Causes of Chronic Liver Injury – Three Mechanisms

• (1) Hepatocyte destuction – usually by inflammation (disease or autoimmunity); also toxins, virus, or genetic abnormality
• Autoimmune – usually affects young women, 10 - 30 years old(women may have more active immune system)
• activated lymphocytes destroy hepatocytes (and other tissues too) by antibody-mediated cellular cytotoxicity
• autoantibodies often produced against a -actin (smooth muscle)
• other possibilities: a -KM1 (present in liver/kidney microsomes) and SLA (soluable liver antigen)
• 80% of all cases are related to lupus; some autoimmunity possibly due to superantigens from drug metabolism
• high dose steroid therapy – can be much better in weeks
• Viral – due to hepatitis B, delta, or C (A and E are not chronic) – often subclinical acute infection
• in hepatitis B, damage is due to inflammatory response, NOT direct cytotoxicity
• nucleocapsid peptides (HBcAg) are presented by MHC-I, leading to CD8+ mediated cell death
• chronic is due to partial immune tolerance – impaired T-cells, fail to display or recognize viral or MHC
• chronic viral hepatitis does not respond to steroid treatment, but interferon may be used successfully
• direct antiviral effects – stimulates cellular RNAses, inhibition of viral entry, inhibition of replication
• immunomodulatory effects – enhance CD8+, stimulate NK cells, amplify MHC-I
• disease determined by immune reaction to virus – appropriate will eliminate virus with minimal liver damage
• too aggressive – fulminant liver failure – eliminate virus at expense of liver
• not sufficiently aggressive – viremia – no hepatitis, but virus multiplies unchecked
• Drug Induced – caused by many drugs; those with strongest correlation are no longer used
• include: oxyphenisatin (laxitive), nitrofurantoin (UTI antibiotic), alphamethyldopa (antihypertensive), dantrolene (smooth muscle relaxer)
• many other drugs (e.g., isoniazid, papaverine, acetominophen) might cause hepatitis
• alcohol is the cause of 60-70% of cirrhosis
• Hemochromatosis – absorb too much iron all life – genetic basis now understood
• more often men – women somewhat protected because of menstruation
• also: skin bronzing, cardiomyopathy and conduction dissorders, diabetes mellitis (pancreatic), testicular atrophy and arthritis
• Wilson’s Disease – too much copper – not enough serum ceruloplasmin (copper-binding), or inactive
• accumulates in brain and liver
• also: Kayser-Fleischer ring (around iris), neuropsychiatric, cardiomyopathy, Fanconi syndrome (kidney), osteopenia/arthropathy
• Alpha-1-antitrypsin deficiency – very common (1/30 Caucasians are heterozygous)
• enzyme produced in liver – protects lung from protease (emphysema)
• protein is made appropriately, but not exported – can produce neonatal hepatitis and hepatocellular carcinoma
• (2) Biliary Outflow Obstruction ("cholestasis") – accumulate bile acids and copper – can be at any point along bile tract
• alteration in canilicular membrane and tight junctions, condensation of microfilaments Þ no longer transported
• obstruction of bile ducts:
• primary biliary cirrhosis (autoimmune – mostly middle-aged women)
• primary sclerosing cholangitis (inflammation of ducts)
• biliary atresia
• pancreatitis (compress bile duct)
• Dubin-Johnson Syndrome
• viral or alcoholic hepatitis
• pregnancy
• cholangiocarcinoma,
• protoporphyria (liver disease also resulting in severe sunburns)
• results in:
• ß bilirubin excretion (sometimes causes jaundice)
• ß excretion of bile salts (fat malabsorption, deficiency in vitamins A, D, K, and pruritis)
• ß cholesterol excretion (xanthomas)
• (3) Hepatic Venous Outflow Obstruction – not common; occurs in heart failure or constrictive pericarditis
• heart failure
• low cardiac output Þ low liver O₂ Þ zone 3 necrosis, reticulin collapse, fibrosis Þ "cardiac cirrhosis"
• low right atrium pressure Þ increased hepatic venous pressureÞ sinusoidal distention and hemorrhage
• hepatic vein occlusion (Budd-Chiari syndrome) – thrombosis, congenital web, tumor
• central vein occlusion (venoocclusive disease) – from chemotherapy, especially with concurrent radiation therapy
• also caused by plant alkaloids that are combined in various herbal remedies

Results of Chronic Liver Injury – usually cirrhosis

• Classical Grading System – based upon extent of inflammation
• portal triads only: chronic persistent hepatitis (CPH)
• portal and periportal regions: chronic active hepatitis (CAH)
• entire lobule (acini): chronic lobular hepatitis (CLH)
• Modern Grading System – based upon four hitological criteria
• (1) periportal or bridging necrosis (1-10)
• (2) parenchymal injury(interlobular HC degen/necrosis) (0-4)
• (3) portal inflammation (0-4)
• (4) also fibrosis (0-4)– used to grade

• Normally, there is clean connective tissue around the portal triad with a layer of hepatocytes ("limiting plate").
• Piecemeal necrosis – inflammation at interface between the lobule and connective tissue of the portal area
• piecemeal necrosis can occur even after cirrhosis occurs, producing periportal hepatitis
• the portal area broader, becomes fibrotic, bridging – inflammation then becomes fibrous – develop into steatosis
• Different forms of hepatitis look superficially similar – non-specific morphology, so history taking is vital for diagnosis
• viral hepatitis – fine granular occlusions (cytoplasmic) – viral antigens stain brown with immunoperoxidase
• portal triad is main area involved; lymphocyte infiltrate with piecemeal necrosis ("blue polka dot" liver)
• bile duct changes, steatosis of hepatocytes
• autoimmune hepatitis – extensive bridging necrosis, much inflammation between portal areas, many plamsa cells
• inflammatory bile duct disease – portal and bile duct inflammation – bile duct epithelial damage and loss
• frequently includes granulomas and secondary bile duct proliferation
• primary sclerosing cholangitis – "onion-skin" periductal fibrosis – circular fibers
• liver loaded with bile – looks black rather than green; enormous amount of bile histologically (greenish-brown)
• staging – 1 (minor portal hepatitis) to 4 (cirrhosis)
• hepatic iron overload – stain blue with Prussian blue stain (very clear – do not need microscope)
• often accompanied by micronodular cirrhosis – often bile duct damage only if genetic (hemocromatosis)
• ferritin and hemosiderin stored in liver lysosomes – liver looks grossly chocolate brown
• Fe seen in hepatocytes (especially periportal), less in kruppfer and bile ducts Þ fibrosis micronodular cirrhosis
• staging – 1 (pre-scarring iron loading) to 3 (cirrhosis)
• Wilson’s disease – accumulation of copper in liver
• staging – 1 (mild iron deposits) to 3 (cirrhosis)
• Alpha-1-Antitrypsin – synthesis of antitrypsin in liver, but not exported
• enormous globules under PAS stain or antiperoxidase
• dilated rough and smooth ER
• Drug Toxicity – looks like chonic viral hepatitis
• steatosis and inflammatory damage – very few get cirrhotic – bridging fibrosis
• low doses of methotrexate used for psoriasis and rheumatoid arthritis – stopped just before cirrhosis
• Cirrhosis – whole liver transformed into structurally abnormal nodules surrounded by fibrosis
• micronodular (<3 mm) or macronodular (>3 mm, can be more than 1 cm) – may be mixed
• no lobules architecture visible – little nodules, large amounts of fibrous tissue (collagen)
• sometimes inflammation or bile duct proliferatio
• Hepatocellular Carcinoma – large N/C ratio, huge amount of fibrosis
• large cell vs. small cell displasia – small cell is predominant pathway – NOT same as small cell of lung
• may be white, often green or show necrosis/hemorrhage, sometimes pseudoglandular (bile production)
• often stain for AFP by immunoperoxidase
• Cholangiocarcinoma – cancer of bile ducts
• can be extrahepatic or intrahepatic – look like adenocarcinomas

• the end result of several forms of chronic liver disease—the normal lobular and vascular architecture is destroyed. Cirrhosis is associated with the formation of fibrous septa and regenerating nodules. In such nodules the liver cell plates are more than two cell layers thick and the zonal arrangement of hepatic blood flow is absent. Ito cells switch over to producing collagen because of cytokines and lipid peroxidation.
• D P = Q x R with cirrhosis there is Ý portal pressure due to ß blood flow (Q) and Ý resistance (R)

Portal Hypertension – when WHVP exceeds IVC pressure by more than 4 mmHg

• Wedge pressure- measured by catherization; a catheter with a balloon isolates a segment of liver. The "Wedge pressure" (WHVP) is measured. The balloon is deflated and the "Free pressure" (FHVP) is measured. The difference is equal to the pressure gradient across the sinusoids(HVPG). WHVP – FHVP = HVPG (Ý HVPG in cirrhosis)
• Portal vein pressure may be elevated Pre-sinusoidal (before hepatic sinuses, e.g. Schistosomiasis), Sinusoidal (cirrhosis), or Post-sinusoidal (hepatic vein occlusion)
• Collateral circulations – 4 major collateral circulations shunt portal blood from the portal system to the caval system
• (1) Esophageal varices – common finding, common site of hemorrhage
• (2) Rectum (internal hemorrhoids) – common, rarely hemorrhage
• (3) Umbilical vein (Caput Medusea) – rare site of bleeding
• (4) Retroperitoneal varices – rare bleeders barring trauma
• The mid esophagus drains in the azygous. Esophageal varices are visualized as filling defects in a barium swallow.
• Varices can rupture and bleed out (often with arterial like force including pulsations!)
• Red Wail Signs – veins on veins that form on large varices.
• DOGMA – there has to be a gradient greater than 12 mmHg to bleed
• Treatment – protect the airway, nitroglycerine and drugs that reduce mesenteric blood flow, Band ligation via endoscope, TIPS (transjugular intrahepatic portal shunt), endoscopic sclerosing of varices (not used as much anymore)

Acites – most common complication of cirrhosis, Ascites does not develop without portal hypertension

• 50% prevalence after 10 years with cirrhosis, 50% survival rate at 2 years once ascites develops
• at the one year mark, survival is much better with a liver transplant
• 2 theories on the development of ascites
• (1) Classic "Underfill" theory – urinary Na⁺ and H₂O retention after the development of ascites
• (2) "Overfill" theory – urinary Na^{+ and} H₂O retention before the development of ascites
• hypoalbuminemia – due to chronic liver disease leads to a low plasma oncotic pressure
• impaired reabsorption of peritoneal fluid – contributes to the maintenance of ascites
• Treatment – Na⁺ restriction, paracenteses, diuretics that block Aldosterone (Loop diuretics aren’t as effective since the elevated Aldosterone level will only reabsorb
• he Na⁺ placed in the lumen of the proximal tubule in the distal tubule)
• Some causes of acites:
• Umbilical Hernia – 35% ulceration, 14% incarceration, 7% rupture
• Treatment – control ascites, elective surgery, if ruptures Þ emergency surgery
• Hepatic Hydrothorax– due to a direct communication in the diaphragm. (66% right sided / 17% bilateral)
• fluid accumulates in the thorax due to communication with the peritoneum. Fluid is ascites like when tested
• Treatment – diuretics, needle drainage of thorax, TIPS, or liver transplant
• Infection – most serious consequence of ascites Þ will kill the patient
• Lymph flow is 10-20 x’s increased with ascites, bacteria in lymph have systemic access, if not opsonized by WBC’s the bacteremia may go into the ascitic fluid and cause Spontaneous Bacterial Peritonitis (SBP)
• SBP – 70% one year mortality, frequent reoccurances, MOST SERIOUS COMPLICATION of ascites
• Treatment – broad spectrum IV antibiotics (no aminoglycosides because of vulnerable kidneys)

• neuropsychiatric abnormalities in patients with significant liver failure. Hepatocerebral syndromes – ABC’s:
• Acute liver failure associated with HE (HE within 8 weeks of liver dysfunction)
• Encephalopathy with Bypass
• Encephalopathy in Cirrhosis / Chronic liver disease
• Diagnosis – identify hepatic dysfunction, identify motor disturbances and/or alterations in mental status, rule out other causes (CNS trauma, septic encephalopathy, drug intoxication, etc), identify and treat precipitating factors (GI bleed, sedative drugs, hypokalemia, alkalosis, uremia, dehydration, constipation, etc).
• 60-70% of patients with cirrhosis have evidence of subclinical encephalopathy
• Modified West Haven HE staging –
• 0 – no abnormality detected
• 1 – change in personality, shortened attention, insomnia, arithmetic difficulty
• 2 – lethargy, monotone voice, loss of time orientation
• 3 – somnolent but responsive to stimuli
• 4A – coma, responsive to major stimuli
• 4B – coma, anesthetized (rate comas on the Glasgow Coma Scale)
• Asterixis – a clinical sign of HE, when holding arms out (like "stop" sign) the hands "flap"
• On CT scan – HE brains have prominent sulci and ventricles; EEGs have slow, high voltage spikes, MRI’s show manganese deposits.
• Pathogenesis – no one knows for sure, commonly thought that toxic neurotoxins produced by bacteria in the colon get into the brain and wreck havoc. (possibly ammonia, benzodiazepine like compounds, and/or GABA)
• GABA – opens Cl^- channels to achieve a hyperpolarized state (keeps one from convulsing) // benzodiazepines are in meat and elevated levels have been found in HE patients in comas.
• Treatment – supportive for Coma
• Stop production of neurotoxins in colon by reducing the time substrate is in the colon or bacteria in colon
• Lactulose – a disaccharide that can only be broken down by colonic bacteria Þ diarrhea
• Antibiotics – Neomycin or Metronidazole to knock out colonic flora

Hepatorenal Syndrome – unexplained renal failure in patients with severe liver disease