**7. NAFLD in special populations**

**Patients with insulin resistance.** Insulin resistance can be estimated using the homeostasis model for assessing of insulin resistance (HOMA-IR), calculated as the product of fasting in‐ sulin level (mUI/ml) and plasma glucose level (mmol/ml), divides by 22,5 [29]. Portal fibro‐ sis has been linked to the ductular reaction (ductularproliferation at the portal tract interface arising from progenitor cells in the periportal area and accompanied by neutrophils and stromal changes). These findings correlate the insulin resistance with advanced stages of fib‐ rosis and provide a pathway for fibrosis progression [30].

In some cases in a study with a few number of patients treated with an insulin sensitizer, histologic evaluation of post-treatment liver biopsy showed that increased portal inflamma‐ tion is a feature related to resolution of NASH, and it is associated to a change in the quality of zone 3 perisinusoidal fibrosis from dense to delicate [19].

**NAFLD in bariatric surgery patients.** Patients undergoing bariatric surgery for weight loss are at a risk of NAFLD. They often have comorbidities such as: severe obesity, diabe‐ tes, hypertension, sleep apnea or coronary artery disease. And high percentage will have metabolic syndrome [31] (see table 7). The prevalence of steatosis and steatohepatitis in these patients undergoing liver biopsy when surgery is performed, is 91% and 37%, re‐ spectively [32]. At least a third of morbidity obese patients have portal inflammation, and this is related to the presence of fibrosis [20, 33]. In early stage, localization of fibrosis dif‐ fers from those nonbariatric populations, in bariatric is portal and in nonbariatric is perisi‐ nusoidal [19].

The Adult Treatment Panel III clinical definition of the metabolic syndrome:


Waist circumference greater than 102 cm in men or greater than 88 cm in women.

Triglyceride level 150mg/dl or greater.

High-density lipoprotein (HDL) cholesterol level less than 40 mg/dl in men and less than 50 mg/dl in women.

**8. Imaging tecnology in NAFLD**

(body mass index) is over 35 Kg/m2

posterior beam attenuation can be seen.

Liver echotexture Liver parenchyma is homogeneous and

clearly visualized

and kidney

Echo penetration an visibility of diaphragm

Clarity of liver blood vessel structure

no difference in contrast between liver

Liver structure is clearly defined from the surface to diaphragm. The outline of the diaphragm is clearly visualized.

Vessel wall and lumen of vessel can

**Table 8.** Ultrasonographic grading system for diagnosis of fatty liver, adapted from [41].

Ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) can identi‐ fy liver steatosis but not steatohepatitis, nevertheless they provide anatomical and morpholog‐ ical information. The sensitivity of these imaging methods is optimal for steatosis over 33%. When advance liver disease, radiology techniques can provide indirect signs of cirrhosis, such as portal hypertension, or may be useful for the screening and diagnosis of hepatocellular carci‐ noma (HCC)[41]. Imaging technique may help to differentiate diffuse from focal form of steato‐ sis. Hepatic fatty infiltration can present as focal steatosis (a focal area of steatosis in an otherwise normal liver) or as focal fatty sparing (fatty change with sparing of certain areas) [42]. **Abdominal US** is the most commonly used imaging technique to clinically evaluate the pres‐ ence of liver steatosis. Advantages include low cost, lack of radiation exposure and wide availa‐ bility. The brightness of the liver echo is compared with the kidney, the attenuation of the sound beam by the fat results in relatively hypoechoic kidney. For detailed description of sono‐ graphic features for staging fatty liver see table 8. This US feature is not characteristic of NAFLD because it can be present in other diffuse parenchymal liver disease. The US can be accurate de‐ tecting hepatic steatosis when there is a moderate to severe infiltration [43]. Overall sensitivity and specificity are 60-94% and 66-95%, respectively, however the sensitivity is lower when BMI

vide reproducible quantitative information. US scoring system for fatty liver is based on hyper‐ echogenic liver tissue, the increased discrepancy of echo amplitude between liver and kidney and the loss of echoes from the walls of the portal system [44]. US cannot differentiate between steatosis and fibrosis, but with advance degrees of fibrosis an increase in coarse echoes without

Slight increase in echo

Mild attenuation of sound beam through

pattern

the liver

**Computer Tomography** provides an accurate and a reliable visualization of whole liver, so that not only diffuse but also focal fatty infiltration of the liver parenchyma can be accurately diagnosed. CT enables the evaluation of absolute measurement of attenuation values which are given in Hounsfield units, the difference of attenuation between liver and spleen as well as

Slight decrease definition of portal venule walls

**Features NORMAL MILD MODERATE SEVERE**

. Although this acceptable level of sensitivity it does not pro‐

Intermediate Gross discrepancy of the

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echogenicity

Intermediate Marked attenuation of sound

Intermediate Only the main portal walls can be

increased hepatic to renal cortical

beam through the liver, the diaphragm is not visualized.

visualized with absence of all smaller portal venule walls

Systolic blood pressure 130 mmHg or greater or diastolic pressure 85 mmHg or greater.

Fasting plasma glucose level 110 mg/dl or greater.

**Table 7.** Definition of the metabolic syndrome [31].

**NAFLD after bariatric surgery.** Improvements of major histological features of disease ac‐ tivity, grade of steatohepatitis and rarely fibrosis following therapy (dietary, medicines or surgery) have been reported [34]. After surgical intervention liver histology improve in these features: lobular steatosis, necroinflammatory changes and fibrosis, against no im‐ prove in portal abnormalities [35]. Recent meta-analysis [36] shows that patients after bariat‐ ric surgery have improvement or resolution in steatosis (91,6%), in steatohepatitis (81,3%), in fibrosis (65,5%) and for complete resolution of NASH was 69,5%.

In the near future, we will have to get used to new types of treatment, for example, "meta‐ bolic surgery", which might be performed to non-morbid obese patients with diabetes, and to the new changes in hepatic parenchyma following endoscopic procedures performed to treat obesity.

**NAFLD in children.** Pediatric NAFLD can have a different histologic presentation than adult NAFLD. In the first large biopsy series of pediatric NAFLD [37], two different histo‐ logic patterns were described with differences in race and gender. Type 1 NASH: similar to adults, more common in Caucasian children. Histologic characteristics are: steatosis, bal‐ looning degeneration and perisinusoidal fibrosis. On the other hand, Type 2 NASH was more common in Asian, Native American and Hispanics. Typical features in the liver biopsy are: steatosis with lymphocytic portal inflammation and portal fibrosis. Children with type 2 were younger and had a greater severity of obesity, and advanced fibrosis. This kind of pat‐ tern was described in adult morbid obese patients undergoing bariatric surgery, these pa‐ tients mean age were slightly lower [33]. Overlap cases with characteristic of both histological types may also be observed in pediatric NASH. A multicentre retrospective co‐ hort study reviewed 130 liver biopsies of children according to these criteria of pediatric NAFLD [38]. The majority of the biopsies presented an overlapping pattern (82%). Ad‐ vanced fibrosis was associated with the presence of lobular and portal inflammation.

Portal fibrosis is common in pediatric NAFLD and may evolve to periportal fibrosis and bridging fibrosis in some patients, whereas progression to cirrhosis is observed in rare cases [39].

It is not clear, that Type 2 NASH, described as pediatric NASH, is an entity by itself or it is another stage of the spectrum of NASH which could be a predictor of those who have a se‐ vere disease [40].
