Current status and agenda in the diagnosis of nonalcoholic steatohepatitis in Japan

Table 1 The pathological criteria for the diagnosis of nonalcoholic fatty liver disease

Matteoni’s classification[45]
Type	Histological findings	Liver related deaths (mean observation period)		Diagnosis
		8.17 years[31]	18.5 years[32]
Type 1	Fatty liver alone	1.70%	2.70%	non-NASH
Type 2	Fat accumulation and lobular inflammation
Type 3	Fat accumulation and ballooning degeneration	11.00%	17.50%	NASH
Type 4	Type 3 and either Mallory-Denk body or fibrosis
NAFLD activity score (NAS)[47]
Item	Definition		Score	Diagnosis
Steatosis	< 5%		0	Total score
	5%-33%		1	0-2: non-NASH
	> 33%-66%		2	3-4: borderline
	> 66%		3	5-8: NASH
Lobular inflammation	No foci		0
	< 2 foci per 200 × field		1
	2-4 foci per 200 × field		2
	> 4 foci per 200 × field		3
Ballooning	None		0
	Few balloon cells		1
	Many cells/prominent ballooning		2

NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis.

Table 2 Noninvasive biomarkers previously studied or currently under evaluation

Insulin resistance	Inflammation and apoptosis
HOMA-IR	TNF-α
Leptin	hsCRP
Adiponectin	CK-18 fragments
	TNF-α/adiponectin ratio
Hepatic fibrosis	Interleukin-6
Hyaluronic acid	CC-chemokine ligand-2
Type IV collagen 7S
TGFβ	Endocrine
	DHEA-S
Oxidative stress
Ferritin	Imaging studies
TBARS	US elastography
Oxidized-LDL	Fibroscan
Total antioxidant response	ARFI
Total lipid peroxide levels	Contrast enhanced US
Thioredoxin	MRI (SPIO, Gd-EOB-DTPA)
Advanced glycation end products

HOMA-IR: homeostasis model assessment for insulin resistance; TGFβ: transforming growth factor β; TBARS: thiobarbituric acid-reacting substance; LDL: low-density lipoprotein; TNF: tumor necrosis factor; hsCRP: high sensitivity C-reactive protein; CK: cytokeratin; CCL2: CC-chemokine ligand-2; DHEA-S: dehydroepiandrosterone-sulphate; ARFI: acoustic radiation force impulse elastography; SPIO: super-paramagnetic iron oxide; US: ultrasound; MRI: magnetic resonance imaging.

Table 3 Panel markers for nonalcoholic steatohepatitis diagnosis

Index	Author (Nation)	Paper	Parameter	Patient selection	N	AUROC
HAIR score	Dixon JB (Australia)	Gastroenterology 2001	HTN, ALT, insulin resistance (1/QUICKI)	patients with BMI	105	0.900
				> 35 undergoing
				laparoscopic banding
	Palekar NA (USA)	Liver Int 2006	Age, female, BMI, AST, AST/ALT ratio, HA	biopsy proven NAFLD	80	0.763
NashTest (NT)	Poynard T (France)	BMC Gastroenterol 2006	Age, sex, height, weight, TG, AST, ALT, TC, α2-macroglobulin, apolipoprotein A1, haptoglobin, γGT, T-Bil	biopsy proven NAFLD	257	0.790
	Gholam (USA)	Am J Gastroenterol 2007	AST, DM	Severely obese subjects (BMI ≥ 40 kg/m2) undergoing Rouxen-Y gastric bypass surgery	97	0.820
NASH clinical scoring system	Campos GM (USA)	Hepatology 2008	HTN, DM, AST, ALT, sleep apnea, non-black	Patients undergoing laparoscopic banding	200
NAFIC score	Sumida Y (Japan)	J Gastroenterol, in press	Ferritin, fasting insulin, type IV collagen 7S	Biopsy proven NAFLD	1771	0.8511
					4422	0.7822

HA: hyaluronic acid; TG: triglyceride; TC: total cholesterol; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; HTN: hypertension; AST: aspartate aminotransferase; ALT: alanine aminotransferase; BMI: body mass index; γGT: γ-glutamyl transferase; T-Bil: total bilirubin; DM: diabetes mellitus; AUROC: area under the receiver operating characteristic curve;

¹Estimation group;

²Validation group.

Table 4 Panel markers for fibrosis in nonalcoholic fatty liver disease

Index	Author (Nation)	Paper	Parameter	Patient selection	N	Stage	AUROC
	Angulo P (USA)	Hepatology 1999	Obesity1, age, AST/ALT ratio, DM	NASH	144	F0-2 vs F3-4
BAAT	Ratziu V (France)	Gastroenterology 2000	BMI, age, ALT, TG	Patients with BMI>25, raised transaminse	93	F0-1 vs F2-4	0.840
FibroTest (FT)	Ratziu V (France)	BMC Gastroenterol 2006	Age, sex, α2-macroglobulin, , apolipoprotein A1, haptoglobin, T-Bil, γGT	Biopsy proven NAFLD	267	F0-2 vs F3-4	0.840
N score	Miyaaki H (Japan)	Liver Int 2008	Female, age, DM, HT	Biopsy proven NAFLD	182	F0-2 vs F3-4	0.780
NAFLD fibrosis score	Angulo P (USA, UK, Australia, Italy)	Hepatology 2007	Age, BMI, AST/ALT ratio, IFG/DM, platelet count, albumin	Biopsy proven NAFLD	4802	F0-2 vs F3-4	0.8802
					2533		0.8203
ELF panel	Guha IN (UK)	Hepatology 2008	TIMP1, HA, P3NP	Biopsy proven NAFLD	192	F0 vs F1-4	0.820
						F0-1 vs F2-4	0.900
						F0-2 vs F3-4	0.930
BARD score	Harrison SA (USA)	Gut 2008	BMI, AST/ALT, DM	Biopsy proven NAFLD	827	F0-2 vs F3-4	0.8102
							0.7803
FIB4 index	Shah (USA)	Clin Gastroenterol Hepatol 2009	Age, AST, ALT, PLT	Biopsy proven NAFLD	541	F0-2 vs F3-4	0.802
FibroMeter	Calès (France)	J Hepatol 2009	Glucose , AST, ferritin, PLT, ALT, BW, age	Biopsy proven NAFLD	235	F0-1 vs F2-4	0.9362
							0.9523
PAF	Hossain (USA)	Clin Gastroenterol Hepatol 2009	Male , Caucasian, DM, ALT, AST	Biopsy proven NAFLD	432	F0-1 vs F2-4	0.742

¹BMI > 31.1 (male), 32.2 (female);

²Estimation group;

³Validation group; TG: triglyceride; IFG: impaired fasting glycemia; TIMP1: tissue inhibitor of metalloproteinases; HA: hyaluronic acid; P3NP: type III procollagen; AST: aspartate aminotransferase; ALT: alanine aminotransferase; BMI: body mass index; PLT: platelets; γGT: γ-glutamyl transferase; T-Bil: total bilirubin; DM: diabetes mellitus; BW: body weight; AUROC: area under the receiver operating characteristic curve; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis.

Table 5 NAFIC score[80]

Variables	Cut-off values	Score values
Ferritin (Female/Male) (ng/mL)	200/300	1 point
Insulin (μU/mL)	10	1 point
Type IV collagen 7S (ng/mL)	5.0	2 point