Liver Pathology

Cirrhosis and portal hypertension

Definition. Cirrhosis is the end stage of chronic liver injury: diffuse fibrosis with regenerative nodules that destroy normal lobular architecture. Activated hepatic stellate (Ito) cells lay down the collagen. Two sets of problems follow: portal hypertension and hepatocellular insufficiency.

Liver failure signs.

• Hypoalbuminemia: edema and ascites.
• Coagulopathy: high PT/INR from reduced clotting factor synthesis.
• Jaundice and asterixis (hepatic encephalopathy).
• Hyperestrinism: failed hepatic estrogen clearance causes spider angiomata, palmar erythema, and gynecomastia.

Portal hypertension. Increased resistance to portal flow forces blood into portosystemic collaterals: esophageal varices, anorectal varices (distinct from ordinary hemorrhoids), and periumbilical caput medusae. It also causes congestive splenomegaly with thrombocytopenia (platelet sequestration) and ascites. Shunted blood bypasses hepatic ammonia clearance, which drives hepatic encephalopathy.

Hepatitis and fatty liver disease

Viral hepatitis. Hepatitis A and E spread fecal-orally and cause acute disease only; hepatitis E is dangerous in pregnancy. Hepatitis B, C, and D spread parenterally or sexually and can become chronic; D needs HBV's surface antigen to replicate. Hepatitis C is the leading chronic viral cause progressing to cirrhosis and HCC, while HBV can cause HCC even without cirrhosis.

Autoimmune hepatitis. Typically affects young women, with anti-smooth muscle antibodies (type 1) or anti-LKM-1 antibodies (type 2), and responds to corticosteroids.

Alcoholic liver disease. Injury progresses through three stages:

Mallory bodies are clumps of damaged cytokeratin intermediate filaments. In alcoholic hepatitis AST exceeds ALT by more than 2:1 ("make a toAST"), and both usually stay below 500 U/L. AST predominates because alcohol injures mitochondria, a major source of AST, and alcoholics are often deficient in the pyridoxal phosphate (vitamin B6) that ALT needs.

Nonalcoholic fatty liver disease. NAFLD and nonalcoholic steatohepatitis (NASH), now renamed MASLD and MASH, arise from obesity, insulin resistance, and metabolic syndrome. ALT exceeds AST, the opposite of alcohol. It is the most common chronic liver disease in the US and can progress to cirrhosis and HCC; histology can mimic alcoholic hepatitis, so history separates them.

Reye syndrome. Aspirin (salicylate) given to a child during a viral illness (influenza, VZV) causes mitochondrial injury: microvesicular hepatic steatosis, encephalopathy, hypoglycemia, and hyperammonemia. Avoid aspirin in children; Kawasaki disease is the classic exception.

Inherited metabolic liver disease

Wilson disease. Autosomal recessive mutation of ATP7B (chromosome 13), the copper transporter that excretes copper into bile and loads it onto ceruloplasmin. Copper accumulates in the liver (hepatitis, cirrhosis), basal ganglia (parkinsonism, dysarthria, psychiatric change), and cornea, where copper in Descemet membrane forms Kayser-Fleischer rings. Free copper also causes hemolytic anemia. Labs show low ceruloplasmin and high urinary copper. Treat with copper chelation (penicillamine, trientine) or zinc, which blocks copper absorption.

Hereditary hemochromatosis. Autosomal recessive HFE mutation (C282Y) lowers hepcidin, so the gut absorbs iron without restraint. Labs: high ferritin, high transferrin saturation, and low TIBC. The classic triad is cirrhosis, diabetes, and skin pigmentation ("bronze diabetes"), plus cardiomyopathy, arthropathy, and HCC risk. Women present later because menstruation removes iron. Treat with phlebotomy, or chelation if phlebotomy is not possible.

α1-Antitrypsin deficiency. In the PiZZ genotype, a misfolded protein cannot leave the endoplasmic reticulum and accumulates in hepatocytes as PAS-positive, diastase-resistant globules, causing cirrhosis. In the lung, the resulting lack of antiprotease lets neutrophil elastase destroy alveolar walls, causing panacinar emphysema that smoking worsens. Liver disease comes from protein accumulation; lung disease comes from protease deficiency.

Complications: encephalopathy, HCC, and Budd-Chiari

Hepatic encephalopathy. Ammonia from gut bacteria escapes hepatic clearance and reaches the brain, causing asterixis and altered mentation. Precipitants either raise ammonia production or bypass the liver: GI bleeding, infection, constipation, hypokalemia, alkalosis, and TIPS. Lactulose is acidified by colonic bacteria, trapping ammonium (NH₄⁺) in the gut for excretion; rifaximin reduces ammonia-producing flora.

Hepatocellular carcinoma. The most common primary liver cancer. Risks include HBV (which can integrate and cause HCC without cirrhosis), HCV, cirrhosis of any cause, hemochromatosis, and aflatoxin from Aspergillus on stored grains, which causes a characteristic p53 mutation. Serum α-fetoprotein (AFP) is the marker. HCC tends to invade the portal and hepatic veins; hepatic vein invasion can cause Budd-Chiari syndrome.

Budd-Chiari syndrome. Obstruction of hepatic venous outflow (hepatic vein or IVC) causes congestive hepatomegaly with a nutmeg liver, ascites, abdominal pain, and varices. Causes are hypercoagulable states: polycythemia vera and other JAK2 neoplasms, pregnancy, and HCC. The absence of jugular venous distension separates it from right heart failure.

Unconjugated vs conjugated jaundice

Solubility is the key. Unconjugated (indirect) bilirubin is bound to albumin and is not water soluble, so it never appears in urine. Conjugated (direct) bilirubin is water soluble; when it backs up into blood, it spills into urine and darkens it, and obstruction also produces pale stools. Gilbert syndrome flares with stress or fasting and is benign. Dubin-Johnson syndrome gives a grossly black liver; Rotor syndrome does not.