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Liver Pathology
1. Pathology associated with exposure to toxic agents1. Exposure to cigarette smoke2. Occupational and environmental exposure to dusts (particulates) and
gases3. Chronic alcohol exposure 4. Drug abuse
2. Pathology related to physical injury 1. Hyperthermia and hypothermia2. Trauma3. Radiation
3. Pathology related to nutritional deficiencies1. Malnutrition2. Vitamin deficiencies
• Metabolic– Glucose homeostasis: glycogenesis and gluconeogenesis
• Synthetic– Albumin, coaggulation factors, complement, acute phase proteins, metal binding proteins, vitamin A
• Storage– Glycogen, triglycerides, Fe, Cu, lipid soluble vitamins
• Catabolic processes– Hormones, serum proteins, detoxification of xenobiotics
• Excretory function– Bile (conjugated bilirubin, bile acids, phospholipids, cholesterol and electrolytes)
Liver functions
Liver architecture: anterior view
Liver architecture: inferior view
Segmental anatomy
The liver lobule
Alcoholic liver disease (ALD)
1.Fatty liver2.Acute alcoholic hepatitis3.Cirrhosis
• 90‐100% of heavy drinkers have alcoholic fatty liver disease• 1 in 4 drinkers with fatty liver disease will develop alcoholic hepatitis• 1 in 5 drinkers with fatty liver disease will develop cirrhosis
DALY rates from liver cirrhosis (per 100,000 inhabitants)
The disability‐adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill‐health, disability or early death
The spectrum of alcoholic liver disease
SteatosisAbnormal retention of lipids within a cell
1. Moderate alcohol intake: small (microvesicular) lipid droplets acculmulate in hepatocytes, which don’t compress and displace nucleus to periphery
2. Chronic alcohol intake: large (macrovesicular) globules, compress and displace the nucleus to the periphery of hepatocytes
3. Initially, cell damage produces centrilobular fat depositions.
4. In severe cases entire lobule may be involved.
5. Little or no perivenular fibrosis
In alcoholic steatosis of the liver fat accumulation is fully reversible on discontinuation of alcohol intake.
1. Increased fatty acid and triglyceride synthesis
2. Enhanced hepatic influx of free fatty acids from adipose tissue and of chylomicronsfrom the intestinal mucosa
3. Increased hepatic lipogenesis4. Decreased lipolysis5. Decreased mitochondria
oxidation of fatty acids6. Accumulation of VLDL
Steatosis
Alcoholic Hepatitis(1) Necrosis of hepatocytes; (2) hyaline inclusions in hepatocytes;
(3) neutrophilic inflammation; (4) perivenular fibrosis
BC – balloon cells; MB – Mallory bodies; N – neutrophils; L – lymphocytes; M – macrophages; THV –terminal hepatic venule; C – connective tissue; F – fat laden hepatocytes; LP – limiting plate
Mallory bodies(cytokeritin)
Liver cell necrosis
Acute Alcoholic Hepatitis
Alcoholic fibrosis
Pericellular "chicken wire“ fibrosis
Centrolobular fibrosis
• Diffuse involvement of the whole liver by fibrosis due to heptocellular injury (toxins, drugs, viruses), or deposition of metabolites or minerals (glycogen, copper)
• The normal liver architecture is diffusely replaced by regenerated nodules of liver cells, separated by bands of collagenous fibrosis
• Micronodular (yellow, fatty, enlarged >2 kg)• Macronodular (Brown, Non‐fatty, Shrunken <1 kg)
Cirrhosis
Micronodular Cirrhosis(Laennec's cirrhosis or portal cirrhosis)
Diffuse nodularity of the surface induced by underlying scarring; average nodule size approx. 3mm
Alcoholic Micronodular Cirrhosis
Alcoholic Micronodular Cirrhosis
Macronodular Cirrhosis(post‐necrotic cirrhosis)
Macronodular Cirrhosis
Macronodular Cirrhosis
Relationship between the amount of alcohol consumed and the likelihood of developing cirrhotic alcoholic liver disease
Portal Hypertension
Complications of Cirrhosis
Hepatocellular carcinoma
Hepatocellular Carcinoma Arising in Cirrhosis
Pathogenetic pathways leading to progression of alcoholic liver disease
Alcoholic liver disease as a complex trait
Non alcoholic fatty liver disease
NAFLD ‐ fat accumulation in the liver exceeding 5‐10% by weight in subjects without significant alcohol consumption (<20 g/day, the equivalent of less than two or three glasses of wine per day) and without any other known causes of chronic liver disease.
Non‐alcoholic fatty liver disease (NAFLD) is defined as fat accumulation in the liver, ranging from simple steatosis to non‐alcoholic steatohepatitis (NASH)
• Affects 10 to 24% of the general population in various countries • 57% to 74% in obese persons • 2.6% of children • 22.5% to 52% of obese children
Associated with insulin resistance and metabolic syndrome
Natural history of nonalcoholic fatty liver disease
Pathogenesis of nonalcoholic steatohepatitis
What you should know
• Understand the basic anatomical features of the liver and specifically the liver lobule.
• Be able to describe the major pathologies associated with alcoholic liver disease: fatty liver, acute alcoholic hepatitis, cirrhosis and hepatocellular carcinoma .
• Describe the symptoms associated with advanced cirrhosis.
• Outline the pathogenetic pathways leading to progression of alcoholic liver disease.
• Discuss the causes and pathologic features of non‐alcoholic liver disease
Additional reading
1. Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010 Apr;7(4):195‐203.
2. Altamirano J, Bataller R. Alcoholic liver disease: pathogenesis and new targets for therapy. Nat Rev Gastroenterol Hepatol. 2011 Aug 9;8(9):491‐501
3. Stickel F, Hampe J. Genetic determinants of alcoholic liver disease. Gut. 2012 Jan;61(1):150‐9