Serum immunoglobulin A levels and non-alcoholic fatty liver disease
Abstract
Background: Intestinal immunity, and immunoglobulin A (IgA) in particular, may play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to document the prevalence of elevated serum IgA levels in NAFLD patients and determine whether the severity and course of NAFLD differs in those with elevated (E-IgA) versus normal (N-IgA) levels. Methods: A retrospective review of a clinical database containing demographic, laboratory, and histologic findings of adult NAFLD patients was undertaken. Liver biochemistry, model for end stage-liver disease (MELD) and Fib-4 scores served to document disease severity and progression. Results: Of 941 NAFLD study subjects, 254 (27%) had E-IgA at presentation. E-IgA patients were older, and had lower serum albumin levels and higher MELD scores than N-IgA patients. The percent of E-IgA patients with Fib-4 scores >3.25 (suggestive of cirrhosis) was also higher (25% vs. 5.5%, p<0.001). E-IgA patients had higher METIVIR fibrosis scores (2.2 ± 1.4 vs. 1.0 ± 1.2, p<0.0001) than N-IgA patients. After mean follow-ups of 47 (E-IgA) and 41 (N-IgA) months, serum albumin levels remained lower, INR values were now more prolonged and MELD scores higher in E-IgA patients. Of the non-cirrhotic patients at baseline, a larger percent of E-IgA patients developed cirrhosis by Fib-4 testing at last visit (11% vs. 2.9%, p<0.001). Conclusions: Elevated serum IgA levels are common in NAFLD patients and when present, are associated with more advanced disease. Patients with elevated serum IgA levels are also more likely to progress to cirrhosis than those with normal levels.
Introduction
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in North America, with reported prevalence rates of 10%–50% in the general population (1–3). However, only 10%–30% of NAFLD patients progress to advanced fibrosis, cirrhosis, and/or hepatocellular carcinoma (4). Why some individuals progress while others do not, and what markers are predictive of progression, remain to be determined.
Recently, alterations in the gut microbiota and/or intestinal mucosal integrity have been implicated in the pathogenesis of progressive NAFLD (5). This enteric/hepatic immune hypothesis poses that excess bacterial endotoxins and/or loss of intestinal barrier function results in activation of enteric and hepatic immune systems, increased pro-inflammatory cytokine expression and ensuing hepatocyte injury.
There are a number of reasons to implicate immunoglobulin A (IgA) in the pathogenesis of NAFLD. These include: 1) serum IgA levels have previously been reported to be elevated in NAFLD patients (6); 2) the extent of IgA elevation distinguishes simple steatosis from non-alcoholic steatohepatitis (NASH) (7); 3) serum IgA levels correlate with NASH stages (8); 4) the histologic findings of NASH are similar to those of alcoholic hepatitis, a condition in which serum IgA levels are high and IgA deposition along hepatic sinusoids is common (9–11); and 5) IgA polymers activate compliment which could serve as a mechanism of hepatocyte injury (12). Alternatively, IgA responses to bacterial endotoxins may be of potential benefit in NAFLD, as gut-derived IgA possess anti-endotoxin properties, which conceivably could attenuate the severity of NAFLD (13).
In this study, we documented the prevalence of elevated serum IgA levels in a large number of adult NAFLD patients, determined whether associations exist between serum IgA levels and non-invasive markers of NAFLD severity, documented the value of baseline serum IgA levels in predicting disease progression and examined IgA synthesis in vitro in NAFLD patients with elevated and normal serum IgA levels compared to healthy controls.
Methods
A retrospective, single-centre study design was employed. The study population consisted of patients identified from a search of the Section of Hepatology’s outpatient Philip and Ellie Kives clinical database. The database includes demographic, laboratory, imaging, and—where available—histologic findings of adult patients referred for evaluation and/or management of acute or chronic hepatobiliary disorders.
Diagnoses were entered into the database on the basis of assessments by consultant hepatologists. In the case of NAFLD, the diagnosis was based on clinical findings (the presence of risk factors such as obesity, diabetes, dyslipidemia, and/or hypertension), radiologic and/or histologic evidence of fatty liver disease, and absence of secondary causes of hepatic steatosis. In line with current guidelines, liver biopsies were only performed when the diagnosis was uncertain or when additional information on disease severity or stage was required.
Using the diagnostic search terms fatty liver, NAFLD, and NASH, the database was searched for patients with a diagnosis of NAFLD in whom serum immunoglobulin levels had been measured on at least one occasion within 6 months of initial evaluation. NAFLD patients with co-existing liver disease were excluded, as were those with durations of follow-up of less than 90 days, or those missing data that precluded calculating disease severity indices. The remaining patients were classified by the initial serum IgA level into elevated (E-IgA) and normal (N-IgA) cohorts, using the hospital’s laboratory reference ranges for serum IgA of 0.7–3.8 g/L.
Non-invasive markers of disease severity included standard liver function tests (total bilirubin, INR, and albumin levels), model for end stage-liver disease (MELD), and Fib-4 scores. These indices were calculated as described previously (14).
Disease progression was determined by calculating differences in the first and last available data for liver disease severity.
All laboratory testing was performed by the Centre’s accredited diagnostics laboratories using standard, laboratory techniques.
For in vitro IgA synthesis studies, 32 sequential NAFLD patients attending the liver diseases outpatient clinic and 8 healthy volunteers with no evidence of liver disease consented to provide 30 ml of blood for peripheral blood mononuclear cell (PBMC) isolation and exposure to various concentrations of lipopolysaccharide (LPS) endotoxin. Briefly, PBMCs were isolated using a density gradient solution, Ficoll (Sigma-Aldrich, St. Louis, Missouri), as described previously (15). Cell viability was determined by trypan blue exclusion. Fresh PBMCs were cultured to 2.5 × 105 cells/well in 96-well round bottom plates (Corning Inc., Corning, New York) with complete medium containing 10% heat inactivated fetal bovine serum (HyClone Laboratories Inc., Logan, Utah) 0.1% 2-Mercaptoethanol (Sigma), and 1% Antibiotic-Antimicotic Pencillin Streptomycin Fungizone (Invitrogen, Grand Island, NY) in RPMI-1640 (Invitrogen Life Technologies, Grand Island, New York). LPS (Sigma) was added at final concentrations of 0.2 ng/ml, 2ng/ml and 20 ng/ml LPS. Supernatants were harvested at 24 hours and stored at −80°C until analyzed by a human IgA ELISA kit (Invitrogen) according to the manufacturer’s instructions. Supernatants were pre-diluted to 1:2. The assay detection limit is 1.6 ng/ml.
Student’s t-test, Chi-square test, and Pearson correlation coefficient were used to assess for statistical significance. Unless otherwise stated, results provided represent mean ± SD values. Cox proportional hazard models were developed for risk factors associated with the development of cirrhosis as indicated by the Fib-4 score >3.25 at the end of the follow-up period in those who had Fib-4 scores <3.25 at baseline. Stepwise backward selection of variables was used to fit the final model. Any p values less than 0.05 were considered significant.
The study was approved by the University’s Conjoint Ethics Committee.
Results
Study population
The initial database search identified 1,676 NAFLD patients with serum immunoglobulin levels documented within 6 months of presentation: 527 were excluded due to durations of follow-up <90 days; 208 due to the presence of co-existing liver disease, and 12 due to insufficient data to calculate disease severity indices (Figure 1).
Figure 1: Initial search results, excluded patients, and final NAFLD study cohort
The sum of individual diagnoses does not add up to the total number of excluded patients as some patients had more than one co-existing liver disease.
NAFLD = non-alcoholic fatty liver disease
Demographic and laboratory findings
Baseline demographic and laboratory findings of the 929 subjects who constituted the study population, are provided in Table 1. Two hundred and fifty-four patients (27%) had an initial serum IgA level >3.8 g/L, and 687 (73%) had values ≤3.8 g/L.
| Normal range | All patients | E-IgA | N-IgA | p | |
|---|---|---|---|---|---|
| Total | 941 | 254 (27%) | 687 (73%) | ||
| Male | 459 (48.8%) | 120 (47.2%) | 339 (49.3%) | 0.57 | |
| Age at Dx | 50.4 ± 13 | 52.9 ± 12 | 49.5 ± 13 | 0.0003 | |
| Hemoglobin | 140–180 g/L | 140 ± 24 | 139 ± 21 | 141 ± 25 | 0.23 |
| WBC | 4.5–11.0 × 109/L | 7.1 ± 2.2 | 7.3 ± 2.5 | 7.0 ± 2.1 | 0.03 |
| Platelets | 140–440 × 109/L | 235 ± 80 | 215 ± 91 | 242 ± 74 | 0.00001 |
| IgA | 0.7–3.8 g/L | 3.1 ± 1.8 | 5.4 ± 1.6 | 2.2 ± 0.8 | 0.000001 |
| IgG | 6.9–16.2 g/L | 12.0 ± 4.2 | 15 ± 5 | 11 ± 3 | 0.000001 |
| IgM | 0.6–2.6 g/L | 1.3 ± 0.8 | 1.4 ± 0.9 | 1.2 ± 0.8 | 0.0007 |
| ALT | <30 U/L | 83 ± 71 | 85 ± 87 | 83 ± 63 | 0.63 |
| AST | 10–32 U/L | 57 ± 60 | 71 ± 93 | 52 ± 41 | 0.00001 |
| ALP | 30–120 U/L | 111 ± 76 | 124 ± 60 | 107 ± 80 | 0.002 |
| GGT | 5–38 U/L | 155 ± 232 | 212 ± 318 | 135 ± 187 | 0.00001 |
| Albumin | 33–45 g/L | 41 ± 13 | 38 ± 6 | 42 ± 15 | 0.0002 |
| Bilirubin | 5–21 mmol/L | 14 ± 49 | 18 ± 44 | 13 ± 52 | 0.131 |
| INR | 0.9–1.1 | 1.1 ± 0.8 | 1.1 ± 0.4 | 1.1 ± 0.9 | 0.30 |
| MELD* | 6.4 (6.4, 7.6) | 7.5 (6.4, 8.5) | 6.4 (6.3, 7.5) | 0.000001 | |
| FIB-4* | 1.2 (0.7, 1.9) | 1.7 (0.9, 3.2) | 1.09 (0.7, 1.6) | 0.000001 | |
| FIB-4<1.45 | 587/941 (62%) | 106/254 (42%) | 481/687 (70%) | 0.000001 | |
| FIB-4 >3.25 | 101/941 (11%) | 63/254 (25%) | 38/687 (5.5%) | 0.000001 |
NAFLD = non-alcoholic fatty liver disease; ALT = alanine aminotransferase AST = aspartate aminotransferase;
ALP = alkaline phosphatase; GGT = gamma-glutamyltransferase; MELD = model for end stage-liver disease
ALP = alkaline phosphatase; GGT = gamma-glutamyltransferase; MELD = model for end stage-liver disease
* median (IQR)
Four hundred and fifty-nine (49%) patients were male with no significant difference between E-IgA and N-IgA patients (47% vs. 49% respectively). The E-IgA cohort was 3 years older than the N-IgA cohort (53 ± 12 vs 50 ± 13 years, p = 0.0003).
Although hemoglobin levels were similar, E-IgA patients had lower WBC and platelet counts than N-IgA patients.
As per patient selection criteria, E-IgA patients had higher serum IgA levels than N-IgA patients (5.4 ± 1.6 vs 2.2 ± 0.8, p<0.00001). They also had higher IgG and IgM levels (Table 1). In terms of percentages, 98 patients (10.4%) had elevated serum IgG and 89 (9.5%) IgM levels.
Baseline serum ALT levels did not differ between the two cohorts, but AST (71 ± 93 vs. 52 ± 41, p = 0.00001), ALP (124 ± 60 vs. 107 ± 80, p<0.002), and GGT (212 ± 318 vs. 135 ± 187, p = 0.00001) levels were significantly higher in E-IgA patients.
Liver disease severity
Serum albumin levels were significantly lower in E-IgA patients (38 ± 6 g/L vs. 42 ± 15 g/L, p<0.0002) but bilirubin and INR values were similar. Median MELD scores were higher in E-IgA patients (7.5 IQR 6.4, 8.5) and the percent of E-IgA patients with Fib-4 scores suggestive of cirrhosis (>3.25) was higher than that of N-IgA patients (25% vs. 5.5%, p = 0.000001). E-IgA patients were also less likely to have Fib-4 scores in keeping with no or minimal fibrosis (Fib-4 <1.45) than N-IgA patients (42% vs. 70%, p = 0.000001).
Liver histology reports were available for 148 (16%) of patients (40 E-IgA and 108 N-IgA). Demographic and laboratory findings of biopsied patients did not significantly differ from the remainder of the study group as a whole or in comparisons between E-IgA and N-IgA patients. Forty-nine (19%) patients had steatosis only, and 199 (81%) NASH. When reviewed for histologic grade and stage of disease (by METIVIR criteria), E-IgA and N-IgA patients had similar mean grades (3.4 ± 1.8 vs. 3.2 ± 2.0, p = 0.75) but E-IgA patients had more advanced stages of fibrosis (2.2 ± 1.4 vs. 1.0 ± 1.2, p = 0.0000001).
Disease severity at follow-up
The mean duration of follow-up in the overall study population was 42 ± 37 months; 47 ± 39 (range 3.4 to 228) in E-IgA and 41 ± 36 (range 3.4 to 179) in N-IgA patients (p = 0.55).
As shown in Table 2, at the last follow-up visit, serum albumin levels were significantly lower (37 ± 6 vs. 41 ± 6, p = 0.00001), INR values more prolonged (1.1 ± 0.3 vs. 1.0 ± 0.3, p = 0.0012) and median MELD scores higher (7.5, IQR 6.4, 8.9 vs. 6.4, IQR 6.0, 7.5, p = 0.00001) in E-IgA patients. In addition, a larger percent of E-IgA patients had Fib-4 scores suggestive of cirrhosis (26% vs. 6.4%, p = 0.000001) and in those without Fib-4 scores suggestive of cirrhosis (Fib-04 <3.25) at baseline, more E-IgA patient developed Fib-4 scores >3.25 than N-IgA patients (11% vs. 2.9%, p = 0.000001).
| Normal range | All patients N = 941 | E-IgA N = 254 | N-IgA N = 687 | p | |
|---|---|---|---|---|---|
| Albumin | 33–45 g/L | 40 ± 6.5 | 37 ± 6 | 41 ± 6 | 0.000001 |
| Bilirubin | 5–21 mmol/L | 11 ± 21 | 14 ± 15 | 11 ± 23 | 0.037 |
| INR | 0.9–1.1 | 1.1 ± 0.3 | 1.1 ± 0.3 | 1.0 ± 0.3 | 0.0012 |
| MELD* | 7.4 ± 3.2 | 8.5 ± 4.3 | 7.1 ± 2.6 | 0.000001 | |
| FIB-4* | 1.9 ± 3.0 | 2.9 ± 4.1 | 1.6 ± 2.3 | 0.000001 | |
| FIB-4 <1.45 | 574/941 (61%) | 104/254 (41%) | 47/687 (68%) | 0.000001 | |
| FIB-4 >3.25 | 110/941 (12%) | 66/254 (26%) | 44/687 (6.4%) | 0.000001 | |
| FIB-4 >3.25 | 40/840 (4.8%) | 21/191 (11%) | 19/649 (2.9%) | 0.000001 | |
| from FIB-4 <3.25 at baseline |
MELD = model for end stage-liver disease
*median (IQR)
Because serum immunoglobulin levels can increase as a result of non-specific, polyclonal gammopathy associated with cirrhosis and/or portal-systemic shunting, the above analyses were repeated in subjects with normal IgG and IgM values (16). The results obtained in this subpopulation were in keeping with those obtained for the entire study population (data not shown).
Following univariate analysis, baseline AST, ALP, GGT, albumin, bilirubin, IgA, Hgb, WBC, platelets, histologic stage, Fib-4 and MELD scores predicted the development of cirrhosis (Fib-4 >3.25), however only age at diagnosis, baseline IgA, ALP and platelet levels remained predictive following multivariate analyses (p<0.005) (Table 3).
| Risk factor | Risk ratio | 95% CI | p |
|---|---|---|---|
| Baseline IgA | 1.135 | 1.051–1.225 | 0.0013 |
| Age at diagnosis | 1.078 | 1.056–1.1000 | 0.00001 |
| Baseline Alk. Phos. | 1.004 | 1.002–1.005 | 0.00001 |
| Baseline platelets | 0.986 | 0.984–0.989 | 0.00001 |
One hundred and eighty-six (20%) patients had serum IgA levels measured on more than one occasion, with a median time interval between measurements of 71 ± 45 months. In these individuals, serum IgA levels remained elevated in 79% patients. Amongst N-IgA patients at baseline, 13% developed E-IgA during follow-up.
IgA synthesis in vitro
To determine whether NAFLD patients with elevated serum IgA levels have increased responsiveness to gut-derived endotoxins, IgA synthesis by PBMCs following exposure to various concentrations of LPS (0.2–20 ng/ml) was documented. As shown in Figure 2, IgA synthesis was similar in E-IgA and N-IgA patients.
Figure 2: In vitro synthesis of IgA immunoglobulin in response to exposure to varying concentrations of LPS by peripheral blood monocytes derived from healthy controls (N = 8) and NAFLD patients (N = 20) with normal or elevated serum IgA levels.
LPS = lipopolysaccharide; NAFLD = non-alcoholic fatty liver disease
Discussion
We evaluated serum IgA levels as an indicator of the severity of liver disease and predictor of disease progression in a large cohort of NAFLD patients. The findings revealed that serum IgA levels were elevated in 27% of NAFLD patients and these patients were more likely to have biochemical and non-invasive test results suggestive of advanced disease. In addition, progression of NAFLD to suspected cirrhosis was more common in those with elevated compared to normal serum IgA levels at baseline.
There are a paucity of reports describing serum IgA levels in NAFLD patients and in only one, a study by McPherson et al., is the actual prevalence of elevated serum IgA levels provided (6). In that study of 285 patients with biopsy-confirmed NAFLD, 46% had elevated levels, more than the 27% documented in our 941 patients. The reason(s) for this discrepancy is unclear. Given that similar percentages of the McPherson study population had elevated serum IgG and IgM levels (10% and 8%, respectively) it is unlikely the higher percent of elevated IgA level subjects in their study reflects more patients with cirrhosis-associated polyclonal hypergammaglobulinemia. Thus, additional studies from other centres are required to document the prevalence of elevated serum IgA levels in NAFLD patients.
Due to the large number of NAFLD patients and invasive nature of liver biopsies, investigators are increasingly utilizing non-invasive means of documenting disease severity in NAFLD. In addition to the traditional “liver function tests” of serum albumin, bilirubin, and INR levels, calculation of MELD and Fib-4 scores have been employed for this purpose. MELD scores incorporate serum bilirubin, INR and creatinine values. They were initially developed for predicting prognosis in patients undergoing portal-systemic shunting, but have since been validated as reflecting severity of liver disease in a number of cirrhotic and non-cirrhotic liver conditions including NAFLD (17). Similarly, Fib-4 scoring systems which incorporate patient age, AST, ALT, and platelet counts were initially developed as noninvasive predictors of fibrosis in chronic viral hepatitis but have since been validated in NAFLD populations (18). Thus, by employing standard liver function tests, MELD and Fib-4 scores and obtaining similar results with each measure, it is likely the elevated serum IgA levels observed reflect more advanced disease and predict disease progression.
That serum IgA levels correlated with disease severity is in keeping with the results obtained by Tomita et al., wherein serum IgA levels were lower in 108 NASH patients with histologic evidence of early stage disease (stages 0–2) compared to 19 with more advanced disease (stage 3) (8). Similarly, Maleki et al. reported that serum IgA levels in 28 NASH patients were higher than in 22 non-NASH, presumably simple steatosis, NAFLD subjects (7). Unfortunately, neither study followed their patients to determine whether serum IgA levels predicted the subsequent course of the disease.
Because serum IgA levels can increase as a result of the non-specific hypergammaglobulinemia associated with portal-systemic shunting, it was important to rule out that explanation for the association between elevated serum IgA levels and disease severity (16). The prevalence of elevated IgA being approximately twice that of serum IgG and IgM levels argues against such a possibility. Moreover, the findings remained unchanged when patients with normal serum IgG and IgM levels were considered separately.
Increased intestinal permeability to gut-derived endotoxins is thought to stimulate host immunity and thereby contribute to the pathogenesis of NAFLD. To determine whether NAFLD patients with more severe and progressive disease exhibit an enhanced response to these endotoxins, we documented IgA release in PBMCs derived from E-IgA and N-IgA patients and found no significant difference. Whether enteric plasma cells or other endotoxins would result in the same findings remains to be determined.
The present study has several limitations. Principal amongst these is the limited number of biopsies available for analysis and the bias inherent in selecting patients for biopsy. In addition, as in the majority of such studies, exclusion of patients with alternative explanations for elevated serum IgA levels such as alcohol abusers was based solely on self-reported accounts of alcohol intake. Due to the relatively recent development of transient elastography (TE), TE data were not available, however, Fib-4 scores have shown correlations with TE findings in NAFLD populations (19). Finally, as with all retrospective, single-centre studies, not all data points were available and the potential for unidentified confounding factors to influence the results could not be eliminated.
In conclusion, serum IgA levels were elevated in approximately 25% of adult NAFLD outpatients. Patients with elevated serum IgA levels were more likely to have biochemical evidence and non-invasive indices of advanced disease and more often progressed to cirrhosis than those with normal serum IgA levels. While these observational findings are in keeping with IgA contributing to the pathogenesis of NAFLD, further research is required to document the mechanism(s) involved.
Acknowledgements:
The authors wish to thank RV for her prompt and accurate typing of the manuscript.
Funding:
No funding was received for this work
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Information & Authors
Information
Published In
Canadian Liver Journal
Volume 1 • Number 4 • Fall 2018
Pages: 248 - 255
Copyright
Copyright © 2018.
History
Published online: 1 December 2018
Published in print: Fall 2018
Published ahead of print: 6 December 2018
Keywords:
Authors
Contributions:
Conceptualization, GYM; Methodology, GYM, JU; Investigation, EDE, QL, MZ; Writing – Original Draft, GYM; Writing – Review & Editing, GYM, EDE; Funding Acquisition, GYM; Supervision, GYM.
Disclosures:
The authors have nothing relevant to disclose.
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