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Top 10 Facts You Need to Know about Non-Alcoholic Fatty Liver Disease: A Review for the Primary Care Provider

VOLUME LIX • NO. 6/7 • 2018

Top 10 Facts You Need to Know about Non-Alcoholic Fatty Liver Disease: A Review for the Primary Care Provider

JARED R. BECK, DO; KARIN S. GILKISON, MD, MPH; JOHN D. MCKEE, MD; ERIC V. PLOTT, MD

Nonalcoholic fatty liver disease (NAFLD) is found worldwide and is the leading cause of hepatic disorders in Western industrialized countries. Even more alarming is the prevalence of NAFLD; it is higher than originally thought with some studies reporting upwards of 40% of the middleaged population. 1 This figure is even more prevalent in the Southern United States in which 70% of the obese and diabetic population were found to have NAFLD. 1 NAFLD is now the second leading indication for liver transplant in the United States and based on current trends, recent studies have reported that NAFLD will become the leading cause of liver transplant both in Europe and in the United States. 2 Despite these egregious statistics, NAFLD often times goes unnoticed leading to increased overall mortality and morbidity in aged matched populations. 3 Here are the top 10 things primary care providers should know about NAFLD in order to help identify and treat these patients.

1

NAFLD is defined as the presence of hepatic steatosis in individuals who consume little or no alcohol after exclusion of other causes of liver disease. As the name implies, nonalcoholic fatty liver disease is a clinical pathological entity in which the liver’s histological appearance demonstrates accumulation of fat within hepatocytes, or “steatosis.” This fatty accumulation of NAFLD can range from simple hepatic steatosis, to steatohepatitis (fat with inflammation), to end stage fibrosis, or “cirrhosis,” and is the leading cause of cryptogenic cirrhosis after other probable causes have been ruled out. 4 The histologic appearance of NAFLD is very similar to alcohol induced liver injury, and can be difficult to exclude from a varying spectrum of hepatic insults. Therefore, the vital distinguishing feature of NAFLD, even though it is the most common liver disease in the United States, is that it can only be diagnosed after other causes of liver disease have been eliminated.

2

The primary pathogenesis of NAFLD includes insulin resistance and fat accumulation. The exact pathogenesis and mechanism of fatty liver disease has yet to be fully elucidated. There are a handful of proposed mechanisms, but the most commonly accepted theories involve insulin resistance and triglyceride accumulation leading to hepatocellular injury. One proposed “two-hit” theory proposes a first hit of insulin resistance which promotes hepatic steatosis. The fatty liver becomes less capable of coping with oxidative stress leading to the second hit: inflammation. 5

3

The risk factors for NAFLD are unfortunately common. The most common risk factor for NAFLD is obesity, which affects greater than 35% of the US population. 6 Other risk factors include insulin resistance, type 2 diabetes, metabolic syndrome, dyslipidemia, systemic hypertension, and cardiovascular disease. 7 Males are two times more likely to have NAFLD than their female counterparts. Cohort studies have also found that Hispanic individuals have a significantly higher prevalence when compared to the general population. 8 The prevalence of NAFLD increases with age with peak between 40 and 65 years old. 8 There is evidence to suggest that NAFLD is a heritable condition in which family members of children with NAFLD should be considered at high risk for NAFLD even in the absence of obesity. 8

4

The signs and symptoms of NAFLD are non-specific. Unfortunately, most patient with NAFLD are neither asymptomatic nor presenting with specific complaints. The most common symptoms are fatigue and malaise. Patients can complain of vague, colicky, right upper quadrant pain. On physical exam, they may have evidence of hepatomegaly, but this may be difficult to discern in an obese patient. Patients are more likely to come to the attention of a provider from lab abnormalities, such as low platelets, or elevation in AST, ALT, bilirubin, creatinine, or INR, or evidence on imaging studies suggesting steatosis, which is often an incidental finding. Patients who have progressed to cirrhosis may demonstrate physical stigmata of chronic liver disease, displaying signs of splenomegaly, ascites, caput medusae, palmar erythema, jaundice, asterixis and/or spider telangiectasias, 9 or have no signs and symptoms at all. Patients with decompensated cirrhosis may present with hepatic encephalopathy, gastrointestinal tract bleeding, spontaneous bacterial peritonitis, acute renal failure, or shortness of breath indicative of hepatorenal or hepatopulmonary syndrome. 10

5

Nonalcoholic fatty liver (NAFL) and Nonalcoholic steatohepatitis (NASH) are not the same entity. These terms are not the same. NAFLD is the larger umbrella term that encompasses two very distinct subdivisions: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The primary distinguishing factor between the two is inflammation. In NAFL, there is hepatic steatosis only, without evidence of inflammation. In NASH, there is hepatic steatosis with inflammation, and hence the designation “hepatitis.” NASH is commonly associated with an increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) above normal, generally defined as greater than 19 in women and 30 in men, regardless of assigned lab “normal” ranges. 11 These lab values are commonly elevated two-to threefold upper limit of normal, but can oscillate between normal and elevated levels even with persistently active disease. Ultimately, a liver biopsy is needed to differentiate between the two entities. 12

6

NAFLD is a diagnosis of exclusion. It is paramount to differentiate NAFLD from other etiologies. This requires a thorough evaluation to identify potential risks for, or presence of, other etiologies that can cause similar presentations as treatment can vary dramatically. These include alcohol abuse, toxin-mediated injury, medication insult, infectious hepatitis, and genetic-related liver disease such as hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson’s disease. Auto-immune etiologies and pregnancy-related liver disease must also be considered. In the right clinical setting, the diagnosis of NAFLD can often be made after these disease processes have been ruled out. Laboratory tests such as the serum aminotransferases, alkaline phosphatase and ferritin can be helpful but are neither required nor sufficient for making the diagnosis. Imaging in the right clinical setting is sufficient to support the diagnosis of NAFLD. Ultrasound is relatively sensitive and specific for NAFLD and should be the first mode of imaging obtained when suspicion exists. Liver biopsy is the gold standard for definitive diagnosis, but often not required. Biopsy is the only way, however, to differentiate between the two histologic subtypes of NAFLD: NAFL and NASH. 13

7

To treat NAFLD, treat the underlying risk factors. The cornerstone for managing patients with NAFLD is to treat the underlying risk factors for this liver disease, with primary target of weight loss through lifestyle interventions including reduced caloric intake, a regular exercise regimen, and increasing muscle mass to increase the metabolic potential at rest. This is the foundation of treatment. Weight loss of 3-5% has been shown to provide significant improvement in steatosis. A greater weight loss goal of at least 10% can improve and reverse steatohepatitis, and has even been shown to reverse and resolve fibrosis! 3 Metformin remains a foundational treatment for type 2 diabetes but is not currently recommended as a NAFLD-specific treatment. Pioglitazone was shown to improve steatohepatitis, but in a predominantly nondiabetic population. A more recent randomized trial has further demonstrated that long-term pioglitazone treatment is safe and effective in patients with prediabetes, type 2 diabetes and NASH. 14 Vitamin E has also shown to improve liver histology in patients with NASH, but required a high dose of 800 units daily, and was unfortunately associated with an increased risk of prostate cancer in men and a controversial increase in all-cause mortality. 15 Ultimately, it is important to continue to treat and manage the patient’s underlying chronic comorbidities to include diabetes mellitus type 2, dyslipidemia, and obesity with primary treatment focus on 10% weight loss. 3

8

Consider a liver biopsy in patients diagnosed with NAFLD. Timing liver biopsy in patients with NAFLD should be thoughtfully deliberated. It may even be deferred until after a gastroenterology or hepatology consult is obtained. This outpatient procedure of liver biopsy is fairly straight-forward, but carries risks of morbidity and even rare mortality. The primary indications for liver biopsy in these patients include: confirmation of diagnosis, differentiation between NAFL and NASH, and staging of fibrosis. Outside of diagnostic question, however, it will rarely change active management, because primary treatment for all NAFLD patients is weight loss. Patients who are found to have NASH, and are at increased risk of advancing to fibrosis and cirrhosis, may have the most benefit from liver biopsy. Liver biopsy data may also provide a needed incentive to reach their weight loss goal. Studies have indicated that patients with increased risk of NASH include uncontrolled diabetes, severe obesity, advanced age and elevated AST/ALT ratio. 16 Alternatives to biopsy available to assess the severity of NAFLD and fibrosis include the NAFLD fibrosis score, fibrotest, magnetic resonance elastography and transient elastography depending on available resources.

9

Current guidelines do not recommend screening for NAFLD. Current guidelines do not recommend screening for NAFLD in primary care, including the high-risk obese and diabetic patients. This is primarily due to remaining uncertainties regarding the best method of diagnosis and treatment of NAFLD. However, there is supporting evidence from multiple studies that screened for NAFLD in high risk patients with non-invasive methods which could potentially lead to a change in future guideline recommendations. 17,18 As mentioned previously, liver chemistries can be within normal range despite having NAFL or NASH, thus does not make for an adequate screening test. Liver ultrasound is relatively more sensitive compared to liver chemistries, but this test can be expensive and time consuming as a screening test. However, incidental findings on imaging of hepatic steatosis does warrant further evaluation and should be worked up accordingly. 3

10

Refer to a specialist when you have exhausted your resources. Currently there are no definitive recommendations that delineate when to refer to a specialist. In general, if a patient has failed attempts of trying to manage their chronic comorbidities, or you are unsure of what to do next, it is reasonable to refer the patient to a specialist within that field. For NAFLD, it is generally recommended that a patient with evidence of steatohepatitis on biopsy, severely elevated aminotransferases, or suspicion of cirrhosis be referred to a gastroenterologist or hepatologist for further risk stratification and management, 3 and very reasonable to refer earlier in the course of disease to assess for liver diseases, need for liver biopsy, and treatment recommendations.

NAFLD is seen worldwide and is the leading cause of liver disorders in developed countries. In the Southern United States, among the middleaged population, it is thought that greater than 40% have NAFLD, which could lead to increased morbidity and mortality in a significant number of patients if left untreated. Therefore, it is important as primary care physicians to recognize NAFLD and the risk factors associated with NAFLD. Primary care physicians and mid-level providers are at the front lines of health care. Primary care providers have regular interaction with general patients in which the identification of lab abnormalities and incidental findings on imaging are first encountered. If identified, these findings are what will lead to the workup and subsequent diagnosis of NAFLD, which then allows for intervention, and hopefully prevention of advanced liver disease and transplant. Regular office visits provide a platform for patient education and counseling with a focus on weight loss and lifestyle modifications which are the cornerstones of treatment for NAFLD. If needed, primary care providers can then also appropriately refer patients to a specialist for further evaluation or continued surveillance of NAFLD. n

JUNE/JULY • JOURNAL MSMA 281

References

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5. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37: 917–923. doi:10.1053/ jhep.2003.50161.

6. https://www.cdc.gov/obesity/data/adult. html. Accessed June 22, 2017.

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12. Lall C, Aisen A, Bansal N, Sandrasegaran K. Nonalcoholic Fatty Liver Disease. Am J Roentgenol. 2008;190:4, 993-1002. doi: 10.2214/AJR.07.2052

13. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016;165:305-315. doi: 10.7326/M15-1774.

14. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Ann Intern Med. 2005;142:37-46. doi: 10.7326/0003-4819-142-1-200501040-00110.

15. Bedogni G, Nobili V, Tiribelli C. Epidemiology of fatty liver: An update. World J Gastroenterol. 2014;20(27):9050-9054. doi:10.3748/wjg.v20.i27.9050.

16. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology. 2006;43: S99–S112. doi:10.1002/hep.20973.

17. Doycheva I, Cui J, Nguyen P, et al. Non-invasive screening for NAFLD and advanced fibrosis in diabetes in primary care setting by MRI and MRE. Alimen Pharmcol Ther. 2016;43(1):83-95. doi:10.1111/apt.13405.

18. Kwok R, Choi KC, Wong GL, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut. 2016;65:1359-1368. doi: 10.1136/gutjnl-2015-309265.

Author Information: Internal Medicine Resident, ACP resident/fellow, Division of Internal Medicine, Captain, United States Air Force, Keesler Medical Center, Biloxi (Beck). Staff Gastroenterologist and Internal Medicine Teaching Faculty, Department of Gastroenterology, Hepatology, and Internal medicine, Major, United States Air Force, Keesler Medical Center, Biloxi (Gilkison). Post doctorate trained at Harvard Medical School, President of the Mississippi Chapter of the Gastroenterology Society, Partner of Digestive Health Center of Ocean Springs (McKee). Staff Gastroenterologist and Internal Medicine Teaching Faculty, Department of Gastroenterology, Hepatology, and Internal medicine, Lt. Colonel, United States Air Force, Keesler Medical Center, Biloxi (Plott).

Corresponding Author: JARED R. BECK, Internal Medicine Resident, ACP resident/fellow, Division of Internal Medicine, Captain, United States Air Force, Keesler Medical Center, Biloxi, MS becksta3@gmail.com.

282 VOL. 59 • NO. 6/7 • 2018