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HanneleYki-Järvinen
PanuLuukkonen
SamiQadri
PerttuArkkila

Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)

Essentials

  • Obesity and diabetes, as well as alcohol consumption, are the most significant predictors of severe liver events in many countries.
  • The term non-alcoholic fatty liver disease (NAFLD) covers a spectrum of diseases from pure non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), advanced fibrosis (NAFLD and F3 or F4 fibrosis), and liver cirrhosis (NAFLD and F4 fibrosis). NAFLD also increases the risk of hepatocellular carcinoma.
  • Pure fatty liver (NAFL) need not be looked for in patients with metabolic syndrome or type 2 diabetes, and they need not be referred for assessment in specialized care for this purpose.
  • In outpatient care, at least patients presumed to have advanced fibrosis should be identified (see Examination and diagnosis).
  • A person may have several risk factors for fatty liver disease, such as type 2 diabetes, obesity and alcohol consumption.
  • The primary steps in treating fatty liver are provision of lifestyle guidance (weight loss and avoiding food and drink containing saturated fat and ‘fast' sugars, such as soft drinks and sweets, and physical activity).
  • See also the articles on Assessing patients with abnormal liver function test results Assessing a Patient with an Abnormal Liver Function Test Result and Metabolic syndrome Metabolic Syndrome.

Examination and diagnosis

Diagnostic criteria for NAFLD

  • Presence of fatty liver. This may be suggested by slightly elevated ALT levels but ALT levels are normal in 50% of patients with fatty liver.
    • Fatty liver is often an incidental finding made in ultrasonography or other imaging (MRI/CT).
    • However, imaging specifically to look for pure fatty liver (NAFL) is not necessary.
  • Patients are usually, albeit not always, overweight (BMI ≥ 25 kg/m2 ) or have type 2 diabetes or metabolic syndrome.
  • To diagnose NAFLD, other causes of fatty liver and particularly excessive alcohol consumption (in men ≥ 3 units/day [≥ 36 g/day] and in women ≥ 2 units/day [≥ 24 g/day], on an average) must have been excluded.
  • Patients with mainly non-alcoholic fatty liver should be diagnosed with fatty liver (ICD-10: K76.0).
  • For causes of fatty liver, see table T1.

Causes of fatty liver (steatosis)

Metabolic syndrome (type 2 diabetes / insulin resistance, obesity)
Alcohol consumption
Hepatitis C (genotype 3), hepatitis B
Drugs (methotrexate, glucocorticoids, tamoxifen, amiodarone, oestrogens, anti-retroviral medication)
Rare causes: autoimmune diseases, haemochromatosis, psoriasis, Wilson's disease, apoprotein B deficiency, hypothyroidism, starvation, parenteral nutrition, excessive intake of medium-chain triglycerides (MCT; coconut fat and oil, tube feeding formulas with MCT), HIV
Causes of microvesicular steatosis, such as drugs (valproate, tetracycline), pregnancy

Detection of advanced fatty liver disease in patients with metabolic syndrome or type 2 diabetes

  • There is no need to look specifically for pure fatty liver (NAFL) because these patients probably do have fatty liver.
  • Among these patients, those with advanced liver disease (fibrosis, cirrhosis) or hepatocellular carcinoma should be identified.
  • Advanced liver disease cannot be diagnosed based on liver enzymes or ultrasonography.
    • Upper abdominal ultrasonography is not sufficiently sensitive to exclude advanced fibrosis.
    • NASH can only be diagnosed by liver biopsy.
  • A recommended means of detecting advanced fibrosis is determining the FIB-4 index http://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis based on the patient's age, AST, ALT and platelet levels (see figure ).
  • If the FIB-4 index is in the ”grey area” (see the flow chart), you can additionally calculate the NAFLD Fibrosis Score (NFS) http://www.mdcalc.com/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score, for which you will need, in addition to the data listed above, the patient's body mass index and information about any impaired fasting glycaemia or diabetes and plasma albumin concentration.
  • In people with type 2 diabetes, FIB-4 should be determined in association with every regular checkup to assess any increased risk of fibrosis.
  • If a patient has metabolic syndrome without type 2 diabetes, and an elevated ALT level is found in association with some other examination, according to the flow chart FIB-4 should be calculated, as well as NFS, as necessary.
  • Elastography is a non-invasive examination for quite reliable detection of advanced fibrosis. But elastography is not always available, as yet.
  • For workup, see table T2.

Aetiological workup in patients with fatty liver disease

Detection of metabolic syndrome (BMI, lipids, blood pressure, fasting glucose, HbA1c)
Detection of high-risk alcohol consumption (see Detecting substance abuse Recognition of Alcohol and Drug Abuse)
History: family history of cirrhosis, use of alcohol (AUDIT calculator Audit), drugs, hormonal or natural products
Clinical examination to exclude advanced liver disease: spider naevi, palmar erythema, yellow skin and sclerae, ascites, muscular wasting
Upper abdominal ultrasonography
Elastography, if available
Laboratory tests, as far as applicable:
  • To define the functional capacity of the liver, albumin, bilirubin levels, thromboplastin time (PT or INR, if PT is not available)
  • To exclude viral hepatitis, HCVAb, HBsAg

Workup for fatty liver found in association with other imaging

  • Causes of fatty liver, see table T1.
  • Assessment of the risk of fibrosis: see figure
  • Fatty liver found incidentally in imaging studies (ultrasonography, CT, MRI) is a reason to find out whether the patient has one of the conditions listed below.
    • Metabolic syndrome Metabolic Syndrome or risk factors for diabetes Newly Diagnosed Type 2 Diabetes
      • Fatty liver significantly increases the risk of metabolic syndrome regardless of body mass index or alcohol consumption.
      • In patients with NAFLD, weight loss is particularly important because it can decrease both the cardiovascular risk and the risk of NAFLD progressing to advanced liver disease (fibrosis, cirrhosis, hepatocellular carcinoma).
      • Persistently high liver enzyme values are an indication for further examinations to find out whether the patient has advanced liver disease with a more serious prognosis than just fatty liver.
    • Signs of advanced fibrosis can be sought clinically or with risk calculators; see table T2, figure .
    • Other reasons for elevated liver values, such as alcohol or drugs, etc. (see also Assessing a Patient with an Abnormal Liver Function Test Result)
  • First-line tests

Treatment

  • Treatment plans for patients with pure fatty liver (NAFL) should be made in primary health care.
  • Patients with NAFL should undergo medical assessment of the risk of fibrosis every 1-2 years (figure ), even though pure fatty liver disease probably progresses slowly. Follow-up is mainly performed within primary health care.
  • For overweight or obese patients, the primary treatment is weight loss Conservative (Non-Surgical) Treatment of Obesity, the target being 10% per year.
  • Suitable patients can be referred for locally available healthy weight loss coaching or to a weight control group. Relevant services may also be available online.
  • Persistently obese, motivated patients should be referred to an outpatient obesity clinic in specialized care for consideration of bariatric surgery, for instance, if the BMI is ≥ 35 kg/m2 (see also Bariatric Surgery (Obesity Surgery))
  • Weight loss will improve all histological changes in the liver, including fibrosis, in direct proportion to the weight loss (see e.g. Table 1 and Figure 3 in http://www.gastrojournal.org/article/S0016-5085(15)00496-5/fulltext).
  • Dietary intake of saturated fats (such as butter, coconut fat, sausages and cheeses high in fat) and energy dense fast sugars, such as soft drinks with sugar, energy drinks and sweets, should be avoided, in particular. Provide the patient with adequate guidance.
  • Both aerobic exercise and exercise increasing muscle strength and endurance (strength training) reduce liver fat content. The average recommendation is to take moderately intense exercise (aerobic or gym exercise) 3-5 times a week for a total of 150-200 min.
  • Avoiding alcohol and drugs or natural products contributing to the accumulation of fat in the liver

Consulting specialized care

  • If a FIB-4 or NFS calculator shows a high risk of advanced fibrosis, the patient should be referred to specialized care (figure ).
  • If elastography is available in primary health care, it can be used to screen for patients needing referral to specialized care.
  • Before referral to specialized care, the examinations listed in table T2 should be performed.
  • For the workup in specialized care, see table T3.

The tasks of specialized care in non-alcoholic fatty liver disease

The aetiology of fatty liver should be confirmed by additional workup, as necessary
  • For rare causes of steatosis, see table T1.
  • Elastography, if not already performed, and a decision on liver biopsy
If liver biopsy shows NASH and fibrosis F2-F3
  • Exclusion of hepatocellular carcinoma
  • Close cooperation with a unit specialized in treating obesity
  • Cooperation with a bariatric surgery team; consider bariatric surgery if the BMI exceeds 35 kg/m2 despite conservative treatment and pharmacotherapy
  • Planning and follow-up of pharmacotherapy
NAFLD cirrhosis
  • Determining the severity of liver disease based on the Child-Pugh score http://www.mdcalc.com/child-pugh-score-cirrhosis-mortality
  • Gastroscopy to exclude oesophageal varices
  • Exclusion of hepatocellular carcinoma
  • Consultation of a bariatric surgeon particularly if there are signs of liver fibrosis, if conservative treatment and pharmacotherapy have been used for several years with no success, and if there are no contraindications for surgery (such as decompensated liver cirrhosis, jaundice, ascites, bleeding oesophageal varices)
  • Planning of follow-up and treatment
The PNPLA3 gene http://medlineplus.gov/genetics/gene/pnpla3/ test can be considered in specialized care for patients whose fatty liver is not explained by metabolic syndrome.

    References

    • European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-402. [PubMed].
    • Canbay A, Sowa JP, Syn WK, et al. NASH Cirrhosis - the New Burden in Liver Transplantation: How Should It Be Managed? Visc Med 2016;32(4):234-238. [PubMed].
    • Non-alcoholic fatty liver disease (NAFLD): assessment and management. NICE guideline NG49. Published: 06 July 2016 http://www.nice.org.uk/guidance/ng49
    • Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014;2(11):901-10. [PubMed]
    • Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142(7):1592-609. [PubMed]