Preface

Agam is a group of budding medicos, who are currently doing their under graduation in
various Medical Colleges across Tamil Nadu and Pondicherry. The group was initiated on 18th
November 2017, in the vision of uniting medicos for various social and professional causes.

We feel delighted to present you Agam Pathology notes prepared by Agam Divide and Rule
2020 Team to guide our fellow medicos to prepare for university examinations.

This is a reference work of 2017 batch medical students from various colleges. The team
took effort to refer many books and make them into simple notes. We are not the authors of the
following work. The images used in the documents are not copyrighted by us and is obtained from
various sources.

Dear readers, we request you to use this material as a reference note, or revision note, or
recall notes. Please do not learn the topics for the 1st time from this material, as this contain just the
required points, for revision.
Acknowledgement

On behalf of the team, Agam would like to thank all the doctors who taught us Pathology.
Agam would like to whole heartedly appreciate and thank everyone who contributed towards the
making of this material. A special thanks to Vignesh M, who took the responsibility of leading the
team. The following are the name list of the team who worked together, to bring out the material in
good form.

• Neelavathi S
• Fredrick Snowin William
• Subhashree B
• Swathikrishna S
• Sweta Laxmi S
• Varsha L
• Vignesh J
• Vikram R R
• Vimal K
• Habeeb Nathira
• Vennmadhi Vellentina D
• Joy Christy A
• Kirubakaran T
• Swathika N G
• Afrah Marzook
• Dhyaneshwar Ra
• Vimala Veeraiyan
• Kirubakaran T
• Nirupama Sriram
• Subhashree Karishma Choudhury
• Amrutha Priya Devi B
• Vignesh. M
 LIVER, GALL BLADDER AND PANCREAS
ESSAY:
1. Classify cirrhosis. Details about Portal cirrhosis.
2. Tumors of Liver.
3. Etiopathology of Viral Hepatitis. Details about serologic evaluation.

SHORT NOTES:
1. Chronic vs acute hepatitis.
2. Metabolic cirrhosis
3. Pathophysiology of Fatty liver
4. Amoebic liver abscess
5. Gall stones
6. Hemochromatosis.
7. Chronic calcific pancreatitis.
8. Acute pancreatitis.
9. LDL.
10.Wilson Disease

SHORT ANSWERS:
1. Conditions of hereditary unconjugated hyperbilirubinemia.
2. Mallory bodies
3. Post Mortem changes of cirrhosis of liver

UPDATES

PATHOLOGY AGAM
ESSAY
1. CIRRHOSIS
End stage of chronic liver disease characterised by:
 Entire liver architecture damage
 Bridging fibrous septa
 Regenerating parenchymal nodules
 Variable degrees of vascular (often portosystemic) shunting.

CLASSIFICATION: BASED ON SIZE OF THE NODULES

MICRONODULAR MACRONODULAR
[NODULE SIZE- LESS THAN 3mm IN [NODULE SIZE- MORE THAN 3mm IN
DIAMETER] DIAMETER]
1) Early stage alcoholic cirrhosis 1) Late stage alcoholic cirrhosis
2) Indian childhood cirrhosis 2) Post- necrotic cirrhosis (Viral
hepatitis)
3) Hemochromatosis 3) Wilson’s disease
4) Primary biliary cirrhosis (PBC)
5) Jejunoileal bypass
6) Venous outflow obstruction
(Budd-chiari syndrome)

CLASSIFICATION: BASED ON ETIOLOGY (Mnemonic: A2B2CDEH2WI)

1. Alcoholic Cirrhosis
2. Autoimmune liver Disease
3. Biliary disease (PBC,PSC)
4. Biliary obstruction
5. Cryptogenic cirrhosis; Eg: Non-alcoholic steatohepatitis (NASH)
6. Drug induced and toxins
7. Enzyme deficiency (Alpha1antitrypsin deficiency)
8. Hepatitis
9. Hemochromatosis
10.Wilson’s disease
11.Indian Childhood cirrhosis

AGAM PATHOLOGY
PORTAL CIRRHOSIS:
 Also known as Laennec’s cirrhosis, alcoholic cirrhosis, nutritional cirrhosis.
 Common cause- chronic alcohol consumption.

ALCOHOLIC LIVER DISEASE:

 Excessive alcohol consumption- 80gm or more
ethanol causes significant liver injury.
 Consists of three distinct forms:
 Hepatocellular Steatosis or fatty
change
 Alcoholic (-steato) hepatitis
 Fibrosis and cirrhosis

PATHOGENESIS:
 Alcohol NADH Acetaldehyde NADH Acetate
Alcohol dehydrogenase Aldehyde dehydrogenase
 Hepatic Steatosis:
 Accumulation of intracellular lipids.
 NADH used for lipid biosynthesis and ethanol impairs assembly of lipoproteins.

 Alcoholic hepatitis:
 Acetaldehyde- induces lipid peroxidation, disrupt cytoskeleton and membrane
function.
 Alcohol- affects mitochondrial function and membrane fluidity.
 ROS- Kupffer cell activation, oxidative damage to hepatocyte membrane.
 Cirrhosis: Pericellular and sinusoidal fibrosis first develops, connecting portal triad with
central veins forming regenerative nodules.
 Loss of hepatocyte and liver shrinks.

MORPHOLOGY:
 STEATOSIS:
 Initially microvesicular type and later macrovesicular type.
 Start at Centrilobular area and become panlobular.

PATHOLOGY AGAM
 ALCOHOLIC HEPATITIS:
 Hepatocyte ballooning (hepatocyte swelling)
 Mallory-Denk bodies(intracytoplasmic hyaline inclusion, Cytokeratin 8 and 18
intermediate filaments)
 Neutrophilic infiltrations
 Centrilobular necrosis
 STEATOFIBROSIS:
 Central vein sclerosis
 Chicken wire fence pattern(perisinusoidal scarring spreads outward,encircling small
clusters of hepatocyte)
 Central portal fibrous septa
 Irreversible stage- initially micronodular and later macronodular
 Entire liver lobe is replaced by tough pale scar tissue.
GROSS: Liver is yellow-tan, fatty and enlarged, with persistent damage liver turns into
brown shrunken, non-fatty organ composed of cirrhotic nodules.

CLINICAL FEATURES:
Symptoms and laboratory abnormalities range from minimal to severe.
 Malaise, anorexia, weight loss, upper abdominal discomfort, nausea and vomiting,
tender hepatomegaly and fever.
 Development of jaundice and encephalopathy.
 Scleral icterus, palmar erythema, spider angioma, parotid gland swelling, ascites,
edema, clubbing and muscle wasting.
 Male- decreased body hair, Gynecomastia, testicular atrophy.
 Women- menstrual irregularities.
LABORATORY TESTS:
 Serum total bilirubin elevated  Prolonged prothrombin time
 Direct bilirubin mildly elevated  Serum AST and ALT elevated
 Neutrophilic leukocytosis  Deficiency of vitamin B12, thiamine.
COMPLICATIONS:
 Hepatic failure  Intercurrent infection
 Pancreatitis  Hepatorenal syndrome
 Massive gastrointestinal haemorrhage  Hepatocellular carcinoma

AGAM PATHOLOGY
2. TUMORS OF LIVER
The liver is the most common site of metastatic cancers from primary tumors of colon,
lungs and breast.
BENIGN TUMORS:
A. CAVERNOUS HEMANGIOMA
 Most common benign tumor of liver.
 It is composed of large,dialated vascular channels filled with blood.
 They do not spontaneously regress.
 Difficult to distinguish from malignant tumor.
 Morphology:
 Red blue, soft nodules, usually less than 2 cm in diameter.
 Located beneath the capsule.
 Histological examination: It consist of vascular channel in the bed of connective tissue.

B. HEPATOCELLULAR ADENOMA
 Benign neoplasms from Hepatocytes
 Detected – incidentally
 After abdominal pain(due to pressure by growing tumour on the capsule)
 After haemorrhagic necrosis
 May rupture → Intraabdominal bleeding → Surgical importance
 Risk factors – Oral contraceptives, Anabolic Steroids

Based on molecular analysis, HCA is of 3 types:

Hepatocellular Carcinoma

HNF1-α Inactivated β-Catenin Activated Inflammatory

Hepatocellular Adenoma Hepatocellular Adenoma Adenocarcinoma

PATHOLOGY AGAM
 TYPE PATHOGENESIS MORPHOLOGY
HNF1-α • 90% - Inactive somatic • Tumors are fatty and devoid of
Inactivated mutation of HNF1-α cellular or architectural atypia
Hepatocellular • 10% - Genetic Mutation • Liver Fatty Acid Binding
Adenoma • HNF1-α codes for a Protein(LFABP) is absent in tumor
transcription factor cells (expressed in normal cells)
• Commonly found in women • Thus, immune staining for LFABP is
diagnostic
β-Catenin • Activating mutations of β- • Have high degree of cytological or
Activated catenin architectural Dysplasia
Hepatocellular • Have a high risk for Malignant • Immuno staining for β-Catenin
Adenoma transformation shows nuclear translocation
• Should be resurrected even indicative of its activated sites
when asymptomatic • Glutamate synthase, a target of β-
Catenin is also positive (usually
around perivenular hepatocytes
Inflammatory • Activating mutations of gp130, • Unlike other HCAs, these lesions
Hepatocellular a coreceptor for IL-6, which have areas of fibrotic stroma,
Adenoma lead to JAK-STAT signalling and mononuclear inflammation,
overexpression of cute phase ductular reactions, dilated
reactants sinusoids and telangiectatic vessels
• Associated with Non-Alcoholic • Express Acute Phase Reactants like
Fatty Liver Disease CRP
• 10% of IHA have concomitent
β-Catenin Activated mutation

MALIGNANT TUMOR
 Hepatocellular Carcinoma -Most common malignant tumor
 Hepatoblastoma- M/C malignant tumor in Children
 Angiosarcoma- M/C Sarcoma

AGAM PATHOLOGY
HCC:
 Primary liver cancer arise from hepatocytes.
 Cirrhosis is not required for hepatocarcinogenesis.
 Western country-90% HCC develop into cirrhotic liver.
 Asian country-50% HCC develop into non cirrhotic liver.
 Accounts for 5.4% of cancers worldwide.
 85% of cases are associated with chronic HBV infection.
 Peak incidence: 20 – 40 years of age.
 It is also called hepatoma
 High risk Areas
 Asia.
 Africa.
 Increasing incidents in USA.
ETIOLOGY:
 Chronic liver disease are most common setting for emergence of HCC
 Etiological factors-
 viral infections : HBV,HCV
 Toxins: aflatoxin(mycotoxin) produced By aspergillus
 Other risk factors:
 Alcohol
 Cigarette smoking
 Inherited disorders:
 alpha AT deficiency
 Wilson's disease
 Hemochromatosis
 Metabolic disorders: obesity, DM, NAFLD
PATHOGENESIS:
 HCC is induced by acquired driver mutations in oncogenes and tumor suppressor genes.
 Gain of mutations in beta-canenin.
 Loss of mutations in P53.
 More recent studies implicate a role or signalling through the IL-6/JAK/STAT pathway in
HCC. IL-6 is overproduced in many chronic hepatitides.
 IL-6 can suppress hepatocyte differentiation and promote their proliferation by regulatory
the function of transcription factor HNF4-α.

PATHOLOGY AGAM
 Premalignant precursors of HCC
 Hepatic Adenoma
 Chronic liver disease associated with cellular Dysplasia
 Low grade dysplastic nodules
 High grade dysplastic nodules (viral hepatitis and Alcohol liver disease)

MORPHOLOGY:
 Masses appears grossly as unifocal / multifocal, diffuse.
 Intrahepatic metastasis occurs through vascular invasion and direct extension.
 Extra hepatic metastasis by vascular invasion through portal vein and inferior venacava.
 Color:
 White (abundant stroma),
 Yellow (predominant fatty changes)
 Green (malignant hepatocytes secrete bile).

HISTOLOGY:
 Large pseudo acinar space
 Malformed dilated bile canaliculi
 Thickened hepatocyte trabeculae

DIAGNOSIS:
 50% cases -elevated serum alpha feto protein level
 Ultrasonography, computed tomography, magnetic resonance imaging
 Mass will progressively increase

CLINICAL FEATURES:
 Upper abdominal pain, malaise, fatigue, weight
 Other inconstant findings-jaundice, fever, gastrointestinal or oesophageal varices
 Death occur due to cachexia, liver failure with hepatic coma, rupture of tumor with fatal
hemorrhage, gastrointestinal or oesophageal varices
 Majority of patients dies within 2years of diagnosis

TREATMENT:
 Small tumors removed surgically or through embolisation, microwave radiation and
freezing.
 Advanced stage -liver transplantation.
 Life can be prolonged by Sorafenib(kinase inhibitor).

AGAM PATHOLOGY
CHOLANGIOSARCOMA (CHOLANGIOCARCINOMA)
 Second most common primary tumour inn liver next to HCC.
 It is the malignancy of biliary tree within or outside the liver.
 More common in areas with liver fluke is endemic.
 Risk factors:
 Infestation by liver fluke  Fibropolycystic liver disease
 Primary sclerotic cholangitis  HBV, HCV
 Hepatolithiasis  Non-alcoholic fatty liver
disease
Cholangiosarcoma

Intrahepatic (10%) Extrahepatic (90%)

Perihilar (Klatskin tumour) Distal tumours

 60%  20 – 30 %
 Located at junction of right  Arises in common
and left hepatic ducts bile duct

CLINICAL FEATURES:
 Intrahepatic: Usually asymptomatic during early course of the tumour. They become
detectable only in their late course. Hence, median time from diagnosis to death is only 6
months even after surgery.
 Extrahepatic; present with symptoms of biliary obstruction, cholangitis and right upper
quadrant pain. Median time from diagnosis to death is 2 years.
MORPHOLOGY:
 Cholangiosarcomas, regardless of the site, are Adenosarcomas and secrete Mucin.
 Most are differentiated with clearly defined glandular/tubular structures
 Extrahepatic CSs:
 Generally small when diagnosed as they cause rapid obstructive symptoms
 Firm, gray / diffusely infiltrative/ papillary polypoid.
 Intrahepatic CSs:
 Occur in non cirrhotic liver
 Track along the intrahepatic portal tract system.

PATHOLOGY AGAM
3. ETIOPATHOLOGY - VIRAL HEPATITIS & SEROLOGICAL EVALUATION:
VIRAL HEPATITIS:
Defined as viral infection of hepatocyte that produces bridging necrosis and
inflammation.
BRIDGING NECROSIS
 Bridging necrosis is a more severe form of hepato-cellular injury in acute viral hepatitis
and may progress to fulminant hepatitis or chronic hepatitis.
 In bridging necrosis, the necrotic zone may link central veins to portal tracts or bridge
adjacent portal tracts (often with an inapparent central vein within the zone of injury).
CAUSES: It is caused by hepatotropic viruses such as hepatitis A, B,C,D,E viruses.
INVESTIGATIONS OF VIRAL HEPATITIS:
COMMON CONSIDERATIONS:
 Total bilirubin /urine bilirubin: Elevated.
 Liver panel / serum aminotransferases: Elevated.
 Prothrombin time: If prolonged indicates severe impairment of liver function.
 Blood urea nitrogen (BUN) and serum creatinine: Decreased renal function indicates
Fulminant hepatic disease.
 Mild normochromic normocytic anaemia with thrombocytopenia and leukopenia is
present even before portal hypertension and splenomegaly.
 Demonstration of virus in faeces, blood, bile by immunoelectron microscopy.
 Detection of antibody by ELISA and molecular diagnosis by RT-PCR.
 Serum ammonia: if raised then hepatic encephalopathy.

HEPATITIS A VIRUS:
 Usually benign condition.
 Viral genome: Non enveloped single stranded RNA.
 Receptor: HAVcr-1(membrane glycoprotein).
 Transmission-feco-oral route and close personal contact with.
 Incubation period-2 -6 weeks.
 Affected individual develop nonspecific symptoms (fatigue, loss of appetite) and jaundice.
 It will not cause chronic hepatitis.
 HAV mediated Hepatocellular injury caused by CD8+ T cells.
 HAV is shed in stool (2-3 weeks before and 1 week after onset of jaundice).
 It can be also detected in serum and saliva.

AGAM PATHOLOGY
SEROLOGICAL EVALUATION:
 Detection of serum Ig M.
 IgM response usually decline after few months followed by appearance of IgG anti HAV
(no test for Ig G anti HAV-(total anti HAV-IgM anti HAV)

HEPATITIS B VIRUS
 Antigen: Hepatitis B virus
 Viral Family: Hepadnavirus
 Genome: Partially ds circular DNA with 4 open reading frames which code for markers -
 Core Region : HBcAg (Hepatitis B core antigen) - participates in the assembly of
complete virions in hepatocytes
 Precore Region : HBeAg (Hepatitis B e antigen) - directs the secretion of the HBeAg
polypeptide into blood
 Envelope glycoprotein : HBsAg (Hepatitis B surface antigen) - synthesised and secreted
by infected hepatocytes
 DNA Polymerase: Pol -DNA polymerase and reverse transcriptase activity.
 HBx Protein: Virus replication and pathogenesis of HBV associated liver carcinoma.
TRANSMISSION:
 High prevalence region – perinatal transmission (during childbirth)
 Intermediate prevalence region – horizontal transmission (common in children)
 Low prevalence region – unprotected sex, IV drug abuse
HBV INFECTION :
 Incubation period – 2 to 26 weeks.
 Outcomes – The outcome is determined by host immune response
 Innate immunity acts during initial phase.
 Acute hepatitis followed by recovery and clearance of the virus.
 Non progressive chronic hepatitis.
 Progressive chronic disease ending in cirrhosis.
 Fulminant hepatitis with massive liver necrosis.

ACUTE INFECTION WITH RESOLUTION:

CLINICAL MANIFESTATION:
 Subclinical or anicteric hepatitis.
 Icteric hepatitis
 Fulminant hepatitis.
Nonspecific Symptoms: Right upper quadrant discomfort, nausea, jaundice, anorexia, fever.

PATHOLOGY AGAM
SEROLOGIC MARKERS:
 HBsAg - appears before onset of
symptoms, Peaks during overt disease,
Declines within 12-24 weeks.
 HBeAg , HBV-DNA, DNA pol – appears
after HBsAg, Indicates continued viral
replication, Persistence of HBeAg is an
indicator of progression to chronic
hepatitis
 Anti-HBs Antibody – appears after
HBsAg declines, May persist for life and
confer protection – rationale for current vaccines containing HbsAg.
 IgM-Anti-HBc – detectable shortly before the onset of symptoms, Concurrent with onset
of elevated ALT/AST, IgM replaced by IgG in due course of time
 Anti-HBe Antibody – signifies acute infection peak has been reached and will continue to
subside.
Resolution of acute infection is associated with CD4+ and CD8+ IFN – gamma producing
cells (hepatocyte injury is caused by CD8+ cytotoxic T cells attacking infected cells).
CHRONIC INFECTION
GROUND GLASS HEPATOCYTE: Cases of chronic
hepatitis B show scattered Ground-glass
hepatocytes indicative of abundance of HBsAg in
the cytoplasm. Endoplasmic reticulum of
hepatocyte is swollen by the antigens. It is a
diagnostic hallmark of HBV infection.
 The progression rate from acute to chronic HBV
infection decreases with age
 Complete resolution is not possible as the virus
inserts itself in the host DNA.
 Leads to impairs development of immune response.
CLINICAL MANIFESTATION:
Asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
Advanced liver disease there may be clinical signs of chronic liver disease including
splenomegaly, spider angioma, caput medusae, palmar erythema, testicular atrophy,
gynecomastia.

AGAM PATHOLOGY
HEPATITIS C VIRUS:
 It is a small enveloped ssRNA.
 Etiological factors-intravenous drug abuse, multiple sex patterns, surgery within last 6
months, needle stick injury, employment in medical field
 In children vertical perinatal transmission present
 It has viral proteases for processing NS5A( protein for assembly )and RNA polymerase
 Incubation period-4-26 weeks
 More often it causes chronic hepatitis.
SEROLOGICAL EVALUATION:
Serum aminotransferases : The values do not predict the severity of clinical findings, the
degree of histologic abnormalities, the patient’s prognosis, or the therapeutic response.
Normalization of AST and ALT levels after acute infection may signal clearance of HCV.
SEROLOGIC ASSAYS :
 Anti-HCV test :
 Recombinant HCV antigens are used in enzyme-linked immunosorbent assay
(ELISA) to detect IgG anti-HCV in patients’ sera.
 Can remain negative even after months of acute infection.
 Anti-HCV is not a protective antibody.
 Recombinant immunoblot assays (RIBAs): More specific.
 HCV RNA testing.

HEPATITIS D VIRUS:
 It is a circular defective ssRNA.
 Delta agent depends on HBV for it’s life cycle.
 Superinfection of HBV carrier by HDV has two phase.
 Acute phase
 HDV replicate by suppression of HBV
 ALT level is high.
 Chronic phase
 HBV replicate by suppression of HDV
 ALT level fluctuates
SEROLOGICAL EVALUATION:
 Detection of HDV RNA in Blood and liver at onset of acute symptomatic disease.
 Coinfection of HBV and HDV-IgM against HD AG and HBcAg is detected.
 HDV superinfection-HBsAg and anti HDV antibody (IgM and IgG).

PATHOLOGY AGAM
HEPATITIS E VIRUS:
 It is ssRNA.
 Enterically transmitted waterborne self limited disease
 Zoonotic disease-epidemic
 Cause 30-60% acute hepatitis
 High mortality among pregnant woman
 Incubation period-4-5 weeks
 Undeveloped RNA virus in the hepavirus genus.

SEROLOGICAL EVALUATION:
 HEV RNA and HEV virion detected by PCR in stools and serum.
 Rising serum aminotransferase.
 Elevated IgM anti HEV and latter IgG anti HEV.

AGAM PATHOLOGY
SHORT NOTES:
1. ACUTE VS CHRONIC:
ACUTE CHRONIC

Histological findings
 Gross: Normal or slightly mottled and  Mononuclear portal inflammation.
greenish.  Interface Hepatitis
Might shrunk under acute liver failure. (At the interface between hepatocellular
 Microscopically: parenchyma and portal tract stroma)
Mononuclear infiltrate  Scarring and Fibrosis.
Portal inflammation: absent or minimal  Microscopically: Piecemeal necrosis,
Hepatocellular injury - ballooning portal tract lesions, intralobular lesion’s,
degeneration, councilman body or bridging necrosis
acidophil body, dropout necrosis,
bridging necrosis
Spotty necrosis or Lobular hepatitis
 Severe Acute hepatitis : confluent
necrosis around central vein

HBV
 Subclinical or anicteric hepatitis.  Asymptomatic or healthy carriers
 Icteric hepatitis.  In advanced Cases:
 Fulminant hepatitis. splenomegaly, spider angioma, caput
 Nonspecific Symptoms: Right upper medusae, palmar erythema, testicular
quadrant discomfort, nausea, jaundice, atrophy, and gynecomastia.
anorexia, fever.  In decompensated cirrhosis, jaundice,
ascites, peripheral edema, and
encephalopathy may be present
 Ground glass hepatocytes with ER
swollen with HBsAg (diagnostic hallmark)
is a histological finding

PATHOLOGY AGAM
More common in adults. Advancement to chronic is more common in
Children.

HCV:
 Asymptomatic.  Asymptomatic.
 Symptomatic (milder than HBV  Severe cases cirrhosis.
infection)  Persistent elevation in serum
transaminases (wax and wane)
 gives rise to insulin resistance and NAFLD
(met syndrome)
 Lymphoid aggregates and Fatty change
are histological findings.

AGAM PATHOLOGY
2. METABOLIC CIRRHOSIS:
A number of metabolic conditions involving the liver can cause chronic liver disease
leading to cirrhosis.
CIRRHOSIS: Diffuse transformation of the entire liver into regenerative parenchymal
nodules surrounded by fibrous bands and variable degrees of vascular shunting.

ALPHA1-ANTITRYPSIN DEFICIENCY:
Autosomal Recessive Protein Folding Disorder

↓ circulating α-1-
AT
Destructive proteases are not inhibited

Hepatocellular accumulation of misfolded protein (Pi-ZZ:

defect in migration of protein from ER to Golgi apparatus)

ER stress → Unfolded protein response

Apoptosis → Liver injury

Attacks of hepatitis may subside with apparent recovery / become chronic

Cirrhosis (middle or later life)

GENOTYPE ALPHA1-AT LEVELS

Pi-MM Normal
Pi-ZZ 10% of normal
Pi-MZ Intermediate

PATHOLOGY AGAM
NON ALCOHOLIC FATTY LIVER DISEASE:

HEMOCHROMATOSIS

AGAM PATHOLOGY
WILSON DISEASE

PATHOLOGY AGAM
3. PATHOPHYSIOLOGY - FATTY LIVER
Fatty change in liver may results from one of the two types of causes

CONDITIONS WITH EXCESS FAT: Conditions in which capacity of the liver to metabolise
fat is exceeded:
 Obesity, Diabetes mellitus.
 Congenital hyperlipidaemia.
LIVER CELL DAMAGE: Conditions in which fat cannot be metabolized due to liver cell
injury:
 Alcoholic liver disease (most common)
 Starvation.
 Protein calorie malnutrition.
 Chronic illnesses (e.g. tuberculosis)
 Acute fatty liver in late pregnancy
 Hypoxia (e.g. anaemia, cardiac failure)
 Hepatotoxins (e.g. carbon tetrachloride, chloroform, ether, etc)
 Drug induced liver cell injury (steroids, CCl4, etc)
 Reye's syndrome.

PATHOPHYSIOLOGY – ALCOHOLIC FATTY LIVER

 Gender: Women are more prone to fatty liver than men may be due to alcohol
pharmacokinetics and metabolism and estrogen dependent response to gut derived
endotoxins (LPS) in liver.
 Estrogen increases gut permeability to endotoxins which in turn increase the expression
of LPS receptor CD14 in kupffer cells which increases production of proinflammatory
cytokines.
 Ethnic and genetic difference: US cirrhosis higher for African Americans than white
American.
 Genetic polymorphism in detoxifying enzymes and some cytokines promoters plays a
significant role.
 ALDH*2 variant of aldehyde dehydrogenase unable to oxidise acetaldehyde and do not
tolerate alcohol leading to alcohol intolerance- upper body flushing, nausea and lethargy.
 Combined conditions: Iron over load and infection with HCV and HBV synergize alcohol
leading to severity of liver disease.

AGAM PATHOLOGY
Hepatocellular steatosis results from:
 Shunting of normal substrates towards lipid biosynthesis resulting in increased NADH.
 Impaired assembly and secretion of lipoprotein.
 Increased peripheral catabolism of fat releasing free fatty acids into circulation.
 Acetaldehyde intermediate metabolite of alcohol induces lipid peroxidation and
acetaldehyde protein adduct formation and dysrupts cytoskeleton membrane function.
 Alcohol impairs metabolism of methionine and decrease glutathione, and thereby
sensitizing liver to oxidative injury.
 Converts drugs like acetaminophen to toxic metabolites (by induction of cytochrome
P450 enzyme, which causes alcoholic catabolism in endoplasmic reticulum).
 Release of bacterial endotoxins into portal circulation induce inflammatory response by
NF-kB and TNF, IL-6.
 Alcohol also stimulates release of endothelins from endothelial cells causing
vasoconstricton and contraction of activated myfibroblastic cell leading to decrease in
hepatic sinusoidal perfusion.

NON-ALCOHOLIC FATTY LIVER DISEASE:

 Insulin resistance leads to hepato steatosis
 Hepatocellular oxidative injury leads to liver cell necrosis and inflammatory reactions.
 Hepatic steatosis like obesity occurs due to overabundance of calorie rich food,
diminished exercise and epigenetics modifications.
 In insulin resistance and metabolic syndrome visceral adipose tissue becomes
dysfunctional leads to reduced production of lipid hormone, adiponectin and increased
inflammatory cytokines such as TNF and IL-6 promoting hepatocyte apoptosis.
 Diminished autophagy leads to mitochondrial injury and formation of Mallory-Denk
bodies.
 Kupffer cells produce TNF and TGF activating the stellate cells and leading to scar
formation.
 Stellate cell is activated through hedgehog pathway thus, stages of fibrosis correlates to
the level of hedgehog pathway.

PATHOLOGY AGAM
4. HEPATIC AMOEBIASIS:
 It’s a common extra intestinal complication.
 Amoebic dysentery absent in 50 percent
 Patients with amoebic colitis develop a tender liver without impairment of liver function
 It might be because of repeated invasion of amebae from colonic infection or toxic
substance reach the liver, causing damage (lysosomal enzymes of lysed
polymorphonuclear neutrophils and monocytes and cytokines from inflammatory cells
surrounding the trophozites).

AMOEBIC LIVER ABSCESS:

 It is a type of liver abscess caused by amebiasis.
 It is the involvement of liver tissue by trophozoites of the organism Entamoeba
histolytica and of its abscess due to necrosis.
 Grossly :
 The center of abscess-thick chocolate brown pus (anchovy sauce pus) Liquified
necrotic liver tissue.
 Periphery-normal tissue contains invading amoeba.
 It might be multiple or solitary usually in the upper right lobe (poesteriosuperior
portion)
 Histologically:
 The necrotic area consists of degenerated liver cells, leucocytes, red blood cells,
strands of connective tissue and debris.
 Amoebae are most easily found in the liver tissue at the margin of abscess.
 PAS-staining is employed to confirm the trophozoites of Entamoeba histolytica.

CLINICAL FEATURES:
 Painful hepatomegaly, fever, anorexia, nausea.
 Weight loss and fatigue.
 Leukocytosis , increased serum transaminases, jaundice develops when they obstruct
biliary tract.
 Untreated abscess penetrate into diaphragm into lung or pleural
cavity,pericardium,peritoneal cavity, stomach and IVC.

AGAM PATHOLOGY
5. GALL STONES:
RISK FACTORS:
 Age and sex- middle to older age
 Prevalence high in female, hyper secretion of biliary cholesterol plays the role in age
and sex difference.
 Risk increases with sex and metabolic syndrome.
 Environmental Factors: Estrogen exposure- oral contraceptive and pregnancy increase
expression of hepatic lipoprotein receptor and stimulate HMG-CoA activity and enhance
cholesterol uptake and biliary secretion
 Acquired Disorder: Gall bladder stasis either neurogenic or hormonal favorable for gall
stones.
 Hereditary Factor: Genes encoding hepatocyte proteins that transport biliary lipids
known as ATP- binding cassette (ABC). The sterol transporter encoded by ABCG8 is also
involved.
 Demographic – Western world.
 High calorie diet and obesity.
 Drugs – clofibrate, exogenous estrogens.
 Gastrointestinal disorders.
 Pigment gallstones – disorders associated with erythrocytes, cirrhosis of any cause, and
infection of the biliary tract by liver flukes.

PATHOGENESIS OF CHOLESTROL STONES: (crystalline cholesterol monohydrate)

Cholesterol concentration exceeds the solubilizing capacity of the bile.
 Super saturation of cholesterol with bile
 Hypo motility of gall bladder
 Accelerated cholesterol crystal nucleation
 Hyper secretion of mucus in gall bladder trapping nucleated Crystal’s

PATHOGENESIS OF PIGMENT STONES: (bilirubin calcium salts)

 Complex mixtures of inorganic calcium salts of unconjugated bilirubin.
 Common in elevated unconjugated bilirubin- chronic hemolytic anemia (secretion of
conjugated bilirubin increases lots of deconjugated bilirubin to pigment stones).
 Severe ileal dysfunction.
 Bacterial contamination of biliary tree- release of microbial glucoronidases which
hydrolyze bilirubin glucuronides.
PATHOLOGY AGAM
MORPHOLOGY:
 Cholesterol stone:
 Pale yellow, round to ovoid, fine granular, hard external surface
 Transection-glistening radiating crystal palisade.
 Multiple stones are present, may be rounded or faceted because of tight apposition.
 Mostly they are radiolucent, stones with sufficient calcium carbonate are radiopaque.
 Pigment gall stones:
 Brown- found in sterile gall bladder bile.
 Black- infected large bile ducts.
 Contours are spiculated and molded.
 Brown stones are:
 Laminated
 Soft-soap like or greasy
 Radiolucent
 Black stones are: radiopaque.

CLINICAL FEATURES: PATHOLOGICAL EFFECTS OF GALL STONE:

 Asymptomatic
 Biliary colic after a fatty meal
 Pain localized to right upper quadrant or right epigastric radiating to right shoulder or
back
 Complications: empyema, perforations, fistulas, inflammation of the biliary tree
(cholangitis), obstructive cholestastis and pancreatitis.
 Large stones erode in small bowel causing intestinal obstruction -gall stone ileus or
Bouveret syndrome.
 Increased risk of gall bladder carcinoma

AGAM PATHOLOGY
6. HEMOCHROMATOSIS
 Caused by excessive iron absorption.
 Liver; pancreas; heart; joints; endocrine glands.
 3 types:
 Hereditary hemochromatosis: mutations of genes encoding
HFE; TfR2; HJV
 Secondary hemochromatosis/hemosiderosis: transfusions; sideroblastic anemia;
thalassemia; chronic liver disease
 Neonatal hemochromatosis/congenital hemochromatosis: manifested by severe liver
disease and extrahepatic hemosiderin deposition.
 Triad of features:
 Micro nodular pigment cirrhosis.
 Diabetes mellitus.
 Skin pigmentation.

BRONZE DIABETES:
Pathogenesis:
 HFE / HJV / TFR2 gene mutations.
 Reduced hepcidin synthesis –
diminished circulating hepcidin.
 Decreased hepcidin-ferroportin
interaction.
 Increased ferroportin activity.
 Increased iron efflux from enterocytes –
systemic iron overload.
Morphology:
 Deposition of hemosiderin {liver > pancreas > myocardium > pituitary gland > adrenal
gland > joints > skin} – appear as golden yellow pigment granules in the cytoplasm of
affected parenchymal cells.
 Cirrhosis.
 Pancreatic fibrosis.
Clinical features:
 Hepatomegaly.  Deranged glucose homeostasis / Diabetes mellitus.
 Abdominal pain.  Cardiac dysfunction (arrhythmias, cardiomyopathy).
 Abnormal skin pigmentation  Atypical arthritis.

PATHOLOGY AGAM
7. CHRONIC CALCIFIC PANCREATITIS
Prolonged inflammation of pancreas with the presence of stones in it and does not
heal or improve.
 Etiology:
 Heavy alcohol abuse.  Blocked pancreatic duct / common bile duct.
 Autoimmune conditions.  Familial pancreatitis.
 Genetic mutation due to cystic fibrosis.
 Pathophysiology:
 Mislocation of cystic fibrosis transmembrane conductance regulator chloride channel
in pancreatic duct cells.
 Decrease in pancreatic HCO3 secretion.
 Low pH of pancreatic juice leads to fluid mal secretion.
 Protein plug formation in the pancreatic ducts.
 CALCIFICATION – Pancreatic stone formation.

MORPHOLOGY:
 Gross appearance:
 Pancreas – enlarged, firm, nodular.
 Cut section – smooth grey appearance with loss of normal lobulation .
 Foci of calcification and tiny pancreatic concentrations to large visible stones –
Present.
 Microscopic examination:
 Obstruction of the ducts by fibrosis in the wall and protein plugs or stones in the
Lumina.
 Chronic inflammatory infiltrate around the lobules and ducts.
 Atrophy of acinar tissue.
 Diagnosis: Visualization of calcifications within the pancreas by CT or Ultrasonography.

CLINICAL FEATURES:
 Epigastric abdominal pain which radiates to back.
 Pancreatic insufficiency {malabsorption with steatorrhea and fat-soluble vitamin
deficiencies}.
 Dystrophic calcification of pancreatic parenchyma on imaging.
 Weight loss and edema.

AGAM PATHOLOGY
8. ACUTE PANCREATITS
 Characterized by reversible pancreatic parenchymal injury associated with inflammation.
 Acute hemorrhagic pancreatitis / Acute pancreatitic necrosis.

ETIOLOGY:
 Alcoholism: Gene Polymorphism for UDP (Uridine-5-Diphosphate) Glucuronyl Transferase
 Increase risk for Alcohol Induced Pancreatitis.
 Certain drugs (e.g. azathioprine, thiazide, sulfonamides, oral contraceptives).
 Mutation in cationic trypsinogen (PRSS1) & Trypsin inhibitor (SPINK1) genes
 Extension of inflammation from the adjacent tissues.
 Hypercalcaemia from hyperparathyroidism.
 Blood-borne bacterial infection.  Shock.
 Cholelithiasis.  Hypothermia.
 Trauma.  Hyperlipoproteinemia.
 Ischaemia.  Mumps

PATHOGENESIS:
 Destructive changes in
the pancreas are
attributed to the
liberation and activation
of pancreatic enzymes –
proteases, lipases and
phospholipases, elastases
 Activation and release of
this enzyme is brought
about by:
 Acinar cell damage
 Duct obstructions
 Block in exocytosis

GROSS APPEARANCE:
 Pancreas (early stage) – swollen, edematous.
 Variegated appearance of grey-white pancreatic necrosis..
 Chalky – white fat necrosis.
 Blue – black hemorrhages are seen
PATHOLOGY AGAM
MICROSCOPIC EXAMINATION:
 Necrosis of pancreatic lobules and ducts.
 Necrosis of arteries and arterioles with area of hemorrhages.
 Fat necrosis.
COMPLICATIONS:
 Systemic complications:  Local complications:
 Chemical and bacterial peritonitis.  Pancreatic abscess.
 Endotoxic shock.  Duodenal obstruction.
 Acute renal injury.

9. LDL:
 LDL stands for Low-Density Lipoprotein.
 Nearly 7% of body’s cholesterol circulate in the plasma, predominantly in form of LDL.

LDL RECEPTOR PATHWAY AND REGULATION OF CHOLESTEROL METABOLISM:

AGAM PATHOLOGY
FAMILIAL HYPERCHOLESTEROLEMIA:
 Is is a receptor disease that results from mutations encodingthe receptor for LDL.
 Since, the LDL receptor levels are reduced, catabolism of LDL is impaired leading to
increase in plasma cholesterol level.
 IDL also uses LDL receptors and hence high levels of IDL are diverted to synthesis of even
more LDL.
 Elevated seum cholesterol levels increases the risk of ischemic heart diseases,
atherosclerosis and other coronary artery diseases.
 More than 900 mutations are found responsible for Famiilial Hypercholesterolemia and
are classified into 5 classes:

Class I : Failure of synthesis of receptors.

Class II : Folding defects in ER leading to impaired
transport of proteins synthesised in ER to Golgi
bodies.
ClassIII : Defect in LDL binding domain in the
receptor. Receptor reach the surface of cell, but
LDL will not be able to bind to its receptors.
Class IV : Failure in formation of coated pits. LDL
bind to receptor, but fails to internalise.
Class V : pH dependant dissociation of receptor is
affected. LDL gets inernalized but fail to get
recycled.

PATHOLOGY AGAM
10. WILSON’S DISEASE / HEPATOLENTICULAR DEGENERATION
Causes & etiology:
 Autosomal Recessive.
 Mutation of ATP7B Gene (chromosome 13) which encodes transmembrane copper
transporting ATPase protein.
 Mutation results in impaired in copper excretion into bile & failure to incorporate copper
into Ceruloplasmin.
Pathogenesis:
 Normally in Liver copper binds to alpha 2 Globulin (Apo ceruloplasmin) to form
Ceruloplasmin, which is sent into blood. It is affected in Wilson’s disease.
 Accumulated Copper causes Toxic Liver injury by 3 mechanisms
 Promoting the Formation of Free Radicals by FENTON REACTION
 Binding to Sulfhydryl Groups of Cellular Protein
 Displacing other metals from Hepatic metalloenzymes
Morphology:
 FATTY CHANGE (Steatosis)
 May be mild to moderate with Focal hepatocyte Necrosis
 Acute Fulminant Hepatitis mimic Acute Viral Hepatitis
 Chronic Hepatitis in Wilson’s Exhibits – Inflammation, Hepatocytes Necrosis,
Fatty Change, Features of Steatohepatitis (Mallory-Denk bodies)
 Toxic injury to the brain primarily affects the basal ganglia, particularly
the putamen, which shows atrophy and even cavitation.
Clinical features:
 Liver: cirrhosis, liver failure.
 Brain: movement disorders, dementia, and psychiatric issues.
 Kidney: renal disease.
 Eye: Kayser–Fleischer’s ring, sunflower cataract.
 Blood: Hemolytic anemia.
Diagnosis:
 ↓Serum Ceruloplasmin.
 ↑ Hepatic copper content (most Sensitive & Accurate)
 ↑ Urinary excretion of Copper (most Specific).
Treatment: Copper Chelation therapy with D Penicillamine/Trientine, Zinc Based therapy.

AGAM PATHOLOGY
SHORT ANSWERS:
1. HEREDITARY UNCONJUGATED HYPERBILIRUBINEMIA
DISORDER INHERITANCE DEFECT CLINICAL FEATURES
Criggler-Najjar AR Absence of Fatal in neonatal
Syndrome 1 UGT1A1 activity period.
Criggler-Najjar AD Decreased Generally mild, Occasional
Syndrome 2 UGT1A1 activity Kernicterus.
Gilbert Syndrome AR Decreased Jaundice during Stress
UGT1A1 activity otherwise, Innocuous.

2. MALLORY BODIES:
 Mallory Bodies are usually present as clumped, amorphous, eosinophilic
material in ballooned hepatocytes.
 They are made up of tangled skeins of intermediate filaments such as keratins 8 and 18 in
complex with other proteins such as ubiquitin.
 Seen in: (MNEMONIC: New Indian WATCH)
 Non-alcoholic fatty liver disease  Tumors of liver
 Indian Childhood Cirrhosis  Cholestasis
 Wilson’s disease  Hepatic/biliary disease
 Alpha1anti trypsin deficiency

3. POST-MORTEM CHANGES OF CIRRHOSIS OF LIVER.

 Softened and flabby-12 to 24 hours in summer
 Multiple blisters- 24 to 36 hours
 Cl.Welchii form characteristic small clumps in tissue space and produce gas
 Small, opaque, yellowish-grey, dendritic figures in parenchyma
 Honeycombed appearance
 Putrefaction crystals (composed of tyrosine and leucine) on surface of liver
 Colour changes:
 Deep blue- passive congestion
 Green-oozing of bile from gall bladder
 Blue-black- in subcapsular area, pigment from adjacent loop of intestine
 Green a few hours after- jaundice, pigment oxidised to biliverdin
 In advanced putrefaction- liver becomes green or black

PATHOLOGY AGAM
UPDATES
1. SINUSOIDAL CAPILLARISATION:
 If the injury and inflammatory stimuli persist, ECM deposition and scarring commence,
often in the space of Disse; there is concurrent loss of sinusoidal endothelial cell
fenestration, a change termed sinusoidal capillarization.
 It is a particularly prominent feature in nonalcoholic steatohepatitis and also is a feature
of the abnormal sinusoids seen in hepatocellular carcinoma.

2. INCOMPLETE SEPTAL CIRRHOSIS

 If the chronic injury leading to scar formation is interrupted (e.g., clearance of hepatitis
virus infection or cessation of alcohol use), then stellate cell activation and scarring ceases
and fibrous septae may begin to be broken down by metalloproteinases produced by
hepatocytes, leading to partial resolution and an appearance termed incomplete septal
cirrhosis.
 vascular remodeling and other architectural changes that occur in cirrhosis may not
revert to normal
 Vascular abnormalities such as portal hypertension fail to improve in some patients.

3. PATHOGENESIS OF ACUTE LIVER FAILURE

 Triggering event for acute liver failure is hypothesized to be portal hypertension and 2o ↑
production of vasodilators such as nitric oxide by endothelial cells in the splanchnic
vasculature.
 This in turn leads to systemic vasodilation and diminished renal perfusion, which is sensed
by the kidney, provoking activation of the renin/angiotensin axis.
 In the setting of portal hypertension and persistent vasodilator production, the principal
effect of renin/ angiotensin activation is to further diminish renal perfusion and
glomerular filtration rate, leading to renal failure.
 The decline in renal function is reversible if liver function is restored, for example, by liver
transplantation

4. VIRAL HEPATITIS-C PROTEINS

 Two envelope proteins, E1 and E2, and five core proteins: p7, NS2, NS3/4a (protease),
NS5A (replication complex), and NS5B (RNA polymerase).

AGAM PATHOLOGY
5. AUTOIMMUNE HEPATITIS
 Autoimmune hepatitis has a strong association with specific HLA alleles in Caucasians
(DR3), Japanese (DR4), and in South Americans (DRB1).
 Proposed triggers for the immune reaction include viral infections, drugs/toxins, and
vaccination
Morphology:
 Extensive inflammation and hepatocellular injury at the interface, as well as in the hepatic
parenchyma, is characteristic of autoimmune hepatitis.
 Lymphocytes and plasma cells may be seen within the cytoplasm of hepatocytes, often at
the interface, a curious phenomenon called emperipolesis.
Type of necrosis seen:
 confluent necrosis
 Panacinar necrosis
 Bridging necrosis
 “rosettes,” a circular arrangement of hepatocytes around a dilated canaliculus

6. MC TYPE OF DRUG INDUCED HEPATITIS-

 Idiosyncratic reactions are the most common form of drug-induced liver injury and usually
occur after 1 to 3 months of exposure
 Metabolism of isoniazid (an antituberculous agent) is slow in individuals
 Variant of N-acetyltransferase (NAT2) with decreased enzymatic activity, raising drug
levels in the liver and leading to susceptibility to isoniazid hepatotoxicity. Antimicrobial
drugs are the most common culprits in idiosyncratic reactions, accounting for nearly one-
half of cases
 N-acetyl_P-benzquinone immine (NAPQI), produced by the cytochrome P-450 system.
Pericentral zone 3 hepatocytes are most sensitive to NAPQI,

7. LIVER ENZYME ROLE IN DIAGNOSIS OF DRUG INDUCED HEAPATITIS:

Liver enzyme tests can be used to gauge whether the injury is primarily
 Hepatocellular (alanine aminotransferase [ALT] ≥5 times the upper limit of normal, or
ALT/alkaline phosphatase [ALP] ratio >5),
 Cholestatic (ALP ≥2 times the upper limit of normal, or ALT/ALP ratio <2), or
 Mixed (increased ALT and ALP with ALT/ALP ratio between 2 and 5)

PATHOLOGY AGAM
8. MORPHOLOGY OF DRUG AND TOXIN INCLUDED LIVER INJURY
 Idiosyncratic reactions show typical features of acute hepatitis dominated by
inflammation and varying degrees of necrosis.
 centrizonal necrosis is a common feature.
 Injury caused by intrinsic hepatotoxins is dominated by necrosis with minimal
inflammation. Injury centered on bile ducts is characterized by varying combinations of
cholestasis and ductular reactions, which can progress to chronic cholestasis and duct
“dropout” in a minority of cases
 Drugs like- amiodarone (antiarrhythmic), tamoxifen (anti-estrogen), irinotecan
(antineoplastic), methotrexate (immunosuppressive) can cause a steatohepatitis-like
pattern of injury.
 Mitochondrial dysfunction caused by drugs such as tetracycline (antibiotic), valproic acid
(anticonvulsant), zidovudine (antiretroviral) can result in microvesicular steatosis.
 Endothelial injury to sinusoids and central veins can be caused by cytotoxic agents
(azathioprine, oxaliplatin), leading to sinusoidal obstruction syndrome.

9. NONALCOHOLIC FATTY LIVER DISEASE-

Pathogenesis-
 Complex associations with genetic variants, diet, and the intestinal microbiome
established association between increased gut-derived endotoxin production and liver
inflammation and injury.
 High-fructose diets have also been associated with increased risk of NAFLD-related
fibrosis, and dietary fat, particularly trans-fat, may have a role in producing liver injury.
 Obstructive sleep apnea, usually occurring in the setting of obesity, has been associated
with disease progression, possibly related to intermittent hypoxia.
 Fibrosis may be accelerated when injury from another liver disease
 Reduced production of the hormone adiponectin from adipocytes, which decreases
oxidation of free fatty acids by skeletal muscle and increases free fatty acid uptake into
hepatocytes
 Hepatocytes in NAFLD down-regulate lipolysis, an alteration that may further contribute
to the accumulation of lipids.
 Lipolysis occurs through a mechanism called lipophagy that closely resembles
macroautophagy, which you will recall is the process by which cells remove excessive or
dysfunctional cellular components and (in times of starvation) generate metabolites for
energy production
AGAM PATHOLOGY
Morphology
 Steatosis (≥5% of hepatocytes), lobular inflammation, and ballooned hepatocytes are
required for its diagnosis.
 Alcoholic hepatitis has on average less steatosis and more ballooned hepatocytes, lobular
inflammation, Mallory hyaline, neutrophilic infiltrates, cholestasis, and obliterated central
veins.
 Fibrosis typically develops around the central vein as a fine “spider web” of pericellular
collagen deposition
 Ballooned hepatocytes may not be present.

10. FATTY LIVER DISEASE

 Hepatic steatosis (fatty liver) is an early, predictable effect of alcohol consumption.
 Macroscopically, the fatty liver of chronic alcoholism is enlarged (as heavy as 4 to 6 kg),
soft, yellow, and greasy.
 Macrovesicular steatosis is the predominant form in alcoholic liver disease. An unusual
exception is alcoholic foamy degeneration, a form of microvesicular steatosis sometimes
seen with chronic heavy alcohol use that is associated with endoplasmic reticulum and
mitochondrial damage.
 Ballooned hepatocytes - These are injured, swollen hepatocytes with cleared-out
cytoplasm and cytoskeletal damage,
 Mallory hyaline may reflect a failed attempt to sequester and degrade damaged
cytoplasmic proteins.

11. NEONATAL CHOLESTASIS

Morphology: Inflammation and fibrosis of the hepatic or common bile ducts is the hallmark
of the disease.
Diagnosis-
 The combination of clinical presentation, imaging (ultrasound and hepatospecific
iminodiacetic-acid [HIDA] scans), and biopsy can confirm the diagnosis in a vast majority
of cases.
 Ultrasound findings of a small or absent gallbladder and fibrosis at the porta hepatis
support the diagnosis of extrahepatic biliary atresia, as do HIDA scans with technetium-
99m (99mTc), which is excreted in bile.
 In extrahepatic biliary atresia, there is total lack of secretion of 99mTc into the bile, and
the biliary tree is not visualized.
PATHOLOGY AGAM
13. NONOBSTRUCTIVE NEONATAL CHOLESTASIS-
Causes
 Loss-of-function mutations JAG1 or the receptor NOTCH2, both of which are required for
normal development of the biliary tree.
 Certain inborn errors of metabolism, particularly galactosemia& Niemann-Pick disease
 Nonsyndromic causes of nonobstructive cholestasis include α1-antitrypsin deficiency
Morphology
 Decreased numbers of bile ducts within portal regions profiles is the most characteristic
and constant feature.
 The most striking features are hepatocanalicular cholestasis and giant-cell or syncytial
cell change with multinucleated hepatocytes

14. CHRONIC CHOLECYSTITIS

 Morphology: There is complete replacement of the gallbladder wall and mucosa by
dense fibrosis (hyalinizing cholecystitis), with or without calcification.
 Other rare forms of chronic cholecystitis include IgG4-related sclerosing cholecystitis,
another manifestation of IgG4-related fibrosing disease.
3

15. MUTATION SEEN IN CHOLANGIOCARINOMA

 KRAS mutations are common in both tumors.
 Intrahepatic cholangiocarcinoma have distinctive driver mutations in IDH1 and IDH2
(isocitrate dehydrogenase) that generate “oncometabolites”
 Fusion genes involving FGFR2 (fibroblast growth factor receptor 2) are also common.
 By contrast, in addition to KRAS mutations, extrahepatic biliary adenocarcinomas are
most likely to have mutations in TP53 and SMAD4, genetic features that are similar to
those of pancreatic adenocarcinoma.

16. PRIMARY SCLEROSING CHOLANGITIS

 The gold standard for diagnosis is the characteristic “beading” seen in the large
intrahepatic & extrahepatic biliary tree seen in ERCP/MRCP, involving attributable to
irregular biliary strictures and dilations
 Inflammatory bowel disease, particularly ulcerative colitis, affects approximately 70% of
individuals with PSC, whereas 8% of inflammatory bowel disease patients develop PSC.
 Mostly in association with inflammatory bowel disease, there is involvement of smaller
bile ducts only and the ERCP/MRCP examination is normal. This is referred to as small-
duct PSC and can progress to typical large-duct PSC.

AGAM PATHOLOGY
17. FOCAL NODULAR HYPERPLASIA:
 Focal nodular hyperplasia (FNH) is a benign, non-neoplastic lesion that is most common in
adult women.
Pathogenesis-
 Altered blood flow that leads to hyperplastic changes in hepatocytes.
 FNH-like nodules can occur adjacent to other tumors and in vascular conditions such as
hemangiomas and Budd-Chiari syndrome.
 Multifocal FNH can occur in a/w hepatic or extrahepatic hemangioma, vascular
malformations, or (curiously) brain tumors, such as meningioma and astrocytoma.
Morphology-
 poorly formed elastic lamina
 A prominent ductular, reaction is often present, but interlobular bile ducts are absent.
 The hepatocytes in the nodules are arranged in one- to two cell-thick plates; cytologic and
architectural atypia is not present.
 Immunohistochemistry for glutamine synthetase (GS), an enzyme normally present in
centrizonal hepatocytes, is very useful for diagnosis.
 In FNH, a highly characteristic “maplike pattern” of strong cytoplasmic GS staining is seen
within anastomosing groups of hepatocyte.
Clinical feature-
 Large regenerative nodules can occur in noncirrhotic liver in vascular conditions such as
Budd-Chiari syndrome, hemangioma, and vascular malformations.
 In some conditions, the entire liver becomes nodular without significant fibrosis, a
condition referred to as nodular regenerative hyperplasia (NRH).
 NRH can lead to portal hypertension and mimic cirrhosis on imaging bile duct adenoma
and biliary hamartoma (von Meyenburg complex).
 Both are asymptomatic and generally less than 2 cm
 Both lesions show haphazard bile ducts in a fibrous stroma, and lack atypical cytologic or
architectural features.
 The ductular profiles in bile duct adenoma tend to be round and nondilated, while those
in biliary hamartoma are dilated, curvilinear and often show inspissated bile or secretions.

BECKWITH WIEDEMANN SYNDROME.

 Caused by abnormal epigenetic imprinting of a region of chromosome 11 →
overexpression of insulin-like growth factor-2 and loss of expression of CDKN1C, a tumor
suppressor gene that encodes the cyclin-dependent kinase inhibitor p57

PATHOLOGY AGAM
ONE LINERS
 Fibropolycystic liver disease often occurs in association with autosomal recessive
polycystic renal disease. Persons with fibropolycystic liver disease are at increased risk for
cholangiocarcinoma
 Rare causes of acute liver failure include abnormalities of blood flow, metabolic disorders,
and malignancies, most commonly leukemia or lymphoma (33%), followed by breast
cancer (30%) and colon cancer (7%).
 The receptor for HAV on hepatocytes is HAVcr-1 (also known as TIM-1), a glycoprotein
that is a member of a family of proteins that serve as receptors for several other viruses
as well.
 HAV is not cytopathic, and the hepatocellular injury is inflicted by cytotoxic T-lymphocytes
and NK cells that recognize and kill hepatocytes infected by the virus.
 Entry of HBV into hepatocytes is enabled by binding of large HbsAg to the bile salt
transporter known as sodium taurocholate cotransporting polypeptide (NTCP)
 The supersaturated cholesterol in bile that forms cholesterol stones may diffuse into the
mucosa and manifest as cholesterolosis
 Resection is recommended for β-catenin–activated tumors as well as tumors 5 cm or
larger due to the risk of hemorrhage and malignant transformation
 Loss-of-function mutations in the HNF1-α gene, which encodes a transcription factor that
regulates many genes in hepatocytes and in pancreatic islets, one of the causes of hepatic
adenoma
 The liver may also be secondarily involved by other infections during pregnancy. These
include hepatitis caused by herpes simplex virus, a rare cause of acute liver failure in
pregnancy, and liver abscess caused by Listeria monocytogenes, an organism that thrives
in placental tissue, from where it may seed the liver
 Fibrolamellar HCC: One unusual histologic subtype that often occurs in adolescents and
young adults in the absence of preexisting liver disease, fibrolamellar HCC, is strongly
associated with a fusion gene that leads to aberrant activity of protein kinase A, an
enzyme that participates in a signaling pathway regulated by cAMP.
 Adenocarcinomas arising from the intrahepatic biliary tree are referred to as intrahepatic
cholangiocarcinoma, while similar tumor arising from the extrahepatic bile ducts are
referred to as biliary adenocarcinoma.
 Intrahepatic cholangiocarcinoma is the most common primary malignant tumor of the
liver after HCC.

AGAM PATHOLOGY
 Microscopically, gallbladder carcinoma are usually characterized by the presence of
glands embedded in desmoplastic stroma, but in some cases cytologic atypia and stromal
response are minimal; in these instances, identification of perineural and vascular
invasion help establish the diagnosis.
 Alagille syndrome is an autosomal dominant disorder associated with cholestasis and
paucity of bile ducts as well as other abnormalities such as dysmorphic facies, butterfly-
shaped vertebra, eye defects, and cardiac defects.
 Dubin-Johnson syndrome is caused by mutation in the MRP2 gene (multidrug resistant
protein 2), which is required for transport of non–bile salt organic anions at the
canalicular membranes. Deposition of brown-black melanin-like pigment in the
hepatocytes is a striking feature in this disease and can lead to blackening of the liver.
 The hallmark on liver biopsies in hereditary hyperbilirubinemia is portal expansion due to
edema, prominent ductular reaction at the portal-parenchymal interface, and infiltrating
neutrophils associated with ductules (“pericholangitis”)
 In ascending cholangitis, the neutrophils also involve the bile duct epithelium and lumens.
Persistent obstruction leads to fibrosis, which can eventually proceed to biliary cirrhosis
 Levels of UGT1A1 (uridine diphosphate-glucuronyl transferase family, peptide A1), the
enzyme that is responsible for bilirubin glucuronidation, are low at birth and do not reach
adult levels until 3 to 4 months of age
 In most infants, phototherapy with blue light (which converts bilirubin to a soluble isomer
that is readily excreted in the urine) is sufficient to keep the levels of unconjugated
bilirubin within a safe range until the hepatic machinery for conjugation
 Erythroferrone released from an expanded population of erythroid progenitors in the
bone marrow suppress hepcidin production by the liver, leading to increased iron
absorption causing hemochromatosis
 Transporter proteins examples: MRP2 (multidrugresistant protein-2) for conjugated
bilirubin, bile salt export pump (BSEP) for bile salts, MDR3 (multi-drug resistance-3) for
phosphatidylcholine, and sterolins 1 and 2 for cholesterol
 Consequence of hepatocellular accumulation of the misfolded protein in ∝1-Antitrypsin
Deficiency is an example of a “toxic gain-of-function” mutation
 Toll-like receptor 4. Toll-like receptor signaling triggers the release of cytokines and
chemokines, which may contribute to the inflammation that accompanies alcoholic liver
disease.

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