Liver plays an important role in maintaining the blood glucose stability and hormone metabolism. Impaired liver function often affects the normal glucose metabolism, thereby leading to impaired glucose tolerance or even diabetes mellitus (DM). A variety of chronic liver diseases, especially liver cirrhosis, are associated with DM (1-3). DM in liver cirrhosis is primarily divided into classical type 2 DM (T2DM) and hepatogenous DM secondary to liver damage (4).
The prevalence of DM is increasing with age. An epidemiological investigation in China reported that the percentages of DM were 3.2%, 11.5%, and 20.4% among persons who were 20–39, 40–59, and ≥60 years of age, respectively (5). On the other hand, patients with liver cirrhosis have a high probability of developing DM (6,7) and the incidence of DM may be 5 times higher in patients with cirrhosis than in age-matched controls without liver diseases (8). In a retrospective analysis from France including 348 patients with chronic hepatitis C and liver cirrhosis, DM was an independent prognostic factor for the outcome of cirrhosis (9).
Some studies have investigated the prevalence and clinical features of DM in patients with liver cirrhosis (10-12). However, considering that both older age and DM are important risk factors for the progression to liver cirrhosis (13-17), the prevalence, risk factors, and in-hospital outcomes of DM in elderly patients with liver cirrhosis needs to be further clarified.
We conducted a retrospective, single-center, observational study at the General Hospital of Shenyang Military Area from January 2012 to June 2014. Patients were consecutively included. The inclusion criteria were: (I) patients diagnosed with liver cirrhosis; (II) no limit to age and sex; and (III) no limit to the etiology of liver cirrhosis. A diagnosis of liver cirrhosis was primarily established according to the history of liver diseases, clinical symptoms and signs, laboratory tests (e.g., liver function and coagulation tests), abdominal images (e.g., liver and spleen morphology) and/or liver biopsy, if necessary. The exclusion criteria were: (I) patients with non-cirrhotic portal hypertension; (II) patients with malignant tumors, especially hepatocellular carcinoma, etc.; and (III) patients with other endocrine diseases but DM. In the present study, repeated admissions were excluded to avoid over- or under-estimating the number of patients with DM.
All electronic records of patients were retrospectively collected. They were classified into two groups: (I) elderly patients; and (II) non-elderly patients. Additionally, the elderly patients were further divided two groups: (I) patients with DM; and (II) patients with non-DM. The elderly patients with DM were further classified into two groups: (I) patients with good diabetic control; and (II) patients with poor diabetic control.
Some relevant data were reported in our previous papers (18-22). This study was approved by the Medical Ethical Committee of our hospital [approval number k (2016)16]. Due to the retrospective nature of this study, the requirement for written informed consent was waived.
The following data regarding demographic, clinical, and laboratory profiles and in-hospital outcomes were collected from the electronic medical records. Notably, the diagnosis of DM, duration of DM, fasting plasma glucose (FPG), and glycosylated hemoglobin (HbA1c) were recorded. We calculated the Child-Pugh (23) and model for end-stage of liver disease (MELD) scores (24).
Diagnosis of DM
DM was diagnosed according to the World Health Organization (WHO) diagnostic criteria in 1999: (I) a FPG level of >7.0 mmol/L (126 mg/dL); (II) a plasma glucose level of >11.1 mmol/L (200 mg/dL) at 2 h in a 75-g oral glucose tolerance test; and (III) typical symptoms related to DM together with a plasma glucose level of >11.1 mmol/L (200 mg/dL).
Diagnostic criteria for hepatogenous DM
Hepatogenous DM was diagnosed as a state of impaired glucose regulation caused by impaired liver function as a consequence of liver cirrhosis. In short, DM develops after the onset of cirrhosis (25,26).
Definition of elderly patients
The elderly person should be over 60 years old in China.
Evaluation of good or poor diabetic control
According to the “expert consensus on measures for the diagnosis and treatment of elderly DM (2013 Edition) (27)” in China, the good diabetic control was defined as “HbA1c <7% or FPG<7.0 mmol/L”. If a patient had both HbA1C and FPG, we preferred to choose the HbA1c as the evaluation criterion.
Categorical data were expressed as frequencies (percentages) and were compared by using the chi-square test. Continuous data were expressed as mean ± standard deviation (SD) or median (range) and were compared by using the independent-sample t test. A two-sided P<0.05 was considered statistically significant. A multivariate logistic regression analysis was performed to explore the prognostic role of DM. An odds ratio with 95% confidence interval was calculated. All statistical analyses were performed using SPSS software version 17.0 (SPSS Inc. Chicago, IL, USA).
A total of 1,225 patients were eligible for our study. The patient characteristics were summarized (Table S1). The mean age was 56.74±11.76 years. The mean Child-Pugh score was 7.51±2.07. The percentages of Child-Pugh class A, B, and C were 38.3%, 44.5%, and 17.3%, respectively. The etiology of liver cirrhosis primarily included viral hepatitis B alone (39.0%), viral hepatitis C alone (8.1%), alcohol abuse alone (29.9%), viral hepatitis plus alcohol abuse (11.9%), and others (11.1%). Among them, 36.9% (452/1,225) were elderly patients with a mean age of 68.59±6.84 years and 20.6% (252/1,225) had DM.
The characteristics were compared between elderly and non-elderly patients with liver cirrhosis (Table S1). Elderly patients had significantly higher percentages of DM (P=0.001) and Child-Pugh class B (P=0.005), platelet (PLT) (P=0.040), and blood urea nitrogen (BUN) (P=0.003), but significantly lower percentage of Child-Pugh class A and C (P=0.005), total bilirubin (TBIL) (P=0.030), indirect bilirubin (IBIL) (P=0.008), activated partial thromboplastin time (APTT) (P=0.002), prothrombin time (PT) (P<0.001), and international normalized ratio (INR) (P=0.022). Elderly patients had a higher percentage of viral hepatitis alone and a lower percentage of alcohol abuse alone than non-elderly patients (P<0.001). All of the 1,225 patients had available data to assess the prevalence of DM; among them, the percentages of DM in elderly and non-elderly patients were 25.9% (117/452) and 17.5% (135/773), respectively. A total of 206 patients with DM had available data to assess the prevalence of hepatogenous DM; among them, the percentages of hepatogenous DM in elderly and non-elderly patients were 28.8% (30/114) and 33.3% (34/102), respectively.
The characteristics were compared between elderly patients with and without DM (Table 1). Elderly patients with DM had significantly higher albumin (ALB) (P=0.022) and BUN (P=0.015), percentage of hepatic encephalopathy (HE) (P=0.035), and in-hospital mortality (P=0.002), but significantly lower age (P=0.002), TBIL (P=0.001), direct bilirubin (DBIL) (P<0.001), IBIL (P=0.016), alkaline phosphatase (P=0.021), and Ɣ-glutamine transferase (P=0.007). The in-hospital mortality of elderly patients with DM was significantly higher than without DM [8.5% (10/117) vs. 1.8% (6/335), P=0.002]. After adjusting the age and Child-Pugh score, the DM was an independent risk factor for death in a multivariate logistic regression analysis (odds ratio =5.675, 95% confidence interval: 1.886–17.072, P=0.002). Causes of death were shown in Table 2.
The characteristics were compared between the elderly DM patients with good and poor diabetic control (Table S2). A total of 108 patients had available data to assess the glycemic control. Among them, the percentages of good and poor diabetic control patients were 43.52% (47/108) and 56.48% (61/108), respectively. The poor diabetic control group had significantly higher TBIL (P=0.015), DBIL (P=0.014), Child-Pugh score (P=0.049), and percentage of acute upper gastrointestinal bleeding (AUGIB) (P=0.018), but significantly lower age (P=0.009), ALB (P=0.014), and sodium ion (P=0.008).
DM is a well-known risk factor for the development of liver cirrhosis in patients with non-alcoholic hepatitis. It might also constitute an important confounding risk factor for the prognosis of elderly patients with liver cirrhosis due to viral hepatitis or alcohol abuse. This had been exemplary demonstrated for a small cohort of patients with hepatitis C-related cirrhosis in France (9). We conducted a large retrospective single-center analysis on patients with liver cirrhosis admitted to our center in order to assess the relevance of DM for disease presentation and outcome. Our study had several major findings.
First, the prevalence of DM in elderly patients with liver cirrhosis was about 1.5 times higher than non-elderly patients. Similarly, Petit et al. found that DM patients with liver cirrhosis were older (28); and Iovanescu et al. also mentioned that an age of above 60 years in patients with chronic hepatitis was significantly associated with a higher risk of DM (29). On the other hand, the percentage of DM was 25.9% in our elderly patients with liver cirrhosis, which was higher than in general elderly patients (20.4%) (5). This phenomenon seems to be consistent with previous findings that liver cirrhosis may increase the morbidity of DM in elderly population (6-8).
Second, the prevalence of hepatogenous DM might be lower in elderly patients than non-elderly patients, suggesting that elderly patients were more prone to develop classical T2DM, rather than hepatogenous DM.
Third, the elderly patients with liver cirrhosis had significantly higher PLT and BUN, but significantly lower TBIL, IBIL, APTT, PT, and INR. This finding suggested that the elderly patients with liver cirrhosis might be prone to worse nutritional status and liver and renal dysfunction.
Fourth, the elderly patients with DM had a 4.7 times higher in-hospital mortality than those without DM. Similarly, Quintana et al. conducted a prospective study of compensated liver cirrhosis patients and found that 40% of patients with DM and 20% of patients without DM died at the end of follow-up (30). In addition, a recent study showed that DM was significantly associated with an increased mortality of patients with liver cirrhosis (HR: 2.80; 95% CI: 2.04–3.83) (16).
Fifth, the elderly patients with DM had a 1.8 times higher incidence of HE than those without DM. Butt et al. reported similar conclusions that patients with decompensated cirrhosis and DM had significantly higher prevalence of HE (58.5% vs. 42.6%; P=0.03) and more severe HE (P=0.01) than those without DM and that older patients with DM had a significantly higher incidence of HE (P=0.03) (31). A study from Germany also mentioned that the risk of HE was significantly more frequent in diabetic cirrhotic patients than non-diabetic cirrhotic patients (36.6% vs. 20.7%) (32). The potential mechanisms should be that DM might increase the glutamine activity and risk of constipation, intestinal bacterial overgrowth, and bacterial translocation, thereby causing the HE (33).
Sixth, the elderly patients with DM had significantly higher BUN. In clinical practice, BUN is often considered as a sign of renal function. As known, both DM and liver cirrhosis contribute to the development of renal dysfunction. Indeed, our study also demonstrated that creatinine (Cr) level was higher in the elderly patients with DM, but no significant difference was observed. A Taiwanese study found that DM had an effect on renal function in cirrhotic patients and a BUN/Cr ratio was a better index of predicting the in-hospital mortality in cirrhotic patients with normal renal function (34). These results suggested that elderly patients with DM might aggravate the development of liver cirrhosis by affecting the renal function. By contrast, DM was not associated with Child-Pugh or MELD score, indicating that liver function was not significantly affected by DM. Indeed, our study found that patients with DM had higher ALB than those without DM.
Seventh, the elderly DM patients with poor diabetic control had significantly higher TBIL, DBIL, Child-Pugh score, and percentage of AUGIB. The percentage of HE, ascites, Child-Pugh class B and C, and mortality were not significantly different between them. A study from New Zealand found that poor diabetic control (HbA1c ≥7.0%) was a predictor of liver cirrhosis complications (35). Another study also reported that DM patients had a significantly higher ratio of history of AUGIB than non-DM patients (36). AUGIB might be the most frequent complication affected by poor diabetic control. Besides, our results also indicated that elderly cirrhotic patients with poor diabetic control had more abnormal biochemical indicators and worse prognosis. It should be essential for the elderly cirrhotic patients with DM to improve the diabetic control.
There were several limitations in our study. First, this was a retrospective, single-center, observational study; second, the data regarding FPG and HbA1c were incomplete in some patients; third, anti-diabetic agents can affect the risk of developing liver cirrhosis complications and postprandial blood glucose may be a better evaluation criterion for the diabetic control in the DM with liver cirrhosis (37,38), but our retrospective study failed to examine these issues due to the absence of relevant data.
In conclusion, age was positively associated with the risk of DM in liver cirrhosis. DM may be a risk factor for the in-hospital mortality of the elderly patients with liver cirrhosis, but was not significantly associated with the severity of liver dysfunction. Poor diabetic control may lead to abnormal biochemical indicators and worse outcomes. Altogether, DM is an independent adverse prognostic factor in elderly patients with liver cirrhosis, suggesting that improving diabetic control may be beneficial in the management of these patients.
Funding: Liaoning Provincial Startup Foundation for PhD (No. 201501023) for Dr. Y Zhang.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The study was approved by the Medical Ethical Committee of our hospital [No. k (2016)16]. Due to the retrospective nature of this study, the requirement for written informed consent was waived.
- Huang YW, Wang TC, Lin SC, et al. Increased risk of cirrhosis and its decompensation in chronic hepatitis B patients with newly diagnosed diabetes: a nationwide cohort study. Clin Infect Dis 2013;57:1695-702. [Crossref] [PubMed]
- Huang YW, Yang SS, Fu SC, et al. Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new-onset diabetes: a nationwide cohort study. Hepatology 2014;60:807-14. [Crossref] [PubMed]
- Lallukka S, Yki-Jarvinen H. Non-alcoholic fatty liver disease and risk of type 2 diabetes. Best Pract Res Clin Endocrinol Metab 2016;30:385-95. [Crossref] [PubMed]
- Orsi E, Grancini V, Menini S, et al. Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? Liver Int 2017;37:950-62. [Crossref] [PubMed]
- Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010;362:1090-101. [Crossref] [PubMed]
- Tellez-Avila FI, Sanchez-Avila F, Garcia-Saenz-de-Sicilia M, et al. Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis. World J Gastroenterol 2008;14:4771-5. [Crossref] [PubMed]
- Hsieh PS, Hsieh YJ. Impact of liver diseases on the development of type 2 diabetes mellitus. World J Gastroenterol 2011;17:5240-5. [Crossref] [PubMed]
- Wlazlo N, Beijers HJ, Schoon EJ, et al. High prevalence of diabetes mellitus in patients with liver cirrhosis. Diabet Med 2010;27:1308-11. [Crossref] [PubMed]
- Elkrief L, Chouinard P, Bendersky N, et al. Diabetes mellitus is an independent prognostic factor for major liver-related outcomes in patients with cirrhosis and chronic hepatitis C. Hepatology 2014;60:823-31. [Crossref] [PubMed]
- Kato M, Asano H, Miwa Y, et al. Both insulin sensitivity and glucose sensitivity are impaired in patients with non-diabetic liver cirrhosis. Hepatol Res 2000;17:93-101. [Crossref] [PubMed]
- Ahmadieh H, Azar ST. Liver disease and diabetes: association, pathophysiology, and management. Diabetes Res Clin Pract 2014;104:53-62. [Crossref] [PubMed]
- Yilmaz Y, Senates E, Yesil A, et al. Not only type 2 diabetes but also prediabetes is associated with portal inflammation and fibrosis in patients with non-alcoholic fatty liver disease. J Diabetes Complications 2014;28:328-31. [Crossref] [PubMed]
- Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-32. [Crossref] [PubMed]
- Qi X, Peng Y, Li H, et al. Diabetes is associated with an increased risk of in-hospital mortality in liver cirrhosis with acute upper gastrointestinal bleeding. Eur J Gastroenterol Hepatol 2015;27:476-7. [Crossref] [PubMed]
- Elkrief L, Rautou PE, Sarin S, et al. Diabetes mellitus in patients with cirrhosis: clinical implications and management. Liver Int 2016;36:936-48. [Crossref] [PubMed]
- Goh GB, Pan A, Chow WC, et al. Association between diabetes mellitus and cirrhosis mortality: the Singapore Chinese Health Study. Liver Int 2017;37:251-8. [Crossref] [PubMed]
- Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008;134:1699-714. [Crossref] [PubMed]
- Qi X, Li H, Chen J, et al. Serum Liver Fibrosis Markers for Predicting the Presence of Gastroesophageal Varices in Liver Cirrhosis: A Retrospective Cross-Sectional Study. Gastroenterol Res Pract 2015;2015:274534.
- Deng H, Qi X, Zhang Y, et al. Diagnostic accuracy of contrast-enhanced computed tomography for esophageal varices in liver cirrhosis: A retrospective observational study. J Evid Based Med 2017;10:46-52. [Crossref] [PubMed]
- Qi X, Han G, Ye C, et al. Splenectomy Causes 10-Fold Increased Risk of Portal Venous System Thrombosis in Liver Cirrhosis Patients. Med Sci Monit 2016;22:2528-50. [Crossref] [PubMed]
- Wang R, Qi X, Peng Y, et al. Association of umbilical hernia with volume of ascites in liver cirrhosis: A retrospective observational study. J Evid Based Med 2016;9:170-80. [Crossref] [PubMed]
- Deng H, Qi X, Peng Y, et al. Diagnostic Accuracy of APRI, AAR, FIB-4, FI, and King Scores for Diagnosis of Esophageal Varices in Liver Cirrhosis: A Retrospective Study. Med Sci Monit 2015;21:3961-77. [Crossref] [PubMed]
- Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9. [Crossref] [PubMed]
- Kamath PS, Kim WR. Advanced Liver Disease Study G. The model for end-stage liver disease (MELD). Hepatology 2007;45:797-805. [Crossref] [PubMed]
- Jeon HK, Kim MY, Baik SK, et al. Hepatogenous diabetes in cirrhosis is related to portal pressure and variceal hemorrhage. Dig Dis Sci 2013;58:3335-41. [Crossref] [PubMed]
- Megyesi C, Samols E, Marks V. Glucose tolerance and diabetes in chronic liver disease. Lancet 1967;2:1051-6. [Crossref] [PubMed]
- Chinese Geriatric Endocrine Society. Chinese Elderly Diabetes Expert Consensus on Diagnosis and Treatment Measures. Chin J Intern Med 2014;53:243-51.
- Petit JM, Hamza S, Rollot F, et al. Impact of liver disease severity and etiology on the occurrence of diabetes mellitus in patients with liver cirrhosis. Acta Diabetol 2014;51:455-60. [PubMed]
- Iovanescu VF, Streba CT, Ionescu M, et al. Diabetes mellitus and renal involvement in chronic viral liver disease. J Med Life 2015;8:483-7. [PubMed]
- Quintana JO, Garcia-Compean D, Gonzalez JA, et al. The impact of diabetes mellitus in mortality of patients with compensated liver cirrhosis-a prospective study. Ann Hepatol 2011;10:56-62. [PubMed]
- Butt Z, Jadoon NA, Salaria ON, et al. Diabetes mellitus and decompensated cirrhosis: risk of hepatic encephalopathy in different age groups. J Diabetes 2013;5:449-55. [Crossref] [PubMed]
- Gundling F, Seidl H, Strassen I, et al. Clinical manifestations and treatment options in patients with cirrhosis and diabetes mellitus. Digestion 2013;87:75-84. [Crossref] [PubMed]
- Ampuero J, Ranchal I, del Mar Diaz-Herrero M, et al. Role of diabetes mellitus on hepatic encephalopathy. Metab Brain Dis 2013;28:277-9. [Crossref] [PubMed]
- Chen YW, Wu CJ, Chang CW, et al. Renal function in patients with liver cirrhosis. Nephron Clin Pract 2011;118:c195-203. [Crossref] [PubMed]
- Hsiang JC, Gane EJ, Bai WW, et al. Type 2 diabetes: a risk factor for liver mortality and complications in hepatitis B cirrhosis patients. J Gastroenterol Hepatol 2015;30:591-9. [Crossref] [PubMed]
- Yang CH, Chiu YC, Chen CH, et al. Diabetes mellitus is associated with gastroesophageal variceal bleeding in cirrhotic patients. Kaohsiung J Med Sci 2014;30:515-20. [Crossref] [PubMed]
- Nkontchou G, Cosson E, Aout M, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab 2011;96:2601-8. [Crossref] [PubMed]
- Nishida T, Tsuji S, Tsujii M, et al. Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis. Am J Gastroenterol 2006;101:70-5. [Crossref] [PubMed]
Cite this article as: Han H, Sun Y, Zhang Y, Tacke F, Zhao H, Deng H, Hou F, Wang R, Sugawara Y, Mancuso A, Qi X. Prevalence and in-hospital outcomes of diabetes mellitus in elderly patients with liver cirrhosis. AME Med J 2017;2:103.