Diagnosis of NAFLD relies on abdominal imaging tests such as ultrasound or CT scan showing signs of fatty liver and excluding other conditions that can cause fatty liver or elevated liver tests. However, definitive diagnosis and determining whether a patient has NAFL or NASH currently requires doing a liver biopsy.

NAFLD is usually suspected based on findings of unexplained elevated aminotransferases or incidental finding of hepatic steatosis on abdominal imaging. Routine imaging studies such as ultrasound, CT scan, and MRI can only detect significant steatosis (>30 % steatosis), but cannot distinguish NAFL from NASH [39, 40]. Exclusion of concomitant chronic liver disease is done by testing for viral, autoimmune, and metabolic liver diseases. Other noninvasive methods are designed primarily to detect the fibrotic, but not the inflammatory component of NASH. These include different panels of serum markers or measurement of liver stiffness via a specially designed ultrasound or MRI (elastography) [13, 14, 41–44]. However concerns about their performance in detecting NASH and particularly NASH with advanced fibrosis are triggered by less than optimal accuracy when some of these noninvasive markers are tested in different cohort [44–46]. Liver biopsy remains the “gold standard” for the diagnosis of NAFLD and the identification of patients with NASH, despite its clinical risks and limitations [47].

Many patients with NAFLD have normal liver tests including those at risk for NASH with advanced liver fibrosis. Routine liver tests have poor sensitivity to detect liver damage in the setting of NAFLD and NASH.

Normal liver tests are common in patients with NAFLD [14]. When compared to those with elevated transaminases, patients with NAFLD and normal aminotransferases had the entire spectrum of NAFLD including NASH with advanced fibrosis [16]. In a recent report for a cohort with type 2 diabetes and normal aminotransferases, NAFLD diagnosed with magnetic resonance spectroscopy was diagnosed in 76 % of the patients, and NASH was diagnosed in 56 % of the subgroup of patients that agreed to liver biopsy, highlighting the poor sensitivity of ALT as a predictor of NAFLD or NASH [12].

Not every patient with NAFLD will need a liver biopsy but in some patients with NAFLD and risk factors for having NASH and significant liver fibrosis, a liver biopsy may be necessary. Such risk factors for severe NAFLD need to be carefully evaluated for by managing physician. Risk and benefits of the liver biopsy and potential change in management should also be discussed in details before proceeding with the biopsy.

The definitive diagnosis of NAFLD and its subphenotypes NAFL versus NASH is based on histological analysis of a liver biopsy sample. The presence of steatosis, hepatocellular ballooning, and lobular inflammation, with or without fibrosis, are necessary criteria for diagnosis of NASH (Fig. 14.1) [1, 2]. Although liver biopsy is generally a safe procedure, its invasive nature and associated small risk of complications limits its wide scale routine use to diagnose NASH [48, 49]. Therefore, selection of patients with NAFLD for liver biopsy should be based on their estimated risk for having NASH with advanced fibrosis and after discussing the risks of liver biopsy and impact of information obtained on prognosis and management. Validated risk factors for NASH include diabetes or glucose intolerance, advanced age, high body mass index, high ALT, sleep apnea, high triglycerides, and low platelets [13, 14, 50, 51]. The current multisociety guidelines recommends using the NAFLD fibrosis score (http://​nafldscore.​com) as an easily accessible tool that includes many of the validated risk factors for NASH and advanced fibrosis, to choose NAFLD patients at risk for NASH with advanced fibrosis for liver biopsy [13, 47].

Serious liver-related complications such as cirrhosis, liver failure, and cancer may develop in some patients. Current evidence suggests that these complications are most likely to happen in patients with NASH and particularly those who have significant fibrosis. The majority of patients with NAFL will not develop these complications.

While patients with NAFL do not usually develop liver complications , those with NASH are at increased risk for progressive hepatic fibrosis (in 32–41 %), development of cirrhosis (in 5–25 %), liver failure (in 45–52 % of NASH cirrhosis), and hepatocellular carcinoma (HCC) (in 2.5–7 %) [52–59]. Therefore, the liver-related outcomes largely depend on the baseline NAFLD phenotype [7, 40, 47]. In patients with NASH, the single histological lesion that is most predictive of liver-related events is fibrosis and particularly advanced fibrosis [40, 59, 60]. There are emerging reports of HCC in patients with NAFLD without cirrhosis or even significant fibrosis [61–63]. While this phenomenon is interesting, it is unknown if it reflects co-occurrence of a common disease, NAFLD, with HCC which is known to occur without cirrhosis in some patients (estimated at 5 % in the US and Europe and 40 % in Asia) [64] or if it is related to sampling error of surrounding hepatic tissue resulting in underestimation of fibrosis.

NAFLD increases the risk for cardiovascular disease (CVD ) and type 2 diabetes. The top three causes of death in patients with NAFLD are CVD, nonhepatic malignancies, and liver-related death, with the later tending to occur mainly in patients with NASH.

NAFLD, regardless of the underlying phenotype, is also an independent risk factor for CVD and type 2 diabetes [11, 40, 65–67]. CVD is the leading cause of death in patients with NAFLD followed by nonhepatic malignancies and cirrhosis-related events [52, 65, 68, 69]. Patients with NASH are at much higher risk for cirrhosis-related death than those with NAFL [40, 52, 59].

Weight loss is recommended for all patients with NAFLD. Mild to moderate weight loss of 3–7 % of baseline body weight may result in significant improvement in NAFL and NASH. Bariatric surgery in the morbidly obese patients with NAFL or NASH may result in improvement or resolution of NAFLD. For patients with biopsy proven NASH without cirrhosis or diabetes, vitamin E or pioglitazone can be considered as a treatment that may improve liver injury with long-term use.

The most tested effective options are weight loss, vitamin E, and pioglitazone. Mild weight loss of 3–5 % of starting body weight is sufficient to improve insulin sensitivity, aminotransferases, hepatic steatosis by various imaging modalities, and liver histology [70–88].

Improvement in NASH histological lesions such as steatosis, ballooning, and lobular inflammation usually requires more weight loss of ≥7 % of baseline weight [72, 77, 86, 87, 89, 90]. Regardless of the degree of associated weight loss, resistance or aerobic exercise can improve insulin sensitivity and hepatic steatosis [77, 80, 88, 91]. Furthermore, physical fitness predicts the risk of NAFLD and increased fitness correlates with resolution of fatty liver by magnetic resonance spectroscopy [91].

Bariatric surgery results in sustainable and considerable loss of excess weight (>30 %) in the morbidly obese, which is associated with remarkable improvement or resolution of liver injury in patients with NAFL and NASH, in addition to significant improvement in the associated metabolic comorbidities [92–102]. Certain types of bariatric surgery such as jejunoileal and biliointestinal bypasses are associated with worsening hepatic fibrosis in patients with NAFLD [95, 99, 103]. There is paucity of data about the safety of bariatric surgery in patients with NASH cirrhosis with or without portal hypertension.

Of the many antioxidants , vitamin E has been the best studied in patients with NAFLD [4, 104–108]. In the largest randomized study to date in NASH, the PIVENS, vitamin E 800 IU daily was compared to pioglitazone 30 mg daily or placebo for 96 weeks in NASH patients without underlying cirrhosis or diabetes [4]. Vitamin E and Pioglitazone resulted in improvement in hepatic steatosis, lobular inflammation, hepatocellular ballooning but without significant improvement in fibrosis. NASH resolution was observed in 43 % of subjects on vitamin E, 34 % of subjects on pioglitazone and 19 % of subjects on placebo. Unlike pioglitazone , there was no increase in weight seen in subjects taking vitamin E. The associations of vitamin E with increased mortality and prostate cancer have been subject to debate [109–114]. The safety and efficacy of vitamin E in patients with diabetes and cirrhosis is unknown. Vitamin E is considered a first line option for NASH patients without cirrhosis or diabetes according to the recent multisociety guidelines [47].

Several other studies showed similar beneficial effects of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on NASH histology [115–117]. Concerns about long term safety of thiazoloidinediones (TZDs) in diabetic patients have been raised with reports of increased risk of congestive heart failure, bladder cancer, and bone fractures [118, 119]. The current multisociety guidelines recommend that pioglitazone may be used with caution to treat nondiabetic patients with biopsy-proven NASH [47].

A recent large randomized trial testing the effects of 72 weeks of obeticholic acid , a farnesoid X receptor portent agonist, in patients with NASH showed significant improvement in all NASH histological lesions compared to placebo [5]. While these results are encouraging, additional clinical trials are needed to confirm the efficacy and define the safety profile of obeticholic acid.

Available data from clinical trials do not convincingly show efficacy for other agents for NASH such as metformin, ursodeoxycholic acid, or long-chain polyunsaturated fatty acids and therefore these cannot be recommended for patients with NASH at the present time [107, 120–124].

Statins can be safely used in patients with NAFLD with or without elevated liver tests. Having NAFLD does not increase the risk for liver toxicity from statins. The benefit of cardiovascular disease risk reduction with statins far outweighs the remote risk of severe liver toxicity in patients with NAFLD.

The safety of statins in patients with NAFLD has been demonstrated in several studies [125–127]. The incidence of severe elevations in transaminases in patients with presumed NAFLD and underlying increased transaminases was not significantly different than that in patients with dyslipidemia and normal transaminases receiving statins or patients with liver disease and elevated transaminases who did not receive a statin [126]. Another study evaluated the course of baseline increased liver enzymes in patients with coronary artery disease who either received or did not receive statin [125]. A decline in increased liver tests with statin use was observed compared to continued increase in patients not receiving statin. The number of cardiovascular events was significantly higher in patients who did not get statin (30 % versus 10 %; relative risk reduction 68 %, p < 0.0001). The improvement in liver tests and potential improvement in liver histology with statins use in patients with NAFLD has been reported in other smaller studies [128–134]. Acute liver failure due to statin use necessitating liver transplantation is very rare [135]. Based on this data, the strong relationship between NAFLD and increased risk of CVD and the fact CVD is the leading cause of death in patients with NAFLD [7, 40, 65, 66, 136], there is no justification to withhold statins from NAFLD patients who have appropriate indications for their use. Statins should only be stopped in the rare situation of severe liver injury manifesting as severe elevation in the liver enzymes, jaundice, or liver failure [137].

NAFLD is the most common liver disease in children. A diagnosis of NAFLD in a family member, adult or child, increases the risk of NAFLD in other family members.

NAFLD is the most common liver disease in children in the US [138]. In an Autopsy series, 13 % of children had NAFLD, of whom 18 % had NASH [139]. The prevalence of NAFLD increases with age and follows the same ethnic distribution observed in adults [139]. A combination of shared environmental factors such as dietary habits and activity patterns in families, with genetic factors may increase the risk of first degree family members with NAFLD to have the disease. Family studies suggest increased frequency of NASH or cryptogenic cirrhosis in addition to obesity and diabetes in relatives of patients with NASH [140]. Another study reported one out of five patients with NASH had a first degree relative with NASH [141]. On the other hand, NAFLD in children is associated with a high risk of NAFLD in their families with a study showing 78 % of parents and 59 % of siblings having NAFLD [142].

In patients with NASH cirrhosis who develop liver failure or HCC , liver transplantation should be considered as an option to improve patient survival and quality of life. Careful systematic evaluation of patients is necessary to determine candidacy. In particular, meticulous evaluation and optimization of CVD is necessary for excellent outcomes. With proper selection of candidates, and optimal control of associated obesity, cardiac and metabolic conditions, the outcomes of liver transplantation for patients with NASH are excellent.

Patients with NASH cirrhosis who develop liver failure or early stage HCC should be evaluated for liver transplantation . Liver transplantation for NASH is increasingly common and is currently the third most common indication for liver transplantation in the US [143–145]. Patients with NASH cirrhosis who are listed for liver transplantation are usually older, and have higher body mass index and lower incidence of HCC than those listed for other indications [143, 146]. And because they have high prevalence of CVD, a thorough cardiac evaluation prior to listing is critical to ensure optimization of the cardiac status and outcomes post-transplantation [147]. The patient survival at 1- and 3-year following transplantation for NASH cirrhosis is excellent [143–145, 148]. Patient or graft survival is not affected by NAFLD recurrence post-transplantation, which has been reported in up to 40 % of patients [145, 149–151]. Excellent control of associated metabolic comorbidities and obesity is essential for successful outcome after liver transplantation [152].