Heterogeneity of fibrosis patterns in non-alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways.
BACKGROUND
Adult non-alcoholic fatty liver disease (NAFLD) involves lobular necroinflammatory activity and fibrosis is typically centrilobular, whereas paediatric NAFLD has predominantly portal fibrosis. The reasons for these differences are unclear. We aimed to determine (a) how centrilobular and portal fibrosis in children relate to histological parameters; and (b) whether atypical fibrosis patterns exist in adults that are unexplained by current fibrogenesis models.


METHODS
Histological features of paediatric (n = 38) and adult (n = 56) NAFLD were assessed using conventional scoring systems. Keratin-7 immunostaining was used to assess hepatic progenitor cell numbers and the ductular reaction. Centrilobular and portal components of fibrosis were independently scored and fibrosis patterns were classified according to accepted types. Post-treatment (rosiglitazone/gastric banding) biopsies were also examined in adults.


RESULTS
Twenty-six children (68.4%) had portal-predominant fibrosis, although the typical "adult" pattern was seen in 11 (28.9%). Portal fibrosis was associated with a ductular reaction (P = 0.021) and hepatic progenitor cell expansion (P < 0.001), whereas centrilobular fibrosis was associated with lobular inflammation (P = 0.026) and ballooning (P = 0.001). Before intervention, six adults (10.7%) had atypical fibrosis including 3 (5.4%) with a previously unrecognized pattern of very fine, non-zonal sinusoidal fibrosis. Despite improvements in steatosis and inflammation, more patients developed this unusual pattern after intervention with most having had surgery (9 of 10 adults; P < 0.001).


CONCLUSIONS
Differing associations with portal and centrilobular fibrosis in children and atypical fibrosis patterns in adults suggest that multiple fibrogenic pathways exist in NAFLD. This has implications for therapy and understanding pathogenesis.
Centre for Liver Disease Research, The University of Queensland, Brisbane, Australia.
Richard
R
Skoien
Michelle M
MM
Richardson
Julie R
JR
Jonsson
Elizabeth E
EE
Powell
Elizabeth M
EM
Brunt
Brent A
BA
Neuschwander-Tetri
Prithi S
PS
Bhathal
John B
JB
Dixon
Paul E
PE
O'Brien
Herbert
H
Tilg
Alexander R
AR
Moschen
Ulrich
U
Baumann
Rachel M
RM
Brown
Richard T
RT
Couper
Nicholas D
ND
Manton
Looi C
LC
Ee
Martin
M
Weltman
Andrew D
AD
Clouston
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001315:Australia; D001653:Bile Ducts, Intrahepatic / Q000737:chemistry / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005234:Fatty Liver / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015390:Gastric Bypass; D006801:Humans; D007150:Immunohistochemistry; D053552:Keratin-7 / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology*; D008103:Liver Cirrhosis / Q000145:classification / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008923:Missouri; D065626:Non-alcoholic Fatty Liver Disease; D012307:Risk Factors; D000077154:Rosiglitazone; D013234:Stem Cells / Q000737:chemistry / Q000473:pathology; D045162:Thiazolidinediones / Q000627:therapeutic use; D016896:Treatment Outcome
D015415:Biomarkers; C507497:KRT7 protein, human; D053552:Keratin-7; D045162:Thiazolidinediones; D000077154:Rosiglitazone