1. Gastroenterology Service, Department of Internal Medicine, Walter Reed National Military Medical Center, Bethesda, MD, USA
2. Department of Internal Medicine, Walter Reed National Military Medical Center, Bethesda, MD., USA
3. Department of Medicine, Uniformed Services University, Bethesda, MD, USA
Academic Editor: Tatsuo Kanda
Received: January 31, 2019 | Accepted: June 13, 2019 | Published: June 28, 2019
OBM Hepatology and Gastroenterology 2019, Volume 3, Issue 2, doi:10.21926/obm.hg.1902025
Recommended citation: Sadowski B, Ordway S, Bobeck K, Tritsch A, Singla M. Nonalcoholic Fatty Liver Disease and Inflammatory Bowel Disease: Complex Interactions, Evaluations, and Management Decisions. OBM Hepatology and Gastroenterology 2019;3(2):15; doi:10.21926/obm.hg.1902025.
© 2019 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in the United States [1,2]. Patients with NAFLD are at risk for developing nonalcoholic steatohepatitis (NASH), a progressive disease associated with progression to cirrhosis. The worldwide rise of obesity and the metabolic syndrome (MetS) has led to a rise in prevalence of NAFLD the past 20 years . NAFLD has been shown to be a risk factor for incident diabetes and MetS in a large meta-analysis, suggesting a bidirectional relationship . One large study in the U.S. found a 2.5 fold increase in the prevalence of NASH cirrhosis between 2009-2012 as compared to 1999-2002 . By 2030, the rates of NAFLD are projected to increase by 21% . NAFLD is frequently diagnosed in patients with inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, despite having differences in the rates of traditional risk factors [6,7,8]. Patients with these chronic, immune-mediated inflammatory conditions of the luminal gastrointestinal tract may be at increased risk for developing NAFLD due to the inflammatory process or dysbiosis related to their underlying disease [5,9,10,11,12]. Just like NAFLD, IBD has an increasing incidence and prevalence around the world making an understanding of the interactions between the two important to recognize [10,11,12]. This narrative review serves to offer guidance on the relationship between the conditions, and considerations for approach and management strategies for these patients. We conducted a literature search through the PubMed database using the following search terms: obesity, obese, non-alcoholic steatohepatitis, NASH, non-alcoholic fatty liver, NAFLD, ulcerative colitis, UC, colitis, inflammatory bowel disease, IBD, Crohn’s disease. Additional references were found via reference analysis of the results of this search and during the review process.
2. Differential Diagnosis for Elevated Liver Transaminases
Diseases of the liver and the biliary tract are commonly encountered in patients suffering from IBD. The prevalence of elevated liver associated enzymes (LAEs) in patients with inflammatory bowel disease nears 30% , compared to the general population of 7.9% . IBD patients with elevated LAEs demonstrated a 4.8 times higher age-adjusted risk of death when compared to IBD patients with normal LAEs .
We consider a broad differential diagnosis of hepatobiliary diseases and tailor that it further to fit the patient with IBD. The differential diagnosis for elevated LAEs includes NAFLD, alcoholic fatty liver disease, autoimmune hepatitis, hemochromatosis, alpha-1-antitrypsin deficiency, viral hepatitis, drug-induced liver injury, Wilson disease, and cholelithiasis, among others . IBD patients also carry increased risk of primary sclerosing cholangitis (PSC), small duct PSC, Immunoglobulin G, Subclass 4 (IgG4)-related cholangiopathy and primary biliary cholangitis (PBC) [8,9,16,17,18]. IBD patients are frequently treated with medications that have been shown to cause hepatobiliary injury including glucocorticoids, sulfasalazine, azathioprine, and tumor necrosis factor inhibitors (infliximab and adalimumab) [10,19,20]. Rare diseases of the hepatobiliary system associated with IBD include granulomatous hepatitis, hepatic amyloidosis, portal vein thrombosis and liver abscess [21,22,23]. While the differential diagnosis for elevated LAEs in the IBD patient is broad, NAFLD is more common and occurs in younger patients with IBD compared to patients without IBD . Although the prevalence of PSC in IBD patients is significantly higher than that of the general population, it still much lower than NAFLD .
3. Prevalence of NAFLD
The most common cause of liver disease in North America is NAFLD, with a prevalence of 23.5% [24,25,26,27,28,29], while the prevalence of NASH is estimated to be 1.5%-6.5% [24,25,26,27,28,29,30]. A study of four hundred asymptomatic patients found the prevalence of NAFLD based on ultrasound was 46% with NASH confirmed in 12.2% of total cohort and the highest prevalence of both NAFLD and NASH in Hispanics . These rates are similar to those in other developed countries .
Components of metabolic syndrome (MetS) including central obesity, diabetes mellitus and hyperlipidemia are strongly associated with NAFLD and have been shown to increase the risk of mortality in patients with NAFLD . A global meta-analysis of patients with diabetes reported the prevalence of NAFLD to be 57.8% ; studies in the U.S. have reported the prevalence of NAFLD in diabetic patients to be as high as 75% [31,35]. In morbidly obese patients undergoing bariatric surgery, 74%-98% have NAFLD, 30% have NASH, and 10% have cirrhosis .
Despite the known association of NAFLD with MetS, the prevalence of lean NAFLD is reported to be 7% (and up to 25% in rural areas of Asia) [23,30,37]. Non-obese patients with NAFLD are more commonly younger, and less likely to have insulin resistance, diabetes or hypercholesterolemia than their overweight or obese counterparts . There are several theories about the role of inflammation in the development of NAFLD and some authors propose that IBD patients are at increased risk for this condition . The reported prevalence of NAFLD may be as high as 55% in patients with IBD [7,8,9]. Some data suggest differences between UC and CD when it comes to risk of MetS: UC patients have been reported to have higher BMI, waist circumference, systolic and diastolic blood pressures and insulin resistance than in CD patients who tended to be leaner . This suggests that these cohorts may not be equivalent.
4. Clinical Features of Patients with NAFLD and IBD
The relationship between NAFLD with IBD has been the subject of debate over the last several years, owing to the growing recognition that the two conditions often co-exist and affect patient prognosis . While conclusions on the interplay between the diseases are varied, patients with both diagnoses are unique compared to those with one or the other. Studies investigating the connection are varied in their findings as well as their definitions and use of clinical diagnostic tools (e.g. non-invasive assessment of fibrosis, degrees of steatosis). One retrospective study of IBD patients found an NAFLD incidence rate of 9.1/100 patient years, correlating to a 33.6% prevalence after a mediation of 3.2 years of observation . Having a longer duration of active IBD and having prior IBD-related surgery were independent risk factors for the subsequent diagnosis of NAFLD. A retrospective report comparing 78 IBD patients with NAFLD and 148 without NAFLD found that patients with fatty liver disease were younger and had lower BMI, rates of obesity, and less MetS . Glassner et al reported that, compared to a population with NAFLD-alone, patients with both IBD and NAFLD had lower rates of hypertension (33% vs 55%), hyperlipidemia (17.5% vs 53%), diabetes (16% vs 40%) and obesity (40% vs 59%), suggesting an a component of chronic inflammation beyond the contributions of the MetS . The severity and degree of control had an impact on the stage of hepatic steatosis with active IBD correlating with increased steatosis. Interestingly, patients with mild IBD had more traditional NAFLD risk factors but less steatosis on ultrasound, while patients with severe IBD had fewer metabolic risk factors but high hepatic fat . This variety in clinical NAFLD-phenotype suggests additional risk factors in patients with concomitant IBD.
Not all of the data supports a connection between IBD severity and the development of NAFLD. Principi et al reported that disease activity was not associated with difference in NAFLD prevalence, nor was there a correlation with IBD location or behavior . Non-specific serological markers of inflammation (erythrocyte sedimentation rate and C-reactive protein) were no different in IBD patients versus those with both conditions . Carr et al reported that UC and CD severity and extent were not associated with severity of NAFLD as determined by NAFLD Fibrosis Score (NFS). We lack data on the impact of deep remission of IBD on the progression of NAFLD using liver biopsy . Using transient elastography, researchers found a correlation between higher BMI levels and liver stiffness in those with IBD and NAFLD; interestingly, the use of azathioprine for IBD tended towards improved liver stiffness, though this did not reach significance. This finding may be from efficacy for IBD or a direct effect on the liver [38,39,40,41,42,43,44,45].
Just as IBD has an impact on the phenotype of NAFLD, NAFLD may have an impact on clinical characteristics of IBD. Compared to those with IBD alone, IBD patients with NAFLD were older with higher BMI, high density lipoprotein, blood pressures, and more likely to have MetS [39,40,41,42]. Taken in full, the clinical characteristics of patients with both IBD and NAFLD are distinct from those traits in patients who have one or the other, suggesting that the underlying pathophysiological mechanisms of each condition are linked.
Treatment of IBD may have an impact on NAFLD. A large retrospective cohort study showed significantly higher rates of small bowel surgery and current use of steroids in patients NAFLD, though use of anti-TNFα biologics was associated with protection from NAFLD . A recent meta-analysis, showed no significant associated between medications used for IBD and the risk of NAFLD was observed . While most cases of IBD in patients who had undergone liver transplant are in those with PSC, the rising prevalence of NAFLD will likely to lead to more transplantation of NAFLD-IBD patients. In the largest case series available, both anti-TNFα and anti-integrin biologics were safe in the post-transplant population, though some infectious and neoplastic complications were reported . A nuanced discussion of this topic is beyond the scope of this report.
5. Possible Connections between IBD and NAFLD
The pathogenesis of NAFLD is complex with major drivers being insulin resistance, genetic predisposition, dietary factors as well as the potential role of intestinal dysbiosis . The impact of gut permeability has been assessed in an observational study of biopsy-proven NAFLD who underwent chromium-51 ethylene diaminetetracetate (51Cr-EDTA) excretion testing. There was a significant increase in permeability and small intestinal bacterial overgrowth in NAFLD patients compared to healthy controls . Impaired permeability is increased in patients with IBD through the use of confocal laser endomicroscopy (CLE), even in those with mucosal healing . The extent of the contribution that intestinal permeability has in NAFLD is not fully understood, but should be the target of further study, particularly in an era when treating with a goal of endoscopic remission is becoming more widely accepted .
As noted above, pooling data from several studies related to the impact of anti-TNFα biologics showed no significant difference in NAFLD, though conclusions regarding this are difficult to draw for multiple reasons. Studies to date have no clearly delineated the duration of time prior to initiation of biologic therapy. Biologic therapies are not the index therapy for many patients which potentially leaves those patients at risk for persistent mucosal inflammation and an increased risk of NAFLD. Alternatively, early treatment with biologics may exchange one risk for NAFLD with another, since they will be have better mucosal absorption and possibly develop metabolic risk factors .
In mouse-models , gram negative bacterial lipopolysaccharide (LPS) has been shown to influence inflammatory cascades while also increasing insulin resistance. Similar findings have supported the influence of the microbiome on obesity. Additional mechanisms linking gut microbiota with NAFLD include impacts on bile acid synthesis and fermentation of polysaccharides into short chain fatty acids such as butyrate . Higher abundance of Bacteroides and lower abundance of Prevatella species have been seen in patients with underlying biopsy-proven NASH. In addition to these microbiota signatures, Ruminococcus was significantly more abundant in patients with more advanced stages of hepatic fibrosis . While causality is more difficult to prove than association, decades of effort to evaluate the impact of changing the microbiome composition has demonstrated that the development of steatosis and fibrosis can possibly be modulated . The interaction between the changes in gut flora and both the development and course of IBD is complicated and variable based on disease phenotype and extent (i.e. UC vs CD and ilealvs colonic), as has been described by McIlroy et al. . While some changes in signature are reported to overlap with those that alter the risk of NAFLD and NASH, no consistent evidence linking beneficial microbiome modulation with more aggressive management of IBD is available.
6. Approach to NAFLD in IBD
Given that IBD patients have a number of possible reasons for elevated liver enzymes, we take a deliberate approach to evaluating elevated liver enzymes (Figure 1). We begin with a screening for alcohol use and a right upper quadrant ultrasound for steatosis. Due to potential obesity-related limitations on ultrasound to detect steatosis, controlled attenuation parameter (CAP) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) can reliably assess for steatosis, the former generally being available in conjunction with transient elastography measurements, discussed below [55,56,57]. We have generally found ultrasound to be sufficient to make the assessment of steatosis in our patients.
Figure 1 Proposed approach to elevated liver enzymes in patients with inflammatory bowel disease. Abbreviations: CBC: Complete blood count; ANA: Anti-nuclear antibody; ASMA: Anti-smooth muscle antibody; TTG: tissue transglutaminase; RUQ US: Right upper quadrant ultrasound; AMA: antimitochondrial antibodies; MRCP: Magnetic resonance cholangiopancreatography; TPMT: thiopurinemethyltransferase; PBC: primary biliary cholangitis; ULN: Upper limit of normal
In accordance with societal guidance, we perform a serologic examination for autoimmune hepatitis, viral hepatitis, hemochromatosis, Wilson disease, and alpha-1 antitrypsin deficiency . If the alkaline phosphatase is also elevated, we typically assess the GGT level. If the patient is on a thiopurine we add an assessment of thiopurine metabolites (to assess serum 6-methylmercaptopurine levels), and if on methotrexate or biologics we evaluate the time-association and perform a causality assessment for drug-induced liver injury. This is a major consideration given that the DILI Network has identified both thiopurine and biologic medications, specifically azathioprine and infliximab, as a Category A drug, indicating over 100 reported cases of liver toxicity . A prospective cohort of treated IBD patients were followed with serial assessments of aminotransferase, bilirubin and alkaline phosphatase levels and most events were transients and did not require any significant change in IBD management . A recent meta-analysis showed that immunomodulators and methotrexate did not result in an increase in NAFLD development; TNF alpha inhibitors had no association with rate of progression . We do not recommend adjusting medical therapy in the presence of NAFLD/NASH unless drug-induced liver injury (DILI) is suspected. Based on the current evidence, there is no data to suggest more frequent monitoring of liver associated enzymes in IBD patients with NAFLD. When we suspect PSC, we typically proceed with cholangiography in the setting of cholestasis, with an R-factor (i.e. (ALT/upper limit of ALT)/(alkaline phosphatase/upper limit of alkaline phosphatase) less than 2. If non-diagnostic, we consider a liver biopsy to look for small-duct PSC [15,60,61,62].
If these tests are negative and the patient has steatosis on ultrasound, we utilize one of multiple testing strategies to assess for hepatic fibrosis. Fibrosis stage is particularly important in predicting long term outcomes in patients with NAFLD . We prefer non-invasive strategies given the risks of liver biopsy (pain, damage to adjacent organs, bleeding, and death) . The NAFLD Fibrosis Score (NFS)  and FIB-4  are two serologic and clinical systems that have reasonable test characteristics in terms identifying the presence or absence of advanced fibrosis/cirrhosis, though a wide range of indeterminant results hinder their utility . Transient elastography (TE) has grown in popularity as a non-invasive assessment of fibrosis. By using serial shear wave velocity measurements to assess liver stiffness measurement (LSM) and using a cutoff for LSM of 9.9 kPA, TE performs with 95% sensitivity and 77% specificity for advanced fibrosis on histology . TE has been used to evaluate for liver injury and stiffness in patients with IBD, though widespread screening with the modality is not recommended [44,67]. We recommend that patients with IBD with concerning non-invasive testing see a liver specialist equipped to consider a liver biopsy to formally stage steatohepatitis.
7. Treatment Focal Points
We aggressively approach IBD patients similarly to those in general gastroenterology clinic. It can be difficult to counsel patients with IBD on weight loss given that they are at risk for malabsorption, but an effort to decrease fats and sugars from their diets and increase exercise activity to help with weight loss is imperative even in these patients. We frequently employ the use of a dietitian for weight loss counseling, in addition to several general dietary recommendations (Table 1). Diets rich in fruits, vegetables, whole grains, monounsaturated fats, and omega-3 polyunsaturated fats with servings of fish and rare consumption of red meat are associated with beneficial effects in patients with NAFLD [68,69,70,71,72,73,74,75,76,77]. Coffee consumption (>3cups/day) is inversely associated with metabolic syndrome, including NAFLD [73,74,75,76,77]. Diets high in fructose, processed foods, saturated fats and alcohol consumption have been shown to be risk factors for progression of NAFLD [78,79,80,81]. There are multiple studies demonstrating significant benefit of the Mediterranean diet on those patients with NAFLD [69,70,71,72,82], however, all of these studies lacked sufficient follow up and small patient populations.
Table 1 Dietary patterns and their effects on patients NAFLD.
There is modest evidence that a Mediterranean diet in patients with IBD decreases markers in inflammation and IBD was less prevalent in those regions along the Mediterranean [83,84,85]. Investigation on the semi-vegetarian diet showed significantly improved remission rates with significantly lower inflammatory markers . There may be beneficial effects of the individual components of the Mediterranean diet such as, vegetables, fruits, legumes, occasional fish, rare red meat consumption, increased dietary fiber and monounsaturated fats [86,87]. The discussion of appropriate diets for patients with structuring Crohn’s disease, however, is best left to the individual patient.
Approximately 20%-40% of patients with IBD in Western countries are obese which is comparable to the general population. By contrast, only 3% of patients with Crohn’s disease and 0.5% of patients with ulcerative colitis were underweight (BMI <18.5 kg/m2) . There is a paucity of data on whether treating obesity can favorably affect outcomes in patients with IBD and there are no interventional studies of interventional weight loss in IBD. However, trials of diet and/or lifestyle-induced weight loss in other autoimmune diseases suggest improvement in outcomes with this form of adjunctive therapy .
Long-term effectiveness of lifestyle interventions is limited by small average weight loss with commercial weight-loss programs and frequent re-gain of lost weight over time. We have engaged our bariatric surgery colleagues for weight loss surgeries in some of our patients. The long-term consequences of bariatric surgery (including major restrictive and malabsorptive procedures) in patients with IBD are poorly understood. The Guidelines for Clinical Application of Laparoscopic Bariatric Surgery of the Society of American Gastrointestinal and Endoscopic Surgeons, state that CD may be a relative contraindication to the Roux-en-Y gastric bypass (RYGB) . A recent study challenged these recommendations, reporting that restrictive as well as malabsorptive procedures appear safe and effective in the IBD population for at least up to 2 years after surgery . It seems reasonable to perform gastric procedures (such as the sleeve gastrectomy (SG)), as they can still be surveyed during an upper endoscopy and do not decrease the available remaining small bowel in cases where the terminal ileum has to be partially resected . A study comparing RYGB to SG for IBD patients found that 1/3 of patients experienced improvements in IBD post-bariatric surgery. However, in CD patients, RYGB was associated with a greater number of patients with increased IBD-medication requirements. SG led to less weight loss but had a lower rate of severe complications compared to RYGB . The gastric balloon may be a safe alternative for weight loss in IBD patients. Gastric balloon placement improves transaminases, and decreases steatosis on MRI and histologic parameters . While there is some trepidation in elective abdominal operations in patients with IBD, patients with disease localized to the colon and well-controlled on medication should at least have a conversation about the risks and benefits of weight loss surgery. The choice of which procedure is offered is patient specific.
While liver enzyme elevation in patients with IBD can be due to various etiologies, including medication induced injury and additional autoimmune conditions, the most common cause mirrors that of the general population, fatty liver disease. Obesity and the MetS play a key role in NAFLD, and patients with IBD continue to be at risk. The conditions should be managed aggressively to help patients reduce the risk of developing chronic liver disease in addition to IBD. The possibility that early endoscopic remission decreases intestinal permeability and alters the microbiome, thus altering the course of NAFLD in this patient population, is a target of future research.
Drs. Sadowski, Ordway, Bobeck, Tritsch, Singla did the literature search and manuscript writing. Drs. Tritsch and Singla provided manuscript editing, and research mentorship.
The authors have declared that no competing interests exist.
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