Liver Pathology😍

Jaundice (Hyperbilirubinemia)

• Jaundice = Hyperbilirubinemia (increased bilirubin levels).

• Types of bilirubin:
• Indirect (unconjugated) &
• Direct (conjugated)

• Site: Sclera.

Unconjugated Hyperbilirubinemia

• Hemolytic anemia.

• Gilbert syndrome.

• Crigler-Najjar syndrome types 1 & 2.

Conjugated Hyperbilirubinemia

• Dubin Johnson syndrome.

• Rotor syndrome.

• Primary biliary cirrhosis.

• Biliary atresia

• Obstruction
• Stones, strictures, cancer, parasites (e.g., Clonorchis).

• Biliary Diseases: 
• Primary Biliary Cholangitis (PBC)
• Primary Sclerosing Cholangitis (PSC).

Hyperbilirubinemia Syndromes: Comparison

Feature	↑ Unconjugated Bilirubin Syndromes	Increased Conjugated Bilirubin Syndromes
UGT Enzyme Status	Conjugation by UGT deficient (UDP Glucoronyl transferase)	Conjugation by UGT is normal.
Defect Cause	UGT deficiency.	Defect in excretory proteins
Syndromes	Crigler-Najjar Type 1	Dubin-Johnson Syndrome
ㅤ	Crigler-Najjar Type 2	Rotor Syndrome
ㅤ	Gilbert Syndrome	Mnemonic: Doctors always united or
ㅤ	ㅤ	Doctors always conjugated (D+R)

Unconjugated Hyperbilirubinemia Disorders

Characteristic	Crigler-Najjar Type 1	Crigler-Najjar Type 2	Gilbert Syndrome
Genetics	AR	Autosomal dominant	AR
UGTA1 Deficiency	Complete	Partial	Very Mild defect
Clinical Features	Intrauterine deaths/Stillbirths 100% fatal	Patients survive	Asymptomatic Manifests under stress: - Fever - Pregnancy
Treatment	Exchange transfusion intensive phototherapy Orthotopic liver transplant Phenobarbitone has no role	Phenobarbitone: * Increases UGT activity	No treatment needed
ㅤ	ㅤ	Koch indirect ayitt swapnathil 2 (CN T2) pambine kand karanju (cry Naja) Apo, Baribie (Phenobarbitone) kanich samadanipichu	ㅤ

What is the most probable diagnosis for a neonate who continues to have unconjugated hyperbilirubinemia after three weeks of birth, with normal liver enzymes, PT/INR, and albumin levels, no evidence of hemolysis on a peripheral blood smear, and a decrease in bilirubin levels following treatment with phenobarbital?
A. Rotor syndrome
B. Crigler Najjar type 2
C. Dubin Johnson syndrome
D. Crigler Najjar type 1

Conjugated Hyperbilirubinemia

• Mnemonic: Direct → Dr → Doctor → Need both
• D → DJ → MRP (money) → MRP2
• Dubin is dark
• R → Rotar → ATP → OATP
• Raw ATP

Condition	Defect in	Key Features	ㅤ
Dubin Johnson Syndrome	ABCC2 gene (ATP Binding Cassette) MRP2 protein	- Dark pigmented liver - Pigment is epinephrine Mnemonic: Dubin is dark	Dubbing Johnson → A busy (ABC) dubbing artist → needs MRP (MRP2)
Rotor Syndrome	Organic anion transporter protein	- No pigmentation in liver	Row cheyyan ATP venam

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ABC Terms	Seen in
ABCG2	• Marker for Limbus/Pterygium (with CD34)
ABCA4 gene mutation	Stargardt Disease • Juvenile boy (Juvenile hereditary macular dystrophy) • Star (stargardts) → studies ABC (ABCA4 gene mutation) ◦ At night (bcz blind during day → Hemeralopia) • Eat fish (fish flecks) & bulls eye (Bulls eye maculopathy) • Everyone beat him (copper beaten on Fundus exam) ◦ Became Dark & Silent (dark/silent choroidal sign on FFA)
ABC1 (ATP Binding Cassette transporter 1) Mutation	Tangier's Disease • Reduced levels of apo A1→ very low HDL levels • Features • Greyish-orange tonsils • Hepatosplenomegaly • Mononeuritis multiplex • ABC students drink Tang → don't get A1 → cant multiply
ABCC2 gene mutation / MRP2 protein	Dubin Johnson Syndrome • Dark pigmented liver • Pigment is epinephrine Dubbing Johnson • Dubin is dark • A busy (ABC) dubbing artist • needs MRP (MRP2)
ABC Pump	• Digoxin dosage is adjusted based on loss via efflux (GI) • Loperamide does not cross BBB (no CNS S/E) • Bacteria / Tumor Cells: Drug resistance
ABC Pump Inducer (CRP in CRAP GPs)	Cause Drug Failure
↳ Rifampicin	Digoxin failure
↳ Phenytoin	ㅤ
↳ Carbamazepine	ㅤ
ABC Pump Inhibitor (CAVE Q itra neram)	Cause Toxicity
↳ Cyclosporine	Cholestatic jaundice
↳ Amiodarone	ㅤ
↳ Verapamil	Reversal of drug resistance ↳ Verapamil → Vera kalayan → Bacteria kalayan • (cancer, bacteria)
↳ Erythromycin / Clarithromycin	Digoxin toxicity
↳ Quinidine	Loperamide-induced central S/E
↳ Itraconazole	ㅤ
↳ Neratinib	ㅤ

• ZONES OF LIVER
• Zone 1: Periportal.
• Zone 2: Midzonal.
• Zone 3: Centrilobular.
• Most susceptible to ischemia.

Biliary Diseases: PBC and PSC

• Cause ↑↑ conjugated bilirubin.

Primary Sclerosing Cholangitis

Feature	Primary Biliary Cholangitis (PBC)	Primary Sclerosing Cholangitis (PSC)
Age Group	Elderly, ~50 years ("big people").	Younger people, ~30s ("smaller people").
ㅤ	Pruritis Xanthalesma Osteopenia	ㅤ
Antibodies	AMA (Anti-mitochondrial antibody), ANA	P-ANCA.
Associated Disease	Sjögren syndrome.	Ulcerative colitis →→ ↑ risk of Ca Colon (both linked to P-ANCA). ↑↑↑ risk of cholangiocarcinoma
Gender	More common in females  ("AMA" sounds like 'amma').	More common in males  ("P-ANCA" sounds like 'papa').
Affected Bile Ducts	Primarily affects  intrahepatic bile ducts	Affects intrahepatic and extrahepatic bile ducts
Radiology	ㅤ	Pruning & beading of bile ducts
Pathology	Duct Florid lesions	Onion skinning of the bile duct.
Mnemonic:	PBC → Busy AMMA (AMA) → elderly female → stays inside home (intrahepatic), but goes for jogging (Sjogrens) → likes flower (Florid lesions in duct)	30 year old () man → became a tree (tree pattern on MRCP) → After repeatedly trying for PSC () Stays inside and outside home (Intra/extra) PAN (PANCA), Beedi (Beading) valikkan thudangi

Cirrhosis

• Underlying cirrhosis
• Indicated by:
• Irregular surface of the liver.
• Ascites.

• Hepatorenal syndrome (Prerenal AKI)
• FeNa <1%
• No s/o shock
• DOC: Terlipressin

• Hepato Pulmonary syndorme:
• Platypnea
• Orthodeoxia
• DOC: Terlipressin + Albumin

• Definition: 
• Nodule formation in liver due to extensive fibrosis (scarring).
• Fibrosis consists of collagen.

HEPATIC ENCEPHALOPATHY

• EARLIEST SYMPTOM: Alternate sleep wake cycle

• SPECIFIC SIGN: Asterixis

• EEG: Triphasic wave → becomes Delta at end

• Staging: WEST HAVEN

Grade	Description
0	No obvious changes; only psychometric deficits.
1	Mild confusion; short attention span; sleep–wake reversal.
2	Lethargy; disorientation to time; behavior changes.
3	Marked confusion; disorientation to place; somnolent but arousable.
4	Coma; unresponsive.

• Mx: Rifaximin + Lactulose

Types of Nodules

• Micronodular cirrhosis:
• Nodules < 3 mm.



• Causes: Indian childhood cirrhosis, hemochromatosis, PBC.
• Amma, Iron Tab, Indian Child → Kunju liver

• Macronodular cirrhosis:
• Nodules > 3 mm 



• Causes: Viral hepatitis, Wilson disease (V for very very big nodules)

Note

• Alcoholic liver disease can show both micronodular and macronodular cirrhosis.

Collagen & Cells

• Collagen in fibrosis: Primarily collagen type 1 and 3.

• Cells laying down collagen: Stellate cells (hyperactive Ito cells).

Stellate terms	Seen in
Stellate cells	• Cirrhosis • NAFLD • Chronic pancreatitis • Young stella → alcoholic → liver and pancreas
Stellate Keratin Precipitates	• Herpetic uveitis • Toxoplasmosis • Fuchs Heterochromia Iridocyclitis • Young stella → Fucked () by Toxic () Herpes () Guy
Stellate Granuloma	• Cat Scratch Disease • LGV • Leprosy • Syphillis • Stella granny → has a Cat, Lgtv, has leprosy and syphillis
Stellate scar	• Kidney → Oncocytoma, Chromophobe RCC • Liver → Focal Nodular Hyperplasia, Fibrolamellar Carcinoma • Pancreas → Serous Cystadenocarcinoma • Breast → Radial Scar: Premalignant

Space of Disse

• Space between hepatocytes & sinusoids.

• Site of amyloid deposition in liver.

• Contains Ito cells or stellate cells.

Key Points regarding Ito cells

• Ito cells = hepatic stellate cells, located in space of Disse.

• Store vitamin A in lipid droplets (80% of liver’s retinoids).

• Transform into myofibroblasts in liver injury, causing bridging fibrosis.
• Key role in liver regeneration, fibrosis, and cirrhosis.

• Produce collagen (types I, III) and other matrix proteins.

• Act as antigen-presenting cells and regulate sinusoidal blood flow.

• Identified by gold chloride, cytoglobin, or ASMA staining

Ito Cells vs. Stellate Cells

• Anatomically same, functionally different states.
• Stellate cells: "hyperactive" version
• active in collagen formation
• relevant in cirrhosis.
• Ito cells: "eat, sleep, chill" version
• primarily Vitamin A storage.

Stem Cells

• Liver stem cells for regeneration are oval cells.

• Found in canals of Hering.

Staining

• To visualize collagen/fibrosis: 
• Mason trichrome stain.

• Stains collagen blue.

Causes of Cirrhosis

• Mnemonic: ABCDE + 3 things

Letter	Cause of Cirrhosis
A	• Alcoholic liver disease • Autoimmune hepatitis
B	• Biliary diseases (PBC, PSC)
C	• Cryptogenic cirrhosis (now largely NAFLD) • NAFLD + metabolic syndrome
D	• Drug induced cirrhosis
E - enzyme	• Alpha-1 antitrypsin deficiency

• + Three other things:
• Hepatitis (especially B and C)
• Hemochromatosis
• Wilson disease

Candy (Gundy) and Nutmeg

ㅤ	Heart Failure	Site	Notes
Nutmeg Liver	Right	Liver	Congested hepatic veins with centrilobular hemorrhagic necrosis of hepatocytes (dark color) Periphery → fatty changes (light color)
Gamma Gandi Bodies	Right	Spleen	Venous congestion
Heart Failure Cells/ Hemosiderin Laden macrophage	Left	lungs	Macrophages that have engulfed hemosiderin  (iron-containing pigment).

Alcoholic Liver Disease 

• Steatosis (fatty liver) → Steatohepatitis (inflammation) → Cirrhosis (scarring).

Maddreys discriminant function

• In ALD → decide whether to give steroid

• Give steroid if > 32

• Monitor response after steroid → Lille index

• Mad () Lille () took steroid after alcohol

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1. Steatosis (Fatty Liver):

• Alcoholic liver disease shows both
• Macrovesicular steatosis >>?
• Microvesicular steatosis

Other causes of Microvesicular fatty liver
(Mnemonic: Butchas and pregnancy):

• Fatty liver of pregnancy.

• HELLP syndrome.

• Reye's syndrome.

• Certain drug toxicities in children.

Other causes of Macrovesicular fatty liver:

• Metabolic/dietary factors

• Hepatitis C

• Hepatitis B is least likely to cause steatosis.

2. Steatohepatitis:

Mallory hyaline bodies (or Mallory-Denk bodies)

• Made of cytokeratin 8 and 18 (or intermediate filaments)
• Malathy aunty did intermittently () → 2 kids of 8 and 18 ()

Diseases showing Mallory bodies

• Mallory → Malathy Wilson (Wilson) → Indian (ICC) serial Obese (NAFLD) Auntie (antitrypsin) → Cola PBC

• Diseases that do NOT show Mallory bodies:
• Secondary biliary diseases.
• Hemochromatosis.

• Non-alcoholic and Alcoholic liver disease.

• Indian childhood cirrhosis.

• Wilson disease.

• Alpha-1 antitrypsin deficiency.

• Tumors of the liver (hepatocellular carcinoma).

• Cholestasis.

• Hepatic primary biliary diseases (e.g., PBC).

Chicken wire fibrosis

3. Cirrhosis:

• End-stage scarring is Laennec cirrhosis.
• Liver → Fibrous scar

Clinical Features

• Jaundice.

• P/A → Soft, Painful.

• Hepatomegaly.

Laboratory Features

• Neutrophilia: ↑

• MCV ↑

• PT/INR: ↑

• Liver enzymes: 300 - 500 U/L.
• GGT (Gamma-Glutamyl Transferase)
• Most sensitive marker
• AST:ALT ratio:
• ≥ 2:1 → Likely
• ≥ 3:1 → Highly suggestive

Non-alcoholic Liver Disease (NAFLD)

• Similar to alcoholic liver disease.

• Difference is cause (metabolic syndrome vs. alcohol).

• Definition
• Hepatic steatosis
• Absence of any secondary cause for fat accumulation in > 5% of hepatocytes

• Divided into
• Nonalcoholic fatty liver (NAFL)- steatosis without inflammation
• Nonalcoholic steatohepatitis (NASH) - steatosis with inflammation

• Associated with
• Obesity and insulin resistance
• ↑↑ levels of serum ferritin.

• Diagnosis requires
• Demonstration of hepatic steatosis
• Exclusion of
• Significant alcohol consumption
• Other causes of hepatic fat accumulation.

MASH (Metabolic dysfunction-associated steatohepatitis)

• Updated term for NASH

• Focus on metabolic conditions
• like diabetes, insulin resistance, dyslipidemia, and hypertension

• Diagnosis
• metabolic risk factors and elevated LFTs
• even without imaging evidence

• Support early diagnosis and treatment

ALCOHOLIC VS NON-ALCOHOLIC STEATOHEPATITIS

Treatment

Hepatitis (Viral)

• partial dsDNA

• Portal tract expansion

• ALT > AST

Classification

• Incubation period
• A & E → 15 - 50 days
• Both non enveloped
• B & D → 50 - 150 days
• C → 15 - 150

• Only cultivable
• Hep A

• No vaccine
• C (quasispecies) and E

• All RNA
• except Hep B → partial dsDNA

(Mnemonic: Private Hospitals Favour Rich Clients)

Virus	Family	Transmission	Envelope	Vaccine
HAV	Picornaviridae (Enterovirus)	Feco-oral	Non-enveloped	✅
HBV	Hepadnaviridae	Parenteral, sexual, MTC	Enveloped	✅
HCV	Flaviviridae	Parenteral	Enveloped	❌ (quasispecies)
HDV	With HBV assist	Parenteral	Enveloped	✅ (via HBV vaccine)
HEV	Hepeviridae (Calicivirus)	Feco-oral	Non-enveloped	❌

• Precore mutant → cannot produce HBeAg

Important facts

Hep Virus	Notes	Extrahepatic Manifestations
HEV	• MC cause sporadic acute hepatitis in India • 25 % fulminant hepatitis in pregnancy • [(1-2%) otherwise]	ㅤ
HDV	• MC cause fulminant viral hepatitis • (5-20%)	Co-infection: ↳ HBV + HDV simultaneously Superinfection: ↳ HDV in pre-existing HBV patient
HBV	MC cause • transfusion hepatitis • chronic hepatitis, carrier state • hepatitis-causing cancer	• Polyarteritis Nodosa (30%), • Membranous GN
HCV	• Maximum chronicity risk • Strongest cancer association	• Membranoproliferative GN, • Mixed cryoglobulinemia, • Lichen planus (colloid / civatte bodies)
Hepatitis G	• No known human infection • infects mononuclear cells • Transmitted via transfusion • protects against HIV	ㅤ

Hepatitis B:

• Dane Particle (Hepadna virus)

• DNA virus, partially double-stranded

• Susceptible to
• Hypochlorite
• Heat labile

• Reservoirs: Human.

• Mode of transmission:
• Parenteral: IV drug use.
• Vertical: Mother to child.

• Incubation period: 30-180 days.

• Period of communicability: 
• Till HBSAg +ve in blood.

• Clinical features:
• Low grade fever.
• Icterus.
• Malaise.
• Clay stools.

ㅤ	Genome	ㅤ
P	DNA Polymerase	Reverse transcriptase + RNAase
C	HBcAg (core) HBeAg (pre-core)	ㅤ
S	HBsAg	Australia Antigen, different sizes ↳ Orcein Shikata Stain (eosinophilic appearance)
X	HBX	Carcinogenesis in liver

• Pathogenesis
• Ground glass hepatocytes (hazy cytoplasm)
• Surface antigen
• Orcein shikata

Prevention

HBV vaccine:

Feature	Description
Content	• HBSAg  • Aluminium Hydroxide (Adjuvant)
Cold chain	• 2°C to 8°C (Freeze sensitive)
Dose	• Adult: 1 mL (10-20 mcg)  • Birth: 0.5 mL
Duration of protection	• Lifelong (After 3 doses)
Schedule	• 0, 1, 6 months (3 doses)  • If interrupted: Resume schedule
C/I	• Anaphylaxis

Accidental Needle Prick

• Timing: <2 h (up to 48h).

• Dose: 0.05 - 0.07 mL/Kg in 2-3 doses.

• Check HBSAg in the victim:
• + ve: Don't give vaccine.
• - ve:
• HB Vaccine (Recombinant) + HbIg → both can be given

WHO 5C's concept for prevention of Hepatitis B:

• Consent.

• Counselling.

• Confidentiality.

• Connection (For prevention, treatment and care services).

• Correct test results.

Note

• For Hep B
• Orcein shikata stain

• For Ceruloplasmin:
• Orcein stain

• Markers
• Anti-HBs → epidemiological marker
• IgM anti-HBc → window period marker
• Anti-HBe → decreased infectivity

Treatment

• LET → Lamivudine, Emtricitabine, Tenofovir

• Latest guidelines: TEA
• Tenofovir
• Entecavir
• Pegylated interferon-alpha (PEG-IFN-α)

Lab Diagnosis of HAV

• Shedding:
• Stool → 2 weeks before to 2 weeks after symptom onset

• Antibodies:
• IgM → with jaundice onset
• IgG → appears 2–4 weeks later

Hepatitis C:

• Liver biopsy:
• Grading = Inflammation + Necrosis (GIN)
• Staging = Fibrosis

• Fatty liver change
• Show macrovesicular steatosis
• with lymphoid aggregates

• Ballooning degeneration (Swollen hepatocytes).

• Bile duct proliferation

• Councilman bodies 
• apoptotic bodies
• An Eosinophilic apoptotic body (pinkish small body).

• Lymphoplasmocytic infiltrates.

• No portal inflammation.

• Spotty necrosis.

Autoimmune Hepatitis

Types:

Histology

• Dense lymphoplasmacytic infiltrate.

• Interface hepatitis.

• Hepatic rosettes.

• Emperipolesis: Cell within a cell appearance.

Microscopic features:

• Interface hepatitis:
• Inflammation at hepatocyte-portal triad junction.

• Emperipolesis:
• Larger cell (hepatocyte) engulfing smaller cell (lymphocyte).
• Seen in: Mnemonic: Emperor → Marc → Lazy (cell sits inside a cell lazily)



• Myelodysplastic Syndrome
• Myeloproliferative Neoplasms
• Autoimmune Hepatitis
• Rosai-Dorfman Disease
• Chronic Lymphocytic Leukemia
• Mnemonic:
• Marc (MARC) rose (Rosai dorfman) ne Call (CLL) cheyth karalu (Autoimmune Hepatitis) anenn paranj.
• Pinne My (MDS) my (MPN) nnu therim vilich

• Hepatic rosette:
• Liver cells in round, petal-like fashion.

Treatment

• Steroids + Azathioprine

• Overall prognosis - Good if treatment is started before cirrhosis.

• Cirrhosis - Transplant.

• Recurrence Post Transplant is seen.

DRUG INDUCED Autoimmune Hepatitis

• Minocycline

• Nitrofurantoin

• Methyl dopa

• Statins

Wilson Disease (Copper Overload)

• It is autosomal recessive.

Genetic Factor:

• Caused by ATP7B gene mutation on chromosome 13.

Organs Affected:

• Liver → Causes cirrhosis.

• Eye
• Leads to Kayser-Fleischer rings in Descemet membrane of cornea.
• Sunflower cataract

• Brain → Copper deposits in putamen (basal ganglia).
• Also called hepatolenticular degeneration.
• Basal ganglia: Lenticular nucleus.
• Leads to Psychosis or Parkinson-like symptoms.
• Dystonia, tremors, rigidity.

Investigations:

• Biochemical Tests:
• Screening/Most specific: 24h urinary copper
• Increased
• Decreased serum ceruloplasmin
• Increased serum copper (unreliable)

• Histology (Liver Biopsy):
• Confirmatory
• >250 µg/g
• Acute and chronic inflammation
• Steatosis
• Mallory hyaline bodies

Stains

• For Copper:
• Rhodanine
• Rubeanic acid
• Mnemonic: Copper ends with R, stains begin with R.
• Differentiation: 
• Rhodamine 
• (M for M) is for Mycobacterium TB.
• Mnemonic:
• Wilson nte Molu (Tetrathiomolybdate) → 13 year old in 7B
• He is Desp (Descmet)
• He like Puttu (Putamen)
• He does Nine in Road (Rhodanine)

MRI head:

• KF ring seen in eyes.
• Deposits in Descemet's membrane

• Giant face of Panda
• in midbrain on T2 MRI.

NOTE

• Panda sign is seen in sarcoidosis with Gallium-67 scan.

Treatment: 

• Copper chelators:
• Trientine (Triethylenetetramine)
• D- Penicillamine

• DOC (in maintenance phase):
• Zinc acetate

• DOC For neurological features:
• Tetrathiomolybdate

Reye's Syndrome

• Mitochondrial injury occurs in liver and brain.

• This leads to:
• Defective β-oxidation of fatty acids → accumulation of fat in hepatocytes → microvesicular fatty change.
• ↓ ATP production → contributes to encephalopathy and hypoglycemia.

• Features of hepatic encephalopathy + History of aspirin intake in a child with fever.
• Hepatic encephalopathy presents with:
• Nausea.
• Vomiting.
• Hypoglycemia.
• Early: Persistent vomiting, lethargy.
• Later: Irritability, confusion, seizures, coma.
• Signs of ↑ intracranial pressure.

• Histopathology:
• Microvesicular steatosis.

• CSF: Usually normal (helps differentiate from meningitis/encephalitis).

• Note: Vim Silverman liver biopsy needle is used for liver biopsy.

• Paracetamol overdose is the most common cause of acute liver failure