Diabetes Association with Liver Diseases: An Overview for Clinicians

Author(s): Abd Elkhalek Hamed, Nadia Elwan, Mervat Naguib, Reda Elwakil, Gamal Esmat, Mohamed El Kassas, Sherief Abd-Elsalam*, Shorouk Moussa.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 3 , 2019

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Graphical Abstract:


Abstract:

Background: There is a strong association between liver diseases and diabetes (DM) which is higher than expected by a correlation between two very common diseases. Liver diseases may occur as a result of diabetes, and the reverse is true as well.

Aim: To review the etiology of this association between liver diseases and diabetes and how to diagnose it.

Methods: Studies that identified this association between liver diseases and diabetes and how to diagnose it was reviewed.

Results: This association can be divided into the following categories: liver disease related to diabetes (Diabetic hepatopathy), hepatogenous diabetes (HD), and liver diseases that occur in conjunction with Diabetes mellitus. Two hours after glucose loading is the best screening test for HD. HbA1c may neither be suitable for diagnosis nor monitoring of diabetes that links liver disease.

Conclusion: NAFLD, hepatogenous diabetes, glycogenic hepatopathy and diabetic hepatosclerosis are the most important association between liver diseases and diabetes. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is the best screening test for HD due to the fact that fasting glucose can be normal early in the disease. The tool used for diabetes monitoring depends on stage and severity of liver condition.

Keywords: Liver, diabetes mellitus, diabetic hepatopathy, hepatogenous diabetes, NAFLD, glycogenic hepatopathy.

[1]
Upadhyay, R. Diabetic hepatopathy. In:API Text Book of Medicine; Munjal, Y.P., Ed.; , 2017, p. 314.
[2]
Rubio-Rivas, M.; Montero-Alía, P.; Ordi-Ros, J.; Labrador, M. Hepatic glycogenosis and diabetes mellitus. Med. Clin. (Barc.), 2005, 125, 279.
[3]
Nazzari, E.; Grillo, F.; Celiento, T.; Picciotto, A.; Ferone, D.; Murialdo, G.; Ameri, P. Diabetic hepatosclerosis presenting with severe cholestasis. Diabetes Care, 2013, 36(12), e206.
[4]
Levinthal, G.N.; Tavill, A.S. Liver disease and diabetes mellitus. Clin. Diabetes, 1999, 1, 431-443.
[5]
Nishida, T.; Tsuji, S.; Tsujii, M.; Arimitsu, S.; Haruna, Y.; Imano, E.; Suzuki, M.; Kanda, T.; Kawano, S.; Hiramatsu, N.; Hayashi, N.; Hori, M. Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis. Am. J. Gastroenterol., 2006, 101, 70-75.
[6]
Kim, M.G.; Choi, W.C. Differential diagnosis of diabetes mellitus caused by liver cirrhosis and other Type 2 diabetes mellitus. Korean J. Hepatol., 2006, 12, 524-529.
[7]
Zhang, X.; Shen, W.; Shen, D.M. A clinical analysis of liver disease patients with abnormal glucose metabolism. Zhonghua Gan Zang Bing Za Zhi, 2006, 14, 289-292.
[8]
Hamed, A.E.; Abas, B.; Shaltout, I.; Esmt, G.; Gomez, R.; Kumar, A.; Assad, S.H.; Elsahar, M.; Elweakil, R.; Salih, S.; Elkhatib, A.; Hamed, H.; Elwan, N.; AbdelMaqsod, A.; Sakr, M.A.; Emil, S.; Mogawer, S.; Magdeldin, H.; Zakaria, A.; Elgarem, H.; Soltan, S.; Salih, O.; Shawki, M.; Kamel, M.; Hamza, I. Managing diabetes and liver disease association guidelines (consensus) development. J. Endocrinol. Diabetes Obes., 2015, 3(3), 1073.
[9]
Petäjä, E.M.; Yki-Järvinen, H. Definitions of normal liver fat and the association of insulin sensitivity with acquired and genetic NAFLD-A systematic review. Int. J. Mol. Sci., 2016, 17(5), pii: E633.
[10]
Abdeldyem, S.M.; Goda, T.; Khodeir, S.A.; AbouSaif, S.; Abd-Elsalam, S. Nonalcoholic fatty liver disease in patients with acute ischemic stroke is associated with more severe stroke and worse outcome. J. Clin. Lipidol., 2017, 11(4), 915-919.
[11]
Ahmed, M. Non-alcoholic fatty liver disease in 2015. World J. Hepatol., 2015, 7(11), 1450-1459.
[12]
Prashanth, M.; Ganesh, H.K.; Vima, M.V.; John, M.; Bandgar, T.; Joshi, S.R.; Shah, S.R.; Rathi, P.M.; Joshi, A.S.; Thakkar, H.; Menon, P.S.; Shah, N.S. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. J. Assoc. Physicians India, 2009, 57, 205-210.
[13]
Leite, N.C.; Salles, G.F.; Araujo, A.L.; Villela-Nogueira, C.A.; Cardoso, C.R. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int., 2009, 29, 113-119.
[14]
Chan, W.K.; Tan, A.T.; Vethakkan, S.R.; Tah, P.C.; Vijayananthan, A.; Goh, K.L. Non-alcoholic fatty liver disease in diabetics--prevalence and predictive factors in a multiracial hospital clinic population in Malaysia. J. Gastroenterol. Hepatol., 2013, 28(8), 1375-1383.
[15]
Stepanova, M.; Rafiq, N.; Younossi, Z.M. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut, 2010, 59, 1410-1415.
[16]
Hazlehurst, J.M.; Woods, C.; Marjot, T.; Cobbold, J.F.; Tomlinson, J.W. Non-alcoholic fatty liver disease and diabetes. Metabolism, 2016, 65(8), 1096-1108.
[17]
Ming, J.; Xu, S.; Gao, B.; Liu, G.; Ji, Y.; Yang, F.; Jia, Y.; Fang, Y.; Ji, Q. Non-alcoholic fatty liver disease predicts type 2 diabetes mellitus, but not prediabetes, in Xi’an, China: A five-year cohort study. Liver Int., 2015, 35, 2401-2407.
[18]
Li, W.D.; Fu, K.F.; Li, G.M.; Lian, Y.S.; Ren, A.M.; Chen, Y.J.; Xia, J.R. Comparison of effects of obesity and non-alcoholic fatty liver disease on incidence of type 2 diabetes mellitus. World J. Gastroenterol., 2015, 21, 9607-9613.
[19]
Fukuda, T.; Hamaguchi, M.; Kojima, T.; Hashimoto, Y.; Ohbora, A.; Kato, T.; Nakamura, N.; Fukui, M. The impact of non-alcoholic fatty liver disease on incident type 2 diabetes mellitus in non-overweight individuals. Liver Int., 2016, 36, 275-283.
[20]
Shibata, M.; Kihara, Y.; Taguchi, M.; Tashiro, M.; Otsuki, M. Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care, 2007, 30, 2940-2944.
[21]
Bae, J.C.; Rhee, E.J.; Lee, W.Y.; Park, S.E.; Park, C.Y.; Oh, K.W.; Park, S.W.; Kim, S.W. Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes: a 4-year retrospective longitudinal study. Diabetes Care, 2011, 34, 727-729.
[22]
Li, X.; Stevens, P.D.; Liu, J.; Yang, H.; Wang, W.; Wang, C.; Zeng, Z.; Schmidt, M.D.; Yang, M.; Lee, E.Y.; Gao, T. PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice. Gastroenterology, 2014, 146, 1301-1312.
[23]
Ghalali, A.; Ye, Z.W.; Hogberg, J.; Stenius, U. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and PH domain and leucine-rich repeat phosphatase cross-talk (PHLPP) in cancer cells and in transforming growth factor beta-activated stem cells. J. Biol. Chem., 2014, 289, 11601-11615.
[24]
Ballestri, S.; Zona, S.; Targher, G.; Romagnoli, D.; Baldelli, E.; Nascimbeni, F.; Roverato, A.; Guaraldi, G.; Lonardo, A. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J. Gastroenterol. Hepatol., 2016, 31, 936-944.
[25]
Bae, J.C.; Cho, Y.K.; Lee, W.Y.; Seo, H.I.; Rhee, E.J.; Park, S.E.; Park, C.Y.; Oh, K.W.; Sung, K.C.; Kim, B.I. Impact of nonalcoholic fatty liver disease on insulin resistance in relation to HbA1c levels in nondiabetic subjects. Am. J. Gastroenterol., 2010, 11, 2389-2395.
[26]
Pardina, E.; Baena-Fustegueras, J.A.; Catalán, R.; Galard, R.; Lecube, A.; Fort, J.M.; Allende, H.; Vargas, V.; Peinado-Onsurbe, J. Increased expression and activity of hepatic lipase in the liver of morbidly obese adult patients in relation to lipid content. Obes. Surg., 2009, 19(7), 894-904.
[27]
Mittendorfer, B.; Magkos, F.; Fabbrini, E.; Mohammed, B.S.; Klein, S. Relationship between body fat mass and free fatty acid kinetics in men and women. Obesity (Silver Spring), 2009, 17(10), 1872-1877.
[28]
Adams, L.A.; Sanderson, S.; Lindor, K.D.; Angulo, P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J. Hepatol., 2005, 42, 132-138.
[29]
Valenti, L.; Bugianesi, E.; Pajvani, U.; Targher, G. Nonalcoholic fatty liver disease: Cause or consequence of type 2 diabetes? Liver Int., 2016, 36(11), 1563-1579.
[30]
Targher, G.; Day, C.P.; Bonora, E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med., 2010, 363, 1341-1350.
[31]
McPherson, S.; Hardy, T.; Henderson, E.; Burt, A.D.; Day, C.P.; Anstee, Q.M. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J. Hepatol., 2015, 62(5), 1148-1155.
[32]
Raff, E.J.; Kakati, D.; Bloomer, J.R.; Shoreibah, M.; Rasheed, K.; Singal, A.K. Diabetes mellitus predicts occurrence of cirrhosis and hepatocellular cancer in alcoholic liver and non-alcoholic fatty liver diseases. J. Clin. Transl. Hepatol., 2015, 3(1), 9-16.
[33]
Lomonaco, R.; Bril, F.; Portillo-Sanchez, P.; Ortiz-Lopez, C.; Orsak, B.; Biernacki, D.; Lo, M.; Suman, A.; Weber, M.H.; Cusi, K. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care, 2016, 39(4), 632-638.
[34]
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(5), 1212-1218.
[35]
Mantovani, A.; Pernigo, M.; Bergamini, C.; Bonapace, S.; Lipari, P.; Pichiri, I.; Bertolini, L.; Valbusa, F.; Barbieri, E.; Zoppini, G.; Bonora, E.; Targher, G. Nonalcoholic fatty liver disease is independently associated with early left ventricular diastolic dysfunction in patients with type 2 diabetes. PLoS One, 2015, 10(8), e0135329.
[36]
Jia, G.; Di, F.; Wang, Q.; Shao, J.; Gao, L.; Wang, L.; Li, Q.; Li, N. Non-alcoholic fatty liver disease is a risk factor for the development of diabetic nephropathy in patients with type 2 diabetes mellitus. PLoS One, 2015, 10(11), e0142808.
[37]
Yamazaki, H.; Tsuboya, T.; Tsuji, K.; Dohke, M.; Maguchi, H. Independent association between improvement of nonalcoholic fatty liver disease and reduced incidence of Type 2 diabetes. Diabetes Care, 2015, 38, 1673-1679.
[38]
Sherigar, J.M.; De Castro, J.; Yin, Y.M.; Guss, D.; Mohanty, S.R. Glycogenic hepatopathy: A narrative review. World J. Hepatol., 2018, 10(2), 172-185.
[39]
Gutch, M.; Philip, R.; Saran, S.; Tyagi, R.; Gupta, K.K. Re-emergence of a rare syndrome: A case of mauriac syndrome. Indian J. Endocrinol. Metab., 2013, 17, 283-285.
[40]
Silva, M.; Marques, M.; Cardoso, H.; Rodrigues, S.; Andrade, P.; Peixoto, A.; Pardal, J.; Lopes, J.; Carneiro, F.; Macedo, G. Glycogenic hepatopathy in young adults: a case series. Rev. Esp. Enferm. Dig., 2016, 108(10), 673-676.
[41]
Van den Brand, M.; Elving, L.D.; Drenth, J.P.; van Krieken, J.H. Glycogenic hepatopathy: a rare cause of elevated serum transaminases in diabetes mellitus. Neth. J. Med., 2009, 67(11), 394-396.
[42]
El-Karaksy, H.M.; Anwar, G.; Esmat, G.; Mansour, S.; Sabry, M.; Helmy, H.; El-Hennawy, A.; Fouad, H. Prevalence of hepatic abnormalities in a cohort of Egyptian children with type 1 diabetes mellitus. Pediatr. Diabetes, 2010, 11, 462-470.
[43]
Imtiaz, K.; Healy, C.; Sharif, S.; Drake, I.; Awan, F.; Riley, J.; Karlson, F. Glycogenic hepatopathy in type 1 diabetes: an under recognized condition. Diabetes Care, 2013, 36(1), e6-e7.
[44]
Umpaichitra, V. Unusual glycogenic hepatopathy causing abnormal liver enzymes in a morbidly obese adolescent with well-controlled type 2 diabetes: resolved after A1c was normalized by metformin. Clin. Obes., 2016, 6(4), 281-284.
[45]
Resnick, J.M.; Zador, I.; Fish, D.L. Dumping syndrome, a cause of acquired glycogenic hepatopathy. Pediatr. Dev. Pathol., 2011, 14, 318-321.
[46]
Parmara, N.; Atiqb, M.; Austinb, L.; Miller, R.A.; Smyrk, T.; Ahmed, K. Glycogenic hepatopathy: Thinking outside the box. Case Rep. Gastroenterol., 2015, 9, 221-226.
[47]
Torbenson, M.; Chen, Y.Y.; Brunt, E.; Cummings, O.W.; Gottfried, M.; Jakate, S.; Liu, Y.C.; Yeh, M.M.; Ferrell, L. Glycogenic hepatopathy: An under recognized hepatic complication of diabetes mellitus. Am. J. Surg. Pathol., 2006, 30, 508-513.
[48]
Masuoka, H.C.; Chalasani, N. Nonalcoholic fatty liver disease: An emerging threat to obese and diabetic individuals. Ann. N. Y. Acad. Sci., 2013, 1281, 106-122.
[49]
Morton, A. Is it possible to distinguish between glycogenic hepatopathy and non-alcoholic fatty liver disease without liver biopsy? Intern. Med. J., 2016, 46(10), 1232.
[50]
Al-Hussaini, A.; Sulaiman, N.; AlZahrani, M.; Alenizi, A.S.; Khan, M. Prevalence of hepatopathy in type 1 diabetic as a cause of recurrent liver damage. BMC Pediatr., 2012, 12, 160.
[51]
Ikarashi, Y.; Kogiso, T.; Hashimoto, E.; Yamamoto, K.; Kodama, K.; Taniai, M.; Torii, N.; Takaike, H.; Uchigata, Y.; Tokushige, K. Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy. Hepatol. Res., 2017, 47(3), E201-E209.
[52]
Deemer, K.S.; Alvarez, G.F. A rare case of persistent lactic acidosis in the ICU: Glycogenic hepatopathy and mauriac syndrome. Hindawi Publishing Corporation. 2016, Article ID 6072909, pp.1-4.
[53]
King, R.J.; Harrison, L.; Gilbey, S.G.; Santhakumar, A.; Wyatt, J.; Jones, R.; Bodansky, H.J. Diabetic hepatosclerosis: another diabetes microvascular complication? Diabet. Med., 2016, 33, 5-7.
[54]
Hudacko, R.M.; Sciancalepore, J.P.; Fyfe, B.S. Diabetic microangiopathy in the liver: an autopsy study of incidence and association with other diabetic complications. Am. J. Clin. Pathol., 2009, 132, 494-499.
[55]
Harrison, S.A.; Brunt, E.M.; Goodman, Z.D.; Di Bisceglie, A.M. Diabetic hepatosclerosis: Diabetic microangiopathy of the liver. Arch. Pathol. Lab. Med., 2006, 130(1), 27-32.
[56]
Garcia-Compean, D.; Jaquez-Quintana, J.O.; Gonzalez-Gonzalez, J.A.; Maldonado-Garza, H. Liver cirrhosis and diabetes: Risk factors, pathophysiology, clinical implications and management. World J. Gastroenterol., 2009, 15(3), 280-288.
[57]
Orsi, E.; Grancini, V.; Menini, S.; Aghemo, A.; Pugliese, G. Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? Liver Int., 2017, 37, 950-962.
[58]
García-Compeán, D.; González-González, J.A.; Lavalle-González, F.J.; González-Moreno, E.I.; Villarreal-Pérez, J.Z.; Maldonado-Garza, H.J. Hepatogenous diabetes: is it a neglected condition in chronic liver disease? World J. Gastroenterol., 2016, 22, 2869-2874.
[59]
El-Zayadi, A.R.; Selim, O.E.; Hamdy, H.; Dabbous, H.; Ahdy, A.; Moniem, S.A. Association of chronic hepatitis C infection and diabetes mellitus. Trop. Gastroenterol., 1998, 19, 141-144.
[60]
Kawaguchi, T.; Taniguchi, E.; Itou, M.; Sakata, M.; Sumie, S.; Sata, M. Insulin resistance and chronic liver disease. World J. Hepatol., 2011, 3, 99-107.
[61]
American Diabetes Association. Classification and diagnosis of diabetes: Standards of medical care in diabetes-2018. Diabetes Care, 2018, 41(1), 13-27.
[62]
Cacciatore, L.; Cozzolino, G.; Giardina, M.G.; De Marco, F.; Sacca, L.; Esposito, P.; Schnedl, W.J. Abnormalities of glucose metabolism induced by liver cirrhosis and glycosylated hemoglobin levels in chronic liver disease. Diabetes Res., 1988, 7, 185-188.
[63]
García-Compeán, D.; Jáquez-Quintana, J.O.; Lavalle-González, F.J.; Reyes-Cabello, E.; González-González, J.A.; Muñoz-Espinosa, L.E.; Vázquez-Elizondo, G.; Villarreal-Pérez, J.Z.; Maldonado-Garza, H.J. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study. Ann. Hepatol., 2012, 11, 240-248.
[64]
Zhang, L.; Shi, Y.L.; Hong, W.X.; Jia, W.D.; Li, L.H. Diagnostic value of serum islet autoantibody in hepatogenic diabetes mellitus. Nan Fang Yi Ke Da Xue Xue Bao, 2006, 26(7), 1034-1036.
[65]
Krishnan, S.M.; Dixit, N.M. Estimation of red blood cell lifespan from alveolar carbon monoxide measurements. Transl. Res., 2009, 154, 15-17.
[66]
Mittman, N.; Desiraju, B.; Fazil, I.; Kapupara, H.; Chattopadhyay, J.; Jani, C.M.; Avram, M.M. Serum fructosamine versus glycosylated hemoglobin as an index of glycemic control, hospitalization, and infection in diabetic hemodialysis patients. Kidney Int., 2010, 117, 41-45.
[67]
Koga, M.; Kasayama, S. Clinical impact of glycated albumin as another glycemic control marker. Endocr. J., 2010, 57(9), 751-762.
[68]
Clar, C.; Barnard Katharine, D.; Cummins, E.; Royle, P.; Waugh, N. Aberdeen Health Technology Assessment Group. Self-monitoring of blood glucose in type 2 diabetes: Systematic review. Health Technol. Assess., 2010, 14(12), 1-140.
[69]
Poolsup, N.; Suksomboon, N.; Kyaw, A.M. Systematic review and meta-analysis of the effectiveness of continuous glucose monitoring (CGM) on glucose control in diabetes. Diabetol. Metab. Syndr., 2013, 5, 39.
[70]
Blendea, M.C.; Thompson, M.J.; Malkani, S. Diabetes and chronic liver disease: etiology and pitfalls in monitoring. Clin. Diabetes, 2010, 28(4), 139-144.
[71]
Younossi, Z.M.; Loomba, R.; Rinella, M.E.; Bugianesi, E.; Marchesini, G.; Neuschwander-Tetri, B.A.; Serfaty, L.; Negro, F.; Caldwell, S.H.; Ratziu, V.; Corey, K.E.; Friedman, S.L.; Abdelmalek, M.F.; Harrison, S.A.; Sanyal, A.J.; Lavine, J.E.; Mathurin, P.; Charlton, M.R.; Chalasani, N.P.; Anstee, Q.M.; Kowdley, K.V.; George, J.; Goodman, Z.D.; Lindor, K. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology, 2018, 68(1), 361-371.
[72]
Wasfy, E.; Elkassas, G.; Elnawasany, S.; Elkasrawy, K.; Abd-Elsalam, S.; Soliman, S.; Badawi, R. Predicting esophageal varices in cirrhotic hepatitis C virus patients using noninvasive measurement of insulin resistance variables. Endocr. Metab. Immune Disord. Drug Targets, 2018, 18(6), 573-580.
[73]
Abdelmoemen, G.; Khodeir, S.A.; Zaki, A.N.; Kassab, M.; Abou-Saif, S.; Abd-Elsalam, S. Overexpression of hepassocin in diabetic patients with nonalcoholic fatty liver disease may facilitate increased hepatic lipid accumulation. Endocr. Metab. Immune Disord. Drug Targets, 2019, 19(2), 185-188.


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VOLUME: 19
ISSUE: 3
Year: 2019
Page: [274 - 280]
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DOI: 10.2174/1871530318666181116111945
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