Dr.

Dilip MMS
GIT & HEPATOLOGY
 Table Of Content
SL NO. CHAPTER PAGE NO.

I GASTROINTESTINAL TRACT

1 Esophagus 10

2 Diarrhoea and Malabsorption 34

3 IBD 73

4 IBS, Colonic Polyps and Colon Cancer 91

II HEPATOLOGY

1 Introduction to Hepatology 125

2 Congenital causes of Hyperbilirubinemia 140

3 ALF, Paracetamol poisoning and Cirrhosis 145

4 Variceal Bleeding & Introduction to Viral Hepatitis 160

5 Alcoholic liver disease, NAFLD and Auto-immune Liver disease 194

6 Portal Hypertension 203

7 Metabolic Liver Disease 228

8 Tumors of the liver 245

 9

GASTRO INTESTINAL TRACT

 10

Esophagus
GERD
GE NERD (Non-Erosive Reflux Disease) 50 ~ 70%
RD
ERD (Erosive Reflux Disease) 30 ~ 50%

Pathophysiology
TRLES (Transient Relaxation of Lower Esophageal Sphincter)

Increased due to :
Mucosal damage i. Idiopathic
/

Decreases quality of life ii. Life style

iii. Drugs
(a) Barbiturates
Strictures Columnar metaplasia
(b) CCB’s (Eg - Verapamil)
(c) PG E2/ 12 (vasodilators)
Dysplasia (d) Benzodiazepines
(Diazepam)
(e) Nitrates
Adenocarcinoma
(f) Anticholinergic drugs
(Eg - Amitriptyline)
(g) Dopamine antagonists
(Eg - Levodopa)
iv. Tea/ coffee
v. Alcohol
vi. Smoking
- Baclofen (antispasmodic)
decreases TRLES.

Risk factors
i. Hiatus hernia (Because Angle of HIS is lost)
ii. Severe obesity (increased abdominal pressure)
iii. Gastric hypersecretory states (Zollinger syndrome)
iv. Delayed gastric emptying (in diabetes mellitus due to autonomic neuropathy)
 11
v. Drugs
vi. Life style

Precipitating factors
i. Supine position
ii. Fatty foods (delayed gastric emptying)
iii. Caffeine, alcohol
iv. Smoking
v. Pregnancy
vi. CCB

Clinical features
Esophageal symptoms Extra-esophageal symptoms GERD

i. Heart burn i. Chronic cough

ii. Atypical chest pain ii. Asthma Increased vagal
iii. Regurgitation iii. Laryngitis activation
iv. Water brush (increased (Laryngopharyngeal
saliva secretion due to reflux - LPR)
reflex vagal activation) iv. Severe - dental Increased
v. Dysplasia (stricture, erosions cholinergic
cancer) action

Worsen asthma

- Increased risk of development of ILD (due to chemical pneumonitis) (During sleep due
to aspiration of acid causing chemical pneumonitis leads to the risk of developing ILD
later)(Not completely proven)
- Scleroderma patients have severe GERD (Because of low sphincter tone due to fibrosis,
and also have low peristaltic contractions)
- Important risk factor for development of ILD in scleroderma is GERD
 12
Investigations & management
Suspected GERD

(Dysphasia, odynophagia, Age > 75, anemia,

Alarm symptoms weight loss, Family history of GI malignancy)

Yes No

UGI Endoscopy Empirical trial of PPI

+
Life style modifications
Specific diagnosis

Normal
No/ poor Good response
response (in 2 weeks)
24 hr pH monitoring

UGI Endoscopy
Continue PPI for 8 weeks

Maintenance dose of
PPI or H2 blocker

Relapse after discontinuing

or refractory symptoms

UGI Endoscopy
 13
Investigations
i. UGI Endoscopy
- Sensitivity : < 30%
- Specificity : > 95%
ii. 24 hour pH monitoring (DeMeester score - > 14.72)
- Traditional gold standard of investigation
- Probe with the help of endoscope is placed just 5 cm above the gastro-
esophageal junction
- Patient not on PPI : pH < 4 for at least 4% of time (diagnostic cut off)
- Patient on PPI : pH < 4 for at least 1.6% of time (diagnostic cut off)
iii. Barium swallow - not sensitive or specific test
iv. Bernstein test/ acid infusion test (older test)
- Infuse 0.1 N HCl and normal saline
- Symptoms (atypical chest pain) present when infusing 0.1 N HCl and
absent when infusing Normal Saline is diagnostic of GERD
v. Wireless pH capsule (Bravo capsule)
- Without a nasogastric tube, endoscopy is put in with capsule attached to
the probe.

Types
1. Acid Reflux
- Initially pH > 4, during reflux pH < 4
2. Acid Re-reflux
- Already pH < 4, reflux happening on the background of ph < 4
3. Weakly Acidic Reflux
- pH 4 ~ 7
4. Weakly Alkaline Reflux
- Bile reflux, reflux with pH > 7

Scoring systems
i. Savary Miller score
ii. Hetzel Dent score
iii. Los Angeles scoring system (most widely used)
 14
Treatment
i. Life style - elevation of head end while sleeping, avoiding sleeping immediately
after eating, avoiding late meals at night, avoid alcohol at night
ii. Antacids (treats the symptoms)
iii. Acid suppression
- H2 Blockers
- PPI (more effective)
- Minimum therapy duration : 2 weeks
iv. Pro-kinetic agents (increases gastric emptying)
- Metoclopramide
- Domeperidone
v. Baclofen (side effect - heavy sedation)
vi. If treatment fails, surgery
- Fundoplication (in patients with refractory symptoms)
- Nissen’s fundoplication most commonly used surgical procedure
performed for GERD
- An alternative to PPI (In case, the patient does not respond to PPI, then
fundoplication surgery is not performed, those who respond to PPI are the
candidates for fundoplication procedure)
vii. LINX reflux management system
- Anti-relfux device
- Used for mild to moderate GERD
- Used in the absence of hiatus hernia.

- Nissen’s fundoplication - 360° wrap (Complete wrap)

- Toupet fundoplication - 270° wrap
- Dor Anterior fundoplication - 180° wrap
- Watson Anterior fundoplication - 90° wrap

Complications of GERD
i. Stricture
ii. Dysplasia - Adenocarcinoma (Barrett’s esophagus
is a precursor of esophageal cancer)
iii. Bleeding - Anaemia
iv. Esophageal rings
- B rings (Schatzki rings) - most common.
 15
Barrett’s esophagus

Long standing reflux

Metaplasia (intestinal metaplasia)

(Reversible)
Dysplasia
Columnar epithelium and goblet cells (Partially reversible)

Adenocarcinoma
(Irreversible)
- British guidelines : Barrett’s esophagus = columnar epithelium (± goblet cells)
:- American guidelines : Barrett’s esophagus = columnar epithelium + goblet cells
Pathology
- Transformation of squamous epithelium to columnar epithelium
- Barrett’s mucosa on endoscopy appears salmon in color

Barrett’s esophagus
(Based on pathology - length)

Short segment Barrett’s esophagus Long segment Barrett’s esophagus

i. Less than 3 cm i. More than 3 cm
ii. Between GEJ and Z line (place ii. Between GEJ and Z line (place
where transformation occurs) where transformation occurs)

Prague Classification
- C classification (circumferential extent)
- M (proximal extent)
- More the area of barrett’s including
circumferential area, more is the risk of
cancer/ dysplasia.
 16
Complication
- Adenocarcinoma (common in lower parts of esophagus)
(Squamous carcinoma is common in upper part of esophagus)
- Common in females

Management of barrett’s esophagus

Non-dysplastic barrett’s Dysplastic barrett’s
(No dysplasia)
Grade of dysplaisa
Repeat endoscopy in
3 ~ 5 years Low grade High grade

Repeat endoscopy i. Endoscopic surveillance

in 12 months in < 3 ~ 6 months
ii. Treatment - better
(Level C evidence)

Treatment

Type of dysplasia

Flat dysplasia Nodular dysplasia

Endoscopic EMR (Endoscopic

radiofrquency mucosal resection)
ablation

- Gold standard treatment : Esophagectomy (highest rate of avoiding malignancy)

7

- High complications with high mortality associated

- Not done
 17

Dysphagia
Dysphagia

Difficulty initiating swallow

Sensation of food
Regurgitation (nose)
being stuck
Dysarthria

Oropharyngeal Esophageal
dysphagia cause of
dysphagia
Reason : stroke (MC)

Clinical evaluation

± Barium swallow
± ENT evaluation
± Endoscopy

Structural disorder Neuromuscular disorder

i. Oral cancer i. Stroke (most common)
ii. Zenker’s diverticulum ii. Parkinson’s disease
iii. Post neck irradiation iii. ALS
iv. Myopathies
v. GBS
 18

Esophageal
cause of
dysphagia

Endoscopy
± Barium swallow

Abnormal Normal

Inflammatory Structural
Esophageal Manometry
cause cause
(Mechanical
obstruction) Normal Abnormal
Esophagitis
Including Dysphagia
infective for solids > Motility disorder
esophagitis liquids

Progressive Intermittent
symptoms symptoms
i. Peptic stricture i. Rings
ii. Esophageal cancer ii. Webs
iii. Eosinophilic
Esophagitis
 19

Motility disorder

Intermittent Progressive Progressive

symptoms symptoms symptoms
Esophageal spasm without GERD with GERD
Nut cracker esophagus Achalasia Scleroderma
Jack hammer esophagus Rare causes : Diabetes mellitus
Amyloidosis

Zenker’s diverticulum Killian jamieson diverticulum

Weak point : Killians dehiscence
(between thyropharyngeus
and cricopharyngeus muscles
of the inferior pharyngeal
constrictor in the posterior part
of pharynx)
Direction of : Posterio-inferior out
the pouch pouching (lateral X ray taken).
Killian jamieson space
(congenital weak part in the cervical
part of esophagus below the
cricopharyngeus)
Antero-lateral outpouching
(AP view in barium swallow)
 20

Cricopharyngeus

Achalasia

i. Rare disease seen commonly in males

ii. Two types :
- Primary (Idiopathic)
- Secondary (pseudo achalasia)
iii. Most common neuromuscular disorder of esophagus

Primary achalasia
i. Probably due to viral illness (HSV 1)
ii. Results in loss of myenteric neurons that produce NO, VIP in lower
esophageal sphincter further resulting in loss of peristalsis and results
in achalasia
iii. Occurs in younger patients (35 ~ 60 years)
 21

Secondary achalasia
i. Due to cancers (GE junction tumors), chaga’s disease
(travel history to South America required)
ii. Occurs in > 60 year olds

iv. Clinical features (primary achalasia) : triad

Weight loss

Dysphagia Regurgitation
- Insidious onset dysphagia
- Slow progression (over the years)
- Neuromuscular dysphagia
- Difficulty to both solids and liquids

± Atypical chest pain (seen in 1/3rd of patients)

v. Investigations :
(a) Barium swallow
- Dilated esophagus which tappers down and produces bird beak like appearance
- Air fluid level within the esophagus
- Hurst phenomenon

Dilated esophagus (Megaesophagus) is

due to reduced peristalsis.

. Detected in manometry
Air fluid level

Bird beak like Due to increased LES tone

*
appearance
Hurst phenomenon : due to hydrostatic pressure of
barium given, it bursts and leaks (intermittently)
into stomach when in up right position
 22

(b) Esophageal manometry

- Confirmatory, specific and sensitive test for achalasia
- Aperistalsis seen (Amplitude of contractions are < 40 mmHg) - diagnostic of
achalasia
- Incomplete LES relaxation (LES pressure does not fall by > 8 mmHg compared
to intragastric pressure)
- Increased resting LES tone (> 45 mmHg)
(c) UGI scopy
- All patients should be taken to rule out pseudo-achalasia (cancer)
vi. Treatment :
1) Endoscopic dilatation of lES
- first line procedure
(4 % chance of perforation)
2) Esophageal Myotomy (11 % chance of perforation)
Laparoscopy myotomy (Hellers) - gold standard
Endoscopic myotomy (POEM - Per Oral Endoscopic Myotomy)
- preferential
- 90% success rates
- Complication : GERD
3) Botox injection into LES
- adjunctive option
- Short term effect only
4) Medical therapies (smooth muscle relaxants)
- CCB
- Nitrates
vii. Complication :
a. Aspiration
b. Pneumonia
c. Squamous cell cancer (middle and lower third of esophagus)

<
- Premalignant lesions to esophagus are :
(i.) Achalasia cardia (middle and lower third squamous cell carcinoma)
(ii.) Plummer Vinson syndrome (upper third squamous cell carcinoma)
(iii.) Barrett’s esophagus (lower third adenocarcinoma)
 23
Chaga’s disease

- Causative agent : Trypanosoma cruzi

- Endemic in South America (American Trypanosomiasis)
- Produces :
i. Cardiac involvement (cardiac myopathy, heart failure and arrhythmias)
ii. Colonic involvement (megacolon)
iii. Esophageal involvement (megaesophagus)
- Treatment :
1. Benznidazole (first line option, lower side effects)
2. Nifurtimox
- 2 Types :
a) Acute Chagas
b) Chronic Chagas

Acute Chagas
1. Produces :-
i. Fever
ii. Lymphadenpathy
iii. Skin induration (Chagoma)
iv. Eye swelling (Romaña sign)
± heart failure (due to acute myocarditis)
2. Diagnosis :
(A) PCR for detecting T. cruzi
(B) Peripheral smear examination - visualise trypomastigotes of T. cruzi

Chronic Chagas
- involving heart, colon, esophagus
- Diagnosis :
(A) Serological studies - Antibodies against T. cruzi
 24
High resolution manometry (hrm)
i. IRP : Integrated Relaxation Pressure
Average LES pressure in response to swallowing
Normal swallowing - average LES should be < 15 mmHg
Abnormal IRP > 15 mmHg

Due to - outflow obstruction

Achalasia
Pseudo-achalsia (GE junction tumor)
ii. DL : Distal Latency
From time of swallowing to time of initiation of contractions
Normal > 0.45 sec
Abnormal < 0.45 sec

Premature esophageal contractions

- Seen in Diffuse esophageal spasm
iii. DCI : Distal Contractile Integral
Measures contractile vigour (the power of esophageal contractions)
Normal 450 ~ 8000 mmHg. s. cm
Abnormal < 450 mmHg. s. cm - Weak peristalsis
> 8000 mmHg. s. cm - Hyper contractile peristalsis

< 100 Failed peristalsis

100 ~ 450 Weak peristalsis
450 ~ 8000 Normal peristalsis
5000 ~ 8000 Hypertensive peristalsis (high normal range)
(Nut cracker esophagus)
> 8000 Hyper contractile peristalsis
(Jack hammer esophagus)

iv. Breaks in peristalsis - Fragmented peristalsis

- Should not happen normally
- < 3 cm : Minor breaks
- > 5 cm : Major breaks
 25
Chicago classification of esophageal motility disorders
IRP > 15 mmHg

Yes No

Achalasia Peristaltic disorders

l
l

100 % failed 100 % failed Some (>20 %) l

l
peristalsis without peristalsis with normal peristalsis l
pan esophageal pan esophageal l
pressurisation pressurisation l
Type III Achalasia l
l
Type I Achalasia Type II Achalasia l
l

IRP > 15 mmHg l

l
+
l
Not meeting criteria for Type I, II, III achalasia l
l
l
Pseudo-achalasia l
l
-
-

Peristaltic disorders

Major Minor

Failed Normal DCI DCI > 8000

Ineffective Fragmented
peristalsis +
peristalsis peristalsis
> 20%
Jack Hammer (DCI < 450 in (Normal DCI
premature
Esophagus > 50% of > 50%)
DCI < 100 contractions
swallows)

Diffuse
(Corkscrew
Esophageal
esophagus)
Spasm
 26

Diffuse Esophageal Spasm Hyper contractile peristalsis

-F>M
- IRP < 15
- Premature contractions present
- HRM data : normal DCI, premature
contracture in > 20% of swallows
(DL < 4.5 sec)
(Jack hammer esophagus)
Hypertensive peristalsis
(Nut cracker esophagus)
- Dysphagia to both solids and liquids
- Chest pain is a prominent feature
- F = M (young)
- No reflux symptoms
- Symptoms worsened by emotions, cold
drinks
- ECG is normal
- IRP < 15
- Increased vigour of contractions
- HRM data : DCI is very high (hallmark)
- 5000 ~ 8000 :- Hypertensive

: peristalsis
- > 8000 :- Hyper contractile
peristalsis
- No premature contractions.

Treatment in peristaltic disorders

- Medical :
i. CCB - First line treatment
ii. Nitrates
iii. Anticholinergics (Imipramine)
iv.Trazadone
v. Sildenafil
vi.Botox
- Interventions :
i. POEM
ii. Routine dilatation

Conventional manometry
- Finding : > 20% simultaneous contractions with esophageal pressures > 30 mmHg
- Distal esophageal pressures in Nut cracker and Jack hammer esophagus > 200 mmHg
 27
Esophagitis
Esophagitis

Non-infectious Esophagitis Infectious Esophagitis

Non-infectious Esophagitis

Reflux Pill induced Corrosive Eosinophilic

Esophagitis Esophagitis Esophagitis Esophagitis
- Odynophagia - MCC of dysphagia
> Dysphagia Alkali (worse), (western countries) in
MC overall
- Drugs associated : acids young patients
cause
i. Bisphosphonates - Typically involves
(oral) cervical esophagus
Long term risk - Present with dysphagia
Barrett’s esophagus ii. Doxycycline of developing
iii. Potassium > odynophagia
(Increased risk of Squamous cell
chloride (tablets) - Family/ personal
Adenocarcinoma) cancers
iv. NSAIDs history of atopy
v. Iron sulphate - Empirical PPI does not
tablets respond
- Endoscopy
Multiple tracheal
rings (Feline
esophagus,
Trachealisation of
esophagus)
- Definitive diagnosis
by biopsy : > 15%
eosinophils/ high
power field
- Treatment : 3D’s
Dilatation
± steroids
+ Life style modifications
 28

3 D’s

Drugs Dilatation Diet

Steroids Pneumatic Avoid milk, soya,

dilatation eggs, wheat, nuts, fish

Infectious Esophagitis
- Odynophagia > Dysphagia (except in Candida)
- More common in immunocompromised individuals (HIV, Post chemotherapy,
transplants)
- MC infection : Candida (Invasive Candidiasis/ Esophageal Candidiasis)

Infectious Esophagitis
HIV
Candida Esophagitis HSV Esophagitis CMV Esophagitis
Esophagitis

i. Fever : Rare Rare Common Variable

ii. UGI : White Vesicles Giant serpiginous Giant ulcers

scopy yellowish (Numerous) ulcers
plaques Satellite (Idiopathic)
No ulcer Ulcers lesions
formation (shallow)
On removal Volcano
no bleeding appearance
iii. Biopsy : Hyphae and Inclusion bodies Basophilic intranuclear Non-specific
Pseudohyphae. (Cowdry type A) owls eye type of (Necrosis)
inclusion body
iv. Rx : Fluconazole. Acyclovir/ Valacyclovir Gancyclovir (IV) Self limiting
HAART
Thalidomide/
steroids
 29

Eosinophilic Esophagitis Candida Esophagitis

HIV Esophagitis
HSV Esophagitis

' Satellite lesions

-
-
i

CMV Esophagitis
 30

[ WHO stages :
Stage III - Oral thrush
Stage IV - Candida Esophagitis

HIV + decreased CD 4 count + Dysphagia (or odynophagia)

Empirical Fluconazole trial

Symptoms resolve in 48 ~ 72 hrs Symptoms not resolved within 48 ~ 72 hrs

Continue Fluconazole for UGI Endoscopy + Biopsy

2 ~ 4 weeks + initiate/
modify HAART
Diagnosis obtained

Plummer Vinson Syndrome

i. A.k.a Paterson Brown Kelly Syndrome
Siderophilic dysphagia
ii. Triad : IDA
Esophageal webbing (upper cervical esophagus)
Dysphagia (intermittent type)
iii. Increased risk of squamous cell cancer of upper third of esophagus
iv. Associated findings of IDA :-
a) Angular cheilitis
b) Koilonychia (spoon shaped nails)
c) Glossitis
d) Splenomegaly
e) Thyromegaly
v. Treatment : Esophageal Dilatation
vi. Premalignant condition
 31
Esophageal webs
i. Plummer Vinson Syndrome (most common cause)
ii. Epidermolysis Bullosa
iii. Bullous Pemphigoid, Pemphigus Vulgaris
iv. Stevens Johnson Syndrome & TEN complex
v. Psoriasis
vi. GVHD (Graft vs Host disease)

Webs
i. Eccentric (incomplete)
ii. < 2 mm protrusion in to esophagus
iii. Common in upper esophagus
(cervical esophagus)
iv. Plummer Vinson syndrome
Rings
i. Concentric (complete)
ii. 2 ~ 5 mm protrusion in to esophagus
iii. Common in lower esophagus
(thoracic esophagus)
iv. Different types :- A, B, C

Rings

A B C
i. Commonly symptomatic
i. Muscular ii. A.k.a Schatzki rings
i. Completely
ii. 1.5 cm proximal to iii. Not muscular in nature,
asymptomatic
squamo-columnar mucosal in nature
ii. Anatomical
junction iv. Near or at the squamo-
problem, due to
iii. Completely columnar junction
diaphragmatic
asymptomatic v. Schatzki rule :-
indentation
iv. Broad and smooth - < 13 mm - asymptomatic
:- > 25 mm - symptomatic
vi. Thin, small and smooth
vii. Causes intermittent dysphagia
to solids (especially if improperly
chewed) - Steakhouse syndrome/
Backyard Barbeque syndrome
viii. Reduces the risk of Barrett’s
esophagus (mechanical barrier)
ix. Treatment for symptomatic
rings : Endoscopic dilatation ± PPI
 32

esophageal cancers
i. Symptoms : weight loss, anemia, dysphagia
ii. Barium swallow shows : apple core lesion/ rat tail appearance
iii. Investigation of choice for staging : Endoscopic ultrasound (US)
iv. Gold standard for T staging : US
v. Investigation for N and M stages : PET CT scan/ CECT
vi. Treatment : Surgery
vii. Treatment for advanced cancer : Palliative therapy (using self expanding metallic
stents (SEMS) that improves dysphagia).

Risk factors
Adenocarcinoma Squamous cell carcinoma
i. GERD/ Barrett’s esophagus i. Alcohol
ii. Obesity ii. Smoking
iii. Smoking iii. Achalasia cardia (SCC > Adenocarcinoma)
iv. Systemic sclerosis (scleroderma) (middle or lower 1/3 rd of esophagus)
iv. Plummer Vinson syndrome (upper 1/3rd
of esophagus)
v. Alkali strictures (Corrosive Esophagitis)
vi. Radiotherapy to head & neck
vii. Coeliac disease
viii. Howel Evans syndrome (genetic
association - mutation of RHBDF 2 gene
- planto-planar tylosis) (Tylosis with
esophageal cancer)

Palmoplantar Tylosis
(Howel-Evans Syndrome)
 33

Palmoplantar Tylosis

Type A Type B

i. Onset in first year of life i. Onset for hyper keratosis starts in

ii. Esophageal cancer is rare 10 ~ 15 years of age
ii. High risk of Esophageal cancer
 34

Diarrhea & Malabsorption

Diarrhea
i. ≥ 3 times/ day ≠ Diarrhea
ii. Absolute increase in stool quantity
or Altered stool consistency (> 70% water content)
iii. Normal stool quantity in adults: < 200 mL/ day
Adults: > 200 mL/ day stool quantity = diarrhea
Children’s: > 10 mL/ kg/ day = diarrhea
iv. Pseudo-diarrhea : absolute increase in stool frequency
Example - IBS
- Hyperthyroid disorders (hyperthyroidism)
- Proctitis
- Fecal impaction (vaginal pessary)

Diarrhea

Acute Persistent Chronic

i. ≤ 14 days of i. Between 14 ~ 30 days i. > 30 days induration

induration ii. Can be infectious or non- ii. MC due to non-
ii. MC reason : infectious (most often) infectious in immuno-
Infectious nature competent individuals

Diarrhea
Based on pathophysiology

Osmotic Secretory Altered motility Mucosal damage

 35
Osmotic Secretory Altered motility Mucosal damage
i. Stool < 1 L/day > 1 L/ day — —
volume

ii. Content Water Water, — —

electrolytes

iii. Fasting Diarrhea Diarrhea — —

stops does not stop

iv. Stool
osmolar gap > 100 < 50 — —

v. Pain Painless Painful — —

vi. Etiology - Disaccharide

↳ - Infection
↳ o Increased - Invasive
o

deficiency (Eg - ETEC motility: diarrhea (blood in

(Eg - Lactase (Traveller’s i. Hyperthyroidism stool) due to
deficiency in diarrhea), Cholera) ii. Post infection (Eg -
children after - Undigested bile
b
gastrectomy Salmonella,
viral infection acid (Bile diarrhea) iii. Dumping shigella)
of GI tract) - Stimulant
w
syndrome - Ischemic colitis
u

- Undigested
w laxatives iv. Carcinoid - Vasculitis
b

sugars (Eg - - Neuro-endocrine

w
syndrome/ - Radiation
b

lactose) tumors (Gastrinoma VIPoma/ others enteritis

- Taking
w (due to gastrin), - Severe
b

osmotic VIPoma (due to w Decreased diverticulitis

laxative (Eg - VIP)), motility:
PEG, lactulose) Carcinoid syndrome
i. Diabetes
- Taking
b (due to serotonin),
ii. Hypothyroidism
artificial Medullary thyroid
iii. Amyloidosis
sweeteners (Eg cancer (due to
iv. Post vagotomy
- Sorbitol) calcitonin)
v. Neurodegenerative
- Diabetics (due to

:
disorders
osmotic effect of
vi. On opioid drugs
glucose)
- Microscopic colitis
 36
Stool osmolar gap
Normal osmolality for stool : 290 - [2 x (Na + K)]
: Osmolal gap = (measured stool osmol gap - calculated osmol gap)
= > 100 —— Osmotic diarrhea
= < 50 —— Secretory diarrhea

Acute infectious diarrhea

± Vomiting

Vomiting predominant Diarrhea predominant

Short incubation Blood in stools

period within 6 hrs
No Yes

Toxin mediated diarrhea

(Preformed diarrhea) Predominantly Mucoid diarrhea
watery diarrhea
S. aureus
S. cereus Inflammatory
Non-inflammatory diarrhea
diarrhea

Supportive management
Immunocompetent Immunocompromised

Short history of diarrhea Long history of diarrhea

(Persistent/ chronic) (Afebrile)
 37
Non-inflammatory
watery diarrhea

Immunocompromised

Long history of diarrhea

(Persistent/ chronic) (Afebrile)

HIV
- Cryptosporidium parvum (MC)
Treatment -
Not HIV : Nitazoxamide
HIV : HAART ± Nitazoxamide
- Isospora belli
- Cyclospora cayetanensis
Trimethoprim/
Sulfamethoxazole
- Microsporidium species
Albendazole

Giardiasis
- Malabsorption
- Foul smelling diarrhea
- Treatment : Metronidazole
 38

Non-inflammatory
watery diarrhea

Immunocompetent

Short incubation period Longer incubation period

(within 16 ~ 18 hrs) (24 ~ 72 hrs)

No travel history Travel history/ cholera endemic zone

Yes No
Bacillus cereus (diarrheal type)
Cl. perfringens ETEC
(Traveller’s Viral gastroenteritis
diarrhea)
- Rotavirus
Preformed toxins (Afebrile) Treatment : - Children
Ciprofloxacin - Norwalk virus
(Nora virus)
Supportive management Cholera (rice - Adults
water stools) (Crew-ship diarrhea)
(epidemic) - From eating
Treatment : seafoods
3 doses of (crustaceans -
Doxycycline prawns, crabs)
stat

Toxins Listeria
(formed after - Rare cause
ingestion) - Eating raw cheese/
(Afebrile) unprocessed cheese
- ± Febrile (Extremes of
age/ pregnant women)
 39

Inflammatory
diarrhea

Fever (common)

- High grade fever

- Child with mild fever
- Adult
- Frank bloody stool
- Occult blood

EHEC Invasive
Salmonellosis (Non-typhoid salmonella)
Treatment : Treatment : Ciprofloxacin
Antibiotics are Shigella
contraindicated
Treatment : Ciprofloxacin
Yersinia enterocolitica
Treatment: Doxycycline
Campylobacter jejuni
Treatment: Doxycycline

Entamoeba histolytica
(Amoebic gastroenteritis)
(Flask shaped ulcers on colonoscopy)
Treatment : Metronidazole + Paromomycin
Clostridium difficile (History of
broad spectrum antibiotics use)
Treatment : Oral Vancomycin/
metronidazole (oral or IV)

Differential diagnoses :
(i) IBD - very common
 40

- Preformed toxins do not require antibiotics

(supportive management only)
- ETEC : Ciprofloxacin/ Azithromycin
- Cholera : Doxycycline
- Viral Gastroenteritis : no antibiotics required
(supportive management only)
- Listeria : Ampicillin
- Giardiasis :Metronidazole
-EHEC : No antibiotics (contraindicated)

Rehydration
- Most important strategy for treatment of diarrhea (acute infectious diarrhea) is
rehydration (ORS > IV fluids (preferred only in case of inability to take orally))

Standard ORS Low osmolarity ORS

Glucose : 13.5 g/ dL
Trisodium citrate dehydrate : 2.9 g/ dL
KCl : 1.5 g/dL
NaCl : 2.6 g/dL

Standard ORS Low osmolarity ORS

Glucose 111 75

Na 90 75

Cl 80 65

K 20 20

Citrate 10 10

Net osmolarity 311 245

 41

- IV fluids are preferred in 2 conditions :

(a) Severe dehydration
(b) Patients who are not able to tolerate oral feeds

Low osmolarity ORS

- Low osmolarity ORS is preferred because :

:
i. Reduce the need for IV fluids (any ORS)
ii. Reduce vomiting
iii. Reduced stool volumes (more osmolar ORS could cause osmotic diarrhea)

Diet recommended in diarrhea

- Diet recommended by WHO is BRATS (poor evidence)
B - Banana
R - Rice
A - Apple
T - Toast
S - Soup
(Avoid dairy products especially in children as most of the childhood diarrhea cases will be
of viral gastroenteritis which results in some amount of lactose intolerance and taking
dairy products can result in more diarrhea)

Adjunctive therapy for diarrhea

i. Zinc - best evidence (to decrease diarrhea and increase mucosal regeneration) for
children
- 10 ~ 20 mg/ day x 7~10 days
ii. Antibiotics -
(a) Contraindications :-
i. Gross blood in stools
ii. Patients having STEC - O157:H7 or O104:H4 grown in stool culture
(b) Indications :-
i. Stool leukocytes are positive
ii. Guaic positive (stool occult blood positive)
iv. Sepsis, high total count, fever, mucoid diarrhea
v. Immunocompromised
vi. Age > 65
 42
vii. Persistent diarrhea
viii. Cholera endemic zone (cluster of cases with rice water stools)
- Doxycycline 3 stat (300 mg stat dose)
iii. Anti-diarrheal agents :
- Can be given in watery diarrhea
- 2 types :-
(1) Anti-motility agents - Loperamide (1~2 mg/ day)
(2) Anti-secretory agents - Bismuth, Racecadotril (Redotil 100 mg 2~3
times/ day) (Intestinal enkephalinase inhibitor)
Intestinal enkephalinase inhibitor

Block enzyme enkephalinase

Increase levels of enkephalins in intestine

Reduce cyclic AMP’s

Reduced chloride and water secretion

 43
Malabsorption
- Classic triad seen in < 20% of patients :
Chronic diarrhea ± Steatorrhea

Weight loss Anemia

(Catabolic
state)
- Complications associated with malabsorption :
i. Renal stones (made of oxalate)
ii. Gall stones (cholesterol gall stones)

Malabsorption

Fat in intestine (not absorbed)

Fat chelates the calcium (saponification)

Calcium indirectly chelates oxalate
Free calcium decreases in intestine

Free oxalate

Freely absorbed in intestine

More oxalate in blood

Filtered by kidney (Hyperoxaluria)

Oxalate renal stone

Oxalate renal stone
- Most common type of renal stones in the world
- Most common type of renal stones in malabsorption
- Most common type of renal stones in chron’s disease
(GIT pathology due to fat malabsorption)
 44

Malabsorption

Bile acids not absorbed properly Bile (form of fat)

Reduced bile acids in bile

Cholesterol (high) : Bile acids (low)

Enterohepatic circulation of bile acids lost

Bile acids lost in stools

Reduced bile acids in bile

More cholesterol in bile

Super-saturation of cholesterol in bile

Development of gall stones in bile

Areas for development of malabsorption

- Small Intestine is the commonest area of pathophysiology in malabsorption
or due to a pancreatic problems
- Isolated stomach issues (post gastrectomy) or isolated colonic issues
(ulcerative colitis, post colectomy) do not cause malabsorption, causes micro-
nutrient deficiency.
 45
MICRONUTRIENT ABSORPTION SITES
 46

Iron and calcium is absorbed

from proximal part of intestine
(duodenum)
Proximal part pathology (Coeliac
disease) affecting duodenum -
IDA, Hypocalcemia.
Water
and Disaccharides are absorbed in
sodium is jejunum.
absorbed Folic acid is typically absorbed in
from duodenum & jejunum.
entire
intestine.
B12 and bile salts and acids are absorbed in distal intestine.
Distal intestine pathology (Ileal resection in crohn’s disease,
crohn’s disease affecting terminal ileum, tuberculosis affecting
terminal ileum) tend to have B12 deficiency or bile acid diarrhea

Colon secretes potassium.

Classification of malabsorption

Malabsorption due to Impacted Intra-luminal digestion

(Problem in digestive enzymes)
Eg : (a) Pancreatic diseases
- Chronic Pancreatitis : secretion of pancreatic enzymes is defective because
of intra-luminal digestion will be poor and hence loss of content of
gastrointestinal tract
(b) Hepato-biliary disease
- Bile secretion is defective, hence no fat absorption, hence deficiency of fat
and fat soluble vitamins, development of steatorrhea.
(c) Post-gastrectomy
- Emptying occurs fast, movement of content faster than that absorption can
happen/ enzyme action leading to malabsorption and diarrhea.
 47

Malabsorption due to Mucosal damage

Eg : (a) Sprue
- Mucosal damage, villus atrophy present
- 2 types - Celiac disease
Tropical sprue
(b) Crohn’s disease - typical mucosal damage due to ulceration
(c) Whipple’s disease - mucosal damage due to parasitic infections
(d) Abetalipoproteniemia
(e) Radiation enteritis
(f) Eosinophilic gastroenteritis
(g) Systemic mastocytosis
(h) Carbohydrate intolerance
(i) IPSID - Immuno-proliferative Small Intestinal Disease - due to a lymphoma
leading to malabsorption.
(g) Heavy chain disorders etc
Malabsorption due to Defect in Lymphatic transport (mucosal transport)
Eg : (a) Primary intestinal lymphangectasia
(b) Secondary intestinal lymphangectasia

Mucosal
damage

-
-
'

} Mucosal
transport
Lymph
Impacted Lumen
Intra-luminal
digestion
is
us
Defect in
Lymphatic
transport
 48

Mixed pathologies
(produce mucosal damage and intra-luminal indigestion at the same time)

Eg : (a) SIBO - Small Intestine Bacterial Overgrowth

(b) Short Bowel Syndrome (SBS) - after massive bowel resection
(c) Zollinger Ellison syndrome - due to a gastrinoma

Tests for malabsorption

1) Fat Malabsorption
- Quantitative test : Gold standard
- Qualitative test
- Other tests : Semiquantitative test, serum test, breath test, etc.

Quantitative Analysis 72 hr fecal fat More reliable test

Gold standard test

Excretion of fat in stool

considered to be abnormal

≥ 7 g/ day in 72 hr fecal fat Test Positive

Tests to estimate fecal fat

Van de Kamer method (older test)

Near Infra Red Absorbimetry (NIRA)
 49
Qualitative test Sudan Black (Sudan III) staining

Fat globules presence in stool

under microscope

Semiquantitative test Both quantitative and qualitative

Acid steatocrit

> 31 % is abnormal

Serum test β carotene in serum

β carotene level is reduced in fat malabsorption

Breath test Triglycerides labelled with radioactive carbon is given

14
C Triolein
Check breath for radioactive carbon (C14 ) C14 Trioctanoin

Good absorption of triglycerides taken/ Metabolised

consumed goes into blood and reaches lung
End product CO 2

Radioactive carbon elimination is increased Normal

Malabsorption of triglycerides

Absorption into blood from intestines is less

Radioactive carbon going into blood and reaching lung is less

Reduced radioactive carbon elimination Abnormal

Test Positive
 50

2) Carbohydrate malabsorption
- Lactose deficiency (Lactose malabsorption)

50 g Lactose

Serum glucose increased Urinary glucose

By > 30 ~ 40 % in 30 minutes Increased normally

< 5 g over 5 hrs

< 20 mg/ dL at 30 minutes

Positive test for Positive for Lactose

Lactose malabsorption malabsorption

Breath test (H2) More reliable test

Measure the amount of H 2 in breath

No absorption of lactose

Due to fermentation of lactose in intestine

Leads to production of more H 2

H2 is absorbed

H2 eliminated in lungs

> 20 ppm Diagnostic of lactose malabsorption

 51

False negative Lactose malabsorption present

but report is negative

Due to lung disease Due to antibiotic use

Test is based on lungs capacity Intestine bacterias

for excretion of H are killed

Lung unable to excrete H2 Malabsorption present

Lactose in intestine
and not absorbed

Bacteria absent to ferment

Low breath H2

False positive Too much bacterial growth in intestine

SIBO

Too much fermentation

For normal amount of glucose

More H2 production

False positive
 52

3) D-Xylose test
- Differentiate intra-luminal disease vs mucosal damage
- D-xylose test is positive in patients having mucosal disease/ damage

25 g D-xylose given

Should be absorbed by intestine Urinary D-xylose More reliable test

Serum D-xylose should increase Levels should increase

< 20 mg/dL at 1 hour Normal : > 5 g in 5 hours

Positive test < 4.5 g over 5 hrs

Positive test

False positive Reduced urinary D-xylose

Patients with no malabsorption

Drugs
Reduced gastric Old age
emptying Urinary retention NSAIDs
Low GFR Glipizide
3rd space loss Neomycin
SIBO
In severe ascites
Too much bacteria in intestine
D-xylose may enter the
ascitic fluid and not urine
Bacteria will fermenting D-xylose

Amount of D-xylose absorbed is less

 53
4) B12 Malabsorption
B12 deficiency

Gold standard test to tell

the site of malabsorption Schilling test

Alternative test Test for B12 levels +

Homocysteine +
Methylmalonic acid

Blood B12 levels low

Site of
malabsorption Homocysteine + Methylmalonic acid levels high
unspecified
Most specific : Methylmalonic acid levels

Only in B12 deficiency

Homocysteine levels increase in both

B12 deficiency and folate deficiency

Schilling test Multiple steps

I.M. B12 given To saturate B12

Step 1
receptors in liver
+
Oral radioactive B12

Check urinary radioactive B12 levels

Increased levels Reduced levels

Dietary deficiency

Seen in vegetarians, vegans Vegans > vegetarians > non-vegetarians

 54

Step 2 Administer intrinsic factor

+
Oral radioactive B12

Check urinary radioactive B12 levels

Increased levels Reduced levels

Pernicious anemia Not pernicious

anemia

Step 3 Administer course of antibiotics

+
Oral radioactive B12

Check urinary radioactive B12 levels

Increased levels Reduced levels

SIBO

Bacterial consumption of B12

Step 4 Supplement pancreatic enzymes

+ (Deficiency of pancreatic enzymes)

Oral radioactive B12

Check urinary radioactive B12 levels

 55

Check urinary radioactive B12 levels

Increased levels Reduced levels

Exocrine pancreatic insufficiency Not dietary deficiency, not SIBO,

not pancreatic deficiency, not
pernicious anemia

Terminal ileal disease

i. Tropical sprue
ii. Crohn’s disease
iii. Celiac disease
iv. Intestinal resection

5) Bile acid malabsorption

75 Common test used

Sc HCAT scan

6) Protein malabsorption (For research purposes)

α1- Antitrypsin plasma clearance test

99m
Tc Albumin infusion scintigraphy test

-
To evaluate the leakage of albumin in intestine

Radio-labelled C octanoic acid and Radio-labelled C egg white

analysis or urinary phenol and cresol measurement
Fecal nitrogen estimation
 56

Endoscopy biopsy
r Diagnostic (Diffuse)
i. Whipple’s disease
- PAS positive diastase resistant AFB negative macrophages
ii. MAC enteritis (Mycobacterium avium complex)
- Show PAS positive AFB positive
iii. Abetalipoproteinemia
- Cannot form chylomicrons (fat absorbed cannot be packaged into
chylomicrons and put into lymph)
- Fat globules will be accumulating within the enterocytes
(lipid laden enterocytes)

Macrophages in PAS positive macropahges

routine H&E

Whipple’s disease
Lipid laden enterocytes

Acanthocytes

Abetalipoproteinemia
 57

May be diagnostic (patchy and hence missed)

:
i. Intestinal lymphoma
ii. Primary and secondary intestinal lymphangectasia
iii. Eosinophilic Enteritis
iv. Systemic mastocytosis
v. Amyloidosis
vi. Crohn’s disease
vii. Giardiasis (definitive diagnosis by biopsy)
viii. Coccidiosis (due to cryptosporidiosis or isosporiasis)

Cryptosporidiosis Isosporiasis

Organism visualised Organism visualised

attached on surface within the intestinal
of the intestinal epithelial cells
epithelial cells

Non-diagnostic
i. Celiac sprue
ii. Tropical sprue
iii. Viral gastroenteritis
iv. SIBO
v. Radiation enteritis
vi. Folate/ B12 deficiency
 58

Normal Celiac sprue

Loss of villi
Villous
projections
Increased
intraepithelial
lymphocytes

Crypt hyperplasia

Arrows indicate
scalloping of
intestinal folds
 59

Luminal issue Mucosal damage Lymphatic

obstruction

i. Stool fat

(> 9.5 g/ day) (<9.5 g/ day)

Maximum stool fat

Eg - pancreatic
disease

ii. Fecal Elastase Normal Normal

testing
Only in patients
with exocrine
pancreatic
insufficiency

iii. Serum
carotene
levels

iv. Serum
cholesterol

v. Serum albumin Normal

(Except in SIBO)

vi. Serum
Normal
calcium

vii. Vitamin D
(Calcidiol test)

viii. Serum iron Normal Normal

(Celiac disease)

ix. Serum folate Normal Normal

 60

x. Schilling test Abnormal Abnormal Normal

xi. Lactose Normal

Abnormal Normal
absorption (Except SIBO)

False positive
H2 breath test

xii. D-xylose test Normal Abnormal Normal

xiii. Antibodies — + —
Celiac disease : anti-
trans-tissue-glutaminase
Ig G antibodies

xiv. Endoscopy Normal Abnormal Abnormal

and biopsy
Diagnostic/ may Diagnostic/ may
not be diagnostic not be diagnostic
 61

Celiac disease
i. Genetic predisposition : HLA DQ 2 - 90 ~ 95%
HLA DQ 8 - 5 ~ 10%
- Patients with celiac disease will have HLA DQ 2 or 8 where as patients with HLA DQ 2 or
8 may or may not have celiac disease
ii. Incidence :
-F>M
- Caucasians (Northern Europe)
iii. Site of pathology :
- Entire intestine is affected usually
- Usual site of pathology is proximal small intestine - typically duodenum (IDA,
hypocalcemia, Vitamin D deficiency)
iv. Bimodal distribution
- First peak happen at 8 ~ 12 months of age group - on first time exposure to gluten
related diet (whining of breast milk)
- Second peak at 20 ~ 40 year olds (young adults) - most common age for diagnosis

All gluten related disorders does not mean celiac disease.

 62

Autoimmune
Celiac disease Non-autoimmune
with antibody
association - Non-celiac gluten
hypersensitivity
- Long history,
antibodies positive, - Present with same
enteropathy on symptoms as celiac’s
endoscopy with villous disease but no
hypertrophy, intestinal autoimmune condition
and extra-intestinal - HLA DQ 2 or 8 may or
symptoms, coexisting may not be present
conditions present, long
term complications
present if not adhered
to gluten free diet
Wheat allergy
Gluten ataxia
- Short history, - Type I hypersensitivity
antibodies negative, no Gluten - Short history, antibody
enteropathy [normal related negative, no enteropathy,
disorders
endoscopy and biopsy], intestinal and extra-
intestinal and extra- intestinal symptoms
intestinal symptoms indistinguishable from
same as celiacs disease, celiacs disease,
coexisting conditions coexisting conditions
absent, long term absent, long term
complications absent complications absent

- HLA DQ 2 or 8 may or
Dermatitis herpetiformis
may not be present
- Ig G related disorder, condition with intense pruritus,
vesicular bullous rash typically in elbows, gold standard
investigation is skin biopsy- Ig G deposition on tips of
dermis , treatment is gluten free diet and Dapsone

- Celiac disease may or may not be associated with gluten ataxia, dermatitis herpetiformis
 63
Gluten components
i. Glutenin
ii. Prolamins - considered problematic
Mnemonic : BROW - to be
- Gluten related prolamins (more problematic)
avoided in celiac disease
- Oats :- Avenins (safety is controversial)
B Barley
- Triticeae tribe :-
R Rye
(unsafe components in the following are)
O Oats
i. Wheat - Gliadins (Most unsafe)
W Wheat
ii. Rye - Secalin
iii. Barley - Hardin
- Non-gluten prolamins
- Seen in maize, corn, rice, millets, sorghum
- Safe for patients

Wheat
In tight junctions of enterocytes

Gliadin
Zonulin signalling

Zonulin signalling modulated

Modulate the permeability of
Alters the permeability tight junctions of enterocytes

Tight junctions resolves

Gliadin entry into gut

HLA DQ 2
HLA DQ 8

Starts an inflammatory reaction

Causes
Increased Intra-epithelial lymphocytes
Antibodies (Anti-TTG Ig G/ Ig A)
Damage to mucosa
Anti-endomysial antibodies
Anti-gliadin antibodies
 64

Risk factors for celiac disease

i. First degree relatives
ii. Presence of Type I DM
iii. Hashimoto thyroiditis (Any autoimmune thyroiditis)
iv. Autoimmune liver disease (Autoimmune Hepatitis, Sjorgen
syndrome, Ig A nephropathy)
v. Down syndrome
vi. Turner syndrome
vii. Ig A deficiency

Clinical features
INTESTINAL FEATURES
i. Chronic diarrhea
ii. Other features of malabsorption
iii. Bloating and distension (fermentation of substances in
intestine releasing CO2 and H2)
iv. Aphthous ulcers

EXTRA-INTESTINAL FEATURES
i. IDA - most common feature, sometimes patients present
only with IDA and no other intestinal features
ii. Increased liver enzymes
iii. Associated Dermatitis herpitiformis
iv. Gluten ataxia
v. Hypocalcemia and Low vitamin D
 65
Complication
- Complications are most commonly seen in patients who are not adherent to
gluten free diet
i. Osteoporosis (due to malabsorption of fat soluble vitamins A, E, K;
hypocalcemia)
ii. Hyposplenism (increased risk of infections)
iii. Infertility
iv. Neuro-psychiatric complications like ataxia, seizures ± cerebral calcifications
v. Ulcerative jejuno-ileolitis (strictures and perforations) - most commonly in
those not adherent to gluten free diet
vi. Cancers
- Enteropathy Associated T-cell Lymphoma (EATL)
- Jejunoadenocarcinoma
- Oropharyngeal cancers
- Esophageal cancers
- Right sided colon cancers
- Primary Liver cancers

Diagnosis
i. Serological tests (Antibodies)
- Anti-TTG Ig G antibodies
- Most sensitive investigation (sensitivity > 95%, specificity > 95%)
- First screening investigation
- Best investigation
- Anti-endomysial Ig A antibodies
- Most specific (Sensitivity > 90%, specificity > 99%)
- Ig G anti-gliadin antibodies
- Not used as specificity and sensitivity are very less
- HLA FQ 2 and HLA DQ 8
- Very sensitive (sensitivity is 91 ~ 100%)
- Specificity very poor (specificity is < 50%)
ii. Endoscopy/ biopsy
- Showing enteropathy (non-specific, similar findings in tropical sprue,
SIBO, viral gastroenteritis)
- Gross view : Scalloping of intestinal folds
- Microscopic view : villous atrophy, Increased intraepithelial
 66

lymphocytes, Crypt hyperplasia.

iii. Test for malabsorption :
- Abnormal D-xylose test Damaged mucosa
- Abnormal schilling test
- Increased fecal fat
Normal pancreatic function
- Normal fecal elastase

histological classification systems

Based on the microscopic findings on biopsy for enteropathy
- 2 histological classification systems present :
(1) Marsh classification system
- Type I
- Increased intraepithelial lymphocytes seen
- Type II
- Increased intraepithelial lymphocytes, Crypt hyperplasia seen
- Type III
- Increased intraepithelial lymphocytes, Crypt hyperplasia,
Villous atrophy seen

Villous atrophy is of 3 types:

i. Partial villous atrophy/ 3a
ii. Subtotal villous atrophy/ 3b
iii. Total villous atrophy/ 3c

(2) Corazza classification system

Treatment Mnemonic for liquors : SLAB

- Gluten free diet for life long S Stout
i. Avoid BROW L Lager
ii. Avoid liquors (stout, lager, ale, beer) A Ale
B Beer
 67
Monitoring
i. Anti-TTG Ig A
- With strict gluten free diet, it completely
disappears over a period of time
ii. Clinical improvement within 2 weeks
iii. Histological improvement (complete histological
reversal within 6 ~ 24 months)

Tropical sprue
i. Similar to celiac disease
- No antibodies present
- Enteropathy present
- No gluten hypersensitivity
ii. Occurs in tropics (India) might be due to infection in gut
iii. Distal intestine is affected more than proximal intestine
- Can develop IDA, hypocalcemia
- More B12 deficiency (Distal intestine involvement) - early feature
iv. Features of malabsorption present (chronic diarrhea, weight loss, anemia, steatorrhea,
cramps, bloating, fatigue)
v. Diagnosis
- Endoscopy & biopsy :
- Gross view : Scalloping of intestinal folds
- Microscopic view : villous atrophy, Increased intraepithelial lymphocytes, Crypt
hyperplasia
- D-xylose test is abnormal
- Abnormal schilling test
- Increased fecal fat and normal fecal elastase
- Antibodies are absent
vi. Treatment
- Antibiotics : Doxycycline 3 ~ 6 months 100 mg BD along with folate and B12
supplementation (improvement seen)
 68
Whipple’s disease
i. Causative agent : Tropheryma whipplei (intracellular organism, gram positive
bacillus, PAS positive diastase resistant)
ii. Route of transmission : unknown (medical enigma)
iii. Rare disease affecting including immunocompetent persons
iv. Affects proximal and distal intestine in equal proportions
v. Clinical features :
- Intestinal features (typical malabsorption symptoms)
- Extra-intestinal features :
(1) Arthralgia and arthritis
- most common seen in 2/3rd (70~80%) of patients
(2) Sacroilitis (back pain)
- seen in almost half of the patients
(3) Fever is very common
(4) Polyserositis
- Peritoneal and pericardial involvement (abdominal pain, chest pain)
(5) Lymphadenopathy
- Especially mediastinal lymphadenopathy
- Peripheral lymphadenopathy is also seen
(6) Cardiac involvement
- Infective endocarditis, myocarditis, pericarditis
(7) Neurological involvement
- Dementia (most common), myoclonus, nystagmus,
supranuclearophthalmoplegia, ataxia
(8) Hepatosplenomegaly
(9) Skin involvement - hyperpigmentation
(10) Uveitis - rare
vi. Investigations :
- PAS positive AFB negative macrophages in intestine on endoscopy and biopsy
vii. Treatment :
(difficult to treat, relapse rates are high)
- 2 weeks of I.V. Ceftriaxone 2 g once a day dose
- Followed by maintenance dose of trimethoprim and sulfamethoxazole for 1 year
- 100 % fatal if not treated
 69
Abetalipoproteinemia
i. Malabsorption that presents early in life (genetic disorder)
ii. Acanthocytes in peripheral smear
iii. Lipid laden enterocytes on endoscopy and biopsy
iv. Deficiency of fat soluble vitamins (inability to produce chylomicrons)
v. Severe fat malabsorption
vi. Fat steatorrhea, failure to thrive
vii. Mutation seen in MTTP (microsomal triglyceride transport protein)
viii. Inability to produce LDL, VLDL, any lipoprotein molecules
ix. Very low cholesterol levels (undetectable), absent LDL
x. Complication :
- Osteoporosis
- Ataxia
- Spinal cord involvement
(due to vitamin E deficiency)
xi. Treatment : Restricting long chain fatty acids that are difficult to absorb and
high dose of vitamin E
SIBO
i. Etiology :
(a) Structural abnormalities
- Diverticula (out pouching of intestinal mucosa)
- Strictures
- Adhesions (common after surgeries, cause partial obstruction leading to
reduction in fecal matter)
- Post gastrectomy (Billroth II)
- Fistula (intra-intestinal fistulas)
(b) Motility disorders
- Scleroderma
- Amyloidosis
- Vagotomy
- Diabetes (autonomic neuropathy by damaging vagus nerve endings)
- Intestinal Pseudo-obstructions
(c) Functional disorders
- Hypochlorhydria/ Achlorhydria
- Hypogammaglobulinemia/ Agammaglobulinemia
 70

ii. Pathophysiology :
SIBO

Increase B12 Fermentation of Increased deconjugation

utilisation by carbohydrates
+ of bile acids
bacteria
H CO2
2 Reduced fat emulsification
B12 deficiency

Severe abdominal symptoms

Steatorrhea
Bloating
Megaloblastic anemia (chronic diarrhea)
Abdominal pain
Recurrent flatus

iii. Diagnosis :
- Breath H2 test - Measure post-lactulose
- Breath methane test

Breath H ≥ 20 ppm at 90 minutes

Breathe methane ≥ 10 ppm regardless of time
(more specific)

- Gold standard - Jejunal aspirate of culture

- > 103 Organisms/ mL Suggestive of SIBO
- > 105 Organisms/ mL Diagnostic of Iatrogenic SIBO

iv. Treatment :
- Correct the correctable lesions (for structural abnormalities)
- Antibiotics - Amoxiclauv (Augmentin) ± Metronidazole
- Alternative drug - Refaximin
 71
Short bowel syndrome
i. Due to massive resection of intestine (for surgical reasons)
ii. Intestinal functions are deranged and affected leading to short bowel
iii. Causes :

Adults
i. Crohn’s disease
(most common reason)
ii. Massive intestinal trauma
iii. Mesenteric ischemia
iv. Malignancy
v. Radiation enteritis
Child
i. Necrotising enterocolitis
(most common reason in neonates)
- significant length of bowel is
resected resulting in short bowel
ii. Mid gut volvulus (congenital anomalies)
- whorl sign in CT scan
iii. Gastroschisis

- Normal length of small bowel in adults : 250 ~ 300 cm

- Normal length of small bowel in infants at term : 150 ~ 160 cm

iv. SBS occurs in :

- Adults when bowel length after resection is < 180 ~ 200 cm
- Infants when bowel length is < 75 cm
- If > 70 ~ 80% small bowel is resected.
v. 3 types of SBS based on anatomical effects (anastomosis) :
(1) Jejunocolic anastomosis
- Resection of ileum, ileocecal valve, part of colon, some part of jejunum
- Most common anastomosis
- Prognosis is variable intermediate (depends on the length of jejunum)
(2) Jejunoileocolic anastomosis
- Resection of part of ileum
- Remaining are - jejunum, part of ileum, ileocecal valve, entire colon
- Prognosis is best
- Residual ileum is advantageous as it prevents B12 deficiency, prevents bile
acid malabsorption, less electrolyte and water loss, produces maximum
intestinal adaptation
(3) End jejunostomy
- Resection of ileum, colon (Part of jejunum only remaining)
- Worst prognosis of all.
 72

vi. Clinical features :

- Features of malabsorption (severe diarrhea, weight loss, failure to thrive in infants,
steatorrhea, oxalate stones, cholesterol gall stones)
- Gastric hypersecretion (compensating for resection)
- Increased incidence of peptic ulcer disease
vii. Treatment
- Acute phase : 3 ~ 4 weeks
- High volume loss in stools
- Metabolite derangements
- Death common in this phase
- Adaptation phase : 1 ~ 2 years
- Improvement occurs
- Maximum with ileum
a) Fluid and electrolyte replacement
b) ± Total parenteral nutrition (Enteral nutrition on improvement)
c) Acid suppression for 2 ~ 3 months
d) Anti-motility drugs (Loperamide, codeine)
e) Adjunctive drugs :
- Octreotide/ Clonidine
- Unable to wean from TPN — use GLP 2 analogues (Teduglutide)
- To decrease intestinal motility action (not incretin drug)
f) Surgery :
- Intestinal transplantation
- In TPN life long dependance (Complication - Liver failure)
- Intestinal lengthening procedures
- Longitudinal Intestinal Lengthening and Tailoring procedure (LILT), Serial
Transfer Enteroplasty procedure (STEP)
- For children (not adults)
 73

IBD
Crohn’s disease Ulcerative colits
i. Risk factors :
- Smoking
- Appendectomy
ii. Pathophysiology
- HLA association HLA DR 1 HLA DR 2
HLA A 2
(Extra-intestinal manifestation)

- T helper pathway Th 1 (TNF, IFNγ) Th 2

Th 17 (IL-17, IL-23)

- Genetic IL-23 polymorphism IL-10 polymorphism

polymorphism is protective (increased risk)

Innate Autophagy
- Genes pathway Epithelial barrier genes
pathway
mutation
OCTN 2 gene
- Typical IBD - ATG gene CDH 1
1 gene - IRGM gene HNF 4 α
present in LAMB 1
chromosome
16 produces
protein NOD2 NOD 2
(CARD15) PTPN 22
- PTPN22 ATG genes
associated
with Not associated with
autoimmune ulcerative colits
disorders
IRGM gene mutation is associated with development
of both ulcerative colitis and crohn’s disease
 74

NOD2 (CARD15) is linked with Studies show NOD 2 and PTPN 22 genes
development of mucosal immunity are associated with decreased risk of
against certain bacterial components. ulcerative colitis.

- Syndromes 1. Turner syndrome (45 XO

associated chromosomal aberration,
with IBD or females, streak gonads-
IBD like infertile, ± cardiovascular
picture defects, ± growth retardation,
no mental retardation)
2. Heřmanský–Pudlák syndrome
(AR disorder, triad :
oculocutaneous albinism +
bleeding diathesis (due to
platelet aggregation disorder) +
pulmonary fibrosis)
3. Von Gierke disease (Glycogen
storage disorder)
4. Wiskott Aldrich Syndrome (X
linked disorder)
5. IPEX syndrome (immune
dysregulation,
polyendocrinopathy,
enteropathy, X-linked) :
mutation of FOX P3 gene
mutation causing neonatal
diabetes mellitus, neonatal
diarrhea, malabsorption.

- Infection - Johne’s bacillus (M. paratuberculosis,

seen in cattle)
- Chlamydia \ Crohn’s > Ulcerative
- Listeria disease colitis
- Pseudomonas (cell wall deficiency )
- Strains of E. coli
- Clostridium species
 75

- Anti-Outer Membrane Protein C

\

(OMPC) found in E.coli

- Anti-I2 found in pseudomonas
:
- Anti-CBRIL (against flagellum of
clostridium species)

- If antibodies present, implies - Anti-OMPC and anti-

high severity, increased risk of CBRIL is associated with
strictures and fistulas pouchitis in patients with
ulcerative colitis

iii. Pathology :
- Site - Entire GIT from mouth to anus - Involves only the
- Not curative colon
- Controllable with current therapies - Curative disease
(Total colectomy)
- MC site Ileocecal > Terminal ileum Rectosigmoid > rectum
(small intestine alone is rare) (Rectum alone is rare)

- Rectal Absent Invariable (100 %)

involvement
- Ileal Absent
Invariable (95 ~ 100 %)
involvement (Backwash ileitis
is rare)
- Nature Transmural involvement Superficial involvement
- Discontinuous skip lesions (Mucosa and submucosa)
present - Continuous lesions

- Ulcers - Deep - Superficial in nature

- Produces cobble stone
appearance in mucosa

- Microscopy Non-caseating granulomas No granulomas

(transmural) Cryptitis ± crypt abscess
± crypt abscess (if colon involved) - Leads to crypt
distortion
 76

Normal i Normal r

Focal lesion Focal

- Dysplastic changes are rare inflammation
Background also
inflammed
- Dysplasia are common
(risk for colon cancers)

- Inflammatory - Rare - Common

pseudo-polyps - If present seen in terminal - Seen commonly on
ileum colonoscopy
throughout in colon
(diffuse)
- Risk is high patients
with pancolitis
(severe)
(Pancolitis : high risk
back wash ileitis ,
inflammatory
pseudopolyps, high
risk of dysplasias and
colon cancers)

iv. Clinical features :

- Intestinal 1) Abdominal pain - colicky in nature 1) Abdominal pain

features over RIF , most common symptom +/-
2) Abdominal mass - RIF lumps 2) +/ -
3) Abdominal tenderness common 3) +/ -
4) Rectal bleeding and tenesmus +/- 4) Presenting feature
5) Initially diarrhea 5) Diarrhea associated
Strictures with bleeding PR
Constipation (severe strictures)
 77

6) Constitutional symptoms : 6) +
Fever, malaise, anorexia, weight loss
7) Aphthous ulcers common (early) 7) common

- Extra -intestinal 1) Rheumatological involvement

features - Arthritis - peripheral arthritis - Arthritis not as common
(Joint more common
involvement is - Axial involvement arthritis
most common) (spondylitis, sacral iliac joint
(Most common involvement - rare)
organ system
involved) Arthritis

Type I Type II
arthritis arthritis

- Oligoarticular - Polyarticular
- Large joint - Small joint
involvement involvement
- Acute/ self - Chronic course
limiting - Independent of
condition intestinal
- Correlated diseases
with IBD

- Development of Hypertrophic - HPOA is less correlated

Pulmonary Osteoarthropathy with UC
(HPOA) more correlation with
crohn’s

2) Ophthalmologic manifestation
(second most common)
- Iritis (uveitis) good Crohn’s > U. colitis
correlation with crohn’s disease
- Episcleritis/ scleritis has good Crohn’s > U. colitis
correlation with crohn’s
 78

3) Skin manifestations
- Erythema nodosum is very - Erythema nodosum is
common in crohn’s rare in U. colitis
- Pyoderma granulosum is common - Rare
in crohn’s
- Skin granulomas (Metastatic - Rare
crohn’s disease) more common

Crypt abscess
n .

- l l '
,
l l l
l
l l ! I
- l
-

l l
- l r -n
-
I
-

p r n , l
l l - I
' i -
n-
-
'
I ---
e- - - - y
l - l l
'
l - --
-
r

t '
r
-
-
-
- s
s

Li
-
-
-
l
y
l r
l r
-
- - r
e -

Granulomas Neutrophilic
(non-caseating) infiltration

Erythema nodosum
- Clinical features :
i. Shin of tibia is affected (most common
f -
n
site)
'
' '
l l
'
-
ii. Multiple erythematous painful lesions
l -

t - Biopsy : characteristic inflammation of fat

1 ~ 5 cm in (panniculitis)
diameters,
- Most common cause of erythema nodosum
painful lesions
in India is streptococcal infection
 79

- Differential diagnosis for Erythema nodosum :

i. Tuberculosis
ii. Sarcoidosis
iii. Inflammatory bowel disease (Crohn’s disease)
iv. Histoplasmosis
v. Coccidioidomycosis
vi. Yersinia infections
vii. Blastomycosis
viii. Behcets (pseudofolliculitis, acne form lesions, vesiculobullous lesions,
erythema nodosum and pyoderma gangernosum)

Pyoderma gangrenosum
- Clinical features :
i. Most commonly affected area is leg
ii. Has a necrotic lesion (necrosis of local area) with
neutrophilic pus (neutrophilic infiltration)
- Pathergy positivity seen (only seen in Behcet and
pyoderma gangrenosum )
- Differential diagnosis for Pyoderma gangrenosum :
i. Rheumatoid arthritis
ii. Myelofibrosis
iii. Hairy cell leukemia

- Psoriatic lesions common in

crohn’s
4) Hepatobiliary features :
- Gall stones (ileal area commonly - Very rare in U. colitis
affected, causes bile acid
malabsorption, leading to
development of cholesterol
stones)

After ileal resection - most common type of stones = cholesterol

Before ileal resection - most common type of stones = bilirubin
 80

- Primary sclerosing cholangitis is - Common

rare - PSC has strong risk for
5) Renal manifestations : cholangiocarcinomas
- Nephrolithiasis (stone disease)
most common type is oxalate
stones (because of ileal
malabsorption resulting in
hyperoxaluria and more oxalate
absorption) are common in
crohn’s.
6) Complications :
i. Strictures and fibrosis is i. Rare
common
ii. Fistula common ii. Rare
iii. Abscess formation common iii. Absent
iv. Malabsorption common iv. Rare
v. Toxic megacolon is rare v. Most common
vi. Cholangiocarcinoma is absent vi. Common
vii. Colon cancer is rare (dysplasia vii. More common
is rare) (dysplasias are
common)
Risk factors are -
(a) Pancolitis disease
> 8 yrs,
(b) Left sided colitis
of > 15 ~ 20 yrs

v. Investigations :
- Serology
Z Antibodies are more common

ASCA +++ (40 ~ 70 %) — ( < 5 %)

p-ANCA — (< 20 %) +++ (> 65 %)

- Anti-OMPC
- Anti-I 2 +++ —
- ANti- CBRIL (Indicates very severe disease)
 81

I
'- Inflammatory
markers
(At high risk for developing thrombosis in any area
especially venous thrombosis during active stage)

Fecal calprotectin
- Important investigation for differentiating IBS and IBD
- Screening test
- Fecal calprotectin is positive, proceed to colonoscopy (If negative fecal calprotectin,
defer colonoscopy)
- Has very high predictive value (Test is negative — rules out IBD)
- Low specificity investigation in case the test is positive
- Levels of fecal calprotectin correlates with IBD (marker for monitoring the response
to therapy)

Fecal lactoferrin
- Marker of mucosal injury
- Alternative to fecal calprotectin proposed to be more specific for patients
with IBD.

vi. Radiology : - Cobble stone mucosa - Loss of

- Horse pipe/ Garden hose haustrations of
appearance (in terminal ileum) colon (Featureless
- String sign of kantor (due to colon)
stricture) - Lead pipe colon/
pipestone colon
- Collar button ulcers
- Inflammatory
pseudopolyps
- Thumbprinting sign
(non-specific
finding)
 82

Ascending colon

Small
H Terminal
H
ileum
-
l
l

' ' Normal

l l
l l colon
Cecum l l
haustra
l l
l l

µ l

Loss of
(
l

haustra
(Lead pipe
appearance)

Collar
button
ulcers
÷:
÷÷
.

÷.
Ei
Ii
iii.

- CT/ MRI Creeping fat sign (surrounding Fat halo sign

inflammation)
Comb sign

Colonoscopy with biopsy is the current gold standard for IBD
- Colonoscopy
- Ileo-colonoscopy is required
for crohn’s disease
Linear serpiginous ulcers
in terminal ileum
(transmural)
Cobblestone mucosa
like appearance
83
Ulcerations with pus
(exudates due to
fibrin deposits
Edematous colon
with thin and
friable mucosa
(bleeds easily)
- Exudates with pus can be
severe — Severe
ulcerative colitis and can
exhibit the formation of
pseudomembranes.
- In colon,
pseudomembranes are
associated with
Clostridium
(Pseudomembranous
colitis)
- -n
Pseudopolyps
 84

vii. Monitoring :
(Activity scoring) Crohn’s Disease Activity index(CDA) -
1. Number of liquid stool/ day
(score max 2)
2. Abdominal pain (score 0 to 2)
3. General well being (score 0 to 4)
4. Total number of complications
5. Use of opiates for diarrhea
6. Presence of abdominal mass
7. Hematocrit variation
8. Weight loss
Other indexes :- Van Hees index,
Telstad index, De-Domballs index,
International organisation of IBD
index by Oxford university etc
Truelove and Witts criteria
for ulcerative colitis -
(Travis criteria for
severe)
1. Mild UC
2. Moderate UC
3. Fulminant/ severe UC
Other indexes :- MAYO
score, Ulcerative colitis
disease index (UCDI).

Truelove and Witts criteria

Mild Moderate Fulminant/
severe
i. Stools/ day : <4 >6 > 10

ii. Blood in stool : + +++ Continuous

iii. Temperature : Normal Febrile Febrile

iv. Pulse rate : Normal Tachycardia Tachycardia

(> 90) (> 90)

v. Hemoglobin : Normal < 75% of normal Hb Transfusion is

(> 75% of normal Hb) (Reduced Hb) required

vi. ESR : < 30 > 30 > 30

(Normal)
 85

Travis criteria for severe ulcerative colitis

I. > 8 stools/ day + CRP > 45
or
ii. 3 ~ 8 stools/ day + CRP > 45

- Severe ulcerative colitis

- Shows 85% chance of developing very severe UC
- Indicates change of treatment to next line of therapy

viii. Treatment : Incurable (can go for remission Curable by surgery

[CDAI > 150])
- Medical
Mild to moderate UC :-
management : Mild [CDAI 150 ~ 220] :-
- 5-ASA derivatives
(a) 5-ASA derivatives - Colonic
(first line if only colon
predominant crohn’s
is affected)
(rectal suppositories)
(b) Steroids (Budesonide) -
No remission
ileocolonic crohn’s (most
common)/ typical small
- Combination of 5-ASA
intestinal crohn’s
and oral steroids
Moderate to severe [CDAI >220] :-
(topical steroids -
(a) Steroids - main stray
Budesonide
treatment
suppositories if colon
and rectum are
If not responding (complete involved)
remission not achieved)
No response

Anti-TNF α drugs like Infliximab, - I.V steroids and

Adalimumab (Biological drug) Azathioprine

Alternatively either : No response

Azathioprine, Mercaptopurine,
Methotrexate (Disease - Anti-TNF α drugs
modifying drug) (Infliximab)
 86

Severe UC :-
If still not responding - Admit and start I.V
(complete remission not fluids immediately
achieved)
No response
Combination of Anti-TNF α
- Cyclosporine or
drugs (subcutaneous) + either
Anti-TNF α drugs
Azathioprine/ Mercaptopurine/
Methotrexate (oral)
No response

If still no response - Surgery (curative)

- Natalizumab (monoclonal antibody

directed towards α4 β1 integrin
inhibitor which binds to vCAM 1
present in both brain blood barrier,
gastrointestinal mucosa, has a risk
of developing Progressive Multifocal
Leukoencephalopathy PML) also used
in Multiple sclerosis

- Vedolizumab (monoclonal antibody

directed towards α4 β7 integrin
which binds to Mucosal vascular
Addressin-CAM 1 (MADCAM 1)
present only GI mucosa)

ix. Complications : A) Fistulas - complex, doesn’t obey

Goodsall’s rule (anterior -
straight tracts and posterior -
curved tracts)
- Parks classification
:
- Diagnosis - gold standard is
examination under anesthesia
 87

u- Noninvasive investigation -
(i) Endo-anal ultrasound
- not useful as penetration
dept is only 2 cm around
the anal verge
(ii) MR Fistulogram
- Most useful investigation
- Noninvasive investigation
of choice in crohn’s
- Treatment - medical
management using antibiotics
(Metronidazole), Anti-TNF α
(most effective), Disease
modifying agents

- ± Combined surgery (adjunctive)

for complicated fistulas - Loose
setons where the fistula is kept
open and the secondary tracts
are abolished
[Cutting setons are avoided as it
leads to incontinence and heals
by secondary healing]

Young patients with non-healing fistulas

differentials :

Crohn’s disease
 88
Crohn’s disease
- Classification :
i. Montreal classification system (most commonly used)
ii. Vienna classification system
Montreal classification system
a. Age :
A1 - ≤ 16 years
A2 - 17 ~ 40 years
A3 - > 40 years
b. Location :
L1 - Terminal ileal disease
L2 - Colonic disease
L3 - Ileocolonic disease
c. Behavior :
B1 - Non-stricturing and non-penetrating
B2 - Stricturing
B3 - Penetrating

- Indications for surgery :

1. Symptomatic small intestine disease — common indication
- Usual symptom - stricture or obstruction
- Surgery - Terminal ileal resection (segmental resection)
2. Perianal disease (fistula and abscess)
- Second most common symptom
(abscess are drained out)
3. Intra-abdominal abscess in severe crohn’s disease

- Surgery is not curative, but to reduce severity of symptoms

 89
Surgical treatment of ulcerative colitis
(1) Acute Severe Colitis
- Emergency surgery (in case of toxic megacolon)

Total colectomy (Rectum is not removed) with End Ileostomy

(Damage control surgery)

Later, after 3 months

Proctectomy and IPAA

(2) Intractable Colitis/ dysplasia/ colon cancer

- Elective surgery

Total proctocolectomy
(The remaining ileum is combined with anus)
+
Ileal Pouch Anal Anastomosis (IPAA)
(Single stage or 2 stage procedure)
 90
Screening colonoscopy for ulcerative colitis
i. Start at 8 years from diagnosis
ii. Done every 1 ~ 3 years
iii. Colonoscopic biopsy showing high grade dysplasias/ cancer/ mass

Surgery : colectomy

Inflammatory bowel disease associations

i. Pregnancy : Quiescent disease (Increased risk of pregnancy related complications
like antepartum hemorrhage, prematurity, low birth weight)
ii. Fertility : no changes
Treatment using methotrexate/ sulfasalazine causes decreased sperm count
(reversible male infertility)

- In active disease avoid pregnancy.

Extra-intestinal manifestation and course with intestinal disease

Dependent on ibd Independent of ibd
i. Type I Peripheral arthritis i. Type II peripheral arthritis
ii. Erythema nododsum ii. Pyoderma gangrenosum
iii. Episcleritis iii. Scleritis (uveitis)
iv. Aphthous ulcers iv. Sacroiliitis and Ankylosing spondylitis
(dependant on underlying v. Primary sclerosing cholangitis
intestinal disease)

t Good response to biological agents (anti-TNF α drugs)

— More effective for conditions dependant on IBD

Primary sclerosing cholangitis

a. No treatment
b. Only supportive treatment
c. Transplantation (later stage)
 91

IBS, Colonic polyps & Colon Cancer

Ibs
i. Most common functional bowel disorder
ii. Age specific : 20 ~ 40 yr olds
iii. Females > Males (Indians : M > F)
iv. Pathophysiology :

Increased pain perception

- Genetic background factors:

- SCN5A gene
- Environmental factors:

Altered gut Visceral - Childhood abuse history

motility hypersensitivity - Physical stress
- Low birth weight (< 1.5 kg)
- People with generalised
anxiety
- Post-infectious
gastroenteritis
- Psychosocial disorders
(depression, schizophrenia)
- Altered gut microbiome

v. IBS with diarrhea/ constipation treatment : Infiximab

vi. Diagnosis : ROME IV criteria

ROME IV criteria
1. Abdominal pain of long duration (≥ 1/ week for ≥ 3months)
+ 2 out of 3 of the following :-
2. Pain related to defecation (increase or decrease)
3. Change in stool frequency
4. Change in form/ appearance of stool

+ Absence of red flag signs

 92
Red flag signs :
1. Age > 50 yrs
2. Rectal bleeding/ Malena
3. Anemia
4. Nocturnal diarrhea
5. Absolute increase in stool
6. Unexplained weight loss
7. Elevated ESR, CRP, fecal calprotectin
8. Family history of colon cancer/ IBD

Bristol stool chart

 93

- IBS-C : IBS of constipation type

≥ 25% of bowel motion of type 1 and 2
IBS-D : IBS of diarrheal type

: ≥ 25% of bowel motion of type 6 and 7

IBS-U : IBS of unclassified type
> 25% of type 1 and 2, > 25% of type 6 and 7
IBS of pain type is included here (earlier classification)

vii. Investigations : Fecal calprotectin (for differentiating IBS and IBD)

- Normal means IBD is ruled out, defer colonoscopy and consider IBS
vii. Treatment :
(A) Avoid FODMAPS
F - Fermentable
O - Oligosccharides
D - Disaccharides
M - Monosaccharides
A - And
P - Polyols
- Refer to an expert dietician
- Oligosaccharides : Fructans
Mnemonic BROnW :
B Barley, Beetroot
R Rye
On Onions
W Wheat
And cashews
- Disaccharides : Dairy products
- Monosaccharides : Free fructose foods :- Honey (highest)
Mangoes (second highest)
Cherries
Apples
Watermelon

— Causes more pain and causes gut changes

 94

- Polyols : sorbitol, mannitol, maltitol, xylitol(Raffinese)

— Apples, pears, cherries, plums, mushrooms, cauliflower, cabbage
(B) Dietary fibres : stool softeners
— for both IBS-D [stool tightening] and IBS-C [stool softening]
— Psyllium [available routinely] > Bran
(C) Pharmacological treatment :

E-
Proximal area Distal area

Contraction Relaxation

*
Proximal Distal

Distention NO, VIP

ACh
(Relaxative)

Proximal Distal
neuron neuron
(sensory)
5-HT 4 Serotonin 5-HT 3
receptors receptors

Dopamine
 95

Cholinergic overactivity Increased contraction/ motion

(Bethanecol)
Diarrhea

Anticholinergics Decreases contraction

(Atropine)
Constipation

Modulators :
1. Serotoninergic neurons
(serotonin)

Stimulates receptors

5-HT 4 Increases contraction

5-HT3 Increases relaxation

5-HT4 agonists : Cisapride (banned)

Tegaserod (banned)
Prucalopride 2 mg/ day starting dose

5-HT3 receptor suppressants : act on emetic centre in brain

Increase secretions in gut

Increase pain transmission

5-HT3 antagonists : Ondasetron (not used for IBS as it crosses BBB)

(IBS-D) Alosteron (low BBB penetration)
- Increased risk of ischemic colitis, perforations

2. Dopaminergic receptors (part of sympathetic system)

- Dopamine

D2 receptors D3 receptors
 96
Dopamine Blocks contraction and relaxation

Typical dopamine antagonists : Domeperidone (low BBB penetration)

(blocking D2) Levosulprides (low BBB penetration)
- Increase risk of Parkinsonism symptoms
Atypical (Prokinetic agents) : Metoclopramide (D2 — and 5-HT 4 + )
- Penetrates BBB barrier
- Dystonia (extra-pyramidal side effects)
Itopride (D2 — and AChE — )
- Local action (in gut)
- Cholinergic

Increase contractions

- Not used in IBS (Dopaminergic receptors are more in upper GIT)

3. µ receptors - Opioids

ACh inhibition

Long use — Constipation (consistent issue)

Require fibre rich diet

Loperamide (agonist on µ receptor) - not first line therapy

4. Enkephalin receptor (Enkephalins)

- Eluxadoline — Enkephalinase inhibitor
µ opioid receptor agonist

Reduced contractions
(IBS-D)
5. GC Agonist : Linaclotide
More secretions Makes stool soft (IBS-C)
Plecatide

Drugs directly activating ClC2 Channels : Lubiprostone (IBS-C)

 97

Enkephalins
- Inhibitor : Racecadotril
Eluxadoline
Enkephalinase enzyme
- Increase enkephalins

Enkephalin Indirect action on cAMP

Bacterial toxins
receptor
(cholera)
Increases
Decreases GC cGMP
cAMP
Stimulates

Indirect Cl channels

ClC2 Channel
Lumen
Cl influx

Pulls out Na+ , H2O More chloride efflux

Increases secretions

Increases diarrhea
(more pain)

Ibs - d

i. Anti-motility agents : Loperamide

(Opioid agonist) Eluxadoline (µ receptor agonist, δ antagonist, enkephalinase
inhibitor) - more beneficial, no central side
effects
- Contraindications :- Pancreatitis, biliary disorders,
severe liver impairments (CTD-C), Heavy alcohol
use.
Diphenoxylate (little penetration of BBB)
 98

ii. Antibiotics : down regulate/ modulate gut microbiome

Rifampicin (for both IBS-D > IBS-C)
iii. 5-HT3 Antagonist : Ondansetron
Alosetron
iv. Bile acid sequestrants : Cholestyramine
Colestipol
Colesevelam

Ibs-c
i. Laxatives : reduce constipation and increase bowel motion
PEG (most common)
Lactulose
- No benefit in pain
ii. ClC2 agonist : Lubiprostone
iii. GC agonist : Linaclotide
Plecatide
iv. 5-HT4 agonist (prokinetic agents) : Prucalopride (only used for slow transit constipation)

Pain
i. Anti-spasmodic agents (anticholinergics) : Dicyclomine
Hyoscyamine
ii. Antidepressants (TCAs) : Amitriptyline
Imipramine
iii. Antibiotics : Rifaximin
iv. Probiotics : VSL #3 (most commonly used)
v. Emerging drugs :-
- Opioid receptor agonist : Asimadoline (IBS-D)
- CCK antagonist : Dexloxiglumide (IBS-C)
(Cholecystokinin)
- CRH antagonist : Pexacerfont
(Corticotropin releasing hormone)
 99

Colonic polyps
i. Mucosal overgrowth
ii. Most common type : Adenoma > Hypertrophic polyps > Hamartamous polyps
iii. Colon cancer develops from colonic polyps (Adenomacarcinoma)
iv. Among adenomas
- Highest risk of malignancy is for :
Villous > Tubuloovillous > Tubular adenomas

(Most common type)

- Lowest risk
v. 95% cancers : adenoma to carcinoma (Exception :- colon cancers that don’t follow
adenoma carcinoma rule)
Ulcerative colitis
- Only inflammatory polyps (pseudopolyps)
- Not premalignant
- Patient with ulcerative colitis can develop colon cancers without a
characteristic polyp
(Cancer not from polyps, but from background inflamed mucosa)

vi. Colonic polyps are more common in elderly (Age > 50)
(Younger patients — single polyp/ multiple polyps — Familial syndromes)
vii. Clinical features : asymptomatic (most common 95%)
Exception :- large villous adenomas cause secretory diarrhea
Incidental findings
If symptomatic :- most common symptom is bleeding
Hematochezia - commonest presentation
viii. Investigation of choice : colonoscopy

ix. Classification based on malignant potential :

A. Low malignant potential
B. Moderate malignant potential
C. High malignant potential
 100

Low malignant potential

Hamartamous polyps
i. Increased risk of colonic, extra-colonic malignancies
ii. Seen throughout GIT
iii. Not premalignant (low malignant potential)
iv. Associated with multiple familial syndromes :-
1. Peutz Jeghers syndrome
2. Juvenile Polyposis syndrome
3. Cowden syndrome
4. Cronkhite Canada syndrome
5. Bannayan Ruvalcaba syndrome
Peutz jeghers syndrome
i. Autosomal dominant inheritance
ii. Gene LKB-1 mutation (STK11) located on chromosome 19
iii. Develops in second decade of life
iv. < 20 polyps
Intestinal
v. Most common location : Jejunum
features
vi. Life time chance of developing colorectal cancer is 40%
vii. Increased risk of small bowel cancer

Extra-intestinal features :-
viii. 95% — mucosal hyperpigmentation in lips, buccal mucosa, extends to palms
and soles (lentigens from melanosomes)

ix. Mild risk of developing ovarian cancers, breast cancers, pancreatic cancers.
 101
Juvenile polyposis syndrome
i. Autosomal dominant with incomplete penetrance
ii. Mutation : SMAD-4 transcription factor gene present on chromosome 9
iii. > 10 polyps present throughout GIT
iv. Happens within first decade of life
v. Presents with GI bleeding, anemia
vi. High risk of developing colorectal cancer, stomach cancer

Cowden syndrome
i. Autosomal dominant disorder
ii. PTEN gene mutation in chromosome 10
iii. Typical hamartamous polyps in colon (low malignant potential)
- Not premalignant
iv. No increased risk of developing GI malignancies
v. Extra-intestinal symptoms :-
Skin manifestations : Acral hyperkeratosis and facial papules
(Some skin tumors : Trichemommas)
Thyroid manifestation : Multinodular goitre, thyroid adenoma (toxic)
Benign breast disorder : Papillomas, fibroadenomas

Facial
papules Cobblestone
(yellowish) appearance in
lip mucosa

Pits in palms
and soles
 102
Cronkhite Canada syndrome
i. Immune mediated disorder
ii. Not a genetic disorder (as per current studies)
iii. GIT polyps (no increased risk of GI malignancies)
iv. Extra-intestinal features :-
Diffuse hyperpigmentation (peripheral)

Alopecia Nail changes (dystrophy, atrophy)

Alopecia

Hyper-pigmented areas
(acral)

Nail atrophy Colonic polyps

Bannayan ruvacaba syndrome

i. Autosomal dominant
ii. PTEN mutation in chromosome 10
iii. Increased hamartomatous polyps
iv. No incraesed risk of colon cancers
v. Manifest in children as microcephaly, chemoangiomas, multiple fibromatosis
throughout body, speckled penis (childhood disorder)
 103
Inflammatory polyps
i. Pseudopolyps
ii. Seen in setting of IBD (ulcerative colitis)
iii. Low malignancy potential (not premalignant)

Mucosal polyps
i. Benign
ii. Small, < 5 mm
iii. Not associated with any syndromes

Submucosal poylps
i. Benign
ii. Most common : submucosal lipoma

Moderate malignant potential

- Not associated syndromes
Hyperplastic polyps
i. Small < 5 mm
ii. Low malignancy risk
iii. Recto-sigmoid : Most common site (distal colon)
iv. Diagnosis based on histology (colonoscopic appearance)

Sessile serrated polyps

i. > 5 mm
ii. Malignancy risk - 5%
iii. Seen in ascending colon (proximal)
iv. Sessile lesions

Serrated adenomas
i. Shows dysplastic changes with serrated changes
ii. Increased risk of malignancy
iii. Seen in recto-sigmoid colon - most common (distal colon)
 104
High malignant potential
- Adenomatous polyps (distal colon — recto-sigmoid)
c

Tubular Tubulovillous Villous

i. 80 %, most common i. 50% malignancy risk
i. 25 ~ 75 % villous
ii. < 5% malignancy risk ii. > 75% villous
component
iii. > 75% tubular component
(Mixture)
component iii. 5 ~ 15 % frequency
ii. 5 ~ 15 % frequency
iv. 80% frequency iv. Risk of malignancy -
iii. Risk of malignancy -
v. Risk of malignancy - 5% 50%
20%
vi. Location - sigmoid v. Location - rectum
iv. Location - distal
colon (most common) (most common)
colon
vi. Produce secretory
diarrhea

Associated with
McKittrick Wheelock
syndrome

McKittrick Wheelock syndrome

- Large villous adenomas result in development of secretory diarrheas
- Protein losing enteropathy (mucin)
- Hypoalbuminemia
- Produce dehydration, Acute kidney injury

Syndromes linked to adenomatous polyps

1. Familial Adenomatous Polyposis (FAP)
- Autosomal dominant
- Mutation in APC gene in chromosome 5
(Adenomatosis polyposis coli gene)
- 25% sporadic cases (Not familial origin)
- 75% cases hereditary
- > 100 polyps — FAP
- Most common in colon (but spread through GIT)
 105
- Present in third decade of life
- Mostly asymptomatic
- If not treated, 100% risk of developing colon cancer
- Extra-intestinal features :
Congenital Hypertrophy of Retinal Pigment Epithelium (CHRPE)

CHRPE seen during infancy with > 4 lesions bilaterally in FAP (> 90% cases)

Multiple polyps indicating FAP

- Variants of FAP : Attenuated FAP

(a) Polyps < 100 (>10)
(b) Most commonly distributed in right side of colon
(c) Present anywhere between 0 ~ 60 yrs of age
(d) Life time risk of developing colon cancer - 80%
 106

2. Gardeners Syndrome
- FAP + Extra-colonic tumors (Bone and soft tissue tumors like osteomas, desmoid
tumors, lipomas, fibromas, multiple sebaceous cyst)
3. Turcot syndrome (overlap syndrome)
- FAP + brain tumors (most common : Medulloblastoma)

Lynch Polyposis absent

FAP
syndrome

Polyposis present
Turcot syndrome

Gives rise to colorectal cancers

- Turcot syndrome associated with FAP : Medulloblastoma (most common brain tumor)
:- Turcot syndrome associated with Lynch syndrome : Glioma (most common brain tumor)
without polyposis

Lynch syndrome FAP

- Mutation in mismatch repair - APC gene mutation
genes MLH1, MLH2, MLH6 - No micro-satellite
(No APC gene mutation) instability
- Micro-satellite instability

4. MUTYH Associated Polyposis syndrome

- MUTYH gene mutation
- AR inheritance pattern
- 100% risk of developing colon cancers at age of 65
- Multiple polyposis syndrome
 107

Advanced adenoma
- Any one of the 3 — implies advanced adenoma
i. ≥ 10 mm in size — high risk of malignancy and dysplasia
ii. Villous component
iii. High grade dysplasia

Polyp —— Colonoscopic assessment

Biopsy Histology Risk of malignancy

(1) Haggitt classification system (pedunculated)

(2) Kikuchi classification system (sessile)

Morphology Risk of malignancy

Kudopit classification system

 108

Kudopit classification system

Type I
Round pit pattern (Normal)
Normal mucosa
Do biopsy for confirmation

Type II
Astrid pit pattern
(Non-neoplastic)
Hyperplastic

Type III S
Tubular round pit pattern
Smaller than normal pit pattern (Type I)
Neoplastic proliferation
Treatment : Endoscopic Mucosal Resection (EMR)
Type III L
Tubular or round pit pattern that is larger than
normal pit pattern (type I)
Neoplastic (send for histology)
Treatment : EMR

Type IV
Dendritic or gyrus like pit pattern
Neoplastic
Treatment : EMR

Type V
Amorphous or non-structural pit pattern
± Deep invasion present
Highly neoplastic (penetrate to submucosa)
Treatment : EMR and send for histology or
Endoscopic Submucosal Resection (ESR) and send
for histology or Alternative surgery
 109

Haggitt classification system

- For pedunculated polyps
- 4 levels
Level 1 : limited to head of polyp
Level 2 : goes into neck of polyp (dysplastic)
Level 3 : Invasion to stalk
Level 4 : invasion to submucosa (above muscularis)

Kikuchi classification system

- For sessile polyps
- Levels 1, 2, 3 based on depth of submucosa

Proximal 1/3rd : Level 1

Middle 1/3rd penetrated : Level 2
Distal 1/3rd : Level 3 (more risk of malignancy)

Treatment : EMR/ ESD

Screening colonoscopy based on histology :

1. Hyperplastic polyp < 10 mm present in sigmoid colon/ rectum — Once in 10 yrs
2. Histology shows low risk adenoma With 1 ~ 2 polyps < 10 mm in size, no
intra-epithelial neoplasia — Once in 5 ~ 10 yrs
3. Any one of the following — Screening every 3 yrs [depending on syndrome]
(i) High risk adenoma with 3 ~ 20 polyps
(ii) At least 1 polyp > 10 mm or 1 villous/ tubulovillous polyp
(iii) 1 polyp with high grade dysplasia
 110

Colon cancer
i. Third most common cancer over all
(Males : prostate and lung are respectively the most common cancers)
(Females : breast and lung are respectively the most common cancers)
ii. Age > 50 (< 50 — possible familial syndromes)
iii. Risk factors :
1. Adenomas
2. Syndromes associated with Hamartomatous polyps
- FAP for age by 40 yrs
- HNPCC (Lynch syndrome) - risk of 80% for age of 40 ~ 80
- Peutz jeghers sydrome
- MUTYH associated polyposis - risk of 80 ~ 100 % by age 60
- Familial juvenile polyposis syndrome
3. Family history
4. IBD (Ulcerative colitis > Crohn’s disease)
5. Diet and life style (sporadic) - smoking, alcoholism, low fibre diet and high fat,
obesity
HNPCC
- Related to colon cancer, endometrial cancer, ovarian tumors etc
- AD disorder
- Most common cause of inherited colorectal cancer
- Usually right sided cancers (ascending colon cancers more common)
- Sporadic types those related to life style is more commonly seen on left side
(Most common - sporadic)
- DNA mismatch genes mutation (MLH1, MLH2, MLH6, PMS2 genes) resulting in
micro-satellite instability (classic feature)
- No polyposis
(Does follows adenoma-carcinoma sequence rule)
- Risk for :-
a. Colorectal cancers - 70 ~ 80%, average age of onset is 40 yrs
b. Extra-colonic cancers
- Ovarian cancers (second most common) with risk of 10%
- Endometrial cancers (most common cancer) with a risk of 40% (Patients
with Lynch syndrome require endometrial sampling along with colonoscopy)
- Gastric risk is 10% (stomach cancer)
 111

- Bladder cancer risk is 10%

- Small intestinal cancer risk of 2%
- Brain tumor risk of 2% (Associated brain tumors with colorectal cancer
is Lynch syndrome (Gliomas are the most common tumors))
- Biliary tumors risk of 2%
- 2 sutypes :-
- Turcot syndrome
- Muir Torre syndrome
- Diagnosis is based on Amsterdam II criteria (3-2-1 rule) :-
1. ≥ 3 relatives with colorectal cancer (lynch associated cancers)
2. + At least one should be a first relative degree
3. + Evidence of AD inheritance (with at least 2 consecutive generations
affected)
4. + At least 1 relative should have a diagnosis of colorectal cancer within
50 yrs of age
5. Exclude FAP (by screening tests)
6. Pathological confirmation (polyps containing micro-satellite instability)
- Another classification system : Revised Bethesda system (more preferred)

iv. Protective factors :

a. Exercise
b. High fibre diet, low meat diet and high vegetarian diet
c. Long term risk of colorectal cancer can be reduced by using aspirin (long term use)
(any COX-2 inhibitors) (as it causes regression of adenomatous polyps)
v. Sites of development of colorectal cancer : Rectum > sigmoid colon
(Left sided colonic cancers are most common in origin)
Least common site is Descending colon
vi. Most common histological type of colorectal cancer : Adenocarcinoma (> 95%)
vii. Molecular classification :-
1. Cancers that have adenoma-carcinma sequence (> 95%)
2. Serrated polyp pathway
3. Lynch pathway
 112
Cancers that have adenoma-carcinma sequence
First mutation : APC gene No micro-satellite instabilities
No BRAF mutations

Increased cell proliferation

Increased loss of cell adhesion Development of adenomas
(part of early cancer)

Accumulation of mutations

KRAS/ SMAD mutations

More cellular proliferation

More cell signalling

Accumulation of mutations

TP53/ DCE genes

Complete malignant transformation

and invasion (carcinoma)

Serrated polyp pathway

(follows CPG Island Methylation Phenotype pathway, CIMP)
- Micro-satellite instabilities suggesting hyper-methylation of
mismatch repair genes (becomes inactive) along with BRAF gene

Lynch pathway
- Only micro-satellite instability (due to mutation of mismatch repair genes)
- No BRAF mutations
 113

viii. Clinical features :-

Sigmoid-rectum > Ascending colon > Descending colon
(Most common) (Least common)

Left sided colon cancer Right sided colon cancer

(distal colon) (ascending colon)

1. Altered bowel habits 1. Occult chronic bleeding

(very common) (common presentation is IDA)
- Elderly patient with IDA do
- Elderly patient with constipation
colonoscopy to rule out colon
- Elderly patient with overflow diarrhea
cancer
- Elderly patient with low stool calibre
2. ± Malena
(pencil like stools)
3. ± Obstruction / hematochezia
— Rule out colon cancer
4. Polypoidal, exophytic fungating
type of cancer
2. + Abdominal pain
3. ± Hematochezia
4. More stenosing — Annular or Napkin
ring type
— Classic lesions : Apple core lesions

Altered bowel habits

Having obstruction

Constipation

Proximal colon distends

More contractions

Overflow diarrhea
 114
ix. In case of metastatic disease — Liver is the most common site of metastasis
(RUQ pain, ascites, elevated alkaline phosphatase) (Treatment is palliative care)
- Patients are at high risk for developing infective endocarditis (Streptococcus bovis/
S. gallolyticus is associated with colorectal cancer)

Contrast-enhanced CT scan of the liver demonstrates

multiple hypovascular metastases throughout all
lobes of the liver, lesions are typical of metastatic
colon cancer.

Apple core lesion

(Descending colon)

x. Screening :
- Routine (normal risk individuals/ normal population) :-
- Start at age ≥ 50 (risk for colon cancer increases)
- Full colonoscopy (Gold standard), If normal, repeat every 10 yrs.
- Sigmoidoscopy + Fecal occult blood testing - alternative test, if normal
repeat every 5 yrs
- CT colonography (virtual colonoscopy), if normal repeat every 3 yrs
- Fecal occult blood testing, if normal repeat every year.
 115
- High risk patients :- Colonoscopy
(1) Positive family history of colon cancer
- Significant
≥ 2 first relative degrees with colorectal cancer (any age)
≥ 1 first degree relative with colorectal cancer diagnosed < 60 yrs
Screening by age 40 yrs OR 10 yrs earlier than the diagnosis of
colorectal cancer in a family member
If screening normal, repeat every 5 yrs
(2) Patient with IBD
- > 8 yrs of pancolitis OR > 15 yrs of left sided colitis
- If normal, repeat every 1 ~ 2 yrs
(3) Acromegaly
- Start screening by 40 yrs of age
- Repeat every 5 yrs
(4) Lynch syndrome
- Start by 20 ~ 25 yrs of age OR 10 yrs before the diagnosis of colorectal
cancer in a family member
- If normal, repeat every 1 ~ 2 yrs
- ± Female patient with lynch syndrome — pelvic examination, pelvic ultrasound
along with endometrial biopsy starting at age 30 ~ 35 yrs, repeated every
1 ~ 2 yrs if normal
(Most common extra-colonic cancer associated with lynch syndrome is
endometrial cancer)
(5) FAP Positive FAP mutation
Genetic testing for
Start sigmoidoscopy at all family members
age 10 ~ 12 yrs

Adenomas No adenomas

Full colonoscopy
(every year) r Upto 25 yrs, yearly colonoscopy
26 ~ 35 yrs, 2 yearly colonoscopy
> 100 polyps : > 35 yrs , 3 yearly colonoscopy

Prophylactic proctocolectomy If not willing

Selective COX2 inhibitors
+ IPAA at age of 16 ~ 20 yrs
 116

xi. Investigations :
- Colonoscopy - Gold standard investigations
- Sigmoidoscopy (inadequate investigation for right side colon cancer)
- CT colonography (virtual colonoscopy) (inadequate data)
- Double contrast barium enema (adjunctive, if colonoscopy is inadequate)
- Serum CEA : not diagnostic (assessing prognosis, used for assessing follow up
after treatment)
xii. Staging :
- CECT abdomen, pelvis and chest (for nodal disease and metastasis)
- PET-CT : most commonly used investigation for staging
- If nodal disease is present : Stage III
- If metastasis is present : Stage IV
- Assess KRAS mutations in case of metastasis disease
- In patients with colon cancer and age < 50, test for micro-satellite instability (MSI)
to rule out lynch syndrome.

Older staging : Astler collar staging

Duke’s staging

Duke’s staging
Stage A Tumor confined to intestinal wall (within muscularis properia)
Satge B Tumor not confined to intestinal wall (spread to adjacent areas)
Stage C Nodal disease
Stage D Distant metastasis

Tnm staging
Duke’s stage TNM stage
A I
No lymph node involvement and no distant metastasis
B II
C III Lymph node involvement
D IV Distant metastasis like liver cancer
 117

TNM stage

I
T1 : tumor is limited to submucosa
T2 : Invading muscularis properia

II
T3 : going to subserosal connective tissue
T4 : directly invading adjacent structures (including visceral
peritoneum, peri-rectal tissue)

III
Lymph node involvement

IV
Distant metastasis like liver cancer

xiii. Treatment :

Colon cancer treatment

Right hemicolectomy - Right sided colon cancers
Extended right hemicolectomy - Hepatic flexure cancers
Left hemicolectomy - Left sided colon cancers (most common)
Sigmoid colectomy
Total colectomy
 118

Right hemicolectomy Left hemicolectomy

- Right sided colon cancers - Areas supplied by left colic
- Removal of part of ileum, ileocecal artery is removed
valve, entire cecum & ascending - Removal of descending colon,
colon, proximal 1/3rd of transverse sigmoid colon, along with splenic
colon, including hepatic flexure flexure
- Supplied by right colic artery
supplies right colon (ascending colon,
hepatic flexure) , ileocolic artery
supplies the distal part of ileum &
proximal part of colon (cecum and
ascending colon), right branch of
middle colic artery

Extended right hemicolectomy

- Done for cancers found in
the hepatic flexure, proximal
transverse colon

Total colectomy done for hereditary

tumors, familial syndromes
 119

Middle colic artery

¥
Right sided middle
Left sided middle
colic artery
colic artery
Right colic artery ,
K Ii l l
f f
↳ ax
i

, Left colic artery

From IMA
Ileocolic artery
From SMA
¥
Left sided middle
Middle colic artery colic artery

¥
Right sided middle
colic artery

Right colic artery ,

K Ii l l
f f
↳ ax
i

, Left colic artery

Ileocolic artery
¥
Left hemicolectomy
Right hemicolectomy
 120

Middle colic artery

¥
Right sided middle
Left sided middle
colic artery
colic artery
Right colic artery ,
K Ii l l
f f
↳ ax
i

, Left colic artery

From IMA
Ileocolic artery
From SMA
¥
Extended right hemicolectomy

Rectal cancer treatment

Local excision
- Usually not performed
- Criteria’s are :
i. T1 tumor
ii. No lymph node involvement
iii. Mid-to-distal rectum cancers
iv. Clear distal margins
v. Tumor size < 3 cm, occupy only 30% of bowel circumference
vi. No high risk features
vii. Reliable post-op surveillance (due to high risk)

Low anterior resection (LAR) (sphinctal sparing resection or colo-anal resection)

- Most common surgery for rectal cancers, sphincter sparing hence
colostomy is not required
- Removal of sigmoid, rectum, along with total meso-rectal excision (TME)
i.e. peritoneum is also removed, fat associated with rectum and reconstruction
- Tumor has a clear distal margins, tumor is located > 2 ~ 5 cm from anal verge
 121
Abdominal perineal resection (APR)
- Not a sphincter sparring surgery
- Removal of sigmoid colon, rectum, along with TME, and anus
- Permanent colostomy is performed
- Done in patients with a failed LAR
- Done when tumor is located < 2 ~ 5 cm from anal verge, distal margins are
positive
- Most common indication for APR : local recurrence after LAR

Chemotherapy for colon cancer

Neo-adjuvant chemotherapy (given before surgery to down stage)
- No role in colon cancer
Adjuvant chemotherapy
- Indications : Stage III/ IV disease (nodal disease)
III : curative intent
IV : palliative intent

r First line regime : FOLFOX

FOLFIRI
Capeox

FOLFOX
Folinic acid (Leucovorin), 5-fluorouracil, and oxaliplatin
- most commonly used regime in India

FOLFIRI
Folinic acid (Leucovorin), 5-fluorouracil, and irinotecan

Capeox (Xelox)
Capecitabine and oxaliplatin
- First line regimen in western countries
 122

Second line regime : Biological agents (targeted)

i. VEGF : Bevacizumab (active against VEGF A)
Ziv-aflibercept (active against VEGF A and B)
ii. EGFR : Cetuximab
Panitumumab
- No effect in KRAS mutation patients
iii. Multi-targeted kinases : Regorafenib
iv. Anti-CEA molecules : Labetuzumab

Chemotherapy for rectal cancer

Neo-adjuvant chemotherapy
- Done when tumor is within 2 ~ 5 cm from anal verge (to perform LAR)
Adjuvant chemotherapy
- Indications : all patients who have received neo-adjuvant chemotherapy
are candidates for adjuvant chemotherapy (regardless of nodal status
or pathological data)
- Mainstay for rectal cancers
 123

Radiotherapy
- Radiotherapy in colon cancer has absolutely no role
(Results in strictures, stenosis, radiation enteritis)
- Rectal cancer :-
a. Neo-adjuvant radiotherapy - most commonly used techniques to
bring down the tumor for LAR category
b. Adjuvant radiotherapy

Colon cancer

Node — Node +
Distant metastasis
No distant metastasis No distant metastasis

Surgery Surgery + chemotherapy Surgery + palliative

chemotherapy

Rectal cancer

Neo-adjuvant therapy (chemo-radiation) Used only for node +

and > T1 disease

Surgery

Adjuvant chemotherapy ± radiotherapy

xiv. Surveillance :-
- CEA : every 6 month for 5 yrs
- CT abdomen, chest, pelvis or PET-CT : every year for 5 yrs
- Colonoscopy at first year — normal, then repeat every 3 yrs — normal, then repeat
every 5 yrs
 124

HEPATOLOGY
 125

Introduction to Hepatology
LFT
Enzymes

Live cell damage Cholestasis

AST (SGOT) ALP

ALT (SGPT) GGT

5’ nucleotidase
Leucine aminopeptidase

Synthetic markers

Albumin PT/ INR Cholinestrase

Bilirubin handling

Hepatitis ≠ Liver failure

Hepatitis = hepatic inflammation (increased liver enzymes- lab)
Liver failure = coagulapathy (PT/ INR elevation) and encephalopathy (clinical)

Liver failure

Acute liver failure Chronic liver failure

< 26 weeks > 26 weeks
6 months > 6 months
Jaundice Jaundice
Liver failure Liver failure
Hepatitis Hepatitis

Fulminant hepatitis/ fulminant liver failure

(outdated term)
 126

AST ALT
i. Normal levels < 40 i. Normal levels < 40
ii. Non-specific ii. Very specific for liver injury
(seen in liver, heart, (predominantly seen in liver)
RBC, muscles, kidney)
iii. ASTm - 80% iii. 100% cytosolic type
ASTc - 20%
(ASTm : AST of
mitochondrial type,
ASTc : AST of cytosolic
type)
iv. Half life : ASTm > ASTc iv. Half life : 47 hrs
(87 hrs) (17 hrs)

AST and ALT elevated :-

i. Hepatocellular injury (liver injury) (> 3 times upper limit of normal)
ii. Cholestasis (can cause liver injury) (< 3 times upper limit of normal)

AST elevated and ALT normal :-

(No hepatocellular injury)
i. Hemolysis — LDH/ AST ratio = ≥ 30 (LDH2 > LDH1)
ii. Rhabdomyolysis
iii. Acute MI (LDH1 > LDH2)

AST and ALT elevated > 3 times upper limit of normal = Hepatocellular injury
 127

Hepatocellular injury

AST/ ALT < 1 AST/ ALT > 1

Hepatocellular injury of Hepatocellular injury of

inflammatory type post-necrotic type

i. Uncomplicated hepatitis i. Alcoholic hepatitis

(ALT levels high) (AST/ ALT ≥ 2 : De Ritis ratio)
- Eg: Viral hepatitis ii. Fulminant liver failure/ cirrhosis
ii. NAFLD iii. HCC/ metastasis (cholestatic pattern,
not hepatocellular injury pattern)
ALP
i. Normal limit : 40 ~ 120
ii. Half life : 72 hrs
iii. Non-specific enzyme — present in :- (a) Biliary radicals,
(b) Intestine,
(c) Germ cells,
(d) Placenta,
(e) Liver,
(f) Bone & kidney

iv. Elevated ALP :-

i. Biliary pathology (> 2 times of upper limit of normal)
ii. Hepatocellular disease (< 2 times of upper limit of normal)
iii. Extra-hepatic sources :
(a.) Pregnancy [third trimester] and children [physiological]
(b.) High bone turn over - children, Hyperparathyroidism, Paget’s disease,
(osteoblasts) Bone metastasis

v. Reduced ALP :-
i. Wilson’s disease (clinically relevant)
ii. Hypothyroidism (decreased T4)
iii. Zinc deficiency
iv. Pernicious anemia
v. Hypophosphatasia (AR disorder affecting the bone)
 128
GGT
i. Normal limit : 10 ~ 60
ii. Enzyme is membrane bound in the biliary radicals
Important for glutathione metabolism and amino acid transport
Induced by various drugs
iii. More sensitive for biliary disease (more specific)

iv. Elevated GGT :-

i. Biliary disease
ii. Hepatocellular disease
iii. Alcohol abuse (isolated GGT elevation)
iv. Phenytoin (induces GGT)
v. Diabetes
vi. CKD

Patterns

AST & ALT elevated > 3 times AST & ALT elevated < 3 times
upper limit of normal upper limit of normal
ALP elevated < 2 times upper ALP elevated > 2 times upper
limit of normal limit of normal

Hepatocellular injury pattern Cholestatic pattern (Biliary disease)

Albumin
i. Predominant protein circulating in blood
ii. Function : Maintaining colloidal osmotic pressure (fluids stay within vascular
compartment)
Transport protein (Liver — albumin carries unconjugated bilirubin)
iii. Half life : 21 days

iv. Low albumin :-

i. Reduced synthesis (chronic conditions)
- Liver disease
- Malnutrition
 129

ii. Increased loss (chronic conditions)

- Nephrotic syndrome
- Protein losing enteropathies
iii. Internal redistribution (within interstitial compartment)
(acute conditions)
- Sepsis
- CHF
+ Chronic inflammatory diseases — low albumin (negative acute phase reactant)

Pt/ inr
Elevated PT/ INR :-
i. Reduced synthesis of clotting factors
- Liver disease
- Vitamin K deficiency
- Important in cholestasis disease
— Loss of bile
— Preventing the absorption of vitamin K
— Elevated PT/ INR
— Coagulopathy
- Malnutrition - typical vitamin K deficiency
- Malabsorption
[fat malabsorption- celiac disease/ ileal disease/ pancreatic disease]
- Broad spectrum antibiotics
- Hemorrhagic disease of newborn
- Warfarin (affects vitamin K dependant clotting factors)
ii. Increased consumption of clotting factors
- Disseminated Intravascular Coagulation (DIC - elevated APTT, low
fibrinogen, elevated D-dimer)
 130
Bilirubin handling

Macrophages Liver
Bilirubin
RBC (Unconjugated -
attached to albumin)
Conjugated bilirubin
Enterohepatic (Bile)
circulation

Reabsorb

Intestine
(Bacterias)

Urobilinogen
Kidneys
Stercobilinogen

Urobilinogen
Excreted as stercobilin
Urobilin

Yellow color of stools

Straw yellow color of urine

Loss of Enterohepatic circulation :- Sever cholestasis

— Causing : i. Pale stools
ii. Absent urobilinogen in kidney (Not conjugated bilirubin)

Hepatocyte handling of bilirubin :-

 131
Blood
Hepatocyte
Albumin UGT 1A1
enzyme Bile canaliculi
Bilirubin
Unconjugated Bilirubin diglucuronide
bilirubin UGT 1A1
bound to enzyme MRP2/ CMOAT
Ligandin
albumin Bilirubin glucuronide

Cytoplasmic area ER area Cytoplasmic area

Excreted into bile

Conjugated bilirubin

Jaundice
Elevation of bilirubin : Jaundice (Hyperbilirubinemia)
Serum bilirubin > 3 mg/ dL
(Icterus : clinical diagnosis, yellowish discoloration of sclera)
Serum bilirubin ≥ 4 ~ 5 mg/ dL — mucous membranes discoloration
Hyperbilirubinemia

Unconjugated Hyperbilirubinemia Conjugated Hyperbilirubinemia

i. Due to overproduction
a. Hemolysis (peripheral hemolysis)
b. Ineffective erythropoiesis
ii. Reduced uptake of bilirubin by hepatocytes
a. Porto-systemic shunt — Cirrhosis
b. Drugs
- Rifampicin
- Probenecid
- Sulphonamides
- Penicillin
- Contrast agents
iii. Defective conjugation
 132

Defective conjugation

Inherited causes Acquired causes

i. Gilbert syndrome i. Breast milk jaundice (compound

ii. Crigler najjar syndrome in breast milk : 3α 20β-pregnanediol
causing defective conjugation)
ii. Hyperthyroidism (elevated T4)
iii. Drugs : Atazanavir/ Indinavir
Chloramphenicol
Gentamicin
Novobiocin

NORMAL
Hepatic
Hepatic artery vein
Sinusoids
IVC Heart
Portal vein Systemic
circulation
Space of disse
Mesenteric Hepatocytes
circulation

- Stellate cell is the most important constituent of space of disse (maintains the integrity)
 133
PHYSIOLOGICAL PORTO-SYSTEMIC SHUNT
Hepatic
Hepatic artery vein
Sinusoids
IVC
Portal vein Systemic
circulation

Liver cell failure

Unconjugated
bilirubin
Sinusoids Elevated
unconjugated
bilirubin

Liver cell failure

Causes :
i. Elevation of bilirubin in cirrhosis/ liver failure
ii. Ammonium levels in encephalopathy
iii. Coagulopathy

Conjugated Hyperbilirubinemia

Elevated ALP Normal ALP

Cholestasis Canalicular defects

Intra-hepatic Extra-hepatic Congenital :

cholestasis cholestasis - Dubin Johnson syndrome
Obstructive - Rotor syndrome
- Choledocholithiasis
- Bile duct injury/ stricture
- Cholangiocarcinoma
- Periampullary cancer
(Pancreatic head tumors)
 134

Intra-hepatic
cholestasis

Obstructive Non-obstructive
- Space occupying - Primary biliary cirrhosis
lesions of liver - Progressive familial intra-hepatic cholelithiasis
- Intra-hepatic cholelithiasis of pregnancy (ICP)
- Drugs : especially OCP

Liver enzymes
± Jaundice
Elevated Normal

Pattern

Hepatocellular Cholestatic
pattern pattern

- ALT & AST elevated - ALT & AST elevated

> 3 times upper < 3 times upper
limit of normal limit of normal
- ALP elevated < 2 - ALP elevated > 2
times upper limit times upper limit
of normal of normal

USG
Albumin

Normal Low Dilated ducts Mass lesion Normal USG

Acute Chronic
hepatitis hepatitis
 135

Acute hepatitis

History (Drug history : ATT)

USG
Viral markers
ANA
Cerruloplasmin

Patterns :

1. AST/ ALT ratio < 1

AST, ALT in 1000s (> 600)

i. Acute viral hepatitis

ii. Paracetamol poisoning
iii. Ischemic hepatits (after cardiac arrest - Shock liver)

2. AST/ ALT > 1

AST, ALT in 1000s (> 400)

Fulminant hepatitis
- Wilson’s disease (Acute fulminant Wilson’s)
- Auto-immune hepatitis (Acute fulminant auto-immune hepatitis)

3. AST/ ALT > 1

AST < 400
AST/ ALT ratio - 2 : 1

Alcoholic hepatitis (De Ritis)

 136

Chronic hepatitis

History (drugs)
USG
Viral markers
ANA
Cerruloplasmin (to rule out Wilson’s disease)
Ferritin/ Transferrin saturation (Hemochromatosis - rare)
α1- Antityrpsin deficiency (rare)

Pattern

AST/ ALT elevated (50s/ 100s)

AST/ ALT < 1

AST/ ALT > 1 — sign of cirrhosis

Enzymes : normal (cirrhosis)
 137

Cholestatic pattern

USG

Dilated ducts Mass lesion Normal USG

Extra-hepatic Intra-hepatic
Triple phase CT
cholestasis choelstasis
± AFP ± Biopsy

MRCP/ ERCP
- Serum Anti-mitochondrial
Known causes, antibody (AMA) to rule out
ERCP is both Primary biliary cirrhosis
therapeutic and - Drug history
diagnostic (OCPs, β-lactams)
- Sepsis — cholangitis lenta
(sepsis causing inflammation
of biliary radicals with
bilirubin 7 ~ 8)
- Pregnancy (third trimester)
 138

Liver enzymes

Normal

Isolated Isolated low Isolated increase

hyperbilirubinemia albumin in PT/ INR

Prior history of Acute

Congenital cause Non-hepatic cause
liver failure :
- Chronic inflammatory - Total liver failure
Check disease (severe case
- Malabsorption requiring transplant)
Unconjugated Conjugated - Nephrotic syndrome
- Sepsis
- Gilbert - Dubin If no prior history of
- CHF
syndrome Johnson acute liver failure :
- Crigler syndrome - DIC
najjar - Rotor - Vitamin K deficiency
syndrome syndrome - Warfarin use
 139

Jaundice

Pre-hepatic Heptatocellular/ Post-hepatic

jaundice Intra-hepatic jaundice
janudice
Due to : Hemolysis Obstruction

Bilirubin : Elevated Mixed bilirubin Elevated

unconjugated elevation conjugated
bilirubin bilirubin

DB/ TB ratio : < 20% 20 ~ 50 % > 50%

Urinary bilirubin : Normal/ mild

Urobilinogen : Normal/ Normal/ Absent

increased increased

Liver enzymes : Normal Hepatocellular Cholestatic

pattern pattern
- Hemolysis
- Drugs - Enzymes
- Congenital normal in
causes congenital
conditions
 140

Congenital causes of Hyperbilirubinemia

- 2 causes
i. Gilbert syndrome (common, 5 %)
ii. Crigler najjar syndrome (rare)

CN I CN II Gilbert

Main problem : Conjugation defect UGT 1A1 deficiency (AR condition)

Severity : Severe Moderate Mild

Activity of enzyme : No activity < 10 % activity > 10% activity

Serum bilirubin : ≥ 20 < 20 3 ~ 6 mg%

Age of onset : Infancy Children Adults

Liver enzymes : Normal Normal Normal

Effect of No effect Decline in bilirubin Decline in bilirubin

phenobarbitone :

Bile composition : No glucuronides Increased Increased

monoglucuronide, monoglucuronide
absent
diglucuronide
Biopsy : Normal Normal Normal

Treatment : Phototherapy No treatment No treatment

(8 ~ 16 hrs/ day) (During illness
(Irinotecan can
± Calcium in childhood,
increase toxicity)
carbonate Small increased
± Plasma risk of
exchange kernicterus)
(during illness)
± Liver
transplantation
(Adjunctive)
 141

Dubin Johnson syndrome Rotor syndrome

Inheritance : AR AR

Defect : MRP 2 (secretion defect) Unknown (G-S-T defect)

(Uptake defect)
Serum bilirubin : 3~6 3~6

Liver enzymes : Normal Normal

Brown black liver : ++ —

(Due to accumulation of
polymerised epinephrine
molecules)

Coproporphyrin levels : Normal Increased

Coproporphyrin I > III III > I

fraction : (Normal III > I) (Normal)

HIDA uptake : + —

HIDA excretion : — —

BSP test : Slow elimination + Slow elimination

(Bromsulphthalein secondary peak (no secondary peak)
test)

Conjugated birlirubin
+
Normal liver enzymes

Dubin Johnson syndrome Rotor syndrome

Brown black liver

 142

Familial Hepatocellular cholestasis

- 2 types
Benign recurrent intra-hepatic cholestasis (1-3)
Progressive Familial Intra-hepatic Cholestasis (PFIC) (1-3)

PFIC Type 2
Bile canaliculus
Bile salts PFIC Type 1
Defective
Phosphatidyl serine
— BSEP
FIC 1 — Defective
Bilirubin glucuronides
Phospahtidyl choline
GSH
MRP 2 MDR 3
Other organic anions —

— Defective

Defective PFIC Type 3

Dubin Johnson syndrome

PFIC 1 PFIC 2 PFIC 3

(Byler’s disease)
Defect in : BSEP (ABCB 11) MDR (ABCB 4)
FIC 1 (ATP8 B1)

Phosphatidylserine Bile salt Phosphatidylcholine

(flippase) export protein (lecithin) (lecithin
floppase)

Enzyme elevation : Mild increase Moderate increase Severe increase

ALP

Serum bile acids

GGT Normal Normal

 143
Serum AFP Normal
Biliary
Normal Normal
phospholipids

Pruritus : Severe Severe Moderate

Biopsy : Biliary cirrhosis Biliary Biliary cirrhosis

cirrhosis +
+ Ductular
Giant cells proliferation

Bile appearance : Coarse/ granular Amorphous Needle like crystals

Progression to 2 ~ 7 yrs 6 months to 5 months to

cirrhosis : 10 years 20 years

Treatment : UDCA
Orthotopic liver transplantation (best)
Alternative surgery : Partial External Biliary Diversion (PEBD)
(Cholecystojejunocutaneostomy)

Clinical scenario : Young child with family history of liver disease

Cholestasis
Pruritus
Fat malabsorption
Vitamin K deficiency (bleeding)

Associated deafness — PFIC 1 specific clinical finding

 144
Intrahepatic cholestasis of pregnancy (ICP)

i. Due to BSEP/ MDR 3 defects (Estrogen is thought to be the cause)

ii. Benign intra-hepatic cholestasis of pregnancy (earlier name)
iii. High risk of stillbirth, premature delivery
iv. Clinical feature : presents in third trimester
- Severe pruritus in palms and soles worst at night
v. Liver enzymes :
- Increased ALP
- ± Increased AST and ALT levels
- GGT can be normal or increased (BSEP defect - normal, MDR 3 defect - increased)
- ± Elevated conjugated bilirubin
vi. Serum bile acids : elevated — Prognostic factor
- ≥ 40 µmol/ L
- Associated with increased risk of adverse fetal outcomes
vii. USG is normal (No dilation of biliary radicals)
viii. Treatment : UDCA (hepato-protective)
ix. Recurrence rate : 60 ~ 70 %
x. Not a contraindication for breast feeding

alagille syndrome
i. JAG 1 defect
ii. Clinical features : present within 6 months of age
- Jaundice (because of cholestasis due to ductopenia - proliferation of ducts are less)
- Failure to thrive
- Cardiovascular complications (congenital cardiovascular defects)
(Most common cardiovascular complication : Primary pulmonic stenosis)
- Dysmorphic facies
- Prominent schwalbe’s line
- Butterfly shaped vertebra (due to persistence of notochord which actually prevents
the fusion of lateral halves of 2 vertebral bodies)
(Differential for Alagille syndrome, Anterior spina bifida, Jarcho Levin syndrome)
iii. Treatment : Liver transplantation
iv. Associated with little to poor prognosis
 145

ALF, Paracetamol Poisoning & Cirrhosis

Acute liver failure
< 26 weeks
Liver injury < 6 months
Liver failure
(increased liver enzymes (Encephalopathy ,
or jaundice) coagulopathy [INR > 1.5])

- Most common cause in India : Viral hepatitis (HEV - mainly in pregnant women)
- Most common cause in children : HAV
- Most common cause in adults : HEV
- Most common cause in developed countries : Paracetamol (Acetaminophen) overdose

- Causes :
A - Acetaminophen
Amanita phylloides (mushroom poisoning)
Auto-immune hepatitis
HAV
B - HBV
Budd chiari syndrome
C - HCV
CMV
Cryptogenic cause (idiopathic)
D - HDV (+ HBV)
Drugs (idiosyncratic drug reaction)
E - HEV
EBV
F - Fatty infiltration
(Reye’s syndrome, AFLP - Acute fatty liver of pregnancy requiring delivery)
G - Genetic cause (Wilson’s disease)
H - Hypoperfusion (ischemic liver — shock liver)
HSV
HELLP syndrome
Hemophagocytic lymphohistiocytosis (HLH)
 146
Liver failure — subclassifications (old):-
Hyperacute ALF Subacute
Timing : < 1 week 1 ~ 4 weeks 4 ~ 26 weeks

Prognosis : Guarded Guarded Poor

Coagulopathy : +++ ++ +
Encephalopathy : +++ ++ +
Jaundice ; + ++ +++
Survival : 35 % 10 ~ 20 % 10 ~ 15 %
(without transplant)

Management in ALF
1. Encephalopathy :-
- Lactulose ± phosphate
enemas

& Coagulopathy :-
- I.V. Vitamin K ± FFP Indication for FFP :-
i. Active bleeding + INR ≥ 1.5
2. Cerebral edema/ increased ICP :-
ii. Procedure planned + INR ≥ 1.5
- Head end elevation
- Mannitol/ 3% NaCl
- Hyperventilation
- Phenobarbitone (Avoid
benzodiazepines, sedatives)
- Others : Epoprostenol/ NAC

ALF Target :-
i. Cerebral Perfusion Pressure
HTN > 50 ~ 60 mmHg (CPP = MAP-ICP)
ii. ICP < 20 ~ 25 mmHg

Increased ICP
 147

3. Renal failure due to :-

- HRS (Hepato-renal syndrome) — Terlipressin + Albumin/
Continuous renal replacement therapy (in ICU)
- De novo renal failure — diagnose the cause
4. Prophylactic antibiotics for infections :- Antibiotics ± antifungals
5. Respiratory failure :- Intubation (in grade 3/ 4 encephalopathy)
6. Hypoglycemia :- continuous dextrose infusions
7. Disease specific management
Drugs/ Toxins :-
- Acetaminophen : NAC
- Idiosyncratic (chloramphenicol) : withdrawal
- Amanita phylloides : Penicillin G/ Silymarin ± Hemodialysis (renal failure)
Hepatotoxic :-
- HAV/ HEV : supportive
- HBV : Tenofovir/ Entecavir
- HCV (rare)

Acute hepatitis without liver failure : only supportive treatment

Non-hepatotoxic :-
- HSV : Acyclovir
- CMV : Ganciclovir
- EBV : Acyclovir ± Steroids
- Parvovirus B 19 : supportive treatment
- Adenovirus : Cidofovir
Autoimmune :-
- Auto-immune hepatitis : Prednisolone ± Azathioprine
- Metabolic disorders (Wilson’s) : Chelators + Zinc ± Plasma exchange
AFLP :- Delivery
HEELP syndrome :- Delivery
Budd chiari syndrome :- I.V. Heparin
Sinusoidal obstruction syndrome (post transplant) :- Defibrotide
Infiltrative disorders :-
- Malignancy : chemotherapy
- Amyloidosis (AL type) : chemotherapy
 148

Cryptogenic cause :- N-Acetyl Cysteine (NAC)

8. Liver transplant — indications :-
King college criteria

ALF due to acetaminophen overdose Non-acetaminophen ALF

i. pH > 7.3 (serum lactate > 3.5) despite i. INR > 6.5 + Encephalopathy (any grade)
good fluid resuscitation OR
OR ii. 3 out of 5 :
ii. 3 out of 3 for transplantation : - Age <10 or > 40
- Grade 3 or 4 encephalopathy - Total bilirubin > 17.5 mg/ dL
- INR > 6.5 (PT > 100 sec) - Coagulopathy with INR > 3.5
- Severe AKI (PT > 50 s)
(serum creatinine ≥ 3.4 mg/dL) - Duration (not hyper-acute)
- Etiology (idiosyncratic drug
reaction)

Paracetamol poisoning

i. Acetaminophen therapeutic dosage : 325 ~ 1000 mg/ dose - every 4 ~ 6 hrs

10 mg/ kg/ dose (child)
Maximum safe dose : ~ 4 g/ day or 80 mg/ kg/ day (children)
ii. Single toxic dose : 7.5 ~ 10 g (adults)
150 mg/ kg/ dose (children)
iii. Cumulative dose : > 12 g/ day
iv. Toxic dose : ≥ 350 mg/ kg/ day — 100 % toxicity
v. Pharmacokinetics :
Acetaminophen

Sulfation Glucorunidation
≥ 90 % 5% 5% ≥ 90 %

Cy P 450 enzymes Renal route Urine

Urine
(ZE1) (unchanged)

NAPQI Adding glutathione

Non-toxic NAPQI
(toxic)
 149
Too much paracetamol intake

NAC
Glucorunidation saturated

Glutathione stores depleted Replenishes

Very high NAPQI Converted to non-toxic NAPQI

Liver injury

ALF

Biopsy : centrilobular necrosis (maximum concentration of Cy P 450)

Central vein

Classic lobule

Hepatic artery Hepatic vein

Sinusoid IVC
Portal vein
Hepatocytes

Space of disse

NO Stellate cell

Sinusoid
 150
NO produced by stellate cells keep the sinusoids open

Injury/ damage to stellate cells

Cannot produce sufficient amount of NO

Stellate cell retraction

Sinusoidal size becomes smaller

Blood cannot flow easily through sinusoids

Sinusoidal Hypertension Seen in patients with cirrhosis

Portal hypertension ≠ Liver failure

- Due to increased portal pressure
(can be due to sinusoidal HTN)
i. Variceal bleed
ii. Ascites
iii. Hepato-renal syndrome
iv. Pulmonary complications
(Hepatic Hydrothorax, Portal
pulmonary HTN, Hepato-
pulmonary syndrome)
- Due to loss of function of liver
cells
i. Synthesis of coagulation
factors are affected
ii. Encephalopathy (as toxins are
not filtered by the liver)

Jaundice
- Due to poor functioning of hepatocytes
- Sign of decompensation liver disease
 151

Portal triad

Rappa port zones

Zone III

Zone I
Portal lobule
Zone II

Rappa port zones

Zone I : Peri-portal zone (2 portal triads)
Affected in viral hepatitis (councilman bodies), phosphorus &
iron toxicity, cocaine abuse, eclamptic patients
Zone II : Intermediate zone
Affected in yellow fever, beryllium poisoning
Zone III : Centri-lobular/ peri-venous zone
Affected in ischemic hepatitis, alcoholic hepatitis, sensitive to
metabolic toxins (CCl 4 , chloroform, Halothane), paracetamol
poisoning

vi. Clinical features :-

- Stage 1 : < 24 hrs
Symptomatic (can be asymptomatic) - nausea & vomiting, right
hypochondrial pain, normal LFT

- Stage 2 : 24 ~ 72 hrs
Asymptomatic, LFTs becomes abnormal

- Stage 3 : 72 ~ 48 hrs
Symptomatic, LFTs with maximum abnormality (AST, ALT in 1000s),
ALF with coagulopathy/ encephalopathy leading to death ± jaundice
 152
(indirect hyperbilirubinemia), hypoglycemias, acidosis (HAGMA) due
to oxyproline metabolite that accumulates in paracetamol
poisoning and lactate elevation, AKI (due to ATN)

- Stage 4 : > 96 hrs (upto 2 weeks)

Stage of recovery (complete, no sequelae)

vii. Treatment :-
- Activated charcoal dose of 1g/ kg to 50g within 4 hrs of injection
- NAC oral or i.v.
Oral I.V.
- For patients with no symptoms like - For patients with severe
nausea or vomiting gastrointestinal symptoms
- Start with loading dose of 140 mg/ - Loading dose of 150 mg/ kg given as
kg 1 hr infusion
- Followed by maintenance dose of - Followed by maintenance dose
70 mg/ kg given every 4th hourly (20 hr I.V. Accelerated Protocol) of
for a minimum of 17 doses 50 mg/ kg over 4 hrs (12.5 mg/kg/ hr
(72 hr Oral Protocol) for 4 hrs), followed by 100 mg/ kg
dose given over 16 hrs (6.25 mg/ kg/
hr)
- NAC is best if started < 8 hrs
- 8 ~ 16 hrs also beneficial but > 16 hrs benefit is highly questionable

Rumack Matthew Nomogram

- Helpful in estimating and continuing the doses of NAC in paracetamol poisoning
- Applied only for single dose toxicity coming with in 24 hrs

Paracetamol
levels in
blood

4 hr Time
 153

- Serum acetaminophen levels first level monitoring done at 4 hrs, then at every
4 hr interval
- If patients comes > 4 hrs then taken immediately
- If patient coming within 2 hrs of paracetamol intake, no need of serum
paracetamol, load with NAC (don’t wait for serum levels)

Paracetamol
Beyond this : start treatment
levels in
blood
Below this : withheld treatment and wait

4 hr 6 hr

- NAC is safe in pregnancy(crosses placenta and protects fetal liver), children

(mild allergic reactions like urticaria)
- NAC is not protective for AKI

- Most common side effects : gastrointestinal symptoms

- Second common side effects : hypersensitivity reactions (rashes, urticaria)
- If patients vomits within 1 hr of dose, repeat dose
- If patient vomits after 1 hr of dose, no need to repeat dose

- Indications to stop NAC :

(a) Undetectable acetaminophen levels
(b) ALT is normal OR decreased by 50 % of initial value
(c) INR < 2

- Most strongest predicator of toxicity is the dose

 154

Acute alcohol binge + paracetamol — Less damage

Alcohol uses Cy P 450 enzymes for its metabolism

Less toxicity of paracetamol

Chronic alcoholics + paracetamol poisoning — More toxic

Induction of Cy P 450 enzymes

Produces more NAPKI

More toxicity

- Cirrhosis patients have lesser effect

Effect on liver poor as liver is damaged
Have very less Cy P 450 enzymes

Less NAPKI

Can’t predict more or less toxicity

- Smoking has a higher risk

Smoking induces Cy P 450 enzymes
- Age > 40 has a higher risk
 155

Reye’s syndrome
i. Previously known as Jamshedpuri fever
ii. Features : children < 19 years (most common in 5 ~ 10 years of age)
+ recent viral illness (influenza, varicella)
+ History of salicylate use (Aspirin)
+ presenting with Acute liver failure (encephalopathy due to
hyperammonemia ± jaundice/ coagulopathy, acidosis, hypoglycemia)
iii. Biopsy : steatosis (micro-vesicular)

Due to salicylate use

Causing hepatic mitochondrial injury

Produces decreases Inhibits fatty

Viral illness
ATP production acid oxidation

Dangerous to liver cells Steatosis

Acute liver failure

iv. Treatment : supportive management

Aspirin use in children (mostly < 1 year olds) with Kawasaki disease is not associated
with Reye’s syndrome. (No evidence supporting it found during studies)

In children using valproate, reye’s syndrome like picture presentation.

Valproate causes severe steatosis.
Valproate use causing reye’s syndrome like picture is Valproate hepatotoxicity.
 156

Chronic liver disease

Cirrhosis :- Most common cause in India : Alcohol > chronic viral hepatitis
Chronic liver disease :- Most common cause in India : chronic HBV > chronic HCV
(Non-cirrhotic disease) (Western countries : HCV)
HCC :- Most common cause in India : chronic HBV > chronic HCV
(Western countries : HCV)
Orthotopic Liver Transplantation :- Most common cause in the entire world : chronic HCV
i. Etiology :-

Hepatotoxicity Inflammatory damage Metabolic disease

Alcohol Chronic viral hepatitis NASH

Drugs (methotrexate, Primary biliary cholangitis/
amiodarone) primary sclerosing cholangitis
Aflatoxin Auto-immune hepatitis
Parasitic infection
(schistosomiasis,
leishmaniasis)
Hemochromatosis
Wilson’s disease
α1-antitrypsin deficiency
(specific forms)
Hepatic vein congestion
(Budd Chiari syndrome,
cardiac cirrhosis)

Cirrhosis

≤ 3 mm > 3 mm

Micro-nodular Macro-nodular
(Uniform (Non-uniform involvement of hepatic lobules)
Alcohol
involvement
Metabolic diseases Chronic viral hepatitis
of hepatic
Primary biliary cholangitis Auto-immune hepatitis
lobules)
Galactosemia/ Indian childhood
cirrhosis
Budd Chiari Syndrome

Late stages
Becomes
Macro-nodular cirrhosis
 157

ii. Clinical features :-

Hand/ nail Face Chest wall Abdomen

1) Leukonychia 1) Telangiectasia 1) Gynecomastia 1) Caput
2) Palmar 2) Paper dollar in males 2) Splenomegaly
erythema skin 2) Breast 3) Ascites
3) Clubbing 3) Tongue atrophy in 4) Loss of
4) Duphytren’s erythema females secondary
contracture 4) Scleral icterus 3) Spider sexual hairs,
5) Terry’s nails 5) Xanthelasma angioma Testicular
6) Asterixis (PBC) (hyper- atrophy
(negative 6) Fetal estrogen) 5) Cruveilhier
myoclonus) 7) Bilateral Baumgarten
parotid murmur
enlargement

iii. Investigations :-
a. LFT
Serum protein electrophoresis (decreased albumin, increased γ-globulin fraction)
with reversal of A/G ratio
b. PT/ INR
c. CBC : Thrombocytopenia (Hypersplenism)
(Platelets > 50,000)
± Leukopenia ± Anemia
d. Peripheral smear : Macrocytes, spur cells, target cells
e. Ultrasound : If cirrhosis
— Nodular liver surface
± Reduced liver span
± Relative hypertrophy of caudate lobe (Budd Chiari syndrome)
± Atrophy of right lobe
± Heterogenic echoes
± Ascites Signs of portal hypertension
± Splenomegaly
Portal vein doppler — portal vein diameter ≥ 1.3 cm : Portal hypertension
(+ Reversal of flow)
 158

f. Others : Strain elastography

Acoustic Radiation Force Impulse strain imaging (ARFI)
Shear wave imaging (PSWE : Point Shear Wave Elastography)
(2D Shear wave elastography)
(1D Transient Elastography/ Fibroscan)
- Liver stiffness < 6 kPa : Normal
- Liver stiffness > 7 kPa : Probable fibrosis
- Liver stiffness ≥ 11 kPa : Cirrhosis
- More applicable in patients suffering from viral hepatitis
(non-invasive scan)
Child-pugh score (cpt)
- Tells the prognosis of CLD
- 5 factors :

1 2 3
A. Albumin > 3.5 2.8 ~ 3.5 ≤ 2.7
Signs of liver dysfunction
B. Bilirubin <2 2~3 ≥3
C. INR < 1.7 1.7 ~ 2.3 > 2.3
Signs of liver failure
D. Encephalopathy None Mild to Severe
moderate Grade 3, 4
Grade 1, 2
Sign of portal hypertension E. Ascites None Diuretic Diuretic
repsonse resistant

- CPT score : 5 ~ 15 1 yr survival 2 yr survival

Score 5 ~ 6 :- Child class A — Observe and medical 100 % 80 ~ 100 %
(Score 5 in normal people) management
Score 7 ~ 9 :- Child class B — Medical management 80 % 60 %
± Orthotopic liver
transplantation
Score 10 ~ 15 :- Child class C — Palliative care 40 % 35 %
 159

Meld scoring
- Commonly used for allocating organs for transplantation
= 3.8 x log e (Serum Bilirubin) + 11.2 log e (INR) + 9.6 log e (Serum creatinine) + 6.4
- Factors used are :- Bilirubin
INR Mnemonic : CBI
Serum creatinine
- Model for End stage Liver Disease score
- MELD-Na includes sodium levels also

Hormones in cirrhosis, liver failure

Increased Decreased
i. Renin i. Cortisol
ii. Noradrenaline
iii. ADH
 160

Variceal Bleeding &

Introduction to Viral Hepatitis
Ugi bleed Lgi bleed

(Proximal to ligament of Treitz) (Distal to ligament of Treitz)

1. Etiology :
i. Erosive/ inflammatory etiology (MC)
- PUD (30 %, most common cause) - Diverticulosis (30 %, MC)
- Gastritis/ duodenitis/ esophagitis - IBD (ulcerative colitis)
- (Infectious) Diarrhea
ii. Vascular cause
- Variceal bleed (2nd MC) - Hemorrhoids
- Esophageal varices - Ischemia (Ischemic colitis,
- Gastric varices mesenteric ischemia)
- Dieulafoy lesion - Rectal varices
- Angiodysplasia
(right colon - MC)
- Most common vascular
cause of LGI bleeding
- Common in age > 60
- Patients with End Stage
Renal Disease
- Von Willebrand disease
- Aortic stenosis
(Heyde’s syndrome)
iii. Tumors
- Esophageal/ gastric cancers - Colorectal cancers
(right sided - colon)
iv. Traumatic
- Mallory weiss tears - Iatrogenic
v. Miscellaneous
- Portal hypertension gastropathy - Anal fissures
- Anticoagulants - Anticoagulants
 161

2. Clinical features :
- IDA - IDA
- Hematemesis - Hematochezia
- Malena (5 ~ 14 hrs)

UGI bleed

Hemo-stability

Stable Unstable
Stabilize

Endoscopy < 24 hr Endoscopy ASAP

i.v. PPI x 72 hrs
continued post
Identify the source
endoscopy

Yes No

Specific treatment Colonoscopy

Normal Abnormal

Small bowel source of Specific treatment

bleeding suspected
 162

Bleed categorized based on

PUD Forrest classification
the endoscopic appearance

Class I Class II Class II

Active bleeding Signs of recent Clean ulcer base

bleeding (no active No evidence of bleed
bleeding)

I A : Active spurting of
bleeding
II A : Non-bleeding visible vessel
(highest risk of re-bleeding
& hemo-instability)
II B : Adherent clot
I B : Oozing bleed (non-pulsatile)
II C : Flat pigmented base

High
risk
stigmata No endoscopic
treatment
i.v. PPI x 72 hrs
Endoscopically treated post endoscopy

Epinephrine injection
(1 : 10,000)
+
Any 1 :
- Thermocoagulation
- Hemoclips
 163

Dieulafoy lesion Dilated submucosal artery

Location Causes Treatment :

Routine endoscopic
Fundus Intermittent therapy
(6 cm from bleeding
gastro-esophageal
junction)

Mallory weiss syndrome

Retching, vomiting Location Bleeding self

of unrelaxed cardia limiting
Precipitating
Partial tear Cardia of esophagus factor : alcohol
(at lesser curve)

Cameron’s lesion

Occult GI bleed

IDA

GAVE
Common in :
Watermelon stomach - Portal Hypertension
Chronic bleed
- End stage Liver disease
Stripes of ectopic vessels Slow UGI bleeds - Scleroderma
(venules) in stomach (occult bleed)
Treatment : Endoscopic Argon
plasma anticoagulation (MC)
IDA
 164

Portal hypertension gastropathy

Chronic blood loss

Treatment : Reduce portal
pressure using Propranolol
IDA or TIPS

Hemobilia Post-procedural (MC - post-ERCP)

UGI bleed
Treatment : conservative

Quincke’s
If uncontrollable bleeding
traid
Obstructive Biliary colic
jaundice Auto-embolization

hemosuccus pancreaticus

Pseudocyst (Pancreatic Endoscopy

pathologies), post-ERCP
(Biliary pathologies)
Source of bleed : Pancreatic duct
(Ampulla of vater)
UGI bleed
 165

Aortoenteric fistulla’s
i. Primary
ii. Secondary Location Diagnosis : based
Clinical features :
on CT contrast
- Transient initial
Post AAA repair D3 Duodenum (MC) self limiting
(3 ~ 5 years after) bleeding (warning)
Aorta
- Followed by
D1
Massive UGI bleeding massive bleeding

D2

D3 Communication formed

complete Rockall score for PUD bleed

- Predictor of mortality after UGI bleed
A Age
(more the age - more points - poor prognosis)
B Blood pressure (SBP)
(more hypotension- worse prognosis - more risk of death)
C Co-morbidities
(more the co-morbidities - more the risk of death)
(Renal & Hepatic failure [3 points] >> Cardiac failure [2 points])
D Diagnosis made in endoscopy
(normal - score 0, mallory weiss tear - score 0,
malignant lesions - score 2, benign lesions - score 1)
E Endoscopic stigmata of recent bleeding
(Lower stigmata - 0 points, higher stigmata - 2 points)
+
PR Pulse rate
(more PR - higher risk of death)
 166

Variceal bleed

History of liver disease,

portal hypertension Supportive management
+
Endoscopy within 12 hrs
UGI bleed = Variceal bleed (or ASAP)

Broad spectrum Esophageal varices Gastric varices

antibiotics (ciprofloxacin,
levofloxacin, Ceftriaxone, EVL (EVBL) Local cyanoacrylate
piperacillin tazobactam) glue injection (MC)
for 5 ~ 7 days (to reduce Success OR
Fail
risk of spontaneous Endoscopic ultrasound
bacterial peritonitis) Repeat endoscopy guided coil
Secondary embolisation (Most
Vasoactive agents prophylaxis effective)
Success
(decrease portal (propranolol) Fail
pressure) : terlipressin
(reduces mortality, Success Fail
Interim balloon Rescue/
preferred), octreotide for
3 ~ 5 days salvage
Secondary
+ - Sengstaken
TIPS
prophylaxis
Salvage
Transfusion TIPS
blakemore tube
Hb < 7 PRBC (gastric and
+ esophageal balloons Interim balloon
Platelet transfusion with 3 ports)
Platelets < 50,000 - Minnesota tube
+ (gastric and
i.v. Fluids esophageal balloons
with 4 ports)
Urine output > 0.5 ~ 1
- Linton Nachlas
mL/ kg/ hr or > 50 mL/ hr
tube (gastric
balloon only)
Mnemonic : T I V A
 167
MD

GG GG
GG
EE
E
Sengstaken Minnesota tube
Linton Nachlas tube
blakemore tube

Sarin’s classification for Gastric varices

Gastroesophageal varices 1 : gastric varices on lesser curve
GOV 2 : gastric varices on greater curve
Intra-gastric varices 1 : varices located on fundus of stomach
IGV 2 : varices on body/ antrum/ pylorus of stomach

- Gastric varices due to splenic vein thrombosis is treated with :

- Emergency Splenectomy (best treatment
 168

Viral Hepatitis

Acute infection
— Depends on the type of infection

HAV HBV HCV HDV HEV HGV

Picornaviridae Only DNA virus Flaviviridae Deltaviridae Calciviridae

group group group group
Hepadnaviridae
(incomplete
group
particle)

Incubation phase Prodromal phase Icteric phase Recovery phase

i. Asymptomatic i. Flu like symptoms i. Jaundice i. Asymptomatic

ii. Infectious ± mild RUO pain ± mild RUQ pain ii. ALT : normal
iii. ALT : variable ii. ALT : invariable elevated ii. ALT : elevated iii. Bilirubin :
iv. Serology : variable iii. Serology : + iii. Serology : + normal
v. HAV : 2 weeks iv. Duration : 3 ~ 5 days iv. Develops
HBV : 3 months (Progress to icteric phase) protective
HCV : 6 weeks antibodies

Anicteric phase ALF (< 1%)

Risk factors :-
No jaundice
1. Age > 40
2. History of CLD (HAV, HEV)
Outcomes 3. Seroconversion
4. HDV superinfection with HBV
Resolution Chronic hepatitis Cirrhosis 5. Pregnancy with HEV infection
± HCC - increases risk of ALF by 15 ~ 20 %

CLD
 169

- HCV has not been demonstrated to produce ALF.

ALF

Coagulopathy/ encephalopathy

Bilirubin > 10
+
ALT > 10,000

- HAV and HEV are not associated with chronicity (No chronicity, no cirrhosis, no HCC)
- HCV has maximum risk of chronicity
- Risk of developing chronicity in HBV is 100%
- Chronicity of HBV α Age
- Lower immunity — higher risk of chronicity :-
Risk of chronicity
Newborns 90 % Most of chronic cases : Perinatal
Infants 50 % transmission during childbirth
Children 20 % (Indian subcontinent)
Adults <1~5% (Western : needle stick injury)
 170

HAV HEV
i. Feco-oral route i. Feco-oral route
ii. Food and water ii. Food and water
(Sea food)
iii. Person-to-person transmission
iv. Sexual transmission (especially MSM)

Transmission
route
25 ~ 30 % cases : Unknown route of
transmission (especially for HBV, HCV)
HCV
i. Parenteral route
(I.V. drug users - MC in west)
HBV ii. Blood transmission (rare)
i. Parenteral route iii. Sexual route (rare)
ii. Perinatal transmission (MC in India) iv. Vertical transmission (rare)
iii. Sexual transmission (Hetero, MSM)
iv. I.V. drug users
v. Blood transmission
vi. Needle stick injury (MC in west)

- HAV and HEV :

- No chronicity
- No cirrhosis or HCC
- Produces ALF

- Most common cause of ALF in India : Viral hepatitis (HEV)

- Children : HAV
- Adults/ pregnant women : HEV
- Most common cause of ALF in Western countries : Paracetamol poisoning
 171
Extra-hepatic manifestation

HAV HEV
i. Arthritis i. Cryglobulinemia
ii. Adult onset Still’s syndrome ii. Glomerulonephritis
iii. Aplastic anemia iii. Pancreatitis
iv. Interstitial nephritis iv. Oden Barre syndrome (GBS0
v. ATN v. Myocarditis
vi. Polymyosis vi. Aplastic anemia, hemolytic anemia
vii. Rhabdomyolysis vii. Myositis

HBV

i. Glomerulonephritis (MC)
(Most common - membranoglomerulonephritis)
ii. PAN
iii. Cryoglobulinemia (rare)
iv. Polyarthritis
v. Serum sickness
vi. GBS
vii. Lichen planus
viii. Bullous pemphigoid

HCV
i. Cryoglobulinemia (MC extra-hepatic manifestation)
ii. Glomerulonephritis (most common - MPGN type I, immune complex type)
iii. Metabolic syndrome X - predisposed to T2DM
iv. Porphyria cutanea tarda
v. Lichen planus
vi. Secondary sjögren
vii. Vasculitis
viii. Polyneuropathy
ix. B cell NH lymphoma
 172
Antibodies produced :

Protective antibodies Non-protective antibodies

- Formed against the external viral - Developed against internal viral

proteins (coat, surface proteins) proteins
- Conveys long lasting immunity - Not long lasting
- Eg :- Anti-HAV (HAV) - Coveys partial immunity
Anti-HbS — Recovered - Helps with diagnosis
(HBV) - Eg :- Anti-HbC
Anti-HbE
Anti-HCV
Anti-CMV/ EBV/ HBV

Hepatitis a virus
i. Genotype 1 (MC in India)
ii. Sero-prevalence α Age (increased age : increased HAV)
iii. Fecal excretion α Infectivity
iv. Infectivity :
2 weeks Symptoms 1 week
Infectivity period
(Neonates, immunocompromised — months)
v. Serology : Antibodies developed

Anti-HAV IgM Earliest evidence of infection

Diagnostic antibody of acute
infection of HAV
Anti-HAV (total) - later formed.

Anti-HAV IgM Anti-HAV (total)

+ + Acute infection

- + Remote infection (recovered)

- - No evidence of current/ past infection

 173

vi. Treatment : supportive only

vii. Prophylaxis :-
- Pre-exposure prophylaxis : Inactivated vaccine
- 2 doses at 0 and 6 ~ 18 months
- Age > 19 : full dose
- Age < 19 : half dose
- Post-exposure prophylaxis :
- Vaccine within 2 weeks and HAV Immunoglobulin (ASAP, 0.02 mL/ kg IM)

Hepatitis e virus
i. Most common in India : Genotype I
ii. ALF especially in pregnant individuals
- 15 ~ 20 % chance of developing ALF
- Treatment for ALF with HEV : Ribavirin ± PEG-IFN α
(Contraindicated in pregnancy)
iii. Asymptomatic infection
Subclinical infection (anicteric infection)
Symptomatic infection (acute hepatitis)
iv. Infectivity :
2 weeks Symptoms 4 weeks
Infectivity period
v. Serology :-
- Anti-HEV IgM : Acute infection
(persist for 4 ~ 6 months)
- Anti-HEV IgG : remote infection
vi. Prophylaxis : Vaccine only in China and Nepal
 174

HAV HEV

i. Feco-oral route transmission (MC)

ii. Spectrum of infection : Subclinical

Jaundice

iii. Most common in children
iv. Vaccine + HAV immunoglobulin
v. Infectivity : 3 weeks
vi. Treatment : supportive
vii. Diagnosis : Anti-HAV IgM
ALF
iii. Most common in adults
Endemic in Indian subcontinent
ALF risk very high in pregnant women
iv. Vaccine only available in China and Nepal
v. Infectivity : 6 weeks
vi. Treatment : supportive
If ALF : Ribavirin ± PEG-IFN α
(contraindicated in pregnant women)
vii. Diagnosis : Anti-HEV IgM

Hepatitis b virus
Natural history

Asymptomatic (mostly) Symptomatic (20 ~ 25 %)

Mostly subclinical anicteric course Acute hepatitis (jaundice clinically

(75 ~ 80%) indistinguishable)

Recovery Chronic HBV > 99% : recovery

(65 ~ 70 %) (< 5 ~ 10%) < 1% : ALF
Chronic HBV α Age Treatment : supportive
No treatment
Spontaneous clearance management
(1%/ year) If ALF : TDF (Tenofovir) or
Chronic hepatitis Entecavir
(progresses to CLD)
Cirrhosis
HCC (with or without cirrhosis)
Treatment based on indications
 175

- Baltimore classification : HBV — Class 7 (polymerase and reverse transcriptase activity)

Genome

ORF

ORF-P ORF-S ORF-C ORF-X

Produces Produces Produces core Produces X antigen

polymerase surface protein and E thought to be a
antigen antigen transcriptional
- HBV activator (postulated
polymerase to have a roll in HCC)
(having 4
domains)

Pre S1 Pre S2 S protein Pre C C gene

S protein : produces small surface antigen
S protein + Pre S2 : produces medium surface HB C Ag
antigen
S protein + Pre S2 + Pre S1 : produces large HB E Ag
surface antigen (Main surface antigen) HB C Ag : not present in blood
- Non-infectious (used for vaccine formations)
- Forms protective antibody
(outer envelope protein)
- Produced in excess.
- Minor surface antigens :- Small and Medium
surface antigens.
 176
Australia antigen

Envelope

Small surface antigen

Medium surface antigen

Large surface antigen

Envelope alone with with only surface antigen = Australia antigen

(No DNA, empty inside)
Australia antigen present in 2 forms :-
- Spherical form (22 nm in diameter)
- Tubular form
 177
Dane particle

DNA polymerase

Capsid
Envelope

Genome

Partially closed ds DNA

(3.2 kilo base pairs) Large surface antigen

Dane particle (infectious)

Serological subtypes

1st antigen 2nd antigen 3rd antigen

a y or d w or r

ayw : Genotype D and E

(D is most common in India)
adw : Genotype A, B, F, G, H (most common in world)
ayr : Genotype C
adr : Genotype C

- Genotype D > A/ C — most common in India

- Genotyping not important for HAV, HEV, HBV
Genotyping is important for HCV
 178

Life cycle

Heparan sulfate
NTCP (bile acid transport protein)
Endocytosis
(unsheathed)

Viral particles
Enveloping
Proteins
Host Host mRNA
Ribosomes

ccc DNA Pg mRNA

Partial ds DNA

Infect
HBV polymerase other
cells
Partial ds DNA

Pg mRNA (template)
Reverse transcriptase
Complimentary DNA
Polymerase activity
Partial ds DNA
 179

Immunopathogenesis

Not cytopathic Immune damage

(least cytopathic - HBV) Antibodies formed

CD 8 cytotoxic
Non-protective Protective lymphocytes
Anti-HbC Anti-HbS
Anti-HbE (outer particle) Damage hepatocytes
(inner particles)
 180

Anti-HBc (total)
Surface antigen i. Acute infection
i. Very sensitive marker for HBV ii. Window period
ii. Screening test iii. Chronic infections
- Surface antigen positive : HBV infection iv. Flare
- Surface antigen negative : Can be infectious v. Occult HBV
(usually non-infectious) Window period vi. Resolved
Occult HBV infection vii. Not seen in resolved individuals

HBcAg
Anti-HBc IgG
- Not measured (not seen in blood)
- Not measured in India
i. Chronic infections
ii. Resolved infection
Serology iii. Occult HBV
Anti-HBcAg iv. Flare

i. Acute infection
ii. Window period
iii. Flare (acute on chronic infection)
HBeAg (from Pre C region)
- Directly proportional to infectivity
i. Needle stick injury (6 ~ 30%)
- E antigen positive : risk 30%
- E antigen negative : risk 6%
ii. Vertical transmission
Anti-HBs - E antigen positive : risk 70 ~ 90 %
i. No infection (exception : occult HBV) - E antigen : risk 10~ 30 %
ii. Protective antibody
iii. Anti-HBs positive : Resolved infection
Vaccinated status
Possible occult HBV infection

HBV-DNA
i. Most important marker of replication
ii. Most important marker predicting cirrhosis
iii. Most important marker predicting risk of developing HCC
iv. HBV-DNA positive : Infection (viral load)
v. HBV-DNA negative : infectious — window period
vi. HBV-DNA negative : non-infectious
 181

E antigen positive : high degree of infectivity

E antigen negative : low degree of infectivity
Seroconversion : conversion of E antigen from being positive to negative either
spontaneously or by treatment, simultaneous appearance of Anti-HBe (partially
protective antibody) marks disappearance of E antigen.
E antigen negative : virus can still replicate

Escape mutants (Pre C mutants)

Chronic HBV infection

Immune tolerance phase
- Poor immunity
- Virus proliferation is high DNA > 20,000
- DNA > 1 million ALT elevated (< 2 x)
- ALT : normal E antigen positive
- E antigen : positive
- Risk of HCC

Immune escape phase Immune active phase

- Proliferation of escape mutants - Killing of virus infected cells
- Viral production of E antigen withheld - Virus load decreases
(Pre C mutants) - DNA > 20,000
- ALT : elevation - ALT : elevated (> 2 times upper limit)
- E antigen : negative - E antigen : positive
- Proliferation of DNA (killing hepatocytes) - Highest risk of cirrhosis
- Risk of HCC - Risk of HCC
- Highest risk of cirrhosis (maximum risk)

IMMUNE control phase DNA > 20,000

ALT elevated
- Formation of anti-HBe antibodies ALT elevated (> 2 x)
DNA < 2,000
- E antigen negative : seroconversion E antigen positive
E antigen negative
- Virus dormant inside DNA
- ALT : normal (no proliferation)
- DNA undetectable (< 2,000)
- Risk of HCC
 182

Mechanism of HCC
i. Inflammation (50 ~ 80 %)
- From background inflammation
- Present in immune active phase, immune escape phase
ii. Insertional mutagenesis (20 ~ 50 %)
- Some cccDNA integrate with host genome
- Viral integration with host DNA
(natural process in viral life cycle)

Error prone

Induce mutations in host DNA

HCC development

Serological findings
HBsAg HBV-DNA Anti-HBc IgM Anti-HBc HBeAg Anti-HBs Interpretation
(total)
+ + + + + — Acute infection

— — + — — — Window period

— — — + — + Resolved infection/
vaccinated status
— — — — — + Vaccinated status

+ + — + +/ — — Chronic infection

+ + + + — — Flare

— + — + — + Occult HBV

- Flare : Acute on chronic HBC

Usually anti-HBe positive
 183

- Chronic infection :
- e antigen positive :-
i. ALT - normal, biopsy - mild/ no hepatitis

Chronic Inactive Hepatitis e antigen positive (Immune tolerance)

ii. ALT - elevated, biopsy - moderate to severe hepatitis

Chronic Active Hepatitis e antigen positive (Immune active)

- e antigen negative :-
i. ALT - normal, biopsy - no hepatitis

Chronic Inactive Hepatitis e antigen negative (Immune control)

ii. ALT elevated, biopsy - moderate to severe hepatitis

Chronic Active Hepatitis e antigen negative (Immune escape)

Hepatitis d virus
i. Rare in India
ii. Co-infection : HBV and HDV together — increases risk of chronic HBV
iii. Superinfection : chronic HBV with HDV — increases risk of ALF

Clinical scenario :- Patient with chronic HBV

Sudden decompensation (increased bilirubin. Coagulopathy,
encephalopathy

1. Flare (Anti-HBc IgM positive, Anti-HDV IgM negative)

2. HDV super-infection (Anti-HBc IgM negative, Anti-HDV IgM positive)
3. Co-infection (Anti-HDV IgG positive, Anti-HDV IgM negative)
 184

Immune Active phase Immune control

tolerance (immune active, (inactive phase) Grey zone
immune escape)

HBsAg + + + +
Anti-HBc + + + +
HBcAg + +/ — + +/ —
Anti-HBe — —/ + + +/ —
(No seroconversion) Later
DNA levels > 1 million > 20,000 : e Ag + < 20,000 Variable
(> 2 lakh IU) < 20,000 : e Ag —

Biopsy Normal Moderate to Normal Variable

severe hepatitis

ALT levels Normal Elevated Normal Variable

Treatment None Required None Depends on

biopsy

No/ mild hepatitis Moderate/ severe hepatitis

No treatment Treatment required

 185

Indications for treatment of chronic HBV :-

i. e Ag +, DNA > 20000, ALT elevated (> 2 times normal upper limit)
- Immune active
ii. e Ag —, DNA > 2000, ALT elevated
- Immune escape
iii. e AG +, DNA > 20000, ALT elevated (< 2 times)
- Grey zone
- Biopsy shows moderate to severe hepatitis
iv. e Ag —, DNA < 2000, ALT elevated
- Grey zone
- Biopsy shows moderate to severe hepatitis
v. Evidence of cirrhosis (irrespective of phases of HBV)
vi. Extra-hepatic manifestation of HBV
vii. Pregnancy (treatment to reduce vertical transmission)

Any chronic HBV patient should be monitored for HCC

(by AFP, ultrasound every 3 ~ 6 months)
 186
Treatment
Oral (first line) Parenteral

Nucleoside Nucleotide
PEG-IFN α
analogues analogues
IFN α 2a (MC used)
Entecavir Tenofovir (TDP, TAF) IFN α 2b (used only in HBV
- 0.5 ~ 1 mg/ day - TDP : 300 mg/ day and HDV infection)
(Cirrhosis — 0.5 mg) - TAF : 25 mg/ day, Not used
Most potent drug prodrug, less Given subcutaneously
Very well tolerated nephrotoxicity Side effects present includes :-
Known side effects :- Side effects :- Flu like reaction (MC)
Lactic acidosis i. Nephrotoxic Contraindications :-
(mitochondrial toxicity, ii. Reduce bone density i. Pregnancy (carrying)
rare) iii. Fanconi syndrome ii. Cytopenia
iii. Decompensated cirrhosis
Others (less potent) :- Others : Adefovir (elevated bilirubin,
Lamivudine
elevated INR)
Telbivudine
iv. Cardiac failure
Disadvantages :-
Advantages :-
i. Difficult to eradicate
i. Given for finite duration
ii. Reduced rates of
(48 weeks)
seroconversion compared
ii. No resistance found
to IFN- α
iii. Higher rates of
iii. Prolonged treatment
seroconversion
(Entecavir shows resistance)
Better in young, non-cirrhotic,
Best endpoint : till s Ag negative,
low DNA and elevated ALT,
Anti-HBs positive
favourable genotype (A > B> D)
(virus eradication)
[D : common in India]
Practical endpoint :-
[A : common in USA]
i. e Ag positive : from beginning
till e Ag negative
(seroconversion) + 6 ~ 12 mon
consolidation therapy
ii. e Ag negative : indefinite
therapy (till s Ag negative,
Anti-HBs positive)
 187

Treatment in pregnancy

HBsAg positive mother : Risk

- e Ag positive — 70 ~ 90 %
- e Ag negative — 10 ~ 30 %

Achieve seroconversion

Treatment

Mother Child
(optional)

Definite treatment in neonate period

TDF at third trimester
(if DNA levels > 2 lakh IU/ mL)

High risk of vertical transmission Hepatitis B immunoglobulin (0.02 mL/ kg)

approximately 0.5 mL intra-muscular
injection
+
HBV vaccine series (first dose) given as
soon as child is born, within 12 hrs of
birth.
 188

Vaccination

i. Course : at 0, 1, 6 months (3 doses)

ii. Immunity achieved in > 95% individuals
iii. Check response : Anti-HBs at 1 ~ 2 months post completion of vaccine series
(In high risk health care workers, patients with CKI)

Check response

Levels > 10 IU/ mL Levels < 10 IU/ mL

Responder Non-responder

Immunocompetent Immunosuppressed or Second full course vaccination

chronic hemodialysis
(CKD patient)
No further need for Responder Non-responder
repeat anti-HBs in
life, no booster Repeat annually
i. Rule out chronic
injection required
HBV
(no development of
If Anti-HBs < 10
Anti-HBs)
ii. No further need of
vaccination
Give single booster
 189

Post exposure prophylaxis

Source
Needle stick injury etc..

HBsAg +
HBsAb —
or
Untested
No treatment
(If not vaccinated — vaccinate)

Check vaccination status of exposed individuals

1. Vaccinated 2. Unvaccinated or 3. Undergoing

partially vaccinated vaccination

i. Known responder : no
treatment Hepatitis B Hepatitis B
ii. Known non-responder :- immunoglobulin immunoglobulin
(a) Hepatitis B given given
immunoglobulin given + +
+ complete complete the
reinitiate vaccine series vaccination vaccination
(b) Hepatitis B series
immunoglobulin 2
doses given
(if already 2 doses of
vaccine given )
iii. Antibody response
unknown : immediately
initiate booster + recheck
Anti-HBs
- > 10 :- no further treatment
- < 10 :- treatment like
non-responder
 190

- Dose of Hepatitis B immunoglobulin : 0.04 ~ 0.07 mL/ kg

- Site of Hepatitis B immunoglobulin : different from site of vaccine

If HBV presents as ALF ——— Chance of CLF is very less (most recover)

Depends on age :-
ALF in adults : clear off virus once recovered
ALF in children : chronic carrier state

HBV presenting as ALF :-

i. Acute infection presenting as ALF (rare)
- Recover
ii. Chronic HBV infection presenting as ALF
- In flare (spontaneous seroconversion)
or
In HBV superinfection with HDV and progress to ALF
 191

Hepatitis c virus
i. Flaviviridae group (RNA virus with RNA polymerase)
ii. Genotype is important (treatment, virulence factors, disease characteristics are
dependent on genotypes.
iii. Risk of chronicity : very high
iv. Most common genotype in India : 3 (3A)

Natural history

Subclinical Acute hepatitis

(most common) (rare, 10 ~ 15 %)

Majority
5% recover

Chronicity
No ALF

Chronic hepatitis, CLD, cirrhosis, HCC within 25 ~ 30 years

- Chronic HCV : HCV RNA persisting > 3 months

- Chronic HBV : HbsAg persisting > 6 months

Tests
Anti-HCV (total) HVC RNA

+ — Remote infection (recovered)

+ + Active infection

— — No evidence of remote/
active infection
 192

Anti-HCV

+ —

Check
No infection

HCV RNA

— +

Remote Active
infection infection

Check genotype

Start treatment

- Genotype 3A : causes maximum steatosis, steatohepatitis.

Treatment

Parenteral regime Oral (currently in use)

PEG-INF α - Direct acting anti-virals

(outdated) - Ribavirin (used in certain
conditions)

- Duration : 12 ~ 24 weeks
- Completely curable
- Sustainable viral remission > 95%
 193

Cytoplasm
Cytopathic
HCV

Nucleus

Ribosomes Tight junction

Single polypeptide chain

Non-structural proteins
C E1 E2 P7 NS2 NS3-4A NS5A NS5B
Structural
P7 : Ion channel
proteins
NS3-4A complex : Acts as protease
NS5A : Acts as viral polymerase Direct acting antivirals
NS5B : Transcription activator

NS3-4A complex NS5A NS5B

-previrs NS5A inhibitors (-asvirs) -buvirs

Simeprevir (not used) Sofosbuvir
Boseprevir (not used) Ladipasvir Dasabuvir
Paritaprevir (used) Ombitasvir
Daclatasvir
Velpatasvir
(Velpatasvir and Ladipasvir
- commonly used in India)
- No vaccine/ immunoglobulin for HCV
- Breast feeding is not a contraindication
- LSCS is not indicated in HCV.
 194

Alcoholic Liver disease, NAFLD,

and Auto-immune Liver disease
Alcoholic Liver disease
i. Most common cause of liver cirrhosis in India
Western countries : Most common cause of liver cirrhosis is : HCV > alcoholic liver disease
ii. Risk of liver cirrhosis is directly proportional to amount of alcohol consumption

1 standard drink : 14 g = 18 mL of 100% alcohol

(Standard)
10 g in Australia
20 g in Japan
Beer : 5% alcohol = 350 mL = 1 standard drink
Wine : 12% alcohol = 150 mL = 1 standard drink
Hard liquor : 40% alcohol = 44 mL = 1 standard drink
(Whiskey, gin, vodka, tequila)

Recommended safe limit :-

Males : ≤ 2 standard drinks
Females : ≤ 1 standard drinks

Alcoholic liver disease :-

Males : > 21 standard drinks per week for ≥ 2 years
OR > 210 g/ week
Females : > 14 standard drinks per week for ≥ 2 years
OR > 140 g/ week

Pathophysiology

Alcohol dehydrogenase
Alcohol Acetaldehyde
NADH Aldehyde
NADH dehydrogenase
Acetate
 195
Excessive NADH

Energy full/ replete state in liver

Energy storage

Increased fat

Increased steatosis

Increased steatohepatitis

Injury

Alcoholic fatty liver

i. Asymptomatic, reversible
ii. USG : increased liver echogenicity
iii. CT : decreased attenuation (sign of fatty liver)
iv. Biopsy : steatosis
(can’t differentiate from NAFLD)
v. Differentiating factor for alcoholic fatty liver
disease and NAFLD :-
- H/O of alcohol consumption
- If LFT is deranged (AST > ALT)
vi. Treatment : alcohol cessation

Alcoholic hepatitis
i. Symptomatic : Constitutional symptoms
± Tender hepatomegaly (RUQ)
± Jaundice
± Splenomegaly
± Ascites (portal hypertension)
± Evidence of liver failure (increased PT/ INR, encephalopathy)
ii. Partly reversible
 196

iii. LFT :-
AST > ALT
AST / ALT = ≥ 2 : 1 (de Rittis ratio)
Elevated bilirubin
Elevated PT/ INR
iv. USG : hepatomegaly ± fatty liver
v. CT : hepatomegaly ± decreased attenuation
vi. Histology : steatohepatitis (lobular inflammation)
± Mallory Denk bodies (if absent, does not rule out alcoholic hepatitis)
± fibrosis
vii. Using USG, CT, biopsy cannot differentiate NASH (non-alcoholic steatohepatitis) :-
- Significant history of alcohol
- LFT : AST/ AKT ≥ 2 : 1
viii. Treatment : Prednisolone 40 mg/ day x 18 days
Followed by tapering for 16 days

Assess response at 1 week

Using Lille’s score :-

Score > 0.45 at 1 week — Indicates poor prognosis

No improvement : discontinue steroids

- Alternative to steroids : Pentoxyfylline

ix. MELD score > 11 : predicts increased 30 day mortality

Mallory Denk bodies

- Made of misfolded intermediate filaments (cytokeratin 8 + 18)
+ P 16 ± ubiquitin
- Most commonly seen in ballooned hepatocytes
- Increased risk of development of cirrhosis
 197

Maddrey discrimination function

- Indication for steroids : discrimination factor ≥ 32
- Maddrey Discrimination function = 4.6 x [PT (T - C)] + Total serum bilirubin
PT : Prothrombin time
T : test
C : control
- Example : PT test = 35 sec
PT control = 28 sec
Total serum bilirubin = 10
DF = 4.6 x [35 - 28] + 10
= 42.2
— > 32 — Indication to start steroids

Contraindication for steroids

1. Active UGI bleed
2. Active infection (bacterial/ fungal)
3. HBV/ HCV

Cirrhosis
i. USG, CT : nodular liver
± signs of portal hypertension
± biopsy : destruction of liver architecture with nodules and with fibrotic bands
ii. Irreversible
iii. Treatment : standard cirrhosis management
 198

Non-alcoholic fatty liver disease

NAFLD NASH Cirrhosis

NASH is most common cause of cryptogenic cirrhosis

- Presents with cirrhosis for first time (no other cause for explanation)
Associated with obesity, metabolic syndrome, HAIR-AN syndrome, insulin resistance
NAFLD and NASH are diagnosed by exclusion

NASH diagnosis :
i. Absence of significant alcohol use
ii. LFT : normal
AST/ ALT < 1
Most common cause of asymptomatic LFT derangement in OPD is NASH
iii. USG : increased echoes
CT : increased attenuation
MRI : increased fat signals
or MR Spectroscopy : ≥ 5% fat in liver
Biopsy : steatosis (stage I)

Steatohepatitis
progress to
Fibrosis/ cirrhosis
iv. Biopsy scoring system : NAS (NAFLD activity score)
- Components :-
Steatosis (score 0 ~ 3)
Ballooning degeneration (score 0 ~ 2)
Inflammation - lobular inflammation (score 0 ~ 3)
- Score minimum 0, maximum 8 (in significant absence of alcohol history)
- Scores 0 ~ 2 :- No NASH
3 ~ 4 :- Probable NASH
≥ 5 :- Definite NASH

Mnemonic : S B I
 199
NAFLD diagnosis :
i. Absence of significant alcohol use
ii. Rule out other conditions that produce steatosis such as :-
(a) HCV
(b) Wilson’s disease
(c) Nutritional conditions (severe starvation, PEM, total parenteral nutrition,
rapid weight loss, bariatric surgery)
(d) Medicines :- Methotrexate,
Valproate,
Tamoxifen,
Estrogen,
Amiodarone/ Diltiazem
(e) Abetalipoproteinemia
(f) Reye’s syndrome
(g) Acute fatty liver of pregnancy
(h) HELLP syndrome
(i) Inborn errors of metabolism
iii. ± LFT deranged (AST > ALT)
iv. USG : Fatty liver
v. Biopsy : steatosis/ steatohepatitis/ fibrosis

Scoring system for NASH

- Only used after the diagnosis of NASH is made.
1. ALT AST Ratio (AAR)
- ALT/ AST < 0.6 in NASH
- ALT/ AST > 0.8 — increases risk of fibrosis in NAFLD (cirrhosis)
2. FIB 4 score
- Age x AST
Platelets x √ALT
- Score > 3.25 : increases risk of advanced fibrosis
< 1.45 : decreases risk of fibrosis
3. BARD score
B BMI (1 point)
AR AST ALT Ratio (≥ 0.8 — 1 point)
D DM type 2 (1 point)
Score ≤ 2 — rules out fibrosis
 200

4. AST Platelet Ratio Index (APRI)

= AST (patient)
AST (upper limit of normal)
Platelet count
> 1.5 — predicts fibrosis
< 0.3 ~ 0.5 — rules out significant fibrosis
5. NAFLD fibrosis score
- Age
- BMI
- AST/ ALT ratio
- T2 DM
- Platelet count
- Albumin count
- Score > + 0.675 : advanced fibrosis
< - 1.455 : no fibrosis

Gold standard for predicting fibrosis : Biopsy

Treatment of NAFLD
i. Weight loss (not rapid, gradual) of approximately 7 ~ 10 kg
- Obtained by drugs/ bariatric surgery
Drugs :- Orlistat
Liraglutide (maximum weight loss)
- Victoza used for T2DM
- Saxenta used for weight loss
Phentermine + Topiramate combination (overall MC)
Bupropion + Naltrexone combination
Bupropion
- Contraindicated in patients with seizure disorders
- Used both in weight loss and smoking cessation
Lorcaserin (banned)
Bariatric surgery indications :
1. BMI ≥ 40 (morbid obesity)
2. BMI 35 ~ 39.9 (moderate obesity) with co-morbidities
(Most commonly performed bariatric surgery : Sleeve gastrectomy)
 201

ii. Metformin
Piaglitazone DM beneficial
Liraglutide
Vitamin E (non-DM) — proven beneficial
Fish oil
Statins
ACEI
Pentoxyphylline
iii. Exercise : 10,000 steps or 200 minutes/ week of moderate exercise.

Autoimmune liver disease

Increased risk of cholangiocarcinoma (contraindication for orthotopic liver transplantation)

with PSC

Auto-immune Primary biliary Primary sclerosing

hepatitis
i. Incidence :
F>M
2 peaks :-
- children, adults
(middle age)
ii. Presentation :
- Asymptomatic, later
cryptogenic cirrhosis
- Symptomatic with :-
Jaundice/ constitutional
symptoms/ ALF
- CLD
iii. LFT :
Hepatocellular pattern
ALT, AST increased
(≥ 3 times upper limit of
normal)
ALP elevated < 2 times
upper limit of normal
cirrhosis cholangitis
i. Incidence : i. Incidence :
F>M M>F
Middle aged females Middle to old age males
ii. Presentation : ii. Presentation:
- Asymptomatic - History of IBD (> 85 %)
- Symptomatic with :- (Ulcerative colitis - MC)
Pruritus - Pain, jaundice, pruritus
± Sicca syndrome (due to increased
± Jaundice accumulation of bile
acids)
iii. LFT : iii. LFT :
Cholestatic pattern Cholestatic pattern
AST & ALT elevated < 3 AST & ALT elevated < 3
times upper limit of times upper limit of
normal normal
ALP elevated > 2 times ALP elevated < 2 times
upper limit of normal upper limit of normal
 202

iv. Auto-antibodies : iv. Auto-antibodies : iv. Auto-antibodies :

ANA + Type 1 AMA of M2 type Not required
ASMA + AIH (MC), (Antigen - M2 component p-ANCA
in adults of pyruvate dehydrate IBD related antibodies
complex of mitochondria) U. colitis :- ASCA —,
Anti-LKM 1 Type 2 pANCA +
(rare) in Crohn’s disease :- ASCA
children +, pANCA —
(Europe)
Ig G elevated Ig M elevated Ig G or Ig M elevated
v. Biopsy : Interface v. Biopsy : Ductopenia ± bile v. Biopsy : Periductular
hepatitis ± Ig G secreting duct granulomas fibrosis (onion skin.
plasma cell infiltrate Required only in some fibrosis)
Biopsy required conditions Required only in some
conditions
vi. Cholangiography : vi. Cholangiography : vi. Cholangiography :
(ERCP, MRCP) not needed (ERCP, MRCP) not needed (ERCP, MRCP) required
(Normal findings) (Normal findings) Strictures of bile ducts
(beard appearance)
MRCP/ ERCP is
completely normal in 15%
cases intrahepatic PSC
vii. USG : variable vii. USG : variable vii. USG : most commonly
Biliary tree is normal Biliary tree is normal shows extra-hepatic
biliary radical dilatation
(Rarely in intra-hepatic
PSC 15% cases are normal)
viii. Treatment : Steroids ± viii. Treatment : UCDA (best) viii. Treatment : unknown
Azathioprine
Orthotopic liver End-stage :- Orthotopic
Orthotopic liver transplantation liver transplantation
transplantation
Interim :- avoid stricture
and pain by biliary
stenting (palliative)
 203

Portal Hypertension
- Classified into 3 :-
1. Pre-hepatic portal hypertension
2. Intra-hepatic portal hypertension
3. Post-hepatic portal hypertension

Normal portal pressure : 5 ~ 10 mmHg (7 ~ 14 cm H2O)

Portal hypertension > 10 mmHg

Pre-hepatic portal hypertension

- Causes :
i. Extra-hepatic portal vein obstruction (EHPVO)
- due to portal vein thrombosis
ii. Splenic vein thrombosis
iii. Banti syndrome
- Massive splenomegaly + variceal bleed + features of hypersplenism + no EHPVO

Intra-hepatic portal hypertension

(1) Pre-sinusoidal Intra-hepatic portal hypertension
- Caused by : Schistosomiasis
Non-cirrhotic portal fibrosis (NCPF) or Idiopathic
non-cirrhotic portal hypertension
Congenital hepatic fibrosis
(2) Sinusoidal Intra-hepatic portal hypertension
- Caused by : Cirrhosis
Drugs - Amiodarone, Methotrexate
- Most common in world
(3) Post-sinusoidal Intra-hepatic portal hypertension
- Caused by : Hepatic sinusoidal obstruction syndrome (SOS)
or
Hepatic veno-occlusive disease in setting of
post-hematopoietic stem cell transplant
Angiosarcoma
Vitamin A deficiency
 204
- Vinyl chloride can cause both pre-sinusoidal and sinusoidal Intra-hepatic portal
hypertension
- Mineral oil granulomas and sarcoidosis can both cause pre-sinusoidal and post-
sinusoidal Intra-hepatic portal hypertension
Post-hepatic portal hypertension
- Above liver
- Caused by :-
i. IVC obstruction (Budd Chiari syndrome)
or
Hepatic vein obstruction
ii. Cardiac cirrhosis due to cardiac disease
(Constructive pericarditis, restrictive cardiomyopathy, chronic RV failure)

Complications of portal hypertension

SVC

Hepatic Vein IVC

RA LA

Sinusoids
RV
LV
Porto-systemic
Aorta
shunt
PA
Portal Vein (physiological)

β2
α1 α1
Portal circulation
β2 Mesenteric
vasculature
Mesenteric
capillaries Kidneys
 205

Stellate cell retraction,

reduced production of NO Increased
Hyper-
HR & net
dynamic
Sinusoidal hypertension CO
circulation

Strong increased
Cirrhosis sympathetic activity
SVC
Decreased flow
CO unchanged
Hepatic Vein IVC
RA LA

Increased Sinusoids Heart

obstruction RV LV

Porto-systemic
Liver
shunt Aorta
PA
Portal Vein (physiological)
80%
2 Varices Increased
adaptation in
Increased Decreased NO mesenteric
portal resistance circulation
pressure
β2 β2 β2
α1

Increased capillary
Kidney
hydrostatic pressure
Due to RAAS activation

Sodium overload Reduced NO

Ascites Long time, severe
Reduced perfusion
1 hypoperfusion
Coupled increased
resistance
Edema Volume overload 3 Hepato-Renal Syndrome

Increased sodium reabsorption (Urinary Na+ extremely low) Hyper activation of RAAS
 206
- Hepatic encephalopathy is not due to hepatic portal hypertension

Hepatic artery
NH3 Sinusoid IVC
NH3 Portal vein
Urea Hepatic

Space of disse Hepatocytes vein

Hepatic failure Hepatic encephalopathy

High levels of ammonia

Hepatic artery
Sinusoid IVC
NH3
Portal vein Hepatic
vein
Hepatocytes
Hepatic failure

Treatment
1. Acute variceal bleed
- Reduce portal pressure :
- Increase splanchnic resistance
(a) Terlipressin
Vasoconstriction of splanchnic circulation
(b) Octreotide
Acute drop in portal pressure
- Prophylactic drugs : non-selective β blocker — propranolol
(β2 receptors are up-regulated in portal circulation)
- Prophylactic drug used in patients with cirrhosis to reduce the risk of variceal
bleed : Nitrates (less effective)
- Increases NO through first pass metabolism
- 2nd line drug
 207

2. Ascites
(Sodium overload : most important cause)
- Diuretics (loop diuretics) + spironolactone combination
- ACEI are not given as it worsens the hypoperfusion leading to severe renal failure
- Prevent sodium resorption by giving aldosterone blocker
- High aldosterone in patients with cirrhosis : results in remodelling of liver
towards fibrosis, causing cirrhosis
- Other drugs :- Midodrine (α-agonist, vasoconstriction of splanchnic circulation)
3. Hepato-renal syndrome
- Terlipressin (primary modality) + 5% albumin (to increase vascular volume,
pre-renal failure)
Acute variceal bleed
+
Becomes refractory Orthotopic liver transplant
Ascites
+
HRS Bridging therapy to prolong life

Trans-jugular intra-hepatic porto-systemic shunt (TIPSS)

To reduce portal pressure

Shunt portal blood to systemic circulation directly

Graft : Poly-Tetra-Fluoro-Ethylene graft (PTFE)

Make connection between hepatic vein and 1

major branch of portal vein

Bypassing of sinusoids

Portal venous pressure is moving into hepatic veins

Effective procedure to reduce portal pressure

(alleviates all 3 complications)
 208

Punctures hepatic TIPSS Hyper-

parenchyma dynamic
Decreased flow SVC circulation
Hepatic Vein IVC
RA LA

Sinusoids
RV LV

2 Varices Aorta
PA
PTFE graft
placed bypassing
the sinusoids

Decreased
Increased resistance
portal
β2 β2 β2
pressure α1

Ascites
Portal pressure decreased Kidney
1
Hyper activation of RAAS

Volume overload
Edema

3 Hepato-Renal Syndrome

Liver failure : TIPSS increases the risk of hepatic encephalopathy

Moderate to severe encephalopathy : contraindication for performing TIPSS
 209
Complications of portal hypertension :-
1 Ascites

2 Varices

3 Hepato-Renal Syndrome

4 Pulmonary complications

i. Pleural effusion due to volume overload state, &

Hepatic hydrothorax = massive pleural effusion (due to ascitic fluid entering the
pleural space, more commonly on right side)
ii. Hepato-renal syndrome
iii. Porto-pulmonary hypertension (PPH)

5 Spontaneous bacterial peritonitis

- due to ascites

Diagnosis of portal hypertension

i. Clinical features : Ascites ± pleural effusion

Splenomegaly
Other signs of cirrhosis
ii. USG (doppler) :
- Portal vein diameter > 1.3 cm
- Portal flow mean velocity < 12 cm/ sec

Sinusoidal portal hypertension

(Stagnant blood, away from liver, Porto-systemic collaterals)
- Etiology : cirrhosis - nodular liver
iii. HVPG : Hepatic venous pressure gradient
- Gold standard investigation
- Diagnostic and prognostic
- Highly invasive procedure (not routinely done

HVPG = Wedge hepatic venous pressure (WHVP) — Free hepatic venous pressure (FHVP)
Gives the pressure within the sinusoids
 210

IVC
PV

FHVP
Sinusoids
WHVP
FHVP = IVC pressure + sinusoidal pressure

Pre-hepatic Pre-sinusoidal Sinusoidal Post-sinusoidal Post-hepatic

portal intra-hepatic intra-hepatic intra-hepatic portal
hypertension portal portal portal hypertension
hypertension hypertension hypertension

FHVP Normal Normal Normal Normal Elevated

WHVP Normal Normal Elevated Elevated Elevated

HVPG Normal Normal Elevated Elevated Normal

Eg :- cirrhosis
Normal HVPG = 1 ~ 5 mmHg
Portal sinusoidal hypertension ≥ 6 mmHg

Compensated cirrhosis Decompensated cirrhosis

≤ 16 mmHg > 16 mmHg

10 mmHg : patient develops variceals

12 mmHg : develops variceal bleed (mild ~ moderate)
16 mmHg : first clinical decompensation

jaundice, signs of liver failure, more variceal bleed

> 16 mmHg : risk of variceal re-bleeding
20 mmHg : increased risk of uncontrolled variceal bleed
22 mmHg : increased risk of mortality from cirrhosis
30 mmHg : increased risk of spontaneous bacterial peritonitis
 211

Treatment for portal hypertension

- Drugs :-
Increase splanchnic resistance :

1. Non-selective β blocker
2. Terlipressin/ Octreotide
3. α1 agonist - Midodrine

Decrease sinusoidal pressure

1. Nitrates
Infrequently used due to high complications
2. α blockers/ ARB’s

- Interventional therapy :-
(1) TIPSS
- Indications :
i. Refractory variceal bleed
ii. Refractory ascites
iii. Refractory hepato-renal syndrome
iv. Hepatic hydrothorax
v. SOS
vi. Budd Chiari syndrome (due to failure of conventional treatment)
- Not effective in :
i. Hepatic encephalopathy
ii. Pre-hepatic portal hypertension or pre-sinusoidal portal hypertension
(Portal vein thrombosis or splenic vein thrombosis, schistosomiasis)
iii. Coagulopathy
iv. Primary prophylaxis of variceal bleed
v. Other pulmonary complications of portal hypertension
(Porto-pulmonary hypertension, hepato-pulmonary syndrome)
vi. Hypersplenism
- Contraindications :
i. Hepatic encephalopathy
ii. Severe heart failure/ tricuspid regurgitation
iii. Mean pulmonary arterial pressure > 45 mmHg
 212

iv. Uncontrolled infection/ sepsis

v. Unrelieved biliary obstruction
vi. HCC
vii. Hepatic cyst
- Complications of TIPSS :
i. Cardiac arrhythmias (AF)
iii. Capsular punctures (33 % cases) leading to hemoperitoneum (rare)
iv. Bleeding from main portal vein (avoided by using major branches to conduit)
v. Thrombosis of graft (TPFE graft - rare)
vi. Porto-systemic encephalopathy (PSE)
- A.k.a Post TIPSS encephalopathy
- Early/ late complication
- Most common after 2 ~ 3 weeks after stent
- Refractory case : orthotopic liver transplant

Bridging procedure - Iatrogenic stent occlusion

(Embolize the stent to prevent ammonia entry into circulation)

- Most common complication after TIPSS placement is : Capsule rupture > PSE
(Not significant)

vii. Microangiopathic Hemolytic anemia (shearing of RBC due to stent)

viii. Hyperbilirubinemia
ix. Stent infection - late complication
x. Stent stenosis - late complication

(2) Surgical stent

Non-selective shunt Selective

a. Total non-selective shunt a. Distal spleno-renal shunt

- Porto-caval (directly anastomose
portal vein with IVC)
- Meso-caval = Drapanas shunt
(Superior mesenteric vein with IVC)
- Proximal spleno-renal shunt = Linton
shunt (artificial connection between
= Warren shunt (preferred)
- No splenectomy
b. Left gastric-venocaval shunt
= Inokuchi shunt (left gastric
vein to vena cava)
 213
splenic vein with IVC + splenectomy)
b. Partial non-selective shunt = Sarfeh
shunt (small diameter porto-caval shunt)

Ascites

- Serum Albumin and Ascites gradient (SAAG) :

SAAG = [serum albumin] — [ascitic fluid albumin]

SAAG

≥ 1.1 (High SAAG) < 1.1 (Low SAAG)

Protein content : < 2.5 g/ dL Rare

- Sinusoidal cause : cirrhosis - Hypoalbuminemia (eg :

Nephrotic syndrome,
protein losing
enteropathy)
- Myxedema

> 2.5 g/ dL - TB
- Pre-sinusoidal, pre-hepatic, - Pancreatic ascites
post-hepatic, post-hepatic (due to pancreatitis)
portal hypertension - Chylous ascites
- Malignancy

= Portal hypertension ≠ Portal hypertension

- Most sensitive investigation to diagnose ascites : USG (including < 30 mL)

(Best initial test, best screening test)

- Treatment :
i. Treat underlying disease (complete alcohol abstinence)
ii. Sodium restriction (sodium overload avoided)
(< 2 g/ day = < 88 mEq/ day)
± Fluid restriction (with associated hyponatremia)
 214

iii. Diuretics
- Furosemide + Spironolactone (1 : 2.5 ratio)
10 mg : 25 mg
40 mg : 100 mg
160 mg : 400 mg (maximum dose)
Target : weight of patient
- Weight loss — 1 kg/ day for patients with peripheral edema
- Weight loss — 0.5 kg/ day for patients with only ascites and no peripheral edema
- Diuretics are tittered on basis of weight of patient
iv. Therapeutic paracentesis
- Achieve rapid reduction of ascites
- > 5 L = Large volume paracentesis (LVP)
+ 20% albumin replacement
(6 ~ 8 g per every litre of ascitic fluid removed)
Eg :- For 4 L — No albumin replacement
6 L — 36 ~ 48 g albumin
10 L — 60 ~ 80 g albumin
Diuretic resistant ascites
- Diuretic resistant ascites (over-a-period of time) = Refractory ascites
i. Persistent ascites + on sodium restriction diet + on maximum diuretic dose
- Having rapid re-accumulation of fluid after therapeutic paracentesis + on sodium
restriction diet
ii. Confirm diuretic resistant ascites by checking 24 hr urinary sodium, urinary
sodium-potassium ratio, weight loss

24 hr U Na + U Na +/ K + Weight loss

≥ 78 mEq ≥1 Yes Diuretic sensitive + low adherence

to sodium restricted diet

≥ 78 mEq ≥1 Diuretic sensitive + poor adherence

No
to sodium restricted diet

< 78 mEq <1 No Diuretic resistant

iii. Therapies :
 215

- Diuretic resistant ascites : due to hyper-RAAS activation

a. Drugs to be avoided :- ACEI/ ARB’s (promotes hypoperfusion)
(NSAIDs

Decrease prostaglandins

Vasoconstriction

Increased hypoperfusion

Increased renin)
b. Drugs useful : Midodrine (α1 agonist)
c. Serial LVPs
d. TIPSS
e. Best :- Orthotopic liver transplant
f. Experimental :- clonidine, vaptans (tolvaptan : highly hepatotoxic)
iv. Complications : Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis

i. Pathophysiology :
Due to very high portal pressure

Bacterial translocation

Spontaneous bacterial peritonitis

ii. Clinical features : Fever (MC)
Abdominal pain (well localized)
± Altered mental status
± Paralytic ileus and constipation/ hypotension or shock
iii. Investigation : Ascitic fluid analysis

Ascites Infection : Spontaneous Bacterial Peritonitis

Infection Ascites : Secondary Bacterial Peritonitis

- Diagnosis made based on neutrophil count in ascitic fluid.

 216
Start empirical
antibiotics
Ascitic PMN
Poor prognosis
< 250 > 250
No empirical
antibiotics
Runyon criteria
Not spontaneous
bacterial peritonitis i. Ascitic fluid protein ≥ 1 g/ dL
ii. Ascitic fluid glucose < 50 mg/ dL
iii. Ascitic fluid LDH > upper limit of
Culture normal serum LDH

+ — More than 2 of the following

Bacterial ascites Normal

Yes No

(Likely) Secondary
bacterial peritonitis Culture

CT Abdomen + —

Spontaneous Recent
If perforation empirical
bacterial
peritonitis antibiotic
use
Laparotomy
+
—

Culture
negative
neutrocytic
ascites
 217

iv. Treatment :-
Gram negative organisms - most common (70 % - E. coli)
30 % Gram positive - Streptococcus/ Enterococcus
< 5% Anaerobes
- Empirical antibiotics (any one) : Ciprofloxacin
Cefotaxime 1 g TID
Ceftriaxone 2 g QD
Piperacillin tazobactam
Spontaneous bacterial peritonitis : monobacterial
Secondary bacterial peritonitis : polymicrobial
v. Complications :-
a. Increased risk of HRS, renal failure (most common cause of death)
b. Increased risk of hepatic encephalopathy
vi. Prophylaxis :-
- Secondary prophylaxis for all patients (high chance of recurrence)
Norfloxacin 400 mg QD (most common)
Ciprofloxacin 500 mg QD
Cotrimoxazole
- Primary prophylaxis (not developed spontaneous bacterial peritonitis, at high risk)
(1) UGI bleed
(2) Ascitic fluid protein low < 1.5 g/ dL
(3) Serum creatinine > 1.2 mg/ dL
Or BUN ≥ 25 mg/ dL
(4) Serum sodium < 130 mEq (Hyponatremia)
(5) Child Turcotte Pugh score ≥ 9 + Bilirubin ≥ 3
(Child class C with bilirubin)
 218

Hepatic hydrothorax
- Treatment of ascites results in resolution of hepatic hydrothorax
- Never insert chest drain (causes maximum volume depletion)
- Avoid pleurodesis (done in cases of refractory pleural effusion in malignancies)

Hepato-renal syndrome
- Criteria to diagnose HRS :-
i. Should have cirrhosis/ advanced portal hypertension
ii. Progressive AKI (serum creatinine > 1.5 or AKI)
iii. Features suggestive of pre-renal azotemia :
- UNa+ < 10
- FeNa < 1%
- BUN/ Cr > 20
iv. No evidence of intrinsic renal disease
(not glomerular or tubular)

Protein Bland urine

< 500 mg/ day (no sediments)
RBC < 50/ hpf
v. No shock
vi. No recent nephrotoxic drug use (Vancomycin, aminoglycosides)
vii. No evidence of obstruction
ix. No evidence of parenchymal renal disease in ultrasound (eg: Pyelonephritis)
x. Stopped diuretics + Giving volume expansion
(Albumin 1 g/kg/day for 2 days)
- No improvement in renal failure and AKI is progressing
(Not due to hypovolemia)
 219
Type 1 HRS Type 2 HRS

i. More serious i. Less serious

ii. AKI is rapid
iii. Creatinine doubles in < 2 weeks
iv. Survival very low
(2 weeks if untreated)
v. Less ascites
(major reason : infection)
ii. Kidney injury more insidious and gradual
iii. Better survival
(6 months without treatment)
iv. Massive ascites (refractory)
(major precipitating cause)

- Treatment : Terlipressin + Albumin for 2 weeks

Alternative for terlipressin - Norepinephrine

No improvement

TIPSS
- Best treatment for refractory HRS : Orthotopic liver transplant
 220

Hepatopulmonary Porto-pulmonary
syndrome hypertension
i. Pathophysiology : Unknown Unknown
Vasodilatation Vasoconstriction
Endothelin 1 levels very high Endothelin 1 levels very high

VQ mismatch (VQ ratio > 1)

Vasoconstriction

Increased resistance to blood flow

across pulmonary vasculature

Increase right ventricular pressure

Right Left
RV hypertrophy
Severe vasodilation
RV failure
Deoxygenated blood

Shunt formation
ii. CXR : Increased vascularity Reduced vascularity (oligemia)
iii. ECHO : Contrast echocardiography ECHO
iv. Clinical - Asymptomatic - Symptomatic (early dyspnea)
features : ± Dyspnea - Orthopnea (=erect breathing)
- Orthdeoxia (manifestation of - Syncope/ fatigue
shunt formation)
- Platypnea (=flat breathing)
- Clubbing (due to A-V shunting)

v. Treatment : Long term oxygen therapy Standard pulmonary artery

(poor response) hypertension management + LTOT
Definite therapy :- orthotopic Definite therapy :- orthotopic liver
liver transplant transplant
 221
Liver disease Liver disease

A-a
gradient > 15 IPVD MPAP > 25 PCWP < 15

Right heart catheterisation

IPVD : Intrapulmonary vasodilation (gold standard for diagnosis)

Hepatic encephalopathy
Protein (diet) Intestinal bacteria Liver
NH3 Urea
Substrate
Liver
failure
Hyperammonemia

Astrocyte damage α-ketoglutarate

(Alzheimer’s type 2 NH3
astrocytes) Glutamate
NH3
Glutamine

Low α-ketoglutarate High Glutamine

Low ATP production Cerebral edema

Excess GABA Hepatic encephalopathy

 222

- Precipitating factor :
i. UGI bleed (increases protein)
ii. Infection (spontaneous bacterial peritonitis)
iii. Hypokalemia & metabolic alkalosis
(Increases renal ammonia genesis)
Alkalosis
NH 4+ NH 3
Acidosis
iv. Renal failure (decreased ability of kidney to utilise ammonia)
v. Hypovolemia — — Activates RAAS

More hypokalemia and metabolic alkalosis

vi. Hypoxia
vii. Sedatives (especially Benzodiazepines)
viii. Hypoglycemia
ix. Constipation (contact of protein and bacteria is more)
x. High protein diet
xi. Portal vein thrombosis/ hepatic artery thrombosis
- HCC
- Triple phase contrast CT : gold standard for diagnosing HCC

- Clinical features : Staging system

West Haven staging Four score

(Most commonly followed)
 223
West Haven staging

Neurological Pupillary Risk of

Stage Consciousness Intellect cerebral
finding response
edema
0 Normal Normal Normal exam Normal No risk
(Except : impaired
psychomotor testing)

1 Mild decrease Attention Difficulty with Normal Rare

in awareness span mathematical
reduced problems (+, —)

2 Lethargic Disoriented Flaps Brisk Rare

Speech slurred response

3 Sleepy Gross Muscular rigidity/ Slow High

(arousable) disorientation Clonus, response (30 %)
Increased deep
tendon reflexes
4 Comatose — Posturing Dilated & Extremely
(Decerebrate) Fixed high (70 %)
(Untreated
100 %)

Stage 0 & 1 : Covert hepatic encephalopathy

Stages 2 + 3 + 4 : Overt hepatic encephalopathy

- 3 different types of hepatic encephalopathy :-

Type A : ALF
Type B : No ALF/ cirrhosis, some other reasons of porto-systemic shunt causing HE
Type C : Cirrhosis
- Serum ammonia : Diagnostic marker of hepatic encephalopathy
High sensitivity, high negative predictive value
Extremely low specificity
- Normal serum ammonia rules out hepatic encephalopathy
 224

- 3-Nitrotyrosine : New diagnostic marker of hepatic encephalopathy

Better correlation with hepatic encephalopathy
- Clinical test for diagnoses : Constructional apraxia test (Reitan number connection test)
- EEG findings : Triphasic waves (suggestive of hepatic encephalopathy)
- Treatment :-
i. Correct precipitating factors
ii. Never use benzodiazepines (precipitate and worsen the HE)
iii. Drugs to control HE :
(a) Lactulose/ Lactitol (laxative)
NH + NH 3
4
Acidic
Excreted in stools
Lactulose
- 30 ~ 40 mL to 90 mL/ day
- Target : 2 ~ 4 soft stools
(b) Gut sterilisation by using Rifaximin 550 mg BD
(previously used : Neomycin)
iv. Low protein diet
v. Other experimentals :
- L-Ornithine L-Aspartate (LOLA - accelerate urea cycle
and thereby ammonia is utilised)
- BCAA infusions
- In brain, BCAA levels decreased with Aromatic amino acid levels high
- Giving BCAA infusion reverses levels of BCAA in brain and research
based evidence shows to be beneficial in HE
- Sodium benzoate and sodium phenylacetate
- Given to correct congenital urea cycle defects
- Flumazenil
- Zinc
- Melatonin
- Memantine
- L-Carnithine
 225

Non-cirrhotic Extra-hepatic
portal fibrosis portal vein Cirrhosis
obstruction
Age : 30 years 10 years 40 years

Gender : M>F M>F M>F

Site : Intra-hepatic, Pre-hepatic Intra-hepatic,

pre-sinusoidal sinusoidal
Site of portal Peripheral Main portal vein None
vein blockage : small branches
Extremely frequent,
Less frequent, Less frequent,
GI bleed : recurrent and poorly
well tolerated well tolerated
tolerated

Encephalopathy : Rare Rare Common

Jaundice : Rare Rare Common

Ascites,
peripheral Rare Rare Common
edema :

Spider nevi : Rare Rare Common

Splenomegaly : +++ ++ +
> 7 cm < 7 cm < 5 cm

LFT : Normal Normal Abnormal

Splenomegaly, no Splenomegaly, no
Imaging :
evidence of cirrhosis evidence of cirrhosis Nodular liver
Angiography : Angiography :
withered tree cavernomatous
appearance transformation of
(peripheral pruning) portal vein
Collagen bands
Biopsy : Portal fibrosis Normal Nodules
 226

Hepatic vein
pressure Normal Normal Increased
gradient :

Prognosis : Better Better Poor

Treatment : Varices management Varices management Standard cirrhosis

management
No response TIPSS not indicated

Advanced stage OLT not indicated

Orthotopic liver Alternative

transplant treatment : Rex shunt

Hepatic vein
Non-Cirrhotic Portal Fibrosis

Increased portal pressure

Splenic
Portal vein vein

Superior mesenteric vein

TIPSS
 227

Rex Shunt/ Mesenterico-

Left portal bypass (SMV
to left portal vein)

Splenic
Portal vein vein

Superior mesenteric vein

Increased portal pressure

Extra-Hepatic
PortalVein Obstruction
Splenomegaly, variceal bleed

NCPF clinical presentation :-

Middle aged man with massive splenomegaly, with variceal bleed. No jaundice,
normal LFT, PT/ INR, no evidence of HE. Features of hypersplenism like anemia
and thrombocytopenia present.

EHPVO clinical presentation :-

Child with splenomegaly and variceal bleed, with complian of hypersplenism.
No jaundice or HE. Normal LFT, PT/ INR.
 228

Metabolic Liver Disease

Wilson’s disease

i. Age of onset : 12 ~ 20 years

ii. Autosomal recessive disease : ATP 7B gene mutation on chromosome 13
iii. Pathophysiology :-

Dietary Cu++
Portal circulation ++
Cu
ATP 7A

—
Liver
Menkes Kinky
Hair syndrome
++ ++
Cu Cu Bile

++ ATP 7B
6 Cu
Apocerruloplasmin Cerruloplasmin
ATP 7B

—
Blood
Wilson’s disease

Reduced formation of cerruloplasmin

++
Total Cu level in blood decrease
 229

ATP 7B defect

Increased free copper Decreased cerruloplasmin

within the hepatocyte (Decreased total serum copper)

Free radical damage

Hepatocyte death

Increase serum free copper

Progressive Release free copper
liver damage into circulation
Increase urinary free copper levels

Copper deposition

Free radical damage

Organ deposition Hemolysis

Eyes : Kayser– CNS : basal ganglia

Fleischer ring (neurodegeneration)

iv. Clinical features :-

Hepatic presentation Neurological presentation Psychiatric presentation

Variable Extra-pyramidal features : - Poor school performance

- Dystonia - Depression
Asymptomatic
- Ataxia - Irritability
Cirrhosis (common)
- Tremors (mild, wing beating) - Labile mood
CLD (common)
ALF - Bradykineasia - Frank psychosis
Acute hepatitis - Drooling of saliva (dysthymia) (bipolar)
- No associated sensory changes
CT/ T2 MRI : hyper-intensity in
basal ganglia
 230

ALF due to Wilson’s disease :

1. Hemolytic anemia (Coombs negative)(Intra-vascular hemolysis)
2. AST > ALT
— OT
>1
PT
3. Very low alkaline phosphatase (< 40)
— ALP
<4
Bilirubin
4. Very low serum uric acid levels

Extra-presentation
Kayser–Fleischer ring :
- Brownish ring due to deposition of copper in descemet membrane of the cornea
- Intensity of KF ring is proportional to CNS copper
- Association of KF ring and CNS disease is ~
~ 98%
- Visualised by slit lamp examination
- Disappears with treatment (takes 3 ~ 5 years)
- Can develop cataract (Sunflower cataract)
KF ring in slit lamp exam Sunflower cataract C KF ring

Nail findings in Wilson’s disease

Azure lunula
 231

Renal presentation : RTA (proximal > distal) (like inborn errors of metabolism)
Cardiomyopathy (restricted)
Infertility

v. Investigations :-
(a) Serum cerruloplasmin : screening test
- Decreased (Normal > 20 mg%)
- Normal in 10 ~ 25 % people
- Levels ≤ 4 confirms the diagnosis of Wilson’s disease
(b) Slit lamp examination : KF rings
- KF ring is not 100% specific for Wilson’s disease
- KF rings are also seen in any cholestatic conditions
(c) 24 hr urinary copper (increased)
- 100 µg/ day : diagnostic
(d) Liver biopsy : gold standard
- Amount of copper per gram of dry weight of liver - High
(> 250 µg/ g of dry weight of liver )
(Normal copper = < 35 µg/ g of dry weight of liver)
- Increased hepatic copper is seen in both Wilson’s and Cholestatic conditions
(e) Genetic testing
- ATP 7B gene defect testing in chromosome 13
- Tested only if liver biopsy test is inconclusive (50 ~ 250 µg/ g) + Strong
suspicion of Wilson’s disease
(f) Serum copper : Not tested (most unreliable investigation)
- Free serum copper elevated
- Total serum copper decreased
 232
Serum cerruloplasmin + slit lamp + 24 hr urinary copper

Serum cerruloplasmin

Elevated Normal

KF ring KF ring

+ — + —

Urinary copper
Liver biopsy Urinary copper
or
High Low
Genetic testing
High Low
Diagnostic Liver biopsy

Liver biopsy Wilson’s

Not suggestive or excluded
(50 ~ 250 µg/g) Genetic testing

Genetic testing
vi. Diagnostic criteria : Leipzig meeting criteria (2001)
≥ 4 - most likely Wilson’s disease
3 - probably Wilson’s disease
≤ 2 - unlikely to be Wilson’s disease
vii. Prognostication : Nazer score
- AST
- Total bilirubin Mnemonic : A T P
- Prothrombin time
- Score ranging from 0 ~ 12
- Score 0 ~ 6 : Good prognosis, managed with medication
- Score 7 ~ 9 : Intermediate prognosis, medical management/ Liver transplant
- Score 10 ~ 12 : Poor prognosis, require liver transplant
 233

Hepatic copper

Rhodanine staining

viii. Treatment :-
Asymptomatic Symptomatic
Initial Chelation - first line therapy Chelation therapy
Zinc - second line
Maintenance Zinc or Low dose chelating agent

Chelating agents used :- d-Pencillamine

Trientine (better side effect profile)
Can be given in pregnancy (dose reduced by 30 ~ 50 %)

Target :-
1. Increase urinary copper
- Initially 200 ~ 500 µg/ day
- By 6 ~ 12 months, < 200 µg/ day
2. Non-cerruloplasmin bound serum copper (free copper) < 15 µg/ dL
3. Normalisation of LFT

Duration of chelation : 6 months ~ 5 years

Followed by
Maintenance therapy
 234

Hemochromatosis
Hemochromatosis

Primary/ Hereditary Secondary

I : AR, HFE gene - HFE protein Due to :

(most common) i. Multiple transfusional overload
II A : AR, HJV gene - HJV protein - Hemoglobinopathies
II B : AR, HAMP gene - hepcidin protein ii. Ineffective erythropoiesis
III : AR, TFR gene - TFR 2 protein - Thalassemia, sickle cell disease,
IV : AD, SLC40 A1 - Ferroprotein (rare) sideroplastic anaemia
(Rare in India, common among caucasians) iii. Alcohol
iv. Chronic liver disease
v. Porphyria’s
HFE gene mutations are of 2 types :- C282Y (most common, 85%)
H63D mutations (15%)
I : adults
II A : children Iron seen in peri-portal region
II B : children (maximum amount of iron)
III : young adults
IV : adults Iron is seen more in kuppfer cells

i. Clinical features :-
- Liver : First organ to be affected
Results in the development of cirrhosis
and HCC Classical triad of
- Pancreas : results in DM hemochromatosis
- Skin : deposition can lead to development of Bronze
hyperpigmentation diabetes
- Pituitary/ gonads : can result in hypogonadism
- Joints : can cause hemochromatic arthropathy
(Joints affected are 2nd and 3rd MCP joints)
Result in chondrocalcinosis (causes CPPD)
- Increased risk of infections (Listeria, Yersinia
enterocolitica infection, Vibrio vulnificus)
 235

ii. Pathophysiology :-

Normal :
Fe
BMP 6 HJV HFE
TFR 2

SMAD 4

Decreases serum
HAMP gene activation Hepcidin iron in response to
sensing of iron
(negative feedback)

Inhibition of ferroportin

Dietary Absorption of iron

Fe Ferroportin Fe
requires ferroportin

Senescent RBC swallowed

and destroyed by
RBC Ferroportin Fe
reticuloendothelial system
Reticuloendothelial and release iron which
system requires ferroportin
 236
Inflammation :
Fe
Anemia of
BMP 6 HJV HFE chronic disease
TFR 2

SMAD 4 Inflammation

HAMP gene activation Hepcidin

(+ APR)

Inhibition of ferroportin

Dietary
Fe Ferroportin Fe

RBC Ferroportin Fe

Reticuloendothelial
system

Increased ferritin
Inflammation
Increased hepcidin

IDA Decreased ferritin, decreased hepcidin

 237
Pathophysiology :
HFE gene defect

Fe
BMP 6 HJV HFE
TFR 2

SMAD 4

HAMP gene activation Hepcidin

Inhibition of ferroportin
Unregulated
absorption of iron
Dietary
Fe Ferroportin Fe
Serum iron increase

Free iron in
RBC Ferroportin Fe body increases

Reticuloendothelial
system Deposition of
iron in organs

Iron not sensed

Hemochromatosis
 238
iii. Clinical features :-
Asymptomatic coming with LFT abnormalities - most common presentation
Symptomatic presentation is rare
- Most common symptom is fatigue
- Hyperpigmentation
- Arthralgia
- Impotence
- DM
- Cardiomyopathy
Complications of hemochromatosis
(hypertrophic/ restrictive/ dilated)
- Cirrhosis, HCC
iv. Investigation :-
Transferrin saturation (TSAT) : first investigation to be done
(most sensitive, screening test)
± Serum ferritin
Suspected iron overload

TSAT

< 45% > 45%

Likely iron overload

Rule out hemochromatosis

Serum ferritin
Serum ferritin

Normal Increased
Normal Increased
Close follow up Iron overload
Normal person Other causes of
increased ferritin Evaluate for the cause
(Inflammation)

MRI (best non- Genetic

Liver
invasive test to testing
biopsy
quantify hepatic (best)
Traditional
& cardiac iron)
gold standard
 239

Iron deposition

Perl’s Prussian blue stain

- liver biopsy (Hemochromatosis)

Indications for liver biopsy :- (a) ALT, AST elevated

(b) Serum ferritin > 1000
Based on liver biopsy
- Severity depending on iron :- Mild : 71 ~ 98 µg/ g of dry weight
Moderate : 99 ~ 200 µg/ g of dry weight
Severe : > 200 µg/ g of dry weight
> 80 : Iron overload
v. Treatment :
Hereditary hemochromatosis Secondary hemochromatosis

Asymptomatic + Symptomatic +
serum ferritin < 500 Thalassemia
serum ferritin > 500

Annual follow up Phlebotomy + Chelating agents : first line

decrease dietary
iron

Contraindication for phlebotomy :- Anemia

Second line :
chelating agents
 240

Phlebotomy : 1 ~ 2 sittings/ week (Initially)

500 mL of blood removed in each session

Target : serum ferritin (50 ~ 100 ng/ dL) - normal

Maintenance phlebotomy once every 3 months

Outcomes :
Resolution No resolution
A. Cardiomyopathy A. Hypogonadism
B. Fatigue B. Arthropathy
C. Diabetes C. Cirrhosis & HCC
D. Skin hyperpigmentation
E. Hepatomegaly

Contraindications for phlebotomy :- i. Anemia (most important)

ii. Poor vascular access
iii. Heart failure

α1-Antitrypsin deficiency
i. Autosomal co-dominant inheritance > Autosomal recessive
ii. Defective gene : SERPINA-1 present on chromosome 14
iii. Synthesis of α1-antitrypsin occurs in liver

α1-antitrypsin deficiency
affects

Lung Liver
(most common)
CLD
Emphysema (pan-acinar, Cirrhosis HCC
affects the lower lobes)
iv. Pathophysiology : Actual deficiency of α1-antitrypsin causes emphysema Lungs
Impaired secretion of α1-antitrypsin Liver
 241

Protease Anti-protease (α1-antitrypsin)

Normal

Neutrophils Anti-protease

Protease ficiency
ypsin de
α1-antitr

Damage elastin

Hyperinflation

Emphysema

Allele Plasma levels Lung disease Liver disease

M (normal) Normal None None

Z
(intracellular
accumulation Reduced Yes Yes
of α1- (Moderate)
antitrypsin)
S
(intracellular Reduced Yes None
degradation of (Mild)
α1-antitrypsin)

φ (Null) Reduced Yes None

(no synthesis of (absent) (Severe)
α1-antitrypsin)

F (Functional
defect)
(impaired binding Normal Yes None
(Variable)
with neutrophil
elastase)
 242

Genotype α1-antitrypsin Intracellular Lung Liver

levels accumulation disease disease
Pi MN Normal
No No No
(normal) (150 ~ 350 mg/ dL)

Pi MS Near normal No No No
(mild)
Pi SS Mild decrease No No No
(carriers) (100 ~ 200)

Pi MZ Mild decrease Yes Yes Possible

(100 ~ 200) (mild) (No)

Pi SZ Moderate decrease Yes Yes

Yes
(45 ~ 30) (mild) (mild)

Severe decrease Yes Yes Yes

Pi ZZ
(10 ~ 40) (very severe) (severe)

Pi φφ Undetectable No No Yes
(< 10) (very severe)

i. Pan-acinar
ii. Age < 45
iii. Non-smoker
Emphysema + iv. + LFT abnormality
v. Lower lobe emphysema α1-antitrypsin
vi. Associations :- deficiency
- ANCA associated vasculitis
- Bronchiectasis
- Necrotising panniculitis
(thighs and buttocks)
 243
v. Investigations :
- Best - Genetic testing
- Serum protein electrophoresis

Normal

Albumin α1 α2 β γ

α1-
Antitrypsin
deficiency

Albumin α1 α2 β γ

- Liver biopsy - diagnosis only in Z phenotype

Intracellular accumulation of α1- Antitrypsin

in cytoplasm of hepatocytes

PAS [positive] Diastase resistant

 244
PAS positive Diastase resistant globules
Intracellular globules

Bridging fibrosis

Cirrhosis

vi. Treatment :-
- Supportive management only
(Smoking contraindicated)
- α1- Antitrypsin replacement
- Indication : levels < 57 mg/ dL + severe emphysema not responding to medical
management
- No effect in liver disease
 245

Tumors of the Liver

Benign tumors
Hemangioma (most common benign tumor of liver)
Focal Nodular Hyperplasia
Hepatic adenoma
Hemangioma Focal Nodular Hepatic adenoma
Hyperplasia
i. Incidence : 0.4 ~ 20% 2nd most common Uncommon (rare)
most common
Common in young to middle age population
F > M (6 : 1)

ii. Etio- Congenital (Focal) injury to Mutations

pathogenesis : vascular portal tract due to i. HNF 1α (MODY +
malformations congenital anomaly hepatic adenomas)
(enlarging by ii. IL-6 pathway
ectasia) activating mutations
Hypo-perfusion to
(inflammatory
hepatocytes
mutations) - most
common mutations,
Hyperplastic response + maximum risk of
stellate cell activation bleeding
iii. β-catenin
mutations - seen in
Central scare males, high chance
of transformation to
HCC because of high
degree of atypia
iv. SHH mutations
(rarest) causes
obesity, bleedings,
hepatic adenomas
iii. Origin : Hepatocytes
Mesenchyme Hepatocytes
(monoclonal)
(polyclonal)
Monoclonality
 246
iv. OCP OCP is not OCPs have strong
Unknown
association : associated to origin association with
(growth of tumor growth, enlargement
is attributed to the and progression of
hormones) tumors
v. Malignant
None None Have high risk
transformation :
(Highest risk for
tumors with β-catenin
mutations)

vi. Pathology : Cavernous vascular Polyclonal hepatocytes - Sheets of enlarged

spaces lined by forming nodular hepatocytes
endothelial cells appearance - No central scar
+ central stellate scar - No portal tract
+ large portal tracts - No fibrosis
+ abnormal kuppfer cells - No kuppfer cells
and sinusoids
(Normal liver architecture)
vii. Ultrasound : - Well defined mass - Homogenous, hypoechoic - No features
- Homogenous and to isoechoic in nature - Appears hyperechoic
hyperechoic - Central scar (20 % seen) - Ill defined
appearance - Heterogenous in nature
Hyperechoic mass of hepatic hemangioma

99m
Nuclear testing used to diagnose FNH : Tc Sulfur collide scan
(which can be taken up by kuppfer cells and appears hot on scan)
Best investigation for benign liver tumors : Triple phase CECT
 247

viii. Treatment : - No treatment - No treatment - Surgical resection

- Huge hemangimas - Indication for
> 5 cm at observation :-
subcapsular location i. Women on OCPs
has a risk of ii. Asymptomatic
bleeding into iii. < 5 cm
peritoneum requires - Managed by
close follow-up stopping OCPs and
- Surgery needed following up closely
only for those in
severe/ refractory
pain (tumor is
subcapsular)

Hemangioma Focal Nodular Hyperplasia Hepatic adenoma

ix. Triple phase CECT :-

Non-contrast Contrast

Arterial Portal Delayed

phase venous venous
phase phase

0 sec 40 sec 80 sec 2 ~ 5 min

 248

Normal liver parenchyma receives blood supply from :-

a. Portal vein (80%, maximum)
b. Hepatic artery (20%)

Almost all hepatic tumors receive blood supply from hepatic artery

Liver Hemangioma
Non-contrast : Low attenuation
Arterial : Peripheral spotty enhancement Centripetal filling
Portal venous : More enhancement
Delayed : Complete enhancement

Non-contrast Arterial

Portal venous Delayed

 249
Focal Nodular Hyperplasia

Non-contrast : low attenuation of mass, central scar is darker

Arterial : homogenous enhancement, central scar remains dark
Portal venous : isodense in nature
Delayed : isodense, central scar becomes enhanced

Non-contrast Arterial

Portal venous Delayed

 250

Hepatic adenoma
Non-contrast : heterogenous in nature (due to bleeding within tumor)
Arterial : enhancement of mass (homogenous/ heterogenous if bleeding
present)
Portal venous : isodense
Delayed : isodense

Arterial

Portal venous
 251

Hepatocellular carcinoma
Non-contrast : low attenuation
Arterial : homogenous enhancement
Portal venous : hypodense
Early contrast washout/ contrast incontinence
Delayed : hypodense

Arterial

Portal venous
 252
Intra-hepatic cholangiocarcinoma
Non-contrast : low attenuation
Arterial : hypo/ isodense
Portal venous : hypo/ isodense
Delayed : typical enhancement

Hepatocellular carcinoma
i. More common in males (M > F)
ii. Age > 40 ~ 50 years at high risk for HCC
More the age, more the risk of HCC
iii. Etiology :
(a) Cirrhosis
[Independent risk factors are as follows :-]
(b) Chronic HBV, HCV infection
- Due to chronic inflammation caused by HBV infection
- Due to insertional mutagenesis in HBV
- X gene (ORF-X)
(c) NASH
(d) Hemochromatosis/ Iron overload
(e) Wilson’s disease
(d) α1-Antitrypsin deficiency
(e) Schistosomiasis
(f) Glycogen storage disorders
(h) Chronic ingestion of aflatoxin
(i) Tobacco and alcohol (smoking has a very low risk)
 253
Chronic ingestion of aflatoxin
Aflatoxin

Induces mutation

Codon 259 of TP53 gene

G:C T:A
Original Mutated

iii. Clinical features : Asymptomatic (most cases)

- Cirrhosis : requires monitoring for HCC
- Chronic HBV/ HCV infection : requires monitoring for HCC with 3 ~ 6 months AFP
and ultrasound
- Symptomatic — advanced stage
- Most common symptom : RUQ pain
- Weight loss
- Fever
- Jaundice (uncommon finding)
Known cirrhosis + HCC Decompensated liver disease

Known cirrhosis + decompensated Workup

(ascites, variceal bleed)
Portal vein/ Hepatic
artery thrombosis

HCC

Known cirrhosis developing One of etiology is

Multiple etiologies hepatic artery/ portal
decompensation
vein thrombosis

One of etiology : HCC

 254
iv. Paraneoplastic syndromes :
(a) Hypoglycemias [mild, asymptomatic]
(b) Erythrocytosis [due to erythropoietin secretion by tumor cells]
(c) Hypercalcemia [due to PTHrP/ osteolytic metastasis]
(d) Diarrhea [ due to VIP/ gastrin]
(e) Dysfibrinogenemia
(f) Increased thyroid binding globulin
(g) Porphyrin cutanea tarda
(h) Cutaneous signs :-
1. Dermatomyositis
2. Sign of Leser-Trélat
3. Pemphigus foliaceus

Multiple seborrheic keratosis/ Sign of Leser-Trélat

v. Extra-hepatic metastasis is very rare

Intra-hepatic metastasis is common
vi. Risk factors for metastasis :
- Size > 5 cm
- Large vessel invasion
vii. Site for metastasis :
Lung (most common) > abdominal lymph nodes > bone > adrenal glands
viii. Investigation :
1) AFP - screening test for high risk patients with cirrhosis to detect the development
of HCC (depends on size of HCC)
Normal AFP = 10 ~ 20 ng/ mL
Sensitivity = 60% 40% HCC have normal AFP (especially small HCC)
Specificity = 80%
 255

2) µRNA - used as marker

3) des-γ-carboxy-prothrombin - new marker, proposed to
be better than AFP Not validated
4) AFP-L3 (different form of ALP)
5) Glypican-3 (cell surface glycoprotein)
ix. Imaging :

Ultrasound (Triple phase) CECT

i. Irregular orders i. Non-contrast : low attenuation
ii. Halo sign ii. Arterial : homogenous enhancement
iii. Vascular invasion iii. Portal venous : early washout of
contrast (hypodense)

Monitoring done with AFP and USG combined Sensitivity = 80 ~ 90%

(For those at high risk for HCC)
History of HCC
USG shows 1.1 cm of mass lesion over caudate lobe
AFP - normal

Next step : Biopsy (high risk for HCC)

Li-rads
LR-NC : Non-Categorisable
LR-1 : Benign
LR-2 : Probably benign
LR-3 : Intermediate probability for malignancy (dysplastic nodules in a cirrhotic liver)
LR-4 : Probably malignant (1 out 3, requires biopsy)
LR-5 : HCC with characteristic features (2 out of 3)
LR-M : Malignant lesion (could be HCC or cholangiocarcinoma)
LR-TIV : Tumor in vein (within portal vein, visualising an enhancing lesion)

Characteristic features of HCC :

i. Typical washout pattern
ii. Enhancing capsule (2 out of 3) LR-5
iii. Growth of tumor (> 50% in < 6 months)
 256
LR-3 requires repeat imaging in 3 ~ 6 months)
LR-5 requires no biopsy Start treatment

Criteria for LR-5

i. Size > 2 cm + arterial phase enhancement + 1 out of 3 characteristic features
ii. Size 1 ~ 2 cm + arterial phase enhancement + 2 out of 3 characteristic features

Features HCC Fibrolamellar variant of HCC

i. M : F 3:1 1:1

ii. Age 55 yrs 25 yrs

iii. Nature of tumor Invasive Circumscribed

iv. Lobar involvement Right > both > left Left

v. Resectability < 25% resectable > 50% resectable

vi. Spread Blood Lymphatic

vii. Association with cirrhosis 80 ~ 90% 5%

viii. Tumor marker AFP Neurotensin (normal AFP)

ix. HCV/ HBV association +++ —

x. Prognosis Poor Average to good

xi. Pathology Shows fibrous bands

(lamellin cut section)
40 ~ 70% have central scar
 257

Molecular classification of HCC

1. Cholestatic and well differentiated HCC : mutation associated is CTN N B1
(most common)
2. Poorly differentiated and highly proliferative HCC : mutation associated is TP-53
3. Serous HCC : due to mutation of TSC 1 and TSC 2
4. Steatohepatic type of HCC : due to IL-6 and JAK-STAT activation

LFT Cholestatic pattern

(commonest)

- Most sensitive marker for HCC with any level of differentiation : Arginase 1
- Glypican 3 : most sensitive marker for poorly differentiated and highly proliferative HCC

x. Management :
a. AJCC-TNM staging
b. OCUDA staging system
Mnemonic : B A S E
Bilirubin
Ascites
Serum albumin
Extend of tumor
- Score 0 /4 : stage 1
- Score 1 ~ 2 /4 : stage 2
- Score 3 ~ 4 /4 : stage 3
c. CLIP score
Mnemonic : P A C E
Portal vein thrombosis
AFP
Child pugh score
Extend of tumor
(occupying less or more than 50% of liver)
d. ALBI score (only 2 parameters : Albumin and bilirubin)
- Non-tumor variables that affect the survival of patients with HCC
e. BCLC staging system
 258

AJCC-TNM staging
T1
T1a : Size ≤ 2 cm ± vascular invasion
T1b : Size > 2 cm with no vascular invasion
T2 : > 2 cm + vascular invasion
Multiple tumors [largest tumor < 5 cm]
T3 : Multiple tumors [largest tumor > 5 cm]
T4 : Invasion of major branch of portal vein
Invasion of adjacent structures (Not peritoneum/ gall bladder)

N1 : Any regional node involvement

M1 : Distant metastases

Tany N1/ M1 : Stage IV

Unresectable
T4 N0 M0 : Stage IIIb
T3/ T2/ T1 N0 M0 : Stage I to Stage IIIa Resectable tumors
 259
BCLC staging system

LFT + tumor burden

(CTP scoring) (resectable or not)

CTPA & resectable CTP B/ C or Unresectable

(Stage I to IIIa) (Stage IIIb / IV)

Liver transplant ?
Intra-op exploration
(MILAN criteria)

Resectable
Unresectable

Complete resection of mass

Partial hepatectomy No Yes

Bridging therapy
Disease extend

Radiofrequency
Extra- Hepatic ablation/
hepatic only Transarterial
disease disease Chemo
(N1/ M1) (N0/ M0) Embolisation
(TACE)
Liver function Liver function Liver transplantation

CTP-A/ B CTP C CTP C CTP-A/ B

Systemic Supportive Supportive Portal vein

chemotherapy care & care & thrombosis ?
palliation palliation
 260

Portal vein
thrombosis ?

No Yes

Number of lesions
Radio-embolisation (Yt : 90)
Stereotactic body radiation therapy (SBRT)
Single + size < 5 cm
TACE + radiotherapy
Radio-frequency ablation
Microwave ablation
Percutaneous ethanol injection (PEI)

Multiple or size > 5 cm

TACE
Radio-embolisation (Yt : 90)
Stereotactic body radiation therapy (SBRT)

MILAN criteria :- Extended MILAN criteria :-

i. Single lesion ≤ 5 cm (USCE)
ii. ≤ 3 lesions (largest ≤ 3 cm) i. Single lesion ≤ 6.5 cm
- No major vascular invasion ii. ≤ 3 lesions + largest ≤ 4.5 cm
- N0 and M0 disease + total diameter ≤ 8 cm

Silva criteria :-
≤ 3 lesions
+ largest lesion ≤ 5 cm
+ total tumor dimeter ≤ 10 cm
 261
Systemic chemotherapy
Tyrosine kinase inhibitors :
i. Sorafenib
- Indication : patient with extra-hepatic disease (unresectable)
with good LFT.
ii. Lenvatinib
iii. Regorafenib
iv. Cabozantinib (also used in thyroid medullary cancers)
Ramucirumab (VEGF receptor 2 inhibitor)

TACE and Radio-

frequency ablation
1. Tumor down staging
2. Bridging therapy
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