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Factors Associated with Deep Vein Thrombosis in Type 2 Diabetics with Biopsy-Proven Non-alcoholic Fatty Liver Disease

  • Amandeep SinghEmail author
  • Aly ElBoraie
  • Nan Lan
  • Mohit Gupta
Medicine
  • 108 Downloads
Part of the following topical collections:
  1. Topical Collection on Medicine

Abstract

Non-alcoholic fatty liver disease (NAFLD) can lead to a prothrombotic stage increasing the risk of deep vein thrombosis (DVT). We aimed to assess the prevalence and factors associated with DVT in patients with type 2 diabetes (T2D) and biopsy-proven NAFLD. Using ICD-codes, all T2D patients who had liver biopsy done for suspected NAFLD were identified and assessed. Patients with secondary causes of hepatic steatosis (Hepatitis, excess alcohol, etc.) were excluded. Liver biopsy was staged as F0-4, advanced fibrosis (AF) being F3-4. A univariable and multivariate analysis was performed to assess factors associated with DVT. A total of 1295 patients were included in the final analysis. DVT was present in 5.5% of these patients. Our cohort consisted of 62% females, 90% were Caucasians, and 90% were obese or overweight (p = 0.59, 0.22, and 0.53, respectively). Mean platelet count was 200.1 ± 82.2 (p = 0.048) and mean HbA1c was 6.9 ± 1.7 (p = 0.71). On multivariate analysis, a 5-year increment in the age at time of T2D diagnosis was associated with 10% increase in likelihood of having DVT (OR {95% CI} 1.1 (1.01, 1.3), p = 0.031). Patients with IBD were 3-times more likely to have DVT than those without IBD and being on furosemide was associated with 2.5-times higher odds of DVT (OR {95% CI} 3.0 (1.3, 7.1), p = 0.012 and 2.5 (1.5, 4.1), p < 0.001, respectively). Our study suggests that older age, stricturing IBD disease, and use of furosemide in T2D with NAFLD increase the risk of DVT. Future prospective studies are required to confirm these findings. Clinical trial registration number: CCF 16-018

Keywords

Non-alcoholic fatty liver disease (NAFLD) Deep vein thrombosis Advanced fibrosis Type 2 diabetes Liver biopsy 

Abbreviations

AF

Advanced fibrosis

AST

Aspartate aminotransferase

ALT

Alanine aminotransferase

ALP

Alkaline phosphatase

APRI

AST to platelet ration index

BMI

Body mass index

CDC

Centers for Disease Control and Prevention

CD

Crohn’s disease

DVT

Deep vein thrombosis

FIB-4

Fibrosis-4

GGT

γ-Glutamyl transpeptidase

HDL

High-density lipoprotein

HbA1c

Hemoglobin A1c

HCC

Hepatocellular carcinoma

HLD

Hyperlipidemia

IDF

International diabetes federation

LDL

Low-density lipoprotein

LD

Liver disease

MetS

Metabolic syndrome

NAFLD

Non-alcoholic fatty liver disease

IR

Insulin resistance

CKD

Chronic kidney disease

IBD

Inflammatory bowel disease

UC

Ulcerative colitis

Introduction

Non-alcoholic fatty liver disease (NAFLD) is one the most common chronic liver disease (CLD) in the world, with an estimated prevalence of 10–40% [1, 2]. It has been ranked as the second leading cause for liver transplantation (LT) in the United States [3], making it a major health concern. NAFLD is defined as increased liver fat accumulation in the form of triglycerides (steatosis), diagnosed either by imaging or histology, due to causes other than excess alcohol consumption, steatogenic medications or hereditary disorders [4, 5]. The disease spectrum includes non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) which significantly increases the risk of cirrhosis, liver failure, and hepatocellular carcinoma [4, 5]. NAFLD is considered as the hepatic expression of the metabolic syndrome. The key component of the MetS is insulin resistance, along with other central features as obesity, hypertension, hyperinsulinemia, and hypertriglyceridemia, which are also the predisposing factors for NAFLD, suggesting an interlink between two conditions [6]. The prevalence of NAFLD in patients with type 2 diabetes (T2D) is 49 to 62% [7, 8] and clinically relevant fibrosis occurs in up to 20% of these patients [9]. T2D increases the overall mortality and liver-related deaths in patients with NAFLD [9]. Moreover, the existence of NAFLD in T2D is also accompanied with increased cardiovascular disease risks and accelerates the progression of macro and microvascular complications [10].

Liver cirrhosis has been suggested to cause a prothrombotic stage and increases the risk of deep vein thrombosis (DVT) [11]. Similarly, T2D has also been indicated as a risk factor for DVT [12, 13]. But, there is a paucity of data on the association of DVT in NAFLD patients, especially with underlying diabetes and advanced stages of fibrosis. We herein aim to detect the prevalence and factors associated with DVT in a large cohort of diabetics with biopsy-proven NAFLD.

Materials and Methods

After obtaining approval from the Institutional Review Board, using ICD-9 codes, all patients between ages 18 and 80 with a diagnosis of T2D and had liver biopsy (n = 1318) done for suspected NAFLD between January 2000 and December 2015, in the Cleveland Clinic system, were identified from electronic medical records. An expert pathologist reviewed the biopsy samples to detect fibrosis. Fibrosis staging was determined using the Metavir liver fibrosis system (F0-4). AF was defined as stages 3–4. Patients with incomplete medical records or with secondary causes of hepatic steatosis (hepatitis C, Wilson disease, lipodystrophy, starvation, parenteral nutrition, abetalipoprotinemia, medications [corticosteroids, valproate, and antivirals]) were excluded. Patients were also excluded if they consumed more than 30 g of alcohol per day for males or more than 20 g per day for females [4, 5]. Laboratory data and use of various medications within 24 months of liver biopsies were used for statistical analysis. The diagnosis of DVT was based on the ICD-9 codes and results of Doppler ultrasound (US).

Statistical Analysis

Data are presented as mean ± standard deviation, median [25th, 75th percentiles] or N (%). A univariable analysis was performed to assess factors associated with DVT. Analysis of variance (ANOVA) or the non-parametric Kruskal-Wallis tests were used for continuous or ordinal variables and Pearson’s chi-square tests or Fisher’s Exact were used for categorical factors. In addition, multivariable logistic regression was done to further assess which clinical factors are associated with DVT. All factors were considered for inclusion in the model and an automated stepwise variable selection method performed on 1000 bootstrap samples was used to choose the final model; variables with inclusion rates of at least 50% were included in the final model.

The same analysis was repeated in the subgroup of subjects who had AF on biopsy; because only 26 subjects with AF had DVT, the multivariable model was restricted to the top 3 variables with highest inclusion rates. SAS (version 9.4, The SAS Institute, Cary, NC) was used for all analyses and a p ≤ 0.05 was considered statistically significant.

Results

Out of 1318 patients, 15 did not have diabetes, 6 patients were found to have excessive alcohol consumption, and 2 were younger than 18 at the time of NAFLD diagnosis and liver biopsy. After exclusions, 1295 were included in the final analysis. Table 1 represents the clinical features and demographics of the included patients. Overall, our cohort consisted of 64.9% females and 85.1% Caucasians (p = 0.59 and 0.22, respectively). Median age at the time of diagnosis of T2D, NAFLD, and at liver biopsy in patients with DVT were 54.0 ± 9.6, 55.1 ± 9.3, and 55.6 ± 9.0 years, respectively (p < 0.05 for all). DVT was present in 5.5% of the patients. Out of which, 62.0% were females and 90.1% were Caucasians (p = 0.59, 0.22). As regards to their smoking habits, 67.1% never smoked, 25.7% were former smokers, and 7.1% were current smokers (p = 0.12). Nearly 90% of patients with DVT were above the normal weight, with mean BMI of 34.4 ± 6.7 (p = 0.3), obesity was seen in 57.7% and severe obesity in 18.3% (p = 0.53). Other co-morbidities included chronic kidney disease (CKD) in 22.5%, inflammatory bowel disease (IBD) in 9.9% (5.6% had Crohn’s disease [CD], 4.2% had Ulcerative colitis [UC]) and stricturing disease in 4.2% in patients with DVT (p < 0.05 for all). Interestingly, none of the patient had active IBD at the time of DVT diagnosis. Hypertension (HTN) was present in 77.5% and hyperlipidemia (HLD) in 73.2% of patients with DVT (p = 0.72 and 0.83, respectively). NASH was present in 35 subjects and clinically significant cirrhosis in 8 subjects. AF on biopsy was present in 36.6% of subjects (p = 0.37) [14]. Out of all patients with DVT, four patients were immobilized in the past 3 months, three had active malignancy, one had trauma, one had underlying thrombophilia, three patients were over the age of 70 years, and three had rheumatologic disorders. Of the four patients with active infection in the past 3 months, all were obese and immobilized, and one had respiratory failure. Also, 12 patients had underlying coronary artery disease and two patients had peripheral vascular disease.
Table 1

Demographic and clinical characteristics (all subjects)

Factor

Overall (N = 1295)

No DVT (N = 1224)

DVT (N = 71)

p value

N

Statistics

n

Statistics

n

Statistics

Age at T2D diagnosis (years)

1295

50.0 ± 11.8

1224

49.8 ± 11.9

71

54.0 ± 9.6

0.003a

Age at NAFLD diagnosis (years)

1295

51.2 ± 11.7

1224

51.0 ± 11.8

71

55.1 ± 9.3

0.004a

Age at biopsy (years)

1295

51.6 ± 11.8

1224

51.4 ± 11.9

71

55.6 ± 9.0

0.004a

Gender

1295

 

1224

 

71

 

0.59c

  Female

 

841 (64.9)

 

797 (65.1)

 

44 (62.0)

 

  Male

 

454 (35.1)

 

427 (34.9)

 

27 (38.0)

 

Caucasian

1295

 

1224

 

71

 

0.22c

  Caucasian

 

1102 (85.1)

 

1038 (84.8)

 

64 (90.1)

 

  Other

 

193 (14.9)

 

186 (15.2)

 

7 (9.9)

 

Smoking

1285

 

1215

 

70

 

0.12c

  Never

 

728 (56.7)

 

681 (56.0)

 

47 (67.1)

 

  Former

 

479 (37.3)

 

461 (37.9)

 

18 (25.7)

 

  Current

 

78 (6.1)

 

73 (6.0)

 

5 (7.1)

 

BMI

1295

35.3 ± 8.2

1224

35.4 ± 8.3

71

34.4 ± 6.7

0.30a

BMI group

1295

 

1224

 

71

 

0.53b

  Normal weight

 

77 (5.9)

 

70 (5.7)

 

7 (9.9)

 

  Overweight

 

251 (19.4)

 

241 (19.7)

 

10 (14.1)

 

  Obese

 

664 (51.3)

 

623 (50.9)

 

41 (57.7)

 

  Severely obese

 

303 (23.4)

 

290 (23.7)

 

13 (18.3)

 

SBP

1295

129.7 ± 17.2

1224

129.8 ± 17.2

71

127.4 ± 17.5

0.24a

DBP

1295

74.0 ± 11.1

1224

74.1 ± 11.1

71

72.6 ± 11.4

0.27a

NAFLD prior to T2D

1295

276 (21.3)

1224

263 (21.5)

71

13 (18.3)

0.53c

Hypertension

1295

980 (75.7)

1224

925 (75.6)

71

55 (77.5)

0.72c

Hyperlipidemia

1295

934 (72.1)

1224

882 (72.1)

71

52 (73.2)

0.83c

CKD

1295

164 (12.7)

1224

148 (12.1)

71

16 (22.5)

0.010c

IBD type

1293

 

1222

 

71

 

0.017c

  CD

 

32 (2.5)

 

28 (2.3)

 

4 (5.6)

 

  UC

 

17 (1.3)

 

14 (1.1)

 

3 (4.2)

 

  None

 

1244 (96.2)

 

1180 (96.6)

 

64 (90.1)

 

IBD

1293

49 (3.8)

1222

42 (3.4)

71

7 (9.9)

0.006c

Stricturing disease

1295

17 (1.3)

1224

14 (1.1)

71

3 (4.2)

0.027c

Advanced fibrosis on biopsy

1295

412 (31.8)

1224

386 (31.5)

71

26 (36.6)

0.37c

Statistics presented as Mean ± SD or N (column %)

p values: a ANOVA, b Kruskal-Wallis test, c Pearson’s chi-square test

In regard to medications as shown in Table 2; 70.4% of the patients with DVT were found to be on oral hypoglycemic, with a median duration of use 43.4 [7.7, 73.0] months (p = 0.94 and 0.21). Insulin was used by 46.5%, with a median duration of use of 17.4 [6.1, 49.5] months (p = 0.20 and 0.40). Although there was no difference in the use of oral hypoglycemics and insulin in patients with and without DVT, compared with patients without DVT, the median duration of pioglitazone was significantly higher (17.1 [6.3, 45.0] vs. 53.3 [32.7, 73.2] (p = 0.006)), and median duration of Humulin was significantly lower (14.6 [3.4, 42.6] vs. 2.5 [0.30, 8.0] (p = 0.019)) in patients with DVT. Approximately 86% of the patients were on antihypertensive medications, for a median duration of 48.1 [13.3, 94.2] months (p = 0.59 and 0.054). Furosemide was used for HTN in 28 (73.6%) patients, for CHF in 8 (21.0%), and for ascites in 2 (5.2%) patients. Use and duration of furosemide was more in patients with DVT than without DVT (53.5% vs. 28.5% and 25.5 [3.7, 57.9] vs. 9.8 [0.80, 44.3] respectively, p < 0.05). Similarly, use of spironolactone was more prevalent in patients with DVT than without DVT (25.4% vs. 13.6%, p = 0.006), but there was no difference in the duration of use amongst two groups (p = 0.054). In terms of antilipid medications and aspirin, there was no significant difference in the use and duration in patients with and without DVT (p > 0.05). As shown in Table 3, the mean platelet count was 200.1 ± 82.2 (p = 0.048) and median HbA1c was 6.9 ± 1.7 (p = 0.71). The median aspartate aminotransferase (ALT) level was 30.0 [20.0, 46.0], median alanine aminotransferase (AST) level was 31.0 [21.0, 52.0], and median alkaline phosphatase (ALP) was 92.0 [80.0, 118.0] (p = 0.15, 0.035, and < 0.001, respectively).
Table 2

Medication use (all subjects)

Factor

Overall (N = 1295)

No DVT (N = 1224)

DVT (N = 71)

p value

N

Statistics

n

Statistics

n

Statistics

Oral hypoglycemics

1295

917 (70.8)

1224

867 (70.8)

71

50 (70.4)

0.94c

  Oral hypoglycemic duration (months)

917

30.4 [7.5, 69.2]

867

29.7 [7.4, 69.1]

50

43.4 [7.7, 73.0]

0.21b

  Metformin use

1295

844 (65.2)

1224

797 (65.1)

71

47 (66.2)

0.85c

  Metformin duration (months)

844

30.8 [7.1, 70.9]

797

30.4 [7.1, 70.9]

47

39.8 [7.6, 69.3]

0.38b

  Glipizide use

1295

161 (12.4)

1224

152 (12.4)

71

9 (12.7)

0.95c

  Glipizide duration (months)

161

17.0 [5.7, 45.0]

152

17.6 [5.2, 44.2]

9

12.5 [9.4, 66.3]

0.50b

  Pioglitazone use

1295

171 (13.2)

1224

161 (13.2)

71

10 (14.1)

0.82c

  Pioglitazone duration (months)

171

19.2 [6.6, 52.2]

161

17.1 [6.3, 45.0]

10

53.3 [32.7, 73.2]

0.006b

  Sitagliptin use

1295

245 (18.9)

1224

234 (19.1)

71

11 (15.5)

0.45c

  Sitagliptin duration (months)

245

6.2 [1.00, 28.8]

234

5.8 [1.00, 28.8]

11

16.1 [5.1, 30.6]

0.46b

  Saxagliptin use

1295

19 (1.5)

1224

18 (1.5)

71

1 (1.4)

0.97c

Insulin

1295

509 (39.3)

1224

476 (38.9)

71

33 (46.5)

0.20c

  Insulin duration (months)

509

13.9 [3.0, 44.4]

476

13.9 [3.0, 44.2]

33

17.4 [6.1, 49.5]

0.40b

  Liraglutide use

1295

127 (9.8)

1224

122 (10.0)

71

5 (7.0)

0.42c

  Liraglutide duration (months)

127

9.9 [1.8, 23.6]

122

9.6 [1.8, 23.6]

5

11.9 [3.5, 13.8]

0.87b

  Detemir/Levemir use

1295

117 (9.0)

1224

106 (8.7)

71

11 (15.5)

0.051c

  Detemir/Levemir duration (months)

117

7.6 [0.90, 21.0]

106

7.6 [0.80, 20.6]

11

12.4 [1.4, 58.9]

0.27b

  Glargine use

1295

306 (23.6)

1224

286 (23.4)

71

20 (28.2)

0.35c

  Glargine duration (months)

306

9.8 [0.60, 42.5]

286

9.4 [0.40, 41.0]

20

14.2 [7.9, 51.3]

0.16b

  Humulin use

1295

82 (6.3)

1224

75 (6.1)

71

7 (9.9)

0.21c

  Humulin duration (months)

82

13.3 [2.8, 40.9]

75

14.6 [3.4, 42.6]

7

2.5 [0.30, 8.0]

0.019b

  Exenatide use

1295

144 (11.1)

1224

135 (11.0)

71

9 (12.7)

0.67c

  Exenatide duration (months)

144

11.5 [3.5, 27.5]

135

11.2 [3.3, 26.9]

9

26.2 [8.6, 40.3]

0.074b

Antihypertensive medications

1295

1083 (83.6)

1224

1022 (83.5)

71

61 (85.9)

0.59c

  Antihypertensive duration (months)

1083

33.0 [4.6, 77.3]

1022

32.4 [4.3, 76.1]

61

48.1 [13.3, 94.2]

0.054b

  Lisinopril use

1295

537 (41.5)

1224

511 (41.7)

71

26 (36.6)

0.39c

  Lisinopril duration (months)

537

22.7 [4.4, 58.0]

511

22.8 [4.5, 57.8]

26

18.6 [1.1, 79.9]

0.87b

  Losartan use

1295

196 (15.1)

1224

182 (14.9)

71

14 (19.7)

0.27c

  Losartan duration (months)

196

16.9 [1.05, 48.4]

182

19.0 [1.3, 49.7]

14

3.2 [0.40, 23.9]

0.23b

  Furosemide use

1295

387 (29.9)

1224

349 (28.5)

71

38 (53.5)

< 0.001c

  Furosemide duration (months)

387

10.0 [1.00, 44.5]

349

9.8 [0.80, 44.3]

38

25.5 [3.7, 57.9]

0.033b

  Hydrochlorothiazide use

1295

461 (35.6)

1224

436 (35.6)

71

25 (35.2)

0.94c

  Hydrochlorothiazide duration (months)

461

41.4 [10.6, 81.9]

436

41.6 [10.4, 82.2]

25

34.7 [11.2, 75.4]

0.81b

  Spironolactone use

1295

184 (14.2)

1224

166 (13.6)

71

18 (25.4)

0.006c

  Spironolactone duration (months)

184

9.3 [1.7, 30.0]

166

9.1 [1.6, 27.9]

18

26.5 [2.0, 73.9]

0.054b

  Amlodipine use

1295

266 (20.5)

1224

246 (20.1)

71

20 (28.2)

0.10c

  Amlodipine duration (months)

266

17.3 [3.0, 51.0]

246

16.6 [2.9, 50.4]

20

27.9 [11.0, 69.1]

0.29b

  Metoprolol use

1295

648 (50.0)

1224

606 (49.5)

71

42 (59.2)

0.11c

  Metoprolol duration (months)

648

0.30 [0.10, 29.9]

606

0.20 [0.10, 28.5]

42

6.0 [0.10, 45.8]

0.22b

  Carvedilol use

1295

89 (6.9)

1224

81 (6.6)

71

8 (11.3)

0.13c

  Carvedilol duration (months)

89

9.0 [0.90, 27.9]

81

9.0 [0.90, 29.0]

8

5.5 [0.60, 16.5]

0.57b

Antilipidemic medications

1295

712 (55.0)

1224

673 (55.0)

71

39 (54.9)

0.99c

  Antilipidemic duration (months)

712

32.9 [8.7, 70.3]

673

31.2 [8.0, 70.0]

39

40.0 [13.0, 83.3]

0.14b

  Rosuvastatin use

1295

130 (10.0)

1224

127 (10.4)

71

3 (4.2)

0.094c

  Atorvastatin use

1295

367 (28.3)

1224

347 (28.3)

71

20 (28.2)

0.97c

  Atorvastatin duration (months)

367

23.1 [5.9, 66.0]

347

23.1 [5.9, 66.0]

20

24.9 [5.3, 64.2]

0.94b

  Simvastatin use

1295

348 (26.9)

1224

330 (27.0)

71

18 (25.4)

0.77c

  Simvastatin duration (months)

348

24.5 [5.6, 54.4]

330

23.5 [5.2, 54.4]

18

34.6 [15.6, 47.6]

0.32b

  Pravastatin use

1295

139 (10.7)

1224

127 (10.4)

71

12 (16.9)

0.084c

  Pravastatin duration (months)

139

16.1 [1.8, 37.7]

127

17.6 [1.3, 39.2]

12

9.1 [3.1, 17.1]

0.33b

  Gemfibrozil use

1295

49 (3.8)

1224

47 (3.8)

71

2 (2.8)

0.66c

  Fenofibrate use

1295

152 (11.7)

1224

142 (11.6)

71

10 (14.1)

0.53c

  Fenofibrate duration (months)

152

23.5 [8.5, 60.3]

142

23.5 [8.7, 56.3]

10

40.6 [5.3, 83.3]

0.54b

  Aspirin use

1295

507 (39.2)

1224

472 (38.6)

71

35 (49.3)

0.072c

  Aspirin dose

499

 

464

 

35

 

0.41c

  81

 

490 (98.2)

 

455 (98.1)

 

35 (100.0)

 

  325

 

9 (1.8)

 

9 (1.9)

 

0 (0.0)

 

Statistics presented as Median [P25, P75] or N (column %)

p values: b Kruskal-Wallis test, c Pearson’s chi-square test

Table 3

Laboratory values (all subjects)

Factor

Overall (N = 1295)

No DVT (N = 1224)

DVT (N = 71)

p value

N

Statistics

N

Statistics

n

Statistics

Platelets

1278

219.7 ± 85.7

1207

220.8 ± 85.8

71

200.1 ± 82.2

0.048a

Total Cholesterol

1159

168.0 ± 44.2

1095

167.9 ± 44.2

64

169.9 ± 44.7

0.72a

Triglycerides

1158

123.5 [84.0, 179.0]

1094

124.0 [84.0, 181.0]

64

110.5 [76.0, 156.5]

0.11b

HDL

1157

47.0 ± 17.1

1093

46.9 ± 16.8

64

48.4 ± 21.4

0.51a

LDL

1156

91.9 ± 36.1

1092

91.9 ± 35.8

64

92.7 ± 40.4

0.87a

HbA1c

1167

6.8 ± 1.6

1104

6.8 ± 1.6

63

6.9 ± 1.7

0.71a

AST

1278

27.0 [20.0, 42.0]

1207

27.0 [20.0, 41.0]

71

31.0 [21.0, 52.0]

0.035b

ALT

1278

27.0 [18.0, 44.0]

1207

27.0 [18.0, 44.0]

71

30.0 [20.0, 46.0]

0.15b

Alkaline phosphatase

1278

82.0 [66.0, 107.0]

1207

81.0 [66.0, 106.0]

71

92.0 [80.0, 118.0]

< 0.001b

Total bilirubin

1278

0.50 [0.30, 0.70]

1207

0.50 [0.30, 0.70]

71

0.50 [0.40, 0.70]

0.36b

Albumin

1185

4.2 ± 0.95

1119

4.2 ± 0.95

66

4.0 ± 1.00

0.19a

Statistics presented as Mean ± SD or Median [P25, P75]

p values: a ANOVA, b Kruskal-Wallis test

Older age, CKD, IBD, stricturing disease, spironolactone use, furosemide use, longer duration of furosemide use, longer duration of pioglitazone use, shorter duration of Humulin use, lower platelet count, higher AST, and higher ALP were found to be significantly associated with DVT on unadjusted analysis (p < 0.05 for all). After performing the variable selection method described above, age, IBD and furosemide use remained in the final model (Table 4). A 5-year increment in age at time of DM2 diagnosis is associated with a 10% increase in likelihood of having DVT (odds ratio [OR] 95% confidence interval {CI} 1.1 (1.01, 1.3), p = 0.031). In addition, subjects with IBD were 3-times more likely to have DVT than those without IBD (OR [95% CI] 3.0 (1.3, 7.1), p = 0.012). Lastly, subjects using furosemide had 2.5-fold higher odds of having DVT than those that were never exposed to furosemide (OR [95% CI] 2.5 (1.5, 4.1), p < 0.001) [14] (Fig. 1a–c). We further calculated Padua prediction score for DVT and identified patients with low (< 4) and high (≥ 4) risk of DVT [15]. We did not find any statistically significant difference in low and high-risk DVT patients when assessed for the use furosemide, presence of HLD, and stricturing disease (Supplementary Table 5-6).
Table 4

Clinical factors associated with DVT: multivariable logistic regression analysis (all subjects)

Factor

OR (95% CI)

p value

Age at DM2 diagnosis (5 year increment)

1.1 (1.01, 1.3)

0.031

IBD

3.0 (1.3, 7.1)

0.012

Furosemide use

2.5 (1.5, 4.1)

< 0.001

OR, odds ratio; CI, confidence interval

Fig. 1

ac Factors associated with DVT

Subgroup with DM2, NAFLD, and Advanced Fibrosis

Out of 1295 patients with T2D and NAFLD, 31.8% had AF and 36.6% of the patients with AF had DVT (p = 0.37). In this subgroup, CKD was present in 42.3%, IBD in 15.4% (11.5% had CD, 3.8% had UC), and 11.5% of the patients had stricturing disease (p < 0.05). When looking over their medications: 53.8% were on oral hypoglycemic medications for a duration of 64.5 [35.0, 88.3] months (p = 0.20 and p = 0.022, respectively). 69.2% of the patients were on furosemide (p = 0.005) while 46.2% were on spironolactone (p = 0.030). As regards to their lab results, the median ALP level was 117.0 [85.0, 133.0] (p = 0.016). (Supplementary tables 7-9 and supplementary figures 2-4). On multivariate logistic regression analysis, in patients with AF, presence of underlying IBD had 6.3-fold higher risk of DVT (OR [95% CI] 6.3 (1.7, 23.5), p = 0.006). Similarly, use of furosemide were associated with 3.3-times higher odds of having DVT (OR [95% CI] 3.3 (1.4, 8.0), p = 0.008). Underlying HLD in these patients also showed a trend towards higher risk of DVT, but this association was not significant (OR [95% CI] 2.5 (0.95, 6.6), p = 0.062) (Supplementary Table 10).

We also analyzed association of furosemide, HLD, and stricturing IBD with individual fibrosis stage (F0–F4) on liver biopsy and found them to be statistically non-significant, which was likely due to spread out of patients leading to smaller number patients in each fibrosis stage (Supplementary Table 11 [A-C).

Discussion

NAFLD leads to a prothrombotic stage and the risk of DVT is significantly higher in patients with underlying diabetes. Our results show that out of 1295 patients with biopsy-proven NAFLD and underlying T2D, 71 (5.5%) were found to have a DVT, and 26 (36.6%) of them had AF on liver biopsy. On unadjusted analysis, older age, CKD, IBD, and stricturing disease, being on spironolactone, furosemide, longer duration of furosemide and pioglitazone, shorter duration of Humulin use, lower platelet count, higher AST, and higher ALP were found to be associated with DVT (p < 0.05). On multivariate analysis, presence of IBD and being on furosemide were associated with 3- and 2.5-times higher odds of having DVT, and a 5-year increment in age at time of T2D diagnosis was associated with a 10% increase in likelihood of having DVT (OR [95% CI] 3.0 (1.3, 7.1), 2.5 (1.5, 4.1), and 1.1 (1.01, 1.3), respectively) [14]. On subgroup-analysis, in patients with AF on liver biopsy, presence of IBD was associated with a 6.3-fold increased odds of DVT. The use of furosemide was also associated with significantly higher risk of DVT in these patients (OR [95% CI] 3.3 (1.4, 8.0), p = 0.008). These findings suggest that all NAFLD patients with diabetes and certain co-morbidities (IBD, HLD) and using specific medication (furosemide) are at a higher risk of DVT, and providers should be vigilant in these cases and make efforts to minimize the risk by treating the underlying disease or switching to medications not associated with DVT.

Both diabetes and NAFLD have been shown to be linked with increased risk of DVT [12, 13, 14, 16, 17, 18]. Diabetes is associated with several defects of fibrinolysis and coagulation that lead to a pro-coagulant and thrombogenic disposition by raised concentrations of fibrinogen, von Willebrand factor, and other endothelium-derived mediators which increase the blood viscosity and promote platelet activation and adhesion [19]. According to Lemkes et al., high glucose levels (1) increase oxidative stress, which leads to an increase in coagulation factors gene transcription; (2) break down the glycocalyx layer of the endothelial wall, which releases coagulation factors and stimulates the coagulation cascade; and (3) increase glycation of proteins involved in coagulation and fibrinolysis, all leading to a pro-coagulant state [20]. The possible underlying mechanism in NAFLD is increased oxidative stress due to continuous inflammation and increased reactive oxygen species, and increased hepatic production of C reactive protein, pro-coagulant, pro-oxidant, and pro-fibrogenic mediators. By worsening systemic/hepatic IR and predisposing to dyslipidemia, NAFLD further worsens cardiovascular disease and T2D [21, 22, 23, 24]. Our study showed a trend towards higher risk of DVT in patients with HLD, which could be due to an “additive effect” of NAFLD and T2D.

It is generally known that the risk of VTE increases dramatically with age especially in the later decades of life [25]. In our study, we also found increased risk of DVT with advancing age, extending the work of recent studies showing higher incidence of VTE in old diabetic patients (≥ 65 years); however, patients in these studies had no NAFLD [12, 13, 14]. We also found that NAFLD patients using furosemide were 3.3-times more likely to have DVT, supporting evidence by Pang H et al evidence stating that diuretics use is a risk factor for VTE [14, 26]. Given that excessive diuresis may cause dehydration and a decrease in blood volume which may possibly lead to vascular thrombosis and embolism [27]. NAFLD patients with advanced disease stages with complications like ascites are usually on furosemide. Similarly, furosemide is commonly used as antihypertensive or for heart failure in diabetics [28, 29, 30]. Overall, regardless of the indication, furosemide use in NAFLD patients with diabetes increases risk of DVT.

Due to significantly high morbidity and mortality, venous thromboembolism (VTE) is one the most important extra-intestinal complications of IBD [31, 32, 33, 34, 35, 36, 37, 38, 39]. IBD has been shown to be associated with abnormal fibrinolysis, abnormal platelet aggregation, increased activated protein C, increased cytokines (interleukin-6, thrombopoietin), increased factors V and VIII, increased plasminogen activator inhibitor, increased fibrinogen, thrombocytosis, leukocytosis, circulating immune complexes, and decreased antithrombin III and factor V Leiden mutation [36, 39, 40, 41, 42, 43, 44]. Hence, IBD patients have a 2- to 3-fold increased risk of developing DVT and pulmonary embolism (PE) compared with the general population [31, 34, 35, 36, 37, 38, 39, 44]. Our findings, a 3-fold increase in the likelihood of developing DVT in patients having IBD and a 6.3-fold increase in the subgroup with AF, are consistent with past research [14, 31, 34, 35, 36, 37, 38, 39, 44]. In the subgroup of patients with AF, patients with underlying HLD also showed higher tendency of having DVT, paralleling previous evidence reporting that HLD is a risk factor for VTE [45, 46, 47].

Although, our study had a large sample size of diabetic patients with biopsy-proven NAFLD, this study had certain limitations. Beside the retrospective design with its own limitations, liver biopsies were reviewed by local pathologists; there is inter-observer variation which is one of the limitations of our study. Also, most of these patients were seen at a tertiary care center leading to selection bias. We also do not know if exposures happened before or after DVT so we can only assess associations. As regards to the medications, we assumed that they were used continuously from the first to the last date of prescription and there is no way for us to know if this is true. Even though we used Padua score to assess the associations in high and low risk patients, Padua score is mainly used for hospitalized patients and its use to predict DVT in outpatient setting is unknown.

In conclusion, presence of underlying diabetes in patients with NAFLD increase the risk of DVT and early detection and risk stratification is particularly important to lighten this growing burden. The detection of NAFLD in a diabetic patient should alert clinicians to the coexistence of multiple underlying DVT risk factors requiring evaluation and treatment as much as the risk for advancing liver disease. Larger long-term prospective studies are suggested to identify risk factors for DVT in NAFLD patients with T2D.

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

Ethical approval was obtained from the Cleveland Clinic (CCF) Institutional Review Board.

Informed Consent

Informed consent was waived due to retrospective nature of the study and no direct patient contact.

Supplementary material

42399_2019_188_MOESM1_ESM.docx (296 kb)
ESM 1 (DOCX 296 kb)
42399_2019_188_MOESM2_ESM.docx (223 kb)
ESM 2 (DOCX 222 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery InstituteCleveland ClinicClevelandUSA
  2. 2.Department of Gastroenterology, Hepatology and Nutrition, Center for Human Nutrition, A5 annexCleveland Clinic FoundationClevelandUSA
  3. 3.Faculty of MedicineCairo UniversityCairoEgypt
  4. 4.Department of Hospital MedicineCleveland ClinicClevelandUSA

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