Non-Neoplastic Liver Disease

• Study notes on non-neoplastic disease of the liver

Normal Anatomy

• Liver weight in adults is typically between 1200-1500 g
• The liver has right and left lobes and is divided into 9 segments
• It has a dual blood supply from the hepatic artery, providing oxygen-rich blood, and the portal vein, providing nutrient-rich blood

Liver Microanatomy

• The liver consists of trabecular plates of hepatocytes, which are 1-2 cells thick
• Sinusoids are vascular spaces between hepatocytes, lined by endothelial cells
• Kupffer cells (macrophages) are scattered within the sinusoids
• Stellate cells are also present.
• Bile drains into the space between hepatocytes, called canaliculi
• Canaliculi drain into bile ducts, which are lined by biliary epithelium
• Zone 1 encircles the portal tracts where oxygenated blood from hepatic arteries enters
• Zone 2 is the liver parenchyma in between
• Zone 3 is located around central veins, where oxygenation is poor
• Histologically, the portal triad consists of the hepatic artery, portal vein, and bile duct
• Central veins are also visible histologically

Steatotic Liver Diseases

• Steatotic liver diseases include alcoholic and non-alcoholic types:
• Steatosis
• Acute alcoholic hepatitis
• Alcoholic steatohepatitis
• Nonalcoholic steatohepatitis

Risk Factors for Fatty Liver Disease

• Risk factors include alcohol consumption
• Metabolic syndrome
• Certain medications/toxins
• Malabsorption syndromes like Crohn's or celiac disease, or surgical resection
• Anorexia nervosa
• Genetic diseases such as Wilson disease, tyrosinemia, cystic fibrosis, and Prader-Willi syndrome

Clinical Features of Fatty Liver Disease

• Laboratory findings include an AST:ALT ratio of 2:1, in addition GGT can show marked elevation
• On imaging, ultrasound cannot detect fat levels below 15% to 20%
• MRI can be used for imaging
• Gross findings include yellow appearance and enlargement of the liver

Alcoholic Liver Disease Etiology and Pathophysiology

• Ethanol (ETOH) is metabolized to acetate in the liver via alcohol and aldehyde dehydrogenases, and the microsomal ethanol-oxidizing system
• Direct hepatotoxic effects are due to acetaldehyde production
• The mechanism of alcohol-induced injury relates to oxidative stress and free radical production
• This results in mitochondrial damage, depletion of glutathione, toxicity by free radicals, and lipid peroxidation
• The key enzyme of the microsomal ethanol-oxidizing system, CYP2E1, is in the endoplasmic reticulum of zone 3 hepatocytes
• System activation leads to the production of reactive oxygen species such as H2O2 and superoxide anions, causing lipid peroxidation of cell membranes
• Other sources of ethanol-induced oxidative stress are endotoxin-activated Kupffer cells, impaired mitochondria, and ferric iron accumulation
• Free radicals cause lipid peroxidation, inflammation, and fibrosis
• Inflammation is also prompted by acetaldehyde covalently bound to cellular proteins, forming antigenic adducts

Nonalcoholic Steatohepatitis Pathogenesis

• Pathogenesis involves mitochondrial dysfunction
• Membrane cholesterol accumulation
• Excessive exposure to gut-derived endotoxin
• Dysregulated adipokine production
• Hypoxia
• Changes in the gut flora
• Dietary deficiencies (like choline)

Histologic Findings in ASH and NASH

• Macrovesicular steatosis (fatty change) begins in centrilobular zone 3 and extends outwards
• Ballooned hepatocytes with Mallory hyaline
• Hepatocyte inflammation and necrosis
• Perivenular/pericellular fibrosis (aka "chicken wire")

Autoimmune Hepatitis

• Hepatitis is caused by an immune response against self-liver antigens
• It is more common in Caucasian and North American populations
• Pathogenesis involves hepatocyte injury that triggers a dysregulated immune response
• It is more common in women, with a 4:1 ratio
• It can occur at any age but is more aggressive in younger individuals
• Diagnosis relies heavily on biopsy
• Associated diseases include type 1 diabetes, celiac disease, autoimmune thyroiditis, and rheumatoid arthritis
• Clinical presentation may include elevated liver enzymes, liver failure, fatigue, lethargy, abdominal pain, and anorexia
• Clinical and serologic features distinguish Type 1 and Type 2 autoimmune hepatitis
• Type 1 is more frequent (95%) and can occur at any age, with autoantibodies like antinuclear antibodies (ANA) and anti-smooth muscle antibodies (SMA); it is often variable in relapse after immunosuppression withdrawal
• Type 2 is less frequent (5%) and occurs mostly in childhood and young adulthood, with anti-liver/kidney microsomal antibody (LKM type 1) and anti-liver cytosol (LC1); it is often common after immunosuppression withdrawal with long-term maintenance needed
• Histologically, autoimmune hepatitis shows +++ plasma cells
• Portal and lobular inflammation composed of lymphocytes and plasma cells
• Necrosis of hepatocytes
• "Interface" activity is the destruction of hepatocytes at the edge of the portal tract

Viral Hepatitis

• Primary viruses that cause hepatitis are hepatitis A, B, C, D (requires HBV co-infection), and E viruses
• Systemic viruses that cause hepatitis are cytomegalovirus, Epstein-Barr virus, adenovirus, HIV, parvovirus B19, rubella, Coxsackievirus B, enteroviruses, and human herpes viruses
• Hepatitis B is a dsDNA virus with an incubation period of 1-6 months and predominantly parenteral transmission; it has a carrier state, ++ severity, and can be prevented with vaccines
• Hepatitis C is a ssRNA virus with an incubation period of 2-26 weeks and parenteral transmission; it has a carrier state, + severity, and active immunization is not available
• Hepatitis results in necrosis and collapse of liver lobules, as well as hemorrhage and tissue loss
• Histological features of hepatitis are Lobular disarray, Parenchymal cells pleomorphism with ballooning, granular cytoplasm and some apoptotic cells, and Mononuclear cell infiltrates that are predominantly lymphocytes and monocytes
• Acute hepatitis is lobular disarray, ballooned hepatocytes and inflammatory cells in sinusoids
• Chronic hepatitis causes periportal mononuclear inflammatory infiltrates, interface activity, and fibrosis
• Hepatitis B has more periportal inflammation, ground glass appearance of hepatocytes when HbsAg is elevated or in active viral replication, and "sanded" nuclei
• Hepatitis C has portal lymphoid aggregates with or without germinal centers in chronic infection, steatosis without zonal distribution, and increased iron deposition, secondary to necroinflammatory activity
• Inflammation is graded from 1-4
• Fibrosis is staged from 1-4

Hemochromatosis

• Primary hemochromatosis is genetic with a mutation in the HFE gene (C282Y/C282Y)
• Rarer genetic cases involve mutation in hemojuvelin (HJV), transferrin receptor 2 (TFR2), Hepcidin (HAMP), ferroportin (SLC40A1)
• Secondary hemochromatosis can occur due to parenteral iron overload, anemias, and chronic liver disease (HCV and ASH)
• Primary hemochromatosis patients with cirrhosis have a 100 times greater chance of developing HCC than the general population
• Sites affected include the liver, heart, pancreas, skin, gonads, and joints
• Biological males develop symptoms around 40-60 years old, biological females develop symptoms after menopause if they were having menstrual cycles
• Histology shows dark brown granular pigment predominantly in hepatocytes and iron in cholangiocytes and Kupffer cells, with fibrosis developing over time
• Iron can be stained with Prussian blue stain or quantified through atomic absorption spectrophotometry

Cirrhosis

• Cirrhosis involves diffuse nodularity of the liver caused by fibrous bands
• These subdivide the liver into regenerative nodules
• Common causes include chronic viral hepatitis B and C, fatty liver disease, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and drug induced liver injury
• Cirrhosis is the end point for liver fibrosis (Stage 4/4) that involves complete bands of fibrosis with regenerative nodules of liver cells (hepatocytes)
• Complications include portal hypertension, dysplastic nodules, hepatocellular carcinoma, and other “stigmata” of liver cirrhosis which are essentially secondary to dysfunction
• Acute hepatitis can be followed by chronic hepatitis, then cirrhosis, and finally possible Hepatocellular carcinoma
• Not everyone with cirrhosis develops Hepatocellular carcinoma