personal history of diabetes and family history of diabetes, as well as their combined effect on NASH and fibrosis. Individuals with no family history and personal history of diabetes were used as the control group for all three models. Age at enrollment, gender, and BMI were controlled for in these models.

To determine whether the association between family history of diabetes and advanced histology in NAFLD is mediated by prediabetes, the cohort was further classified into prediabetic and normoglycemic participants. We conducted multivariate-adjusted logistic regression analyses to examine the association between family history of diabetes and risk of NASH and any fibrosis by adjusting for diabetes as well as prediabetes. In addition, we also examined whether prediabetes was independently associated with risk of NASH and any fibrosis in patients with NAFLD in similar models.

All analyses were performed using SAS statistical software (version 9.2; SAS Institute Inc., Cary, NC). Nominal, two-sided P values were used and were considered to be statistically significant if P ≤ 0.05, a priori.

Results

Baseline Characteristics.

This study included 1,069 patients from the NAFLD Database study and PIVENS trial. Mean age and BMI were 49.6 (± 11.8) years and 34.2 (± 6.4) kg/m2, respectively. Of these 1,069 patients, 596 (56%) reported a family history of diabetes in their first-degree relatives and 30.4% had diabetes. Baseline characteristics of the individuals with a family history of diabetes versus those without a family history of diabetes are shown in Table 1. Those with a family history of diabetes were older in age, females, nonwhite, and had higher BMI and higher prevalence of diabetes. On liver histology, patients with a family history of diabetes were more likely to have NASH (definite/borderline versus none), any fibrosis (any versus none), and advanced fibrosis (stages 3 and 4 versus 0-2), as compared to those without a family history of diabetes.

Table 1. Characteristics of Patients With Nonalcoholic Fatty Liver Disease at Enrollment by Family History of Diabetes Status*
 Family History of Diabetes  
CharacteristicsYes (N = 596)No (N = 473)Total (N = 1,069)P Value
  • Significant P values are shown in bold.

  • *

    Values are N (%) or means ± SD.

  • P values derived from chi-square for categorical variables and from Wilcoxon's rank-sum test for age at enrollment and BMI.

  • Patients were categorized as diabetic based on patient/physician report of diagnosis on the baseline medical history; prediabetes was defined as fasting glucose between 100 and 125 mg/dL or HbA1c between 5.7% and 6.4%; normoglycemia was defined as fasting glucose <100 mg/dL and HbA1c less than 5.7%. Patients with discordant results (e.g., glucose <100 mg/dL and HbA1c >6.4% or patients without diagnosis of diabetes, but with laboratory values in the diabetic range) were set to missing (N = 22).

Age at enrollment, years50.4 ± 11.648.6 ± 12.049.6 ± 11.80.02
BMI (kg/m2)>34.5 ± 6.133.9 ± 6.634.2 ± 6.40.03
Gender (%)   <0.0001
 Male188 (31.5)207 (43.8)395 (36.9) 
 Female408 (68.5)266 (56.2)674 (63.1) 
Ethnicity (%)   0.12
 Hispanic73 (12.3)44 (9.3)117 (10.9) 
 Non-Hispanic523 (87.7)429 (90.7)952 (89.1) 
Race (%)   0.02
 Whites498 (86.8)419 (91.5)917 (88.9) 
 Nonwhites76 (13.2)39 (8.5)115 (11.1) 
Diabetes status (%)   <0.0001
 Diabetes229 (39.3)89 (19.2)318 (30.4) 
 Prediabetes188 (32.3)183 (39.4)371 (35.4) 
 Normoglycemia166 (28.5)192 (41.4)358 (34.2) 
Steatohepatitis (%)   0.03
 Definite354 (59.4)252 (53.4)606 (56.7) 
 Borderline124 (20.8)94 (19.9)218 (20.4) 
 None118 (19.8)126 (26.7)244 (22.9) 
Any fibrosis (%)   <0.001
 Any472 (79.9)330 (70.5)802 (75.7) 
 None119 (20.1)138 (29.5)257 (24.3) 
Advanced fibrosis (%)   <0.01
 Advanced194 (50.9)137 (39.7)331 (45.6) 
 Mild/none187 (49.1)208 (60.3)395 (54.4) 
Cirrhosis (%)   0.45
 Yes50 (8.4)46 (9.7)96 (9.0) 
 No546 (91.6)427 (90.3)973 (91.0) 
PNPLA3, SNP rs738409 (%)   0.91
 GG123 (27.3)101 (27.7)224 (27.5) 
 CC/GC327 (72.7)264 (72.3)591 (72.5) 

Association Between Family History of Diabetes and Liver Histology.

In logistic regression models adjusted for personal history of DM, family history of DM was significantly associated with NASH and any fibrosis, with an adjusted OR of 1.48 (95% CI: 1.11-1.97; P = 0.01) and 1.66 (95% CI: 1.25-2.20; P < 0.001), respectively (as shown in Table 2). In multiple logistic regression analyses adjusted for age, sex, BMI, ethnicity, waist circumference, serum triglyceride, HDL, systolic BP, diastolic BP, glucose, and personal history of diabetes, family history of diabetes increased the risk of NASH and any fibrosis, with an adjusted OR of 1.34 (95% CI: 0.99-1.81; P = 0.06, not statistically significant) and 1.38 (95% CI: 1.02-1.87; P = 0.04), respectively (Table 2), and advanced fibrosis was not statistically significant.

Table 2. Association of Family and Personal History of Diabetes With NASH, Fibrosis, and Advanced Fibrosis
Simple Logistic Regression Analyses
 NASH (N = 824/1,068)Any Fibrosis* (N = 802/1,059)Advanced Fibrosis* (N = 331/1,059)
Family history of diabetes   
 OR1.481.661.18
 95% CI1.11-1.971.25-2.200.91-1.54
 P value0.01<0.0010.22
Personal history of diabetes   
 OR1.933.313.02
 95% CI1.37-2.732.26-4.852.29-3.98
 P value<0.001<0.0001<0.0001
Multiple Logistic Regression Analysis
 NASH (N = 809/1,048)Fibrosis (N = 787/1,039)Advanced Fibrosis (N = 324/1,039)
  • Significant P values are shown in bold.

  • *

    N is lower for models with any fibrosis and advanced fibrosis as outcomes because the Masson's trichrome stain was not available for some patients.

  • Three multiple logistic regression models were run for each of the following outcomes: NASH (definite/borderline versus none); any fibrosis (grades 1-4 versus 0); and advanced fibrosis (grades 3 and 4 versus 0-2). All models included both family history of diabetes and personal history of diabetes as covariates and the following covariates for adjustment: age at enrollment (years); gender (female versus male); BMI (kg/m2); ethnicity (Hispanic versus non-Hispanic); waist circumference (cm); Tg level (mg/dL); HDL level (mg/dL); systolic BP (mmHg); diastolic BP (mmHg); and blood glucose level (mg/dL).

Family history of diabetes   
 OR1.341.380.92
 95% CI0.99-1.811.02-1.870.69-1.24
 P value0.060.040.60
Personal history of diabetes   
 OR1.762.572.39
 95% CI1.13-2.721.61-4.111.68-3.14
 P value0.01<0.0001<0.0001

Association Between Personal History of Diabetes and Liver Histology.

Personal history of diabetes was a more-robust predictor of NASH, any fibrosis, and advanced fibrosis in all models than family history of diabetes, as shown in Table 2. When the models were adjusted for age, sex, BMI, ethnicity, metabolic traits, and family history of diabetes, the association between personal history of diabetes with NASH, any fibrosis, and advanced fibrosis showed an increased adjusted OR of 1.76 (95% CI: 1.13-2.72; P < 0.001), 2.57 (95% CI: 1.61-4.11; P < 0.0001), and 2.39 (95% CI: 1.68-3.14; P < 0.0001), respectively.

Association Between Family History of Diabetes and Liver Histology After Excluding Patients With Personal History of Diabetes.

Personal history of diabetes was present only in 29.7% of the cohort, and family history of diabetes was present in 55.7% of the patients in this cohort (Table 1). Furthermore, family history of diabetes was not concordant with personal history of diabetes, because diabetes increases with age and aging has little effect in adults with a family history of DM. Thus, family history of diabetes can be used to risk stratify patients who either do not have diabetes or have not yet developed diabetes. Therefore, we performed sensitivity analyses after excluding patients with diabetes to further examine whether family history of diabetes increases the risk of NASH or fibrosis in patients with NAFLD. This analysis would assess whether presence of family history of diabetes could be utilized in predicting patients at increased risk of advanced NAFLD either before they develop diabetes or independent of their risk of developing diabetes or without the knowledge of whether the patient has diabetes. Using logistic regression models adjusted for age, sex, BMI, ethnicity, and metabolic traits in this subset of patients with NAFLD after excluding individuals with diabetes, we found that family history of diabetes increased the risk of NASH and any fibrosis, with an adjusted OR of 1.51 (95% CI: 1.01-2.25; P = 0.04) and 1.49 (95% CI: 1.10-2.20; P = 0.04), respectively, and thus results remained consistent.

Interaction between family history and personal history of diabetes.

Because the association between family history and presence of diabetes is known, we further explored a potential effect modification between family history of diabetes and personal history of diabetes in predicting NASH and fibrosis, as shown in Table 3. Wald's test did not reveal an interaction between family history and personal history of diabetes in predicting NASH (P = 0.24), any fibrosis (P = 0.58), and advanced fibrosis (P = 0.13).

Table 3. Individual and Joint Effects of Personal History of Diabetes and Family History of Diabetes on Histological Traits and Interaction Between Personal and Family History of Diabetes
Diabetes StatusN*OR (95% CI)P Value
  • Significant P values are shown in bold.

  • Abbreviations: PH diabetes, personal history of diabetes; FH diabetes, family history of diabetes.

  • *

    N gives the number of patients with outcome and diabetes status.

  • ORs and P values corresponding to PH diabetes, FH diabetes, and PH and FH diabetes were obtained from three separate logistic regression models adjusted for age at enrollment, gender, and BMI for each outcome. The control group for each model was individuals with no personal history or family history of diabetes.

  • P values corresponding to interaction between PH and FH diabetes were obtained using Wald's test.

NASH   
 No PH or FH diabetes2701.00 (—)
 PH diabetes and no FH diabetes762.48 (1.31-4.72)0.01
 FH diabetes and no PH diabetes2851.42 (1.02-1.98)0.04
 PH and FH diabetes1932.13 (1.38-3.30)<0.001
 Interaction between PH and FH diabetes0.24
Any fibrosis   
 No PH or FH diabetes2521.00 (—)
 PH diabetes (yes versus no)782.94 (1.49-5.81)<0.01
 FH diabetes (yes versus no)2691.40 (1.02-1.94)0.04
 PH and FH diabetes (yes versus no)2033.43 (2.11-5.56)<0.0001
 Interaction between PH and FH diabetes0.58
Advanced fibrosis   
 No PH or FH diabetes851.00 (—)
 PH diabetes (yes versus no)526.03 (3.16-11.52)<0.0001
 FH diabetes (yes versus no)921.24 (0.84-1.82)0.28
 PH and FH diabetes (yes versus no)1024.76 (2.96-7.64)<0.0001
 Interaction between PH and FH diabetes0.13

Joint Effects of Family and Personal History of Diabetes.

We conducted further analyses to examine the joint effects of presence of diabetes and family history of diabetes on risk of NASH and fibrosis in patients with NAFLD. The referent group in this analysis was patients with NAFLD with no diabetes and family history of diabetes (Table 3). We found that the presence of diabetes increased the risk of NASH, any fibrosis, and advanced fibrosis, with an age/sex/BMI-adjusted OR of 2.48 (95% CI: 1.31-4.72; P = 0.01), 2.94 (95% CI: 1.49-5.81; P < 0.01), and 6.03 (95% CI: 3.16-11.52; P < 0.0001), respectively. Consistent with results presented in Table 1, family history of diabetes increased the risk of NASH, any fibrosis, and advanced fibrosis, with an adjusted OR of 1.42 (95% CI: 1.02-1.98; P = 0.04), 1.40 (95% CI: 1.02-1.94; P = 0.04), and 1.24 (95% CI: 0.84-1.82; P = 0.28), respectively.

As would be expected, the presence of both diabetes and family history of diabetes increased the risk of NASH, any fibrosis, and advanced fibrosis, with an age/sex/BMI-adjusted OR of 2.13 (95% CI: 1.38-3.30; P < 0.001), 3.43 (95% CI: 2.11-5.56; P < 0.0001), and 4.76 (95% CI: 2.96-7.64; P < 0.0001), respectively.

Sensitivity Analyses.

For the association between prediabetes, diabetes, and family history of diabetes, we conducted sensitivity analyses to examine whether the association between family history of diabetes with NASH and any fibrosis was mediated by prediabetes, as shown in Table 4. We confirmed that the results remained consistent, even after adjusting for prediabetes. Furthermore, prediabetes was not an independent risk factor for worse liver histology in NAFLD.

Table 4. Association Between Prediabetes, Diabetes, and Family History of Diabetes With NASH, Fibrosis, and Advanced Fibrosis
Simple Logistic Regression Analyses
 NASH (N = 805/1,046)Any Fibrosis* (N = 782/1,037)Advanced Fibrosis* (N = 323/1,037)
Family history of diabetes   
  OR1.481.661.18
  95% CI1.11-1.971.25-2.200.91-1.54
  P value0.01<0.0010.22
Personal history of diabetes   
 Diabetes versus normoglycemic  
  OR1.963.773.33
  95% CI1.34-2.882.50-5.702.39-4.65
  P value<0.001<0.0001<0.0001
 Prediabetes versus normoglycemic  
  OR1.001.221.16
  95% CI0.72-1.390.89-1.680.82-1.64
  P value0.980.220.39
Multiple Logistic Regression Analysis
 NASH (N = 790/1,026)Fibrosis (N = 767/1,017)Advanced Fibrosis (N = 316/1,017)
  • Significant P values are shown in bold.

  • *

    N is lower for models with any fibrosis and advanced fibrosis as outcomes because the Masson's trichrome stain was not available for some patients.

  • Three multiple logistic regression models were run for each of the following outcomes: NASH (definite/borderline versus none); any fibrosis (stages 1-4 versus 0); and advanced fibrosis (grades 3 and 4 versus 0-2). All models included both family history of diabetes and personal history of diabetes (two indicator variables for diabetic and prediabetic; normoglycemic is the reference group) as covariates and the following covariates for adjustment: age at enrollment (years); gender (female versus male); BMI (kg/m2); ethnicity (Hispanic versus non-Hispanic); waist circumference (cm); Tg level (mg/dL); HDL level (mg/dL); systolic BP (mmHg); diastolic BP (mmHg); and blood glucose level (mg/dL).

Family history of diabetes   
  OR1.351.410.95
  95% CI0.99-1.831.04-1.910.70-1.28
  P value0.060.030.73
Personal history of diabetes   
 Diabetes versus normoglycemic  
  OR1.832.782.33
  95% CI1.09-3.051.60-4.811.51-3.59
  P value0.02<0.0010.0001
 Prediabetes versus normoglycemic  
  OR1.001.000.93
  95% CI0.70-1.430.71-1.430.64-1.36
  P value0.990.990.72

Discussion

Main Findings.

The principal findings of this study include that family history of diabetes is associated with the presence of NASH and fibrosis in patients with NAFLD. The presence of a family history of diabetes may have clinical implications in risk stratification among patients with NAFLD who do not have a personal history of diabetes or have not yet developed diabetes. We also confirmed previous studies by demonstrating robust association between diabetes and the presence of NASH, any fibrosis, and advanced fibrosis. Furthermore, our results suggest that there was no statistically significant effect modification between diabetes and family history of diabetes in increasing the risk of NASH, suggesting that both factors may be increasing the risk of more-severe histology among patients with NAFLD by mechanisms that may not be identical and perhaps complementary to each other. Therefore, we propose that family history of diabetes may be utilized in risk stratification of patients with NAFLD (especially among nondiabetics), based upon our results that family history of diabetes is a contributing factor of NASH and fibrosis in patients without diabetes (please see Table 3).

Strengths and Limitations.

Strengths of the study include the prospective nature of the NASH CRN cohort as well as detailed description and blinded analyses of the liver histology by an expert committee of pathologists. Because the NASH CRN cohort is a multiethnic, as well as multi-center, study including eight sites across the United States, we believe that the results are generalizable to other patients with NAFLD residing in the United States. Finally, family history data were collected with the help of a standardized questionnaire in all patients enrolled in the NASH CRN cohort using a standard protocol at the baseline visit. However, we acknowledge the following limitations of the study. The NASH CRN cohort does not include healthy individuals; therefore, these findings may not be generalizable to the general population. However, lack of normal controls, and using non-NASH (i.e., a milder form of NAFLD) patients as the referent group, instead of healthy controls, would bias the results toward null. Therefore, we believe that the true association at the level of the population may even be stronger. Last, family history was based upon self-report, as is commonly obtained in cohort studies of a single generation.

Interpretation and External Validity.

Previous studies have shown that familial factors, such as obesity and IR, are associated with suspected NAFLD and/or NASH.7, 11, 23 Willner et al. conducted a retrospective study including 90 patients with biopsy-proven NASH and showed that nine families had familial clustering of NASH.10 Furthermore, they also observed that obesity, diabetes, and IR were commonly observed in these nine families.10 Abdelmalek et al. conducted a familial aggregation case-control study comparing 20 patients with NAFLD versus 20 controls, and showed that IR and diabetes were more commonly observed in the first-degree relatives of patients with NAFLD.11 However, these seminal studies provided important insight into the familial associations in NAFLD, but were limited by small sample size and were single-center studies. Previous studies from the NASH CRN cohort and other independent cohorts have consistently shown that diabetes is associated with NASH and advanced fibrosis among patients with NAFLD.4-6, 24 The presence of diabetes has long-term prognostic significance in patients with liver disease because it is an independent predictor of cirrhosis and HCC.25-27 Family history of diabetes is easily obtainable during a routine clinic visit and can help identify NAFLD patients who may be at increased risk of having NAFLD fibrosis and NASH. Because there are no reliable noninvasive biomarkers that can differentiate between NAFLD alone versus NASH, clinical predictors are commonly utilized by clinicians to identify which NAFLD patients should undergo a liver a biopsy.6 Family history of diabetes may be considered one such risk factor in patients with NAFLD. Familial risk factors suggest either a shared genetic and/or environment susceptibility toward NASH. Therefore, it is plausible that common genetic pathways linking IR and NAFLD may be responsible for fibrosis progression in NAFLD to cirrhosis and, perhaps, HCC.

Potential Utility and Implications of the Findings.

Because incidence of diabetes is related to increasing age, family history of diabetes could be utilized as a risk factor for NASH or NAFLD fibrosis in patients with NAFLD who are either younger or have not yet developed diabetes. In this NASH CRN cohort with an average age of 50 years, 56% (N = 596) had a family history of diabetes, but the prevalence of diabetes among those with a family history of diabetes was only 38% (please see Table 1). Therefore, family history of diabetes without a personal history of diabetes was applicable to 62% (N = 367) of individuals. This suggests the potential clinical utility of this observation and at-risk population that can be identified by taking family history of diabetes among patients with NAFLD who may be at a higher risk of having NASH or fibrosis on a liver biopsy.

Further studies are needed to develop clinical prediction rules that increase the pretest probability of finding NASH or fibrosis among patients with NAFLD, both in the primary care as well as subspecialty settings.

In conclusion, using a large, prospective, clinically and histologically well-characterized cohort of patients with biopsy-proven NAFLD, we showed that personal history of diabetes and family history of diabetes is associated with the presence of NASH and fibrosis among patients with NAFLD. Familial risk factors can help unravel shared genetic and environmental mechanisms underlying the development of NASH, progression to advanced fibrosis, and HCC. Further studies are needed to better understand these mechanistic pathways.

Appendix

Members of the NASH CRN Adult Clinical Centers are: Case Western Reserve University clinical centers: MetroHealth Medical Center, Cleveland, OH: Arthur J. McCullough, M.D.; Patricia Brandt; Diane Bringman, R.N. (2004-2008); Srinivasan Dasarathy, M.D.; Jaividhya Dasarathy, M.D.; Carol Hawkins, R.N.; Yao-Chang Liu, M.D. (2004-2009); and Nicholette Rogers, Ph.D., PA-C (2004-2008); Cleveland Clinic Foundation, Cleveland, OH: Arthur J. McCullough, M.D.; Srinivasan Dasarathy, M.D.; Mangesh Pagadala, M.D.; Ruth Sargent, L.P.N.; Lisa Yerian, M.D.; and Claudia Zein, M.D.; California Pacific Medical Center, San Francisco, CA: Raphael Merriman, M.D., and Anthony Nguyen; Duke University Medical Center, Durham, NC: Manal F. Abdelmalek, M.D.; Stephanie Buie; Anna Mae Diehl, M.D.; Marcia Gottfried, M.D. (2004-2008); Cynthia Guy, M.D.; Meryt Hanna (2010); Christopher Kigongo; Paul Killenberg, M.D. (2004-2008); Samantha Kwan, M.S. (2006-2009); Yi-Ping Pan; Dawn Piercy, F.N.P.; Melissa Smith (2007-2010); and Savita Srivastava, M.D.; Indiana University School of Medicine, Indianapolis, IN: Naga Chalasani, M.D.; Oscar W. Cummings, M.D.; Marwan Ghabril, M.D.; Ann Klipsch, R.N.; Linda Ragozzino, R.N.; Girish Subbarao, M.D.; Sweta Tandra, M.D.; Raj Vuppalanchi, M.D.; Saint Louis University, St Louis, MO: Debra King, R.N.; Andrea Morris; Joan Siegner, R.N.; Susan Stewart, R.N.; Brent A. Neuschwander-Tetri, M.D.; and Judy Thompson, R.N.; University of California San Diego, San Diego, CA: Cynthia Behling, M.D., Ph.D.; Jennifer Collins; Janis Durelle; Tarek Hassanein, M.D. (2004-2009); Joel E. Lavine, M.D., Ph.D. (2002-2010); Rohit Loomba, M.D.; Anya Morgan; Heather Patton, M.D.; and Claude Sirlin, M.D.; University of California San Francisco, San Francisco, CA: Bradley Aouizerat, Ph.D.; Kiran Bambha, M.D. (2006-2010); Marissa Bass; Nathan M. Bass, M.D., Ph.D.; Linda D. Ferrell, M.D.; Bo Gu (2009-2010); Bilal Hameed, M.D.; Mark Pabst; Monique Rosenthal (2005-2010); and Tessa Steel (2006-2008); University of Washington Medical Center, Seattle, WA: Matthew Yeh, M.D., Ph.D.; Virginia Commonwealth University, Richmond, VA: Sherry Boyett, R.N., B.S.N.; Melissa J. Contos, M.D.; Michael Fuchs, M.D.; Amy Jones; Velimir A.C. Luketic, M.D.; Puneet Puri, M.D.; Bimalijit Sandhu, M.D. (2007-2009); Arun J. Sanyal, M.D.; Carol Sargeant, R.N., B.S.N., M.P.H.; Kimberly Noble; and Melanie White, R.N., B.S.N. (2006-2009); Virginia Mason Medical Center, Seattle, WA: Sarah Ackermann; Kris V. Kowdley, M.D.; Jane Park; Tracey Pierce; Jody Mooney, M.S.; James Nelson, Ph.D.; Cheryl Shaw, M.P.H.; Alice Stead; and Chia Wang, M.D.; and Washington University, St. Louis, MO: Elizabeth M. Brunt, M.D. Resource centers: National Cancer Institute, Bethesda, MD: David E. Kleiner, M.D., Ph.D.; National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD: Edward C. Doo, M.D.; Jay H. Hoofnagle, M.D.; Patricia R. Robuck, Ph.D., M.P.H.; and Averell Sherker, M.D.; and Johns Hopkins University, Bloomberg School of Public Health (Data Coordinating Center), Baltimore, MD: Patricia Belt, B.S.; Frederick L. Brancati, M.D., M.H.S. (2003-2009); Jeanne M. Clark, M.D., M.P.H.; Ryan Colvin, M.P.H. (2004-2010); Michele Donithan, M.H.S.; Mika Green, M.A.; Rosemary Hollick (2003-2005); Milana Isaacson, B.S.; Wana K. Jin, B.S.; Alison Lydecker, M.P.H. (2006-2008); Pamela Mann, M.P.H. (2008-2009); Kevin P. May, M.S.; Laura Miriel, B.S.; Alice Sternberg, Sc.M.; James Tonascia, Ph.D.; Aynur Ünalp-Arida, M.D., Ph.D.; Mark Van Natta, M.H.S.; Ivana Vaughn, M.P.H.; Laura Wilson, Sc.M.; and Katherine Yates, ScM.

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