Stellate cells

• Location: Space of Disse

• Resting State - Activated State

  • Resting State – Store vitamin A and regulate extracellular matrix

  • Activated State – Transform into myofibroblasts, producing collagen

• Functions

  • Fibrosis and Cirrhosis

    • excess collagen deposition

  • Reversal of Fibrosis

    • Potential for fibrosis reversal if liver injury is resolved

Kuppfer cells

• Location

  • sinusoids of the liver

• Function

  • Resident phagocytes of the liver

  • Protect against infections --> engulf pathogens

  • Breakdown mature RBC → release bilirubin

  • Remove debris and foreign bodies from the portal system

Bile Flow Pathway

1. Bile Canaliculi:

2. Bile Ductules:

3. Bile Ducts:

4. Common Hepatic Duct:

Gallbladder and Cystic Duct

Common Bile Duct

1. Formed by the junction of the:

   • Cystic duct and Common Hepatic Duct.

2. Ampulla of Vater

3. Sphincter of Oddi

Bile Pathway:

1. Hepatocytes → Bile Canaliculi → Bile Ductules → Bile Ducts → Right and Left Hepatic Ducts → Common Hepatic Duct ↔ Cystic Duct → Common Bile Duct → Ampulla of Vater → Duodenum

Main site of protein synthesis

• Types of proteins produced:

  • Albumin: Maintains oncotic pressure and transports substances (e.g., hormones, fatty acids)

  • Transport and Carrier Proteins:  Includes transferrin (iron transport) and ceruloplasmin (copper transport)

  • Acute Phase Proteins

    • CRP

  • Coagulation Factors: Produces most clotting factors (I, II, V, VII, IX, X, XI, XII, protein C, protein S) for blood clotting

    • does not produce VWF (produced by epithelium)

  • Complement System Components

Storage

• Vitamins: A, D, B12 (large amounts), K and folate (smaller amounts).

• Minerals: Iron (stored as ferritin and haemosiderin), copper

Amino acid breakdown

Urea cycle

Carbohydrate metabolism

Lipid metabolism

Bilirubin

Angiotensinogen

Source

Process

Conjugation

• Conjugation

  • In the liver, unconjugated bilirubin is conjugated with glucuronic acid by the enzyme UDP-glucuronosyltransferase (UGT).

  • Conjugated bilirubin is water-soluble and can be excreted in bile.

Excretion

Liver Function Tests (LFTs)

• Serum albumin

  • Measures the liver's ability to synthesize albumin.

  • Low levels indicate liver dysfunction, malnutrition, or chronic liver disease.

• Serum Bilirubin

  • Measures total, direct, and indirect bilirubin.

  • Elevated levels suggest liver dysfunction or bile duct obstruction.

• Prothrombin Time

  • Assesses liver's ability to produce clotting factors.

  • Prolonged PT indicates liver damage or vitamin K deficiency.

Liver Biochemistry

• Aminotransferases (AST & ALT)

  • Elevated levels indicate liver cell damage (e.g., hepatitis, fatty liver disease).

• Alkaline phosphatase (ALP)

  • Measures cholestasis or bile duct obstruction.

  • Elevated levels can also indicate bone disease or liver metastasis.

• Gamma-Glutamyl Transpeptidase (γ-GT)

  • Elevated levels are associated with liver disease, cholestasis, or alcohol-related liver damage.

• Total Proteins and Globulin Fraction

Viral Markers and Genetic Tests

Immunological Tests

• Serum Immunoglobulins

• Autoantibodies

Markers of Liver Fibrosis

• APRI (AST to Platelet Ratio Index)

  • A non-invasive marker of liver fibrosis and cirrhosis based on AST levels and platelet count.

• Enhanced Liver Fibrosis (ELF) Test

• Transient Elastography (FibroScan)

  • measures stiffness (fibrosis) of the liver with a tranducer

Ultrasound Examination

• First-line imaging for liver disease.

• Uses

  • Assess liver size, texture, and abnormalities (e.g., fatty liver, tumors, cirrhosis).

  • Guide biopsy or liver procedure (e.g., drainage).

Colour Doppler Ultrasound

• Visualizes blood flow within the liver and surrounding vessels.

• Assesses vascular abnormalities, such as portal hypertension or cirrhosis-related changes.

CT

• detailed cross-sectional imaging

• uses

  • Characterize liver lesions (e.g., tumors, cysts).

  • Assess liver vascular anatomy (e.g., portal vein, hepatic artery).

  • Monitor liver conditions like cirrhosis and liver metastasis.

MRI

Magnetic Resonance Cholangiopancreatography (MRCP)

Radionuclide Imaging (Scintiscanning)

Endoscopy

• Upper GI Endoscopy

• Capsule Endoscopy

Endoscopic Retrograde Cholangiopancreatography (ERCP)

Angiography

Hepatic Venous Cannulation:

Gold standard for histological diagnosis.

Indications:

Techniques:

Complications:

Hemolytic Jaundice – Increased breakdown of red blood cells.

• Cause: Excessive destruction of red blood cells (hemolysis) leads to increased production of unconjugated bilirubin.

• Characteristics

  • Increased unconjugated bilirubin in the blood, no significant liver dysfunction.

• Clinical features

• Laboratory findings

  • Increased unconjugated bilirubin.

  • Normal liver enzymes (AST, ALT).

  • Decreased haptoglobin (a protein that binds free hemoglobin).

Congenital Hyperbilirubinemias –Genetic defects in bilirubin metabolism.

• Unconjugated Types

  • Gilbert's Syndrome

    • Cause: Mild reduction in UDP-glucuronosyltransferase (UGT) activity.

    • Clinical Features: Mild jaundice, often triggered by stress or fasting.

    • Laboratory Findings: Elevated unconjugated bilirubin, normal liver enzymes.

  • Crigler–Najjar Syndrome

    • Cause: Severe UGT deficiency.

    • Clinical Features: Severe jaundice from birth, may lead to kernicterus (brain damage) in Type 1.

    • Laboratory Findings: Very high unconjugated bilirubin.

• Conjugated Types

  • Dubin–Johnson Syndrome: rare autosomal recessive

    • Cause: Mutation in ABCC2 transporter responsible for bilirubin excretion.

    • Clinical Features: Chronic mild jaundice, black liver appearance (melanin deposition) on biopsy.

    • Laboratory Findings: Elevated conjugated bilirubin.

  • Rotor's Syndrome

    • Cause: Defect in hepatic bilirubin storage and transport.

    • Clinical Features: Mild jaundice, typically with normal liver function.

    • Laboratory Findings: Elevated conjugated bilirubin, mild elevated liver enzymes.

  • Benign Recurrent Intrahepatic Cholestasis (BRIC)

  • Progressive Familial Intrahepatic Cholestasis (PFIC)

Cholestatic Jaundice – Impaired bile flow, either within the liver (intrahepatic) or outside the liver (extrahepatic).

• Types:

  • Extrahepatic Cholestasis

    • Cause: Obstruction of the bile ducts outside the liver (e.g., gallstones, tumors, strictures).

    • Clinical Features: Jaundice, dark urine, pale stools, itching (pruritus).

    • Laboratory Findings:

      • Elevated conjugated bilirubin.

      • Elevated ALP and GGT.

  • Intrahepatic Cholestasis

    • Cause: Obstruction of bile flow within the liver due to liver diseases (e.g., cirrhosis, hepatitis, drug-induced liver injury).

    • Clinical Features: Jaundice, pruritus, hepatomegaly.

    • Laboratory Findings:

      • Elevated conjugated bilirubin.

      • Elevated ALP and GGT.

• Clinical features

• Lab findings

Jaundice can present as:

• Acute Jaundice

• Chronic/Decompensated Jaundice

Comprehensive Approach to DD of Jaundice

• Demographics and Risk Factors:

  • Age and Weight Loss

  • Country of Origin

  • Occupation and Environment

History of Illness and Symptoms:

• Duration of Illness:

• Abdominal Pain:

• Fevers or Rigors:

Lifestyle and Exposure History

• Intravenous Drug Use, Tattoos, or Recent Injections:

• Sexual History:

  • Men who have sex with men

  • Female sex workers:

• Alcohol Consumption

Medical and Surgical History

• Medical Treatment in Developing Countries

• Recent Surgery

• Drug History

• Family History

Classify jaundice into:

• Pre-hepatic (Hemolytic): Increased RBC breakdown.

• Hepatic (Hepatocellular): Liver cell dysfunction.

• Post-hepatic (Cholestatic): Bile flow obstruction.

Diagnostic Features:

• Chronic Inflammatory Cell Infiltrates:

  • Lymphocytes, plasma cells, and sometimes lymphoid follicles.

• Interface Hepatitis:

  • Loss of definition of the portal/periportal limiting plate.

  • Damage due to apoptosis (not necrosis).

• Lobular Changes:

  • Focal lytic necrosis, apoptosis, and focal inflammation.

• Fibrosis:

  • Types:

    • Bridging fibrosis: Across portal tracts.

    • Cirrhosis

Epidemiology

• Common in developing countries with poor sanitation.

• Young children are often asymptomatic carriers, while adults may experience more severe symptoms.

• Endemic areas: Southeast Asia, sub-Saharan Africa, and parts of the Middle East.

• Global vaccine availability has reduced the incidence in many regions.

Transmission

• fecal-oral or poor water sanitation

Clinical features

• Prodromal Phase:

  • Flu-like symptoms: Fatigue, malaise, low-grade fever, anorexia, nausea, vomiting.

  • Right upper quadrant pain or discomfort from liver inflammation.

  • Dark urine (due to increased bilirubin levels).

  • Jaundice may not be present yet.

• Icteric Phase:

  • Jaundice: Yellowing of the skin and sclera due to bilirubin buildup.

  • Clay-colored stools due to impaired bile secretion.

  • Pruritus (itching) as a result of bile salt accumulation in the skin.

  • Hepatic tenderness may be noted.

Biphasic illness

• The illness often resolves after the icteric phase, with symptoms improving before the return of normal liver function.

Investigations

• Liver biochemistry

• Haematological findings

Prognosis

Management

Epidemiology

Aetiology

• Vertical (mother to child) and horizontal transmission

• Risk factors: People with multiple sexual partners, intravenous drug users, healthcare workers, tattoos

Pathogenesis

4 phases:

• Phase 1: HBeAg-Positive Chronic HBV Infection (High Replication)

  • Key features:

    • High levels of HBV DNA and HBeAg in serum.

    • Active viral replication with minimal immune response.

    • Elevated liver enzymes (ALT and AST).

    • no liver damage yet

    • no treatment yet

  • Who is affected?

  • Management

• Phase 2: HBeAg-Positive Chronic HBV Infection (Immune Activation)

  • Key features

    • Immune system activation leads to hepatitis flares.

    • Inflammation and liver damage can occur despite viral replication.

    • Elevated ALT, HBV DNA, and HBeAg.

  • When does this occur

    • Often in young adults or those with an acute immune response to HBV.

  • Risks

  • Management

• Phase 3: HBeAg-Negative Chronic HBV Infection (Inactive Carrier State)

  • Key features:

    • HBV DNA levels are low or undetectable.

    • HBeAg-negative, but anti-HBe positive.

    • Minimal liver inflammation and stable ALT levels.

  • Clinical outcomes

  • Management

• Phase 4: HBeAg-Negative Chronic HBV Infection (Reactivation Phase)

  • Key features:

    • Increase in HBV replication, with elevated ALT and HBV DNA.

    • Potential for severe liver damage, including cirrhosis or liver failure.

  • Challenges

  • Risks

    • Cirrhosis, liver failure, and hepatocellular carcinoma.

  • Management

Clinical Features of Acute Hepatitis B

• Investigations

  • HBsAg: Indicates active infection.

  • Anti-HBc IgM: Indicates acute infection or recent exposure.

  • Anti-HBc IgG and Anti-HBs: Indicates prior infection and immunity.

  • HBeAg and Anti-HBe: Used to monitor viral replication and immune response.

  • HBV DNA levels: Measure viral replication.

• Prevention

  • Vaccination

  • Avoid risk factors

Chronic Hepatitis B Virus Infection

• Investigations

• Management

  • Indications for therapy

  • Types of therapy (interferon, oral antivirals, monitoring)

  • Goals

  • Prognosis

What is hepatitis D?

• Hepatitis D is a liver disease caused by the hepatitis D virus (HDV).

• HDV is a defective RNA virus that requires hepatitis B virus (HBV) to replicate.

• HDV infection can only occur in individuals already infected with HBV, making it a co-infection or superinfection.

Transmission and geographic distribution

• Bloodborne transmission, through sharing needles, blood transfusions, or unprotected sex.

• Vertical transmission from mother to infant is also possible.

Types of infection

• Coinfection (HDV + HBV at the same time)

• Superinfection

Chronic Hepatitis D:

• Overview

  • Chronic HDV infection can result from superinfection or prolonged coinfection.

  • It can lead to cirrhosis, liver failure, and hepatocellular carcinoma (HCC).

  • The course of the disease can be more severe compared to chronic HBV infection alone.

• Diagnosis

• Management

• Prognosis

Epidemiology

High Risk Populations

• Injecting drug users (due to needle sharing).

• People receiving blood transfusions or organ transplants prior to screening.

• Healthcare workers at risk of exposure to blood (needlestick injuries).

• People with HIV, as co-infection can accelerate liver disease.

• People with multiple sexual partners or those engaging in unprotected sex.

Transmission

Clinical features

• Acute infection:

  • Often asymptomatic or mild, with some patients experiencing fatigue, fever, anorexia, nausea, and jaundice.

  • Most people (75-85%) progress to chronic infection without apparent symptoms.

• Chronic infection:

  • Fatigue and mild discomfort are common.

  • Over time, may lead to cirrhosis, liver failure, and hepatocellular carcinoma (HCC).

  • Extrahepatic manifestations such as kidney disease, rashes, and joint pain.

Investigations and diagnosis

• HCV RNA quantification: Measures the amount of virus present in the blood, used to guide treatment.

Management

• no vaccine

Treatment

Transmission

• Fecal-oral transmission is the primary route, typically through contaminated water or food.

• High-risk areas: Endemic in parts of Asia, Africa, and Central America.

No carrier state

Diagnosis

Prevention and control

• Improved sanitation and access to clean water are key to preventing HEV transmission.

• Hepatitis E vaccine is available in some regions but not widely used globally.

• Avoiding unclean water and food hygiene can reduce risk in endemic areas.

• 
  

Autoimmune Hepatitis (AIH) is a chronic liver disease where the body's immune system attacks the liver cells, leading to inflammation and potential liver damage.

Female predominance: More common in women, with a female-to-male ratio of about 3:1.

Genetic susceptibility

Molecular mimicry

Impaired immunoregulatory networks

Mechanisms of liver damage

Two peaks in presentation

• Peri and postmenopausal women

• Teens and Early Twenties

Liver biochemistry

Haematology

Autoantibodies

Liver biopsy

Management

Definition

• NAFLD refers to the accumulation of fat in the liver in individuals who consume little to no alcohol. It includes a spectrum of liver conditions, ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and liver failure.

Risk factors

• Obesity, especially central obesity (visceral fat).

• Type 2 diabetes and insulin resistance.

• Dyslipidemia (high cholesterol and triglycerides).

• Hypertension.

• Metabolic syndrome (combination of obesity, hypertension, dyslipidemia, and insulin resistance).

• Age: More common in middle-aged and older adults.

• Genetic factors and family history of liver disease.

• Sedentary lifestyle and poor diet.

Clinical features

Pathogenesis

• The accumulation of fat in liver cells leads to inflammation and oxidative stress.

• Insulin resistance is a key mechanism driving fat deposition in the liver.

• In NASH, liver inflammation and damage can progress to fibrosis and eventually cirrhosis.

Diagnosis

• Ultrasound: Commonly used to detect fatty liver (hyperechoic liver).

• Liver biopsy: Considered the gold standard for diagnosing NASH and assessing the degree of fibrosis.

• Elastography (e.g., FibroScan): Non-invasive method to measure liver stiffness, helping assess fibrosis and cirrhosis.

Management

• Weight loss (recommended 7-10% weight reduction) through diet and exercise.

• Physical activity and healthy eating (low-fat, low-sugar diet).

  • Lifestyle advice, orlistat, pioglitazone, vitamin E, weight loss following bariatric surgery

• Medications:

  • Orlistat: A weight loss drug that reduces fat absorption.

  • Pioglitazone: Improves insulin sensitivity and may help with liver inflammation.

  • Vit a: for steatosis

  • Vitamin E: Antioxidant therapy, beneficial for NASH, especially in non-diabetic patients.

Aetiology and epidemiology

•  Caused by excessive alcohol consumption over time.

• Affects 30-50% of heavy drinkers, with a higher incidence in individuals with chronic alcohol use.

• 35-60yr/old

Clinical features

• Often asymptomatic in early stages.

• Symptoms may include fatigue, right upper quadrant discomfort, nausea, and mild hepatomegaly.

• In advanced stages, may progress to alcoholic hepatitis, leading to jaundice, ascites, confusion (due to hepatic encephalopathy), and portal hypertension.

• MDF & MELD scores

Pathophysiology

• Alcohol is transported to the liver.

• Alcohol is converted to acetaldehyde using 1 out of 3 pathways:

  • Alcohol Dehydrogenase (ADH)

  • Peroxisome Pathway.

  • CYP2E1 Pathway

• Consequences of Acetaldehyde formation:

  • Generation of ROS

  • Acetaldehyde binds to proteins, forming adducts.

  • Destruction of hepatocytes

Histological changes:

• Fatty liver

• Alcoholic hepatitis

Treatment

Management

Glasgow Alcoholic Hepatitis Score:

Liver cell necrosis and apoptosis release ROS and cell contents → trigger inflammation → activation of hepatic stellate cells and macrophages → stellate cells transform into myofibroblasts → produce ECM leading to fibrosis --> accumulation of fibrotic tissue replaces normal liver parenchyma, causing liver architecture disruption and impeding liver function.

Characteristic features

• Fibrosis with a distortion of the liver lobules.

• Formation of nodules surrounded by fibrous tissue.

Types of cirrhosis (micronodular, macronodular, mixed)

• Micronodular cirrhosis: Small, uniform nodules, often seen in alcoholic liver disease and viral hepatitis.

• Macronodular cirrhosis: Larger, irregular nodules, often seen in chronic hepatitis or biliary cirrhosis.

• Mixed cirrhosis: Combination of both micronodular and macronodular changes.

Complications and Symptoms

• Portal hypertension: Due to disrupted blood flow, leading to splenomegaly, ascites, and variceal bleeding.

• Liver failure: Progressive dysfunction of liver cells, leading to jaundice, hypoalbuminemia, coagulopathy, and hepatic encephalopathy.

• Hepatocellular carcinoma (HCC): Increased risk of liver cancer in cirrhotic patients.

• Encephalopathy: Impaired liver function leads to the accumulation of toxic substances (e.g., ammonia) that affect brain function.

• Fatigue, weight loss, itching (pruritus), and easy bruising.

Severity Assessment

• Liver function tests:  Assess liver enzyme levels (ALT, AST, ALP, GGT), bilirubin, and albumin to gauge liver performance.

• Liver biochemistry

• Serum electrolytes

Determining type of cirrhosis

• Viral Markers.

• Serum Autoantibodies.

• Serum Immunoglobulins.

• Iron Indices and Ferritin (for haemochromatosis).

• Copper and Caeruloplasmin (for Wilson’s disease).

• α1-Antitrypsin (for α1-antitrypsin deficiency).

• Genetic Markers.

Imaging Techniques

• Ultrasound, fibroscan, CT Scan, MRI and MR Angiography

Endoscopy

Liver biopsy

• Gold standard

Monitor + Screen

• Regular monitoring for complications such as ascites, variceal bleeding, encephalopathy, and HCC (Hepatocellular carcinoma).

• Screening for liver cancer: Routine screening (e.g., ultrasound and alpha-fetoprotein (AFP)) in cirrhosis patients, especially those with hepatitis B or C.

Treat underlying cause

Preventative measure

5-year survival rate, prognostic indicators, scoring systems (Child-Pugh Score, MELD)

• 5-year survival depends on the underlying cause, degree of liver damage, and presence of complications (e.g., liver failure, variceal bleeding, HCC).

• Early stages of cirrhosis (compensated cirrhosis) have a better prognosis than decompensated cirrhosis.

Child-Pugh Score: A scoring system to assess liver function and prognosis based on factors like bilirubin levels, albumin, encephalopathy, ascites, and prothrombin time.

• Child-Pugh A: Mild cirrhosis (best prognosis).

• Child-Pugh B: Moderate cirrhosis.

• Child-Pugh C: Severe cirrhosis (poor prognosis).

Primary Sclerosing Cholangitis

• Definition: Chronic, progressive disease of the bile ducts leading to fibrosis, strictures, and obstruction. Can result in cirrhosis.

• Associations and risk factors

  • Strongly associated with ulcerative colitis (70-80% of PSC patients).

  • Increased risk of cholangiocarcinoma and gallbladder cancer.

  • More men are affected

• Clinical features

  • Can be symptomatic or asymptomatic

  • Fatigue, pruritus (itching), and jaundice.

  • Abdominal pain, particularly in the upper right quadrant.

  • Hepatomegaly and splenomegaly.

• Diagnosis

  • MRCP: shows bile ducts, liver biopsy: bile duct inflammation, fibrosis, and cirrhosis

Primary Biliary Cholangitis: Chronic autoimmune disease characterized by progressive destruction of intrahepatic bile ducts, leading to cholestasis, fibrosis, and cirrhosis.

• Definition

  • 90% of patients are women aged 40-50

• Aetiology (unknown, AMA)

• Clinical features

• Investigations

  • Liver biochem, AMA, Imaging and Biopsy

• Management

  • UDCA: Ursodeoxycholic acid (UDCA): First-line treatment to improve liver function and slow progression.

  • symptom relief: Antihistamines and cholestyramine for pruritus.

  • supplements