Diabetes Metab J.  2019 Oct;43(5):700-710. 10.4093/dmj.2018.0201.

Severity of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus: Relationship between Nongenetic Factors and PNPLA3/HSD17B13 Polymorphisms

  • 1Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy. bellanmattia@yahoo.it
  • 2Division of Internal Medicine, Sant'Andrea Hospital, Vercelli, Italy.
  • 3Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Novara, Italy.
  • 4COQ, Madonna del Popolo, Omegna, Italy.
  • 5Emergency Medicine Department, Maggiore della Carità Hospital, Novara, Italy.
  • 6Diabetes Clinic, ASL VCO, Verbania, Italy.
  • 7Division of Internal Medicine, AOU Maggiore della Carità Hospital, Novara, Italy.


The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is high, though its severity is often underestimated. Our aim is to provide an estimate of the prevalence of severe NAFLD in T2DM and identify its major predictors.
T2DM patients (n=328) not previously known to have NAFLD underwent clinical assessment, transient elastography with measure of liver stiffness (LS) and controlled attenuation parameter (CAP), and genotyping for patatin like phospholipase domain containing 3 (PNPLA3) and 17β-hydroxysteroid-dehydrogenase type 13 (HSD17B13).
Median LS was 6.1 kPa (4.9 to 8.6). More than one-fourth patients had advanced liver disease, defined as LS ≥7.9 kPa (n=94/238, 29%), and had a higher body mass index (BMI) than those with a LS <7.9 kPa. Carriage of the G allele in the PNPLA3 gene was associated with higher LS, being 5.9 kPa (4.7 to 7.7) in C/C homozygotes, 6.1 kPa (5.2 to 8.7) in C/G heterozygotes, and 6.8 kPa (5.8 to 9.2) in G/G homozygotes (P=0.01). This trend was absent in patients with ≥1 mutated HSD17B13 allele. In a multiple linear regression model, BMI and PNPLA3 genotype predicted LS, while age, gender, disease duration, and glycosylated hemoglobin did not fit into the model. None of these variables was confirmed to be predictive among carriers of at least one HSD17B13 mutated allele. There was no association between CAP and polymorphisms of PNPLA3 or HSD17B13.
Advanced NAFLD is common among T2DM patients. LS is predicted by both BMI and PNPLA3 polymorphism, the effect of the latter being modulated by mutated HSD17B13.


Adiponutrin; Body mass index; Diabetes mellitus, type 2; Fibrosis; Non-alcoholic fatty liver disease

MeSH Terms

Body Mass Index
Diabetes Mellitus*
Diabetes Mellitus, Type 2
Elasticity Imaging Techniques
Hemoglobin A, Glycosylated
Linear Models
Liver Diseases
Non-alcoholic Fatty Liver Disease*


  • Fig. 1 Liver stiffness (kPa) distribution based on patatin like phospholipase domain containing 3 (PNPLA3) genotypes. Columns indicate medians, error bars interquartile ranges.

  • Fig. 2 Liver stiffness (kPa) distribution among patatin like phospholipase domain containing 3 (PNPLA3) genotypes among 17β-hydroxysteroid-dehydrogenase type 13 (HSD17B13) (A) wild type and (B) mutated carriers. Columns indicate medians, error bars interquartile ranges. HSD17B13 T/T (wild type), HSD17B13 TA/* (heterozygous and/or homozygous “A” insertional mutation).

  • Fig. 3 Predicted values of liver stiffness (LS) (kPa), based on patatin like phospholipase domain containing 3 (PNPLA3) genotype and body mass index (BMI). Error bars indicate 95% confidence intervals. The upper horizontal dotted line indicates LS value suggestive of cirrhosis, the lower one the value suggestive of absent or minimal fibrosis.

Cited by  1 articles

Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease
Eugene Han, Mi Kyung Kim, Byoung Kuk Jang, Hye Soon Kim
Diabetes Metab J. 2021;45(5):698-707.    doi: 10.4093/dmj.2020.0118.


1. Masuoka HC, Chalasani N. Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. Ann N Y Acad Sci. 2013; 1281:106–122. PMID: 23363012.
2. Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi LE. Nonalcoholic fatty liver disease: evolving paradigms. World J Gastroenterol. 2017; 23:6571–6592. PMID: 29085206.
3. Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, Liu Y, Kozlitina J, Stender S, Wood GC, Stepanchick AN, Still MD, McCarthy S, O'Dushlaine C, Packer JS, Balasubramanian S, Gosalia N, Esopi D, Kim SY, Mukherjee S, Lopez AE, Fuller ED, Penn J, Chu X, Luo JZ, Mirshahi UL, Carey DJ, Still CD, Feldman MD, Small A, Damrauer SM, Rader DJ, Zambrowicz B, Olson W, Murphy AJ, Borecki IB, Shuldiner AR, Reid JG, Overton JD, Yancopoulos GD, Hobbs HH, Cohen JC, Gottesman O, Teslovich TM, Baras A, Mirshahi T, Gromada J, Dewey FE. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018; 378:1096–1106. PMID: 29562163.
4. European Association for the Study of the Liver (EASL). European Association for the Study of Diabetes (EASD). European Association for the Study of Obesity (EA-SO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016; 64:1388–1402. PMID: 27062661.
5. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015; 62:S47–S64. PMID: 25920090.
6. Simeone JC, Bae JP, Hoogwerf BJ, Li Q, Haupt A, Ali AK, Boardman MK, Nordstrom BL. Clinical course of nonalcoholic fatty liver disease: an assessment of severity, progression, and outcomes. Clin Epidemiol. 2017; 9:679–688. PMID: 29276410.
7. Targher G, Marchesini G, Byrne CD. Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: causal association or epiphenomenon? Diabetes Metab. 2016; 42:142–156. PMID: 27142870.
8. Ratziu V, Cadranel JF, Serfaty L, Denis J, Renou C, Delassalle P, Bernhardt C, Perlemuter G. A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France. J Hepatol. 2012; 57:376–383. PMID: 22521354.
9. Castera L. Non-invasive diagnosis of steatosis and fibrosis. Diabetes Metab. 2008; 34:674–679. PMID: 19195629.
10. Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, Clark JM. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011; 54:1082–1090. PMID: 21618575.
11. Qayyum A, Chen DM, Breiman RS, Westphalen AC, Yeh BM, Jones KD, Lu Y, Coakley FV, Callen PW. Evaluation of diffuse liver steatosis by ultrasound, computed tomography, and magnetic resonance imaging: which modality is best? Clin Imaging. 2009; 33:110–115. PMID: 19237053.
12. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, Beaugrand M, Palau R. Transient elastography: a new non-invasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003; 29:1705–1713. PMID: 14698338.
13. Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, Choi PC, Kowo M, Chan AW, Merrouche W, Sung JJ, de Ledinghen V. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010; 51:454–462. PMID: 20101745.
14. de Ledinghen V, Vergniol J, Foucher J, Merrouche W, le Bail B. Noninvasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography. Liver Int. 2012; 32:911–918. PMID: 22672642.
15. Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M, Hyogo H, Sumida Y, Ono M, Eguchi Y, Inoue T, Yamanaka T, Wada K, Saito S, Nakajima A. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016; 150:626–637. PMID: 26677985.
16. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneau TM, Day CP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007; 45:846–854. PMID: 17393509.
17. Martinez SM, Crespo G, Navasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology. 2011; 53:325–335. PMID: 21254180.
18. Landis JR, Koch GG. An application of hierarchical kappa-type statistics in the assessment of majority agreement among multiple observers. Biometrics. 1977; 33:363–374. PMID: 884196.
19. Pimpin L, Cortez-Pinto H, Negro F, Corbould E, Lazarus JV, Webber L, Sheron N. EASL HEPAHEALTH Steering Committee. Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies. J Hepatol. 2018; 69:718–735. PMID: 29777749.
20. Estes C, Anstee QM, Arias-Loste MT, Bantel H, Bellentani S, Caballeria J, Colombo M, Craxi A, Crespo J, Day CP, Eguchi Y, Geier A, Kondili LA, Kroy DC, Lazarus JV, Loomba R, Manns MP, Marchesini G, Nakajima A, Negro F, Petta S, Ratziu V, Romero-Gomez M, Sanyal A, Schattenberg JM, Tacke F, Tanaka J, Trautwein C, Wei L, Zeuzem S, Razavi H. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol. 2018; 69:896–904. PMID: 29886156.
21. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015; 13:643–654. PMID: 24768810.
22. Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, Day C, Arcaro G. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007; 30:1212–1218. PMID: 17277038.
23. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, Subbarayan S, Webb A, Hecht J, Cusi K. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab. 2015; 100:2231–2238. PMID: 25885947.
24. Loria P, Lonardo A, Anania F. Liver and diabetes. A vicious circle. Hepatol Res. 2013; 43:51–64. PMID: 23332087.
25. Giorda CB, Forlani G, Manti R, Mazzotti A, De Cosmo S, Rossi MC, Nicolucci A, Di Bartolo P, Ceriello A, Guida P, Tartaglino B, Russo G. AMD-Annals Study Group. Trend over time in hepatic fibrosis score in a cohort of type 2 diabetes patients. Diabetes Res Clin Pract. 2018; 135:65–72. PMID: 29097288.
26. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, Vizzutti F, Anania FA, Milani S, Rombouts K, Laffi G, Pinzani M, Marra F. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005; 42:1339–1348. PMID: 16317688.
27. Marra F, Bertolani C. Adipokines in liver diseases. Hepatology. 2009; 50:957–969. PMID: 19585655.
28. Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009; 50:604–620. PMID: 19157625.
29. Berzigotti A, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Morillas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS, Groszmann RJ. Portal Hypertension Collaborative Group. Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis. Hepatology. 2011; 54:555–561. PMID: 21567436.
30. Noureddin M, Rinella ME. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis. 2015; 19:361–379. PMID: 25921668.
31. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000; 72:690–693. Erratum in: Am J Clin Nutr 2003;77:1342. PMID: 10966885.
32. Dasarathy J, Periyalwar P, Allampati S, Bhinder V, Hawkins C, Brandt P, Khiyami A, McCullough AJ, Dasarathy S. Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non-alcoholic fatty liver disease. Liver Int. 2014; 34:e118–e127. PMID: 24118743.
33. Cimini FA, Barchetta I, Carotti S, Bertoccini L, Baroni MG, Vespasiani-Gentilucci U, Cavallo MG, Morini S. Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease. World J Gastroenterol. 2017; 23:3407–3417. PMID: 28596677.
34. Bellan M, Sainaghi PP, Pirisi M. Role of vitamin D in rheumatoid arthritis. Adv Exp Med Biol. 2017; 996:155–168. PMID: 29124698.
35. Del Campo JA, Gallego-Duran R, Gallego P, Grande L. Genetic and epigenetic regulation in nonalcoholic fatty liver disease (NAFLD). Int J Mol Sci. 2018; 19:E911. PMID: 29562725.
36. Trepo E, Romeo S, Zucman-Rossi J, Nahon P. PNPLA3 gene in liver diseases. J Hepatol. 2016; 65:399–412. PMID: 27038645.
37. Petit JM, Guiu B, Masson D, Duvillard L, Jooste V, Buffier P, Bouillet B, Brindisi MC, Robin I, Gambert P, Verges B, Cercueil JP, Hillon P. PNPLA3 polymorphism influences liver fibrosis in unselected patients with type 2 diabetes. Liver Int. 2011; 31:1332–1336. PMID: 21745307.
38. Dubuquoy C, Robichon C, Lasnier F, Langlois C, Dugail I, Foufelle F, Girard J, Burnol AF, Postic C, Moldes M. Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes. J Hepatol. 2011; 55:145–153. PMID: 21145868.
39. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, Cohen JC, Hobbs HH. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010; 285:6706–6715. PMID: 20034933.
40. Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M, Stahlman M, Taskinen MR, Orho-Melander M, Perman J, Pujia A, Andersson L, Maglio C, Montalcini T, Wiklund O, Boren J, Romeo S. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol. 2012; 57:1276–1282. PMID: 22878467.
41. Pirazzi C, Valenti L, Motta BM, Pingitore P, Hedfalk K, Mancina RM, Burza MA, Indiveri C, Ferro Y, Montalcini T, Maglio C, Dongiovanni P, Fargion S, Rametta R, Pujia A, Andersson L, Ghosal S, Levin M, Wiklund O, Iacovino M, Boren J, Romeo S. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014; 23:4077–4085. PMID: 24670599.
42. Mondul A, Mancina RM, Merlo A, Dongiovanni P, Rametta R, Montalcini T, Valenti L, Albanes D, Romeo S. PNPLA3 I148M variant influences circulating retinol in adults with nonalcoholic fatty liver disease or obesity. J Nutr. 2015; 145:1687–1691. PMID: 26136587.
43. Kovarova M, Konigsrainer I, Konigsrainer A, Machicao F, Haring HU, Schleicher E, Peter A. The genetic variant I148M in PNPLA3 is associated with increased hepatic retinyl-palmitate storage in humans. J Clin Endocrinol Metab. 2015; 100:E1568–E1574. PMID: 26439088.
44. Carpino G, Pastori D, Baratta F, Overi D, Labbadia G, Polimeni L, Di Costanzo A, Pannitteri G, Carnevale R, Del Ben M, Arca M, Violi F, Angelico F, Gaudio E. PNPLA3 variant and portal/periportal histological pattern in patients with biopsy-proven non-alcoholic fatty liver disease: a possible role for oxidative stress. Sci Rep. 2017; 7:15756. PMID: 29150621.
45. Su W, Wang Y, Jia X, Wu W, Li L, Tian X, Li S, Wang C, Xu H, Cao J, Han Q, Xu S, Chen Y, Zhong Y, Zhang X, Liu P, Gustafsson JA, Guan Y. Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2014; 111:11437–11442. PMID: 25028495.
46. Donati B, Motta BM, Pingitore P, Meroni M, Pietrelli A, Alisi A, Petta S, Xing C, Dongiovanni P, del Menico B, Rametta R, Mancina RM, Badiali S, Fracanzani AL, Craxi A, Fargion S, Nobili V, Romeo S, Valenti L. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology. 2016; 63:787–798. PMID: 26605757.
Full Text Links
  • DMJ
export Copy
  • Twitter
  • Facebook
Similar articles
Copyright © 2023 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr