Summary

This chapter focuses on the relationships of three common chronic liver diseases—nonalcoholic fatty liver disease (NAFLD), viral hepatitis, and cirrhosis—and of gallstone disease with diabetes.

NAFLD requires finding fat (steatosis) in the liver in the absence of heavy alcohol consumption and other secondary causes of hepatic steatosis. In a nationally representative sample of the U.S. population, the prevalence of NAFLD assessed by ultrasonography was greater among persons with diagnosed (45.5%) and undiagnosed (43.1%) diabetes and prediabetes (24.9%) compared to those with normal glucose (15.9%). Diabetes and insulin resistance are thought to be closely linked to the development and progression of NAFLD. However, there is also evidence that NAFLD increases the risk of diabetes. The risk of incident diabetes was at least twice as high among persons with NAFLD in several prospective studies that defined NAFLD based on elevated liver enzymes.

Hepatitis C virus (HCV) infection has been associated with an increased risk of diabetes, although results of population-based studies have been inconsistent. In contrast, there is little evidence that hepatitis B virus (HBV) infection increases the risk of diabetes. In a nationally representative sample of the U.S. population, HCV infection (HCV antibody positive) was not associated with diabetes (odds ratio [OR] 0.8) or prediabetes (OR 1.0). Similarly, HBV infection (HBV core antibody positive) was unrelated to diabetes (OR 1.0) and prediabetes (OR 1.1).

Diabetes is found in a high proportion of patients with cirrhosis (35%–71%), regardless of the liver disease etiology. Furthermore, the proportion of diabetes among those with cirrhosis is particularly high (as much as 71%) in studies that have included oral glucose tolerance testing. Among patients listed as candidates for liver transplantation, more than one-quarter carry a diagnosis of diabetes, which is double the proportion 20 years ago. Patients with diabetes awaiting liver transplantation have an increased risk of removal from the waiting list due to dying before transplantation or to deteriorating health resulting in medical contraindications to transplantation (OR 1.2). After liver transplantation, new-onset diabetes has been commonly reported (as high as 54% of HCV positive patients), usually among patients without adequate glucose testing before transplantation.

Finally, a high prevalence of gallstone disease (gallstones or history of cholecystectomy) was documented by ultrasound among persons with diagnosed (33.3%) and undiagnosed (23.3%) diabetes and prediabetes (20.8%) compared to persons with normal glucose (16.7%) in a nationally representative sample of the U.S. population. This relationship was present across demographic subgroups, for both gallstones and cholecystectomy. Review of published epidemiologic studies of ultrasound-detected gallstone disease likewise indicates a fairly consistent association of gallstone disease with diabetes independent of adiposity or other shared risk factors. An association of insulin resistance with gallstone disease has also been shown among those without diabetes. For example, gallstone disease was 60% more common among the highest compared to the lowest fasting serum insulin quintile among U.S. women. Insulin resistance may be a link between diabetes and gallstone disease.

Introduction

This chapter concerns the relationship between diabetes and certain chronic liver diseases and gallstone disease. It does not address all liver diseases, of which there are many, or chronic liver disease in general. Rather, the authors have examined the association of diabetes with a few significant and relatively common liver diseases for which there are national data. These are fatty liver, especially fatty liver in the absence of significant alcohol consumption (nonalcoholic fatty liver disease [NAFLD]), chronic hepatitis C virus (HCV) infection, chronic hepatitis B virus (HBV) infection, and cirrhosis. Hepatocellular carcinoma (HCC) is addressed in Chapter 29 Cancer and Diabetes. The significance of diabetes in liver transplantation and its occurrence posttransplantation are examined in this chapter. Finally, the association of diabetes with gallstones and cholecystectomy is described.

As the various forms of hepatobiliary disease are discussed in the following sections, the reader is cautioned not to infer causal relationships with diabetes. Diabetes, certain liver diseases, and gallstones share numerous risk factors and pathophysiologic pathways. It has been difficult to establish that one condition precedes another, much less a causal relationship. For example, although a greater than twofold increase in liver disease mortality has been reported among persons with diabetes (1,2), it should not be inferred necessarily that diabetes caused the increase.

Data Sources and Limitations

Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Prevalence of NAFLD in the United States

Despite the limitations of epidemiologic studies to diagnose NAFLD, it is believed that NAFLD is the most common chronic liver disease in the United States. The estimated prevalence of NAFLD in the United States ranges from 5% to 31% of the general population, depending on the diagnostic method used (14), and is increasing over time (15). NAFLD is strongly associated with obesity, insulin resistance, and type 2 diabetes, which are thought to contribute to the underlying pathophysiology of the disease.

Several studies have used data from the NHANES III to estimate the prevalence of NAFLD in those with and without diabetes (16). In new analyses for Diabetes in America, 3rd edition, using abdominal ultrasound data from the NHANES III to detect moderate to severe steatosis, and after excluding heavy drinkers (>2 drinks/day for men or >1 drink/day for women) and standardizing for age, NAFLD was present in 23.9% of adults overall in the general population and affected 45.5% of those with diagnosed diabetes, 43.1% with undiagnosed diabetes, 24.9% with prediabetes, and 15.9% with normal glucose levels (Figure 26.1) (17). The prevalence of NAFLD was higher in middle-aged and older adults, peaking in adults age 45–64 years with diabetes (Table 26.1). NAFLD was more common in men than women and in Mexican Americans compared to whites, with blacks having the lowest prevalence. Among adults with diabetes, however, men and women had the same prevalence, and Mexican Americans and whites had a similar prevalence (Table 26.1).

In the NHANES 1999–2010, using the Fatty Liver Index in the fasting sample to detect NAFLD after excluding HBV, HCV, and heavy drinkers, the prevalence of NAFLD was 46.5% in the general population and affected 70.8% of those with diagnosed diabetes, 79.4% with undiagnosed diabetes, 53.3% with prediabetes, and 30.7% with normal glucose levels (Figure 26.1, Table 26.2). Similar to the data from the NHANES III using ultrasound, NAFLD prevalence peaked in middle age, and the difference in prevalence between men and women and across racial/ethnic groups was substantially reduced in people with diabetes (Table 26.2).

Finally, in the NHANES 1999–2010, the prevalence of an elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), or GGT was used as a measure of liver injury. (Liver enzyme cutoffs were defined as the 95th percentile in a subgroup of adults at low risk for liver injury, that is: negative for HBsAg and HCV antibody; consumption of ≤2 drinks per day for men or ≤1 drink per day for women; BMI <25 kg/m²; waist circumference ≤102 cm for men or ≤88 cm for women; no health care provider-diagnosed diabetes; and A1c <6.5%.) In the total population, the prevalence of an elevated AST, ALT, or GGT was 19.8% overall, including 26.3% in people with diabetes and 19.1% in those without. Exclusion of heavy drinkers did not substantively change these estimates; 19.1% of adults overall had evidence of probable NAFLD, including 25.7% of those with diabetes and 18.4% of those without diabetes (Figure 26.1, Table 26.3). Using this definition, NAFLD was more common in women and more common among those age 20–44 years with diabetes (32.2%).

In a new analysis for Diabetes in America, among persons with diagnosed diabetes, those taking diabetes medications had the same or somewhat increased prevalence of NAFLD defined using the Fatty Liver Index or elevated liver enzymes compared to those not taking the medications (Table 26.4). The two exceptions were those taking thiazolidinediones or insulin. Those taking thiazolidinediones had a lower prevalence of NAFLD than those not taking thiazolidinediones, as defined by elevated liver enzymes (20.6% vs. 27.1%) (Table 26.4), but not by the Fatty Liver Index. This finding is consistent with the results of several treatment trials of NAFLD, which have shown that thiazolidinediones improve steatosis and NASH (18,19) and may improve fibrosis (20). Those taking insulin had a lower prevalence of steatosis on ultrasound (35.8% vs. 49.1%) (Table 26.4), but not by the Fatty Liver Index or liver enzymes. The explanation for this observation is less clear but may reflect patients with more advanced diabetes and more advanced liver disease where steatosis has been replaced by fibrosis. Further research is needed to confirm this finding.

FIGURE 26.1

Age-Standardized Prevalence of Nonalcoholic Fatty Liver Disease, by Diabetes Status, U.S., 1988–1994 and 1999–2010. Diagnosed diabetes is defined as self-reported health care provider diagnosis. Undiagnosed diabetes is defined as glycosylated (more...)

TABLE 26.1

Age-Standardized Prevalence of Nonalcoholic Fatty Liver Disease Diagnosed by Abdominal Ultrasound, by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 1988–1994.

Given the difficulty of diagnosing NAFLD noninvasively with great accuracy, the precision of all of the above estimates is uncertain. What is apparent, however, is that NAFLD is much more common in patients with prediabetes and diabetes and is therefore likely to be important for these populations.

Pathophysiology and Progression of NAFLD in Relation to Diabetes

The pathogenesis of NAFLD remains unclear, but it may result from any number of insults to the liver (21,22,23,24). A common underlying risk factor is insulin resistance with resulting accumulation of steatosis. Progression to steatohepatitis is thought to be due to additional processes, including inflammation, oxidative stress, and apoptosis leading to fibrosis. Thus, insulin resistance, prediabetes, and diabetes are thought to be closely linked to the development and progression of NAFLD.

Although numerous cross-sectional studies have shown a strong association of diabetes and NAFLD, even after adjustments for body weight and age, prospective studies in humans providing clues to the causal relationships are less clear. Several studies have shown that NAFLD, generally based on indirect markers such as liver enzymes, predicts incident diabetes (25,26,27,28,29,30). In the Insulin Resistance Atherosclerosis Study (IRAS), the highest quartile of ALT compared to the lowest was associated with an adjusted odds ratio (OR) of 2.0 (95% confidence interval [CI] 1.2–3.2) for diabetes as assessed by frequently sampled intravenous glucose tolerance test (28). The findings for AST were similar (adjusted OR 2.0. 95% CI 1.2–3.3). A study in Pima Indians also found an increased risk of diabetes for those with ALT levels at the 90th percentile compared to those at the 10th percentile (adjusted hazard ratio [HR] 1.9, 95% CI 1.1–3.3) (25). An analysis from the Nurses’ Health Study showed that both ALT (OR 2.42, 95% CI 1.45–4.04) and GGT (OR 4.84, 95% CI 2.56–9.17) were associated with an increased risk of diabetes when comparing the 5th to the 1st quintile of liver enzyme activity (31).

There is other evidence that insulin resistance and diabetes increase the subsequent risk of NAFLD (32,33). In one 2-year follow-up of a prospective cohort study of workers in Japan, 14% of men and 5% of women developed NAFLD, with a diagnosis based on ultrasonography (33). Both men and women with the metabolic syndrome had a higher odds of developing NAFLD during follow-up compared to those without the metabolic syndrome (adjusted OR 4.0, 95% CI 2.63–6.08 for men and OR 11.20, 95% CI 4.85–25.87 for women). (In that study, the metabolic syndrome was defined by modified third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria as three or more of the following five abnormalities: elevated serum triglyceride level, decreased high-density lipoprotein [HDL] cholesterol level, elevated blood pressure, elevated fasting glucose level, or BMI ≥25 kg/m² used as an index of obesity in Asians in place of abdominal obesity (34).) Furthermore, those with NAFLD and the metabolic syndrome at baseline were less likely to have remission of NAFLD than those without the metabolic syndrome (adjusted OR 0.47, 95% CI 0.26–0.85 for men and OR 0.47, 95% CI 0.26–0.84 for women). In another cohort study of workers in Japan, followed for a median of 5 years, NAFLD defined by elevated liver enzymes developed in 14.7% of adults age 20–39 years and 8.1% of those age 40–59 years (32). While there were no associations in the younger age group (perhaps due to smaller sample size), diabetes or glucose intolerance was the only predictor of incident NAFLD, increasing the risk over fourfold (HR 4.2, 95% CI 1.1–15.7) in the older age group.

TABLE 26.2

Age-Standardized Prevalence of Nonalcoholic Fatty Liver Disease Diagnosed by the Fatty Liver Index, by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 1999–2010.

TABLE 26.3

Age-Standardized Prevalence of Nonalcoholic Fatty Liver Disease Diagnosed by Elevated Liver Enzymes, by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 1999–2010.

Determining the directionality of the association of diabetes and NAFLD has proven difficult for several reasons. First, the preclinical stages of both diseases make it difficult to determine the exact time each condition occurred. This is further complicated by the fact that, in clinical practice, individuals are not routinely screened for both at the same time. In research, most studies have not employed the gold standard tests for both conditions (e.g., fasting glucose, A1c, and/or oral glucose tolerance testing [OGTT], along with liver biopsy or comprehensive serologic or imaging tests that also rule out other causes), and even fewer have done this prospectively in defined cohorts.

Progression of NAFLD

In cross-sectional studies, persons with diabetes have a significantly higher prevalence of NASH and advanced fibrosis/cirrhosis (35,36). In the few prospective studies that examined the progression of liver disease, the presence of NASH was the strongest predictor of progression (14). However, no study has clearly isolated the impact of diabetes on progression independently of other factors, including baseline histology. As mentioned, NAFLD is also known to precede HCC. While prospective data are also limited for this outcome, a number of studies have found that individuals with diabetes are at higher risk for developing HCC with relative risks of twofold to threefold for HCC compared to those without diabetes (37).

TABLE 26.4

Age-Standardized Prevalence of Presumed Nonalcoholic Fatty Liver Disease Among Persons With Diabetes, by Use of Different Diabetes Medications, U.S., 1988–1994 and 1999–2010.

NAFLD, Type 2 Diabetes, and Mortality

NAFLD leads to end-stage liver disease (cirrhosis) and HCC, two conditions that are strongly associated with liver-related mortality. Indeed, some studies have shown an increase in liver-related mortality in patients with NAFLD (38). Several prior population-based studies reported increased liver-related mortality in those with diabetes. As shown in Table 26.5, NAFLD is associated with increased liver-related mortality in most, but not all studies, with hazard ratios ranging from 0.64 to 13.0 compared to those without NAFLD (39,40,41,42). The Verona Diabetes Study found a standardized mortality ratio (SMR) for liver disease and cirrhosis of 2.5 (95% CI 2.0–3.2) in those with diabetes compared to the general population (43). This increased risk was slightly higher in men (SMR 2.82, 95% CI 2.08–3.76) than women (SMR 2.04, 95% CI 1.26–3.12). A study done in individuals with diabetes in Wisconsin had similar findings (SMR 2.3, 95% CI 0.9–4.7), but the results were not statistically significant, perhaps due to a small number of liver-related deaths (44). Neither of these studies determined the underlying liver disease that caused cirrhosis or liver-related mortality.

In addition to liver-related mortality, NAFLD may be associated with an increased risk of all-cause or cardiovascular mortality; however, data supporting this hypothesis are weak. In particular, population-based studies in the United States have shown mixed results (Table 26.5). As with prevalence studies, the diagnostic criteria for NAFLD in these studies have differed substantially. In general, studies using liver enzymes have shown a small, statistically significant risk of all-cause mortality. The highest risk has been shown in those with elevations in GGT. Using ultrasound to identify NAFLD in the NHANES III, there was no increased risk of all-cause mortality overall and no difference in risk in those with NAFLD and diabetes compared to those with NAFLD and no diabetes (p=0.24) (Table 26.5) (41). A population-based study in Minnesota found an increase in all-cause mortality among those with NAFLD compared to the general population (SMR 1.55, 95% CI 1.11–2.11) (45). Those with diabetes also had a significant increase in all-cause mortality, independent of NAFLD; however, no test for interaction was reported.

TABLE 26.5

Population-Based Studies of Nonalcoholic Fatty Liver Disease and Mortality in the United States.

Finally, another analysis of the NHANES III found that an elevation in GGT was associated with increased risk of diabetes-related mortality (HR 3.3, 95% CI 1.4–7.6) even after adjustment for multiple factors, but elevated ALT was not associated with diabetes mortality (40). Because most studies have not reported on diabetes-related mortality, this finding remains to be replicated.

NAFLD is associated with increased liver-related mortality, as well as all-cause mortality, but limited data suggest that this does not differ in people with diabetes compared to those without. NAFLD may be associated with increased cardiovascular mortality, especially in older adults and in those with diabetes, but these findings require verification. Future studies are needed to assess the prognostic implications of different stages of liver disease in people with diabetes on all-cause, cardiovascular, and cancer mortality.

Viral Hepatitis

Hepatitis C and Diabetes

In the United States, chronic HCV is the leading indication for liver transplantation and the leading cause of death from liver disease (46,47,48). The presence of IgG antibody to the virus (anti-HCV) in the blood indicates either past or current infection. A positive blood test for HCV RNA indicates ongoing infection. An association between HCV and type 2 diabetes has been noted beginning shortly after the discovery of HCV in 1989. Subsequently, a meta-analysis found diabetes to be more frequent among persons with HCV with an adjusted odds ratio of 1.68 based on seven cross-sectional studies and a hazard ratio of 1.67 based on three cohort studies (49). However, many of these studies were clinical series, in which ascertainment bias is likely because patients under medical care for one chronic condition (such as diabetes) are more likely to undergo testing for other chronic diseases (such as HCV), especially if they have features in common, such as elevated liver enzyme activity (50). Published population-based studies and other cohort studies that avoided ascertainment bias demonstrated a moderate association of the two conditions, but the results have not been consistent (see below). In addition, patients with HCV are likely to have advanced liver disease, which may increase the risk of diabetes independently of cause. This concern may be somewhat mitigated in studies that include liver biopsies or that compare diabetes in HCV versus other causes of chronic liver disease.

The association between diabetes and HCV has been specifically examined in four population-based studies without consistent results (51,52,53,54). In the NHANES III, a nonstatistically significant association was found between the presence of anti-HCV antibody and diabetes that was either self-reported or detected by glucose tolerance testing (51). A stronger association was found when analysis was restricted to participants age ≥40 years (adjusted OR 3.77, 95% CI 1.80–7.87), but it was not clear why the association was found in only one age group. In the Atherosclerosis Risk in Communities Study (ARIC), persons free of diabetes (determined by self-report or fasting plasma glucose) had three subsequent visits over approximately 10 years (52). In a modified nested case-control study, samples from baseline visits were subsequently tested for anti-HCV antibody. Overall, a nonstatistically significant association of HCV and subsequent diabetes was found with a relative hazard of 1.9 (95% CI 0.6–6.2). However, an increased relative hazard was found for participants at high risk of diabetes (based on age and BMI) of 11.6 (95% CI 1.4–96.6). This finding was based on only eight anti-HCV positive cases. For the low-risk group, the relative hazard was 0.48 (95% CI 0.05–4.4), based on seven anti-HCV positive participants. Among obese participants only, insulin levels were higher at baseline in the anti-HCV positive group. The strongest population-based evidence for an increased risk of diabetes with HCV has come from a Taiwanese community-based cohort (53). Nearly 5,000 persons age ≥40 years without diabetes (diabetes was defined as fasting plasma glucose ≥126 mg/dL or casual glucose ≥200 mg/dL [≥11.10 mmol/L]) were followed for 7 years. At baseline, 812 participants were anti-HCV positive, 544 positive for HBsAg, and 116 positive for both. Cumulative incidence of diabetes was 8.6% for seronegative individuals, 14.3% for anti-HCV positive alone, and 7.5% for HBsAg positive alone. The adjusted hazard ratio for diabetes if anti-HCV positive was 1.7 (95% CI 1.3–2.8). The association was strongest in persons of younger age or higher BMI. In contrast, a cohort study from Italy found no association between baseline anti-HCV positivity and subsequent development of diabetes in multivariate analysis (OR 0.65, 95% CI 0.41–1.04) (54).

In analysis for Diabetes in America, of the cross-sectional, population-based NHANES 1999–2010, among nearly 29,000 tested participants, 566 were anti-HCV positive and 393 were HCV RNA positive. The diagnosis of diabetes was based on self-report, A1c ≥6.5%, or fasting glucose ≥126 mg/dL. Prediabetes was defined as A1c 5.7%–6.4% or fasting glucose 100–125 mg/dL. The definition of normal glucose levels required both an A1c <5.7% and a fasting plasma glucose <100 mg/dL.

TABLE 26.6

Age-Standardized Prevalence and Odds Ratios of Positive Serum Antibody to Hepatitis C Virus (HCV Ab+), by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 1999–2010.

The prevalence of anti-HCV was similar across glucose categories, both overall and by demographic subgroups (Table 26.6). The age-sex-race/ethnicity adjusted odds ratios for anti-HCV positive were not increased for either diabetes (OR 0.8) or prediabetes (OR 1.0) relative to normal glucose levels. Similarly, the prevalence of HCV RNA positivity was not different across glucose categories, and the adjusted odds ratios were not higher for diabetes and prediabetes (Table 26.7). The overall results for anti-HCV and HCV RNA are summarized in Figure 26.2. Diabetes and prediabetes remained unassociated with HCV infection in multivariate analyses that adjusted for additional factors (55).

A finding of increased insulin resistance among persons with HCV would strengthen the evidence for an association of diabetes. Surrogate estimates for increased insulin resistance, such as high homeostasis model assessment of insulin resistance (HOMA-IR), have been found more commonly among persons with HCV than those without (56,57,58). Stronger evidence of a relationship of HCV to insulin resistance comes from HCV treatment studies in which glucose and insulin were measured before and after treatment. Improvement in insulin resistance among treated patients who clear virus (i.e., achieve a sustained virologic response) relative to patients who do not clear the virus would provide support for the hypothesis that chronic HCV infection has a direct effect on glucose dysregulation. Most studies of HCV and insulin resistance used HOMA-IR to estimate insulin resistance (59). In general, a decline was seen in estimated insulin resistance among those who achieved a sustained virologic response that did not occur among patients who were nonresponders to treatment or who had virologic relapse following treatment (60,61,62,63). However, concerns have been raised about the accuracy of HOMA-IR and other surrogate measures of insulin resistance in chronic HCV (64). One small study utilized a more direct measure of insulin resistance—insulin suppression tests (65). The authors found a nonstatistically significant greater improvement in insulin resistance among 14 patients with sustained virologic response than among nine nonresponders (65). At least two studies with longer-term follow-up indicated a lower risk of new-onset diabetes among participants who achieved a sustained virologic response (66,67). It should be noted that an improvement in insulin resistance among patients with sustained virologic response might not be a direct effect of virus elimination. It could also be due to improvement in liver function following virus eradication (68).

TABLE 26.7

Age-Standardized Prevalence and Odds Ratios of Presence of Serum Hepatitis C Virus RNA, by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 1999–2010.

FIGURE 26.2

Age-Standardized Prevalence of Hepatitis B and Hepatitis C, by Diabetes Status, U.S., 1999–2010. Diabetes is defined as self-reported health care provider diagnosis or glycosylated hemoglobin (A1c) ≥6.5% or fasting plasma glucose ≥126 (more...)

In conclusion, it is possible that HCV has a permissive rather than direct effect on the development of diabetes. Thus, HCV may act in concert with other determinants to increase the risk of diabetes.

Hepatitis B and Diabetes

There are several tests for HBV infection. For epidemiologic studies, the most commonly used and useful tests are serum HBcAb, which indicates exposure to HBV, and HBsAg, which indicates current infection.

The distribution of chronic HBV infection is highly regional, being endemic throughout much of eastern Asia and parts of Africa and much less prevalent in North America and Western Europe. In the United States, HBV is a major concern among immigrants from endemic regions. Worldwide, chronic HBV infection may pose a more significant health burden than HCV. The risk of HCC is much higher in HBV than HCV, and HCC remains a leading cause of cancer mortality in much of the world.

Compared to HCV, there is less evidence that HBV increases the risk of diabetes. In fact, several studies have used patients with HBV as the reference group when examining the prevalence of diabetes in HCV (69,70,71,72). In the study from Taiwan in which HCV was shown to increase the rate of new-onset diabetes, the incidence of diabetes among participants with chronic HBV (positive for HBsAg) was not greater than among those who were HBV-seronegative (53).

New analyses of NHANES 1999–2010 data on HBV serology and diabetes were conducted for Diabetes in America. Among over 30,000 tested participants, 1,998 were HBcAb positive and 115 were HBsAg positive. As with the HCV analysis, the diagnosis of diabetes was based on self-report, A1c ≥6.5%, or fasting glucose ≥126 mg/dL. The unadjusted prevalence of HBcAb was higher among those participants with diabetes (8.0%) compared with participants with normal glucose levels (5.6%) (Table 26.8). This difference was more pronounced among women (8.0% with diabetes vs. 4.2% with normal glucose levels). Among the different racial/ethnic groups, prevalence was especially high for non-Hispanic blacks and highest for “other” ethnicities, mostly of Asian origin. With adjustment for age, sex, and race/ethnicity, the odds ratios for HBcAb were not elevated for diabetes (OR 1.0, 95% CI 0.81–1.3) and prediabetes (OR 1.1, 95% CI 0.82–1.4) relative to participants with normal glucose levels. The prevalences and odds ratios for the much smaller number of participants positive for HBsAg were not elevated for participants with diabetes or prediabetes relative to those with normal glucose levels (Table 26.9). Overall results for HBcAb and HBsAg are summarized in Figure 26.2.

TABLE 26.8

Age-Standardized Prevalence and Odds Ratios of Positive Serum Antibody to Hepatitis B Core Antigen (HBcAb+), by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 1999–2010.

TABLE 26.9

Age-Standardized Prevalence and Odds Ratios of Positive Serum Hepatitis B Virus Surface Antigen (HBsAg+), by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 1999–2010.

Diabetes and Cirrhosis

An association of diabetes and liver cirrhosis was established more than 50 years ago (73). In more recent studies of patients with cirrhosis undergoing OGTT, diabetes has been detected in a high percentage of patients with cirrhosis, ranging from 35% to as high as 71% (Table 26.10) (72,74,75,76,77,78). Among patients with chronic viral hepatitis, those with cirrhosis have a higher prevalence of diabetes than those without cirrhosis (72). Furthermore, the prevalence of diabetes increases with declining liver function among patients with cirrhosis. Investigators have differentiated diabetes mellitus (presumably type 2) from hepatogenous diabetes due to chronic liver disease, but the differentiation has been based largely on whether diabetes was recognized before (type 2) or after (hepatogenous) the diagnosis of cirrhosis and not on a pathophysiologic basis (76,79). A striking feature of diabetes associated with cirrhosis is the high proportion of patients with normal fasting glucose.

The incidence of new-onset diabetes is also high among persons with cirrhosis. In an Italian study of 100 patients with compensated cirrhosis (Child-Turcotte class A) who had normal OGTT, 21% developed diabetes during 4 years of follow-up even without overt worsening of liver function (80). The risk was higher among patients who had deteriorating liver function (35%). The presence of portal hypertension appeared to increase the risk of diabetes. Additionally, patients with cirrhosis and diabetes appear to have a worse prognosis than those with cirrhosis without diabetes (75,81).

TABLE 26.10

Prevalence of Diabetes Among Patients With Cirrhosis Who Had Oral Glucose Tolerance Testing.

Diabetes and Liver Transplantation

The large majority of adult liver transplantation is performed for decompensated cirrhosis and for HCC. Most patients with HCC also have cirrhosis, but not necessarily advanced enough to trigger the need for transplantation on its own.

Data on all patients listed for liver transplantation in the United States from the SRTR SAF have been newly analyzed for Diabetes in America. There has been a steady increase in the recognition of diabetes at the time of listing since it was first recorded as a comorbidity in listed patients (Figure 26.3). From 1994, when 13.7% (n=507) of listed patients carried a diagnosis of diabetes, the proportion doubled to 27.9% in 2013 (n=2,321). Although this doubling in prevalence is striking, it is difficult to interpret. As stated, a high proportion of patients with cirrhosis are found to have diabetes when specifically tested for it. Thus, the observed increase might be due to a combination of an actual increase in diabetes and an increase in its diagnosis.

Characteristics of patients with and without diagnosis of diabetes at the time of listing and at transplantation are shown in Table 26.11. Patients with diabetes were more likely to be older, male, Hispanic, less educated, have poorer functional status, on dialysis, hypertensive, and have higher BMI than those without diabetes. Interestingly, Model for End-Stage Liver Disease (MELD) scores (a scale used for prioritizing liver transplant candidates in which a higher score indicates a more urgent need within the next 3 months) were lower among patients with diabetes (mean 16.3) than among patients without known diabetes (mean 17.4). At the time of transplant, a higher MELD score among those without diabetes was still present. Diabetic patients received livers from donors who were slightly older and less likely to be of white race compared with donors of nondiabetic patients. Table 26.11 shows the percentages of patients with a given liver disease by diabetes status. For example, an HCV diagnosis was present among 37.2% of 33,078 listed patients with diabetes and 41.2% of 116,102 listed patients without diabetes. Because patients may have more than one liver disease, the percentages are not mutually exclusive and add to greater than 100%. Regarding the association of diabetes with liver disease diagnosis, it may be more informative to consider the proportion listed with diabetes according to liver disease diagnosis:

• 58.0% for fatty liver
• 35.7% for other causes of cirrhosis
• 27.3% for HCC
• 20.4% for HCV
• 19.5% for HBV
• 19.0% for alcoholic liver disease
• 13.6% for autoimmune liver disease

FIGURE 26.3

Prevalence of Diabetes Among Adult Liver Transplant Candidates, by Listing and Transplant Year, U.S., 1994–2013.

TABLE 26.11

Characteristics of Adult Patients at Listing for Liver Transplantation and at Transplantation, by Diabetes Status, U.S., 1994–2013.

The high percentage for fatty liver is not surprising, given the strong association of fatty liver with diabetes (see the section Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis). A high proportion of those patients with “other causes of cirrhosis” probably also had fatty liver, because the diagnosis has only recently received attention and because the amount of fat declines with advanced cirrhosis and may be difficult to detect. Because diabetes is a risk factor for HCC, the high percentage of cancer cases with diabetes is not surprising. It is noteworthy that the recognition of diabetes among patients with HCV was just modestly higher than for HBV, which as noted, has not been considered to connote as high a risk of diabetes as HCV.

Between the time of listing and transplantation, transplant candidates with diabetes are more likely to die or to be withdrawn from the waiting list, usually because of deteriorating health. These events occurred among 25.8% of those with diabetes and 22.2% of those without diabetes. The odds ratio for death or withdrawal from the waiting list was 1.22 (95% CI 1.19–1.26). Due to this increased risk of death or withdrawal, the proportion of patients with diabetes at the time of transplantation has been slightly less than at listing but has increased just as quickly over time (Figure 26.3).

Diabetes is frequently recognized following liver transplantation regardless of the cause of liver disease due, at least in part, to immunosuppression posttransplantation. It has been suggested that the risk of posttransplant diabetes is greater among patients transplanted for HCV. In a meta-analysis of seven studies, the overall risk of posttransplant diabetes was 37.5% among HCV negative patients and 53.7% among patients who were HCV positive (82). The summary odds ratio was 2.5 (95% CI 1.4–4.2). A 2010 analysis of SRTR data reported that 28.8% of HCV infected recipients and 23.7% of uninfected recipients developed new-onset diabetes over a median follow-up of 685 days (83). The multivariate-adjusted hazard ratio was modest: 1.15 (95% CI 1.07–1.24) for infected versus uninfected patients. Risk factors for development of diabetes for both infected and uninfected patients included older age, higher BMI, the use of tacrolimus and steroid in the immunosuppression regimen, and lack of immunosuppression induction. Posttransplant HCV infection also has a modest association with insulin resistance (84,85). The increased posttransplant risk of diabetes with HCV could be due to a specific diabetogenic effect of HCV. Because liver disease is often accelerated due to the nearly universal posttransplant recurrence of HCV, liver function may have already deteriorated by the time of evaluation for diabetes. In contrast, many other liver diseases do not recur following transplantation or their evolution is slow. Furthermore, none of the analyses of “new-onset” posttransplant diabetes included pretransplant OGTT (86,87,88,89,90,91,92,93). The few studies that have diagnosed diabetes based on OGTT found that a high proportion of those with diabetes after transplant had impaired glucose tolerance or diabetes (as diagnosed by the 2-hour postload plasma glucose) before transplant (78,94).

Gallbladder Disease

Gallstone disease is a common condition affecting more than 20 million adults in the United States (95). The majority of gallstones in the United States are composed primarily of cholesterol. Cholesterol gallstones are believed to develop as a result of three factors: (1) a higher proportion of cholesterol relative to solubilizing bile acids and phospholipids in bile, (2) a higher proportion of pronucleating factors relative to antinucleating factors in bile, and (3) impaired gallbladder motility, which increases the opportunity for cholesterol nucleation in the gallbladder. Abdominal ultrasonography is the criterion standard for diagnosis of gallstones because of its accuracy and safety. The majority of gallstones remain asymptomatic. For symptomatic gallstones, the primary treatment is cholecystectomy (surgical removal of the gallbladder), the majority of which are performed laparoscopically. Gallstone disease can be defined as the presence of gallstones on ultrasound or a history of a cholecystectomy. Established risk factors are older age, female sex, overweight and obesity, higher parity, and family history. Other factors that have been associated with a higher prevalence of gallstone disease are American Indian and, among women, Mexican American ethnicities, rapid weight loss, central adiposity, and cigarette smoking, while a lower prevalence of gallstones has been found in association with non-Hispanic black and some Asian race ethnicities, higher alcohol consumption, and greater physical activity.

Gallstone Disease and Diabetes

The relationship between diabetes and gallstone disease is complicated by their shared risk factors, such as age and obesity. Table 26.12 summarizes studies of the relationship of gallstone disease with diabetes that have been published since Diabetes in America, 2nd edition (96). All listed studies are population-based and, therefore, did not suffer from the ascertainment bias that can occur with selected patient samples. In all studies, gallstone disease was identified using ultrasonography. Diabetes was variably defined based on a self-reported health care provider diagnosis, fasting plasma glucose, or an OGTT.

In the general U.S. population, both men and women reporting a diagnosis of diabetes were over 50% more likely to have gallstone disease compared to persons without a diabetes diagnosis after adjustment for multiple shared risk factors (Table 26.12) (95). Men and women with undiagnosed diabetes (fasting plasma glucose ≥126 mg/dL) were approximately twice as likely to have gallstone disease as persons with normal fasting glucose (<110 mg/dL [<6.11 mmol/L]) (Table 26.12) (97). This relationship reached statistical significance only among women. Impaired fasting glucose (110–125 mg/dL) was unrelated to gallstone disease among either women or men. Two other studies were conducted in the United States. Among Mexican Americans in a Texas county, women with previously diagnosed diabetes who were receiving treatment, or with newly identified diabetes based on two fasting plasma glucose levels ≥120 mg/dL (≥6.66 mmol/L), were twice as likely to have gallstone disease (98), while there was no relationship among men. Among a diverse group of American Indians, women with diabetes (based on an OGTT) had an over 40% higher prevalence of gallstone disease. Among men, the odds ratio was nearly as high (OR 1.29) but did not reach statistical significance (99). These results differ from a much earlier study of Pima Indians using cholecystography to identify gallstone disease that did not find a higher prevalence among those with diabetes (100).

TABLE 26.12

Prevalence and Relative Risk of Ultrasound-Diagnosed Gallstone Disease, by Diabetes Status.

Among non-U.S. studies, an Italian study (which was the largest population-based study of ultrasound-detected gallstones) found an association with diabetes among both men and women; however, the published results were adjusted only for age and not for additional confounders, such as BMI (101). In a nested case-control study from the same Italian population matched on age, sex, and BMI, gallstone disease and diabetes were statistically significantly associated among women (OR 3.85), while the relationship among men just missed statistical significance (OR 2.03) (102). In a Japanese study of men age 48–59 years that included data from two previous smaller studies (103,104) and additional participants, the adjusted odds ratio was 1.3 for both OGTT-detected diabetes and impaired glucose tolerance but neither reached statistical significance (105). Two Taiwanese studies defined diabetes based on fasting plasma glucose. An association was found in the first among women only (OR 2.11) (106), while in the second an over 70% higher prevalence of gallstone disease was found among diabetic men and women combined (107). An older Taiwanese study also found an association with diabetes (108).

Prospective studies of incident gallstone disease can evaluate the temporal relationship with potential disease risk factors and, therefore, provide evidence for a causal association; however, few have been conducted. Two Italian studies found positive relationships with diagnosed diabetes. In the first, during up to 7 years of follow-up, diabetes was related to incident gallstone disease with an odds ratio of 2.62 (109). In the second study, during a mean follow-up time of 8 years, a relationship was found among men, but not women. Among men, the odds ratio was 1.75 for gallstones and was even higher for cholecystectomy (OR 2.72), although the latter did not reach statistical significance (110).

To further evaluate the relationship of gallstone disease with diabetes in the general U.S. population, new analyses for Diabetes in America were conducted using gallbladder ultrasonography data on adults age 20–74 years from the NHANES III. In these analyses, gallstone disease prevalence and odds ratios may not be identical to previously published reports from the NHANES III due to differences in diabetes definitions and adjustment only for age (prevalence), or age, sex, and race/ethnicity. Diabetes can be defined in the NHANES III as diagnosed (self-reported health care provider diagnosis) and, among persons without a diagnosis, as undiagnosed (A1c ≥6.5% or fasting glucose ≥126 mg/dL), prediabetes (A1c 5.7%–6.4% or fasting glucose 100–125 mg/dL), or normal glucose (A1c <5.7% and fasting glucose <100 mg/dL). The prevalence (± standard error) of gallstone disease was 33.3%±2.6% among those with diagnosed diabetes, 23.3%±2.2% among those with undiagnosed diabetes, 20.8%±1.5% among those with prediabetes, and 16.7%±1.7% among those with normal glucose (Figure 26.4, Table 26.13). A similar pattern of increasing gallstone disease prevalence with greater impairment of glucose metabolism was observed among men and women; young, middle-age, and older adults; and non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. Compared with persons with normal glucose, those with diagnosed diabetes had an age-sex-race/ethnicity-adjusted odds ratio of 2.3 (95% CI 1.7–3.2) for gallstone disease. These increased odds ranged from double among Mexican Americans to triple among persons age 20–44 years. There was a trend toward an increased prevalence of gallstone disease among persons with undiagnosed diabetes in the total population (OR 1.5, 95% CI 1.0–2.1), which was statistically significant among women and non-Hispanic blacks. Individuals with prediabetes did not have a statistically significantly higher prevalence of gallstone disease compared with those with normal glucose (OR 1.2, 95% CI 0.94–1.6), although the results were statistically significantly different among men.

When ultrasound-diagnosed gallstones and cholecystectomy were examined separately, the prevalence was higher among those diagnosed with diabetes for both gallstones (15.4%±1.7%) and cholecystectomy (17.9%±2.3%) (Figure 26.4, Table 26.13). Compared to persons with normal glucose, those with diagnosed diabetes had age-adjusted odds ratios of 1.6 (95% CI 1.1–2.4) for gallstones and 2.6 (95% CI 1.7–4.0) for cholecystectomy. Persons with undiagnosed diabetes also had a higher odds ratio for cholecystectomy (OR 1.6, 95% CI 1.1–2.5).

Similar patterns were generally seen across sex, age, and racial/ethnic subgroups, although not all relationships reached statistical significance due to smaller numbers.

Gallstone disease can be examined among those with diabetes by duration of disease and type of treatment. However, no consistent pattern was seen in the U.S. population with a longer duration or more intensive treatment of diabetes (Table 26.14).

FIGURE 26.4

Age-Standardized Prevalence of Gallstone Disease, Ultrasound-Diagnosed Gallstones, and Cholecystectomy, by Diabetes Status, U.S., 1988–1994. Diagnosed diabetes is defined as self-reported health care provider diagnosis. Undiagnosed diabetes is (more...)

Gallstone Disease and Insulin Resistance

Cholesterol gallstones are associated with common metabolic abnormalities, including obesity, glucose intolerance, and dyslipidemia that are also components of the metabolic syndrome (111); hence, gallstone disease has been proposed as the gallbladder manifestation of the metabolic syndrome (112,113). The insulin resistance and hyperinsulinemia that characterize the development of type 2 diabetes play a primary role in the metabolic syndrome. Hyperinsulinemia may be more important in gallstone formation than diabetes itself (21,22,25,26,27,28,29).

TABLE 26.13

Age-Standardized Prevalence and Odds Ratios for Gallstone Disease, Ultrasound-Diagnosed Gallstones, and Cholecystectomy, by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 1988–1994.

Population-based studies of the relationship between ultrasound-diagnosed gallstone disease and insulin resistance, in which an adjusted odds ratio was reported, are summarized in Table 26.15. In studies of the general population, insulin resistance has been defined either as fasting serum insulin concentration, which is typically elevated as a result of insulin resistance, or using HOMA-IR, which is calculated from fasting insulin and fasting glucose and has been validated against the criterion standard for measurement of insulin resistance, the euglycemic hyperinsulinemic clamp (114,115). In the U.S. population, among persons without a previous diabetes diagnosis, the prevalence of gallstone disease rose with increasing fasting serum insulin concentration among women, but not among men (97). The association in women was independent of multiple potential confounding factors, including fasting glucose, BMI, waist-to-hip ratio, and physical activity. However, the relationship of gallstone disease with insulin did not account for the increased risk of gallstones in persons with undiagnosed diabetes. This may have partly resulted from limitations of a cross-sectional study in which insulin levels at the time of examination may differ from those at the time of gallstone formation and limitations of using serum insulin concentration as a surrogate for insulin resistance.

TABLE 26.14

Age-Standardized Prevalence of Gallstone Disease, Ultrasound-Diagnosed Gallstones, and Cholecystectomy, by Diabetes Duration and Treatment, U.S., 1988–1994.

Among non-U.S. studies, in a Chilean Hispanic population at high risk for gallstone disease, persons with insulin resistance in the highest quartile had an 80% higher prevalence of gallstones and over twice the prevalence of cholecystectomy (116). In a large study of nondiabetic Korean men, gallstones on ultrasound were associated with insulin resistance, and this relationship was found regardless of obesity status (117). Persons who met the criteria for the metabolic syndrome had an increased prevalence of gallstone disease in the Chilean study, while there was no statistically significant relationship of the metabolic syndrome with gallstones among Korean men. In the one prospective study of gallstone disease and insulin resistance of which the authors are aware, an increased risk of gallstone disease was found with insulin resistance among those without diabetes. In this Italian nested case-control study, an insulin level in the highest quintile was associated with incident gallstone disease with an odds ratio of 2.64 (118).

TABLE 26.15

Prevalence and Relative Risk of Ultrasound-Diagnosed Gallstone Disease, by Insulin Resistance Status.

In conclusion, among published population-based studies utilizing gallbladder ultrasonography, there has been a fairly consistent association of gallstone disease with diabetes independent of adiposity and other factors. The increased risk has ranged from approximately 40% higher to double among persons with diabetes. The relationship has been more consistent among women than men. This may result from decreased statistical power to detect such a relationship in men, who have a lower prevalence of gallstones. In addition, although the majority of gallstones in the United States are cholesterol stones (119), the proportion of cholesterol stones is lower in men than in women (120,121). An exception with regard to gender difference was a stronger relationship among men in one of the Italian studies of incident gallstone disease (110). In analyses for Diabetes in America, age-standardized analyses of the U.S. population discussed above, a similar pattern of increasing gallstone disease prevalence with greater impairment of glucose metabolism was observed among men and women; young, middle-aged, and older adults; and non-Hispanic whites, non-Hispanic blacks, and Mexican Americans.

With regard to the direction of the relationship, it has generally been considered that diabetes predisposes to gallstone disease, though the majority of studies have been cross-sectional. In contrast, a European prospective study found that self-reported gallstone disease preceded the diagnosis of type 2 diabetes (122). An association of insulin resistance with gallstone disease has been shown among those without overt diabetes (117,118). Insulin resistance may be the link between diabetes and gallstone disease.

List of Abbreviations

A1c

glycosylated hemoglobin

ALT

alanine aminotransferase

AST

aspartate aminotransferase

AUROC

area under the receiver operating characteristic curve

BMI

body mass index

CI

confidence interval

GGT

gamma glutamyltransferase

HBcAb

hepatitis B core antibody

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

HOMA-IR

homeostasis model assessment of insulin resistance

HR

hazard ratio

MELD

Model for End-Stage Liver Disease

MR

magnetic resonance

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NHANES

National Health and Nutrition Examination Survey

OGTT

oral glucose tolerance test

OR

odds ratio

RNA

ribonucleic acid

SAF

standard analysis file

SMR

standardized mortality ratio

SRTR

Scientific Registry of Transplant Recipients

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CONVERSIONS

Conversions for A1c and glucose values are provided in Diabetes in America Appendix 1 Conversions.

DUALITY OF INTEREST

Drs. Ruhl, Clark, and Everhart reported no conflicts of interest.

ACKNOWLEDGMENTS/FUNDING The authors thank Danita Byrd-Clark for assistance with programming of Scientific Registry of Transplant Recipient data and Bryan Sayer for assistance with programming of National Health and Nutrition Examination Survey data.