Nonalcoholic Fatty Liver


Article Author:
Pujitha Kudaravalli


Article Editor:
Savio John


Editors In Chief:
Hela Kchir
Joseph Lee
Savio John


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Khalid Alsayouri
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Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
4/20/2019 10:02:00 AM

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a broad term used to cover a spectrum of conditions which are characterized by evidence of hepatic steatosis on imaging or histology (macro-vesicular steatosis), and absence of secondary causes of hepatic steatosis such as significant alcohol consumption, chronic use of medications that can cause hepatic steatosis, or hereditary disorders. The definition of significant alcohol consumption has not been consistent, and for NASH clinical trials it has been defined as ongoing or recent consumption of more than 14 standard drinks on average per week in women and more than 21 standard drinks on average per week in men. Non-alcoholic fatty liver disease is most often diagnosed incidentally on imaging or when it presents with complications. The prevalence of NAFLD in western countries is around 20 to 30 %.[1] NAFLD is considered to be the liver manifestation of metabolic syndrome. 50 to 70% of people with diabetes are found to have NAFLD.[2]

NAFLD has several phases of progression which include simple steatosis, steatohepatitis, fibrosis, cirrhosis and ultimately could even progress to hepatocellular carcinoma. The disease has a benign course; it is a silent liver disease when the only histological finding is steatosis. The presence of hepatic injury with inflammation with or without fibrosis constitutes non-alcoholic steatohepatitis (NASH).[1][3] Please refer to the chapters on hepatitis, nonalcoholic steatohepatitis under transplant hepatology section for a detailed discussion of this topic.

Etiology

Obesity, diabetes, dyslipidemias, insulin resistance and metabolic syndrome are known to be associated with the development of non-alcoholic fatty liver disease.[3] A temporal association has also been shown between inorganic arsenic exposure and the development of NAFLD reflected by elevated alanine transferase (ALT).[4] Due to its close association with metabolic syndrome, NAFLD correlates with cardiovascular risk factors which also contributes to mortality in these patients in addition to end-stage liver cirrhosis and hepatocellular carcinoma. 

Epidemiology

Non-alcoholic fatty liver disease (NAFLD) incidence is rapidly increasing especially in Western countries. Increasing obesity levels, increasing incidence of childhood obesity, sedentary lifestyles, consumption of unhealthy quick eats, and a longer lifespan are some of the likely contributors.  The incidence and prevalence of NAFLD are underestimated as ultrasonography is commonly used to screen for fatty liver disease. The prevalence of NAFLD is 80 to 90% in obese adults, 30 to 50% in patients with diabetes mellitus, 90% or more in patients with hyperlipidemia, 3 to 10% in children and as high as 40 to 70% among obese children.[5]

Pathophysiology

Both environmental and genetic factors are contributing factors in the development of non-alcoholic fatty liver disease and its progression. First-degree relatives of patients with NAFLD are at higher risk than the general population. Histone amino-terminal ends, maintain the chromatin structure and gene expression that is cAMP-responsive element binding protein H (CREBH) or SIRT1. Genetic studies have shown that activation of SIRT1 is thought to play a role in the development of NAFLD. The trigger of the progression of NAFLD to cancer is via abnormal DNA methylation.[6]

Day and James proposed a two-hit model of pathogenesis in 1998. The first hit is caused by insulin resistance which leads to accumulation of fat droplets that is triglycerides in the cytoplasm of hepatocytes leading to the development of steatosis. Insulin resistance causes excess delivery of free fatty acid and triglycerides to the liver and decreased excretion leading to accumulation. Also, excess carbohydrates are also a stimulus for de no fatty acid synthesis in the liver

The second hit causing hepatocellular injury and the development of NASH is multifactorial. Excessive fatty acids in the liver make the liver more vulnerable to injury. Peroxisomal fatty acid oxidation, ROS production from the mitochondrial respiratory chain, cytochrome P450 metabolism of fatty acids, hepatic metabolism of gut-derived alcohol is hypothesized to cause the injury. Obesity also contributes to the second hit as adipose tissue releases inflammatory mediators such as leptin, TNF- alpha and IL-6 causing hepatocyte damage. The hepatocytes undergo ballooning, cytoskeletal aggregation, apoptosis, and necrosis.[7] 

Insulin resistance is also a part of the second hit. The sinusoidal collagen deposition caused by the activation of hepatic stellate cells and the portal fibrosis caused by the ductular proliferation leads to the development and progression of NASH. These changes have correlated with insulin resistance which is now believed to cause the progression of steatosis to NASH and progressive fibrosis.[8] 

Histopathology

Non-alcoholic fatty liver disease is more than 10 % of hepatocytes with fat droplets on liver biopsy. Functionally, the liver subdivides into 3 zones; the classification is made based on the oxygen supply. Zone 1 has the highest oxygenation (oxygenated blood from hepatic arteries) and encircles the portal tracts, and Zone 3 encircles the central veins where the oxygenation is poor.

American Association for the Study of Liver Diseases (AASLD) defined the histopathological abnormalities required in the diagnosis of NASH which includes steatosis (macro more than micro), lobular inflammation and hepatocellular ballooning is seen most apparently in the zone 3 steatotic liver cells. Fibrosis, although not necessary for the diagnosis is usually present. Some other findings seen are Mallory-Denk bodies (MDB, eosinophilic intracytoplasmic inclusions), megamitochondria, glycogenated nuclei, and iron deposition.[9]

Fibrosis starts in the acinar zone 3 and has the appearance of chicken wire from the deposition of collagen and other extracellular matrices along the sinusoids. NASH-related cirrhosis is macronodular or mixed. When cirrhosis develops the other histological features may not be evident.[8]

History and Physical

Patients with non-alcoholic fatty liver disease could present with many non-specific symptoms way before the diagnosis is made although most patients are asymptomatic. Fatigue is one of the most common presenting symptoms. Sharp or dull aching upper abdominal pain, thirst, bloating and sleep disturbances.[10] Patients who develop NASH-associated cirrhosis, end-stage liver disease or HCC present with symptoms like:

  • Nausea
  • Vomiting
  • Jaundice
  • Pruritis
  • Ascites
  • Memory impairment
  • Easy bleeding
  • Loss of appetite 

The most common clinical sign is mild to moderate hepatomegaly. Advanced stages of the spectrum can demonstrate signs of end-stage liver disease such as:

  • Jaundice
  • Spider angiomas
  • Palmar erythema
  • Caput medusae
  • Gynecomastia
  • Dupuytren contracture
  • Ascites
  • Petechiae

Evaluation

Mildly elevated serum aminotransferases are the primary abnormality in non-alcoholic fatty liver disease although the liver enzymes are normal in the majority of patients. The ratio of AST to ALT is less than 1. GGT, when elevated in NAFLD, can be a marker of increased mortality. With the progression of the disease hypoalbuminemia, hyperbilirubinemia, thrombocytopenia and prolonged prothrombin time present due to hepatic synthetic dysfunction. 

Ultrasound of the abdomen is routinely used to evaluate for fatty liver, but a liver biopsy is considered the gold standard for the diagnosis of NAFLD.  A non-invasive clinical scoring system called NAFLD-MS score was developed to predict the development of NAFLD in patients with metabolic syndrome. The clinical predictors included are BMI greater than or equal to 25, AST/ALT greater than or equal to 1, type 2 diabetes mellitus and obesity. The positive likelihood ratio of developing NAFLD is 2.32 (low when the score is less than 3), and the risk is 7.77 (high when the 5 or more).[11] Some of the other scoring systems are NAFLD fibrosis score (NFS), FIB-4 (Fibrosis-4) Index, original ELF test, AST-to-platelet ratio index (APRI), AAR, FibroMeter, NAFLD-MS score.[12] 

Treatment / Management

Lifestyle changes are recommended for all patients with non-alcoholic fatty liver disease even without NASH as these patients have metabolic derangements and are at risk for the development of cardiovascular diseases. A weight loss of 3 to 5% in simple steatosis and a weight loss of 7 to 10% in NASH is the recommendation. Adequate control of risk factors like hyperlipidemia with statins (it also protects from cardiovascular risks), hypertension, adequate glycemic control is required. Please refer to the chapters on hepatitis, nonalcoholic steatohepatitis under transplant hepatology section for a detailed discussion of this topic.

Patients with NASH are to followed by hepatologists or gastroenterologists. NASH with cirrhosis require hepatocellular carcinoma surveillance with an ultrasound every 6 months. Several clinical trials are being conducted using anti-fibrotic, anti-apoptotic, and immune therapies for the treatment of NAFLD.[13]

Differential Diagnosis

The differential diagnosis of non-alcoholic fatty liver disease  (conditions that can also cause hepatic steatosis) include:

  • Alcoholic liver disease
  • Hepatitis C, particularly genotype 3
  • Wilson disease
  • Medications such as amiodarone, methotrexate, tamoxifen, glucocorticoids, valproate, anti-retroviral agents for HIV
  • Reye syndrome
  • Mitochondrial hepatopathies
  • Kwashiorkar/anorexia nervosa
  • Mitochondrial disorders

Staging

The grading and stages of non-alcoholic fatty liver disease are described below[14][15][9]

Grades:

  • Grade 1 (mild): Steatosis up to 66%, occasional ballooning in zone 3, scattered polymorphs with or without lymphocytes, mild or no portal inflammation
  • Grade 2 (moderate): Any degree of steatosis, obvious ballooning predominantly in zone 3, intralobular inflammation with polymorphs and chronic inflammation and mild to moderate portal inflammation
  • Grade 3 (severe): Panacinar steatosis, ballooning and obvious disarray predominantly in zone 3, intralobular inflammation with scattered polymorphs with or without mild chronic  and mild to moderate portal inflammation

Stages:

  • Stage 0: No fibrosis
  • Stage 1: Zone 3 perisinusoidal fibrosis only
  • Stage 2: Zone 3 perisinusoidal and periportal fibrosis
  • Stage 3: Bridging fibrosis
  • Stage 4: Cirrhosis

Prognosis

Patients with non-alcoholic fatty liver disease exhibit increased mortality rates when compared to the general population.  These patients have a high risk of mortality from cardiovascular causes as these patients have metabolic derangements. Cardiovascular causes of mortality are higher in these patients over liver causes.[13] NAFLD is a slowly progressive disease; simple steatosis is reversible and non-progressive whereas NASH can progress to cirrhosis. Over a 13 year follow up, the progression of cirrhosis presented in 41% in a study done by Ekstedt et al.[16] A meta-analysis was done by White et al., showed that in cohorts of NADLF or NASH with few or no cases of cirrhosis the risk of developing HCC was minimal at 0 to 3% over 20 years and in cohorts with NASH with cirrhosis the risk was high at 2.4 % over 7 years.[17] 

Complications

The most important complications in the descending order are cardiovascular disease, hepatocellular carcinoma, end-stage liver disease. The severity of these complications is proportional to the severity of the histological stage and grade of the liver disease. 

Deterrence and Patient Education

Education of patients is crucial to obtain the best patient outcomes. Some of the resources include:

  • UpToDate: Nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH) - The Basics and Beyond the Basics
  • American College of Gastroenterology

Enhancing Healthcare Team Outcomes

The incidence and prevalence of non-alcoholic fatty liver disease are rising and will continue to rise due to increasing obesity and lifestyle changes. The management of NAFLD will require a multidisciplinary team that consists of a primary care physician, nurse practitioner, hepatologist or gastroenterologist, nutritionist, endocrinologist, bariatrician. Primary prevention with adequate management of metabolic derangement is essential to prevent the rising incidence of NAFLD and its associated complications. To lower the risk of heart disease, patients should be urged to reduce body weight, discontinue smoking, eat a healthy diet and participate in regular exercise.

Management of NAFLD should is optimal with an interprofessional health care team that includes physicians, specialists, specialty-trained nurses, and where appropriate, pharmacists. These different disciplines need to engage in open communication about the patient to assure the best possible outcomes.


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Nonalcoholic Fatty Liver - Questions

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A 40-year-old obese female presents for a routine follow up to her primary care provider. She reported increasing fatigue for the last year. On physical examination the patient was afebrile, heart rate was 71 bpm, blood pressure was 120/76 mm Hg and RR of 10/min. The patient is currently not taking any medications. The patient denied smoking, alcohol or any other illicit drug use. Labs showed hemoglobin -11 g/dl, WBC- 6000/microL, platelet- 320,000, microL, AST -160 u/L, ALT -100 u/L, ALP -70 u/L, total bilirubin -0.8 mg/dL, hepatitis panel -negative, and iron panel -normal. A liver biopsy was done. What is the finding on the biopsy?



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A 70-year-old male follows up for NASH-related cirrhosis. Past medical history is significant for hypertension, diabetes mellitus type II, major depressive disorder, obesity, hyperlipidemia, and obstructive sleep apnea on continuous positive airway pressure (CPAP) at night. The patient's current medications include insulin glargine, insulin lispro, losartan, atorvastatin, and fluoxetine. The patient is doing well during this visit and has no complaints. A surveillance 6-month ultrasound is sought, which shows no signs of hepatocellular carcinoma. Which of his co-morbidities is shown to be the most closely associated with the development and progression of non-alcoholic fatty liver disease (NAFLD)?



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A 65-year-old alcoholic male presents to his primary care provider for an annual visit. The patient has a history of uncontrolled diabetes mellitus type II and hypertension. The patient also has a history of obesity and drinks three sodas every day. Recently he has noticed breast enlargement, excessive nausea, loss of appetite, pruritis and easy bleeding. What surveillance tool is required in these patients to avoid the development of a sinister complication of this disease?



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Nonalcoholic Fatty Liver - References

References

Milić S,Stimac D, Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. Digestive diseases (Basel, Switzerland). 2012;     [PubMed]
Lee YH,Cho Y,Lee BW,Park CY,Lee DH,Cha BS,Rhee EJ, Nonalcoholic Fatty Liver Disease in Diabetes. Part I: Epidemiology and Diagnosis. Diabetes     [PubMed]
Aguilera-Méndez A, Nonalcoholic hepatic steatosis: a silent disease Revista medica del Instituto Mexicano del Seguro Social. 2019 Mar 15;     [PubMed]
Frediani JK,Naioti EA,Vos MB,Figueroa J,Marsit CJ,Welsh JA, Arsenic exposure and risk of nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults: an association modified by race/ethnicity, NHANES 2005-2014. Environmental health : a global access science source. 2018 Jan 15;     [PubMed]
Saokaew S,Kanchanasuwan S,Apisarnthanarak P,Charoensak A,Charatcharoenwitthaya P,Phisalprapa P,Chaiyakunapruk N, Clinical risk scoring for predicting non-alcoholic fatty liver disease in metabolic syndrome patients (NAFLD-MS score). Liver international : official journal of the International Association for the Study of the Liver. 2017 Oct;     [PubMed]
Bellentani S,Scaglioni F,Marino M,Bedogni G, Epidemiology of non-alcoholic fatty liver disease. Digestive diseases (Basel, Switzerland). 2010;     [PubMed]
Khoonsari M,Mohammad Hosseini Azar M,Ghavam R,Hatami K,Asobar M,Gholami A,Rajabi A,Safarnezhad Tameshkel F,Amirkalali B,Sohrabi M, Clinical Manifestations and Diagnosis of Nonalcoholic Fatty Liver Disease. Iranian journal of pathology. 2017 Spring;     [PubMed]
Basaranoglu M,Neuschwander-Tetri BA, Nonalcoholic Fatty Liver Disease: Clinical Features and Pathogenesis. Gastroenterology     [PubMed]
Del Campo JA,Gallego-Durán R,Gallego P,Grande L, Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD). International journal of molecular sciences. 2018 Mar 19;     [PubMed]
Takahashi Y,Fukusato T, Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World journal of gastroenterology. 2014 Nov 14;     [PubMed]
Brunt EM,Tiniakos DG, Histopathology of nonalcoholic fatty liver disease. World journal of gastroenterology. 2010 Nov 14;     [PubMed]
Brown GT,Kleiner DE, Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism: clinical and experimental. 2016 Aug;     [PubMed]
Obika M,Noguchi H, Diagnosis and evaluation of nonalcoholic fatty liver disease. Experimental diabetes research. 2012;     [PubMed]
Ekstedt M,Franzén LE,Mathiesen UL,Thorelius L,Holmqvist M,Bodemar G,Kechagias S, Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology (Baltimore, Md.). 2006 Oct;     [PubMed]
White DL,Kanwal F,El-Serag HB, Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2012 Dec;     [PubMed]
Machado MV,Cortez-Pinto H, Non-alcoholic fatty liver disease: what the clinician needs to know. World journal of gastroenterology. 2014 Sep 28;     [PubMed]
Brunt EM,Janney CG,Di Bisceglie AM,Neuschwander-Tetri BA,Bacon BR, Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. The American journal of gastroenterology. 1999 Sep     [PubMed]

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