Cirrhosis of the liver

1
Cirrhosis of the liver
2
Definition

• Cirrhosis is a common chronic, progressive and
• diffusive liver disease, caused by one or
  several
• agents act repeatedly and persistently.
• Histologically, cirrhosis is an irreversible
• alteration of the liver architecture,
  consisting of
• hepatic fibrosis and areas of nodular
  regeneration

3
Epidemiology

• Worldwide major heath problem
• Over 500,000 deaths per year
• Over 20 were latent
• 2 10 in postmortem examination
• Common and death leading disease in China

4
Etiology and pathogenesis

• Viral hepatitis
• Parasites (schistosomiasis)
• Alcoholic liver disease
• Cholestasis

• Hepatic-Venous outflow obstruction
• Toxicant and drugs
• Metabolic abnormality
• Malnutrition
• Cryptogenic cirrhosis

5
Viral hepatitis

• HBV
• HCV
• HBV HDV

• HAV
• HEV

6
Viral hepatitis (HBV)

• Global prevalence gt300 million carriers
• 5
  world population
• Varies widely
• High prevalence 8 15
• Far East (southeast Asia China
  Philippines Indonesia)
• Middle East Africa parts of South
  America
• Intermediate prevalence 2 7
• Japan parts of south America
  parts of central Asia
• eastern and southern Europe
• Low prevalence lt2
• US Canada northern Europe
  Australia

7
Viral hepatitis

• Elimination of viral infected hepatocytes is
  dependent on recognition of viral determinants in
  association with HLA proteins on the infected
  hepatocytes by cytotoxic T cells.
• HLA protein display is modulated by exposure to
  interferon and cytotoxic T cell, NK lytic
  processes.
• During chronic HBV infection, infected liver
  cells failed to induce IFN. Therefore, viral
  protein synthesis is not decreased, HLA protein
  display is not enhanced.

8
Parasites (Schistosomiasis)

• Ova deposited in the portal zones
• Exciting a fibrous tissue reaction
• Co-existence of malaria and cirrhosis reflects
  
• malnutrition, viral hepatitis and toxic factors

9
Alcoholic liver disease

• 1/3 cause of cirrhosis in Western country
• Most important factor
• threshold dose 600 Kg (men) 150300 Kg
  (women)
• average daily consumption of alcohol
• gt 40 80 g/D, over 10 15 years
• Liver primary site of ethanol metabolism
• Ethanol can be oxidized by three enzymes
  systems
• ADH CYP2E1
  catalase

10
Alcoholic liver disease

• Mechanism
• Direct effect by ethanol, or its first
  metabolite
• (acetaldehyde redox shift
  oxidant stress)
• Cell-mediated immune
• Three histopathologic lesion
• fatty liver, alcoholic hepatitis, cirrhosis

11
Biliary cirrhosis

• Primary Biliary Cirrhosis
• Progressive destruction of small and
  intrahepatic
• bile ducts
• Prevalence 40150 cases/million
• Women gt90 of cases 50y
• Abnormal immunoregulation
• Associated with HLA phenotyeps

12
Biliary cirrhosis

• Secondary biliary cirrhosis
• Obstruction of the biliary tree, further
  divided into
• two groups
• intra-hepatic and extra-hepatic obstruction

13
Hepatic-Venous outflow obstruction

• Veno-occlusive disease
• Budd-chiari syndrome
• Constrictive pericarditis
• Chronic congestive heart failure

14
Toxicant and drugs

• Tetrachloride carbon (????)
• ?- methyldopa (?- ????)
• Tetracycline (???)
• Phosphorus (?)
• Arsenic(?)

15
Metabolic abnormality

• Iron storage disease (Hemochromatosis)
• Copper storage disease (Wilsons disease)

16
Malnutrition

• Chronic inflammatory bowel disease
• Prolonged lack of dietary proteins and vitamins

17
Cryptogenic cirrhosis

• Etiology is unknown
• Viral infection are suscepted in some cases

18
Pathology and classification

• Histopathological diagnosis
• Excessive fibrous tissue
• Regenerating nodules
• Complete distortion of the normal relationship
• of hepatic venous outflow radicles and portal
  veins.

19
Anatomical types of regenerating nodules

• Micronodular
• Macronodular
• Mixed cirrhosis

20
Micronodular cirrhosis

• Features Thick regular septa
• Regenerating small nodules
  (lt3mm)
• Involvement of every lobule
• Alcoholism
• Malnutrition
• Biliary obstruction
• Hemochromatosis
• Venous outflow obstruction

21
Macronodular cirrhosis

• Features Septa
• Nodules of variable size
• (gt3mm, even 1 3 cm)
• Normal lobules in the large
  nodules
• Two subtypes postnecrotic
• posthepatitic

22
Macronodular cirrhosis

• Postnecrotic type
• Coarsely scarred liver
• Large nodules surrounded by broad fibrous septa
• Clumping togathered numerous portal trials
• Toxic cirrhosis
• Cryptogenic cirrhosis
• Multilobular cirrhosis

23
Macronodular cirrhosis

• Posthepatitic type
• Macronodules separated by slender fibrous
  strands
• Connect individual portal areas to each other
• Viral hepatitis
• Wilsons disease

24
Mixed cirrhosis

• Features
• Presenting both micro- and macronodules
• From micronodules to macronodules
• Alcoholism
• Antitrypsin deficiency

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Some aspects of pathology

• The most useful morphologic classification
• gross appearance of the liver
• The morphologic diagnosis of cirrhosis is more
• reliable than the histopathological diagnosis
• Schistosomiasis incomplete septal cirrhosis
• coarse portal
  fibrosis
• Initially enlarged/subsequcetly shrinks

26
Clinical manifestation

• Onset Cryptical and slowly progressive
• Majority 35 years or 10 years
• Minority 36 months
• Stages Compensated
• Decompensated

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Compensated stage

• Fatigue
• Loss of appetite
• Anorexia
• Abdominal discomfort
• Abdominal pain
• Hepatomegaly (slightly or moderately)
• Splenomegaly

28
Decompensated stage

• Deterioration of liver function
• Feature of portal hypertention

29
Deterioration of liver function

• General deterioration
• Deterioration of heath, anorexia, weight
  loss, weakness, fatigue, Flatulent dyspepsia,
  abdominal distress, swelling of legs or abdomen,
  mild fever, loss of libido and hemorrhage.
• Findings of physical examination
• Jaundice
• Dermatological and sexual signs
• Liver (enlarge or shrunken)

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Jaundice

• It always implies liver cell destruction exceeds
  the capacity for regeneration

31
Dermatologic and sexual signs

• Skin pigmentation (??????)
• Clubbing fingers (???)
• Spider angioma (???)
• Liver palms (palmar erythema) (??)
• Purpura (??)
• Spontaneous bruising (??)/epistaxes (???)

32
Dermatologic and sexual signs

• Feminization (???)and hypogonadism (??
• ????)
• Gynecomastia(??????)
• testicular atrophy
• sparse body hair
• changes in hair distribution
• menstrual irregularities
• Mechanism serum testosterone ?
  estrogens ?

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Liver

• Early stage
• Enlarged and palpable
• firm regular edge
• a fine to coarsely nodular surface
• Later stage
• Shrunk and impalpable

34
Features of portal hypertension

• Portal-systemic collaterals
• Ascites
• Splenomegaly

35
Anatomy and physiology of portal venous system

• Begins in the capillaries of the intestines
• Terminates in the hepatic sinusoids (??)
• Formed by the confluence of the superior and
  inferior
• mesenteric veins (????/???)and splenic vein
• Liver receives 1500ml/min, 2/3 from portal vein
• Hepatic artery provides 50 oxygen
• The pressure within the sinusoids is low
• Lack of valves
• Between the splanchnic venules (?????)and
  the heart

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Portal-systemic collaterals

• Esophageal and gastric varices
• Dilation of the remnant of the umbilical vein
• 
  (???)
• Dilation of abdominal veins
• Hemorrhoidial venous (???)collaterals

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Splenomegaly

• Slightly or moderatory enlarged
• Hypersplenism
• Leukopenia
• Thrombocytopenia
• Anemia

38
Ascites

• Prominent feature of portal-hypertension
• 70 of patients are positive
• An early sign in presinusoidal portal
  hypertension
• relative late in intrahepatic portal
  hypertension
• Massive ascites abdominal herniae (??)

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Complications

• Upper gastrointestinal bleeding
• Hepatic encephalopathy
• Infection
• Hepatorenal syndrome
• Primary liver cancer
• Imbalance of electrolytes and acid-alkaline

41
Upper gastrointestinal bleeding

• Major complication
• Incredible high mortality
• Source of bleeding
• esophageal varices
  6080
• gastric varices
  7
• congestive gastropathy
  520
• (paptic ulcer, acute erosive gastritis etc)

42
Hepatic encephalopathy

• The most severe and deadly complications

43
Infection

• Increased risk for bacterial infection
• pneumonia
• biliary infection
• E.coli infection and
• spontaneous bacterial peritonitis (SBP)

44
SBP

• Pathogen of SBP grams negative bacteria
• Features of SBP fever, abdominal pain or
  tenderness
• decreased bowel
  sounds
• Suspected patients sudden onset of HE or
  hypotension
• Diagnosis elevated ascites fluid white
  blood cells
• positive
  ascitic fluid culture

45
Hepatorenal syndrome

• Decreased renal function due to severe liver
  disease
• Histologically normal kidney
• Involved factors
• Sympathetic nervous system
• Renin-angiotensin-aldosterone
• Prostaglandins
• Endotoxemia
• Others ( vasopressin , leukotriene
  etc)

46
Primary liver cancer

• Suspected signs
• Hepatomegaly within short time
• Persistent abdominal pain
• Enlarged liver with uneven surface or mass
• Bloody ascites
• Serum a-fetoprotein (a-FP) 70

47
Imbalance of electrolytes and acid-alkaline

• Hyponatraemia
• Hypokalaemia
• Metabolic alkalosis

48
Laboratory and other tests

• Urine
• Serum
• Hematology
• Ultrasonograply
• Barium esophagogram
• Endoscopy
• Liver biopsy

49
Diagnosis

• Patients with a history of viral hepatitis,
  prolonged
• alcohol overconsumption, schistosome
  infection,
• hemochromatosis
• Features of deterioration of liver function and
• portal hypertension
• Enlarged or shrunk liver with nodular surface
• Abnormal liver function tests
• Liver biopsy shows widespread fibrosis with
• nodular regeneration

50
Complete diagnosis

• Etiology
• Morphology
• Hepatic function

51
Specific clinical clues to etiology of cirrhosis
52
Posthepatitic cirrhosis

• Previous acute hepatitis, transfusion, illicit
  drugs
• Multiorgan involment such as rash, arthritis,
• thyroiditis, colitis etc.
• Serum HBV or HCV positive
• Some markers of hepatitis, elevated gamma
• globulin or positive anti-nuclear antibodies.

53
Schistosomiasis

• Contacting with fresh water contaminated with
• cercariae in epidemic area
• Splenomegaly being the earliest and most
• prominent sign
• Bleeding from esophageal varices may be the
• initial clinical presentation
• Liver function is relatively good

54
Alcoholic cirrhosis

• Alcoholic beverage consumption gt4080 g for over
• 10 years
• Large parotid, myopathy, neuropathy, contraction
• of the palmar fascia
• sGOT gt sGPT, sGOT/sGPT ratiogt2
• Polymorpho-nuclear leukocytosis

55
Primary biliary cirrhosis

• Female (90), middle age (4060y), Pruritus(??)
• before icterus (??)
• Xanthomas(??) Raynauds phenomen
• sclerodactyly (????)telangiectasis (?????)
• skin hyperpigmentation
• Elevated AKP, IgM, antimitochondrial antibody

56
Wilsons disease

• Family history of liver or neurologic disease
• Childhood onset
• Kayser-Fleischer corneal rings
• Grossly flapping tremor, spastic gait, other
• CNS disorder, osteochondritis (????)
• Low serum ceruloplasmin (??????)

57
Hemochromatosis

• Positive family history
• Skin pigmentation, diabetes, pseudogout,
• cardiomyopathy, loss of body hair, testicular
  atrophy
• Elevated serum ferritin

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Hepatic function (Child-Pugh score)

• Index
  Range
  Score
• Neuropathy
  None
  1
• 
  I, II
  2
• 
  III, IV
  3
• Ascite
  None
  1
• 
  Mild
  2
• 
  Massive
  3
• Serum bilirubin
  lt2
  1
• (mg / dl)
  23
  2
• 
  gt3
  3
• Serum albumin
  gt3.5
  1
• (g / dl)
  2.83.5
  2
• 
  lt2.8
  3
• Ratio of prothrombin time activity gt50
  
  1
• 
  3050
  2
• 
  lt30
  3
• A 58 scores B 911 scores C
  1215 scores
• 
  

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Differential diagnosis

• Hepatomegaly
• Ascites
• Complications
• Upper GI bleeding
• Hepatic encephalopathy
• Hepatorenal syndrome

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Hepatomegaly

• Chronic hepatitis
• Primary liver cancer
• Parasitization
• Hemologic diseases (leukemia, lymphoma)
• Metabolic diseases

61
Ascites

• Tuberculous peritonitis
• Constrictive pericarditis
• Chronic glumerulonephritis
• Intraperitoneal tumors

62
Upper GI bleeding

• Peptic ulcer, acute erosive gastritis, gastric
  cancer
• and esophageal varices are four major sources
  of
• upper GI bleeding
• In cirrhotic patients, bleeding are not entirely
  due
• to varices

63
Hepatic encephalopathy

• Hypoglycemia
• Uremia
• Diabetic ketoacidosis
• Nonketonic hyperosmolar syndrome

64
Hepatorenal syndrome

• Prerenal azotemia
• Acute tubular necrosis
• Drug nephrotoxicity
• Diagnosis is supported by avid urinary
• sodium retention
• Urine sodium concentration lt 5 mmol / L
• unremarkable urinary sediment

65
Treatment

• Supportive therapy
• Eliminating the specific causes
• Using antifibrotic drugs
• Management of ascites
• Management of complications
• Liver transplantation

66
Supportive therapy

• Appropriate rest
• 1g protein/kg, 2000 Calories daily
• Vitamin(s), thiamine, vitamin K, iron and
  folic acid
• Removal of exogenous aggravating agents
• liver tonics, offending drugs
• control of infection and electrolyte
• Correction of hypoalbuminemia and coagulation
• fresh frozen plasma, platelet concentrates
  or
• prothrombin complex

67
Etiology and definitive treatment of cirrhosis

• Etiology
  Treatment
• Virus hepatitis
  ? Antivirals
• Schistosomiasis
  Praziquantel 6080mg/kg for 2 days
• Alcohol
  Abstention
• Iron overload
  Vensection. Deferoxamine 0.51g/kg
• Copper overload
  penicillamine 0.81.2 g/day
• a1 antitrypsin deficiency ?
  Transplant
• Tyrosinaemia
  Withdraw dietary tyrosine
• Galactosaemia
  Withdraw milk and milk products
• Cholestasis
  Relieve biliary obstruction
• Budd-Chiari syndrome
  Relieve main venous block
• Immunological factors
  Prednison or predisolon 2060 mg/day
• Toxins and drugs
  Identify and stop
• Cryptogenic
  ---

68
Antifibrotic drugs

• Penicillamine
• Primary biliary cirrhosis
• Wilsons disease
• Inhibiting the formation of cross-links of
  collagen
• Colchicine
• Inhibiting assembly of collagen
• Increasing collagenase production

69
Management of ascites

• Ascites with severe, acute liver disease
• Improvement of liver function
• Ascites with stable or steadily worsening liver
• function
• Maximal reabsorption rate 700900 ml/day
• Goal of management
• weight loss lt 1.0kg/day (ascites
  peripheral edema)
• weight loss lt 0.5kg/day (ascites)

70
Management of ascites

• Sodium restriction
• Fluid restriction
• Diuresis
• Paracentesis
• Side-to-side portacaval shunt
• Peritoneovenous shunt
• Transjugular intrahepatic portosystemic shunts
• (TIPS)

71
Sodium restriction

• 1g sodium retaines 200 ml fluid
• gt 0.75 g will result in ascites in cirrhotic
  patients
• lt 0.5 g/d (22 mEg), restricted in patients
  without
• ascites
• Strict bed rest
• improving renal clearance in the supine
  position

72
Fluid restriction

• 1000 ml/day

73
Diuresis

• If sodium restriction are failed
• Diuretic for ascites
• Urine loss
• loop diuretic
• Na K
  Furosemide (???)
• 
  Bumetamide(????)
• Distal diuretic
• Na K
  Spironolactone (????)
• 
  Triamterene (????)
• 
  Amiloride (????)

74
Diuresis

• Drugs of choice Spironolactone
• ?Inhibiting aldosterone synthesis
• ?Causing natriuresis with sparing potassium
• 100mg400mg/d may induce diuresis
• Furosemide and/or thiazides
• both natriuresis and potassium wasting
• Spironolactone(distal diuretic)Furosemide(loop
  diuretic)
• sufficient to initial diuresis

75
Paracentesis

• Paracentesis of 12 L of ascitic fluid
• effective, less costly
• Albumin or plasma infusion
• expensive
• Ascites reinfusion
• inexpensive
• for refractory or massive ascites

76
Portal-systemic shunts

• Side-to-side portacaval shunts
• Peritoneovenous shunts (Le Veen shunt)
• Transjugular intrahepatic portosystemic shunts
• (TIPS)

77
Management of complications

• Variceal bleeding
• General managements
• maintain intravascular volum
• close monitoring blood pressure, urine output
  and
• mental status
• Medical managements
• use of vasoconstrictors (vasopression or
  somatostatin)
• sclerotherapy
• band ligation
• beta-adrenergic blockade

78
Management of complications

• Spontaneous bacterial peritonitis
• Empirical therapy with cefotoxanine or
  ampicillin
• and an aminoglycoside
• Specific antibiotic therapy are selected
• 1014 days duration
• Recurrent episodes are high

79
Management of complications

• Hepatic encephalopathy
• Hepatorenal syndrome
• Treatment is usually unsuccessful

80
Liver transplantation

• Latest advance in management of cirrhosis
• Frequently done in Western country

81
Summary

• Definition fibrosis nodular regeneration
• Viral hepatitis (China) alcohol (Western
  Country)
• Micro- , Macro- and mixed cirrhosis
• Decompensated stage
• Deterioration of liver function
• Portal hypertension
• Complications
• Hepatic function Child-Pugh score
• Sodium, fluid restriction, diuresis
  (Spirolactone)