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Cirrhosis of the liver

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Title: 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

25
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

27
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)

30
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 ?

33
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

36
Portal-systemic collaterals
  • Esophageal and gastric varices
  • Dilation of the remnant of the umbilical vein

  • (???)
  • Dilation of abdominal veins
  • Hemorrhoidial venous (???)collaterals

37
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 (??)

39
(No Transcript)
40
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

58
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


59
Differential diagnosis
  • Hepatomegaly
  • Ascites
  • Complications
  • Upper GI bleeding
  • Hepatic encephalopathy
  • Hepatorenal syndrome

60
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)
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