Continuing Education Activity

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disease characterized by excess fat accumulation in hepatocytes in the absence of secondary causes such as alcohol use. As excess fat deposits in the liver, hepatosteatosis may progress to nonalcoholic steatohepatitis (NASH). While the frequency of progression of NASH to cirrhosis is low, NASH is considered a significant risk factor for the development of cirrhosis and hepatocellular carcinoma. Risk factors for developing NAFLD include central obesity, insulin resistance, type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension. The prevalence of NAFLD has increased, mirroring the rise in obesity. The primary treatment of NAFLD is weight loss via exercise and diet modifications. There are currently no approved pharmacotherapeutics for NAFLD. However, a potential treatment option for NAFLD is bariatric weight loss surgery. This activity reviews the epidemiology, pathophysiology, clinical findings, and diagnostic evaluation of NAFLD in patients who may benefit from bariatric surgery. The activity also highlights the role of the interprofessional team caring for patients with obesity and NAFLD.

Objectives:

• Identify patients at risk for nonalcoholic fatty liver disease (NAFLD) based on their clinical history.

• Apply best practices when evaluating patients for NAFLD.

• Counsel patients with NAFLD regarding the potential risks and benefits of bariatric surgery.

• Develop and employ interprofessional team strategies to improve long-term outcomes for patients with NAFLD and other obesity-related conditions.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition within hepatocytes without secondary causes such as alcohol use or drug-induced liver injury. Minor amounts of fat deposition in the liver are considered normal, but fat deposition in greater than 5% of hepatocytes is a pathologic finding.[1] NAFLD is a spectrum of disease that includes hepatocellular steatosis (nonalcoholic fatty liver or NAFL) and nonalcoholic steatohepatitis (NASH).[1] NAFL is hepatocellular fat accumulation with little to no inflammation and is completely reversible if the underlying insult is removed.[1] Conversely, NASH is characterized by inflammation and liver damage, which may lead to steatofibrosis, cirrhosis, and hepatocellular carcinoma.[1]

No pharmacotherapies have been approved for the treatment of NAFLD.[2] Lifestyle modifications with an emphasis on weight loss remain the universal clinical management. For patients with obesity that meet the criteria, bariatric surgery is an effective weight loss option and has been shown to decrease obesity-related comorbidities, including NAFL and NASH.[3] However, limited studies are available to determine the full impact of bariatric surgery on patients with NAFLD.[4] Despite the recent acknowledgment of NAFLD and its complications, there is a lack of guidelines to provide consensus recommendations regarding bariatric surgery in the treatment of NAFLD. This lack needs to be addressed, as bariatric surgery may be the only effective treatment for some patients with obesity and NAFLD.

Etiology

The exact etiology of NAFLD is unknown. NAFLD is associated with type 2 diabetes, obesity, dyslipidemia, and metabolic syndrome; patients with these underlying comorbidities are at increased risk for developing NAFLD. Obesity, in particular, has been shown to have a strong association with the development of NAFLD. Genetics and diet may also play a role in the development of NAFLD.[5]

Epidemiology

The global prevalence of NAFLD is approximately 30%.[6] Approximately 25% of adults in the United States have NAFLD, with about 20% of these patients meeting the clinical and histologic criteria for NASH. This equates to 6.5 to 16.3 million Americans.[7] The prevalence of NAFLD is projected to increase with the rise in obesity and metabolic disorders, as overweight and obese individuals are at an increased risk of developing NAFLD.

As many as 75% of patients who are overweight and more than 90% of patients with a body mass index (BMI) greater than 40 kg/m² have NAFLD.[8][9] With an increasing prevalence, NAFLD is estimated to become the leading cause of chronic liver disease worldwide and the most common indication for liver transplantation in the United States by 2030.[10]

Pathophysiology

The pathophysiology of NAFLD is currently under investigation. The initial theory for the pathogenesis of NAFLD was the two-hit hypothesis. Insulin resistance, the first hit, causes the accumulation of triglycerides in hepatocytes, placing the liver at higher risk for injury. Oxidative stress and inflammatory cytokines are the second hit necessary to stimulate the inflammatory response characteristic of NASH. NASH can lead to steatofibrosis.[11] 

However, it is increasingly recognized that the pathophysiologic processes of NAFLD are much more complex than initially thought. The direct and indirect effects of endoplasmic reticulum stress, mitochondrial dysfunction, and particularly lipids, including free fatty acids, all contribute to liver injury.[12] Additionally, emerging evidence is altering the focus on liver-autonomous dysfunction to include the roles of other organs, such as muscle, intestine, and adipose tissue, that play in the development of NAFLD, which now appears to be a systemic metabolic disorder.[13] 

Furthermore, genetic polymorphisms that may increase the risk of developing NAFLD and the progression of NAFL to NASH are being investigated. Many genetic studies have found single-nucleotide polymorphisms (SNPs) associated with NAFLD.[13] Specifically, mutations in or near the protein-encoding genes patatin-like phospholipase domain-containing protein 3 (PNPLA3) and neurocan (NCAN) may be linked to NAFLD development through alterations in serum lipids or changes in lipoprotein secretion.[13] However, the precise contribution of each protein and its associated mutations remains under investigation.

Histopathology

The key histological feature of hepatosteatosis (NAFL) is macrovesicular hepatic steatosis.[14] Macrovesicular hepatosteatosis is not unique to NAFLD and is seen in liver injury due to alcohol use and chronic infection with the hepatitis C virus.

The liver biopsies of patients with NASH are characterized by hepatocyte ballooning and necrosis, Mallory hyaline bodies (eosinophilic intracytoplasmic inclusions), and neutrophilic inflammation.[14][15] A mixed inflammatory infiltrate, predominantly in a lobular pattern, composed of CD4 and CD8 lymphocytes with aggregates of scattered Kupffer cells, eosinophils, and lipogranulomas may also be seen.[16]

As the disease progresses, fibrosis appears in the centrilobular region. Eventually, the hepatic acinus may be affected. The distribution of fibrosis may become irregular.[16]

History and Physical

NAFLD is predominately a silent, asymptomatic disease.[17] Some patients with NASH may report malaise, fatigue, and right upper quadrant abdominal discomfort or pain.[18] 

A comprehensive medical history should be obtained, focusing on past medical and family history and carefully examining the social history to rule out other causes of liver injury, such as alcohol and drug use. A thorough medication history must be obtained, including over-the-counter and supplement use. 

The physical examination of patients with NAFLD is unlikely to reveal any disease-specific findings unless the stigmata of chronic liver disease, such as jaundice, ascites, palmar erythema, spider angiomas, or organomegaly, are present.

Evaluation

NAFLD is usually diagnosed incidentally after routine laboratory testing reveals mildly elevated serum transaminases or abdominal imaging performed for another indication reveals hepatomegaly.[19] Many patients with NAFLD, especially in the hepatosteatosis phase, have normal serum transaminases. Only with the progression to hepatocellular inflammation do laboratory values become abnormal.

Histopathological evaluation of a liver biopsy is the gold standard for confirming the diagnosis of NASH and staging liver fibrosis.[20] However, liver biopsy is an invasive procedure prone to sampling error and risks, particularly in patients with obesity, given excess adipose tissue. Liver biopsy is usually reserved for patients whose diagnoses are unconfirmed and for patients with an increased risk of developing NASH.

One of the most widely utilized evaluation methods is the NAFLD Activity Score (NAS). The NAS includes a numerical score for steatosis (0-3), lobular inflammation (0-3), and hepatocellular ballooning (0-2) based on liver biopsy. A score ≥5 correlates to a diagnosis of NASH.[13] This scoring system was initially developed to evaluate NASH progression or regression in clinical trials and is not intended to distinguish entities on the NAFLD spectrum.[13]  

Due to the inherent invasiveness of liver biopsy, there has been increased interest in noninvasive testing (NIT) and imaging to diagnose fibrosis accurately.[17] NITs utilize patient demographics, such as age and gender, and serum biomarkers, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelets to calculate a score to stage NASH and liver fibrosis.[20] Commonly utilized NITs include the FIB-4 score, NAFLD Fibrosis Score, and Fibrotest.[13] 

Noninvasive imaging techniques to evaluate hepatic inflammation and fibrosis include liver elastography and magnetic resonance elastography. Liver elastography has become a common imaging modality in the clinical setting that converts shear wave velocity measurements into liver stiffness.[21] However, the utility of liver elastography in patients with obesity who are candidates for bariatric surgery may be limited.[21] 

The validity of noninvasive testing and imaging techniques for patients with obesity is unclear. More studies are required to address the clinical challenges of diagnosing NAFLD and staging fibrosis in patients with obesity. 

Treatment / Management

The primary treatment of NAFLD is lifestyle modification through caloric reduction and exercise, emphasizing achieving at least a 5% to 10% loss of total body weight. Studies have shown that patients with NAFLD who lose weight demonstrate biochemical and histological improvement.[22] Therefore, diet and exercise remain the most effective and cost-efficient interventions for managing NAFLD.

No pharmacotherapies are approved by the United States Food and Drug Administration (FDA) for treating NAFLD. Pharmacotherapies currently under investigation include bile acid signal receptor agonists, nuclear receptor protein agonists, and glucagon-like peptide-1 inhibitors. Medications being investigated for NAFLD currently in phase 2 trials include oltipraz and NGM282, an engineered fibroblast growth factor 19 analog. Drugs in phase 3 trials include lanifibranor, dapagliflozin, empagliflozin, aramchol, and resmetirom.[23] While vitamin E and pioglitazone have completed phase 4 trials, the FDA has not approved them for treating NAFLD.[23]

Bariatric surgery is a treatment option for patients with obesity. Bariatric surgery has been shown to induce weight loss and decrease obesity-related comorbidities, including hepatosteatosis and fibrosis.[3] The current American Society for Metabolic and Bariatric Surgery (ASMBS) recommendations for bariatric surgery include individuals with a BMI greater than 35 kg/m² regardless of the presence, absence, or severity of comorbidities; patients with type 2 diabetes and a BMI greater than 30 kg/m²; and bariatric surgery can be considered in individuals with a BMI of 30 to 34.9 kg/m² who do not achieve substantial or durable weight loss or comorbidity improvement using nonsurgical methods.[24] 

Over 95% of patients who undergo bariatric surgery have biopsy-proven NAFLD at the time of surgery.[25] Bariatric surgery improves NAFLD beyond sustained long-term weight loss through alterations in bile acid homeostasis, improvement of glycemic control, stimulation of incretins and satiety-hormone secretion, alterations in the gut microbiome, and changes in responses to food stimuli.[25] Although NAFLD is not currently a specific indication for bariatric surgery, patients with NAFLD who meet ASMBS criteria are routinely referred for bariatric surgery evaluation as bariatric surgery has been shown to improve or resolve comorbidities in most patients with NAFLD and decrease mortality from cardiovascular disease and malignancy.[26] 

Weight loss through diet and exercise may be the first-line treatment for NAFLD, but sustaining weight loss through lifestyle modifications is challenging. Most patients who lose weight using lifestyle modifications will regain more than half the weight lost within 2 years and more than 80% of the weight lost by year 5.[27] Given the lack of pharmacological treatment for NAFLD, if lifestyle modifications are unsuccessful, the only treatment option for patients with obesity and NAFLD is bariatric surgery. Currently, clinical practice surpasses the standardized guidelines for treatment strategies for patients with obesity and NAFLD, given no formal guidelines. NASH is a significant risk factor for the development of hepatocellular carcinoma, and further studies are needed to set specific guidelines to safely recommend bariatric surgery as a treatment option for patients with obesity and NAFLD.

Differential Diagnosis

The differential diagnosis of NAFLD comprises various causes of liver injury, including:

• Alcoholic liver disease
• α1-Antitrypsin deficiency
• Autoimmune liver disease
• Drug-induced liver injury
• Hemochromatosis
• Viral hepatitis A through E
• Wilson disease

Prognosis

The prognosis of patients with NAFLD varies widely. While some patients with NAFLD will never demonstrate a complication of the disease, studies have shown that patients with NAFLD have a higher mortality rate and lower life expectancy when compared to the general population. Patients with NAFLD have a higher mortality risk from cardiovascular disease.[28] Moreover, patients with a higher degree of fibrosis have an increased risk of liver-related complications and a poorer overall prognosis. 

Complications

Patients with NAFLD are at an increased risk of hepatic and extrahepatic complications. Patients with NASH are at an increased risk of cirrhosis, hepatocellular carcinoma, end-stage liver disease, and liver-related mortality. However, cardiovascular disease remains the most common cause of death among patients with NAFLD.[29] Extrahepatic complications of NAFLD include chronic kidney disease, obstructive sleep apnea, polycystic ovarian syndrome, endocrinopathies, and colorectal cancer.[29]

Bariatric surgery carries immediate risks and long-term complications. The specific risks and complications are unique to each type of bariatric procedure. Immediate postoperative risks may include gastrointestinal leaks, stenoses, and bleeding. Nausea and vomiting, new or worsening gastroesophageal reflux, infections, and esophageal dilatation are known risks of bariatric surgery. Long-term complications of bariatric surgery include malnutrition due to malabsorption, gastrointestinal ulcers, bowel obstruction, anastomotic stricture, gastroesophageal perforation, hernias, and dumping syndrome.[30]

Dumping syndrome is a common complication of gastric bypass and may be classified as early or late. Early dumping syndrome occurs due to the rapid emptying of food into the small bowel, causing an osmotic shift and symptoms of lightheadedness, facial flushing, nausea, abdominal pain, and palpitations. Late dumping syndrome is related to hypoglycemia following a significant insulin surge, resulting in confusion, tremors, fainting, and palpitations.[31]

Malabsorption of essential nutrients, vitamins, and minerals may have various manifestations, including anemia and neuropathy. Additionally, medication absorption may be altered, requiring dosage adjustments.[31] 

Deterrence and Patient Education

Patient education is crucial in managing and preventing the complications of NAFLD, as the disease is not well known and likely underdiagnosed. Thoroughly educating patients about nutrition, diet, weight loss, and exercise should be prioritized, as lifestyle modifications have been shown to halt liver damage and may lead to disease reversal. Patients should also be educated about controlling other comorbidities, such as hyperlipidemia and hyperglycemia. Patients should be advised to limit the use of alcohol and over-the-counter supplements.

Enhancing Healthcare Team Outcomes

As obesity rates continue to rise, it is reasonable to assume that the incidence and prevalence of NAFLD will increase. Collaboration among healthcare practitioners is essential to manage obesity-related comorbidities. To effectively mitigate the potential complications of the spectrum of NAFLD, an interprofessional team of primary care practitioners, gastroenterologists or hepatologists, dieticians, endocrinologists, pharmacologists, and possibly bariatric surgeons is required.

Educating patients to prevent and manage obesity and obesity-related comorbidities is paramount to reducing the progression of NAFL to NASH with its associated risks of cirrhosis and hepatocellular carcinoma. Lifestyle modifications with dietary changes and exercise may require the assistance of dieticians and exercise physiologists. Management of dyslipidemia, type 2 diabetes, and hypertension by primary care practitioners with the aid of endocrinologists and cardiologists can potentially reverse NAFLD. Bariatric surgeons can determine if patients may benefit from weight loss surgery. Interprofessional team members should engage in open communication and coordination of care to optimize outcomes for patients with NAFLD.