Nonalcoholic Fatty Liver Disease: What Nurses Need to Know

1.5 0.5 ANCC CONTACT HOURS PHARMACOLOGY CREDITS

Nonalcoholic fatty liver disease: What nurses need to know

BY VINCENT M. VACCA, JR., MSN, RN

Abstract: Nonalcoholic fatty liver disease AFFECTING UP TO 100 million peo- (NAFLD) is defined as storage of excess ple in the US and up to 35% of the fat in the liver not caused by heavy alcohol population worldwide, nonalcoholic consumption. Nonalcoholic steatohepatitis fatty liver disease (NAFLD) is defined is the severe form of NAFLD. This article discusses causes, diagnosis, and nursing as storage of excess fat in the liver interventions for patients with either not caused by heavy alcohol con- disorder. sumption. Nonalcoholic steatohepatitis (NASH) is the more severe form Keywords: cirrhosis, diabetes mellitus, of NAFLD. Unlike NAFLD, NASH is fatty liver disease, hepatic fibrosis, insulin characterized by significant hepatic resistance, magnetic resonance elastography, inflammation.2 An estimated 10% to NAFLD, NAFLD Activity Score, NASH, 20% of people with NAFLD develop nonalcoholic fatty liver disease, nonalcoholic NASH (see How fatty liver develops).1,4 steatohepatitis, transient elastography Worldwide, the number of people age 65 or older is projected to increase from 524 million in 2010 to nearly 1.5 billion in 2050. Because advancing age is a major risk factor for NAFLD, its incidence is expected to increase as the population ages. NAFLD and NASH are now leading indications for liver transplantation in the US.5-8 This article discusses causes, diagnosis, and nursing interventions for patients with NAFLD and NASH. SHUTTERSTOCK / TEFI

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. Metabolic syndrome and • fasting plasma glucose (FPG) damage from alcohol, drugs, and other risk factors 100 mg/dL (5.6 mmol/L) or more, toxins, and less able to regenerate NAFLD is a complex disease dictated or drug treatment for elevated blood or tolerate transplantation.8,11,12 Ad- by both genetic and acquired fac- glucose. ditional stressors affecting the aging tors, including metabolic syndrome Currently, up to 25% of the US liver include systemic metabolic dis- (also called insulin resistance syn- population is affected by metabolic eases and disorders, such as systemic drome). NAFLD is considered the syndrome and approximately 90% inflammation, insulin resistance, hy- hepatic manifestation of metabolic syn- of patients with NAFLD have more pertension, type 2 diabetes mellitus, drome.3,8-10 Under criteria established than one feature of metabolic syn- and obesity.11,12 by the National Cholesterol Education drome.8,11 Metabolic syndrome is as- The loss of hepatocytes associated Program (NCEP) Adult Treatment sociated with cardiovascular disease with the aging process leads to re- Panel III (ATP III), metabolic syndrome and type 2 diabetes. ductions in serum levels of albumin is defined as the presence of any Here is a closer look at major risk and increases in alkaline phospha- three of the following five factors.10 factors associated with NAFLD and tase and aminotransferase levels. • abdominal obesity, defined as a NASH. The metabolism of cholesterol in the waist circumference of 102 cm • Older age. Aging is a significant liver also decreases with the aging (40 in) or more in men and 88 cm risk factor for several chronic liver process, increasing blood cholesterol (35 in) or more in women. diseases and disorders, including levels over time.7 • serum triglycerides 150 mg/dL NAFLD and NASH.7,12 Recent stud- • Obesity. Approximately 30% of (1.7 mmol/L) or more, or drug treat- ies show increased rates of NAFLD obese patients and up to 90% of ment for elevated triglycerides. among older adults compared with morbidly obese patients have a fatty • serum high-density lipoprotein younger patients.12,13 liver.5,6 However, not all patients (HDL) cholesterol less than 40 mg/ Because of age-related cellular, with NAFLD are overweight or dL (1 mmol/L) in men and less than tissue, and functional changes in obese. From 8% to 10% of NAFLD 50 mg/dL (1.3 mmol/L) in women, the aging liver, older patients have patients have a body mass index of or drug treatment for low HDL cho- significantly worse disease than less than 25 and are considered lean, lesterol. younger patients. With advancing supporting the role of genetics in • BP 130/85 mm Hg or more, or age, the liver loses functional capac- development of the disease.4 drug treatment for elevated BP. ity, becoming more susceptible to • Diabetes mellitus. An estimated 1 in 10 middle-aged American adults 11 30 has diabetes mellitus. In a large How fatty liver develops prospective study, patients with dia- Fatty liver is caused betes were shown to have a signifi- by an accumulation of cantly higher incidence of NAFLD triglycerides in liver cells. and hepatocellular carcinoma (HCC) Normally, liver cells contain than individuals without diabetes.11 some fat, which is either Along with cardiovascular disease, oxidized and used for malignancies are common causes of energy or converted to death in patients with NAFLD and triglycerides. This fat is NASH.13 derived from free fatty • acids released from Insulin resistance (IR). Charac- adipose tissue. Abnormal terized by a widespread diminished accumulation occurs cellular response to insulin, IR is when the delivery of free both a key component of metabolic fatty acids to the liver is syndrome and a risk factor for increased, as in starvation NAFLD.5 Normally, insulin is re- and diabetes mellitus, or leased in response to food con- when the intrahepatic metabolism of lipids is disturbed, as in alcoholism. sumption and increased blood glu- The liver shown here was harvested from a patient with risk factors for cose levels, promoting cellular up- nonalcoholic fatty liver disease. It has the characteristic swollen and yellow take of glucose in skeletal muscle, appearance of fatty liver disease. The biopsy showed moderate large-droplet adipose tissue, and the liver. With steatosis but no steatohepatitis or fibrosis. IR, cells cannot readily absorb glu- Photo courtesy of Dr. Amit Mathur, Transplantation Surgery, Mayo Clinic Arizona. cose from the bloodstream, leading

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. to hyperglycemia. Hyperglycemia • Other factors. Additional known stimulates further insulin produc- risks for development of NAFLD tion, resulting in hyperinsulinemia.6 include inflammatory bowel disease, The combined effect of hyperinsu- inborn errors of metabolism, and linemia and IR leads to increased occupational exposure to toxins such free fatty acid in the liver and in- as organic solvents.7 creased production of triglycerides, which can cause or worsen hepatic Notes about NASH steatosis.5,14 Up to 20% of patients with NAFLD The presence of IR is an inde- progress to NASH, which is associ- pendent predictor of advanced liver ated with hepatic tissue damage, in- fibrosis in patients with NAFLD.7 flammation, cirrhosis, hepatocellular Due to the strong association be- necrosis, and liver failure.4,7,18 tween reduced insulin sensitivity and Cirrhosis is a late stage of hepatic increased incidence of cardiovascu- fibrosis and is generally consid- lar disease with NAFLD, diabetes ered to be irreversible in advanced screening for patients with NAFLD stages.19 NASH is associated with is suggested.8 rapid progression of liver fibrosis and • Obstructive sleep apnea (OSA). the potential to develop HCC and Hypoxia secondary to OSA has been eventual liver failure.4,5,7,11 Cirrhosis linked to IR and lipogenesis, causing is present in 70% to 90% of patients a systemic proinflammatory state. with HCC. According to the World Recent research has linked the pres- The most common initial Health Organization, HCC is the fifth ence and severity of hypoxia second- signs and symptoms of most common cancer worldwide and ary to OSA to the severity of liver NAFLD are nonspecific, was the second most common cause 14 11 fibrosis associated with NASH. such as fatigue, and do of cancer-related death in 2015. • Polycystic ovary syndrome (POS). Morbidity from NASH is on the This disorder is also associated with not correlate to disease rise. Cirrhosis caused by NASH in- IR. Because 55% of women with POS severity. creased 170% for individuals on the present with NAFLD, women with US liver transplant waitlist between POS should be evaluated for NAFLD.8 urated fats, high-fat dairy products, 2004 and 2013. NASH-associated • Gender. The incidence of NAFLD and sugary beverages are associated cirrhosis is now the second leading is known to be higher in males and with a greater likelihood for develop- indication for liver transplantation in postmenopausal females than other ment of metabolic disorders such as the US.15 groups.7 type 2 diabetes, obesity, and IR—all • Drugs. NAFLD can be triggered by of which can progress to NAFLD and Assessment and diagnosis many medications, such as amioda- NASH.7,14 The most common initial signs and rone, aspirin, estrogens, glucocorti- In addition, excessive calorie in- symptoms of NAFLD are nonspe- coids, methotrexate, tamoxifen, and take can result in accumulation of cific, such as fatigue and malaise, tetracycline.7 excessive triglycerides and free fatty and do not correlate to the severity • Genetic factors. Recent evidence acids in the liver, leading to hepatic of disease. Some patients report pain supports a strong genetic connection steatosis.7 This effect is known in the right upper abdomen early in between development of NAFLD and to occur rapidly, within days to disease. Hepatosplenomegaly is pres- progression to NASH.13,15,16 Ethnic- weeks.6,7 One study of patients re- ent in up to 50% of patients; how- ity is also considered to be a risk fac- ferred to an urban hospital-based ever, as the disease progresses, the tor, with Hispanic individuals being lipid clinic showed a NAFLD preva- liver shrinks in size and the spleen more susceptible than people in non- lence of 50%.5 Excessive calorie enlarges. Pruritus, hyperbilirubine- Hispanic groups.4 intake of unhealthy diet options mia, and jaundice may also occur.7 • Diet. Poor dietary choices are im- combined with a sedentary lifestyle Diagnostic lab and imaging find- portant factors in the development are known factors contributing to ings suggesting NAFLD include and progression of NAFLD.12,14,17 A fatty liver, making healthy dietary elevated liver enzymes and hepatic diet that is high in red and processed choices essential to prevent or slow steatosis visible on transabdominal meats, refined sugars and grains, sat- progression of NAFLD.4 liver ultrasound.14,18 Transabdominal www.Nursing2020.com March l Nursing2020 l 35

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. liver ultrasound, which is noninvasive and widely available, is the preferred Calculating the FIB-4 index3,23,32 initial radiologic study to assess for fatty infiltration of the liver.11 Age (years) x AST (U/L) FIB-4 = ______= Other noninvasive methods used to assess liver function and Platelet count (109/L) x √ ALT (U/L) structure include a liver fibrosis Using this formula, clinicians can use an online calculator to calculate a patient’s panel. The presence of circulat- FIB-4 index, an indicator of fibrosis severity. ing biomarkers can identify the extent of liver damage.5,7 Common in contrast, TE focuses on a smaller age, platelet count, and AST and serologic biomarkers associated part of the liver. However, MRE ALT levels. FIB-4 calculations are with liver dysfunction include is not widely available. Although simple and results are available im- elevated aspartate aminotransfer- slightly less accurate in estimating mediately (see Calculating the FIB-4 ase (AST), alanine aminotrans- the extent of liver disease than MRE, index).4,23 ferase (ALT), alkaline phospha- TE is portable and widely available FIB-4 results can be used to tase, and cytokeratin-18.4-6 at the point of care.5 guide the decision to perform an Although elevated liver enzymes invasive liver biopsy. For example, can be present, NAFLD cannot be Gauging disease severity a low FIB-4 index may indicate that diagnosed by blood tests alone.20 For patients diagnosed with NAFLD, medical management without an Besides excluding excessive alcohol the nonalcoholic fatty liver activity invasive liver biopsy is appropri- consumption and other possible score (NAS) can be used to guide ate.4 The current American Associa- causes of chronic liver disease, the treatment decisions. Based on biopsy tion for the Study of Liver Disease clinician must establish the presence results, the NAS is the sum of scores (AASLD) guidelines recommend the of hepatic steatosis by imaging or for steatosis (0 to 3), lobular inflam- use of NAS, FIB-4, TE, and MRE, biopsy (see Ruling out alcoholic steato- mation (0 to 3), and hepatocellular if available, to identify patients at hepatitis).2 ballooning (0 to 2).2 high risk for liver fibrosis.4,24 Transient elastography (TE), a Fibrosis, which is not included in noninvasive method to assess the the NAS, can be staged separately as When is liver biopsy extent of liver stiffness, can provide follows:22 indicated? an estimate of liver fibrosis.4 TE • F0: no scarring (no fibrosis) For most patients, clinical assess- measures liver stiffness with a device • F1: minimal scarring ment, noninvasive studies, scoring that utilizes an ultrasound-like probe • F2: significant fibrosis tools, and imaging techniques are to send shear waves to the liver and • F3: fibrosis spreading and forming enough to diagnose NAFLD. How- back to the probe. It has been shown bridges with other fibrotic liver areas ever, a liver biopsy is considered to have a high degree of accuracy in (severe fibrosis) the gold standard for assessing the predicting advanced fibrosis.14 TE • F4: cirrhosis (advanced scarring). extent of hepatocellular damage seen is highly sensitive for distinguishing Another widely used fibrosis in NAFLD and to accurately identify between absent, mild, and severe scoring system is a calculation us- progression to NASH.2,5,12 Liver bi- fibrosis and is useful to track disease ing the fibrosis-4 (FIB-4) index, opsy may be indicated to confirm the progression over time.7,21 which was originally developed to diagnosis, assess the severity of liver Magnetic resonance elastography stage liver disease in patients with damage, and identify the stage of (MRE) is a modification of MRI that chronic hepatitis C virus infection. liver fibrosis.5,25 enables analysis of the entire liver; The FIB-4 index is based on patient Liver biopsy should be considered in patients with NAFLD who 7,31 are at increased risk for advanced Ruling out alcoholic steatohepatitis ﬁbrosis or NASH, but the health- In order to diagnose NAFLD, the clinician must rule out alcohol as the cause of fatty care provider must weigh the risks liver. Alcoholic steatohepatitis may be ruled out when the patient consumes less and benefits.24 A liver biopsy is than 20 g of alcohol a day. In the US, one alcoholic drink contains about 14 g of expensive and carries some risk for pure alcohol. This is the amount found in 12 oz of regular beer, 5 oz of wine, or 1.5 morbidity and mortality. Addition- oz of distilled spirits. The patient’s clinical history, dietary history, medication use, ally, because the liver biopsy speci- occupational exposure to organic solvents, and family history of liver disease should men represents a very small sample also be investigated. of the total liver tissue volume,

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. accurate interpretation requires trials have been conducted to exam- expertise.24,25 ine the benefits of bariatric surgery for patients with NAFLD and the Initial management appropriateness of bariatric surgery A fundamental component of for patients with NAFLD is not yet NAFLD and NASH management is established.7,17 However, the AASLD lifestyle modification. Importantly, states that bariatric surgery improves this includes avoiding alcohol, a or eliminates comorbid disease in known hepatotoxin, to prevent fur- most patients and improves long- ther liver damage.18 term outcomes from cardiovascular The European Association for the disease and malignancy, the two Study of the Liver states that a 7% most common causes of death in weight reduction may be adequate patients with NAFLD, so bariatric for resolving hepatic steatosis and surgery can be considered in eligible liver inflammation. The AASLD obese individuals with NAFLD or recommends that a decrease of 10% NASH.24 body weight may resolve mild to Exercise is known to reduce IR moderate fibrosis, reduce hepatic in- and promote a healthy weight. Aero- flammation, and recover some loss of bic or resistance exercise of moderate liver function.4,7,16 A large random- intensity, three to four times a week ized controlled trial involving 154 for 20 to 40 minutes per session, is patients with NAFLD demonstrated Tight control of diabetes effective for fat mobilization from the that lifestyle modifications including liver. However, it is recommended a 7% to 10% weight reduction and and/or IR, treatment that increased physical activity be aerobic exercise over a 1-year period of dyslipidemia, and accompanied by a healthier diet to resulted in remissions of 64% in the discontinuing causative achieve the desired goals.4,8,17 lifestyle modification group, com- agents are important pared with only 20% in the control Pharmacotherapy group. Remissions were reported as management strategies. The AASLD recommends that improvements in liver enzyme levels, pharmacologic treatments be gener- reduced liver fat, and decreased liver ally limited to patients with biopsy- fibrosis.26 To promote weight loss, if indi- proven NASH and ﬁbrosis.11,20 For Dietary and calorie restriction are cated, and encourage lifestyle and appropriate patients, prescribed med- key interventions in preventing and dietary modifications, nurses should ications may include the following. managing NAFLD. A reduction of explain the implications of metabolic • Pioglitazone, an oral hypoglycemic 450 to 1,000 kilocalories per day syndrome to their patients. Refer- agent, has been shown to improve has proven to be both safe and effec- ral to a dietitian may be beneficial. fibrosis, inflammation, and steatosis tive for this population.7 Nutritional Results from one study revealed that in patients with and without type recommendations for patients with reading a brochure resulted in 6% of 2 diabetes who have NASH con- NAFLD include carbohydrate intake participants achieving a 5% weight firmed by liver biopsy.7,17,24,27 of 40% to 50% of total dietary in- loss but meeting every other week • The use of statins is somewhat take, with an increase in the amount with a dietitian for 3 months pro- controversial due to the potential of complex carbohydrates that are duced a 4% to 11% weight loss.8 for statin-induced hepatotoxicity. rich in dietary fiber.7,14,17 Tight con- For severely obese patients, bar- However, three trials—the Incre- trol of diabetes and/or IR, treatment iatric surgery is effective to reduce mental Decrease in End Points of dyslipidemia, and discontinuing body weight and improve glycemic Through Aggressive Lipid Lowering offending causative agents are also control, quality of life, and long- (IDEAL) trial, Greek Atorvastatin and important management strategies.8 It term survival. Bariatric surgery may Coronary Heart Disease Evaluation is also recommended that fat intake also lead to improvement in some (GREACE) trial, and Action to Control be less than 30% of the daily calorie obesity-related comorbidities, such Cardiovascular Risk in Diabetes intake, with an increase of mono- as OSA. Although bariatric surgery ( ACCORD) trial—all demonstrated the and polyunsaturated fats over satu- offers benefits for appropriate can- improvement of liver enzymes in rated fats.7,14,17 didates, no randomized controlled patients with NAFLD. These trials www.Nursing2020.com March l Nursing2020 l 37

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. endorsed the safe use of statins either by a hypocaloric diet alone even in patients with compensated or in conjunction with increased cirrhosis.7,24 physical activity. A combination of The statin ezetimibe was examined a hypocaloric diet (daily reduction in a 24-month trial with 45 patients by 450 to 1,000 kcal) and moderate- newly diagnosed with NAFLD intensity exercise is likely to provide via liver biopsy. The results of this the best likelihood of sustaining trial demonstrated that ezetimibe weight loss over time and reducing significantly improved visceral fat hepatosteatosis.8,24 areas, fasting insulin, concentration • Educate patients, caregivers, and of triglycerides, total cholesterol, lev- families about managing diabetes with els of small low-density lipoproteins diet choices, medications, exercise, and very small low-density lipopro- and regular blood glucose monitoring. teins, as well as significantly lowering • Advise patients to keep a written levels of serum ALT and C-reactive record or journal including signs protein, an inflammatory marker.7 and symptoms, even those that may A recent meta-analysis showed that seem unrelated to their condition, ezetimibe improved NAS in indi- and to write down any questions viduals with NAFLD but did not they want to ask the provider at the improve hepatic steatosis.28 next appointment. The AASLD states that statins • Recommend maintaining a current do not place patients with NAFLD Collaborating with other list of all prescription and nonpre- or NASH at higher risk for serious healthcare team members, scription medications, vitamins, liver injury; therefore, statins may and supplements, including over- be prescribed to treat dyslipidemia nurses can work with the-counter (OTC) products. Tell in patients with NAFLD and NASH. patients and families patients to follow prescriber or man- However, it is recommended that to develop a practical ufacturer instructions on all medica- statins be avoided in patients with plan of care. tions and OTC drugs and to check decompensated cirrhosis.17,24 with the healthcare provider before • Vitamin E is an antioxidant and choices, and manage comorbidities using any new drugs or herbal rem- free-radical scavenger that protects such as diabetes. Teaching points edies, as not all products are safe.8,24 the structural components of cell include the following. • Bring all relevant and requested membranes. The AASLD states that • Stress the importance of avoiding medical records to healthcare ap- vitamin E may be considered for alcohol and medications or substanc- pointments, including a current adults without diabetes who have es that exacerbate liver disease. medication list. biopsy- proven NASH.5,24 • Inform patients that a diet rich in • Suggest that a family member, care- • Vaccinations against hepatitis A fruits, vegetables, and whole grains giver, or friend accompany patients and hepatitis B are recommended, has been proven beneficial as part of to appointments to ensure that all as are pneumococcal and influenza the treatment plan for NAFLD and discussions and information reviewed vaccines and other standard immuni- NASH. are understood and remembered.24 zations recommended for the general • Advise patients to develop and The American Liver Foundation population.11,27 maintain a safe and effective exercise website, https://liverfoundation.org, and activity plan. Unless contraindi- is a useful resource for healthcare Patient teaching cated, a goal of 30 minutes per day professionals, patients, and families Nurses are in a strategic position several times a week has been shown who want to learn about liver health to educate patients, caregivers, and to have many benefits for patients and disease. ■ families about NAFLD and NASH. with NAFLD and NASH, including Collaborating with healthcare team weight reduction and management, REFERENCES members in other disciplines, nurses cholesterol control, and increased 1. National Institute of Diabetes and Digestive and Kidney Disease. Definition & Facts of NAFLD & 14,29 can work with patients and families exercise tolerance. NASH. 2016. www.niddk.nih.gov/health-information/ to develop a practical plan of care • Tell patients who are overweight liver-disease/nafld-nash/definition-facts. 2. Sheth SG, Chopra S. Epidemiology, clinical features, that will help patients lose and main- that weight loss can help reduce and diagnosis of nonalcoholic fatty liver disease in tain weight, make informed dietary hepatosteatosis and can be achieved adults. UpToDate. 2018. www.uptodate.com.

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. 3. Sharma B, Savio J. Nonalcoholic steatohepatitis. 14. Wisocky J, Paul S. The rising incidence of 25. Isabela Andronescu C, Roxana Purcarea M, StatPearls [Internet]. 2019. www.ncbi.nlm.nih.gov/ nonalcoholic fatty liver disease. Nurse Pract. 2017; Aurel Babes P. The role of noninvasive tests and books/NBK470243. 42(7):14-20. liver biopsy in the diagnosis of nonalcoholic fatty 4. Sayiner M, Lam B, Golabi P, Younossi ZM. 15. Danford CJ, Yao ZM, Jiang ZG. Non-alcoholic liver disease. J Med Life. 2018;11(3):243-246. Advances and challenges in the management of fatty liver disease: a narrative review of genetics. 26. Zelber-Sagi S, Godos J, Salomone F. Lifestyle advanced fibrosis in nonalcoholic steatohepatitis. J Biomed Res. 2018;32(5):389-400. changes for the treatment of nonalcoholic fatty Therap Adv Gastroenterol. 2018;11:17. 16. Kudaravalli P, Savio J. 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Pavlov CS, Casazza G, Nikolova D, et al. co-infection. Hepatology. 2006;43(6):1317-1325. P, et al. Global epidemiology, prevention, and Transient elastography for measurement of liver management of hepatocellular carcinoma. Am fibrosis and cirrhosis in people with alcoholic liver Vincent M. Vacca, Jr., is an associate lecturer at the Soc Clin Oncol Educ Book. 2018;38:262-279. disease. Cochrane. 2015. www.cochrane.org. University of Massachusetts in Boston, Mass., and a 12. Stahl EC, Haschak MJ, Popovic B, Brown BN. 23. Fibrosis-4 (FIB-4) calculator. Hepatitis C Online. member of the Nursing2020 editorial board. Macrophages in the aging liver and age-related www.hepatitisc.uw.edu/page/clinical-calculators/fib-4. liver disease. Front Immunol. 2018;9:2795. 24. Danford CJ, Connelly MA, Shalaurova I, et al. The author and planners have disclosed no potential 13. Albhaisi S, Issa D, Alkhouri N. Non-alcoholic A pathophysiologic approach combining genetics conflicts of interest, financial or otherwise. fatty liver disease: a pandemic disease with and insulin resistance to predict the severity of multisystem burden. Hepatobiliary Surg Nutr. 2018; nonalcoholic fatty liver disease. Hepatol Commun. 7(5):389-391. 2018;2(12):1467-1478. DOI-10.1097/01.NURSE.0000654028.01550.56

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