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Diabetes Mellitus and Pyogenic Liver Abscess: Risk and Prognosis

  1. Reimar W. Thomsen1,
  2. Peter Jepsen1,2, and
  3. Henrik T. Sørensen1,3
  1. 1Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg
  2. 2Department of Medicine V, Aarhus University Hospital, Aarhus, Denmark
  3. 3Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts
  1. Reprints or correspondence: Dr. Reimar Wernich Thomsen, Dept. of Clinical Epidemiology, Aarhus University Hospital, Forskningens Hus, Sdr. Skovvej 15, Postbox 365, DK-9100 Aalborg, Denmark (r.thomsen{at}rn.dk).
 
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Abstract

Background. Pyogenic liver abscess (PLA) is a rare, life-threatening disease with an increasing rate of incidence. Case reports from East Asia suggest that diabetes mellitus is an important risk factor, but formal evidence is limited.

Methods. We performed a case-control study with participants drawn from the entire population of Denmark. Cases of PLA were defined as occurring in all patients who received a first-time diagnosis of PLA on hospital discharge between 1977 and 2002, as identified in the nationwide Danish National Patient Registry. Fifty sex- and age-matched population control subjects were selected for each patient with PLA. We computed the relative risk of PLA associated with diabetes using conditional logistic regression and controlling for major potential confounders. We further examined whether diabetes increased the relative risk of death until 30 days after hospital discharge among patients with PLA.

Results. We identified 1448 patients who experienced a first hospitalization for PLA during the study period (median age, 64 years; male sex, 54.2%). Persons with diabetes had a 3.6-fold increased risk of experiencing PLA, compared with population control subjects (adjusted relative risk, 3.6; 95% confidence interval, 2.9–4.5]. In addition, patients with PLA who had diabetes had a higher 30-day postdischarge mortality rate, compared with patients with PLA who did not have diabetes (24.8% vs. 18.0%). After controlling for other prognostic factors, the relative risk of death for patients with PLA and diabetes was 1.3 (95% confidence interval, 0.9–2.1).

Conclusions. Diabetes is a strong, potentially modifiable risk factor for PLA. PLA is associated with a similarly poor prognosis for patients with diabetes and for other patients.

Pyogenic liver abscess (PLA) is a rare, life-threatening disease that has an increasing incidence rate in the United States and Europe [1–3]. In Denmark, from 1977 to 2002, the incidence rate of PLA increased from 6 cases per 1 million person-years to 18 cases per 1 million person-years for men and from 8 cases per 1 million person-years to 12 cases per 1 million person-years for women [2]. During the same period, mortality rates decreased from 40%–50% to ∼10%; however, this change is perhaps largely explained by the use of more-sensitive diagnostic tools [2, 3]. Obstructive biliary disease, abdominal infections, previous surgical procedures, and immunocompromising medical conditions (including cancer and liver cirrhosis) have been reported as being risk factors for PLA [4, 5]. However, the evidence is based mainly on case reports, and up to 50% of patients with PLA have none of these risk factors (“cryptogenic” PLA) [6, 7]. Knowledge about risk and prognostic factors is needed to develop strategies to prevent PLA and to improve the outcome of this severe infection.

Large population-based epidemiological studies increasingly suggest that diabetes mellitus is an important risk and prognostic factor for severe gram-negative infections, including bacteremia [8]. However, the association between diabetes and PLA remains controversial. The few available studies have been hampered by the absence of control groups, small sample size, lack of covariate information, and incomplete follow-up [5, 9–11]. The evidence for an association between diabetes and PLA comes primarily from case series of Klebsiella species PLA in East Asia [12, 13]. No studies in populations in Europe and North America have focused specifically on the association between diabetes and PLA risk. Because PLA is rare, large datasets are needed to address the issue [5]. Using a nationwide database that included all hospitalizations, we examined diabetes as a risk factor and a prognostic factor for PLA in Denmark over a 26-year period.

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Methods

Setting

The study drew on the entire population of Denmark (∼5.4 million inhabitants), whose tax-supported national health service provides all residents with free access to hospitals and primary medical care [14]. The unique civil registry number assigned to every Danish resident since 1968 permitted data linkage across nationwide administrative and health registries and allowed us to establish a complete hospitalization history for each individual under study.

The Danish National Patient Registry contains computerized records of all patient discharges from Danish hospitals since 1977 [15]. Files for each hospitalization include information on the patient's civil registry number, dates of hospital admission and discharge, surgical procedures performed, and up to 20 diagnoses coded by physicians on the date of discharge according to the Danish version of the International Classification of Diseases (ICD; 8th revision used until the end of 1993, 10th revision used thereafter).

Patients with PLA and Population Control Subjects

The study included all patients who were discharged from a hospital (living or deceased) with a diagnosis of PLA between 1 January 1977 and 31 December 2002. Only the date of each patient's first hospital discharge diagnosis of PLA (the index date) was considered. On the index date for each PLA patient, we randomly selected 50 control subjects, matched by sex and age (same year and month of birth), from the Danish population as a whole by means of electronic linkage with the Danish Civil Registration System. Selection of control subjects was done on the basis of risk set sampling, ensuring that the estimated exposure OR in our case-control study was an unbiased estimate of the relative risk [16].

Diabetes

Diabetes was considered to be present in case patients with PLA and control subjects if a hospital discharge diagnosis of insulin-dependent diabetes, non—insulin-dependent diabetes, unspecified diabetes, or diabetic retinopathy was recorded on or at any time before the index date of the first discharge diagnosis of PLA.

Confounders

Diabetes and risk of PLA. We compiled a complete hospitalization history for each patient with PLA and each population control subject to assess medical or surgical risk factors for PLA that also may be associated with diabetes [5, 7, 9, 10, 17, 18]. The following medical conditions were considered to be risk factors for PLA if they had been recorded as discharge diagnoses before or on the index date: benign biliary obstruction, liver cancer (including metastases to the liver), biliary tract cancer, pancreatic cancer, other gastrointestinal cancers, all other solid-organ cancers, hematological cancers, liver cirrhosis, inflammatory bowel disease, alcoholism, ongoing abdominal infection (acute cholecystitis or cholangitis without cholelithiasis, diverticulitis, appendicitis, or peritonitis), and ongoing systemic infection (sepsis or endocarditis). For cases of infection, only discharge diagnoses from hospitalizations ending <30 days before the index date were considered.

The following surgical procedures were considered to be risk factors for PLA, provided that they had been performed <6 months before the index date: surgical procedures involving the liver, biliary tract (including gall bladder), pancreas, or spleen; upper endoscopy; endoscopy of the biliary tract (including endoscopic retrograde cholangiopancreatography); other gastrointestinal surgery; and any other surgical procedures. Because procedures performed during a hospitalization for PLA may have been related to PLA diagnosis or treatment, procedures performed before and after the date of admission were considered separately. Among the latter, we defined a category of “probably PLA-related” procedures (a list of all ICD codes used is provided in the Appendix).

Diabetes and 30-day postdischarge mortality following PLA. To adjust for the burden of comorbidity in mortality analyses, we computed Charlson index scores for patients with diabetes and PLA and other patients with PLA using records of all hospital discharge diagnoses made up to and including the index date [19]. Diabetes was removed from the Charlson index, because it defined the exposure in this study. We defined 3 comorbidity index levels: low (score, 0), medium (score, 1–2), and high (score, >2). Alcoholism-related diagnoses were handled as a separate variable, because most are not included in the Charlson index.

Statistical Analyses

Diabetes and risk of PLA. For the case-control analysis of PLA risk, we used conditional logistic regression to compute ORs with 95% CIs as a measure of the relative risk of PLA according to diabetes status, adjusted for medical and surgical risk factors. Analyses were conducted both with and without adjusting for surgical procedures performed during the PLA-related hospitalization, excluding “probable PLA-related” procedures.

We further computed ORs stratified by sex and age group (0–39 years, 40–64 years, 65–79 years, and ⩾80 years) and ORs restricted to patients with PLA and control subjects for whom no surgical procedures were performed at any time or who had no recorded PLA risk factors. Because the 1-to-50 technique of matching case patients with control subjects could not be retained for these analyses, we used ordinary logistic regression adjusted for age, sex, calendar year, and the potential confounders listed previously. To examine the public health impact of diabetes on the overall risk of PLA, we calculated the population-attributable risk for a diagnosis of diabetes—that is, the proportion of all cases of PLA that may be attributable to diabetes [16].

The likelihood of receiving a diagnosis of diabetes might have been higher among case patients than control subjects because of more hospitalizations (including the hospitalization for PLA). To address this issue, we performed a sensitivity analysis. A previous report showed that only 63% of individuals with known diabetes in Denmark could be identified through previous discharge diagnoses [20]. In the sensitivity analysis, we assumed that our findings were strongly biased and that the diabetes detection rate was 100% among the patients with PLA but only 63% among the control subjects. Using these rates, we recalculated the diabetes-PLA risk estimate as it would have been if the diabetes detection rate was 100% among both case patients and control subjects.

Diabetes and 30-day postdischarge mortality following PLA. For the analysis of mortality, we obtained data from the Danish Civil Registration System, which records all changes in vital status and migration, including date of death [21]. Six cases of PLA from the case-control study were excluded because of an invalid date of death recorded in the registry. Our outcome measure was the cumulative mortality rate from admission to 30 days after discharge. Logistic regression analyses were used to compute ORs with 95% CIs as a measure of the relative risk of death at day 30 after hospital discharge among patients with diabetes and PLA, compared with other patients with PLA, adjusting for sex, age group, comorbidity index level, alcoholism-related disorders, and time period of hospitalization (1977–1988, 1989–1996, or 1997–2002). Analyses were stratified by sex, age, comorbidity, and time period. All statistical analyses were performed using Stata software, version 9.2 (StataCorp).

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Results

Diabetes and Risk of PLA

Descriptive data. The study involved 1448 patients with PLA. Their median age (interquartile range) was 64 years (50–75 years), and 54.2% were men. Table 1 shows the characteristics of the patients with PLA and the 72,332 population control subjects. A total of 162 patients with PLA (11.2%) had diabetes, compared with 1855 control subjects (2.6%). Among the diabetic PLA patients, 22 (13.6%) received a diagnosis of diabetes for the first time during their hospitalization for PLA; none were recorded as having ketoacidosis. The most common medical risk factors for cases of PLA were benign biliary obstruction (285 patients [19.7%]), any type of cancer (257 patients [17.8%]), and ongoing abdominal infection (210 patients [14.5%]). A total of 464 patients with PLA (32.0%) had undergone a surgical procedure within the prior 6 months; if procedures performed during hospitalizations for PLA were also counted, 811 (56.0%) of patients with PLA had undergone a surgical procedure, compared with only 3867 (5.3%) of control subjects. Commonly encountered surgical risk factors were upper endoscopy and biliary tract procedures (table 1).

Table 1
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Table 1

Characteristics of case patients with pyogenic liver abscess (PLA) and of sex- and age-matched population control subjects, Denmark, 1977–2002.

Risk factor analysis. The crude OR for PLA in persons with diabetes was 5.0 (95% CI, 4.2–5.9). After controlling for confounding factors, the OR decreased to 3.6 (95% CI, 2.9–4.5). Inclusion of surgical procedures performed during PLA hospitalization in the model left the OR unchanged (table 2). Benign biliary obstruction, alcoholism, and liver cirrhosis were the strongest confounders of the association between diabetes and PLA risk, reducing the crude OR from 5.0 to 4.2, 4.4, and 4.6, respectively, when presence of these conditions was included one by one in the analysis. Thus, 15% of the apparent effect of diabetes was caused by a higher prevalence of benign biliary obstruction, and 12% was caused by a higher prevalence of alcoholism among subjects with diabetes.

Table 2
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Table 2

Crude and adjusted ORs for pyogenic liver abscess (PLA) according to the presence of diabetes mellitus.

In contrast, the risk increase conferred by diabetes apparently was not mediated by other ongoing abdominal or systemic infections, because adjustment for them left the crude OR virtually unchanged at 4.9 and 4.8, respectively (data not shown). Adjusted ORs for patients with PLA and diabetes were similarly high, even among patients who had not undergone surgical procedures and patients who were not identified as having any PLA risk factors (table 2). The relative risk increase conferred by diabetes tended to be highest in the youngest age groups: ORs for PLA were 5–6 times higher among subjects with diabetes who were aged <65 years. Assuming that the association between diabetes and PLA is causal, and given a prevalence of diabetes of 2.6% among control subjects, the population-attributable risk of PLA from diabetes was 6.3%.

Sensitivity analysis. Under the very conservative assumption that we were able to identify only 63% of control subjects with diabetes but 100% of PLA case patients with diabetes, the prevalence of diabetes among control subjects would have been 1855/0.63 = 2944 (4.1%) of 72,332 persons. This prevalence adjustment decreases the unadjusted OR for PLA in persons with diabetes from 5.0 to 3.0. Similarly, when we restricted our exposure measurement to a diagnosis of diabetes received only before the date of hospital admission for PLA, the crude OR became 4.2 (95% CI, 3.5–5.0) and was 2.9 (95% CI, 2.2–3.7) in the adjusted analysis.

Diabetes and 30-Day Postdischarge Mortality Attributable to PLA

Descriptive data. A total of 16.8% of patients with diabetes and PLA died during hospitalization, compared with 13.2% of other patients with PLA. At 30 days after hospital discharge, the cumulative mortality for those 2 groups was 24.2% and 17.8%, respectively. Overall, the mortality rate was lower among men than among women, increased sharply with age and comorbidity level, and was substantially higher in the early years of the 26-year study period (table 3).

Table 3
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Table 3

Association between diabetes mellitus and 30-day postdischarge mortality in 1442 patients with pyogenic liver abscess (PLA).

Prognostic factor analysis. The crude OR for death on postdischarge day 30 for patients with diabetes and PLA was 1.5 (95% CI, 1.0–2.2). After controlling for other prognostic factors, the OR for death decreased to 1.3 (95% CI, 0.9–2.1) (table 3). The effect of diabetes on PLA prognosis in early study years, when PLA outcome was poor, was similar to that observed in more recent time periods. In relative terms, diabetes had a particularly strong impact on mortality among patients with PLA who were <40 years of age (adjusted OR, 13.7; 95% CI, 0.8–238.8). Although the estimates showed considerable statistical imprecision, ORs for death due to diabetes were consistently elevated across all strata examined (table 3).

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Discussion

This large nationwide study, which spans a 26-year period, shows that diabetes is a strong risk factor for PLA. In addition, it shows that mortality rates among individuals with diabetes who are hospitalized for PLA are at least as high as those for patients without diabetes who are hospitalized with PLA.

Our study has several strengths. Because nearly all inpatient treatment in Denmark is provided by the national health service, our design is virtually population based for the identification of case patients and control subjects. We were able to adjust for a wide range of potential confounders through access to independent medical databases providing a complete medical history and a record of all surgical procedures performed among study participants.

Some limitations also deserve discussion. The validity of all of our estimates depends on the accuracy of the hospital discharge diagnoses used to identify cases of PLA and diabetes. Patients with PLA usually have severe symptoms, including abdominal pain, fever, and malaise, and are thus unlikely to avoid hospitalization [9, 17]. Still, the onset of PLA may be insidious, with unspecific symptoms, and patients may die before a diagnosis is made [10, 22]. Another potential weakness stems from the clinical practice of keeping patients with diabetes under close surveillance for infection. This could potentially lead to overestimation of the risk and, probably, to underestimation of mortality attributable to PLA. However, the high mortality observed among patients with diabetes and PLA argues against closer surveillance. We consider it unlikely that increased surveillance alone explains the consistently high increases in risk that were observed.

Another concern is possible misclassification of PLA. However, a previous Danish series [3] showed that 51 (98%) of 52 microbiologically confirmed cases of PLA were correctly identified in the regional component of the National Patient Registry used in our study and that misclassification of PLA is unlikely to be associated with diabetes. We also showed that, even assuming considerably less complete ascertainment of diabetes among control subjects than among case patients with PLA, adjusted risk estimates for diabetes remained 2–3 times higher.

Similarly, we find it unlikely that unmeasured or unknown confounders could explain risk estimates of the magnitude observed. We were able to adjust for a wide range of important PLA risk factors that only modestly decreased the relative risk for diabetes. Misclassification of data on confounders might have led to some residual confounding. However, registration of previous diagnoses and procedures should be at least as complete for patients with diabetes as it is for other individuals, leading to conservative risk estimates.

Our findings corroborate those of a recent population-based epidemiologic study conducted in the Calgary Health Region of Canada. In that region, the relative risk for development of PLA among individuals with diabetes was estimated at 11.1 (95% CI, 6.3–19.0) [5]. However, the study relied on estimated diabetes prevalence in the background population and did not adjust for confounding risk factors that were found to play an important role in our study.

The average diabetes prevalence of 11% in our PLA cohort that spanned the years 1977–2002 was comparable to the 13%–17% prevalence of diabetes reported for cohorts of individuals with PLA in the United States and Europe during the 1990s [9–11]. The earlier studies included <100 patients with PLA in most cases, however, and had no control groups for comparison. These studies' estimates are markedly lower than the diabetes prevalence found in recent Taiwanese case series [12, 13, 23]. These series, which encompass several hundred patients with PLA, have reported a prevalence of diabetes of ∼75% among patients with PLA who are infected with Klebsiella pneumoniae, the dominant microbial agent causing PLA in this region [12, 13, 23].

Our study confirmed others' findings that truly “cryptogenic” PLA is rare: only one-quarter (24.5%) of patients with PLA in our study lacked recorded medical or surgical risk factors [17]. Our findings—that gastrointestinal and other malignancies, as well as alcoholism, were frequent underlying risk factors among cases of PLA—are consistent with the findings of the Canadian study [5]. Diabetes appears to increase PLA risk substantially, regardless of the presence or absence of other risk factors. Major mechanisms for PLA development are hematogenous seeding of the liver, either through the portal system or the greater circulation, or local spread from infections within the peritoneal cavity [6]. Diabetes is a documented risk factor for gram-negative bacteremia, including episodes derived from abdominal foci of infection [8]. Underlying biological mechanisms may include tissue hyperglycemia and predilection for certain microorganisms, including Escherichia coli and Klebsiella species [12, 24, 25]. Unfortunately, we lacked the systematic microbiological data needed to investigate this issue further. Hansen et al. [26] studied a subgroup of our cohort and found that enteric gram-negative rods accounted for 45% of PLA-related isolates, anaerobic bacteria accounted for 31%, and gram-positive cocci accounted for 19%. These findings are comparable with those of other Western studies of PLA [7, 17]. Of note, the prevalence of PLA due to Klebsiella species is reported to be currently increasing in the United States [11, 27]. The role of diabetes for this observed shift in PLA epidemiology remains to be elucidated.

Our in-hospital mortality figures were high, but they were comparable with findings from previous, predominantly university hospital—based studies [5, 9, 13, 17]. The decrease in mortality attributable to PLA between the early 1980s and recent years that was documented in our study is consistent with previous observations [3, 18].

We found that diabetes was associated with statistically nonsignificantly increased mortality. Pathophysiological mechanisms might include harmful effects of hyperglycemia [28], general diabetic angiopathy, and decreased immunity. Recently, Chen et al. [29] found that diabetes was associated with a 7.7-fold (95% CI, 2.1–29-fold) increased risk for developing metastatic infections from PLA. There is increasing evidence that diabetes is a factor associated with a poor prognosis among patients with gram-negative bacteremia [8] or conditions associated with abdominal sepsis, such as gastrointestinal perforation [19]. We speculate that latent diabetic organ disease may render patients with diabetes particularly vulnerable to multiorgan failure associated with gram-negative sepsis.

We conclude that diabetes is a strong, potentially modifiable risk factor for PLA. The prognosis for patients with PLA who have diabetes is as poor as the prognosis is for other patients who have PLA.

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Acknowledgments

Financial support. The Western Danish Research Forum for Health Sciences and Klinisk Epidemiologisk Forskningsfond.

Conflicts of interest. All authors: no conflicts.

  • Received October 17, 2006.
  • Accepted January 10, 2007.
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Appendix

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Diagnosis codes used in the study, in accordance with the Danish version of the International Classification of Diseases (ICD; 8th revision [ICD-8] used until the end of 1993, 10th [ICD-10] revision used thereafter).

Diabetes mellitus (ICD-8: 249 and 250; ICD-10: E10, E11, E14, and H36.0) and pyogenic liver abscess (ICD-8: 572.01 and 572.09; ICD-10: K75.0).

Medical risk factors. Benign biliary obstruction (ICD-8: 574; ICD-10: K80), liver cancer (including liver metastases; ICD-8: 155, 197.79, and 197.89; ICD-10: C22 and C78.7), biliary tract cancer (ICD-8: 156; ICD-10: C23 and C24), pancreatic cancer (ICD-8: 157; ICD-10: C25), other gastrointestinal cancers (ICD-8: 150–154, 158, 159, 195.09, 196.29, 197.49, 197.59, 197.69, and 197.99; ICD-10: C15–C21, C26, C76.2, C77.2, C78.4, C78.5, C78.6, and C78.8), other solid-organ cancers (ICD-8: 140–149, 160–194, 195.19–195.99, 196.09, 196.19, 196.39–196.99, 197.09–197.39, 198, and 199; ICD-10: C00–C14, C30–C75, C76.0, C76.1, C76.3–C76.8, C77.0, C77.1, C77.3–C77.9, C78.0–C78.3, C79, and C80), hematological cancers (ICD-8: 200–203, 204–207, and 275.59; ICD-10: C81–C85, C88, C90, C91–C95, and C96), liver cirrhosis (ICD-8: 571.09, 571.90–571.92, and 571.99; ICD-10: K70.3, K71.7, and K74.3–K74.6), inflammatory bowel disease (ICD-8: 563; ICD-10: K50 and K51), alcoholism-related disorders (ICD-8: 291, 303, 979, 980, 577.10, 571.09, and 571.10; ICD-10: F10, G31.2, G62.1, G72.1, I 42.6, K29.2, K86.0, K70, R78.0, T51, and Z72.1 [for adjustment in the prognosis analysis, the codes for alcoholic liver disease {K70, 571.09, and 571.10} were excluded, because they were already included in the Charlson index]), ongoing abdominal infection (acute cholecystitis or cholangitis without cholelithiasis, diverticulitis, appendicitis, or peritonitis; ICD-8: 575, 562.11–19, 540, and 567; ICD-10: K81.0, K83.0, K57.0, K57.2, K57.4, K57.8, K35, and K65), and ongoing systemic infection (sepsis or endocarditis; ICD-8: 038 and 421; ICD-10: A40, A41, and I33).

Surgical risk factors. Probably PLA-related procedures (including liver punctures, biopsies, and drainage; KJJA10A, KTJJ00, KJWC00, 91560, 91900, 47280, 47120, and 49000), other surgical procedures performed on the liver (KJJ [excluding KJJA10A], KTJJ [excluding KTJJ00], and 47000–47291 [excluding 47280 and 47120]), surgical procedures performed on the biliary tract (including the gall bladder; KJK, KTJK, 47320–48299, and 92301), surgical procedures performed on the pancreas (KJL, KJTL, 48320–48895, 91920, and 92305), surgical procedures performed on the spleen (KJL, KJTL, 48320–48895, 91920, and 92305), upper endoscopy (KUJD and 91010–91040), endoscopy of the biliary tract (including endoscopic retrograde cholangiopancreatography; KUJK and 91050–91059), any other gastrointestinal surgery (KJA-KJH, KTJA-KTJG, KTJW, 40020–46990, 92260, 92280, 92300, and 92320–92370), and any other surgical procedure (all other procedure codes).

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  1. Clin Infect Dis. (2007) 44 (9): 1194-1201. doi: 10.1086/513201
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