standard modules for hepatitis

1 |World Health Organization

Western Pacific Region

Standard modules for hepatitisStandard modules for hepatitis



Standard Module 1Liver anatomy and physiology

Standard Module 1Liver anatomy and physiology



Located in right upper abdomen

Protected by the right rib cage

Measures: 12‐15 cm in vertical direction

Weight: ~1500 grams

Two lobes Right: Extends till near the right costal margin

(the lower edge of the rib cage) Left: Extends midway between xiphisternum

and umbilicus

Position of liverPosition of liver

Midline

Umbilical line

Left upperRight upper

Left lowerRight lower



Several functions, including some of the following

Glucose metabolism During the feeding phase Move glucose into glycogen stores (liver)

During fasting Move sugar from stores (liver) to the blood

Excretory function (detoxication) Bile pigments (bilirubin)

Bile salts Important for absorption of fats

Other harmful substances

Synthetic function Albumin

Coagulation factors

Functions of the liverFunctions of the liver



Blood supply of liverBlood supply of liver

Blood flow ~ 1500 ml/min

~ 25% of cardiac output (what the heart pumps)

Dual blood supply

Hepatic artery 1/3rd

Venous blood (portal vein) 2/3rdfrom the intestine



Normal circulationNormal circulationBlood from all the tissues reaches the right heart

and then goes to lungs

Left HeartRight Heart

Arteries

Capillaries

Veins

Lung capillaries



Portal circulationPortal circulationVenous blood goes to another organ instead of to the right heart

Left HeartRight Heart

Arteries

Capillaries

Veins

Lung capillaries

Another organ



Liver blood supplyLiver blood supply



Liver portal systemLiver portal system



Liver: Microscopic anatomyLiver: Microscopic anatomy

Organized as hepatic lobules

Lobules are penta‐ to hexagonal structures, located closely together



Liver: Microscopic anatomyLiver: Microscopic anatomy

Portal tract


Lobules are penta‐ to hexagonal structures, with portal tracts at each corner and central vein in the middle



Microscopy anatomy of liverMicroscopy anatomy of liver



Portal tract

Direction of flow of bloodDirection of flow of blood





Direction of flow of bileDirection of flow of bile



Portal tract



Standard Module 2Laboratory test in liver diseases

Standard Module 2Laboratory test in liver diseases



Common tests of liver functionCommon tests of liver function

Test Normal values Purpose

Total bilirubin mg/dL <2.0 Conjugation, excretion

Conjug. Bilirubin mg/dL <15% of total bilirubin

ALT/SGPT IU/L <40 Enzymes released by liver cell injury/death

AST/SGOT IU/L <40

Alk.phosphatase Varies by method Enzymes released by biliaryinjury or obstruction

GGT IU/L <35

Albumin g/dL 3.5‐5.5 Synthetic function

Prothrombin time INR 0.9‐1.2

The reference ranges for these tests may vary slightly between laboratories and populations



Assessing the liver disease severityAssessing the liver disease severity

Chronic hepatitis Liver cirrhosis(compensated)

Liver cirrhosis(decompensated)

Liver failure



Fibroscan®(http.myliverexam.com/en/lexamen‐fibroscan.html)

AST; aspartate aminotransferase ALT; alanine aminotransferaseAPRI; aspartate aminotransferase‐to‐platelet ratio indexFIB‐4; fibrosis‐4 score

WHO Guidelines, 2015

Assessing the degree of liver fibrosisAssessing the degree of liver fibrosis Non‐invasive tests

Components Requirements Cost

APRI AST, platelets Simple serum andhematology test +

FIB‐4 Age, AST, ALT, Platelets

FibroTest gGT, haptoglobin, bilirubin,A1apoprotein, α2‐macroglobulin

Specialized tests atdesigned laboratories ++

Fibroscan ® Transient elastography Dedicated equipment +++


Western Pacific RegionWHO Guidelines, 2015

Assessing the degree of liver fibrosis

APRI = [ (AST(IU/L)/ AST_ULN(IU/L)) x 100 ] / platelet count (109/L)ULN signifies the upper limit of normal for AST in the laboratory where these investigations were undertaken

FIB‐4 = age(yr) x AST(IU/L)/platelet count(109/L) x [ALT(IU/L)1/2]

Fibrosis stages

assessed

Cut off values for the detection of fibrosis

Cirrhosis(METAVIR F4)

Significant fibrosis(METAVIR ≧F2)

APRI ≧F2, F4 High cut‐off 2.0 High cut‐off 1.5FIB‐4 ≧F3 High cut‐off 3.25

FibroTest ≧F2, F3, F4 0.32‐0.48 0.58‐0.75

Fibroscan® ≧F2, F3, F4 >11‐14 kPa >7‐8.5 kPa



The Child‐Turcotte‐Pugh Classification systemPoints 1 2 3

Encephalopathy None Minimal(grade1 or 2)

Advanced(grade 3 or 4)

Ascites Absent Controlled Refractory

Total bilirubin(μmol/L)(mg/dL)

<34 (<2) 34‐51 (2‐3) >51 (>3)

Albumin(g/dL) >3.5 2.8‐3.5 <2.8

Prothrombin time (seconds) or PT‐INR*

<4 or <1.7 4‐6 or 1.7‐2.3 >6 or >2.3

Child‐Pugh Class A: 5‐6 pointsChild‐Pugh Class B: 7‐9 pointsChild‐Pugh Class C: 10‐15 points

*PT‐INR ; prothrombin time international normalized ratio



Standard Module 3Symptoms and Signs of liver disease

Standard Module 3Symptoms and Signs of liver disease



Features of liver failureFeatures of liver failure Glycogenesis & Gluconeogenesis

Poor glycogen store > hypoglycemia

> hyperglycemia

Poor gluconeogenesis > hypoglycemia

Excretory function

Bile pigment

Impaired excretion > Jaundice

Synthetic function

Albumin > Hypoalbuminemia > edema/ascites

Coagulation factors > Prolonged prothrombin time (INR)



Other signsOther signs

Dark skin pigmentation

Palmar erythema

Vascular spider

Xanthoma

Subcutaneous bleed

Gynecomastia

Palmar erythema

Spider angiomas



Standard Module 4Introduction of viral hepatitis

Standard Module 4Introduction of viral hepatitis



Definitions

Hepatitis: Inflammation of liver

• Acute hepatitis: Hepatitis usually recovered < 3 months

• Chronic hepatitis: Hepatitis continuing for > 6 months

What is hepatitis ?What is hepatitis ?



Cause of hepatitis

Hepatitis viruses infection (HAV, HBV, HCV, HDV, HEV)

Other infections

• Viruses other than hepatitis viruses (e.g. CMV, EBV, …)

• Parasites (e.g. malaria)

• Bacteria (e.g. typhoid)

Toxic substances (Alcohol, Aflatoxin, …)

Autoimmune disease

Ischemia (reduced blood supply)



Hepatitis A virus(HAV)

Chronic infectionLiver cirrhosisLiver cancer

Hepatitis E virus(HEV)

Hepatitis C virus(HCV)

Hepatitis B virus(HBV)

Hepatitis D virus(HDV)

Main hepatitis viruses



HAV HBV HCV HDV HEVAcute hepatitis

Case fatality increases with age

Case fatality increases with age

Uncommon Superinfection in HBV may lead to fulminant disease

Higher case fatality in pregnant women

Chronic infection

No 5% (adults)90% (children)

55‐85%Complicates hepatitis B

Very rare

HCC* No Yes Yes NoRoute of transmission

WaterborneFoodbornePerson‐to person

PerinatalBloodborneSexual

BloodbornePerinatalSexual

Bloodborne WaterborneFoodborne

Vaccine Yes Yes No HBV vaccine NoTreatment options

None Available Available Modified treatment of

HBV

None

Main hepatitis viruses

*HCC; hepatocellular carcinoma



Acute hepatitis and chronic hepatitisAcute hepatitis Chronic hepatitis

Definition Usually recovered <3months Continuing for > 6monthsEtiology HBV, HEV, HAV, … HBV, HCV, Alcohol, …

SymptomAlmost no symptom or

jaundice, dark urine, general fatigue, abdominal pain, …

Almost no symptom orascites, edema, jaundice, …

(decompensated liver cirrhosis)

Sequela Acute liver failure

Liver cirrhosis→Chronic liver failure

Hepatocellular carcinomaEsophageal varices

Findings



Progression of liver fibrosis

Metavir fibrosis stages: F0‐F4

Cirrhosis: An advanced stage of liver fibrosis characterized by – Extensive fibrosis– Nodular regeneration– Distortion of liver architecture = F4 fibrosis



Chronic hepatitis

Ascites, edema, variceal hemorrhage,encephalopathy, jaundice, …

Liver cirrhosis and hepatocellular carcinoma Liver cirrhosis is an advanced stage of chronic hepatitis

Liver cirrhosis(compensated)

Liver cirrhosis(decompensated)

death

Hepatocellular carcinoma

Liver failure



Effect of cirrhosis on liver circulationEffect of cirrhosis on liver circulation

Decreased blood flowthrough the liver leads to

high pressure in the portal venous system

or Portal hypertension



Features of portal hypertensionFeatures of portal hypertension

Ascites

Esophageal Vx Gastric Vx Splenomegaly



Liver disease: Effect on blood circulationLiver disease: Effect on blood circulation

Obstruction of blood flow through the hepatic lobules leads to increased pressure in portal vein

Portal hypertension = increased pressure in portal vein

Manifestations Development of collateral veins Abnormally enlarged veins

(varices) Exudation of fluid into abdomen Ascites Congestion of venous system Splenomegaly > pancytopenia



Standard Module 5Burden of viral hepatitis

Standard Module 5Burden of viral hepatitis



Hepatitis mortality is increasingHepatitis mortality is increasing 1.34 million deaths from viral hepatitis in 2015

7th leading cause of death among all cause mortality

Sources – WHO Global hepatitis report 2017

96% hepatitis deaths from HBV and HCV (cirrhosis and hepatocellular carcinoma)

0

0.5

1

1.5

2

2000 2005 2010 2015

Millions of d

eaths

Year

Hepatitis

Tuberculosis

HIV

Malaria

1.34 milliondeaths in 2015



WHO Global health sector strategy on viral hepatitis 2016‐2021

Regional distribution of hepatitis deathsRegional distribution of hepatitis deaths



GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age‐sex specific all‐cause and cause‐specific mortality for 240 causes of death, 1990‐2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Jan 10;385(9963):117‐71.

Comparison of global and Western Pacific mortality



(2015)

Hepatitis deaths in Western Pacific RegionHepatitis deaths in Western Pacific Region

Liver cancer is second most common cause of deaths.

78% of liver cancer are due to HBV or HCV.



Guidelines for the prevention, care and treatment of personswith chronic hepatitis B infection. WHO: 2015(http://www.who.int/hepatitis/publications/hepatitis‐b‐guidelines/en/)

Global epidemiology of Hepatitis B infection 240 million people around the world infected with HBV

680,000 die every year due to hepatitis B

Children 5‐9 years, 2005 Adults 19‐49 years, 2005



WHO Global health sector strategy on viral hepatitis 2016‐2021

240 million of adults 19‐49 years of age living with HBV infection (HBsAg) worldwide, 2005

Sources – Ott J et al, Vaccine, 2012



Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection. Updated version, April 2016. WHO; 2016 (http://www.who.int/hepatitis/publications/hepatitis‐c‐guidelines‐2016/en/)

Global epidemiology of Hepatitis C infection 80 million people around the world infected with HCV

700,000 die every year due to hepatitis C

standard modules for hepatitis

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