Table 1 Characteristics of studies evaluating non‐invasive markers of fibrosis in non‐alcoholic fatty liver disease (NAFLD).
| Study | Total No of patients | Patient selection | Prevalence of S, I, and F* | Age mean (median) | % male | BMI mean (median) | Alcohol | % diabetes or hypertension | Liver biopsy score† | Non‐invasive variables |
|---|---|---|---|---|---|---|---|---|---|---|
| Angulo 1999 USA11 | 144 | NAFLD on biopsy and persistently abnormal LFTS for more than 3 months. Prospective and retrospective recruitment | 73% grade 2–3 (S) 27% significant fibrosis (F3/4) | (50.5) | 33 | 31.2 | <40 g/week | 28% diabetes | Modified Brunt L (n/s), PT (n/s), O (n/s) | Age, AST/ALT >1, ALT, albumin, transferrin saturation, diabetes |
| Rosenberg 2004 Europe12 | 61 | NAFLD on biopsy and abnormal LFTS for 6 months. Prospective recruitment | 27% significant fibrosis (F3/4) | 44 | 63 | n/s | n/s | n/s | Sheuer L (>12 mm), PT (>5), O (3) | Age, HA, PIIINP, TIMP‐1 |
| Sakuguwa 2005 Japan13 | 112 | NAFLD on biopsy | 63% NASH 43% significant fibrosis (F3/4) | 51 | 32 | 29 | <30 g/day | 30% diabetes | Modified Brunt L (n/s), PT (n/s), O (2) | Female, platelets, albumin, GGT, AST/ALT, HA, type IV collagen |
| Albano 2005 UK14 | 167 (NAFLD) 59 (controls) | NAFLD on biopsy Case controlled: NAFLD v controls. Prospective consecutive recruitment | 44% NASH 17% significant fibrosis (F3/4) | 55 | 61 | 35 | <20 g/day | 29% diabetes | Modified Brunt L (n/s), PT (n/s), O (1) | Age, AST/ALT >1, diabetes, MDA |
| Mofrad 2003 USA15 | 51 | NAFLD on biopsy with normal ALT | 72% grade 2–3 (S) 36% severe fibrosis (F3/4) | 53 | 31 | 29 | <20 g/day | 57% diabetes 47%hypertension | Modified Brunt L (n/s), PT (n/s), O (1) | Diabetes |
| Shimada 2002 Japan16 | 81 | NASH on biopsy Prospective recruitment | 82% grade 2/3 (S) 100% NASH 28% severe fibrosis (F3/4) | (54) | 49 | (26) | <20 g/week | 31% diabetes | Brunt L (n/s), PT (n/s), O (1) | Age, platelet count, AST/ALT >1, albumin, bilirubin, ferritin, platelets, IgA, PT, type IV collagen, raised lipids |
| Dixon 2001 Australia17 | 105 | Patients undergoing laparoscopic banding and liver biopsy with BMI >35. Prospective consecutive recruitment | 25% NASH. 10% severe fibrosis (F3/4) | 41 | 21 | 47 | <200 g/wk | 18% diabetes 39% hypertension | Brunt L (n/s), PT (>6), O (1) | Male, diabetes, hypertension, ALT, C peptide |
| Beymer 2003 USA18 | 48 | BMI >35 undergoing gastric bypass surgery and liver biopsy Prospective consecutive recruitment | 64% grade 2/3 (S) 33% NASH 12% severe fibrosis (F3/4) | 42 | 31 | 60 | <20 g/mth | 19% diabetes | Ishak, L (n/s), PT (n/s), O (1) | Diabetes |
| Bugianesi 2004 Italy19 | 167 | Raised transaminases (>6 months) and bright liver on U/S and NAFLD on biopsy. Prospective recruitment | 47% grade 2/3 (S) 21% severe fibrosis (F3/4) | 41 | 83 | 28 | <20 g/day | 8% diabetes | Modified Brunt L (n/s), PT (n/s), O (n/s) | Age, female, BMI, AST/ALT, Ferritin, OGIS, 1/QUICKI, HOMA‐IR (insulin sensitivity indices‐ see table 2) |
| Dixon 2003 Australia20 | 105 | Patients with BMI >35 undergoing laparoscopic banding and liver biopsy Prospective recruitment | 34% NASH 14% severe fibrosis (F 3/4) | 42 | 26 | >35 | <200 g/wk | n/s | Brunt L (n/s), PT (>6), O (1) | ALT, HOMA‐IR, polymorphisms in TGF factor and angiotensinogen |
| Hui 2004 Australia21 | 109 (NAFLD) 82 (controls) | Patients referred with abnormal LFTS or hepatic steatosis on U/S and NAFLD on biopsy. Controls matched by age and BMI. Case controlled/ prospective | 50% grade 2/3 (S) 73% NASH 28% severe fibrosis (F3/4) | 48 | 63 | 30 | <40 g/wk | 32% diabetes in NAFLD group | Brunt L (n/s), PT (n/s), O (1) | Age, HOMA‐IR |
| Guidorizzi de Siqueira 2005 Brazil22 | 64 | Patients with NAFLD on biopsy. Prospective recruitment | 84% NASH 11% severe fibrosis (F3/4) | 45 | 78 | 28 | <20 g/day | 11% diabetes 27% hypertension | Brunt L (n/s), PT (n/s), O (1) | HOMA‐IR |
| Suzuki 2005 USA23 | 79 | Patients with abnormal LFTs for three months and NAFLD on liver biopsy Prospective and consecutive recruitment | 25% severe fibrosis (F3/4) | 46 | 38 | 33 | <40 g/wk | n/s | Brunt L (>15 mm), PT (n/s), O (1) | Age, serum albumin, platelet count, fasting blood glucose, HA, clinical diagnostic score |
| Angulo 2004 USA24 | 88 | Patients with abnormal LFTS, NAFLD on biopsy and participants in previous trials. Retrospective recruitment | 77% grade 2–3 (S) 83% NASH 22% severe fibrosis (F3/4) | 45 | 35 | 33 | <140 g/wk | 19% diabetes | Brunt L (>15 mm), PT (n/s), O (1) | Age, female, BMI, diabetes, leptin, QUICKI, HOMA‐IR |
| Marchesini 2003 Italy25 | 163 | Patients with abnormal LFTS for 3 months and NAFLD on liver biopsy. Prospective consecutive recruitment | 74% NASH 21% severe fibrosis (F3/4) | 40 | 88 | 28 | <140 g/wk | 67% hypertension | Brunt L (n/s), PT (n/s), O (n/s) | Metabolic syndrome |
| Hashimoto 2005 Japan26 | 247 | Patients with NAFLD on liver biopsy Prospective recruitment | 36% severe fibrosis (F3/4) | (53) | 53 | 67% with BMI >28 | <100 g/wk | 33% diabetes 46% hypertension | Local score | Age, sexAST/ALT, albumin, platelets, diabetes, HA, and type IV collagen. |
| Ong 2005 USA27 | 212 | Patients undergoing bariatric surgery with BMI >40 and obesity related complications. Prospective recruitment | 24% NASH 8% advanced fibrosis | 42 | 20 | 48 | <10 g/day | 24% diabetes | Local score L (n/s), PT (n/s), O (1) | WHR, AST, ALT, diabetes, HT |
| Ledinghen 200428 | 67 | Chronically elevated ALT for six months and liver biopsy Retrospective recruitment | 40% NASH 31% F2/3/4 fibrosis | 47 | 67 | 26 | <40 g/day | n/s | Metavir L (n/s), PT (n/s), O (1) | BMI, AST, ALT, ferritin |
| Ratziu 2000 France29 | 93 | BMI >25, abnormal LFTS and NASH on liver biopsy. Retrospective consecutive recruitment | 30% F2/3/4 fibrosis | 49 | 34 | 29 | 30 g/day | 16% diabetes | Metavir L (n/s), PT (n/s), O (1) | Age, BMI, ALT, diabetes, TG |
| Sorrentino 2004 Italy30 | 80 | Undergoing liver biopsy for operative procedure (gall stones, large bowel or gastric cancer) + metabolic syndrome + high grade obesity + normal LFTS. Prospective recruitment | 53% grade 2/3 (S) 73% NASH 23% severe fibrosis (F3/4) | 58 | 38 | 39 | <30 g/day | 45% diabetes 78% hypertension | Brunt L (>8 mm), PT (n/s), O (2) | Female, BMI >45, duration of obesity, metabolic syndrome |
| Crespo 2001 Spain31 | 181 | Patients undergoing bariatric surgery and liver biopsy. Prospective recruitment | 72% grade 2/3 (S) 23% F2/3/4 fibrosis | n/s | 16 | 47 | <30 g/day | n/s | Modified Metavir L (n/s), PT (n/s), O (1) | Age at liver biopsy, elevated blood sugar level |
| Fierbinteanu‐ Braticevici 2002 Romania32 | 80 | Abnormal LFTS and fatty liver on ultrasound and undergoing liver biopsy Retrospective recruitment | 26% NASH | 51 | 25 | 32 | <200 g/wk | n/s | Local score L (n/s), PT (n/s), O (1) | Age, BMI >30, ALT >3 N, ferritin, TG, MDA, GSH |
| Loguercio 2004 Italy33 | 305 | Abnormal ALT for 12 months and NAFLD on liver biopsy. Prospective recruitment | 68% grade 2/3 (S) Moderate/severe pericellular fibrosis | n/a | 82 | 70% were >25 | <20 g/day | n/s | Local score L (n/s), PT (n/s), O (3) | Ferritin, HOMA‐IR |
| dos Santos 2005 Brazil34 | 30 | BMI >25 + ultrasound diagnosis of steatosis + raised LFTs and undergoing liver biopsy. Prospective recruitment | Fibrosis present in 37% | 45 | 60 | 31 | <20 g/day | 23% diabetes | Modified Brunt L (n/s), PT (n/s), O (n/s) | AST, laminin, HA, collagen IV |
| Yesilova 2005 Turkey35 | 51 (NAFLD) 30 (controls) | Raised LFTS for 6 months and NAFLD on liver biopsy Prospective recruitment | 60% grade 2/3 (S) 88% NASH 10% severe fibrosis (F3/4) | 36 | 100 | 28 | <20 g/day | 0% diabetes | Brunt L (n/s), PT (n/s), O (n/s) | HOMA‐IR, CoQ10, Cu ZnSOD |
| Koruk 200336 | 36 (NASH) 32 (controls) | Steatosis on ultrasound, abnormal LFTs for 3 months and NASH on liver biopsy | 67% Grade 2/3 (S) 100% NASH 0% severe fibrosis (F3/4) | 44 | 75 | (29) | Absent | 20% diabetes | Modified Brunt L (n/s), PT (n/s), O (n/s) | TG, LDL cholesterol, Apo A1 |
| Hartleb 200537 | 47 | Patients with NAFLD on liver biopsy and ALT >1.5 ULN. Retrospective study | 50% Grade 2/3 (S) 65% NASH 20% some fibrosis | 45 | 57 | 29 | <120 g/wk | 13% diabetes | Local L (n/s), PT (>5), O (2) | Age, BMI, diabetes, hypertension |
| Chitturi 2002 Australia38 | 94 | NASH Case‐controlled – prospective and retrospective | 70% Grade 2/3 (S) 45% significant fibrosis (F3/4) | 51 | 57 | 31 | <20 g/d | 47% diabetes | Modified Brunt L (n/s), PT (n/s), O (1) | None |
| Brunt 2004 USA39 | 30 | Subjects in NASH treatment trial. Retrospective | 43% grade1–4 fibrosis | 45 | 46 | 34 | <20 g/day | 25% diabetes | Brunt and Metavir L (n/s), PT (n/s), O (1) | AST/ALT ratio, albumin |
*S, steatosis; I, inflammation; F, fibrosis.
†L, length; PT, portal tract; O, observers.
NASH, non‐alcoholic steatohepatitis; LFTs, liver function tests; MDA, malondialdehyde; TG, triglycerides; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GSH, glutathione; TGF, transforming growth factor; LDL, low density lipoprotein; HA, hyaluronic acid; TIMP‐1, tissue inhibitor of metalloproteinase; PIIINP, aminoterminal peptide of procollagen III; GGT, gamma glutamyl transferase; Apo A1, apoprotein A1; ULN, upper limit of normal; CoQ10, coenzyme Q10; Cu ZnSOD, copper zinc oxide dismutase; WHR, waist to hip ratio; HOMA‐IR, homeostatic insulin resistance; QUICKI, quantitiative insulin sensitivity check index.