Pathology of Biliary Disorders.

Cognito
ergo sum.
…I think, therefore I am…!
- -Rene Descartes

MB4-T2-Wk4-Biliary system
CPC 4.2.3
 Professionalism & Ethics - of out of office consultations..
 Abdominal problems…DD
 Counseling, SNAP & five A‟s…
 Upper abdominal discomfort with bloating & wind.
 after meal burps, stomach feels full & windy. ? worsening.
 Duration Symptoms for many months.
 Relation to food/fat Yes, makes it worse.
 Pain 3-4/10, ill defined, cramping.
 Nausea occasional, no vomiting.
 Wt loss, Anorexia, Dysphagia  No
 Bowel habit constipation, No pus, blood PR.
 Diet usually eats once a day, often fast foods. Little fruits &
veggies. Lots of coffee*
2
CASE STUDY:
Mrs. L.K is your eldest son’s high school teacher. You attend the parent-teacher interview to
discuss his school work and she asks for advice about her abdominal problems. You advise her to
see you at your rooms in the morning. She is 32 years old and married to a local police officer.

CPC 4.2.3
 Alchohol 2-3 glasses of wines/night. 12-15 on
weekends, more when friends. (Hepatitis, pancreatitis, gall
stones)
 Family: Married to an accountant, no children but has 3
lap dogs. (hydatid dis, echinococcosis.)
 MedicationShe is on COCP, (Budd-Chiari sy)
 PSH: Tonsillectomy & adenoidectomy at 5 years,
appendicectomy at 14y. (Viral Hepatitis)
3

Investigations
 Upper abdominal USS – numerous gallstones in thick-
walled gallbladder
 LFT – elevated GGT*, Alk Phos normal*…?
 Fasting glucose- 7.0 mmol/l
 Lipid profile - Total Chol 7.2, Trig. 2.8, HDL 2.0, LDL-
5.1.
 Rectal examination – Hard stool in the rectum, no
hemorrhoids or fissures.
4

CPC 4.2.3: DD – commonest first.
 Gastritis
 Peptic ulcer
 Liver disease..
 Fatty liver *
 Gallstones,
 Cholecystitis.
 Constipation *
 Irritable bowel syndrome
 Diverticulosis / Diverticulitis
 Pancreatitis - chronic
 Any thing else ??
5
Major Learning Issues:
• Gall stones
• Cholecystitis Acute/Chronic
• Pancreatitis Acute/Chronic
• Pancreatic cancer.
Minor Learning Issues:
• Cholangitis
• Biliary Atresia
• Secondary Biliary Cirrhosis
• Carcinoma of Gallbladder
• Cholangiocarcinoma
(bile duct ca)
• Hemochormatosis,
• Wilson‟s
• & α1AT deficiency

6
HBS:
Common
Clinical Presentations.
Why!

Pathological basis of signs and symptoms
7
Sign or symptom Pathological basis
Jaundice Haemolysis, liver disease or biliary obstruction
Dark urine Conjugated hyperbilirubinaemia (water-soluble)
Pale faeces Biliary obstruction causing lack of bile pigments
Spider naevi Gynaecomastia Secondary to hyperoestrogenism
Oedema Reduced plasma oncotic pressure - hypoalbuminaemia
Xanthelasma Cutaneous lipid deposits  hypercholesterolaemia in
chronic biliary obstruction.
Steatorrhoea Malabsorption of fat - (e.g. biliary obstruction)
Pruritus Biliary obstruction resulting in bile salt accumulation
Ascites Hypoalbuminaemia, portal hypertension and secondary
hyperaldosteronism.
Bruising or bleeding Impaired hepatic synthesis of clotting factors – Vit K.
Hepatomegaly hepatitis, infiltration (fat) or tumour (primary or secondary)
Haematemesis Ruptured oesophageal varices due to portal hypertension
Encephalopathy Failure of liver to remove toxins mimicking or altering
balance of neurotransmitters

Self Assessment Questions:
 most common cause of acute Cholecystitis / cholelithiasis /
pancreatitis?
 Common types & pathogenesis of cholelithiasis?
 Clinical features of acute cholecystitis / cholelithiasis?
 Morphology of acute & Chronic cholecystitis? (gross/micro)
 How obesity causes cholelithiasis?
 Pathogenesis of alcohol induced pancreatitis?
 What is cholestasis? common types? PBC, PSC, neonatal.
 Congenital: Hemochormatosis, Wilson‟s & α1AT deficiency?
 Common type & clinical features of of pancreatic cancer?
 What is primary sclerosing cholangitis? Common causes?
 Hepatocellular carcinoma ? Brief notes, diagnosis, AFP..

Core Learning Issues (CLI):
 Major CLI:
• Cholelithiasis
• Cholecystitis – Acute, Chronic
• Pancreatitis – Acute, Chronic
• Pancreatic carcinoma
 Minor CLI:
• Ca. gall bladder & biliary tract.
• Other parasites, atresia, Autoimmune.
• Congenital: Cystic fibrosis.
• Hemochormatosis, Wilson‟s & α1AT deficiency
• Pancreatic cysts, pseudocyst,
• Other Tumours, carcinoid, MEN Types 1 & 2.
9

Thought is Powerful & Free!
--William Shakespeare
Human mind is the most powerful weapon in the
world.- e.g. Osama bin laden.
Great monuments & Great wars have always started in a human mind…!

Pathology of
Biliary & Pancreatic Disorders
Dr. Shashidhar Venkatesh Murthy
A/Prof. & Head of Pathology
School of Medicine.

Physiology:
 Bile is the main pathway for cholesterol excretion.
 Bile: cholesterol, bile salts & bile pigmint (bilirubin, biliverdin)
 Cholesterol made soluble by bile salts (soap) as micielles
 Excess cholesterol / low bile salt  Stone formation*.

Biliary Obstructions:
 Extrahepatic Obstruction:
• Dislodged gallstones
• Ca. CBD, Ca. Head of pancreas.
• inflammatory stricture of CBD
• accidental surgical ligation of CBD.
 Intrahepatic Obstruction:
• Biliary atresia – Congenital.
• Primary Biliary Cirrhosis
• Primary Sclerosing Cholangitis.
• Cystic fibrosis.
Common Disorders:
• Cholecystitis
• Cholelithiasis
• Choledocholithiasis.
(Adeno Carcinoma)
95% - Cholelithiasis (+cystitis)

Cholelithiasis:
 Cholelithiasis/gall stones – 95% of GB dis.
 Incidence: West 20-40%, Asian 2-4%.
 70-80% asymptomatic
 Mixed 80% - (cholesterol, ca+, bile, blood)
 Pure 20% - Pigment *, Cholesterol.
 Severe colicky Upper abdomen  Rt shoulder.
 Conjugated hyperbilirubinemia  Obstruction.
 Fat intolerance  clay stools - typical in chronic.

Risk Factors: Cholelithiasis
Cholesterol Stones:
 Race/Demo: Western
 Age Middle/late.
 Excess Cholesterol
• Female sex
• Oral contraceptives
• Pregnancy
• Obesity
• Rapid weight reduction
• Gallbladder stasis
• Disorders of bile acid
metabolism
• Hyperlipidemia syndromes
Pigment Stones:
 Race – Asians
 Age: early
 Jaundice / Infections
• Hemolysis syndromes
• Biliary infections
• Inflammatory bowel
disorders.
• Ileal resection or bypass.
• Cystic fibrosis
• Chronic Pancreatitis.
80% Idiopathic.
75% in American Pima race.

Cholelithiasis:
Crystallization of bile within biliary system.
 Risk factors:
• female gender, obesity, diabetes mellitus (FFFF…!)
 Pathogenesis:
 Cholesterol is made soluble by bile salts and lecithins.
 More cholesterol or less bile salts  chol. Monohydrate
crystals  stone.
 Etiologic factors.
• Supersaturation – excess Cholesterol – crystals.
• Calcium Microprecipitation - Nucleation.
• Stasis - Mucous  trap crystals – aggregation
• Stone growth environment: infection, stasis, etc.

Cholelithiasis:
 Morphology & Types:
• Mixed Chol (Ca+Bile salt)* Multiple,
faceted, yellow-grey.
• Rarely Pure cholesterol: Round spiky.
• Bile Pigment stones (black/brown).
Infection / Jaundice. % Calcium = radio
opaque.

Gallstones + Chronic Cholecystitis

Cholesterol (Pure) Gallstones, bleeding.
20
Round, yellow, spiky, bleeding. Note thickened inflammed gall bladder.

Cholecystitis + gall stones  Abscess.
21
Pigment stones in Infection: Inflammed, thickened gall
bladder filled with pus & black gall stones.
Small stone is seen obstructing neck  acute pain.
Adherent Omentum
Pus & Stones (black)
Stone in the neck
UNSW Museum
Pigment stones in
Hemolysis - Bilirubin

Gall stones in CBD
Stones in CBD
Stonees in GB
20% of mixed chol. stones and >50% of pigment stones are radio-opaque

Complications of Cholelithiasis:
 Obstruction
 Sec biliary cirrhosis*
 Cholecystitis
 Cholangitis
 Biliary colic
 Jaundice
 Empyema
 Liver abscess
 Mucocele
 Pancreatitis.
 Peritonitis
 Carcinoma
 Fistula formation
 Gall stone ileus.
Gallstone ileus

It is not enough to have a good mind;
the main thing is to use it well…!
- -Rene Descartes

Acute Cholecystitis:
 90% Cholelithiasis. 10% non-calculous
 Females common.
 Outflow obstruction by a small gallstone.
 Infection – E.coli.  Empyema.
 Risk of perforation, peritonitis, fistula
 Gall stone ileus when stone enters GIT.
 Serum amylase normal (high with pancreatitis).
 Mild jaundice in 20% - obstructive.
 Acute inflammation, hemorrhage, edema, neutrophils.
 Gangrenous cholecystitis: when obstruction is severe
compromising blood supply. Green-black necrotic.

Chronic Cholecystitis:
 Females.
 Recurrent / Chronic.
 Thick fibrotic wall.
 Thick bile – biliary gravel.
 Aschoff-Rokitansky sinuses –
diverticula - Due to increased
luminal pressure (obstruction)
 Diffuse infiltration by chronic
inflammatory cells.

What we think,
we become!
--Buddha

Neoplastic Disorders: (rare)
 Benign tumours:
• Bile duct adenoma, cystadenoma
 Malignant tumours:
• Adenocarcinoma Ducts lined by cuboidal to
columnar mucin secreting cells separated by
desmoplastic (fibrotic) stroma.
• Cholangiocarcinoma (Bile duct carcinoma)
• Presents with Jaundice.
• Early spread with very poor prognosis.

Carcinoma Gallbladder:
 Females , Hispanics.
 Mexico & Chile
 5th-7th decade
 Common – Lithiasis *
 abdominal pain, anorexia, High ALP.
 Commonly Adenocarcinoma
 Late diagnosis
 Poor prognosis.
 5% 5 year survival.

Ca Bile duct: Cholangiocarcinoma:
 Adeno Carcinoma of
cholangiocytes.
 Thoratrast exposure?
 Increased incidence in
ulcerative colitis.
 Presents with obstructive
jaundice – early diagnosis.
 Intrahepatic or extrahepatic.
 Increasing incidence. ? toxin

31
Living becomes a glorious experience
only when there is tolerance and love.
Willingness to compromise with other
people’s ways of living and
cooperation. These make happy and
successful societies.
-- Baba.

32
CPC 4.2.4 – HBS – Part 2
2 weeks later she present again to your GP practice.
-Worsening abdominal pain - „The worst I ever had-It’s
terrible, please do something’
 Central, severe 9/10 constant, radiates to back. > 12
hours.
 Associated with vomiting x 3 this morning. No
haematemesis.
 Bowels opened yesterday no blood mucus. Hasn‟t
passed urine in 8 hours. Doesn‟t feel like drinking or
eating.
 „I just want to lie here- Don’t make me move’
 No Pale stools / dark urine. Hasn‟t passed urine since
this morning.

History & Examination:
 Abdomen distended, tender. Guarding ++
epigastrium.
 Investigations.
• FBP –WCC↑, Plt 100 10x9
• urea 7.4 mmol/l [2.5-6.6mmol/l]
• decreased eGFR 70 [>90]
• Crea 140umol/l [60-120umol/l]
• LFT glucose 7.8, Ca+ Decreased, ALT & GGT ↑↑↑
• Amylase lipase - ↑↑
33
DD: Acute Abdomen, Pancreatitis, perforated peptic
ulcer, appendicitis, diverticulitis,

“Outer world is the reflection of
our inner world (thoughts)”
--Baba

Pathology of
Pancreatic Disorders
Shashidhar Venkatesh Murthy
Assoc. Prof & Head of Pathology

Introduction: Pancreas
 Exocrine & Endocrine gland.
• Develops from two embryonic buds (dorsal & ventral)
• Head, neck & body, Portal circulation*
• Susceptible to Obstruction, ischemia, trauma, toxins.
• Highly destructive “lytic” enzymes
 Disorders:
• Congenital: annular, divisum, ectopic, cysts.
• Acute & Chronic pancreatitis.
• Cysts & Tumors: Adenocarcinoma.
 Diagnosis:
• Serum amylase, lipase & ERCP/MRCP*
• Biopsy is hazardous. – don’t mess with pancreas...!

Anatomy
Histology

Congenital Disorders:
 Pancreatic Divisum:
• Most common 3-10%
• Failure of fetal duct union.
• Congenital chronic
pancreatitis.
 Cystic Fibrosis:
• CFTR gene mutation
– thick secretions.
 Annular Pancreas
• 2nd part duodenum
obstruction.
 Ectopic Pancreas
• stomach and duodenum.

Acute Pancreatitis
 Acute Inflammation of pancreas leading to enzymatic
autodigestion & Hemorrhage, fat necrosis of surrounding
tissue with systemic effects & multiorgan failure.
 Release & activation of pancreatic enzymes. Defective
inactivation of trypsin.
 Common Etiology Alcohol & Gall stones (& Idiopathic).
 Trauma, Viral infection, Hyperlipidemia, hypercalcemia,
shock, trauma, drugs, infections, snake bite – rare causes.
 Autoimmune disorders  immune pancreatitis.
 Blacks 10 times common than other races *
 Outcome: Heal, complications or chronic.

Acute Pancreatitis:
Pathogenesis of clinical features:
SUMMARY:
Trypsin  Kallikrein  Thrombosis - Necrosis
Protease  Blood Vessel injury – Bleeding.
Lipase  Fat necrosis  Inflammation.

Grey Turner Sign - Cullen‟s Sign
Severe
Mild

Acute Pancreatitis:
a: The pancreas edematous
and hemorrhagic (H). Pancreatic
tissue becomes necrotic and
may become semi-liquid.
b: fat necrosis seen as white
spots (F) in mesenteric and
retroperitoneal fat.
Histologically these foci are
composed of necrotic adipose
tissue, with adjacent reactive
inflammation.

Acute
Pancreatitis:
K K
Hemorrhage in the
head of Pancreas with
edema.
CT Scan appearance

Acute
Pancreatitis:
L K K
Hemorrhage in the
head of Pancreas with
edema.
CT Scan appearance
A-Stomach
B-Spleen
C-Peritoneum
D-Pancreas

Acute Hemorrhagic Pancreatitis:
Head

Acute Hemorrhagic Pancreatitis:
Fat Necrosis
Acini Necrosis
Hemorrhage
Normal Acini

Acute Pancreatitis: Complications
Pancreatic cancer

At the center of your being you
have the answer; you know
who you are and you know
what you want!
Lao Tzu

CPC 2.7- Mr J.M. 51y, depression.
 Mr J.M. 51 year old High School principal in
Townsville.
 Several months - stress, anxiety and depression.
 Treatment for this with anti depressants and
cognitive behavior therapy has been reasonably
successful although he remains stressed.
 makes an earlier appointment.
 „His trousers are hanging off him. No appetite. my
ankles have been a bit swollen recently.
 Could not walk…. Too tired…!
 Epigastric intermittent pain.
 „Bit dark urine … recently‟

Chronic Pancreatitis:
 Clinical:
• Painful, relapsing, inflammation, fibrosis & exocrine atrophy.
Cystic/atrophic ducts.
• Irreversible loss of pancreatic function *
• Malabsorption, albumin, wt. loss – Exocrine
• Type I DM – Endocrine loss.
• Recurrent obstructive Jaundice – obstruction.
 Causes:
• Toxic metabolic- 70%: Alcohol, Hyperlipidaemia, toxins, drugs,
hypercalcaemia.
• Idiopathic-20%: Early/Late.
• Others: Genetic, autoimmune, Post necrotic.
 Complications:
• Pseudocyst, Calcification, lithiasis & Carcinoma.

Chronic fibrosing Pancreatitis:
Duodenum
Fibrosis
pancreas (P) is atrophic and replaced by rubbery, fibrous tissue, in which dilated
ducts (D) are seen (Clinically by ERCP). In many cases calculi are present in the
dilated ducts. In this example the duodenum is attached (A).

Chronic Pancreatitis
Atrophy, Fibrosis, Calcification
The pancreas is shrunken and fibrotic. The main duct
is dilated and filled with calcified secretions (arrows).

Dilated Ducts
Islets (endocrine)
Fibrosis
Note: Fibrosis replacing exocrine glands. 0nly ducts & Islets remain in late stage.
Inflam

Chronic Pancreatitis: Complications

Chronic Pancreatitis- Pseuocyst

Control your senses and you are
beyond trouble.
Let them loose and you are
beyond help…!
- - Lao Tzu

Pancreatic tumours:
 Cysts:
• True cysts
• Polycystic diseases, MEN syndromes:
• Von-hippel-lindau disease.
 Adenoma:
• Cystadenoma
• Endocrine - Insulinoma, gastrinoma etc.
 Carcinoma:
• Adenocarcinoma – common.
60

Pancreatic Cancer
 Increasing in incidence.
 4th common (next to Colon Ca).
 10-15 per 100 000, more with age >70y.
 Men are affected twice as often as women.
 Unknown etiology,
 Several Risk factors Smoking, Diabetes & Diet.
• High calorie, fat, meat, salt, fried, soy beans & nitrosamines.
 Also increased incidence in Hereditary pancreatitis,
MEN, hereditary non-polyposis colon cancer-HNPCC.

Pancreatic Cancer
 Adenocarcinoma fibrosis stricture, Obstructive
jaundice & weight loss.
 Advanced disease at presentation. Poor
prognosis. 85% only palliative care.
 Palpable gallbladder + jaundice  Ca Pan
(Courvoisier's sign).
 diabetes (due to ß cell destruction)
 Depression*,
 Migratory thrombophlebitis - Trousseau's

Ca. Pancreas : Pathogenesis

Pancreatic Cancer
Tumor
Head
Body Tail

Pancreatic Ca with fibrosis (Chronic pancreatitis)
Note: dysplastic glands infiltrating into fibro (spindle cells) myxoid (pale blue) stroma.
Malignant gl.
Ca. Infiltration
Islet (normal)
Fibrous stroma

Ca Pancreas
Clinical Features
Tumour marker:
CEA & CA19–9 antigen
Trousseau syndrome

Ca Pancreas & Depression
 Cancer pancreas has a reputation of being a deadly and
often painful disease, with very poor prognosis.
 Depression and anxiety occur more frequently
 Depression and anxiety may even precede symptoms or
knowledge of the diagnosis.
 The etiology of depression in patients with cancer of the
pancreas may be traced to more than the disease's
symptoms.
Steve Jobs

A scholar who cherishes the
love of comfort is not fit to be
deemed a scholar.
Lao Tzu

Give someone a fish and you
feed him for a day.
Teach someone to fish and you
feed him for a lifetime!
Lao Tzu

Acute Pancreatitis: Summary
 Gross: Inflammation,
Hemorrhages (red arrows)
and chalky white areas of fat
necrosis (white arrows).
 Microscopy: Hemorrhage,
Acute inflam, fat necrosis.
 Complications:
Mechanisms: Obstruction, Acinar damage, Enzyme anomaly.
Pathogenesis: Activation of enzymes in the acini/ducts 
autodigestion  Fat necrosis  Ca+ soap + inflammation.

Cholesterolosis of gallbladder mucosa
Cholesterol filled Foamy
macrophages in mucosal
folds

To attain knowledge, add
things every day.
To attain wisdom, remove
things every day.
Lao Tzu

5 A‟s & SNAP
74
• Ask: 1. patients with diabetes, hypertension,
hyperlidaemia, obesity or existing vascular disease
• Assess: 2.Number of cigarettes or equivalent/day,
Dependance 3.readiness to change/motivation
• Advise: 4.provide written information, 5.motivational
interviewing
• Assist: 6.NRT ? Bupropion(Zyban) 7.Support
• Arrange: 8.referral to QUIT 9.follow up with the GP
SNAP Counseling: Smoking, Nutrition, Alcohol &
Physical Activity.

Acute Pancreatitis: Clinical Features
 Mild (edema) & Severe (Hemorrhagic) forms.
 Constant severe epigastric pain radiating to the back
 Fever, Nausea and/or vomiting
 Respiratory & circulatory failure
 DIC, Shock, Fat necrosis, hemorrhage.
 Abdominal tenderness, distension, guarding, and rigidity,
Mild jaundice,
 Diminished or absent bowel sounds.
 Hypocalcemia, High Amylase-P (early)
 High Lipase >24h – (only lipase ↑ in chronic)
 CT Scan – diagnostic.
 ? Grey Turner‟s sign ? Cullen‟s sign

“acute abdomen” Differential Diagnosis:
 Acute Pancreatitis: medical emergency of
the first magnitude.
 Multiorgan failure – fatal.
 Differential diagnosis:
• Perforated acute appendicitis.
• Perforated Acute diverticulitis.
• Perforated peptic ulcer.
• Acute cholecystitis & Rupture.
• Infarction of the bowel.
• Intestinal Obstruction.

Acute Pancreatitis: Principles of Lab Diagnosis:
 Full blood count: neutrophil leukocytosis.
 Serum amylase: greatly elevated.
 Serum Lipase: Elevated after 24h. (72-96h)
 Serum albumin: falls (severe inflam. Exud)
 Serum calcium: falls - Complex with necrotic Fat.
 Blood sugar: hyperglycemia if severe – loss of
endocrine part.
 Alkaline phosphatase: mild elevation obstruction of
lower end of bile duct (gall stone)
 Bilirubin: mild direct Bil, oedema & obstruction of lower
end of bile duct.

CPC 4.2.7- May, 35y woman.
 May, 35y, indigenous woman, lives in a remote
Aboriginal community. After hour visit…
 “I’ve got terrible gut pains”, since 2h.
 Students must specifically ask about…?
 Alcohol, DM.. (PUD, IHD, Gall bl, Drugs)
 Tenderness & guarding in epigastrium.
 Absent bowel sounds.
 Social & family History of alcohol abuse.
 Diabetes not well controlled.

CPC 4.2.7- May, 35y woman.
 Differential diagnosis
 Perforated ulcer, Acute Gastro-enteritis,
/infarction, pancreatitis, gall bladder
disease, peptic ulcer.
• Heart – MI
• Lung – pleurisy, PE,
 FBC (Hb 132, WCC 21.9), RFT (Na 136,
urea 6.1, creatinine 0.07, Ca 1.8)
 AXR, USG, CXR, ECG, Lipase- 2400 U/L
 Amylase* lipase *

Pancreatic Cancer
Pleomorphic glands (A) in a densely
fibrotic (desmoplastic) stroma (B)
Section of head of pancreas showing
an ill-defined mass in the pancreatic
substance (arrowheads) and the green
discoloration of the CBD due to
obstruction of bile flow
A
B

Silence…
81
To the question "Who am I?" the only relevant answer is silence. You
need to discard all answers in words, including "I am Nothing" or "I
am the Cosmic Self" or "I am the Self" - and just stick to the question
"Who am I?". All other answers are just thoughts. Thoughts can
never be complete. Only Silence is complete.
Thoughts are not the goal in themselves. Their goal is Silence. When
you ask the question "Who am I?" you get no answer, there is
silence. That is the real answer. For your soul is solidified silence.
This solidified silence is wisdom, is knowledge.
The easy way to silence the thoughts is to arouse the feelings. For,
through feelings only peace, joy and love dawn. And they are all
your very nature.
- Sri Sri Ravishankar

Pathology of Biliary Disorders.

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