Pathology of alcoholic and non-alcoholic fatty liver disease

Question 1

Etiologies of fatty liver disease (FLD)

Answer 1

• Alcoholic FLD: steatosis, hepatitis, fibrosis, cirrhosis
• Non-alcoholic FLD: steatosis, steatohepatitis, fibrosis, cirrhosis
• These two are the most common in US
• Drug induced steatosis: GCCs, antibios (tetracycline, sulfonamides)
• Others: acute fatty liver of pregnancy, metabolic d/os

Question 2

Pathogenesis of alcoholic liver disease 1

Answer 2

• Steatosis: fatty change that develops rapidly (2-3 wks) but can resolve w/ abstinence w/in 4 wks
• Duration of consumption correlates best w/ risk of development of AFLD
• Metabolism of etoh results in increased NADH levels, which promote FFA synthesis and decrease FFA breakdown
• There is decreased mito beta-oxidation and thus accumulation of TAGs

Question 3

Pathogenesis of alcoholic liver disease 2

Answer 3

• Oxidative stress from etoh-induced CYP2E1 leads to formation of superoxides and reactive aldehyde formation, which damage cells w/ lowest O2 levels first (centrilobular hepatocytes)
• Immune system activation of Kupffer cells, PMNs/T cells (in alcoholic hepatitis) promotes cytokine release and free radical, collagen production
• Stellate cells are activated by alcohol/ROS/inflammation and begin to synthesize collagen
• Mallory body formation (seen in alcoholic hepatitis and alcoholic cirrhosis): disruption of microtubules w/ increased intermediate filament synthesis and aggregation leads to hyaline inclusions in hepatocytes

Question 4

Clinical presentation of alcoholic liver disease

Answer 4

• Often ASx (fatty liver), AST/ALT may be nl or mildly elevated in those w/o alcoholic hepatitis
• Most common form of acute alcoholic liver disease is alcoholic hepatitis
• Alcoholic hepatitis presentation: low grade fever, RUQ pain/tenderness, hepatic bruit (portal HTN), leukocytosis, hyperbilirubinemia (D bili), jaundice, AST/ALT 2-3 (b/c acetaldehyde damages mito and releases AST) but both usually <300
• Pt sometimes reports stopping drinking about 1 wk prior b/c not feeling well feel well
• Overall mortality is high (15-25%), but can be as high as 50%

Question 5

Other forms of acute alcoholic liver disease

Answer 5

• Acute alcoholic fatty liver: pt is stable, may have jaundice, may have modest-mildly elevated AST, ALT mildly elevated or nl, ultrasound shows fatty liver, good prognosis
• Alcoholic foamy degeneration: stable, may have jaundice, AST/ALT may be significantly increased (AST>ALT), bilirubin levels variable, alk phos usually elevated, also good prognosis

Question 6

Path of acute alcoholic fatty liver

Answer 6

• Macrovesicular fatty change, initially perivenular (centrilobular) in location
• May see perivenular sinusoidal collagen deposition
• Megamitochondria: finely pink and perfectly round bodies w/in hepatocytes, can be as big as nuclei

Question 7

Path of alcoholic hepatitis

Answer 7

• Sclerosis/fibrosis of terminal hepatic venules and perivenular sinusoidal fibrosis
• Can see occlusion of central hepatic venule (central vein fibrosis can be really bad)
• Often have variable degree of macro vesicular fatty change (was present before hepatitis)
• PMNs present in lobules, portal tracts
• Most important morphology are mallory bodies in hepatocytes, which are often surrounded by PMNs (satellitosis)
• 4 features: mallory bodies, PMNs, pericentral sinusoidal fibrosis, fatty change

Question 8

Path of alcoholic foamy degeneration

Answer 8

• Less common, perivenular hepatocytes have both large and small droplet fatty change (micro vesicular change present)
• Inflammatory reaction is scanty

Question 9

Path of portal and perivenular fibrosis

Answer 9

• Portal tracts are fibrosed, w/ collagen deposition in sinusoids of periportal regions
• Perivenular arachnoid fibrosis seen
• Eventual connection of portal and perivenular fibrosis (bridging fibrosis)
• Eventually there is development of regenerative nodules (cirrhosis)

Question 10

Alcoholic cirrhosis

Answer 10

• Signs: hepatosplenomegaly (liver will be small in late stages of cirrhosis), venous collaterals (esophageal, abdominal varices), ascites, gynecomastia, spiderangiomata, parotid enlargement, low albumin, elevated INR
• Complications: variceal rupture, SBP, encephalopathy, hepatorenal syndrome (due to fall in BP), HCC

Question 11

Path of alcoholic cirrhosis

Answer 11

• Early: bridging fibrosis w/ poorly formed regenerative nodules, variable degree of fatty change
• Moderate to advanced: severe distortion of architecture w/ dense fibrous septa
• W/in septa there is bile duct proliferation and lymphocytic infiltration
• Portal venous proliferation from portal HTN
• Fat is often present

Question 12

Non-alcoholic fatty liver disease (NAFLD)

Answer 12

• Seen in many people who are overweight (BMI >24), but can happen in nl weight individuals
• Liver tests usually nl
• Pathology shows predominantly macrovesicular fat w/ no zonal pattern, no inflammation
• Microvesicular forms can occur too
• Does NOT progress to cirrhosis/fibrosis

Question 13

Non-alcoholic steatohepatitis (NASH)

Answer 13

• Seen in minority of people who are overweight, associated w/ metabolic syndrome pts (most NASH pts have at least 1 metabolic syndrome parameter)
• Most NASH pts are obese, or have T2 DM
• Steatohepatitis DOES progress to cirrhosis after 10-15 yrs
• Clinical: most pts are ASx, or have non-specific findings similar to alcoholic hepatitis
• Labs: AST and ALT usually 100-300 w/ AST≤ALT (AST/ALT ≤1) usually (not the case in alcoholic hepatitis)
• Glc often elevated (many pts are insulin resistant), TAGs often elevated, HDL often decreased

Question 14

Pathophys of NASH

Answer 14

• High levels of hepatic TAGs increase susceptibility of liver to injury
• Insulin resistance and high fat diet greatly contribute to TAG accumulation
• Insulin resistance leads to higher FFA efflux from adipocytes and thus TAG accumulation in liver
• Insulin resistance also decreases beta oxidation, furthering hepatic lipid accumulation
• Mitos in liver become dysfxnal b/c they are overwhelmed w/ lipids, producing increased ROS/oxidative stress
• ROS activate inflammatory pathways (TNFa, IL6, IL8) leading to immune activation
• ROS/inflammation also activates fibrogenesis/stellate cells and inhibits mature hepatocyte differentiation

Question 15

Path of NASH

Answer 15

• Portal and perivenular fibrosis w/ lymphocytic infiltrates (usually in clusters, often around portal tracts)
• Marked macrovesicular fatty change w/ inflammation
• Can also see microvesicular NASH too
• Centrilobular hepatocytes w/ ballooning change and often containing mallory bodies
• Eventually fibrosis and cirrhosis develop