LIVER CIRRHOSIS

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LIVER CIRRHOSIS

• Cirrhosis results from the necrosis of liver
  cells followed by fibrosis and nodule formation.
  The liver architecture is diffusely abnormal and
  this interferes with liver blood flow and
  function. This derangement produces the clinical
  features of portal hypertension and impaired
  liver cell function.

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• Causes of cirrhosis
• Common
• Alcohol
• Hepatitis B D   
• Hepatitis C  
• Autoimmune hepatitis  
• Others
• Biliary cirrhosis primary,  secondary
• Hereditary haemochromatosis  
• Hepatic venous congestion  
• Wilson's disease  
• Drugs (e.g. methotrexate)  
• a1-Antitrypsin deficiency  
•   Idiopathic (cryptogenic)

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• Pathology
• 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 cause
• 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 previous hepatitis, such
  as HBV infection.
• A mixed picture with small and large nodules is
  sometimes seen.

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Liver Cirrhosis
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• Investigations
• These are performed to assess the severity and
  type of liver disease.
• Liver function. Serum albumin and prothrombin
  time are the best indicators of liver function
  the outlook is poor with an albumin level below
  2.8 g/dL. The prothrombin time is prolonged
  commensurate with the severity of the liver
  disease .
• 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. In decompensated
  cirrhosis all biochemistry is deranged.
• In addition, serum a-fetoprotein if gt 400 ng/mL
  is strongly suggestive of the presence of a
  hepatocellular carcinoma.

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• viral markers
• serum autoantibodies .
• serum immunoglobulins .
• iron indices and ferritin.
• copper, caeruloplasmin .
• a1-antitrypsin .
• Serum copper and serum a1-antitrypsin should
  always be measured in young cirrhotics.
• Total iron-binding capacity (TIBC) and ferritin
  should be measured to exclude hereditary
  haemochromatosis.

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• Imaging
• Ultrasound examination. This can demonstrate
  changes in size and shape of the liver. Fatty
  change and fibrosis produce a diffuse increased
  echogenicity. In established cirrhosis there may
  be marginal nodularity of the liver surface. The
  patency of the portal and hepatic veins can be
  evaluated. It is useful in detecting
  hepatocellular carcinoma.
• CT scan .shows hepatosplenomegaly and dilated
  collaterals seen in chronic liver
  disease.Contrast-enhanced scans are useful in the
  detection of hepatocellular carcinoma.
• Endoscopy is performed for the detection and
  treatment of varices, and portal hypertensive
  gastropathy.
• MRI scan.

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• Liver biopsy
• This is necessary to confirm the severity and
  type of liver disease. The core of liver often
  fragments and sampling errors may occur in
  macronodular cirrhosis.
• Special stains may be required for iron and
  copper, and various immunocytochemical stains can
  identify viruses, bile ducts and angiogenic
  structures.
• Chemical measurement of iron and copper are
  necessary to confirm diagnosis of iron overload
  or Wilson's disease.

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• Management
• Management is that of the complications seen in
  decompensated cirrhosis.
• Patients should have 6-monthly ultrasound and
  serum a-fetoprotein measurements to detect the
  development of a hepatocellular carcinoma as
  early as possible.
• There is no treatment that will arrest or reverse
  the cirrhotic changes although progression may be
  halted by correcting the underlying cause .
• Patients with compensated cirrhosis should lead
  a normal life. The only dietary restriction is to
  reduce salt intake. Aspirin and NSAIDs also
  Alcohol should be avoided.

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• COMPLICATIONS AND EFFECTS OF CIRRHOSIS
• Portal hypertension
• The portal vein is formed by the union of the
  superior mesenteric and splenic veins. The
  pressure within it is normally 5-8 mmHg
• 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).

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• 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) are superficial in position
  and tend to rupture. Portosystemic anastomoses at
  other sites seldom give rise to symptoms. Rectal
  varices are found frequently (30) if carefully
  looked for and can be differentiated from
  haemorrhoids, which are lower in the anal canal.

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Gastric esophageal varices
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• Causes of portal hypertension
• Prehepatic
• Portal vein thrombosis
• Intrahepatic
• Cirrhosis
• Hepatitis (alcoholic)
• Schistosomiasis
• Myelosclerosis (extramedullary haemopoiesis)
• Posthepatic
• Budd-Chiari syndrome
• Veno-occlusive disease
• Right heart failure (rare)
• Constrictive pericarditis

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• 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.

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• Variceal haemorrhage
• Approximately 90 of patients with cirrhosis will
  develop gastro-oesophageal varices, over 10
  years, but only one-third 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.
• Management can be divided into the active
  bleeding episode, the prevention of rebleeding,
  and prophylactic measures to prevent the first
  haemorrhage.
• Despite all the therapeutic techniques
  available, the prognosis depends on the severity
  of the underlying liver disease.

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• Urgent endoscopy
• Endoscopy should be performed to confirm the
  diagnosis of varices and to exclude bleeding
  from other sites (e.g. gastric ulceration).
• Portal hypertensive (or congestive) gastropathy
  is the term used for chronic gastric congestion,
  punctate erythema and gastric erosions and is a
  source of bleeding. Varices may or may not be
  present. Propranolol is the best treatment for
  this.
• Injection sclerotherapy or variceal banding can
  be used for treatment.

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• Long-term measures
• Non-selective beta-blockade.
• 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 by a
  decrease in cardiac output (ß1), and by the
  blockade of ß2 vasodilator receptors on the
  splanchnic arteries, leaving an unopposed
  vasoconstrictor effect. This has been shown to
  decrease the frequency of rebleeding, and is as
  effective as sclerotherapy and ligation as it
  also prevents bleeding from portal hypertensive
  gastropathy.
• It is the treatment of first choice.
• Endoscopic treatment.
• The use of repeated courses of banding at
  2-weekly intervals leads to obliteration of the
  varices. This markedly reduces re-bleeding, most
  occurring before the varices have been fully
  obliterated.
• Between 30 and 40 of varices return per year,
  so that follow-up endoscopy with ablation should
  be performed. Banding is superior to sclerotherapy

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• Ascites
• Ascites is the presence of fluid within the
  peritoneal cavity and is a common complication of
  cirrhosis of the liver.
• The pathogenesis of the development of ascites in
  liver disease is controversial, but is probably
  secondary to renal sodium and water retention.
  Several factors are involved.
• Sodium and water retention occur as a result of
  peripheral arterial vasodilatation and consequent
  reduction in the effective blood volume. Nitric
  oxide has been postulated as the putative
  vasodilator, although other substances (e.g.
  atrial natriuretic peptide and prostaglandins)
  may be involved. The reduction in effective blood
  volume activates various neurohumoral pressor
  systems such as the sympathetic nervous system
  and the renin-angiotensin system, thus promoting
  salt and water retention.
• 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.

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• Clinical features
• The abdominal swelling associated with ascites
  may accumulate 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 but, if more severe, should raise the
  suspicion of spontaneous bacterial peritonitis .
• Respiratory distress accompanies tense ascites,
  and also causes difficulty in eating. The
  presence of fluid is confirmed by the
  demonstration of shifting dullness. Many patients
  will also have peripheral oedema.
• A pleural effusion (usually on the right side)
  may infrequently be found and is believed to
  arise from the passage of ascitic fluid through
  congenital defects in the diaphragm.

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• GYNECOMASTIA

• PALMAR ERYTHEMA

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SPIDER NEAVI
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• Investigations
• A diagnostic aspiration of 10-20 mL of fluid
  should be obtained and the following performed
• 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. The ascitic protein level enables a
  division into transudative and exudative ascites.
  
• Cytology - for malignant cells.
• Amylase - to exclude pancreatic ascites

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• Management
• Bed rest alone will lead to a diuresis in a small
  proportion of people by improving renal
  perfusion,.
• 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.
• Remember, many contain significant amounts of
  sodium (could be up to 50 mmol daily). Examples
  include antacids, antibiotics (particularly the
  penicillins and cephalosporins) and effervescent
  tablets. Sodium-retaining drugs (non-steroidals,
  corticosteroids) should be avoided if possible.
• The diuretic of first choice is the aldosterone
  antagonist spironolactone, staring at 100 mg
  daily.
• Chronic administration produces gynaecomastia
  amiloride, 5-15 mg daily, is then substituted.

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• Paracentesis
• This is used to relieve symptomatic tense
  ascites. It is also used as a means of rapid
  therapy in patients with ascites and peripheral
  oedema, thus avoiding prolonged hospital stay.
• The main danger of this approach is the
  production of hypovolaemia as the ascites
  reaccumulates at the expense of the circulating
  volume.

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• Spontaneous bacterial peritonitis (SBP)
• This condition represents one of the more serious
  complications of ascites and occurs in
  approximately 8 of cirrhotics with ascites.
• The infecting organisms are believed to gain
  access to the peritoneum by haematogenous spread.
  The most frequently incriminated bacteria are
  Escherichia coli, Klebsiella and enterococci.
• The condition should be suspected in any patient
  with ascites with evidence of clinical
  deterioration. Features such as pain and pyrexia
  are usually present but may be frequently absent.
  
• Diagnostic aspiration should always be performed
  in patients with ascites . A raised neutrophil
  count in ascites is alone sufficient evidence to
  start treatment immediately.
• A third-generation cephalosporin, such as
  cefotaxime or ceftazidime, is used and is
  modified on the basis of culture results.
  Recurrence is common (70 within a year) and an
  oral quinolone, e.g. norfloxacin, 400 mg twice
  daily is prescribed to prevent it. This also
  prolongs the survival.

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• Portosystemic encephalopathy
• The term 'portosystemic encephalopathy' (PSE)
  refers to a chronic neuropsychiatric syndrome
  secondary to chronic liver disease.
• This condition occurs with cirrhosis, but a
  similar acute encephalopathy can occur in acute
  fulminant hepatic failure .
• PSE is seen in patients with portal hypertension
  that is due to spontaneous 'shunting', or in
  patients following a portosystemic shunt
  procedure.
• Encephalopathy is potentially reversible.

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• Many 'toxic' substances have been suggested as
  the causative factor, including ammonia, free
  fatty acids, mercaptans and accumulation of false
  neurotransmitters (octopamine) or activation of
  the ?-aminobutyric acid (GABA) inhibitory
  neurotransmitter system.
• Increased blood levels of aromatic amino acids
  (tyrosine and phenylalanine) and reduced
  branched-chain amino acids (valine, leucine and
  isoleucine) also occur.
• Nevertheless, ammonia seems to have a major role,
  and ammonia-induced alteration of brain
  neurotransmitter balance is the leading concept
  of the causation.
• Ammonia is produced by the breakdown of protein
  by intestinal bacteria, and a high blood ammonia
  is seen in most patients.

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• Factors precipitating portosystemic
  encephalopathy
• High dietary protein
• Gastrointestinal haemorrhage
• Constipation
• Infection, including spontaneous bacterial
  peritonitis
• Fluid and electrolyte disturbance due to
    diuretic therapy  
•  paracentesis
• Drugs (e.g. any CNS depressant)
• Any surgical procedure
• Progressive liver damage
• Development of hepatocellular carcinoma

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• Clinical features
• An acute onset often has a precipitating factor .
  
• The patient becomes increasingly drowsy and
  comatose.
• Chronically, there is a disorder of personality,
  mood and intellect, with a reversal of normal
  sleep rhythm. These changes may be fluctuating
  and a history from a relative must be obtained.
• The patient is irritable, confused, disorientated
  and has slow slurred speech.
• Signs include
• fetor hepaticus (a sweet smell to the breath)
• a coarse flapping tremor seen when the hands are
  outstretched and the wrists hyperextended
  (asterixis) .

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• Immediate management
• Identify and remove the possible precipitating
  cause, such as drugs with cerebral depressant
  properties, constipation or electrolyte imbalance
  due to over diuresis.
• Give purgation and enemas to empty the bowels of
  nitrogenous substances.
• Lactulose (10-30 mL three times daily) is an
  osmotic purgative that reduces the colonic pH and
  limits ammonia absorption.
• Give antibiotics
• Metronidazole (200 mg four times daily) is also
  effective in the acute situation. Neomycin should
  not be used.
• Stop diuretic therapy.
• Give intravenous fluids as necessary (beware of
  too much sodium).

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• Renal failure (hepatorenal syndrome)
• The hepatorenal syndrome occurs typically in a
  patient with advanced cirrhosis with jaundice and
  ascites.
• The urine output is low with a low urinary sodium
  concentration, a maintained capacity to
  concentrate urine (i.e. tubular function is
  intact) and an almost normal renal histology.
• The renal failure is described as 'functional'.
• It is sometimes precipitated by overvigorous
  diuretic therapy, diarrhoea or paracentesis, but
  often no precipitating factor is found.
• Advanced cases may progress beyond the
  'functional' stage to produce an acute tubular
  necrosis.

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