The Liver and the Biliary Tract

1
The Liver and the Biliary Tract

• Brando Cobanov, M.D.
• Department of Pathology
• UMDNJ-RWJMS
• April 4, 2007

2
Hepatic Injury

• Inflammation hepatitis
• Portal tracts, lobules
• Degeneration
• Damage from toxic or immunologic insult
• Accumulation of substances, e.g., steatosis
• Cell death
• Centrilobular, submassive, massive necrosis
• Fibrosis
• Usually irreversible
• Cirrhosis

3
Bile

• Two major functions
• Elimination of bilirubin, excess cholesterol, and
  xenobiotics that are insufficiently water soluble
  to be excreted in urine
• Emulsification of dietary fat in the gut by bile
  acids (cholic acid, chenodeoxycholic acid)
• Fig 16-1
• Unconjugated ? Conjugated
• Reabsorbed in terminal ileum (enterohepatic
  circulation)

4
Jaundice

• Excessive production of bilirubin
• Hemolytic anemias, ineffective erythropoiesis
• Reduced hepatic uptake
• Impaired conjugation
• Physiologic jaundice of the newborn
• Crigler-Najjar syndromes types I and II
• Gilbert syndrome
• Viral or drug-induced hepatitis, cirrhosis
• Decreased hepatocellular excretion
• Dubin-Johnson syndrome, Rotor syndrome
• Impaired bile flow

5
Cholestasis

• Systemic retention of not only bilirubin but also
  other solutes eliminated in bile, particularly
  bile salts and cholesterol
• Due to hepatocellular dysfunction or biliary
  obstruction
• Accumulation of bile pigment within the hepatic
  parenchyma Kupffer cells
• Bile ductular proliferation
• Bile lakes
• Portal tract fibrosis

6
Hepatic Failure

• 80 to 90 of hepatic functional capacity must to
  destroyed
• Massive hepatic necrosis
• Fulminant viral hepatitis
• Drugs and chemicals, e.g., acetaminophen, carbon
  tetrachloride, mushroom poisoning
• Chronic liver disease
• Hepatic dysfunction without overt necrosis
• Acute fatty liver of pregnancy
• Tetracycline toxicity
• Reye syndrome

7
Clinical Features

• Jaundice
• Hypoalbuminemia
• Hyperammonemia
• Fetor hepaticus
• Palmar erythema
• Spider angiomas
• Hypogonadism
• Gynecomastia

8
Complications

• Multiple organ failure
• Coagulopathy
• Hepatic encephalopathy
• Metabolic disorder of the CNS and NMS
• Elevated blood ammonia level and deranged
  neurotransmission
• Rigidity, hyperreflexia, seizures
• Asterixis
• Hepatorenal syndrome
• Idiopathic renal failure

9
Cirrhosis

• Bridging fibrous septa
• Parenchymal nodules
• Disruption of the architecture of the entire
  liver
• Etiologies
• Alcoholic liver disease 60 to 70
• Viral hepatitis 10
• Biliary diseases 5 to 10
• Hereditary hemochromatosis 5
• Wilson disease rare
• Cryptogenic cirrhosis 10 to 15

10
Portal Hypertension

• Prehepatic
• Occlusive thrombosis, narrowing of the portal
  vein
• Intrahepatic
• Cirrhosis
• Schistosomiasis, massive fatty change, diffuse
  granulomatous diseases (sarcoidosis, miliary TB)
• Posthepatic
• Right-sided heart failure, constrictive
  pericarditis, hepatic vein outflow obstruction

11
Clinical Sequelae

• Ascites
• Portosystemic venous shunts
• Esophageal varices 65 of cases
• Hemorrhoids
• Caput medusae
• Splenomegaly
• Hepatic encephalopathy

12
Drug Induced Liver Disease

• Liver is the major drug metabolizing and
  detoxifying organ in the body
• Direct toxicity
• Hepatic conversion of a xenobiotic to an active
  toxin
• Immune mechanisms
• Table 16-6

13
Alcoholic Liver Disease

• Hepatic steatosis
• Micro and macrovesicular
• Initially centrilobular
• Alcoholic hepatitis
• Hepatocyte swelling and necrosis
• Mallory bodies
• Neutrophilic reaction
• Fibrosis
• Alcoholic cirrhosis
• Micronodular
• Irreversible

14
Pathogenesis

• Shunting of normal substrates away from
  catabolism toward lipid biosynthesis
• Induction of cytochrome P-450
• Free radicals generated by microsomal ethanol
  oxidizing system
• Alcohol directly affects microtubular and
  mitochondrial function
• Acetaldehyde induces lipid peroxidation
• Neutrophil infiltration
• Immunologic attack of hepatocytes

15
Causes of Death

• Hepatic failure
• Massive GI hemorrhage
• Infection
• Hepatorenal syndrome
• Hepatocellular carcinoma

16
Nonalcoholic Fatty Liver

• Elevated serum aminotransferase levels
• Low risk for development of hepatic fibrosis or
  cirrhosis
• Associated with obesity, type 2 DM,
  hyperlipidemia
• Need to exclude other causes

17
Hemochromatosis

• Primary or hereditary
• HLA-linked autosomal recessive disease
• Secondary
• Transfusion dependent
• Chronic liver disease

18
Pathogenesis

• Total body iron pool 2 to 6 gm
• Primary defect in regulation of intestinal
  absorption of dietary iron, leading to a net iron
  accumulation of 0.5 to 1.0 g/yr
• HFE gene on 6p
• Interacts with transferrin receptor of intestinal
  enterocyte and modulates interaction with
  transferrin-iron complexes
• C282Y disulfide bridge disrupted
• H63D
• Lipid peroxidation, collagen formation, DNA
  interactions

19
Morphology

• Deposition of hemosiderin in the liver, pancreas,
  myocardium, pituitary, adrenal, thyroid and
  parathyroid glands, joints, and skin
• Cirrhosis, micronodular
• Pancreatic interstitial fibrosis and parenchymal
  atrophy ? DM

20
Clinical Features

• MF 5-71
• Symptoms usually appear in the fifth to sixth
  decades of life.
• Classic triad cirrhosis with hepatomegaly, skin
  pigmentation, DM (late in course)
• Cardiac dysfunction, e.g., arrhythmias,
  cardiomyopathy
• Atypical arthritis
• Hypogonadism
• Tx phlebotomy, iron chelators

21
Wilson Disease

• Autosomal recessive disorder of copper metabolism
• ATP7B on chr 13 ATP-dependent metal ion
  transporter on the Golgi of hepatocytes
• Failure to excrete copper into bile
• Copper causes progressive liver injury
• Affects brain, cornea, kidneys, bones, joints,
  and parathyroid glands
• Dx ? serum ceruloplasmin, ? hepatic copper
  content, ? urinary copper

22
Morphology

• Liver fatty change, acute hepatitis, chronic
  hepatitis, cirrhosis
• Rhodanine stain for copper
• Orcein stain for copper-associated protein
• Brain Basal ganglia (putamen) shows atrophy and
  cavitation
• Eye Kayser-Fleischer rings
• Aka hepatolenticular degeneration

23
Clinical Features

• Manifestations rare before 6 yo
• Acute or chronic liver disease most common
• Neuropsychiatric manifestations
• Copper chelation therapy with D-penicillamine
• Liver transplantation

24
a1-Antitrypsin Deficiency

• Autosomal recessive disorder
• AAT is a protease inhibitor, particularly
  neutrophil elastase released at sites of
  inflammation
• AAT gene on chr 14
• M allele normal, Z allele abnormal ? misfolding
  of the nascent polypeptide in the hepatocyte ER,
  accumulation, degradation
• Leads to pulmonary emphysema due to tissue
  destructive enzymes

25
Morphology

• Round to oval cytoplasmic inclusions of retained
  AAT
• Periodic acid-Schiff (PAS) positive
• Marked cholestasis with hepatocyte necrosis in
  newborns
• Childhood cirrhosis
• Chronic hepatitis or cirrhosis later in life
• Tx liver transplantation

26
Neonatal Hepatitis

• Not a specific entity
• Not necessarily inflammatory
• Extrahepatic biliary atresia (20), toxic,
  metabolic diseases, AAT deficiency (1.5),
  idiopathic (50 to 60)
• Neonatal cholestasis (prolonged conjugated
  hyperbilirubinemia)
• Present with jaundice, dark urine, light or
  acholic stools, hepatomegaly

27

• Marked bilirubin stasis in hepatocytes,
  canaliculi, and Kupffer cells in neonate with
  extrahepatic bile duct atresia.

28
Reye Syndrome

• Rare disease characterized by fatty change in the
  liver and encephalopathy
• Children lt 4 yo
• 3 to 5 days after a viral illness
• Associated with salicylate (aspirin) use
• Present with vomiting, irritability or lethargy,
  hepatomegaly
• 25 progress to coma
• Death due to progressive neurologic deterioration
  or liver failure
• Tx symptomatic, supportive

29
Morphology

• Liver microvesicular steatosis
• EM mitochondrial enlargement with disruption of
  cristae
• Brain cerebral edema
• Astrocytes swollen, mitochondrial changes
• Skeletal muscles, kidneys, and heart may have
  microvesicular steatosis.

30
Obstructive Biliary Tract Disease
31
Secondary Biliary Cirrhosis

• Most common cause is extrahepatic cholelithiasis
• Biliary atresia, malignancies of the biliary tree
  and head of the pancreas, and strictures
• Cholestasis
• Bile duct proliferation with surrounding
  neutrophils
• Periportal fibrosis

32
Primary Biliary Cirrhosis

• Middle-aged women
• MF 110
• Possibly autoimmune
• Autoantibodies to mitochondrial pyruvate
  dehydrogenase 90
• Insidious onset, usually presenting with pruritus
• Hyperbilirubinemia, jaundice, cirrhosis late
• ? alkaline phosphatase, cholesterol

33

• Nonsuppurative, granulomatous destruction of
  medium-sized intrahepatic bile ducts florid
  duct lesion

34
Primary Sclerosing Cholangitis

• Inflammation, obliterative onion-skin fibrosis,
  and segmental dilatation of the obstructed
  intrahepatic and extrahepatic bile ducts
• String of beads on ERCP
• 70 associated with inflammatory bowel disease,
  particularly ulcerative colitis
• MF 21, third through fifth decades
• Progressive fatigue, pruritus, jaundice
• Chronic course
• Increased risk for cholangiocarcinoma

35
(No Transcript)
36
Circulatory Disorders
37
Hepatic Artery Inflow

• Liver has dual blood supply.
• Thrombosis of hepatic artery in transplanted
  liver ? loss of organ

38
Portal Vein Obstruction

• Extrahepatic
• Peritoneal sepsis leads to phlebitis
• Lymphatic metastases to hilar lymph nodes
• Pancreatitis leads to splenic vein thrombosis
• Postsurgical thromboses
• Banti syndrome umbilical vein catheterization
• Intrahepatic thrombus does not cause an ischemic
  infarction but results in an area of red-blue
  discoloration (infarct of Zahn).
• Invasive carcinoma
• Hepatoportal sclerosis

39
Impaired Blood Flow Through the Liver

• Cirrhosis
• Sickle cell disease
• DIC potentially fatal subcapsular hematoma in
  pts with eclampsia
• Right-sided heart failure ? congestion of
  centrilobular sinusoids
• Left-sided heart failure ? hypoperfusion and
  hypoxia ? centrilobular necrosis
• Peliosis hepatis primary sinusoidal dilation
  associated with anabolic steroids, danazol, and
  oral contraceptives

40
Hepatic Vein Thrombosis

• Aka Budd-Chiari syndrome
• Hepatomegaly, weight gain, ascites, abdominal
  pain
• Polycythemia vera or other myeloprolifera-tive
  disorders, pregnancy, the postpartum state, oral
  contraceptive use, PNH, intra-abdominal cancers,
  esp. HCC
• Massive intrahepatic abscess or parasitic cyst
• Centrilobular congestion and necrosis

41
Veno-Occlusive Disease

• Shortly after bone marrow transplantation
• 25 incidence
• Subendothelial swelling and reticulated collagen
• Due to toxic endothelial injury secondary to
  chemotherapy and radiation therapy

42
Hepatic Neoplasms

• Metastatic carcinomas most common
• Colon
• Lung
• Breast
• Benign tumors
• Primary liver carcinoma
• Hepatocellular carcinoma
• Cholangiocarcinomas
• Hepatoblastoma children
• Angiosarcoma associated with vinyl chloride,
  arsenic, or Thorotrast exposure

43
Benign Tumors

• Cavernous hemangioma most common
• Well-circumscribed, subcapsular, lt 2 cm
• Focal nodular hyperplasia
• Young to middle aged adults
• Poorly encapsulated
• Central fibrous scar
• Response to local vascular injury

44
Focal Nodular Hyperplasia
45
Liver Cell Adenoma

• Women of childbearing age who have used oral
  contraceptives
• Often subcapsular
• Sheets and cords of hepatocytes
• Portal tracts are absent
• Prominent vessels throughout
• Risk for rupture, esp during pregnancy

46
Hepatocellular Carcinoma

• Annual incidence
• Americas, Northern Europe, Australia 3-7
  cases/100,000
• Southern Europe 20 cases/100,000
• Southeast China, Taiwan 150 cases/100,000
• HBV carrier since infancy 200 fold risk
• Cirrhosis in 85 to 90 vs 50
• MF 31 vs 81
• Sixth to seventh decades vs third to fifth

47
Pathogenesis

• Infection with HBV
• Genomic instability with integrated HBV DNA
• Integration pattern is clonal
• HBV X-protein disrupts cell cycle control
• Certain HBV proteins inactivate p53
• Chronic liver disease, esp HCV and Etoh
• Cirrhosis plays an important role.
• Hepatocarcinogens in food (aflatoxins from the
  fungus Aspergillus flavus)
• Repeated cycles of cell death and regeneration,
  i.e., chronic hepatitis, with possible mutations

48
Morphology

• Unifocal, multifocal, or infiltrative
• Strong propensity for vascular invasion
• Portal vein or IVC involvement
• Well-differentiated intracellular bile
• Scant stroma ? soft
• Metastasizes to LN, lung, bone, adrenal
• Fibrolamellar carcinoma
• 20-40 yo, MF
• No assoc. with cirrhosis or other risk factors
• Tumor cells separated by dense collagen
• Better prognosis

49
HCC
50
Clinical Features

• Rapid increase in liver size
• Sudden worsening of ascites
• Appearance of bloody ascites, fever, pain
• ? serum AFP, esp if gt 1000 ng/ml
• Median survival 7 months
• Death due to GI or esophageal variceal bleeding
  or liver failure with hepatic coma
• Surgical resection for smaller tumors
• Recurrence rate 60 at 5 yrs
• Liver transplantation

51
Disorders of the Gallbladder
52
Cholelithiasis

• Very common
• Cholesterol stones
• Bile is supersaturated with cholesterol
• Gallbladder stasis
• FgtM
• Obesity
• Advancing age
• Pigment stones calcium bilirubinate salts
• Asian more than Western
• Chronic hemolytic syndromes

53
Clinical Features

• Asymptomatic
• Biliary colic
• Cholecystitis
• Gallstone ileus

54
Cholecystitis

• Acute calculous
• Obstruction of GB neck or cystic duct
• RUQ pain radiating to right shoulder
• Fever, nausea, leukocytosis
• Potential surgical emergency
• Acute acalculous seriously ill pts
• Chronic
• Recurrent attacks of pain
• Nausea and vomiting
• Associated with fatty meals

55
(No Transcript)
56
Choledocholithiasis

• Stones within the biliary tree
• West from gallbladder
• Asia primary ductal and intrahepatic stone
  formation
• Symptoms due to
• Biliary obstruction
• Pancreatitis
• Cholangitis
• Hepatic abscess

57
Cholangitis

• Acute inflammation of bile ducts
• Due to biliary obstruction, usually
  choledocholithiasis
• Bacterial infection from gut, i.e., gram negative
  aerobes
• Fever, chills, abdominal pain, jaundice
• Latin America and Near East Fasciola hepatica,
  schistosomiasis
• Far East Clonorchis sinensis, Opisthorchis
  viverrini
• AIDS cryptosporidiosis

58
Biliary Atresia

• 1/3 of cases of neonatal cholestasis
• 1 in 10,000 live births
• Complete obstruction of bile flow caused by
  destruction or absence of all or part of the
  extrahepatic bile ducts
• Acquired inflammatory disorder
• Normal stools to acholic stools
• Bile ductular proliferation on liver bx
• Cirrhosis by 3 to 6 months of age.
• Require liver transplantation

59
Gallbladder Carcinoma

• Seventh decade
• FgtM
• Discovered at late stage, usually incidental
• Exophytic and infiltrating types
• Adenocarcinoma
• Local extension into liver, cystic duct,
  portahepatic LNs
• Mean 5 yr survival 1

60
(No Transcript)
61
Cholangiocarcinoma

• Older pts
• MgtF
• Painless jaundice, N/V, weight loss
• Opisthorchis sinensis (liver fluke), PSC,
  inflammatory bowel disease
• Tumors usually small at dx yet not resectable
• Klatskin tumor arises at bifurcation
• Adenocarcinoma
• Mean survival 6 to 18 months

62
(No Transcript)
63
Questions?