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The Nature of Disease
Pathology for the Health Professions
Thomas H. McConnell
Chapter 12
Disorders of the Liver and Biliary Tract
Lecture 12
1
Liver, Portal venous system, and Bile ducts
Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
3
Liver Metabolic Tasks/Actions
Table from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
5
The Liver Response to Injury
• Most important liver diseases:
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Viral hepatitis
Alcoholic liver disease
Non-alcoholic liver disease
Malignancy
• Four common endpoints (clinical syndromes) of liver disease
1. 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
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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?
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Etiology of Jaundice
• What are the three conditions
leading to imbalance of
bilirubin? (Also see 12.4 in McConnell)
Figure from: Huether & McCance, Understanding
Pathology, 5th ed., Elsevier, 2012
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
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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
9
Cholestasis
• Impaired bile formation and bile flow
– Accumulation of bile pigments in liver
– Usually accompanied by jaundice, possibly pruritis
– Several causes
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•
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Liver disease
Biliary obstruction
Drug interference with bile secretion
Pregnancy
– Problems resulting from lack of bile acids
• High blood cholesterol (xanthomas)
• Fat malabsorption
10
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
11
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
12
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
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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)
13
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 causes inflammation of the liver
– Hepatitis viral types differ in
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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
– 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
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Viral Hepatitis - HAV
• HAV
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Fecal-oral route
Anti-HAV IgM ab – marker of acute infection
Only Acute (think of ‘A’ as acute); no carrier state
Vaccine available
Figure from:
McConnell, The
Nature of Disease,
2nd ed., LWW, 2014
17
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
18
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
19
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
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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?
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Alcohol Abuse
- Liver and nutritional disorders most common side effects
of chronic alcohol abuse
- Liver
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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
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Acute gastritis
Cardiomyopathy
Possible systemic hypertension
Regressive changes in skeletal muscle
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Metabolic Liver Disease
• Non-alcoholic Fatty Liver Disease
– Group of related conditions manifesting
with fatty liver
– Closely associated with the metabolic
syndrome
Figure from: McConnell, The
Nature of Disease, 2nd ed., LWW,
2014
• Obesity, hyperlipemia/hyperlipidemia, prediabetic 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
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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
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Biliary Cirrhosis
• Prolonged obstruction in extrahepatic biliary tree can
damage the intrahepatic bile ducts liver
• Two forms
– Primary biliary cirrhosis
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Autoimmune inflammatory 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
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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)
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Obstruction of one or more branches of the hepatic vein
Occlusion of main hepatic vein: Budd-Chiari syndrome (PV)
Pregnancy, oral contraception
Coagulation disorders
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Tumors of the Liver
• *Most common neoplasm IN the liver is metastatic
carcinoma (usually from abdominal organs)
Notice multiple tumor masses
• Benign tumors
– Cavernous hemangioma
• Non-neoplastic vascular mass
• Usually beneath fibrous capsule of liver
Figure from: McConnell, The
Nature of Disease, 2nd ed., LWW,
2014
– Hepatic adenoma
• Hepatocytic tumor
• Most often associated with contraceptive use in young women
• Usually regresses after contraceptive use stops
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Tumors of the Liver
• Malignant tumors
– Hepatoblastoma
• Hepatocytic tumor
• In children
– Hepatocellular carcinoma (HCC)
• Hepatocytic tumor
• Related to chronic HBV and HCV
Notice single primary tumor mass
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
Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014
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Disorders of the Gallbladder and Extrahepatic Ducts
• Gallstones – most important problem of gallbladder
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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
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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
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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
36
Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014