Cirrhosis

LIVER CIRRHOSIS

الدكتور خلدون ذنون- كلية طب نينوى
المرحله الرابعة
Objectives
The student is supposed to know:
Cirrhosis is a terminal event due to a variety of causes injuring the liver.
Features of the disease.
clinical features may be minimal to frank.
Diagnosis needs liver biopsy.
It is an irreversible process.
management of ascites, esophageal varices and hepatic encephalopathy.

Pathophysiology

Progressive & wide spread death of liver cells associated with inflammation, fibrosis & loss of normal liver lobular architecture with regenerating nodule formation.
Liver injury leads to activation of stellate cells by cytokines produced by Kupfer cells and hepatocytes. Stellate cells transform into a myofibroblast producing collagen.
Loss of normal hepatic vasculature with the formation of portal-systemic vascular shunts.
Micronodular cirrhosis: characterized by formation of about 1mm diameter nodules seen in alcoholic cirrhosis.
Macronodular cirrhosis: characterized by larger nodules of various sizes with large fibrous scars e.g posthepatitic & cryptogenic cirrhosis.
Cirrhosis evolve slowly over years and even after removal of the cause.


Causes
Chronic viral hepatitis e.g, B or C.
Alcohol
Non-alcoholic fatty liver disease
Immune: Primary sclerosing cholangitis, autoimmune hepatitis
Biliary: Primary biliary cirrhosis, secondary biliary cirrhosis
Metabolic & hereditary: haemochromatosis, Wilsons disease, (1 antitrypsin deficiency, cystic fibrosis.
Cryptogenic 15%
Veno-occlusive disease e.g Budd-Chiari syndrome.
Most common causes world wide: viral hepatitis & alcoholic.

Clinical features

Cirrhosis can occur at any age with prolonged morbidity &
Premature death
May be entirely asymptomatic or with minimal features.
Frequent complaints : weakness , fatigue , weight loss , anorexia ,
nausea, vomiting, upper abdominal discomfort.
Hepatomegaly is common early in the disease later on liver
shrinks in size due to fibrosis & becomes hard, irregular &
Painless.
Mild jaundice due to failure to excrete bilirubin & mild haemolysis.
Circulatory changes : palmar erythema : of limited diagnostic
value as it occurs in other conditions associated with hyperdynamic
circulation & occurs also in some normal people .
spider telangiectasia: central arteriole from which small vessels
radiate, size 1-2mm 1-2 cm, usually above the nipples, may
occur normally with a number < 3 & in greater number in the 3rd
trimester of pregnancy.
Central cyanosis: late feature, due to pulmonary AV shunt( hypoxia.
Alcoholic cirrhosis: florid spider telangiectasia, gynaecomastia & parotid enlargement are common.
Pigmentation: haemochromatosis & prolonged cholestasis.
Endocrine changes :
- Loss of male hair distribution, impotence, testicular atrophy &
Loss of Libido.
- Gynaecomastia: due to ( estrogen & spironolactone.
- Women: breast atrophy, irregular menses & amenorrhea.
Bleeding tendency: bruises, purpura, epistaxis, menorrhagia.
Portal hypertension: splenomegaly, ascites, collateral vessels, variceal bleeding & foetor hepaticus.
Ascites: due to hypoalbuminaemia & portal hypertension, occurs in advanced disease.
Hepatic encephalopathy: occurs in acute liver failure & advanced cirrhosis.
Clubbing of fingers & toes, low grade fever, Dupuytrens contracture especially in alcoholics.

Investigations
Full blood count, B.sugar, B.urea & S.creatinin, S.electrolytes.
Liver function test: ALT, AST, ALP, S.bilirubin, s.albumin, PT .
U/S of liver, biliary passages, abdomen & CAT scan.
Liver biopsy gives the definitive diagnosis.
Investigation of the cause : viral study , cholestasis , PBC ,
Haemochromatosis, (1-antitrypsin deficiency.
Investigation of complications: ascites, portal hypertension, hepatic encephalopathy, renal failure, liver cancer.


Management
Treatment of the cause: viral, alcoholism, haemochromatosis.
If there is no complication treatment is expectant.
Nutritional therapy: limit protein intake when liver function is impaired to prevent hepatic encephalopathy, encourage CHO intake and avoid saturated fat, total calorie 3000 kcal/day. Vitamin supplement if malnourished.
Treatment of complications: ascites, portal hypertension, bleeding, hepatic encephalopathy, infection.

Liver transplant - indicated in:

Signs of liver failure: sustained or increased jaundice > 100
(mol/ L in cholestatic disease as in PBC, MELD score >12,
Child-Pugh C.
2- First episode of bacterial peritonitis.
3- diuretic resistant ascites.
4- Recurrent variceal bleeding .
5- liver cancer <5cm
6- persistent hepatic encephalopathy

Contraindications: sepsis, extrahepatic malignancy, active alcohol or other substance misuse. , marked cardiopulmonary dysfunction.
Prognosis of liver transplant: 1 year survival is 85%, falling to 70% at 5 year.

Prognosis of liver cirrhosis
Generally poor, as many present with advanced disease or serious complications.
25% of patients survive 5 years but when liver function is good 50% survive 5 years.
Prognosis is better if underlying cause is treatable e.g alcohol misuse, haemochromatosis, Wilsons disease.
Jaundice, ascites, encephalopathy indicate poor prognosis.
Increasing plasma bilirubin, falling plasma albumin < 30 gm / L, hyponatraemia < 120 mmol/ L,( PT are bad prognostic signs.
Child-Pugh classification which assesses prognosis: A, B, C depend on encephalopathy, bilirubin, albumin, PT, ascites. Grades for each disorder: non (1), mild (2), marked (3).
MELD score (model for end-stage liver disease) which includes also renal function if impaired the prognosis is poor.


PORTAL HYPERTENSION
Prolonged elevation of the normal venous pressure (normally 2-5 mmHg) usually > 12 mm Hg.

Pathogenesis

Increased portal vascular resistance which leads to gradual reduction of portal blood flow to the liver.
Formation of collateral vessels allowing portal blood to enter the systemic circulation & bypass the liver.
Collateral vessels: GIT(oesophagus, stomach & rectum. Anterior abdominal wall , renal , lumbar , ovarian & testicular blood vessels

Causes of portal hypertension according to the site of obstruction

A- Hepatic: - sinusoidal: cirrhosis, cystic liver disease, malignancy.
- Pre-sinusoidal: schistosomiasis, sarcoidosis, drugs &
Congenital hepatic fibrosis.
- Post-sinusoidal: veno-occlusive diseases.
B- pre-hepatic: - portal vein thrombosis: sepsis, thrombotic disease,
oral contraceptives, pregnancy.
- Trauma, malignancy of pancreas or liver, pancreatitis.
C- post-hepatic: hepatic vein thrombosis (Budd-Chiari syndrome).

Most common causes of P.H: cirrhosis, schistosomiasis, portal vein thrombosis.

Cirrhosis account for 90% of all causes of P.H.


Clinical features
Splenomegaly of moderate size. Hypersplenism is common ( thrombocytopenia 50-100 ( 109 / L, leukopenia may occur but anaemia is unlikely.
Anterior abdominal wall collaterals e.g caput medusae .
Most important collaterals occur in the oesophagus & stomach and may cause severe bleeding. Rectal varices may also cause bleeding
Partly contribute to ascites .
Fetor hepaticas: due to porto-systemic shunt mercaptans pass directly to the lungs.

Investigations ( Upper GIT endoscopy is the most useful. ( blood count: mild decrease in HB, WBC, platelets due to hypersplenism.
( U/S of abdomen shows splenomegaly, collateral vessels, portal vein thrombosis, ascites.
( CT & MRI angiography identify hepatic vein patency. ( Portal & hepatic venous pressure measurement are rarely needed.
● Balloon catheter through transjugular route to measure wedged hepatic venous pressure.

Complications of portal hypertension

( Oesophageal & gastric variceal bleeding ( Congestive gastropathy
( Hypersplenism ( Ascites ( Renal failure ( Hepatic encephalopathy
● Iron deficiency anemia

VARICEAL BLEEDING

Occurs from oesophageal varices located within 3-5 cm from gastro-esophageal junction or from gastric varices .
( Size of varices, ( portal pressure & liver failure (bleeding tendency) predisposes to bleeding.
Aspirin & NSAIDS precipitate bleeding.
Bleeding is often severe & recurrent.


Management of acute variceal bleeding
Restore blood volume with 0.9% saline 1-2 L, blood transfusion & plasma.
Endoscopy should be done to localise the site of bleeding.
All patients should receive antibiotics e.g oral ciprofloxacin, i.v cephalosporin to reduce peritonitis.

Band ligation or sclerotherapy

Initial treatment at time of endoscopy.
Stops bleeding in 80% & can be repeated if bleeding recurs.
Banding repeated every 1-2 weeks until varices are obliterated.
Banding is safer than sclerotherapy (perforation & stricture).
Now sclerotherapy is rarely done.
Prophylactic PPI reduces risk of bleeding due to banding induced ulceration & prevent peptic ulcer.
Sometimes balloon tamponade is done prior to endoscopic banding.

Drugs

Useful in reducing bleeding while endoscopy is being arranged.
Terlipressin is the drug of choice which releases the vasoconstrictor vasopressin over several hours, reduces portal pressure & acute bleeding.
Phosphate enema or lactulose to prevent encephalopathy.

Balloon tamponade (Sengstaken-Blakemore tube)
Two balloons (with aspiration tubes) exert pressure in the fundus of the stomach & lower oesophagus .
Effective in stopping bleeding and allow time to use definitive therapy.


Transjugular intrahepatic portosystemic stent shunt TIPPS
A stent is placed between the portal vein and hepatic vein within the liver to reduce portal pressure.
Stops and prevent variceal bleeding.
Complication: hepatic encephalopathy, prevented by reducing shunt diameter.
More effective than endoscopic treatment in reducing variceal bleeding, but survival is not improved.

Portosystemic shunt surgery :
Reserved for patients in whom other measures have failed
Provided that the patient has relatively good liver function.
Procedure: selective shunt (distal spleno-renal Warren shunt), Preserves portal blood flow to the liver & associated with less Post operative encephalopathy, but with the passage of time Liver portal blood flow falls & encephalopathy develops
Mortality is high and survival is not improved.

Oesophageal transection

used when TIPPS is not available and
bleeding is not controlled by other measures.
considerable operative morbidity & mortality.

Primary prevention of variceal bleeding

propranolol 80-160 mg /day or nadolol
Effective in reducing portal venous pressure and hepatic venous pressure gradient.
Efficacy of B-blockers is similar to prophylactic banding.
47% reduction in variceal bleeding , 45% reduction in death from bleeding & 22% overall reduction in mortality .


Secondary Prevention of variceal bleeding
B.blockers is also used following banding.
Banding
Sclerotherapy
TIPPS
Portosystemic shunt surgery

CONGESTIVE GASTROPATHY

Endoscopy: multiple areas of punctate erythema.
Repeated minor bleeding leads to iron deficiency anaemia .
Acute bleeding is less common.
Treatment: propranolol 80-160 mg / day or TIPSS, iron or blood transfusion for the anaemia.

ASCITES Accumulation of free fluid in the peritoneal cavity
Causes
Cirrhosis, heart failure, nephrotic syndrome
Hepatic venous occlusion, hypothyroidism
Malignancy, pancreatitis, bacterial peritonitis e.g TB

Pathogenesis in cirrhosis hypoalbuminaemia due to liver failure, portal hypertension & splanchnic vasodilatation which activate renin-angiotensin-aldosterone system.


Clinical features
Small amount: asymptomatic
Abdominal distension, shifting dullness when fluid volume > 1L.
Marked ascites: fluid thrill
Eversion of umbilicus, abdominal herniae, abdominal striae, scrotal oedema, dilated superficial abdominal veins.
10% associated with pleural effusion, usually right sided.

Investigations

Ultrasound is the best mean of confirming ascites.
Paracentesis & ascitic fluid analysis : in cirrhosis clear-straw coloured transudate, protein < 25gm / L or serum - ascitic fluid albumin gradient > 1.5, few cells, normal glucose.
Exudate: suggest malignancy (hepatoma), spontaneous bacterial
Peritonitis, T.B or hepatic venous obstruction. Protein >25 gm/L
Serum - ascitic fluid albumin ratio < 1.5, cytology: malignant cell,
PMN >250/mm3 in SBP.
Amylase level in pancreatic ascites
Appearance of fluid: malignancy (bloody), infection (cloudy) biliary communication (bile stain), lymphatic obstruction (milky-chylous)
Laparoscopy

Management

Sodium & water restriction
- Sodium: 40-80 mmol / day 1-2 gm(no added salt to diet).
- Water intake 0.5-1L/day only when plasma sodium
<125 mmol/L.
- Avoid drugs containing sodium e.g antacids, penicillins, aspirin,
Sodium valproate or drugs causing sodium retention:
carbenoxolone, steroids , NSAIDS , oestrogens .
Diuretic drugs
- Spironolactone 100-400 mg/day is the drug of choice,
side effects: gynaecomastia & Hyperkalaemia.
- Some need loop diuretics e.g frusemide .
- Bed rest improves diuresis.
- Daily weighing: no more than 900 ml of fluid/day should be
Lost.
Paracentesis
- Gross ascites with cardiopulmonary distress: remove 3-5 L over
1-2 hour
- Paracentesis to dryness or removal of 3-5 L/ day is safe provided
the circulation is supported by a colloid e.g albumin solution or
plasma expander.
Leveen shunt :
- Tube from peritoneum to internal jugular vein: effective in
resistant ascites.
- Complications: infection, SVC thrombosis, pulmonary oedema,
Bleeding, oesophageal varices & DIC which limits its use .
TIPSS : Relieves resistant ascites when liver function is
reasonable & or prior to liver transplant .
Prognosis ( Ascites in cirrhosis is a serious sign, 10-20% survive 5 years.
( The prognosis is better when liver function is reasonable, treatable
underlying cause of cirrhosis or excess salt intake.


Complications: spontaneous bacterial peritonitis SBP, renal failure.
Spontaneous bacterial peritonitis
Acute onset of abdominal pain, rebound tenderness, absent bowel
sounds, fever, in 1/3 mild or no abdominal pain.
Paracentesis: cloudy fluid, exudate, neutrophil count > 250/ mm3.
Culture : mainly E.coli, multiple organisms indicate perforated
viscus.
Treatment: immediate broad spectrum antibiotics e.g cefotaxime.
Recurrence is common & is reduced by norfloxacin 400 mg/day.

HEPATIC ( PORTOSYSTEMIC ) ENCEPHALOPATHY

Neuropsychiatric syndrome due to liver disease.
Occurs in cirrhosis & acute hepatic failure from other causes.

Pathogenesis

Biochemical disturbance of brain function which is reversible.
Liver failure is a constant feature with Porto systemic blood shunt.
Neurotoxins: nitrogenous substances from the gut due to bacterial action, normally metabolised by the normal liver e.g ammonia, ( -aminobutyric acid.
False neurotransmitters: octapamine, amino acids, mercaptans, fatty acids
In acute hepatic failure blood brain barrier is disrupted leading to
cerebral oedema.


Factors precipitating hepatic encephalopathy
( Uraemia (spontaneous, diuretics) ( drugs (sedatives, antidepressants, hypnotics) ( GIT bleeding ( excess dietary protein ( constipation ( infection ( paracentesis > 3-5L ( hypokalaemia ● dehydration ( trauma & surgery ( portosystemic shunt (surgical, spontaneous)
Clinical features of hepatic encephalopathy
Change of intellect , personality , emotions , consciousness with or
without neurological signs.
Early features are mild, severe features are characterised by: apathy, inability to concentrate, confusion, disorientation, drowsiness, slurring of speech, coma & convulsion.
Asterixis, inability to perform simple mental arithmetic tasks or draw objects e.g star, later on hyper-reflexia, bilateral extensor planters & fetor hepaticus.
Chronic hepatic encephalopathy ( hepatocerebral degeneration (cerebellar degeneration, Parkinsonism, spastic paraplegia & dementia).

Investigations

EEG: diffuse slowing of the normal alpha waves & appearance of delta waves.
( Arterial ammonia: of little or no diagnostic value.
Investigation of any precipitating factors: infection, Uraemia electrolytes.
Psychiatric tests & sensory evoked potentials.

Differential diagnosis

( Subdural haematoma ( drugs or alcohol intoxications ( delirium tremens ( Wernickes encephalopathy ( primary psychiatric disorders ( hypoglycaemia ( neurological Wilson’s disease
● postictal state

Management

Remove precipitating factors: infection, electrolytes, constipation, &drugs .
Diet : protein restriction is rarely needed and can worsen nutritional state of the patient, in severe state protein< 20 gm /day , glucose 300 gm / day orally or i.v, when the patient starts to improve gradually increase protein 40-60 gm / day.
Suppress production of neurotoxins by bacteria in the bowel :
- Lactulose 15-30 ml / 8hours : oral disaccharide , metabolised by
colonic bacteria & produce osmotic laxative effect, (PH of
colonic contents & so limit ammonia absorption & aids
incorporation of nitrogen into bacteria.
Lactitol (alternative): platable, milder action of the bowel.
- Neomycin 1-4 gm / 4-6 hourly: reduce bacteria in the colon,
Poorly absorbed from the bowel, contraindicated in Uraemia &
cause ototoxicity .
Liver transplant: for chronic or refractory hepatic encephalopathy.


HEPATORENAL FAILURE (SYNDROME)
Occur in 10% of patients with advanced cirrhosis
Due to renal vasoconstriction
Type 1
Oliguria , rapid increase in s.creatinine, no proteinuria
Urine sodium <10mmol/day, urine/plasma osmolality>1.5
Exclude hypovolaemia
Very poor prognosis
Treatment: albumin infusion, terlipressin, hemodialysis should not be used routinely, liver transplant.
Type 11
Refractory ascites
Moderate increase in s.creatinine
Better prognosis

HEPATOPULMONARY FIALURE (SYNDROME)

Resistant hypoxaemia & intrapulmonary vascular dilatation.
Digital clubbing, cyanosis, spider naevi, characteristic reduction in arterial 02 saturation on standing.
Treatment: liver transplant.










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