The document provides an overview of liver disease, including: 1) Jaundice and cholestasis which can occur due to increased bilirubin production, decreased uptake by hepatocytes, or impaired excretion. 2) Liver failure which can be acute or chronic, and results in hepatic encephalopathy, coagulopathy, and other systemic effects. 3) Cirrhosis, defined as diffuse liver scarring leading to regenerative nodules and altered vasculature, with complications including liver failure, portal hypertension, ascites, and hepatocellular carcinoma.

1. LIVER DISEASE
INTRODUCTION, JAUNDICE,
CHOLESTASIS, LIVER FAILURE,
CIRRHOSIS.

3. INTRODUCTION
• Liver weight 1400 - 1600gm.
• Parenchyma - liver cells (hepatocytes) trabeculae 1 cell thick in adults.
- Kupffer cells in sinusoids are phagocytes.
- hepatic stellate cells in space of Disse, store vitamin A,
transform into collagen-producing myofibroblasts,
regulate blood flow in sinusoids.
- liver-associated lymphocytes.
• Biliary drainage system - canaliculi (in centre of liver cell plates).
- canals of Hering & cholangioles.
- intra-hepatic bile ducts.
- extra-hepatic bile ducts.
• Vasculature - portal vein supplies 70% of the blood flow.
- hepatic artery supplies 30% of the blood flow.
- sinusoids lined by fenestrated endothelium.
- hepatic venules, hepatic veins drain into the IVC.

6. • The functional unit of the liver parenchyma is the hepatic acinus with zones 1,2 & 3.
Zone 1 is periportal, zone 3 is perivenular, zone 2 intermediate.
• Portal tracts composed of fibrous tissue ramify in the liver and contain 3 structures,
portal vein, hepatic artery, bile duct (portal triad).
• The liver is important for - metabolism of carbohydrate, protein,lipids.
- protein synthesis, albumin, coagulation factors,
complement factors etc.
- storage of iron, copper, vitamins A,D,B12.
- detoxification/drug metabolism.
- bile production.
• Investigation of liver diseases.
Biochemical - enzymes, proteins, bilirubin.
Haematological - coagulation factors among others.
Immunological - antibodies (viruses, autoimmune).
Imaging - ultrasound,CT,MRI,ERCP,MRCP.
Liver biopsy - percutaneous needle biopsy, transjugular biopsy, wedge biopsy
at laparoscopy or open surgery. Useful in providing information as to the aetiology
and severity of the liver disease, ruling out the presence of other concomitant
disease, monitoring response to therapy. Focal lesions require US or CT guidance.

7. • Morphological patterns of liver injury.
1. Degeneration - ballooning degeneration (hydropic change);
- feathery degeneration (bile-induced damage).
Intracellular accumulations - fat (steatosis), iron, copper, bile, Mallory’s
hyaline.
2. Necrosis - (coagulative or lytic) and apoptosis. Necrosis may be
randomly focal (spotty necrosis), zonal eg zone 3, bridging (bridging hepatic
necrosis, eg portal to venular), involve most or almost all of the liver
(submassive and massive respectively). Zone 3 is most prone to injury as it
is farthest from the blood supply and is the area containing most drug-
metabolising enzymes.
3. Inflammation - acute, chronic or granulomatous. May be portal, periportal
(interface hepatitis) or acinar (focal, or panacinar).
4. Regeneration - hepatocytes have great ability to regenerate. The reserve
compartment is the canal of Hering/bile ductule compartment. Activation is
described as the ductular reaction.
5. Fibrosis forms in response to inflammation or direct toxic injury. Can be
portal, perivenular, form bridging fibrosis, finally cirrhosis.
The great variety of liver diseases and the liver’s limited patterns of response
means that close clinicopathological correlation is required for their diagnosis.

8. JAUNDICE AND CHOLESTASIS
• Jaundice (or icterus) - yellow discolouration of the skin, sclerae and
mucous membranes due to excess plasma bilirubin
(hyperbilirubinemia).
Jaundice appears when plasma bilirubin exceeds 50umol/l.
(Normal 3 -
17umol/l)
Liver disease is not the only cause of jaundice and many
patients with significant liver disease do not have jaundice (are
anicteric).
• Cholestasis - arrest of bile flow. A failure of adequate amounts of bile
to reach the duodenum - due to interference anywhere from liver cell
microsomes to the duodenum.

11. MECHANISMS AND CLASSIFICATION OF JAUNDICE
• Mechanisms - Increased bilirubin production.
- Decreased uptake by hepatocytes.
- Impaired conjugation.
- Impaired excretion - intrahepatic
- extrahepatic.
• Classification.
Pre-hepatic - haemolysis most important of several causes.
Unconjugated bilirubin insoluble in water, not excreted in urine.
Risk of brain damage in neonates (kernicterus); pigment gallstones in
adults. Hepatic - eg hepatitis,intra-hepatic bile duct damage,
congenital hyperbilirubinemias eg Gilbert’s syndrome. Mainly
conjugated (except Gilbert’s syndrome) so soluble in water resulting in
dark urine. Post-hepatic - obstruction to extra-hepatic bile
ducts by gallstone, stricture, tumour, or congenital biliary atresia.
Conjugated bilirubin.

12. • In cases of hepatic jaundice, when there is predominantly hepatocyte
damage, the patient is often very symptomatic and raised serum
transaminases are the predominant biochemical finding. This is
sometimes called “hepatocellular jaundice.”
• In cases where there is biliary obstruction, whether intra- or extra-
hepatic, the patient has what is called “cholestatic jaundice” with
pruritis, dark urine and pale stools, and with time may develop skin
xanthelasmas and steatorrhoea. Serum alkaline phosphatase is
raised.
• Mixed patterns occur.
• Distinction between intra-hepatic and extra-hepatic obstruction requires
imaging. This should be done urgently and the obstruction relieved
where at all possible.

13. LIVER FAILURE
• Classification. Acute - no pre-existing liver disease.
Chronic - pre-existing liver disease.
• Causes. Acute - viral hepatitis, drugs, toxins, severe fatty change (eg
fatty liver of pregnancy, Reye syndrome), vascular.
Chronic - cirrhosis, chronic hepatitis.
• Morphology. Acute - varying degrees of necrosis up to massive liver
necrosis (zonal to panacinar histologically).
Chronic - that of cirrhosis or chronic hepatitis.
Chronic liver failure is more common than acute liver failure.
Mortality from liver failure without liver transplantation is 75% to
90%. Drugs and viruses account for about 80% & 15% of cases of
acute liver failure respectively; figures vary according to geographical
area.

14. FEATURES OF LIVER FAILURE
• Hepatic encephalopathy - a neuropsychiatric disturbance leading to
coma. The cardinal feature of acute liver failure, progressing
over hours to days. More insidious in chronic liver failure when it is a sign
of worsening liver failure.
Pathogenesis:- nitrogenous compounds derived from bacterial action
in the colon are not metabolised in the failing liver; in addition shunting of
portal blood to systemic circulation by-passes the liver.
Compounds involved - ammonia and derivatives of aromatic amino
acids (eg mercaptans, a cause of foetor hepaticus)
- false neurotransmitters (eg octopamine)
- neuroinhibitors, eg gamma-aminobutyric acid
(GABA), endogenous benzodiazepines.
Morphology of brain - oedema; Alzheimer type 2 astrocytic reaction.

15. • Jaundice - hyperbilirubinaemia; deep jaundice = worse prognosis.
• Haematological - decreased clotting factors (II,VII,IX,X) results in a
bleeding tendency.
• Cardiovascular - hyperkinetic circulation.
• Respiratory - hepatopulmonary syndrome.
• Renal - hepatorenal syndrome.
• Endocrine - in chronic failure - gonadal atrophy, gynaecomastia,
amenorrhoea.
• Skin changes - in chronic failure - spider naevi, palmer erythema.
• Others - impaired metabolism of amino acids, carbohydrates
(hypoglycaemia) and drugs; impaired protein synthesis (low albumin),
systemic infections and endotoxaemia.
Laboratory investigations - bilirubin (>300umol/l = poor prognosis).
- prothrombin (>50sec.= poor prognosis).
- transaminases.
- albumin.
Possible factors precipitating liver failure in chronic liver disease:-
increase in liver injury due to virus or alcoholic binge, infection,
GIT haemorrhage (which can precipitate encephalopathy, as can
excess dietary protein,constipation, drugs, uraemia, hypokalaemia).

16. CIRRHOSIS
• Definition. Cirrhosis is a diffuse process in which bridging fibrosis and
regenerative parenchymal nodules result in disruption of the
architecture.
Regenerative nodules surrounded by fibrosis are necessary for
the diagnosis. These may be <3mm (micronodular cirrhosis) or >3mm
(macronodular cirrhosis). A micronodular cirrhosis can transform into a
macronodular cirrhosis.
The microvasculature of the liver is markedly altered.
Cirrhosis is the end stage of chronic liver disease.
It is best classified according to aetiology.

21. • Infections. Viral hepatitis.
• Toxins and drugs. Alcohol.
Therapeutic drugs.
• Autoimmune. Hepatitis.
Primary biliary cirrhosis.
• Metabolic. Haemochromatosis.
Wilson disease.
Alpha-1-antitrypsin deficiency.
Glycogen storage disease and many others.
• Biliary obstruction. Congenital atresia.
Sclerosing cholangitis.
• Hepatic outflow obstruction.
• Cryptogenic.
The aetiology of cirrhosis varies throughout the world. In the Western world, alcohol is
the most common factor at 60% and viral hepatitis 10%. Viral hepatitis is the most common
factor in Asia and Africa. Cryptogenic cirrhosis (cause unknown) forms 10%.
Once cirrhosis has developed, it is usually not possible to determine the aetiology by
morphology alone and results of other investigations are required.

22. • Pathogenesis.
Liver injury results in chronic inflammation and activation of Kupffer
cell, and other endogenous liver cells with the production of cytokines.
These, together with disruption of the extracellular matrix activates
hepatic stellate cells (HSC). Toxins may activate HSCs. These
transform into myofibroblasts which produce collagen and constrict
sinusoids.
Collagen in the space of Disse leads to “capillarisation” of the
sinusoids and loss of endothelial fenestrations, hindering exchange of
solutes.
New vascular channels in fibrous bands link inflow of blood (venous
& arterial) with outflow (hepatic venules) thus by- passing parenchyma.
Existing vascular channels and biliary channels may be obliterated.
The results are internal vascular shunts and portal hypertension.
The hepatocytes in the regenerative nodules may appear normal
microscopically but are unable to adequately fulfill their functions.
Function will be further reduced if there is continuing liver cell damage.

23. CLINICAL FEATURES
• Cirrhosis may be asymptomatic.
• When symptomatic, the features are nonspecific - weakness, fatigue,
weight loss, anorexia, nausea, gaseous abdominal distension, upper
abdominal discomfort.
• The liver may be enlarged, hard and irregular or smaller than normal.
• At this stage the patient is said to have compensated cirrhosis.
• Decompensated cirrhosis manifests as signs of liver failure or
complications of portal hypertension. Deterioration in liver function can
be an indication of the development of hepatocellular carcinoma.
• Death is usually due to one of these 3 conditions.

24. COMPLICATIONS OF CIRRHOSIS
• Liver failure.
• Portal hypertension. Portal venous pressure >10mmHg.
Splenomegaly - hypersplenism leading to thrombocytopenia.
Portal-systemic shunts where portal venous system
anastomoses with the systemic venous system.
Lower end of oesophagus leading to oesophageal varices and risk of
massive GIT haemorrhage. Periumbilical (“caput medusae”), lower
rectum (haemorrhoids), posterior abdominal wall.
Ascites, ie excess fluid in the peritoneal cavity. A transudate
(<3gm/dL protein),straw coloured or pale green, a few mononuclear
cells. Risk of spontaneous infection when polymorphs predominate.
Is due to aldosterone-induced retention of Na & water, low oncotic
pressure (low albumin), and portal hypertension. Excess hepatic lymph
and intestinal fluid leakage also contributes to ascites.
• Hepatocellular carcinoma.