Steatohepatitis

Steatohepatitis
Diagnosis in short
Steatohepatitis. Trichrome stain.
LM	steatosis (usually macrovesicular); hepatocyte injury -- ballooning degeneration (key feature), Mallory bodies; portal bridging (late stage)
Subtypes	by etiology (classically): ASH, NASH -- all almost histologically identical
LM DDx	steatosis, Wilson disease, hepatitis C, drug-induced liver disease
Gross	pale/yellowish, often enlarged
Site	liver - see medical liver disease
Associated Dx	obesity, alcohol abuse
Prevalence	common
Prognosis	dependent on underlying cause
Treatment	dependent on underlying cause

Steatohepatitis is a fatty change of the liver (steaosis) with (histologic) evidence of liver injury. It can be due to a number of different causes.

General

• Steatohepatitis is a label for a set of histopathologic findings.
• Fat accumulation (in hepatocytes) alone is liver steatosis.
  • It may be a pattern seen in drug toxicity, e.g. methotrexate toxicity.

Etiology:

1. Alcohol = alcoholic steatohepatitis (ASH).
2. Not alcohol = non-alcoholic steatohepatitis (NASH).
3. Drug/toxin.

Notes:

• Pathologists can comment on the etiology; however, the histomorphology is not distinctive. In other words, ASH and NASH are clinical diagnoses.
• Steatohepatitis is a misnomer. It is not an -itis; inflammation is not the (predominant) pathologic process.

Microscopic

Features:

• Steatosis (usually macrovesicular) - key feature.
  • If less than 10% ... consider alt. diagnosis/disease process.
• Hepatocyte injury:
  • Ballooning degeneration - key feature. †
  • Mallory bodies.
    • Mallory body wannabes: "occasional cytoplasmic clumping".
• +/-Chicken-wire perisinusoidal fibrosis +/- zone III (centrilobular) fibrosis (early).
  • Late-stage disease - portal bridging.

Note:

• † Brunt does not require ballooning to be present to call steatohepatitis; however, a table in a later paper Brunt paper (surveying pathologists) suggest that a significant number of pathologist may consider it a required finding.

DDx:

• Steatosis - lacks ballooning degeneration and neutrophils.
• Wilson disease.
• Hepatitis C.
• Drug-induced liver disease.

Image

• 

  Steatohepatitis. (WC)

Grading steatohepatitis

A simple grading system

Grade	Characteristics
1	steatosis, occasional ballooning, scattered PMNs
2	steatosis, obvious ballooning, obvious PMNs, chronic inflammation
3	panacinar steatosis, obvious ballooning

Brunt grading system

Brunt's 1999 paper proposed a system:

Grade	Steatosis	Neutrophils	Ballooning	Chronic inflammation
1	<=66%	scattered, rare	occasional or absent (zone 3)	none or mild acinar, none or mild portal
2	any amount (>33%)	present	obvious ballooning	mild or moderate acinar, mild or moderate portal
3	panacinar, zone 3 predominant	present	present, obvious	mild acinar inflammation, mild or moderate (not marked) portal

Clinical Research Network system

Nonalcoholic steatohepatitis Clinical Research Network system for scoring activity - adapted from Brunt and Tiniakos:

Score	Steatotic hepatocytes (%)	Foci of lobular lymphocytes	Ballooning heptocytes
0	<5%	none	none
1	5-33%	<2	few
2	34%-66%	2-4	many
3	>66%	>4	(not assigned)

Staging steatohepatitis

Stage	Fibrosis	Notes
0	none	-
1	zone 3 perisinusoidal	may be focal or extensive
2	perisinusoidal and periportal	no bridging
3	bridging fibrosis	no nodule formation
4	nodule formation	-

Images

Steatohepatitis. Brunt necroinflammatory grade 1. Brunt fibrosis stage 1. Steatosis afflicts about 30% of hepatocytes; note the absence of visible triads (Row 1 Left 20X). Cytoplasmic tufts of ballooning degeneration [violet arrows] were commonly found; a lymphohistiocytic aggregate [blue arrow], important for NAFLD, but not for Brunt, is seen (Row 1 Right 400X). A triad shows a vein [green arrow], an artery [red arrow], an interlobular duct [blue arrow], and proliferating bile ductules [cyan arrows]; only a few lymphocytes are seen (Row 2 Left 400X). Central vein shows only a few endothelial cells, with somewhat packed hepatocytes surrounding it (Row 2 Right 400X). Trichrome shows mostly space of Disse fibrosis [black arrows], sometimes adjoining hepatocytes [green arrows] show this is a stage 1 fibrosis (Row 3 Left 400X). Trichrome shows a central vein with a minimum of sclerosis; an interhepatocyte fibrous extension [arrow] displays the very beginning of fibrosis (Row 3 Right 400X).

Steatohepatitis. Brunt necroinflammatory grade 2. Brunt fibrosis stage 2.

Steatosis is not pan-acinar, precluding grade 3 (Row 1 Left 40X). Cytoplasmic tufts [arrows] were commonly seen establishing frequent ballooning degeneration of grade 2 (Row 1 Right 400X). Trichrome shows periportal fibrosis [arrow] establishing fibrosis stage 2 (Row 2 Left 400X). PAS D shows a triad with mild damage, with an interlobular bile duct [green arrow] with luminal sheered epithelium, not neutrophils, a hepatic arteriole [red arrow], a hepatic venule [blue arrow], proliferating bile ductules [cyan arrows]; PAS-D macrophages [black arrows] in triad & sinusoid evidence damage; Neutrophils [magenta arrows] in proliferating bile ductules mean nothing, but in sinusoids indicate damage  (Row 2 Right 400X). Reticulin fibers in steatosis afflicted areas can appear abnormally lost, which should not be deemed evidence of hepatocellular carcinoma (Row 3 Left 400X). Reticulin stain here shows hepatocyte acini [arrows], evidence of hepatocellular injury (Row 3 Right 400X). 

Steatohepatitis Brunt necroinflammatory grade 3, Brunt fibrosis stage 1 (not shown). Panacinar steatosis with unremarkable, small triads (Row 1 Left 40X). Ballooning degeneration, with cytoplasmic tufts [arrows] (Row 1 Right 400X). Lipogranuloma (Row 2 Left 400X). Triad with mild chronic inflammation without interface hepatitis (Row 2 Right 400X).

Steatohepatitis. Brunt necroinflammatory grade 3, Brunt fibrosis stage 3. Steatosis afflicts almost all hepatocytes (pan-acinar) (Row 1 Left 40X). An isolated septal duct with concentric fibrosis [arrow] should not result in a diagnosis of primary sclerosing cholangitis. The woman who underwent the biopsy had a normal bilirubin level, a normal alkaline phosphatase level, and only slightly elevated transaminase levels. (Row 1 Right 200X). Cytoplasmic tufts [arrows] prove ballooning degeneration (Row 2 Left 400X). PAS with diastase shows PAS-D Kupffer cells (arrows) (Row 2 Right 400X). Reticulin shows thick black lines [red arrows] of collapse, without portal central bridging. The apparent loss of reticulin due to steatosis [double head cyan arrow] should not be considered regeneration or hepatoma (Row 3 Left 200X). Trichrome shows a bridge [arrow] (Row 3 Right 200X).

Fibrosis stage 0 Brunt necroinflammatory grade 1 (WC)	Necroinflammatory grades Brunt 1, NAH 3. Fibrosis stage 0. About 25% of the liver shows steatosis (UL), not pan-acinar. Only rarely identified were either ballooned hepatocytes or inflammatory aggregates. UR shows more macrovesicular (blue arrowhead) than microvesicular (yellow arrowhead) steatosis, with occasional neutrophils in acini ( tip of green arrowhead, benath inflammatory aggregate, with tuft of material in ballooned hepatocyte at base of green arrow), and many glycogenated nuclei (magenta arrowhead). Additional evidence of hepatocellular damage is seen on the reticulin with focal zone III collapse (LL, blue arrowhead) and on the PAS with diastase stain with PAS-D Kupffer cells (LR black arrowheads) Original oculars. UL 4X. UR 40X, LL 40X, LR 40X
Fibrosis stage 1 Brunt necroinflammatory grade 2 (WC)	Necroinflammatory grades Brunt 2, NAH 6. Fibrosis stage 1. About half the hepatocytes show macrovesicular steatosis (UL), with sparing of part of the acinus (UL, Black arrowhead), Lipogranulomas, acomar inflammatory collections, mostly macrophages, about steatosis/ballooning degeneration afflicted hepatocytes or adjacent to them (UR, green arrowheads) are present.Tufts/flocks of ballooning degeneration are readily found (LL, magenta arrowheads). Mild to moderate mononuclear inflammation of portal triads does not exclude steatohepatitis (LL, yellow arrowheads). Trichrome displays the blue thin lines that separate hepatocytes in stage 1 fibrosis (LR blue arrowheads). Original oculars UL 4X, UR 40X (higher pixel photograph), LL 40X , LR 10X
Fibrosis stage 4 Brunt necroinflammatory grade 3 (WC)	Necroinflammatory grades Brunt 3, NAH 8. Fibrosis stage 4. Steatosis is pan-acinar (UL). Acinar inflammatory aggregates More than 4 inflammatory aggregates are seen in a 20X field (UR black arrowheads). Many cells show ballooning degeneration, with tufts/flocks of material cytoplasm (LL yellow arrowheads) Trichrome limns regenerative nodules (LR magenta arrowheads). Original oculars UL 4X, UR 20X, LL 40X (higher pixel photograph), LR 10X

See also

• Medical liver disease.
• Alcohol abuse.