Nonalcoholic Fatty Liver Disease Is an Independent Risk Factor for Nephrolithiasis in Women: Findings from NHANES III

Abstract

Objective:

To determine if radiologically diagnosed nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for nephrolithiasis using data from National Health and Nutrition Examination Survey III (NHANES III).

Patients and Methods:

NHANES III participants aged 20–74 years who underwent hepatobiliary ultrasound were classified as with NAFLD (moderate or severe hepatic steatosis in absence of other known causes of liver disease; n = 2498) or without NAFLD (controls; n = 9361). Risk of nephrolithiasis caused by NAFLD was estimated using logistic regression with propensity score adjustment. Secondary outcomes included medical stone management, lithotripsy, and surgical stone removal.

Results:

Participants with NAFLD were older (48.7 ± 0.4 vs 43.3 ± 0.3 years, p < 0.001) and exhibited greater prevalence of all components of metabolic syndrome: obesity (48% vs 21%), impaired glucose tolerance (17% vs 11%), diabetes mellitus (15% vs 6%), hypertension (36% vs 24%), and gout (4% vs 2%) (all p < 0.001). After adjusting for demographic, lifestyle, and metabolic factors, NAFLD was associated with increased risk nephrolithiasis (odds ratio [OR] = 1.29, 95% confidence interval [CI] [1.02–1.61], p = 0.03). The association persisted in women (OR = 1.65, 95% CI [1.17–2.32], p = 0.004) but not in men (OR = 1.04, 95% CI [0.77–1.40], p = 0.80). NAFLD was not associated with increased occurrence of medical management (OR = 1.31, 95% CI [0.84–2.05], p = 0.24), lithotripsy (OR = 1.61, 95% CI [0.83–3.33], p = 0.20), or surgical stone removal (OR = 0.83, 95% CI [0.48–1.44], p = 0.52).

Conclusions:

In a large U.S. population-based cross-sectional analysis, NAFLD was found to be associated with increased risk of nephrolithiasis in women after adjusting for demographic, clinical, and metabolic factors.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide, with prevalence ranging from 17% to 33% in the general population and approaching 75% among the obese.^1,2 Although the multifactorial pathogenesis of NAFLD remains poorly understood, intrahepatic triglyceride accumulation is considered the hallmark feature of the disease.³ Independent risk factors for NAFLD include truncal obesity, insulin resistance, hypertension, and metabolic syndrome.^4

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Prevalence of nephrolithiasis has risen from 5% of U.S. adults in 1980 to almost 9% in 2012.⁸ Epidemiologic studies have demonstrated associations between nephrolithiasis and the components of metabolic syndrome, including obesity, diabetes mellitus, hypertension, and dyslipidemia.^9
–11 Metabolic syndrome is known to alter the processes of urine concentration and dilution, leading to higher levels of lithogenic metabolites and waste materials in the urine and a concomitantly increased risk of uric acid and calcium oxalate stone formation.¹²

Several studies have shown the incidence of nephrolithiasis to be significantly elevated in patients with NAFLD. Large systematic reviews and meta-analyses of observational studies have found NAFLD to be associated with a 1.73- to 1.81-fold increased risk of urolithiasis.^13,14 Another study demonstrated a modest correlation between NAFLD severity and risk of urolithiasis, whereas a cross-sectional analysis found that NAFLD patients with urolithiasis exhibited higher indices of liver fibrosis.^15,16 Despite the growing body of evidence linking these conditions, the importance of this relationship may be underappreciated in the field of urology, and literature identifying NAFLD as an independent risk factor for nephrolithiasis remains limited. The aim of this study was to determine if radiologically diagnosed NAFLD is an independent risk factor for nephrolithiasis among U.S. adults who participated in the Hepatic Steatosis Ultrasound Examination (HSUE) component of the Third National Health and Nutrition Examination Survey (NHANES III).

Patients and Methods

Study population

NHANES III was conducted in two phases (Phase 1 from 1988 to 1991; Phase 2 from 1991 to 1994) by the U.S. National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC) through household interviews, physical examinations, and laboratory tests. The data set, compiled from a nationwide probability sample, contains information that describes the health and nutritional status of the U.S. population. Over the course of the 6-year study, 33,994 people were interviewed, of whom 30,818 (78%) were physically examined. Participants aged 20 to 74 years at the time of examination were eligible to undergo hepatobiliary ultrasound imaging.¹⁷

Between 2009 and 2010, the NCHS retrieved the archived images to evaluate them for the presence of hepatic steatosis. Under the supervision of an expert radiologist, trained readers, all of whom were blinded to participant clinical and laboratory data, reviewed images for liver-to-kidney contrast, parenchymal brightness, deep beam attenuation, vessel wall brightness, and gallbladder wall definition. Using a standardized rubric, hepatic steatosis was graded as normal to mild or moderate to severe. Internal quality control measures were implemented to maintain inter- and intrareader reliability. A total of 13,856 sonographic images were deemed gradable.¹⁸

Participants for whom gradable hepatic ultrasound imaging and relevant demographic, clinical, and examination data could be obtained were eligible for inclusion in our study. Exclusion criteria included excessive alcohol consumption (>21 drinks per week in men; >14 drinks per week in women); iron overload (serum transferrin saturation ≥50%); and positive result for hepatitis B surface antigen or antihepatitis C virus antibody by enzyme-linked immunosorbent assay.

Survey questions

For each participant, the following data were abstracted from section K (“kidney conditions”) of the NHANES III Household Family Questionnaire: (1) whether the participant reported ever having had kidney stones; (2) how many times the participant reported having passed a kidney stone; and (3) whether the participant reported having been treated for stones with medication, lithotripsy, or surgery.

Measurement

For the purposes of this analysis, participants were deemed to have NAFLD if moderate to severe hepatic steatosis was detected in the absence of any other known cause of chronic liver disease. Individuals diagnosed with NAFLD were subdivided into those with normal liver enzyme levels and those with elevated liver enzymes (alanine aminotransferase ≥29 U/L in men or ≥22 U/L in women; aspartate aminotransferase ≥30 U/L in men or women). The control cohort consisted of subjects exhibiting neither hepatic steatosis on ultrasound nor any other known cause of chronic liver disease.

Participants were grouped by race, age, and body mass index (BMI); obesity was defined as BMI ≥30.0 kg/m². Lifestyle factors (household income, exercise frequency, and smoking status); laboratory markers of metabolic status; and diagnoses of metabolic comorbidities (diabetes mellitus, hypertension, and gout) were recorded. Impaired glucose tolerance was inferred from 2-hour plasma glucose level between 7.8 and 11.0 mmol/L on the 75-g oral glucose tolerance test.

Statistical analyses

To measure the association between NAFLD and nephrolithiasis occurrence, a propensity score was derived from age, sex, race, BMI, smoking status, liver enzyme level, and diagnoses of metabolic comorbidities. Multivariable logistic regression analysis of NAFLD (with and without elevated liver enzymes) as a predictor of nephrolithiasis occurrence adjusted for the propensity score was performed. Secondary outcomes were occurrence of medical management, lithotripsy, and surgical stone removal. Means were compared by independent samples t-test. Statistical analysis was performed using SAS version 9.4 (SAS Institute, Cary, NC). A p-value <0.05 was considered significant.

Results

Out of the initial study population (30,818 adult participants from NHANES III), 13,856 underwent hepatobiliary imaging, of whom 2498 (18%) fulfilled our clinical and radiologic criteria for diagnosis of NAFLD and 9361 (68%) were identified as controls free of known liver disease. Baseline characteristics of the cohort are outlined in Table 1.

Table 1.

Baseline Characteristics of Participants in the Hepatic Steatosis Ultrasound Examination Component of the Third National Health and Nutrition Examination Survey by Sex and Presence of Nonalcoholic Fatty Liver Disease

	Male		P	Female		p
	Non-NAFLD	NAFLD	P	Non-NAFLD	NAFLD	p
n	4235	1215		5126	1283
Demographics
Age (years)	43.4 ± 0.3	48.5 ± 0.4	<0.001	42.3 ± 0.2	48.0 ± 0.4	<0.001
Race (%)^a
White	65.8	75.2	<0.001	64.1	71.4	<0.001
Black	30.6	20.0		32.8	24.5
Other	3.7	4.8		3.1	4.2
Household income <$20,000 (%)	41.9	44.1	<0.001	45.3	55.5	<0.001
Lifestyle factors
Tobacco use (%)
Never smoker	38.8	34.9	<0.001	60.7	62.8	<0.001
Former smoker	29.0	39.7		16.0	19.8
Current smoker	32.3	25.4		23.3	17.5
Exercise frequency (per month)	27.2 ± 0.5	21.3 ± 0.7	<0.001	18.2 ± 0.3	13.6 ± 0.5	<0.001
Comorbidities
Obesity (%)	15.4	41.6	<0.001	26.0	53.3	<0.001
Diabetes mellitus (%)	4.7	11.5	<0.001	6.1	18.4	<0.001
Hypertension (%)	20.5	31.5	<0.001	23.6	37.9	<0.001
Gout (%)	3.0	5.2	<0.001	0.9	2.4	<0.001

Totals may not sum to 100% because of rounding.

Individuals of Hispanic ethnicity were included in their respective racial groups.

NAFLD = nonalcoholic fatty liver disease.

Male sex was associated with an elevated risk of NAFLD (unadjusted odds ratio [OR] = 1.15, 95% confidence interval [CI] [1.05–1.25], p = 0.002). Participants with NAFLD were less likely to be current smokers but more likely to report having smoked at least 100 cigarettes in their lives, and they reported exercising less frequently than individuals without NAFLD.

In general, prevalence of the components of metabolic syndrome was greater in individuals with NAFLD than those without. Men with NAFLD exhibited significantly higher rates of obesity (42% vs 15%, p < 0.001), diabetes (12% vs 5%, p < 0.001), hypertension (32% vs 21%, p < 0.001), and gout (5% vs 3%, p < 0.001). Women with NAFLD exhibited significantly higher rates of obesity (53% vs 26%, p < 0.001), diabetes (18% vs 6%, p < 0.001), hypertension (38% vs 24%, p < 0.001), and gout (2% vs 1%). Men with NAFLD had higher mean levels of total cholesterol (217.4 ± 1.2 vs 206.6 ± 0.7 mg/dL), low-density lipoprotein (134.8 ± 1.7 vs 130.6 ± 0.9 mg/dL, p < 0.025), and triglycerides (214.9 ± 6.2 vs 135.3 ± 0.9 mg/dL, p < 0.001), along with lower levels of high-density lipoprotein (HDL) (42.4 ± 0.4 vs 47.4 ± 0.2 mg/dL). Women with NAFLD had higher levels of total cholesterol (217.5 ± 1.3 vs 207.8 ± 0.6 mg/dL) and triglycerides (180.1 ± 4.8 vs 117.8 ± 1.5 mg/dL) and lower levels of HDL (49.5 ± 0.4 vs 55.5 ± 0.2 mg/dL).

After adjusting for propensity score, NAFLD was found to be associated with an overall increased risk of developing nephrolithiasis (adjusted OR = 1.29; 95% CI [1.02–1.61], p = 0.03). The association remained significant in women (adjusted OR = 1.65, 95% CI [1.17–2.32], p = 0.004) but not in men (adjusted OR = 1.04, 95% CI [0.77–1.40], p = 0.80) (Table 2). There was no increased risk of nephrolithiasis in NAFLD patients with elevated liver enzymes vs those with normal liver enzymes (adjusted OR = 0.81, 95% CI [0.57–1.14], p = 0.22).

Table 2.

Logistic Regression Analysis for Risk of Nephrolithiasis Occurrence Caused by Nonalcoholic Fatty Liver Disease with Propensity Score Adjustment

	Adjusted OR	95% CI	p
Nephrolithiasis occurrence	1.29	1.01–1.62	0.03
Stones requiring medical management	1.31	0.84–2.05	0.24
Stones requiring lithotripsy	1.61	0.83–3.33	0.20
Stones requiring surgical removal	0.83	0.48–1.44	0.52

CI = confidence interval; OR = odds ratio.

Discussion

NAFLD is defined as fatty infiltration of the liver >5% by weight in the absence of hepatocyte injury and other contributing liver disease entities, such as alcohol-related liver disease, hepatic steatosis attributable to medication effects, chronic viral hepatitis, or other chronic liver disease.¹⁹ NAFLD spans an array of disease states from simple steatosis, defined as the presence of lipid droplets within liver parenchyma, to progressive nonalcoholic steatohepatitis with associated fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. NAFLD has come to be recognized as a systemic disease with a multifactorial pathogenesis and protean clinical manifestations. No longer thought of as merely a hepatic manifestation of metabolic syndrome, NAFLD is now regarded as a precursor condition signaling the onset not only of metabolic syndrome, but also potentially of cardiovascular and renal complications.²⁰ Our cross-sectional study of nearly 12,000 NHANES III participants found kidney stones to be one of these potential renal complications. Specifically, after adjusting for potential confounding factors, we found an association between the presence of NAFLD and an overall increased risk of nephrolithiasis in adult U.S. women.

This analysis builds on earlier studies that have shown an association between NAFLD and urolithiasis. Einollahi et al. retrospectively reviewed HSUE reports in the NHANES III database and found both a higher occurrence of fatty liver among patients with a history of stone disease and an elevated risk of stone detection among patients with NAFLD compared with those with healthy livers (OR = 2.4; 95% CI [2.1–2.7]).²¹ Nam et al. evaluated all patients who had undergone CT of the abdomen and pelvis at their center within a 1-month period and demonstrated an association between fatty liver and renal stone disease (OR = 5, 95% CI [3–8], p < 0.05).²² Both analyses were limited by their failure to adjust for confounders or to investigate the interplay between gender and nephrolithiasis in NAFLD.

The liver is a site of important metabolic functions that are disordered in stone disease, among them oxalate metabolism. Serum uric acid levels are elevated in patients with NAFLD, whereas both NAFLD and nephrolithiasis are independently linked to metabolic syndrome and its individual components. The relationships among these disease entities remain difficult to unravel. Just as hepatic steatosis is strongly associated with low urine pH (and vice versa), so also do insulin resistance and obesity—conditions commonly comorbid with NAFLD—impair ammoniagenesis in the renal tubule and predispose patients to uric acid stones.^23

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Indeed, a systematic review and meta-analysis by Wijarnpreecha et al. showed a nearly twofold increase in nephrolithiasis risk before adjusting for potential confounders (pooled OR = 1.81, 95% CI [1.29–2.56]), an association that remained significant after performing a sensitivity analysis to include only studies that adjusted for comorbidities (pooled OR = 1.21, 95% CI [1.00–1.45], I ² = 92%).¹⁴ Similarly, we found that the risk elevation was attenuated but still statistically significant after adjusting for the presence of obesity, diabetes mellitus, and other components of metabolic syndrome.

A 12-year cohort study of 208,578 Korean adults by Kim et al. found that after adjusting for confounding factors, NAFLD was significantly associated with the development of nephrolithiasis in men (adjusted hazard ratio, HR = 1.17, 95% CI [1.06–1.30]) but not in women (adjusted HR = 0.97, 95% CI [0.81–1.16]).²⁸ Interestingly, however, in our NHANES III cohort of predominantly white and black U.S. adults, NAFLD was associated with an elevated risk of nephrolithiasis occurrence in women but not in men. This discrepancy can plausibly be attributed to disparities in the prevalence of metabolic derangements: In the Korean cohort, mean BMI was higher among men than women, and men had an approximately threefold greater prevalence of obesity, diabetes mellitus, and hypertension; whereas in the NHANES III cohort, mean BMI and prevalence of obesity, diabetes mellitus, and hypertension were significantly higher in women than in men. Lifestyle factors and sex-hormone differences may thus have played a role in these contrasting results.

That being said, patients with NAFLD are not known to be more susceptible to symptomatic stones requiring medical or operative treatment;²⁹ our study bears this out. Nevertheless, although there is insufficient evidence to justify routine screening for kidney stones, we do believe that these metabolically complex patients, who manifest a multifactorial predisposition to stone formation, would benefit from a metabolic work-up with 24-hour urine collection. Future research should investigate 24-hour urine parameters in patients with NAFLD to better elucidate their lithogenic risk factors and thereby individualize therapy. Meanwhile, in the absence of effective approved treatments for NAFLD, we continue to manage our patients with a multidisciplinary protocol that counteracts the metabolic derangements underlying this disorder, incorporating (when appropriate) dietary changes, antioxidants, and insulin-sensitizing, lipid-lowering, hepatoprotective, and anti-inflammatory agents.

As with any survey-based analysis, this cross-sectional study is subject to several limitations. Clinically relevant factors such as diagnostic modality and stone composition, location, and burden are not captured in the NHANES III database, possibly impairing the generalizability of our findings. Since the questionnaire elicited participant recall only of discrete nephrolithiasis incidents, we expect stone occurrence to have been under-reported, with symptomatic and/or clinically meaningful episodes predominating over incidentally diagnosed stone burden. Furthermore, this study relied upon ultrasound-proven diagnoses of NAFLD, whereas the gold standard for diagnosis is liver biopsy. Although comparable with histology analysis in detecting moderate to severe fatty liver disease, ultrasound is less specific for diagnosing mild disease; therefore, this study may underestimate prevalence of nephrolithiasis in NAFLD.³⁰ Finally, this retrospective analysis is unable to tease out temporal or causal relationships between the development of NAFLD and the onset of lithogenesis.

Conclusions

In a large U.S. population-based cross-sectional analysis, NAFLD was found to be associated with an increased risk of nephrolithiasis in women, even after controlling for possible confounders such as lifestyle factors and metabolic disorders. This indicates that NAFLD may represent an independent risk factor for stone disease in women. However, reliable data describing calculus composition and 24-hour urine parameter abnormalities in patients with NAFLD remain nonexistent. Further research employing noninvasive measures of hepatic steatosis and fibrosis to stage disease is required to characterize these factors, elucidate mechanisms of stone formation in NAFLD, identify potential therapeutic targets, and assess implications for risk stratification, surveillance, prevention, and treatment.

Footnotes

Acknowledgments

The Einstein Healthcare Network Institutional Review Board was consulted and determined that this cross-sectional study of publicly accessible deidentified data did not fall under the category of human subjects research.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Abbreviations Used

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