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Hepatobiliary system

 Hepatic lobule
 At center = Central vein
 Portal triad = Bile duct + Portal vein + Hepatic Artery
 Right next to portal triad is Zone 1
 Right next to central vein is Zone 3
 Middle is the Zone 2
 Zone 1 is most susceptible to toxin damage
 Zone 3 is most susceptible to ischemic injury
 Cords of Hepatocytes
 In between these cords we can see Sinusoids

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 In between Hepatocytes and sinusoids there is a space known as : Space of Disse
 Space of Disse contains : Ito cells/ stellate cells
 Two functions:
1. Vitamin A storage
2. Fibrosis: Cirrhosis of liver
 In between hepatocytes – Canal of Herring
 Canal of Herring contains Oval cells (Stem cells)
 Kupffer cells: Present of endothelial side of sinusoids.
 What are Kupffer cells: Macrophages in liver

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Liver Function Test

1. Synthetic ability of liver
 S. Albumin
 PT (Prothrombin time/ Clotting factor)
Decreased Clotting factors: PT Increases
Normal Prothrombin time: 11 -15 sec
 BUN:
2. Liver cell necrosis:
 AST (Aspartate transaminase)/ SGOT -also elevated in Myocardial infarction
 ALT (Alanine Transaminase) /SGPT – Most specific for liver
 LDH (Lactate Dehydrogenase)
 AST/ALT ratio: >2 =ALD, <1=NALD
3. Liver excretory functions:
 S. Bilirubin
 U. Bilirubin
4. Tests for cholestasis
 ALP (Alkaline phosphatase)
 GGT (Gamma- Glutamyl transpeptidase)
 S. nucleotidase
 All three are increased in Cholestasis
 More specific/ indicative of Alcohol misuse: GGT
 ALP also increased with increase in B one turn over

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 Bilirubin Metabolism

 Hemoglobin breaks down into heme and globin

 Heme is acted by heme oxygenase and results in formation of biliverdin which is acted
by biliverdin reductase that will result in formation of Bilirubin (unconjugated/indirect
bilirubin: water insoluble, can cause blood brain barrier and can cause – Kernicterus)
 Bilirubin roams around with albumin in the body
 Unconjugated bilirubin enters the liver.

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 I
 Direct Bilirubin : Conjugated Bilirubin
 Total bilirubin = Direct bilirubin + Indirect Bilirubin

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Jaundice
1. Increased Unconjugated Bilirubin
 Hemolytic anemia
 Criggler Najar Syndrome :1,2
 Gilbert Syndrome
2. Increased Conjugated Bilirubin
 Obstruction
 Biliary diseases
 Dubbin Johnson SYNDROME
 Rotor syndrome

Increased Unconjugated Bilirubin:

Criggler Najar Syndrome: 1 Criggler Najar Syndrome: 2 Gilbert syndrome

 UGT complete deficiency
 100% fatal
 Autosomal recessive
 UGT partial deficiency
 Rx- Phenobarbitone
(Increase UGT activity in
liver)
 Autosomal dominant >
Autosomal recessive
 Very mild deficiency of UGT
 Stress (infection): Manifest
 m/c Autosomal dominant >
Autosomal recessive

Increased Conjugated Bilirubin:

A. Obstruction
 Stone
 Stricture
 Cancer
 Clonorchis sinensis

B. Biliary diseases
a) Primary Biliary Cirrhosis:
 Intra hepatic bile duct
 d/t anti-mitochondrial Ab (AMA)
 Female
b) Primary Sclerosing Cholangitis
 Extra hepatic bile duct
 d/t p-ANCA

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  Male
 Microscopic appearance: Onion Skinning

d/d Onion -Skinning

1. Cell injury: Myelin figures

2. Lysosomal storage disorder: Tay sachs
3. SLE: Spleen
4. Blood vessel: Hyperplastic arteriosclerosis (Malignant HTN)
5. Liver: Primary sclerosing Cholangitis

C. Dubbin Johnson syndrome

 Defect in excretion of conjugatedAfraTafreeh.com
bilirubin
 Defect in MRP-2
 Pigmented Liver: d/t: Epinephrine

D. Rotor syndrome
 Defect in excretion of conjugated bilirubin
 Non- Pigmented Liver

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Biliary Disease
Causes of Cirrhosis:

1. Alcoholic Liver Disease

2. Biliary Disease
3. Cryptogenic Cirrhosis
4. Drug induced hepatitis
5. Autoimmune hepatitis
6. Enzyme deficiency
7. Hemochromatosis
8. Wilsons disease
9. Viral hepatitis

a. Alcoholic Liver Disease

b. Biliary Disease
c. Cryptogenic Cirrhosis / Nonalcoholic fatty Liver disease
 Nonalcoholic or ethanol <20 micro gram/ week
 Causes: Diabetes, Obesity, Triglycerides, Syndrome X
 Sequence:
 Non- Alcoholic fatty liver (NAFL)  Non-Alcoholic steatohepatitis  Cirrhosis
 Diagnosis: NALD vs ALD
NALD ALD
AST/ALT <1 >2
Biopsy -ALD
History

 m/c/c death in NALD : Cardiovascular causes

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 Autoimmune hepatitis and Drug induced Hepatitis

a) Autoimmune hepatitis Type – 1

 Ab +
 ANA
 AMA
b) Autoimmune hepatitis Type – 2
 Anti LKM Antibodies
 Liver-Kidney-Microsomal
 Anti LKM -1 Antibodies: a/w Hepatitis C
 Anti LKM -2 Antibodies: a/w Drugs
 Anti LKM -3 Antibodies: a/w Hepatitis D

c) Autoimmune hepatitis Type – 3

 Ab a/g LSA
 Liver soluble antigen

Microscopic Examination:
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a) Interference Hepatitis
b) Emperipolesis

c) Hepatic Rosette

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 Enzyme deficiency
Alpha-1 antitrypsin deficiency

 Anti -elastase
 PiMM : Normal Alpha 1 antitrypsin
 PiMZ: Heterozygous
 PiZZ : Alpha 1 Antitrypsin deficiency: Homozygous
 Alpha-1 antitrypsin deficiency effect two organs:
 Liver: Cirrhosis
 Panacinar emphysema
 Diagnosis: PAS +Diastase resistant, Inclusions inside hepatocytes.

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Hepatocellular Carcinoma

 Male
 20-40 years
 Risk factors:
 Hepatitis B
 Hepatitis C
 Cirrhosis
 Alcohol
 Tyrosinemia
 Aflatoxin (Aspergillus flavus -> peanut contaminant)
 Preneoplastic Conditions:
 Hepatic adenoma
 Small cell dysplastic nodule - : Risk of HCC
 Large cell dysplastic nodule

HCC Fibrolamellar Variant

20-40 years Age 9-20 years
Male > Female Sex Male =Female
(In India: Female > Male)
Hepatitis B Risk Factor Not a/w Hepatitis B
Hepatitis C Not a/w Hepatitis C
Negative Microscopic Fibrosis/ Collagen
examination
AFP Tumor Neurotensin-1
marker
Hematogenous Spread Lymphatic
Prognosis Better

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 Hemochromatosis

 Iron overload
 Classification:
a) Primary Cause: 6p:
Genetic HLA gene
 HFE gene (chr 6p) HFE gene
 HAMP gene (Hepcidin)
 Hemojuvelin (Juvenile hemochromatosis)
b) Secondary Cause

Non-Genetic

 Blood transfusion
 Bantus Siderosis
(Increased oral Fe)
(African)

 Triad: AfraTafreeh.com

 Other organs:
 Hypopituitary axis: Hypogonadism
 Heart: Restrictive cardiomyopathy

 Diagnosis:
Most accurate:
 Blood test: Transferrin saturation

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 Biopsy:

 Diagnosis:
 Drug of choice: Iron chelators, e.g. Desferrioxamine
 Treatment of choice: Phlebotomy

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Wilson disease

 Cu increase
 Due to decrease in Ceruloplasmin: defect ATP 7B gene

 Diagnosis:
Most sensitive- Cu deposition in organs: Coppe r: Rhodamine, Rubeanic acid
Note: Orcein is stain for ceruloplasmin
Most specific- Urinary excretion of copper

 Treatment: Copper chelating drugs

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Viral Hepatitis
Hepatitis Hepatitis B Hepatitis Hepatitis D Hepatitis E
A C
Incubation 2-6 2-26 weeks 4-26 2-26weeks 4-5weeks
period weeks weeks
Chronicity - 5-10 % >80% Superinfection Only if
>90% immunocompromised
Hep D  Hep B

10% Co-
infection

Hep B +Hep D

Diagnosis

 PCR: Viral load

 Antibody: IgM, Ig G

Diagnosis of Hepatitis B

 HBsAg : Australia Antigen

 HBeAg: Active disease, infectivity, Viral replication
 Anti-HbcAg: Never seen in blood (Always remain within viral particle), First Ab: marker of
window period
 HBV-DNA: PCR
 Qualitative marker of HBV replication: Hbe Ag
 Quantitative marker of HBV replication: HBV DNA

Note:

m/c Acute Viral Hepatitis: Hepatitis A

M/c Acute Viral hepatitis:
 Child: Hepatitis A
 Elderly: Hepatitis E
M/c Chronic viral hepatitis: Hepatitis C
m/c/c Cirrhosis: Hepatitis C
m/c Viral Hepatitis:
 H.C.C
 Carrier state Hepatitis B
 a/w Blood Transfusion
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Microscopic Examination:

 Hepatitis B: Ground glass appearance of hepatocytes: due to distension of S.E.R by virions

 Hepatitis C: Lymphoid aggregates, Macro -vesicular steatosis

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 Muscle: Red
 Collagen: Blue
 Nuclei: Blue back

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Miscellaneous topics
1. Peliosis Hepatitis: Reversible Sinusoidal dilation
Causes:
 TB
 OCP
 AIDS
 Cancers

2. Budd Chiari Syndrome:

 Hepatic Vein Obstruction due to Hepatic Vein thrombosis
 m/c due to Polycythemia
 Radiological IOC: Hepatic V enography

3. Congenital anomalies of biliary tree:

a. Von Meyenberg disease
 Bile duct hamartoma
 a/w PKD

b. Carolis disease
 Dilatation of intrahepatic bile duct
 Increased risk of cance r

c. Alagille syndrome
 Absence of intrahepatic bile duct
 Jagged 1 NOTCH signaling pathway

d. Nutmeg liver
 Seen in CVC Liver Chronic venous congestion

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  Due to right sided heart failure

e. Reye’s syndrome/ Jamshedpur fever

 h/o child with viral illness and you give treatment with Aspirin -> it results in
mitochondrial dysfunction
 Resulting in increased ammonia
 Ammonia attaches to brain = Coma, Convulsions

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f. Cholangiocarcinoma
 Bile duct carcinoma
a. Classification: Extrahepatic and Intrahepatic

Extrahepatic

m/c Perihilar region

@ fusion of Left and Right Hepatic duct
Klatskin’s tumor

Risk factors:

 C- Clonorchis sinensis, Opisthorchis sinensis

 C-Carolis disease
 C-Choledocholithiasis, Choledochal cyst

Microscopically:

 Adenocarcinoma,
 Increased amount of desmoplastic reaction,
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 Hard consistency

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 Nodular Hyperplasia of liver

 No fibrosis
 No cirrhosis
1. Focal Nodular Hyperplasia
 m/c in females
 a/w OCP
 Central Stellate Scar

2. Nodular Regenerative Hyperplasia

 a/w change in intrahepatic blood flow
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 m/c/c: R.A
 Other causes: Hyper viscosity, MPN

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Liver Tumors
 m/c Liver tumor: Metastasis: m/c Colo-rectal carcinoma
 Primary Liver tumors:
a. Benign
 Cavernous Hemangioma (m/c benign)
 Hepatic Adenoma: Female, OCP well encapsulated lesion
b. Malignant:
 m/c malignancy is: Hepatocellular carcinoma
 m/c malignancy in children: Hepatoblastoma
 m/c sarcoma occurring in liver: Angiosarcoma
 Note- Angiosarcoma is due to Vinyl Chloride, arsenic, Thorotrast
(Thorium based dye)