Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Table 1 Indexes for the prediction of liver steatosis

Index	Author(nation)	Paper (yr)	No. of subjects(fatty liver/ non-fatty liver)	Parameters	Cutoff values	Sens-itivity	Speci-ficity	AUROC	Diagnostic methods for hepatic steatosis
FLI	Bedogni(Italy)	BMC Gastroenterology (2006)	228/268	BMI, waist circumference, triglyceride, γGT	< 30 > 60	87.0%61.0%	64.0%86.0%	0.84	US
NAFLD liver fat score1	Kontronen(Finland)	Gastroenterology (2009)	470	MetS, type II diabetes, IRI, AST, AST/ALT ratio	-0.64	86.0%	71.0%	0.8720.863	MRS
HSI	Lee (South Korea)	Dig Liver Dis (2010)	5362/5362 (sex- and age- matched)	8 × AST/ALT ratio + BMI + (+ 2 for females, + 2 for diabetes)	< 30 > 36	93.1%	92.4%	0.812	US
ST	Poynaud(France)	Comp Hepatol(2005)	744/140	12 parameters4	0.30 0.72	90%	90.0%	0.7920.8030.8630.723	Biopsy
	Park (South Korea)	Korean J Hepatol(2011)	145/311	ALT/AST > 1.5 (= 1 point)γGT > 50 IU/L (= 1 point)TG > 150 mg/dL (= 1 point)BMI 23-24.9 (= 2 points) ≥ 25 (= 3 points)	3	71.7%	75.9%	0.797	US
	Bajaj(India)	Indian J Med Res (2009)	39/82	IRI +1.6 × BMI + 1.9 × FPG	1.6	84.6%	76.0%	0.76	US

¹PNPLA3 did not improve diagnostic accuracies;

²Estimation group;

³Validation group;

⁴Alanine aminotransferase (ALT), α2-macroglobulin, apolipoprotein A-I, haptoglobin, total bilirubin, γ-glutamyl transferase (γGT), cholesterol, triglycerides, glucose, age, gender and body mass index (BMI). ROC: Receiver operating characteristics curve; US: Ultrasonography; MetS: Metabolic syndrome; MRS: Magnetic resonance spectroscopy, IRI: Immuno-reactive insulin; FPG: Fasting plasma glucose. FLI: Fatty liver index; HSI: Hepatic steatosis index; ST: Steato Test; AST: Aspartate aminotransferase; NAFLD: Nonalcoholic fatty liver disease; AUROC: Area under the receiver operating characteristic curve.

Table 2 Pathological criteria for the diagnosis of nonalcoholic steatohepatitis

Criteria (yr)	Classifications	Definitions of NASH	Characteristics
Matteoni (1999)	Type 1: steatosis aloneType 2: steatosis with inflammationType 3: steatosis with hepatocyte balloningType 4: Type 3 plus MDB or fibrosis	Type 3 or 4	Depend on the subjective judgments of observers(existence of hepatocyte balloning)Well correlation with liver-related mortalityInflammation is not included
NAS (2005)	Steatosis (0-3) Inflammation (0-3) Hepatocyte balloning (0-2) Total: 0 to 8	Total scores: 5 to 8	Numerical scoreLow sensitivity, NAS ≥ 4 may be better Fibrosis is not includedNo significant correlation with liver-related mortality Recommended use for assessing the therapeutic effect during clinical studies
Younossi (2011)	SteatosisHepatocyte balloningMDBFibrosis	Steatosis + Hepatocyte balloningor + MDBor + Fibrosis	Inflammation is not includedWell correlation with Matteoni’s classificationCan diagnose so-called burned-out NASHEssential validation study

MDB: Mallory-Denk bodies; NAS: Nonalcoholic fatty liver disease activity score; NASH: Nonalcoholic steatohepatitis.

Table 3 Scoring systems for picking up nonalcoholic steatohepatitis or severe fibrosis in nonalcoholic fatty liver disease

Index	NAFIC score		NAFLDfibrosis score		FIB4 index
Object	Predicting NASH		Excluding severe fibrosis (stage 3-4)
Formula	Ferritin > 200 (female), 300 (male) ng/mL (= 1 point) Fasting insulin > 10 μU/mL (= 1 point) Type 4 collagen 7S > 5.0 ng/mL (= 2 points) Total: 0-4 points		-1.675 + 0.037 × age (yr) + 0.094 × BMI (kg/m2) + 1.13 × impaired fasting glycemia /DM (yes = 1, no = 0) + 0.99 × AAR – 0.013 × PLT (× 109/L) - 0.66 × Alb (g/dL)		Age (yr) × AST (IU/L)/(PLT (109/L) ×√ALT (IU/L)
Cut-off values	1	2	-1.455	0.676	1.30	2.67
Sensitivity	94%1	66%1	82%1	51%1	74%	33%
	88%2	60%2	77%2	43%2
Specificity	48%1	91%1	77%1	98%1	71%	98%
	43%2	87%2	71%2	96%2
Positive predictive value	31%1	90%1	56%1	90%1	43%	80%
	66%2	85%2	52%2	82%2
Negative predictive value	86%1	67%1	93%1	85%1	90%	83%
	75%2	64%2	88%2	80%2

¹Estimation group;

²Validation group. AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; AAR: AST/ALT ratio; BMI: Body mass index; DM: Diabetes mellitus; PLT: Platelets; NASH: Nonalcoholic steatohepatitis; NAFLD: Nonalcoholic fatty liver disease.