Liver Physiology Cont…

Fatima S. Bajari
Ohood Al Bajri
Malath Al Shereef
• Liver Anatomy
• Physiology
• Liver Cirrhosis
Liver Anatomy
liver is the largest gland of
the body.
the liver is divided into
right and left lobes by the
external marking of the
falciform ligament.
Liver Segments
The Right Lobe
• composed of 4
lobes (left, right,
caudate, quadrate)
and divided into 8
The Left Lobe
• Each segment receives its own portal
pedicle (triad of portal vein, hepatic
artery, and bile duct).
Portal v. 70%
Hepatic a. 30%
The most common anatomy of the hepatic artery
The anatomy of the portal vein
The anatomy of the Bile duct
Liver Physiology
the liver performs several important functions
Protein metabolism (Synthesis and storage)
Carbohydrate metabolism
Lipid metabolism
Formation of bile (Bile secretion and bile acid metabolism)
Hormone and drug inactivation
Immunological function
Liver Physiology Cont…
Protein metabolism (Synthesis and storage)
 The liver is the principal site of synthesis of all circulating proteins, which are
produced in the reticuloendothelial system.
 Plasma contains 60–80 g/L of protein, mainly in the form of albumin, globulin and
fibrinogen .
 Albumin main functions are first to maintain the intravascular oncotic (colloid
osmotic) pressure, and second to transport water-insoluble substances such as
bilirubin,hormones, fatty acids and drugs.
 Transport or carrier proteins such as transferrin and caeruloplasmin.
 The liver also synthesizes all factors involved in coagulation ( fibrinogen,
prothrombin, factors V, VII, IX, X and XIII, proteins C and S and antithrombin as
well as components of the complement system)
 The liver stores large amounts of vitamins, particularly A, D and B12, vitamin K and
folate), and also minerals – iron in ferritin and haemosiderin and copper.
• As The liver receives amino acids
degraded by transamination and oxidative
ammonia, converted to urea excreted by kidneys.
Liver Physiology Cont…
Carbohydrate metabolism
Glucose homeostasis and the maintenance of the blood sugar is a major
function of the liver.
In the immediate fasting state, blood glucose is maintained either by glucose
released from the breakdown of glycogen (glycogenolysis) or by newly
synthesized glucose (gluconeogenesis).
Sources for gluconeogenesis are lactate, pyruvate, amino acids from muscles
(mainly alanine and glutamine) and glycerol from lipolysis of fat stores.
In prolonged starvation, ketone bodies and fatty acids are used as
alternative sources of fuel as the body tissues adapt to a lower glucose
Liver Physiology Cont…
Lipid metabolism
Fats are insoluble in water and are transported in the plasma as protein–lipid
complexes (lipoproteins).
The liver has a major role in the metabolism of lipoproteins. It synthesizes
(VLDLs) and (HDLs).
Hepatic lipase removes triglyceride from (IDLs) to produce (LDLs) which are
degraded by the liver after uptake by specific cell receptors.
Oxidation of FFA occurs in the liver, depending on the availability of dietary
fat .Cholesterol may be of dietary origin but most is synthesized from
acetyl-CoA mainly in the liver, adrenal cortex and skin.
Liver Physiology Cont…
Formation of bile (Bile secretion and bile acid metabolism)
- RBCs >> heme Oxidized into >> bileverdine >> reduction to (indirect bilirubin).
1- Uptake of indirect bilirubin through Y and Z receptors in the liver.
2- Conjugation and Secretion:
- Conjugation occurs in the liver by glucouronyl transferease and the conjugated
bilirubin is secreted with the bile into the small intestine in the form of
stercobilinogen which passing into three directions:
• Part of it enters the enterohepatic circulation.
• Another part escapes to the systemic circulation reaching the kidney and
secreted in urine (urobilinogen).
• The last part passes to the large intestine to be transformed into stercobilin.
Liver Physiology Cont…
Hormone and drug inactivation
The liver catabolizes hormones such as insulin, glucagon, estrogens,
growth hormone, glucocorticoids and parathyroid hormone.
It is also the prime target organ for many hormones (e.g. insulin). It is
the major site for the metabolism of drugs and alcohol .
Fat-soluble drugs are converted to water-soluble substances that
facilitate their excretion in the bile or urine.
Cholecalciferol is converted to 25-hydroxycholecalciferol.
Liver Physiology Cont…
Immunological function
The reticuloendothelial system of the liver contains many
immunologically active cells.
The liver acts as a sieve for the bacterial and other antigens carried to
it through the portal vein from G.I.T., they are phagocytosed by
Kupffer cells, these cells secrete interleukins and tumour necrosis
factor (TNF).
The reticuloendothelial system plays a role in tissue repair, T and B
lymphocyte interaction, and cytotoxic activity in disease processes.
Liver Cirrhosis
• It is a chronic liver disease results from necrosis of
hepatocytes followed by fibrous tissue deposition and
formation of regenerating nodules with loss of hepatic
• This derangement eventually produces portal
hypertension and liver cell failure.
• Alcohol is now the most common cause in the West,
but viral infection is the most common cause worldwide.
• Young patients with cirrhosis must be investigated
carefully as the cause may be treatable (e.g.Wilson’s
Causes of Cirrhosis
- Alcohol
- Hepatitis B ± D
- Hepatitis C
- Biliary cirrhosis:
- Autoimmune hepatitis
- Hereditary haemochromatosis
- Hepatic venous congestion
- Budd–Chiari syndrome
- Wilson’s disease
- Drugs (e.g. methotrexate)
- α1-Antitrypsin deficiency
- Cystic fibrosis
- Non-alcoholic fatty liver disease
- Galactosaemia
- Glycogen storage disease
- Veno-occlusive disease
- Idiopathic (cryptogenic)
• Long standing injury to the liver lead to
inflammation, necrosis and eventually fibrosis
(initiated by activation of stellate cells).
• These liver injuries e.g. (virus, alcohol, .... )
stimulate kupffer cells
release of cytokines
stimulate into (stellate) cells
release and deposition of collagen fibres
of hepatic architecture (cirrhosis).
The characteristic features of cirrhosis are regenerating nodules separated
by fibrous septa and loss of the normal lobular architecture within the
nodules .
Two types of cirrhosis have been described which give clues to the underlying
■ Micronodular cirrhosis:
Regenerating nodules are usually less than 3 mm in size and the liver is
involved uniformly.
This type is often caused by ongoing alcohol damage or biliary tract disease.
■ Macronodular cirrhosis.:
The nodules are of variable size
and normal acini may be seen within the larger nodules. This type is often
seen following chronic viral hepatitis.
A mixed picture with small and large nodules is sometimes seen.
• These are performed to assess the severity and type of liver disease.
1- Severity
■ Liver function:
Serum albumin and prothrombin time are the best indicators of liver function
■ Liver biochemistry:
This can be normal, depending on
the severity of cirrhosis. In most cases there is at least a slight elevation in the
serum ALP and serum aminotransferases.
■ Serum electrolytes:
A low sodium indicates severe liver disease due to a defect in free water clearance
or to
excess diuretic therapy.
■ Serum creatinine:
An elevated concentration > 130 μmol/L is a marker of worse prognosis. In addition,
serum α-fetoprotein if > 200 ng/mL is strongly suggestive of the presence of a
hepatocellular carcinoma.
Cont. Investigations
2- Type This can be determined by:
■ viral markers
■ serum autoantibodies
■ serum immunoglobulins
■ iron indices and ferritin (Total iron-binding capacity
(TIBC) and ferritin should be measured to exclude hereditary
■ copper, caeruloplasmin (Serum copper and serum α1-antitrypsin should always be
measured in young cirrhotics. )
■ α1-antitrypsin
■ Ultrasound examination:
This can demonstrate changes in size and shape of the liver. Fatty change
and fibrosis produce a diffuse increased echogenicity. The patency of the portal and
hepatic veins can be evaluated. It is useful in detecting hepatocellular carcinoma
■ CT scan
■ Endoscopy is performed for the detection and treatment of varices, and portal
■ Biopsy:
This is usually necessary to confirm the severity and type of liver disease.
• Patients should have 6-monthly ultrasound to detect the early
development of a hepatocellular carcinoma.
• Treatment of the underlying cause may arrest or occasionally
reverse the cirrhotic changes .
• Patients with compensated cirrhosis should lead a normal life.
• The only dietary restriction is to reduce salt intake.
Aspirin and NSAIDs should be avoided.
• Alcohol should be avoided ??
What are the Indications?
- Acute liver disease:
Patients with fulminant hepatic failure of any cause, including acute viral hepatitis may
be considered.
- Chronic liver disease:
The indications for transplantation are usually for complications of cirrhosis, no longer
responsive to therapy.
- All patients with end-stage (Child’s grade C) cirrhosis.
. In addition specific extrahepatic complications of cirrhosis, even with preserved liver
function, such as hepatopulmonary syndrome (shunting in the lung leading to hypoxia)
and porto-pulmonary hypertension,can be reversed by liver transplantation.
- Primary biliary cirrhosis: Patients with this disease should be transplanted when their
serum bilirubin is persistently > 100 μmol/L or symptoms such as itching are intolerable.
- Chronic hepatitis B if HBV DNA negative or levels falling under therapy. Following
transplantation, recurrence of hepatitis is prevented by hepatitis B immunoglobulin
Chronic hepatitis C is the most common indication.
Autoimmune hepatitis. In patients who have failed to respond to medical treatment
or have major side-effects of corticosteroid therapy.
Alcoholic liver disease !!
Primary metabolic disorders. Examples are Wilson’s disease, hereditary
haemochromatosis and α1- antitrypsin deficiency.
Other conditions, such as sclerosing cholangitis
Absolute contraindications:
- active sepsis outside the hepatobiliary tree
- malignancy outside the liver,
- liver metastases
- If the patient is not psychologically committed.
Relative contraindications:
- mainly anatomical considerations that would make surgery more difficult, such as
extensive splanchnic venous thrombosis.
With exceptions, patients aged 65 years or over are not usually transplanted.
In hepatocellular carcinoma the recurrence rate is high unless there are fewer
than three small (< 3 cm) lesions, or a solitary nodule of < 5 cm.
Portal hypertension
Variceal haemorrhage
Portosystemic encephalopathy (PSE)
Renal failure (hepatorenal syndrome)
Hepatopulmonary syndrome
Porto-pulmonary hypertension
Primary hepatocellular carcinoma
Cont. complications and effects of cirrhosis: 1-Portal hypertension
Portal hypertension
•The portal vein is formed by the union of the superior mesenteric and splenic
•The pressure within it is normally 5–8 mmHg with only a small gradient across
the liver to the hepatic vein in which blood is returned to the heart via the inferior
vena cava.
•Portal hypertension can be classified according to the site of obstruction:
■ prehepatic – due to blockage of the portal vein before the liver
■ intrahepatic – due to distortion of the liver architecture, which can be
presinusoidal (e.g. in schistosomiasis) or postsinusoidal (e.g. in cirrhosis)
■ posthepatic – due to venous blockage outside the liver(rare).
Cont. complications and effects of cirrhosis: 1-Portal hypertension
Portal hypertension
•As portal pressure rises above 10–12 mmHg the compliant venous system
dilates and collaterals occur within the systemic venous system.
•The main sites of the collaterals are at the gastro-oesophageal junction, the
rectum, the left renal vein, the diaphragm, the retroperitoneum and the anterior
abdominal wall via the umbilical vein.
•The collaterals at the gastro-oesophageal junction (varices)
•Rectal varices are found frequently (30%)
•gut becomes congested giving rise to portal hypertensive gastropathy and
colopathy, in which there is punctate erythema sometimes erosions, which can
Cont. complications and effects of cirrhosis: 1-Portal hypertension
•Portal vascular resistance is increased in chronic liver disease.
•During liver injury: stellate cells are activated and transform into myofibroblasts.
expression of the specific smooth muscle protein α-actin under the influence of
endothelin, nitricoxide or prostaglandins.
• the contraction of these activated cells contributes to abnormal blood flow
patterns and increased resistance to blood flow.
•the balance of fibrogenic and fibrolytic factors is shifted towards fibrogenesis.
leads to portal hypertension and opening of portosystemic anastomoses in both
precirrhotic and cirrhotic livers. Neoangiogenesis also occurs.
•Patients with cirrhosis have a hyperdynamic circulation due to the release of
nitric oxide and glucagon, which leads to peripheral and splanchnic
•This effect is followed by plasma volume expansion due to sodium retention
and this has a significant effect in maintaining portal hypertension.
Cont. complications and effects of cirrhosis: 1-Portal hypertension
Prehepatic causes
Intrahepatic causes
Posthepatic causes
Cont. complications and effects of cirrhosis: 1-Portal hypertension
Prehepatic causes
•Extrahepatic blockage is due to portal vein thrombosis.
•The cause is often unidentified, but some cases are due to portal vein occlusion
secondary to congenital portal venous abnormalities or neonatal sepsis of the
umbilical vein.
•Many are due to inherited defects causing prothrombotic conditions, e.g. factor V
•Patients usually present with bleeding, often at a young age.
•They have normal liver function and, prognosis excellent.
•The portal vein blockage can be identified by ultrasound with Doppler imaging; CT
and MR angiography.
•Treatment is repeated endoscopic therapy or nonselective beta-blockade.
•Splenectomy is only performed if there is isolated splenic vein thrombosis.
•Anticoagulation prevents further thrombosis and does not increase the risk
of bleeding; used when there is a high risk of recurrent thrombosis.
Cont. complications and effects of cirrhosis: 1-Portal hypertension
Intrahepatic causes
cirrhosis is the most common intrahepatic cause of portal hypertension
other causes:
■ Non-cirrhotic portal hypertension.
portal hypertension and variceal bleeding without cirrhosis.
Histologically, the liver shows mild portal tract fibrosis.
The aetiology is unknown, but arsenic, vinyl chloride, antiretroviral therapy and
other toxic agents have been implicated.
A similar disease is found frequently in India.
liver lesion does not progress and the prognosis is therefore good.
■ Schistosomiasis with extensive fibrosis is the commonest cause,
endemic areas such as Egypt and Brazil.
often there may be concomitant liver disease such as HCV infection
■ Other causes include congenital hepatic fibrosis, nodular regenerative
hyperplasia and partial nodular transformation(rare).
The common features of hyperplastic liver cell growth in the form of nodules but in
contrast to cirrhosis, fibrosis is typically absent.
A wedge liver biopsy is usually required to establish the diagnosis.
hormones are none implicated in aetiology or progression.
Cont. complications and effects of cirrhosis: 1-Portal hypertension
Posthepatic causes
•Prolonged severe heart failure with tricuspid incompetence
•constrictive pericarditis
both lead to portal hypertension.
Cont. complications and effects of cirrhosis: 1-Portal hypertension
Clinical features
Patients with portal hypertension are often asymptomatic and the only clinical
evidence of portal hypertension is splenomegaly.
Clinical features of chronic liver disease are usually present.
Presenting features may include:
■ haematemesis or melaena from rupture of gastro-oesophageal varices or
portal hypertensive gastropathy
■ ascites
■ encephalopathy
■ breathlessness due to porto-pulmonary hypertension or
hepatopulmonary syndrome (rare).
Cont. complications and effects of cirrhosis: 2-Variceal haemorrhage
Variceal haemorrhage
•Approximately 90% of patients with cirrhosis will develop gastro-oesophageal
varices, over 10 years, only onethird of these will bleed from them.
•Bleeding is likely to occur with large varices, red signs on varices (diagnosed
at endoscopy) and in severe liver disease.
Cont. complications and effects of cirrhosis: 2-Variceal haemorrhage
•Management can be divided into the active bleeding episode,the
prevention of rebleeding, and prophylactic measures to prevent the first
•the prognosis depends on the severity of the underlying liver disease, with
an overall mortality from variceal haemorrhage of 25%, reaching 50% in
Child’s grade C.
Cont. complications and effects of cirrhosis: 2-Variceal haemorrhage
Initial management of acute variceal bleeding
Cont. complications and effects of cirrhosis: 2-Variceal haemorrhage
■ Assess the general condition of the patient – pulse and blood pressure.
■ Insert an intravenous line and obtain blood for grouping and crossmatching,
haemoglobin, PT/INR, urea, electrolytes, creatinine, liver biochemistry and blood
■ Restore blood volume with plasma expanders or blood transfusion.
Prompt correction of hypovolaemia is necessary in patients with cirrhosis as their
baroreceptor reflexes are diminished.
■ Ascitic tap.
■ Monitor for alcohol withdrawal. Give thiamine i.v.
■ Start prophylactic antibiotics – third generation cephalosporins, e.g. cefotaxime.
These treat and prevent infection and early rebleeding and reduce mortality.
Cont. complications and effects of cirrhosis: 2-Variceal haemorrhage
Urgent endoscopy
•to confirm the diagnosis of varices.
•excludes bleeding from other sites (e.g. gastric ulceration) or portal
hypertensive (or congestive) gastropathy.
•injected with a sclerosing agent that may arrest bleeding by producing vessel
Balloon tamponade is used mainly to control bleeding if endoscopic
therapy or vasoconstrictor therapy has failed
Transjugular intrahepatic portocaval shunt (TIPS)
is used when bleeding cannot be stopped after two
sessions of endoscopic therapy within 5 days.
Emergency surgery
This is used when other measures fail or if TIPS is not
and, particularly, if the rebleeding is from gastric fundal
Cont. complications and effects of cirrhosis: 2-Variceal haemorrhage
Long-term measures
Oral propranolol in a dose sufficient to reduce resting pulse rate by 25% has been
shown to decrease portal pressure.
Portal inflow is reduced by two mechanisms:
1. decrease in cardiac output (β1),
2. blockade of β2 vasodilator receptors on the splanchnic arteries, leaving an
unopposed vasoconstrictor effect.
Cont. complications and effects of cirrhosis:3- Ascites
The pathogenesis of ascites in liver disease is secondary to renal sodium and
water retention.
Several factors are involved:
■ Sodium and water retention results from peripheral arterial vasodilatation and
consequent reduction in the effective blood volume.
■ Portal hypertension exerts a local hydrostatic pressure and leads to increased
hepatic and splanchnic production of lymph and transudation of fluid into the
peritoneal cavity.
■ Low serum albumin (a consequence of poor synthetic liver function) may further
contribute by a reduction in plasma oncotic pressure.
Cont. complications and effects of cirrhosis:3- Ascites
Clinical features
The abdominal swelling associated with ascites develops over many weeks or as
rapidly as a few days.
Precipitating factors include a high sodium diet or the development of a
hepatocellular carcinoma or splanchnic vein thrombosis.
Mild generalized abdominal pain and discomfort are common.
Respiratory distress accompanies tense ascites, and also causes difficulty in eating.
confirmed by the demonstration of shifting dullness also have peripheral oedema.
A pleural effusion (usually on the right side) may infrequently be found and arises
from the passage of ascitic fluid through congenital diaphragmatic defects.
Cont. complications and effects of cirrhosis:3- Ascites
A diagnostic aspiration of 10–20 mL of fluid should beobtained and the following
■ Cell count. A neutrophil count above 250 cells/mm3 is indicative of an
underlying (usually spontaneous) bacterial peritonitis.
■ Gram stain and culture – for bacteria and acid-fast bacilli.
■ Protein. A high serum–ascites albumin gradient of > 11 g/L suggests portal
hypertension, and a low gradient < 11 g/L is associated with abnormalities of
the peritoneum, e.g. inflammation, infections, neoplasia
■ Cytology – for malignant cells.
■ Amylase – to exclude pancreatic ascites
Cont. complications and effects of cirrhosis:3- Ascites
Cont. complications and effects of cirrhosis:3- Ascites
The aim is to reduce sodium intake and increase renal excretion of sodium,
■ Check serum electrolytes and creatinine at the start and every other day; weigh
patient and measure urinary output daily.
■ Bed rest alone will lead to a diuresis in a small proportion of people by
improving renal perfusion, but in practice is not helpful.
■ By dietary sodium restriction it is possible to reduce sodium intake to 40 mmol
in 24 hours and still maintain an adequate protein and calorie intake with a
palatable diet.
■ Drugs: many contain significant amounts of sodium (up to 50 mmol daily).
include antacids, antibiotics (particularly the penicillins and cephalosporins) and
effervescent tablets. Sodium-retaining drugs (nonsteroidals, corticosteroids)
should be avoided.
Cont. complications and effects of cirrhosis:3- Ascites
Cont. Management
■ Fluid restriction is probably not necessary unless the serum sodium
is under 128 mmol/L.
■ The diuretic of first choice is the aldosterone antagonist
■ Paracentesis This is used to relieve symptomatic tense ascites.
■ Shunts a transjugular intrahepatic portosystemic shunt (TIPS) is used for
resistant ascites providing there is no spontaneous portosystemic
encephalopathy and minimal disturbance of renal function.
Cont. complications and effects of cirrhosis:3- Ascites
Spontaneous bacterial peritonitis (SBP)
•A serious complication of ascites with cirrhosis.
•occurs in approximately 8%. The infecting.
•Organisms access to the peritoneum by haematogenous spread
• most are Escherichia coli, Klebsiella or enterococci.
•The condition should be suspected in any patient with ascites who clinically
•A raised neutrophil count in ascites is alone sufficient evidence to start treatment
•A third-generation cephalosporin (cefotaxime or ceftazidime) is used and is
modified on the basis of culture results.
•Mortality is 10–15%.
•Recurrence is common (70% within a year) and an oral quinolone
•SBP is an indication to refer to a liver transplant centre.
Cont. complications and effects of cirrhosis:3- Ascites
Portosystemic encephalopathy (PSE)
•This is a chronic neuropsychiatric syndrome secondary to cirrhosis.
• Acute encephalopathy can occur in acute hepatic Failure.
•can occur in portal hypertensive patients due to spontaneous shunting or in
those with surgical or TIPS shunts.
•Encephalopathy is potentially reversible.
Cont. complications and effects of cirrhosis:3- Ascites
The mechanism is unknown but several factors are involved.
In cirrhosis portal blood bypasses the liver via the collaterals and the ‘toxic’
metabolites pass directly to the brain to produce the encephalopathy.
Many toxic substances may be causative factors including ammonia, free fatty
acids, mercaptans and accumulation of false neurotransmitters (octopamine) or
activation of the γ-aminobutyric acid (GABA) inhibitory neurotransmitter
Increased blood levels of aromatic amino acids (tyrosine and phenylalanine) and
reduced branched-chain amino acids (valine, leucine and isoleucine) also occur.
Ammonia has a major role ammonia-induced alteration of brain
neurotransmitter balance – especially at the astrocyte– neurone interface is
the leading pathophysiological mechanism.
Ammonia is produced by intestinal bacteria breaking down protein.
Cont. complications and effects of cirrhosis:3- Ascites
Clinical features
drowsy and comatose
disorder of personality, mood and intellect, reversal of normal sleep rhythm.
irritable, confused, disorientated and has slow slurred speech.
General features include nausea, vomiting and weakness.
Coma occurs as the encephalopathy becomes more marked, there is always
hyperreflexia and increased tone.
Signs include:
■ fetor hepaticus (a sweet smell to the breath)
■ a coarse flapping tremor
■ decreased mental function
Cont. complications and effects of cirrhosis:3- Ascites
Additional investigations
■ Electroencephalography (EEG) shows a decrease in the frequency of the
normal α-waves
■ Visual evoked responses also detect subclinical encephalopathy.
Cont. complications and effects of cirrhosis:3- Ascites
■ Identify and remove the possible precipitating cause.
■ Give purgation and enemas to empty the bowels of nitrogenous
■ Maintain nutrition with adequate calories if necessary via a fine-bore
nasogastric tube, do not restrict protein for more than 48 hours.
■ Give antibiotics. Rifaximin is mainly unabsorbed and well tolerated long
term. Metronidazole (200 mg four times daily) is also effective in the acute
Neomycin should be avoided.
Stop or reduce diuretic therapy.
■ Give intravenous fluids as necessary (beware of too much sodium).
■ Treat any infection.
■ Increase protein in the diet to the limit of tolerance as the encephalopathy
Cont. complications and effects of cirrhosis:3- Ascites
Course and prognosis
•Acute encephalopathy in acute liver failure has a very poor prognosis with high
•In cirrhosis chronic PSE is very variable and adversely affects prognosis.
•Very rarely with chronic portosystemic shunting an organic syndrome with
cerebellar signs or choreoathetosis can develop
• myelopathy leading to a spastic paraparesis due to demyelination.
•Patients should be referred to a liver transplant centre.
Cont. complications and effects of cirrhosis:4- Renal failure (hepatorenal syndrome)
Renal failure (hepatorenal syndrome)
• occurs in a patient with advanced cirrhosis, portal hypertension with jaundice and
•The urine output is low with a low urinary sodium concentration
•The renal failure is described as functional sometimes precipitated by diuretic,
NSAIDs, diarrhoea or paracentesis, and infection, particularly spontaneous
bacterial peritonitis.
•The initiating factor is thought to be extreme peripheral vasodilatation possibly
due to nitric oxide leading to an extreme decrease in the effective blood volume
and hypotension.
•This activates the homeostatic mechanisms, causing a rise in plasma renin,
aldosterone, norepinephrine and vasopressin leading to vasoconstriction of the
renal vasculature.
•There is an increased preglomerular vascular resistance causing the blood flow to
be directed away from the renal cortex.
•This leads to a reduced glomerular filtration rate and plasma renin remains high.
Salt and water retention occur with reabsorption of sodium from the
renal tubules.
Cont. complications and effects of cirrhosis:4- Renal failure (hepatorenal syndrome)
Cont. Renal failure (hepatorenal syndrome)
•Other mediators have been incriminated in the pathogenesis of the
hepatorenal syndrome, in particular the eicosanoids.
•This has been supported by the precipitation of the syndrome by inhibitors of
prostaglandin synthase such as non-steroidal anti-inflammatory drugs
•Diuretic therapy should be stopped and intravascular hypovolaemia
corrected, preferably with albumin.
•Terlipressin or noradrenaline with intravenous albumin improves renal
function in one-third of patients.
•Liver transplantation is the best option.
Cont. complications and effects of cirrhosis:5-Hepatopulmonary syndrome
Hepatopulmonary syndrome
•This is defined as a hypoxaemia occurring in patients with advanced liver
•It is due to intrapulmonary vascular dilatation with no evidence of primary
pulmonary disease.
•The patients have features of cirrhosis with spider naevi and clubbing as well
as cyanosis.
•Most patients have no respiratory symptoms, but with more severe disease,
patients are breathless on standing.
•Transthoracic ECHO shows intrapulmonary shunting, and arterial blood
gases confirm the arterial oxygen desaturation.
•These changes are improved with liver transplantation.
Cont. complications and effects of 6-Porto-pulmonary hypertension
Porto-pulmonary hypertension
•there is pulmonary hypertension.
•It occurs in 1–2% of patients with cirrhosis related to portal hypertension.
•It may respond to medical therapy.
•Severe pulmonary hypertension is a contraindication for liver transplantation.
Cont. complications and effects of 7-Primary hepatocellular carcinoma
Primary hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide.
•Carriers of HBV and HCV have an extremely high risk of developing HCC.
•In areas where HBV is prevalent 90% of patients with this cancer are positive for
the hepatitis B virus.
•Cirrhosis is present in approximately 80% of these patients.
•The development of HCC is related to the integration of viral HBV DNA into the
genome of the host hepatocyte and the degree of viral replication (> 10 000
•The risk of HCC in HCV is higher than in HBV (even higher with both HBV and
HCV) despite no viral integration.
•Unlike HBV infection, cirrhosis is always present.
•Primary liver cancer is also associated with other forms of cirrhosis, such as
alcoholic cirrhosis and haemochromatosis.
Cont. complications and effects of 7-Primary hepatocellular carcinoma
Cont. Primary hepatocellular carcinoma
•Non-alcoholic fatty liver disease is associated with HCC probably secondary to
the presence of cirrhosis.
•Males are affected more than females.
•Other aetiological factors are aflatoxin (a metabolite of a fungus found in
groundnuts) and androgenic steroids, and there is a weak association with the
contraceptive pill.
Cont. complications and effects of 7-Primary hepatocellular carcinoma
•The tumour is either single or occurs as multiple nodules throughout the liver.
•Histologically it consists of cells resembling hepatocytes.
•It can metastasize via the hepatic or portal veins to the lymph nodes, bones and
Clinical features
•The clinical features include weight loss, anorexia, fever, an ache in the right
hypochondrium and ascites.
•The rapid development of these features in a cirrhotic patient is suggestive
of HCC.
•On examination an enlarged irregular tender liver may be felt.
•Increasingly due to surveillance HCC is found without symptoms in cirrhotics.
Cont. complications and effects of 7-Primary hepatocellular carcinoma
•Serum α-fetoprotein may be raised.
•Ultrasound scans show filling defects.
•Enhanced CT scans identify HCC but it is difficult to confirm the diagnosis in
lesions < 2 cm.
•MRI can further help to delineate lesions.
•Tumour biopsy, particularly under ultrasonic guidance.
Cont. complications and effects of 7-Primary hepatocellular carcinoma
Treatment and prognosis
•Surgical resection is occasionally possible.
•Conventional chemotherapy and radiotherapy.
•Radiofrequency ablation is also effective.
•Antiangiogenic compounds are being evaluated: sorafenib prolongs survival
in patients with non-resectable tumours.
•Liver transplantation is curative in patients with smaller tumours (< 3 nodules
< 3 cm diameter or a single tumour < 5 cm).
•In advanced cases survival is seldom more than 6 months.
Types of cirrhosis
Type of cirrhosis
Less common
Wilsons disease
Alpha -1
Biliary obstruction
biliary cirrhosis
Budd- chiari
Alcoholic cirrhosis
metabolized in the liver
Alcohol( ethanol )
responsible for liver cell damaged
Alcoholic cirrhosis
• The risk of developing
alcoholic liver disease is
related to amount of
daily intake of alcohol .
• Usually 5 – 10 years of
drinking alcohol is
required to produce
Alcoholic cirrhosis .
Alcoholic cirrhosis
• Signs of chronic liver
diseases :
Flapping tremor
Peripheral Oedema
Dupuytren's contracture
Alcoholic cirrhosis
Usually the patient present with one of the Complications of
cirrhosis :
1. Portal Hypertension
Hypersplenism (with or without splenomegaly)
Varices (lower oesophageal and rectal)
2. Synthetic Dysfunction
3. Hepatopulmonary Syndrome
4. Hepatorenal Syndrome
5. Encephalopathy
6. Hepatocellular Carcinoma
• CBC :
1. Macrocytosis in the absence of
anemia .
2. Leukocytosis or leukopenia.
3. Thrombocytopenia.
• LFTs :
All LFTs are high.
• Liver biopsy :
It is diagnostic and shows mallory
( alcoholic hyaline )
Eosinophilic Mallory bodies are
seen in hepatocytes, which are
surrounded by fibrous tissue
• General measures :
1. Stop drinking alcohol .
2. Nutritional support to
improve malnutrition
especially vitamine B1
3. Alcoholic cirrhosis
Management as cirrhosis.
• Be carful
if patient need glucose
administration increase
thiamine requirement and
precipitate wernicke –
korsakoff syndrome
therefore thiamine should
be given IV before glucose
infusion .
Biliary cirrhosis
• Biliary cirrhosis results from
prolonged biliary obstruction
anywhere between the small
interlobular bile duct and papilla of
vater .
• Types of biliary cirrhosis :
1. Primary
2. Secondary
Primary biliary cirrhosis
• Primary biliary cirrhosis is a chronic disease
of liver in which small interlobular bile ducts
of liver become progressively damaged and
leading to cirrhosis and cholestasis.
• Etiology is unknown antimitochondrial
antibodies are found in almost all patients.
Clinical features
Itching (earlist)
Yellow discoloration
eyes and skin (late)
Sign of portal HTN
Liver function test : ALK ( very
Atimitochondrial antibodies (AMA) >
95 % of cases.
Serum cholesterol is high .
Serum IgM may be very high.
Ultrasound : diffuse alteration in
liver architecture.
Liver biopsy show chareacteristic
features such as :
Infiltration of portal tract by lymphocyte
and plasma cells .
B. Loss of small bile ducts
C. Portal tract fibrosis
D. Periductal epithelioid granulomata about
40% of cases.
Ursodeoxycholic acid (Ursodiol) is the most frequently
used treatment. This helps reduce the cholestasis and
improves liver function tests
Pruritus :
A. Cholestyramine.
B. Rifampicin .
C. Opioid antaonists .
3. Malabsorption:
A. Monthly inject vit K.
B. Vit D and calcium supplents
C. Reducing fat intake to 40 g/d.
D. Bisphosphonate for osteoporosis.
4. Statins for hypercholesterolemia.
Secondary biliary cirrhosis
• This develops after
prolonged large bile duct
obstruction due to :
1) Gall stones
2) Bile duct stricture.
Sing and symptoms are same as
that of PBC.
Diagnosis is based on
ultrasound which common
bile duct dilated .
• Hemochromatosis is a condition in which the amount
of total body iron is increase that damaged the
organs . It may be primary or secondary.
• primary Hemochromatosis :
is inherited autosomal recessive disease characterized
by excess iron deposition in various organs in form of
hemosiderin leading to fibrosis and functional organs
primary Hemochromatosis
Mostly organs affected are :
4) adrenals
2) pancreas
5) testes
7) Pituitary
Clinical features
• Mostly affecting men .
1. Hepatic cirrhosis.
2. DM.
3. Cardiomegaly with or without heart
failure & conduction disturbance.
4. Bronze pigmentation.
5. Loss of libido , impotence & testicular
6. Arthritis.
1. Serum ferritin is increased.
2. Serum iron concentration
3. Serum iron binding capacity is
4. Liver biopsy : shows heavy iron
deposition and hepatic fibrosis .
1. Avoid food rich by in iron
such as red meat , vitamin
C , alcohol.
2. venesection of 500ml
(250 mg iron ) weekly
until the serum iron is
normal .
3. Chelating agent
subcutaneous injection. If
the dose not tolerate
venesection .
Secondary Hemochromatosis
• Secondry causes of iron
overload are hemolytic
anemia such as thalassemia
in which multiple
transfusions are required .
• Treatment: chelating
therapy with deferoxamine
is usually required.
Wilson's disease
• autosomal recessive genetic disorder in which copper
accumulates in tissues.
• Increase copper content is due to increase absorption from
small intestine and decrease excretion in bile .
• The most affected organs are:
1) Liver
2)basal ganglia ( brain)
4) Kidneys
5) Skeleton
Clinical features
Liver disease
Heart and
anxiety and
Pain in the face,
legs, and feet
Resting tremor
Abdominal pain
Dystopia of bulbar
muscle such as
dysarthria and
renal tubular
1. Upper GI
2. Abdominal
Muscle cramps
Tetanic contractions
1. serum copper:
Is reduce but it may be normal.
2. Serum Ceruloplasmin :
abnormally low (<0.2 g/L) .
3. 24 – hours urine copper:
Urinary copper excretion is increase (>100-1000 μg/24h .
4. liver function tests :
Are high .
5. Liver biopsy :
May show acute or chronic hepatitis or cirrhosis.
1. Pencillamine: is the drug of choice that
chelates and excretes copper through
kidney in urine. Pyrodoxine 50mg /
week should be added, since
pencillamine is an antimetabolite of
this vitamin and causes deficiency. The
dose can be reduced once the disease
is controlled, but treatment must
continue for life. Side effects are skin
rashes, leukopenia, and renal damage.
2. Trientine dihydrochoride: if patient
develops side effects of pencillamine
Continue Treatment
3. Zinc acetate: Oral zinc acetate
daily promotes fecal excretion of
copper and used as maintenance
therapy after chelation with
pencillamine or as a first-line
therapy in presymptomatic or
pregnant patients.
4. Ammonium tetrathiomolybdate:
is an initial therapy for
neurologic Wilson’s disease.
5. Liver transplantation: indicated
for fulminant hepatic failure, end
stage liver disease and selected
cases of severe neurological
• Prognosis is good in patients
effectively treated before
liver or brain damage has
• Neurological damage is
α1-Antitrypsin Deficienacy
• A deficiency of α1-Antitrypsin (α1-AT) is
sometimes associated with liver disease and
pulmonary emphysema (particularly in
• Autosomal dominant.
• Is synthesized in the liver.
• Main role of alpha1-antitrypsin is to protect the
tissues, and especially the elastic tissueof the lungs,
against the enzyme neutrophil elastase .
• The gene is located on chromosome 14.
α1-Antitrypsin Deficiency
• The genetic variants of α1-AT are characterized by
their electrophoretic mobilities as medium (M), slow
(S) or very slow (Z).
• The normal geneotype is protease inhibitor MM the
homozygote for Z is PiZZ, and the heterozygotes are
PiMZ and PiSZ.
• This results in decreased synthesis and secretion of
the protein by the liver.
• Causes liver disease is uncertain.
• The failure of secretion of the abnormal protein
leads to an accumulation in the liver, causing liver
Clinical features
• The majority of patients with clinical
disease are homozygotes with a PiZZ
• Some may present in childhood and a
few require transplantation.
• 10 -15% of adult patients will develop
cirrhosis, usually over the age of 50
years, and 75% will have respiratory
Clinical features
• Approximately 5% of
patients die of their
liver disease.
• Heterozygotes may
develop liver
disease, but the risk
is small.
• Serum α1- antrypsin:
• Liver biopsy:
Periodic Acid –
Schiff (PAS)positive globules are
present seen in
The periportal red hyaline globules
seen here with periodic acid-Schiff
(PAS) stain are characteristic for
alpha-1-antitrypsin (AAT) deficiency
• No specific treatment is available other
than management of complications of liver
disease. Liver transplantation may be
advised for advanced liver disease.
On physical examination
Sign of Chronic
Cerebellar Signs
Sign of Chronic
Cerebellar Signs
Sign of Chronic
pigmentation of
the skin
Sign of
Chronic Liver
Hepatitis C
Thank You

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