Liver

Functional unit: lobule

Lobule: hexagonal in shape and each of the six points we see a portal triad, consisting of a branch of
portal vein, hepatic artery and bile duct. From these ducts blood gets into the sinusoids (hepatic
open pore capillary) which are in between the hepatocytes and eventually drains away at a branch
of the central vein which then itself drains into the vena cava => systemic circulation => RV and
lungs.

Bilirubin Metabolism

RBC (life span =120 days) break down in the spleen (as a normal process or in blood as a result of
disease process) into haemoglobin => bilirubin and from there via the splenic vein into the portal
vein to the liver. It reaches the liver in an unconjugated form which is fat-soluble and travels through
blood bound to albumin. In the liver, it gets conjugated to glucuronic acid and forms a water-soluble
compound which is excreted in bile and small intestine where bacteria split conjugate into
urobilinogen. 80-90% of urobilinogen is excreted through faeces, with the rest being resorbed into
blood. So, at any given time there is conjugated and un-conjugated circulating bilirubin. Then
conjugated form is excreted via both urine (portal vein & hepatic artery => sinusoid => central vein
=> vena cava => systemic circulation => kidney) or (portal vein & hepatic artery => hepatocytes =>
bile duct => gallbladder = > small intestine => large intestine) faeces.

Hyperbilirubinemia

High levels of bilirubin in the blood could result from the hepatocytes not functioning well and not
being able to conjugate bilirubin and as a consequence the bilirubin goes back into the blood
unconjugated or when there is biliary ducts obstruction and obstruction of bile flow, causing
conjugated bilirubin to go back into the blood.

Biochemical hyperbilirubinemia (indicates that something is wrong with the liver, needs further
investigation):

 Plasma bilirubin above normal level of 18-24 µmol/L

Clinical hyperbilirubinemia (high levels of bilirubin with evidence of jaundice):

 Evident when levels >50 µmol/L Manifests as yellow discolouration of sclera and skin i.e.
jaundice

Jaundice = yellowish pigmentation of skin, sclerae & mucous membranes due to hyperbilirubinaemia
hyperbilirubinaemia due to increased levels of bilirubin in the blood (can be caused by both
conjugated and unconjugated)

When there are high levels of bilirubin in the blood it can deposit in the skin and being a skin irritant
people start to feel itchy.

E.g. if someone’s got cirrhosis of the liver and hepatocytes are dysfunctional because of necrosis and
scar tissue which blocks bile flow there is going to be an increase of both conj. and unconj. bilirubin
in the blood

Unconjugated hyperbilirubinaemia:

 ↑ unconjugated bilirubin in blood

 Due to ↑ red cell destruction (e.g. haemolytic anaemia caused by streptococcal infection in
the blood) OR impaired hepatocyte function (e.g. drugs (some TB antibiotics) may cause ↓
uptake of bilirubin by hepatocytes → impaired conjugation)
 e.g. neonatal jaundice occurs due to impaired conjugation (low glucuronyl transferase
activity)

Conjugated hyperbilirubinaemia:

 ↑ conjugated bilirubin in blood

 Due to obstruction of bile flow (intrahepatic – hepatic ducts and/or extrahepatic – cystic or
common ducts) leading to build up of bile in the liver, ↓ excretion of conjugated bilirubin
and back flow in the blood

Key clinical features are:

 Pronounced jaundice (cholestatic/obstructive jaundice)

 Pale stools (bile not entering intestine & absent in stools)
 Steatorrhoea (runny stools due to impaired fat absorption & therefore ↓ Vit K absorption)
 Itching/pruritus (accumulated bile salts)
 Dark urine (water-soluble conjugated bilirubin excreted in urine)

NB: Hepatitis & cirrhosis can both cause the two types of hyperbilirubinaemia.

Hepatitis

Inflammatory diseases of the liver are termed 'hepatitis' and many things causes inflammation of the
liver not just viruses.

 Acute
o some liver cell necrosis (coagulative) if disease severe, inflammation, apoptosis of
hepatocytes forming Councilman bodies (eosinophilic – stain pink) which is a sign for
acute hepatitis
 Chronic
o liver cell necrosis, inflammation, fibrosis
Aetiology:

 Viral infections (A-E hepatotropic viruses which have an affinity for the liver and replicate in
the liver, but other viral infections that are not hepatotropic), non-viral infections (bacterial,
parasitic), toxins (alcohol)/drugs (anabolic steroids), metabolic (haemochromatosis) &
autoimmune diseases (leads to chronic hepatitis and predispose to cirrhosis), idiopathic.

Hepatitis A Virus (HAV)

 RNA virus
 Mode of transmission:
o Faeco-oral route (infected faecal matter enters mouth)
o Recreational use of waters or eating raw shellfish contaminated by sewage
o Touching nappies/linen soiled with infected faeces
 Does not lead to chronic liver disease, self-limited disease with fool recovery
 Pathogeneses - malaise, jaundice, then recovery
 Infection leads to life-long immunity by development of serum anti-HAV Abs (which can be
detected and used in diagnosis)
 Vaccine available

Hepatitis B Virus (HBV)

 DNA virus
 Most common liver infection
 Mode of transmission:
o Blood to blood
o Mother to child
o Sexual contact via seminal fluid
 IV drug abuse or tattoos can transmit the virus
 It is self-limited and people can fully recover by may also cause in some individuals chronic
liver disease => chronic hepatitis => cirrhosis => liver cancer => liver failure
 Vaccine also available

There are different clinical outcomes of infection with Hep B:

1. Acute self-limited hepatitis: common, short incubation period (about a month), full recovery
& have lifelong immunity; can be symptomatic or asymptomatic - patient have no symptoms
at all (sub-clinical)
2. Fulminant acute hepatitis: rare, there is massive necrosis of liver cells and life threatening
3. Chronic hepatitis: chronic infection that lasts more than 6 months with inflammation,
scaring (fibrosis); may progress to cirrhosis then hepatocarcinoma
4. Asymptomatic chronic infection: the virus goes into the dormancy and the patient becomes
a carrier, may lead to chronic hepatitis & hepatocarcinoma; it is detected in the blood via the
HepBsAg surface antigen but not the HepBeAg envelope antigen which is a marker for viral
replication; this is not all good news because the virus can in certain circumstances come out
of dormancy and start spontaneous replication and develop cirrhosis and hepatocarcinoma
or go straight to hepatocarcinoma

Diagnosting Testing for Hep B:

  High transaminases – liver enzymes due to live cells damage (can be seen with any cause of
liver damage not just viral infection)
 HBsAg - surface protein component (surface antigens)
 HBeAg, HBcAg – envelope, core components
 HBV-DNA detected by PCR - detects how much virus is in the blood (indicates how rapidly
the virus is replicating in the liver, the viral load in the liver)
 HBeAg, HBcAg, HBV DNA - markers of active viral replication

Clinical patterns of Hep B inf.

Markers for Hep B (the acute self-limiting type)

 Initially there is a period of incubation which lasts for about a month

 Liver cell damage causing liver enzymes release – high transaminases
 Formation of antibodies in acute phase of illness which provide life-long immunity – Hep B
surface antibodies
Hepatitis B Virus (HBV) detection

Liver biopsy:

 First detection by H&E stain which if suspicious of Hep B inf. then further testing is required
for surface antigens and immunohistochemistry
 In chronic Hep B infection, liver cells accumulate HBsAg in the cytoplasm (glassy
appearance); to detect this a special stain called immunohistochemistry (IHC) which is
immunostained brown by HBsAg antibodies – IHC

Hepatitis C Virus (HCV)

 RNA virus
 Mode of transmission:
o blood-to-blood
o mother-to-child
 Diagnostic testing:
o Detection of antibodies to the virus
o PCR detection of Hep C viral RNA in blood
 Clinical outcomes:
o Acute hepatitis → full recovery
o Acute hepatitis → fulminant hepatitis
o Chronic hepatitis (relapsing/remitting) → may progress to cirrhosis,
hepatocarcinoma

Hepatitis D Virus (HDV)

 RNA virus
 It is a defective virus requiring the presence of Hep B virus to be able to replicate and infect;
without the B virus the D virus is harmless
 Mode of transmission:
 o Blood-to-blood
 Diagnostic testing:
o Detection of anti-HDV Abs (Hep D antibodies) in presence of anti-HBc Abs (Hep B cor
components antibodies)
o PCR detection of viral genomic material - HDV RNA in blood
 Clinical outcomes:
o Similar to Hep B infection with more severe complications, more damage to the liver
o May cause chronic liver disease due to co-infection of Hep B and D leading to cancer =
highest mortality rate of all hepatitis infections
o Co-infection with hepatitis D prevented through hepatitis B vaccination

Hepatitis E Virus (HEV)

 RNA virus
 Mode of transmission:
o Similar to HepA infection (faeco-oral route)
 Shorter incubation than Hepatitis A (~1month)
 Clinical outcomes:
o Fatigue, malaise, jaundice, then recovery
 Does not lead to chronic liver disease
 Immunity is not lifelong
 However, it has a high mortality rate in infected pregnant women (may result in acute
fulminant hepatitis in ~20% cases)

SUMMARY

Other Viruses Causing Viral Hepatitis:

 EBV (Epstein Barr Virus) – causes glandular fever, but if the virus gets to the liver it can cause
hepatitis
 CMV (Cytomegalovirus) – in patients that are immunocompromised (elderly); virus can go to
the liver and cause inflammation
 Herpes Simplex Virus – can go in the blood and cause inflammation
  Group B arbovirus - transmitted by female mosquitoes, gets into the blood and goes to the
liver and can cause acute haemorrhagic disease (fever, headache, abdominal pain, vomiting,
jaundice) – “Yellow fever” (tropical regions)

Non-viral Hepatitis

Bacterial Hepatitis:

 Leptospira Spp.
o Transmitted by water/food/soil containing urine of infected animals; farmers or vets
are more likely to be infected
o It can cause Weil’s disease (fever, headache, vomiting, jaundice (if the bacteria
enters the blood and goes to the liver), purpuric skin rash (in the blood causes
haemorrhagic blood vessels – petechiae), renal failure (if it goes to the kidney))
o In the liver we see inflammation which causes focal hepatocyte necrosis &
cholestasis (obstruction of bile flow)
 Enteric bacteria
o If bacteria that is in our intestines e.g. E. coli gets into portal circulation and then
into the liver can cause liver abscesses (from haematogenous spread of enteric
bacteria through the portal vein)

Parasitic:

 Protozoal infection
o Infection with amoeba Entamoeba histolytica (Amoebiasis)
 Transmitted by faeco-oral route
 “Anchovy paste” abscess in liver (amoebic abscess contains necrotic tissue
resembling anchovy paste) (also causes specific ulcerative colitis and bloody
diarhhoea i.e. amoebic dysentery)
o Infection and destruction of RBCs with Plasmodium spp. (Malaria)
 Transmitted by female mosquitoes
 Causes fever, vomiting, anaemia, hepatomegaly (because it works harder to
conjugate bilirubin), splenomegaly (because the spleen works hard to
remove excess dead RBC)
 Helminth infection
o Infestation with tapeworm Echinococcus granulosus (Hydatid disease)
 Contact with dog/sheep faeces infected with tapeworm eggs (e.g. handling
soil, dirt or animal hair)
 Hydatid cysts form in vital organs such as the liver (more severe disease
when worm gets to the lungs and forms cysts)
 Fatigue, swollen abdomen, enlarging cyst may cause jaundice

Toxin or Drug induced hepatitis

 Toxins or drugs may lead to liver disease and cause various pathological changes:
o Acute and chronic hepatitis - isoniazid (TB drug)
o Acute necrosis - paracetamol
o Fatty change - alcohol, methotrexate (cancer, autoimmune drug)
o Cirrhosis - alcohol
o Cholestasis - steroids (lead to hepatitis then obstruction to bile flow)
o Tumours - anabolic steroids, oral contraceptives lead to adenoma of the liver
Metabolic liver disease

Haemochromatosis – too much Fe in blood

 May lead to chronic hepatitis and then cirrhosis

 Characterised by increased deposition of iron (as haemosiderin) in tissues (rusty brown)
o chronic liver cell damage which leads to cirrhosis
o if it goes to the pancreas damages the cells that produce insulin (bronzed
diabetes); it can also deposit in the spleen, heart, skin, testes and endocrine
glands and cause tissue damage
o iron in liver tissue stains blue with Perl’s stain
 Primary haemochromatosis – it is inherited autosomal recessive
o Continuous absorption of iron from intestine, high levels of Fe in the blood and
need to be treated with chelating agents; high Fe levels in the blood deposits in
the various tissues in the body e.g. skin, liver and leads to cirrhosis
 Secondary haemochromatosis – secondary to other disorders e.g. thalassemia
o Increased iron accumulation due to thalassemia which requires repeated blood
transfusions which then leads to increased Fe levels

Wilson’s disease – too much Cu in blood

 May cause chronic hepatitis & cirrhosis

 Autosomal recessive disorder of copper metabolism
 Normally Cu goes to the liver to be incorporated into ceruloplasmin (Cu binding protein
synthesised in the liver) => back into the blood as a compound or it gets excreted into
the bile
 In Wilson’s disease Cu does not get incorporated into ceruloplasmin and goes back into
the blood as free Cu and gets deposited in various tissues including liver - hepatocyte
cytoplasm causing chronic damages and cirrhosis, or the brain causing neurological and
psychiatric conditions, cornea causing a Kayser-Fleischer ring
 Damage to liver tissue leads to low ceruloplasmin levels in plasma

α1-Antitrypsin Deficiency – deficiency of antitrypsin enzyme

 May cause chronic hepatitis & cirrhosis

 Inherited autosomal dominant
 α1-antitrypsin production in liver is defective which leads to abnormal levels of α1-
antitrypsin protein in liver cells causing chronic damage and later cirrhosis
 low blood and lung levels of this enzyme can’t inactivate the elastases in the lungs, the
elastases then break down the alveolar wall and enlarged air spaces form in the lungs
causing cause emphysema
 Detected with immunohistochemistry

Chronic Hepatitis

Characterised by:

 Continued hepatic inflammation that lasts for more than 6 months

 Liver cell necrosis, inflammation (many lymphocytes present) & fibrosis (lots of scar tissue)

Caused by:
  Viral infections (Hep B, C, D+B)
 Toxins (alcohol & drugs) that cause chronic damage/metabolic liver disease
 Autoimmune disease can lead to chronic hep and later biliary cirrhosis

Can lead to: CIRRHOSIS

Cirrhosis

End-point of long-standing liver cell destruction and fibrosis (i.e. chronic hepatitis)

Characterised by:

 Diffuse change of the entire liver with gross disruption to liver architecture
 Regenerative nodules surrounded by necrosis, scar tissue deposition (fibrosis), hyperplasia &
dysplasia of bile ducts (because there is so much damage to hepatocytes there is a build-up
of bile and the ducts adapt by increasing in size to drain all that bile); in time you get less and
less regeneration and more and more fibrosis
 Hepatocellular failure, portal hypertension (build-up of blood in the portal vein because it
does not flow freely through the liver due to the scar/fibrotic tissue), potential development
of hepatocarcinoma

Most common causes are:

 Alcohol abuse
 Hep B/C infection

Less common cause

 Biliary obstruction

Alcoholic cirrhosis

 Consumption of >100mL of ethanol/day for a long period of time; different people have diff
levels of tolerance to alcohol
 Alcohol is absorbed unaltered into stomach and small intestine, then absorbed into
bloodstream & distributed to tissues in direct proportion to blood level
 10% or less is excreted unchanged in urine, sweat or breath, but the rest goes to the liver
and it is metabolized by 3 enzyme systems: microsomal enzyme oxidase system, alcohol
dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) => convert the ethanol to
acetaldehyde (v. toxic, carcinogen) => less active byproduct called acetate (acetic acid) =>
H20 + CO2
 Individuals who have low levels of ALDH cannot metabolize alcohol efficiently, but other
individuals have high tolerance to alcohol as their liver adapts to an ever increasing intake of
alcohol and ALDH production increases; over time this leads to pathological changes in liver,
brain, stomach, pancreas and heart occur leading to acute and chronic effects

Acute alcoholism:

 Due to ingestion of large amounts of alcohol at once

 CNS effects – depressant (disordered cortical, motor, intellectual behaviour, speech
impairment and muscle weakness and uncoordination
 Gastric changes (e.g. acute gastritis)
  Hepatic changes (e.g. fatty change of the liver) because alcohol impairs fat metabolism in
the liver, therefore lipids accumulate in the hepatocytes; this is a reactive fatty change which
is reversible

Chronic alcoholism: - only 10% develop cirrhosis of liver

 CNS - cerebral/cerebellar atrophy, cognitive decline, loss of memory

 GI tract - gastric ulcer, carcinoma P
 Pancreas - pancreatitis, carcinoma
 CV - cardiomyopathy
 Liver - cirrhosis, carcinoma
 Initially necrosis around the triads: portal vein, hepatic artery and biliary duct called
Periportal necrosis, then later Midzonal necrosis and last necrosis around the central vein
which drains into the vena cava called Centrilobular necrosis.

Biliary Cirrhosis

Very similar to alcoholic cirrhosis: signs of necrosis, regenerative nodules, fibrosis but in this case
also and accumulation of bile pigments due to biliary obstruction (hence the green colour of the
liver).

Biliary obstruction (conjugated hyperbilirubinaemia, obstructive jaundice evident) => chronic hep =>
cirrhosis

 Primary biliary cirrhosis:

o Autoimmune
o Seen more in women over 50 yo
o Chronic destruction of intrahepatic bile ducts
 Secondary biliary cirrhosis:
o Chronic obstruction of main extrahepatic bile ducts (e.g. gallstones) causing build up
of bile within liver
 Primary sclerosing cholangitis:
o Autoimmune
o More in men 25-40 yo
o Chronic inflammation, fibrosis, & destruction of bile ducts intrahepatic and
extrahepatic

Clinical features of cirrhosis

Hepatocellular failure

 Jaundice
o Occurs with bilirubin levels > 50µmol/L
o Skin, sclerae have a yellow colour
 Xanthelasmata
o If liver cells are not working well and not allowing cholesterol to enter bile,
cholesterol will go back into the blood stream and blood cholesterol levels go up and
will deposit in skin
o Chronic cholestasis (condition where bile cannot flow from the liver to the
duodenum) leads to cholesterol accumulation within macrophages in skin (e.g.
around eyelids)
  Foetor hepaticus (“liver breath”)
o Hepatocytes cannot metabolize toxins, mercaptans (sulphur containing) go into the
blood, diffuse into the alveoli and then exhaled causing bad breath
 Palmar erythema (“liver palms”), gynaecomastia (increased breast size in men), spider naevi
(dilated, ruptured capillaries), testicular atrophy
o due to high oestrogen levels; normally catabolised by liver, but since liver cells are
damaged the oestrogen goes back into the blood causing all of the above
 Systemic oedema
o due to hypoproteinemia – decreased albumin synthesis and hence blood levels
because of damaged hepatocytes
 Haemorrhagic tendency, anaemia
o due to decreased clotting factor production
 Leukonychia (white nails)
o due to ↓ albumin synthesis

Portal hypertension

 Fibrotic liver compromises passage of portal venous blood through it

o leads to splenomegaly (a sign that something is wrong with the liver), because of the
spleen working harder to push blood through the splenic vein against the blood that
has built up in the portal vein increasing hydrostatic pressure
 Alternative channels are sought to bypass liver – because blood cannot pass through the
liver due to fibrosis
o Lower oesophageal vessels - oesophageal varices
o Haemorrhoidal venous plexi – haemorrhoids
o Umbilical veins - caput medusae
 Coupled with poor lymphatic drainage in liver, leads to ascite (local oedema)
o Increased hydrostatic pressure in the portal vein causes fluid to leak out the vessels
in the peritoneal cavity

Hepatocarcinoma

 Causes
o Cirrhosis = premalignant state
o Mycotoxins (e.g. aflatoxin) directly causes cancer of the liver; carcinogens (e.g. azo-
compounds “butter yellow”)
 May lead to 1o adenocarcinoma (liver is a gland, epithelial in origin hence adeno…)
 Single or multiple masses, jaundice
 Rapidly invasive (because the liver has the perfect chemistry and tissue architecture for
tumours to thrive, hence many other primary tumours metastasize in the liver)
 Extrahepatic metastases do not occur because the liver is a great environment for cancer
cells
 Prognosis is grave

Colangiocarcinoma

 Rare and mostly primary

 Malignant tumour of the intrahepatic bile duct epithelium (risen from the cells that line the
ducts) hence also classified as adenocarcinoma
 Rapidly invasive adenocarcinoma
  Signs: jaundice as bile ducts become obstructed
 Metastasizes to lymph nodes, bones, lungs
 Grave prognosis – death within 6 months at time of diagnosis

Secondary liver tumours

 Very common, found in ~1/3 of all cases of malignant deaths

 Primary colon, stomach, pancreas, breast & lung most common
 Metastasis via portal vein, via hepatic artery or via direct spread
 Massive hepatomegaly (up to 10 kg), jaundice, hepatocellular failure, portal hypertension

Cholelithiasis

 Gall stone formation in the gall bladder

 Very common in women especially obese women due to increased cholesterol levels
 Comprise or various concentrations of cholesterol, calcium salts (phosphates, carbonates)
and bilirubin (calcium bilirubinate)
 Cholesterol stones (~80% of all stones, 0.3-3cm, contain ~50% cholesterol)
 Pigment stones that contain bilirubinate (20%, up to 1cm) are dark in colour

Causes:

 Reduced bile acids in bile (due to malabsorption, causing excessive loss of bile acids from
intestine) can lead to an increase in cholesterol synthesis
 Increased cholesterol in bile will lead to the formation of cholesterol stones in the bile, but
also obesity can lead to the formation of this type of stones

Acute cholecystitis

 Gall stones irritate and injure (erosions and ulcerations) the biliary mucosa causing acute
inflammation
 Commonly due to cholelithiasis or obstruction of cystic duct
 Patients may present with pain in right upper quadrant (RUQ) of abdomen, often radiates to
right scapula or shoulder region
 Cholecystectomy

Chronic cholecystitis

 Gall stones found in >90% cases

 Gallbladder markedly contracted but the wall thickens over time and becomes fibrous
(normal wall is thin and translucent and you can see the bile fluid)
 Mucosa is very distorted, scarred, atrophic, may show cystic spaces
 With chronic some patients don’t have any symptoms whereas other might have some
vague discomfort in RUQ of abdomen (esp. after large or fatty meals)
 When at times a stone hits the mucosa, or blocks the cystic canal there is acute
exacerbations which leads to similar symptoms as acute cholecystitis
 Ultrasound imaging will detect stones (most are radiolucent, and sometimes they are not
picked up)
 Biliary colic will result if a gall stone lodges in common bile duct (excruciating pain lasting for
several hours)