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Chapter 12
Disorders of the Liver and Biliary Tract
Lecture 12
The Nature of DiseasePathology for the Health Professions
Thomas H. McConnell
Overview of Today’s Lecture
– Review of Liver and Biliary Tract
– Liver response to injury
– Viral Hepatitis
– Non-viral inflammatory liver disease
– Toxic Liver Injury
– Metabolic Liver Disease
– Diseases of the intrahepatic bile ducts
– Circulatory disorders
– Tumors of the liver
– Disorders of the Gallbladder and extrahepatic bile ducts
Liver, Portal venous system, and Bile ducts
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
The Enterohepatic Circulation
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Liver Metabolic Tasks/Actions
Table from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
The Liver Response to Injury• Most important liver diseases:
– Viral hepatitis
– Alcoholic liver disease
– Non-alcoholic liver disease
– Malignancy
• Four common endpoints (clinical syndromes) of liver disease1. Jaundice and cholestasis (usually occur together)
• Jaundice – Abnormal increase is bilirubin, e.g., in skin, sclera
• Cholestasis – reduced production/flow of bile
2. Cirrhosis – Widespread, irreversible, scarring (fibrosis) of liver
3. Portal hypertension – increased pressure in portal venous system
4. Hepatic failure – Severe enough to cause hepatic encephalopathy
Metabolism of Bilirubin
Figure from: Huether & McCance, Understanding
Pathology, 5th ed., Elsevier, 2012
What if there is an imbalance between the production and excretion of bilirubin?
Etiology of Jaundice
• What are the three conditions leading to imbalance of bilirubin?
1. Overproduction of bilirubin– Prehepatic jaundice
– Unconjugated hyperbilirubinemia
2. Defective liver functioning – Hepatic jaundice
– Both conjungated and unconjugated hyperbilirubinemia
3. Biliary obstruction– Posthepatic jaundice
– Conjugated hyperbilirubinemia
Figure from: Huether & McCance, Understanding Pathology, 5th ed., Elsevier, 2012
(Also see 12.4 in McConnell)
Pathophysiology of Jaundice
• Unconjugated hyperbilirubinemias– Hemolytic Disease of the Newborn
• Liver is typically immature at birth
• Unconjugated bilirubin deposits in brain (Kernicterus)
– Gilbert Syndrome & Crigler-Najjar Syndrome• Autosomal recessive; lack of glucuronyl transferase
• Conjugated hyperbilirubinemias– Dubin-Johnson Syndrome & Rotor Syndrome
• Autsomal recessive
• Neither typically needs treatment
Cholestasis
• Impaired bile formation and bile flow– Accumulation of bile pigments in liver
– Usually accompanied by jaundice, possibly pruritis
– Several causes• Liver disease
• Biliary obstruction
• Drug interference with bile secretion
• Pregnancy
– Problems resulting from lack of bile acids• High blood cholesterol (xanthomas)
• Fat malabsorption
Cirrhosis• Widespread scarring of liver
• Irreversible and Incurable
• Common endpoint for many liver diseases
• 65% from alcoholism and chronic hepatitis
• 25% - cryptogenic cirrhosis
• Intrahepatic pressure rises– Hepatocyte damage
– Portal flow obstructed -> PH
– Portal blood flow is diverted
• Two anatomic types– Portal cirrhosis (normal liver anatomy
disrupted)
– Biliary cirrhosis (normal liver anatomy maintained)
Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Portal Hypertension (PH)• Increased pressure in portal venous system
– Due to increased resistance in portal flow
– May occur at three points• Before blood reaches liver (prehepatic)
– Thrombosis, narrowing, external pressure on portal vein
• As blood flows through liver (hepatic) – cirrhosis
• After blood exits liver (posthepatic)– Severe right sided HF
– Restrictive pericarditis
– Thrombotic (or other) obstruction of hepatic vein
– S & S• Ascites – intraperitoneal accumulation of watery (serous) fluid
• Portosystemic shunts – alternate pathways of blood into veins– Rectal veins (hemorrhoids), esophageal veins (varices), falicform lig (caput medusa)
• Spleomegaly from chronic passive congestion; hypersplenism
Hepatic Failure• Loss of hepatic metabolic function severe enough to cause
hepatic encephalopathy
• Usually 80-90% nonfunctional liver
• Acute (uncommon)– Acetaminophen
– Other drugs, industrial chem., autoimmune and viral hepatitis
• Chronic (most common) – mainly from cirrhosis
• S&S– Bilirubin excretion failure leading to what?
– Decreased albumin production leading to what?
– Factor hepaticus (musty odor of body/breath)
– Hormonal imbalance
– Hepatic encephalopathy (from ammonia, other toxic products) – asterixis
– Hepatorenal and Hepatopulmonary Syndromes (causes unk)
Viral Hepatitis• Viral Hepatitis (Hepatotropic viruses: A, B, C, D, and E; H#V)
– Inflammation of the liver caused by viral infection
– Viral types differ in • mode of transmission and incubation period
• mechanism, degree, and chronicity of liver damage
• ability to evolve to a carrier state
• ability to cause hepatocellular carcinoma
– General phases of acute hepatitis infection• Incubation & Prodromal; about 2 weeks
• Icterus (onset of jandice, dark urine, clay-colored stools); 4-8 weeks post exposure
• Convalescence (Recovery) about 8 weeks after onset
– Diagnosis based on detection of ag (HBsAg) or antibodies, e.g., anti-HAV, anti-HBc
– Pathophysiology• Major route of transmission: fecal-oral, contact with infected blood/body fluids
• Can lead to acute (fecal-oral) or chronic disease (contact with body fluids/blood)
• HBV can exist in asymptomatic carrier state
• Effects vary from death of a few hepatocytes to massive liver necrosis/cirrhosis and HCC
• Can be explosively acute and progress to fulminant liver failure very quickly = catastrophic liver failure (usually HAV or HBV)
Viral Hepatitis
• Viral Hepatitis (Hepatotropic viruses: A, B, C, D, and E)
– Hepatitis viruses designated as HAV, HBV, etc.
– Some other viruses can infect the liver as well, e.g., EBV, CMV, HSV
– Viral infection typically causees inflammation of the liver
– Hepatitis viral types differ in • Mode of transmission
• Length of incubation period
• Mechanism, degree, and chronicity of liver damage
• Ability to evolve to a carrier state
• Ability to cause fulminant hepatitis (sudden, catastrophic liver failure)
• Ability to cause hepatocellular carcinoma
Viral Hepatitis – Clinicopathological Syndromes
Viral Hepatitis - HAV• HAV
– Fecal-oral route
– Anti-HAV IgM ab – marker of acute infection
– Only Acute (think of ‘A’ as acute); no carrier
– Vaccine available
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Viral Hepatitis - HBV• HBV
– IV/Sex
– HBsAg and anti-HBc ab – markers of acute infection
– Can be: chronic, carrier, carcinoma
– 1/3 of world’s population shows evidence of being infected
– Vaccine available
Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Viral Hepatitis - HCV
• HCV– IV/Sex; Healthcare
employment (no vaccine available)
– HCV-RNA as acute marker
– Can be: chronic, carrier, carcinoma
– Major cause of chronic liver disease; most common indication for txplant
Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Non-viral Inflammatory Liver Disease• Most bacterial/fungal infections result in liver abscess
– Ascending cholangitis
– Hematogenous
– Penetrating trauma
• E. histolytica– Poor sanitation (fecal contamination of unwashed food )
– Burrow into intestine, travel up portal vein to liver
– Liver abscesses
• Schistosomiasis– Parasite; one variety causes chronic immune rexn
– Infiltrates portal system -> PH, cirrhosis
• Autoimmune hepatitis– T- cell mediated
– Over 50% have some other autoimmune disease, e.g., UC, Sjogren, SLE
– 80% cases female
Toxic Liver Injury• Two Types
– Dose-related – predictable, proportional to dose• Usually from chemotherapy, accidental/intentional drug overdose
• 50% of cases from acetaminophen (Tylenol)
– Non-dose related (idiosyncratic reactions)• Some causes include sufonamides, isoniazid, halothane, chlorpromazine
• Drug-induced hepatitis same pathology as viral hepatitis• Reye syndrome
– Children
– Fatty liver, acute brain dysfunction
– Following administration of aspirin after acute viral illness
– Sever vomiting, lethargy, irritability, hepatomegaly
– 25% progress to coma
Alterations in Liver Function
From: Pathophysiology: A Clinical Approach, Braun & Anderson, Lippincott, 2011
Alcohol abuse – A Leading Cause of Liver Disease
- More than 10 million chronic alcoholics in US (estimated)
- Contributes to over 100,000 deaths annually (50% drunk driving)- Blood concentration (BAL) of 80 mg/dl (0.08%) = intoxicated in US
- Three drinks is sufficient (1 drink = 12 oz beer, 5 oz wine, 1.5 oz hard)
- Effects vary by age, gender, and percent body fat, genetics
- Fatty foods and milk slow absorption
- Rate of metabolism (mostly hepatic cyt P450) affects BAL
- Absorbed directly from stomach and small intestine
- Effects involve the CNS (and other organs as well)- Depressant
- Affects subcortical structures first, then brainstem
What is the nutritional caloric content of alcohol?
Alcohol Abuse
- Liver and nutritional disorders most common side effects of chronic alcohol abuse
- Liver- Fatty liver and fatty degeneration of hepatocytes (steatosis)
- Alcoholic hepatitis – more severe than fatty liver (steatohepatitis)
- Alcoholic cirrhosis - irreversible; may cause portal hypertension
- Increased risk of hepatocellular carcinoma
- Nutritional- Deficiencies of Mg2+, vit B6, thiamine, P
- Folic acid deficiency (especially serious for pregnant women; may cause Fetal Alcohol Syndrome)
- Vitamin B12 – due to impaired absorption
- Additional effects- Acute gastritis
- Cardiomyopathy
- Possible systemic hypertension
- Regressive changes in skeletal muscle
Is Alcohol Good for Anything Besides a Buzz?
- Association between light to moderate (≤ 25g/day) alcohol consumption and cardiovascular disease
Figure from: http://pubs.niaaa.nih.gov/publications/arh27-1/39-51.htm
Beneficial effects on CVS (coronary heart disease, CHD) believed to be due to:
-Increased levels of HDL-C
- Prevention of clot formation
- Reduction in platelet aggregation
- Increased fibrinolysis
Metabolism/Hepatic Effects of Ethanol
Three enzyme systems in liver that convert EtOH to acetaldehyde:
1.Alcohol dehydrogenase (ADH)
2.Microsomal ethanol oxidizing system (MEOS; activated with high EtOH levels)
3.Catalase
*Hepatic effects of acetaldehyde:- Inflammation- Fat deposition- Hepatomegaly- Microtubular txport defects- Increased cellular H2O- Decreased FA oxidation in mt- Increased membrane rigidity- Necrosis
Metabolic Liver Disease• Non-alcoholic Fatty Liver Disease
– Group of related conditions manifesting with fatty liver
– Closely associated with the metabolic syndrome
• Obesity, hyperlipemia/hyperlipidemia, pre-diabetic insulin resistance
• Pathology: steatosis to steatohepatitis (NASH)
• Hemochromatosis– Autosomal recessive iron storage disorder
– Accumulation of iron in liver, pancreas, heart
– Abnormally high iron absorption from intestine
– Usually men
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Metabolic Liver Disease• Wilson’s Disease
– Autosomal recessive (rare)
– Toxic copper accumulation in liver and brain
– In eye -> Kayser-Fleischer ring
Figure from: http://www.eurowilson.org/en/living/guide/pathway/index.phtml
From: https://lostinzhoushan.wordpress.com/
Metabolic Liver Disease
• Alpha-1 Antitrypsin (AAT)– Recall its role in emphysema
– Genetic form results in low levels of AAT
– Accumulation of excess non-functional AAT in liver causes damage (mechanism unk)
– Death caused by emphysema and cirrhosis
Biliary Cirrhosis
• Prolonged obstruction in extrahepatic biliary tree can damage the intrahepatic bile ducts liver
• Two forms– Primary biliary cirrhosis
• Autoimmune nflammatory destruction of intrahepatic bile ducts
• Most patients have another autoimmune disease, e.g, SLE, Sjogren
• Most are middle-aged women
• Cholestasis: xanthelasma, fat malabsorption
• Death from cirrhois, PH, and hepatic failure
– Secondary biliary cirrhosis• Gallstones, cancer in head of pancreas, surgical scars
• Cholestasis -> inflammation -> scarring -> biliary cirrhosis
• May cause ascending cholangitis
Biliary Cirrhosis
• Primary sclerosing cholangitis– Inflammation of both intra- and extrahepatic bile ducts
– >60% have UC; some with other IBD
– Usually men under age of 40
– Scarring of bile ducts inside and outside liver
– “Onionskin” fibrosis
– Results in chronic cholestatic liver disease
Figure from: www.medscape.com
Circulatory Disorders of the Liver
• Areas of obstruction of blood flow in/out of the liver– Blood flow into liver (prehepatic)
• Arterial obstruction (uncommon; atherosclerosis or thromboembolism)
• Portal obstruction– Thrombosis associated with intra-abdominal disease
– Results in portal hypertension
– Blood flow within liver (intrahepatic)• Cirrhosis
• Right HF -> chronic passive congestion of liver (cardiac cirrhosis)
– Blood flow out of liver (posthepatic)• Obstruction of one or more branches of the hepatic vein
• Occlusion of main hepatic vein: Budd-Chiari syndrome (PV)
• Pregnancy, oral contraception
• Coagulation disorders
Tumors of the Liver
• *Most common neoplasm IN the liver is metastatic carcinoma (usually from abdominal organs)
• Benign tumors– Cavernous hemangioma
• Non-neoplastic vascular mass
• Usually beneath fibrous capsule of liver
– Hepatic adenoma• Hepatocytic tumor
• Most often associated with contraceptive use in young women
• Usually regresses after contraceptive use stops
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Notice multiple tumor masses
Tumors of the Liver
• Malignant tumors– Hepatoblastoma
• Hepatocytic tumor
• In children
– Hepatocellular carcinoma (HCC)• Hepatocytic tumor
• Related to chronic HBV and HCV infections
• Tendency to invade hepatic veins; then metastasize
• Very poor prognosis
– Cholangiocarcinoma• Bile duct epithelium
• Intra- or extrahepatic bile ducts, or gallbladder
• Risk factors: sclerosing cholangitis, HCV, chronic Schistosomiasis
Notice single primary tumor mass
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Disorders of the Gallbladder and Extrahepatic Ducts
• Gallstones – most important problem of gallbladder– In gallbladder or biliary tree – cholelithiasis
– In bile ducts – choledocholithiasis
– Most are cholesterol; minor proportion are pigment stones
– Cholesterol oversaturates bile and stones form
– Small/medium size stones worst
– Some risk factors• Age/sex
• Weight
• Ethnic, hereditary, and geographic
• Drugs
• Acquired conditions
• (Fair, fat, fertile, female, forty)
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Cholecystitis• Inflammation of the gallbladder
– Acute• Most common complication of gallstones
• Most associated with obstruction at neck of gallbladder
• Bacterial infection; pus formation (empyema)
• Can occur without gallstones (pregnancy, burns, sepsis, surgery)
• Gallbladder is enlarged, tense, and inflamed
– Chronic• May occur after repeated acute attacks, or
without history of acute attacks (most often)
• Almost always associated with gallstones
• Complications are the main problem: ascending cholangitis, gallbladder perforation, septicemia
Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
Obstruction in Extrahepatic Ducts
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014