Disorders of the Liver and Biliary Tract

1
The Nature of DiseasePathology for the Health
Professions Thomas H. McConnell

• Chapter 12
• Disorders of the Liver and Biliary Tract
• Lecture 12

2
Overview of Todays 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

3
Liver, Portal venous system, and Bile ducts
Figures from McConnell, The Nature of Disease,
2nd ed., LWW, 2014
4
Placeholder
5
Liver Metabolic Tasks/Actions
Table from McConnell, The Nature of Disease, 2nd
ed., LWW, 2014
6
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 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

7
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?
8
Etiology of Jaundice
Figure from Huether McCance, Understanding
Pathology, 5th ed., Elsevier, 2012

• 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

(Also see 12.4 in McConnell)
9
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

10
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

11
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 -gt 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
12
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

13
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
• SS
• 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)

14
Viral Hepatitis

• Viral Hepatitis (Hepatotropic viruses A, B, C,
  D, and E HV)
• Inflammation of the liver caused by viral
  infection
• 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)

15
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
• 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 Clinicopathological Syndromes
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Viral Hepatitis - HAV

• HAV
• 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
18
Viral Hepatitis - HBV

• HBV
• IV/Sex
• HBsAg and anti-HBc ab markers of acute
  infection
• Can be chronic, carrier, carcinoma
• 1/3 of worlds population shows evidence of being
  infected
• Vaccine available

Figures from McConnell, The Nature of Disease,
2nd ed., LWW, 2014
19
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
20
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 -gt PH, cirrhosis
• Autoimmune hepatitis
• T- cell mediated
• Over 50 have some other autoimmune disease,
  e.g., UC, Sjogren, SLE
• 80 cases female

21
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

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Alterations in Liver Function
From Pathophysiology A Clinical Approach, Braun
Anderson, Lippincott, 2011
23
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?

24
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

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Is Alcohol Good for Anything Besides a Buzz?

• Association between light to moderate ( 25g/day)
  alcohol consumption and cardiovascular disease

• 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

Figure from http//pubs.niaaa.nih.gov/publication
s/arh27-1/39-51.htm
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Metabolism/Hepatic Effects of Ethanol

• Three enzyme systems in liver that convert EtOH
  to acetaldehyde
• Alcohol dehydrogenase (ADH)
• Microsomal ethanol oxidizing system (MEOS
  activated with high EtOH levels)
• Catalase
• Hepatic effects of acetaldehyde -
  Inflammation - Fat deposition
• - Hepatomegaly
• - Microtubular txport defects
• - Increased cellular H2O
• - Decreased FA oxidation in mt
• - Increased membrane rigidity
• - Necrosis

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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
• 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
28
Metabolic Liver Disease

• Wilsons Disease
• Autosomal recessive (rare)
• Toxic copper accumulation in liver and brain
• In eye -gt Kayser-Fleischer ring

From https//lostinzhoushan.wordpress.com/
Figure from http//www.eurowilson.org/en/living/g
uide/pathway/index.phtml
29
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

30
Biliary Cirrhosis

• Prolonged obstruction in extrahepatic biliary
  tree can damage the intrahepatic bile ducts liver
• Two forms
• Primary biliary cirrhosis
• 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 -gt inflammation -gt scarring -gt
  biliary cirrhosis
• May cause ascending cholangitis

31
Biliary Cirrhosis

• Primary sclerosing cholangitis
• Inflammation of both intra- and extrahepatic bile
  ducts
• gt60 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
32
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 -gt 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

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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

Notice multiple tumor masses
Figure from McConnell, The Nature of Disease,
2nd ed., LWW, 2014
34
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
35
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
36
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
37
Obstruction in Extrahepatic Ducts
Figure from McConnell, The Nature of Disease,
2nd ed., LWW, 2014