2. Definition of cirrhosis
Cirrhosis is derived from Greek word
kirros=orange or tawny and osis=condition
-WHO definition :a diffuse process characterized
by liver necrosis and fibrosis and conversion of
normal liver architechture into structurally
abnormal nodules that lack normal lobular
organisation.
8. PATHOGENESIS OF LIVER FIBROSIS
Normal Hepatic SInusoid
Retinoid
droplets
Fenestrae
Hepatic
stellate cell
Space of Disse
Sinusoidal
endothelial cell
Hepatocytes
9. PATHOGENESIS OF LIVER FIBROSIS
Alterations in Microvasculature in Cirrhosis
• Activation of stellate cells
• Collagen deposition in space of
Disse
• Constriction of sinusoids
• Defenestration of sinusoids
10. NATURAL HISTORY OF CHRONIC LIVER DISEASE
Natural History of Chronic Liver Disease
Chronic
liver Compensated Decompensated
cirrhosis cirrhosis Death
disease
Development
of
complications:
• Variceal
hemorrhage
• Ascites
• Encephalopathy
• Jaundice
11. CLINICAL FEATURES
• Hepatomegaly (although liver may also be small)
• Jaundice
• Ascites
• Circulatory changes
– Spider telangiectasia, palmar erythema, cyanosis
• Endocrine changes
– Loss of libido, hair loss
– Men: gynaecomastia, testicular atrophy, impotence
– Women: breast atrophy, irregular menses, amenorrhoea
• Haemorrhagic tendency
– Bruises, purpura, epistaxis, menorrhagia
• Portal hypertension
– Splenomegaly, collateral vessels, variceal bleeding, fetor hepaticus
• Hepatic (portosystemic) encephalopathy
• Other features
– Pigmentation, digital clubbing
12. COMPLICATIONS OF CIRRHOSIS
Complications of Cirrhosis Result from Portal
Hypertension or Liver Insufficiency
Variceal
Portal hemorrhage
hypertension Spontaneous
bacterial
Ascites peritonitis
Cirrhosis Hepatorenal
syndrome
Encephalopathy
Liver
insufficiency
Jaundice
14. DIAGNOSIS OF CIRRHOSIS – CLINICAL FINDINGS
In Whom Should We Suspect
Cirrhosis?
• Any patient with chronic liver disease
• Chronic abnormal aminotransferases and/or
alkaline phosphatase
• Physical exam findings
• Stigmata of chronic liver disease (muscle
wasting, vascular spiders, palmar erythema)
• Palpable left lobe of the liver
• Small liver span
• Splenomegaly
• Signs of decompensation (jaundice, ascites,
asterixis)
15. DIAGNOSIS OF CIRRHOSIS – LABORATORY STUDIES
In Whom Should We Suspect
Cirrhosis?
Laboratory
• Liver insufficiency
• Low albumin (< 3.8 g/dL)
• Prolonged prothrombin time (INR > 1.3)
• High bilirubin (> 1.5 mg/dL)
• Portal hypertension
• Low platelet count (< 175 x1000/µl)
• AST / ALT ratio > 1
16.
17. DIAGNOSIS OF CIRRHOSIS – CAT SCAN
CT Scan in Cirrhosis
Liver with an irregular surface Collaterals Splenomegaly
18. DIAGNOSTIC ALGORITHM
Diagnostic Algorithm
Patient with chronic liver disease and any of the following:
• Variceal hemorrhage
• Ascites
• Hepatic encephalopathy
Physical findings: Laboratory findings:
Yes No Enlarged left hepatic lobe Thrombocytopenia
Splenomegaly Impaired hepatic synthetic
Stigmata of chronic liver function
disease
Radiological findings:
Yes No • Small nodular liver
• Intra-abdominal collaterals
• Ascites
• Splenomegaly
• Colloid shift to spleen and/or bone marrow
Yes
No
Liver biopsy not
necessary for the Liver biopsy
diagnosis of cirrhosis
19. Management of cirrhosis
-Specific treatment in some pre cirrhotic
lesions:wilson disease—
Dpenicillamine,,hemochromatosis---
phlebotomy,,antiviral drugs for chronic viral
hepatitis
-in established cirrhosis---treatment of
complications
-screening for hepatocellular carcinoma
-liver transplantation
-maintenance of nutrition
20. CHILD-PUGH CLASSIFICATION OF PROGNOSIS IN
CIRRHOSIS
Score 1 2 3
Encephalopathy None Mild Marked
Bilirubin (mg/dl) < 2.0 2.0-3.0 > 3.0
Albumin (g/dl) > 3.5 3.0-3.5 < 3.0
Prothrombin time <4 4-6 >6
(seconds prolonged)
Ascites None Mild Marked
Add the individual < 7 = Child's A
scores: 7-9 = Child's B
> 9 = Child's C
21. MELD SCORE
• MELD = 3.8(SERUM BILIRUBIN –MG/DL)+11.2
IN INR + 9.6 IN SERUM CREATININE – MG/DL+
6.4
22. PORTAL HYPERTENSION
Definition:it is an increase in portal venous
pressure.
-normal portal pressure:5-10mmHg.
-portal hypertension;>12mmHg
-normal portal blood flow:1-1.5L/minute
-- increased resistance to portal blood flow
+hyperdynamic circulation-----formation of
porto systemic collaterals that diver blood to
systemic circulation bypassing the liver
23. MECHANISMS OF PORTAL HYPERTENSION
Mechanisms of Portal Hypertension
• Pressure (P) results from the
interaction of resistance (R) and flow
(F):
P=RxF
• Portal hypertension can result from:
• increase in resistance to portal flow
and/or
• increase in portal venous inflow
24. THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW
Normal Liver
Hepatic
vein
Sinusoid Liver
Coronary
Portal vein
vein
Splenic
vein
25. ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE
Cirrhotic Liver
Portal
systemic
collaterals
Distorted
sinusoidal
architecture
leads to
increased
resistance
Portal
vein
Splenomegaly
26. AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION
An Increase in Portal Venous Inflow Sustains
Portal Hypertension 20
Distorted
sinusoidal
architechure
Portal
vein
↑ Flow
Mesenteric
veins Splanchnic
vasodilatation
27. CAUSES
CAUSES OF PORTAL HYPERTENSION ACCORDING TO SITE OF ABNORMALITY
Extrahepatic post-sinusoidal
Budd-Chiari syndrome
Intrahepatic post-sinusoidal
Veno-occlusive disease
Sinusoidal
Cirrhosis
• Cystic liver disease
• Partial nodular transformation of the liver
• Metastatic malignant disease
Intrahepatic pre-sinusoidal
Schistosomiasis
• Sarcoidosis
• Congenital hepatic fibrosis
• Vinyl chloride
• Drugs
Extrahepatic pre-sinusoidal
Portal vein thrombosis due to sepsis* (umbilical, portal pyaemia) or procoagulopathy (thrombotic
diseases, oral contraceptives, pregnancy), or secondary to cirrhosis
• Abdominal trauma, including surgery
• Malignant disease of pancreas or liver
• Pancreatitis
• Congenital
28. Clinical complications of PHT
VARICES:esophageal,gastric,anorectal,retroperit
oneal.
-portal hypertensive gastropathy and colopathy.
-caput medusae
-ascites
-congestive splenomegaly
-hepatic encephalopathy
29. VARICES INCREASE IN DIAMETER PROGRESSIVELY
Varices Increase in Diameter
Progressively
No varices Small varices Large varices
7-8%/year 7-8%/year
Merli et al. J Hepatol 2003;38:266
30. PROGNOSTIC INDICATORS OF FIRST VARICEAL HEMORRHAGE
Variceal hemorrhage Varix with red signs
Predictors of hemorrhage:
• Variceal size
• Red signs
• Child B/C
NIEC. N Engl J Med 1988; 319:983
31. Treatment of portal hypertension
-treatment of complications:variceal
bleeding,,,ascites…
-endoscopic procedures:sclerotherapy +band
ligation+prophylactic propranolol
32. TREATMENT OF ACUTE VARICEAL HEMORRHAGE
Treatment of Acute Variceal Hemorrhage
General Management:
• Iv acess and fluid resuscitation
• Do not overtransfuse (hemoglobin ~ 8 g/dL)
• Antibiotic prophylaxis
Specific therapy:
• Pharmacological therapy: terlipressin,
somatostatin and analogues, vasopressin +
nitroglycerin
• Endoscopic therapy: ligation, sclerotherapy
• Shunt therapy: TIPS, surgical shunt
33. ENDOSCOPIC VARICEAL BAND LIGATION
Endoscopic Variceal Band
Ligation
• Bleeding controlled in 90%
• Rebleeding rate 30%
• Compared with sclerotherapy:
• Less rebleeding
• Lower mortality
• Fewer complications
• Fewer treatment sessions
34. THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT
Transjugular Intrahepatic Portosystemic
Shunt
Hepatic
vein
TIPS
Splenic
Portal vein vein
Superior mesenteric
vein
35. MANAGEMENT OF UNCOMPLICATED ASCITES
Management of Uncomplicated
Ascites
Definition: Ascites responsive to diuretics
in the absence of infection and
renal dysfunction
Sodium restriction
• Effective in 10-20% of cases
• Predictors of response: mild or moderate
ascites, Urine Na excretion > 50 mEq/day
Diuretics
• Should be spironolactone-based
• A progressive schedule (spironolactone
furosemide) requires fewer dose adjustments
than a combined therapy (spironolactone +
furosemide)
36. MANAGEMENT OF UNCOMPLICATED ASCITES: DIURETIC THERAPY
Management of Uncomplicated Ascites
Diuretic Therapy
Dosage
• Spironolactone 100-400 mg/day
• Furosemide (40-160 mg/d) for inadequate weight loss
or if hyperkalemia develops
• Increase diuretics if weight loss <1 kg in the first week
and < 2 kg/week thereafter
• Decrease diuretics if weight loss >0.5 kg/day in patients
without edema and >1 kg/day in those with edema
• Side effects
• Renal dysfunction, hyponatremia, hyperkalemia,
encephalopathy, gynecomastia
37. EARLY DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)
Early Diagnosis of SBP
• Diagnostic paracentesis:
• If symptoms / signs of SBP occur
• Unexplained encephalopathy and / or
renal dysfunction
• At any hospital admission
• Diagnosis based on ascitic fluid
PMN count >250/mm3
Rimola et al., J Hepatol 2000; 32:142
38. TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)
Treatment of Spontaneous Bacterial
Peritonitis
• Recommended antibiotics for initial empiric
therapy
• i.v. cefotaxime, amoxicillin-clavulanic acid
• oral nofloxacin (uncomplicated SBP)
• avoid aminoglycosides
• Minimum duration: 5 days
• Re-evaluation if ascitic fluid PMN count has
not decreased by at least 25% after 2 days of
treatment
Rimola et al., J Hepatol 2000; 32:142
40. TYPE C HEPATIC ENCEPHALOPATHY IS THE ENCEPHALOPATHY OF CIRRHOSIS
Type C Hepatic Encephalopathy
is the Encephalopathy of
Cirrhosis
• Neuropsychiatric complication of cirrhosis
• Results from spontaneous or surgical /
radiological portal-systemic shunt + chronic
liver failure
• Failure to metabolize neurotoxic substances
• Alterations of astrocyte morphology and
function (Alzheimer type II astrocytosis)
41. STAGES OF HEPATIC ENCEPHALOPATHY
Stages of Hepatic Encephalopathy
Stage Mental state Neurologic signs
1 Mild confusion: limited attention Incoordination,
tremor,
span, irritability, inverted sleep impaired handwriting
pattern
2 Drowsiness, personality changes, Asterixis, ataxia,
dysarthria
intermittent disorientation
3 Somnolent, gross disorientation, Hyperreflexia,
muscle
marked confusion, slurred speech rigidity, Babinski
sign
4 Coma No response to
pain,
42. STAGES OF HEPATIC ENCEPHALOPATHY
Stages of Hepatic Encephalopathy
Confusion
Drowsiness
Somnolence
Coma
1 2 3 4
Stage
43. HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS
Hepatic Encephalopathy Is A
Clinical Diagnosis
• Clinical findings and history important
• Ammonia levels are unreliable
• Ammonia has poor correlation with
diagnosis
• Measurement of ammonia not necessary
• Number connection test
• Slow dominant rhythm on EEG
45. PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY
Hepatic Encephalopathy
Pathogenesis
Toxins
NH3
Shunting
Failure to GABA-BD
metabolize receptors
NH3
Bacterial action
Protein load
46. ASTERIXIS IS THE HALLMARK IN THE DIAGNOSIS OF HEPATIC ENCEPHALOPATHY
Asterixis
47. NUMBER CONNECTION TEST
Number Connection Test Draw a star 70
(NCT)
Time to
complete____________________
End
6 10 25
4
7 9 23
1 11
5 Begin
14
8 24
3
2 Sample handwriting
13
12
17
15 16 22
18 21
19 20
48. TREATMENT OF HEPATIC ENCEPHALOPATHY
Treatment of Hepatic Encephalopathy
• Identify and treat precipitating factor
• Infection
• GI hemorrhage
• Prerenal azotemia
• Sedatives
• Constipation
• Lactulose (adjust to 2-3 bowel
movements/day)
• Protein restriction, short-term (if at all)
49. ACTIONS OF LACTULOSE
Actions of Lactulose
NH3
Decreased pH
NH4+
Lactic acid NH3
Lactulose
Urease-producing Increase
bacteria cathartic effect
50. HEPATIC ENCEPHALOPATHY – TREATMENT SUMMARY
Hepatic Encephalopathy
Treatment: Summary
Increase ammonia
fixation in liver:
• Ornithine aspartate
• Benzoate Flumazeni
l
Shunt
occlusion or
reduction
Decrease
ammonia
production in gut:
• Lactulose
• Antibiotics
• Adjustment in
dietary protein
Editor's Notes
Slide 8 HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER Histological images of two livers. On the left, a normal liver with conserved architecture. On the right, a cirrhotic liver with regenerative nodules surrounded by fibrous tissue (stained blue).
Slide 9 HISTOLOGICAL IMAGE OF CIRRHOSIS Histological image of a cirrhotic liver showing regenerative nodules surrounded by fibrous tissue (stained blue).
Slide 10 PATHOGENESIS OF LIVER FIBROSIS The key pathogenic feature underlying liver fibrosis and cirrhosis is hepatic stellate cell activation. Hepatic stellate cells (also known as Ito cells or perisinusoidal cells) are located in the space of Disse between hepatocytes and sinusoidal endothelial cells (that normally are fenestrated). Normally, hepatic stellate cells are quiescent and serve as the main storage site for retinoids (vitamin A).
Slide 12 PATHOGENESIS OF LIVER FIBROSIS In cirrhosis, activated stellate cells deposit collagen in the space of Disse, leading to defenestration of sinusoidal endothelial cells, and acquire contractile properties that lead to sinusoidal constriction, which is partially responsible for increased intrahepatic vascular resistance.
Slide 14 NATURAL HISTORY OF CHRONIC LIVER DISEASE Cirrhosis represents the end histological stage resulting from chronic liver injury of various etiologies. Initially, cirrhosis is compensated. The transition to a decompensated stage is marked by the development of variceal hemorrhage, ascites, hepatic encephalopathy and/or jaundice. Once decompensation occurs, the patient is at risk of death from liver disease.
Slide 17 COMPLICATIONS OF CIRRHOSIS Cirrhosis leads to two clinical syndromes: portal hypertension and liver insufficiency. Development of variceal hemorrhage and ascites are the direct consequence of portal hypertension, while jaundice occurs as a result of a compromised liver function. Encephalopathy is the result of both portal hypertension (portosystemic shunting) and liver dysfunction (decreased ammonia metabolism). Ascites in turn can become complicated by infection (spontaneous bacterial peritonitis) and by the development of a functional renal failure (hepatorenal syndrome).
Slide 19 DIAGNOSIS OF CIRRHOSIS – CLINICAL FINDINGS Cirrhosis should be investigated in any patient with chronic liver disease. Various physical signs suggest the presence of cirrhosis. In particular, a palpable left lobe with a small right lobe (on percussion) and splenomegaly are highly suggestive of cirrhosis. A recent review of several studies concludes that the listed physical findings, when present in chronic liver disease, confer a high specificity for cirrhosis. However the sensitivity is generally low and the absence of these physical signs does not exclude cirrhosis. De Bruyn G and Graviss EA, BMC Medical Informatics & Decision Making 2001; 1: 6
Slide 20 DIAGNOSIS OF CIRRHOSIS – LABORATORY STUDIES Tests that explore liver synthetic function are serum albumin and prothrombin time, while serum bilirubin investigates the ability of the liver to conjugate and excrete bilirubin. With liver dysfunction there is hypoalbuminemia,a prolonged prothrombin time and hyperbilirubinemia and the presence of either of these findings, in the presence of chronic liver disease, indicates the possibility of cirrhosis. However, an even earlier more sensitive finding suggestive of cirrhosis is a low platelet count that occurs as a result of portal hypertension and hypersplenism. An AST/ALT ratio >1 has also been identified as having a high specificity but a low sensitivity, therefore its absence cannot exclude cirrhosis. Poynard and Bedossa. J Viral Hepat. 1997; 4:199 Dienstag JL, Hepatology 2002; 36 (Suppl 1): S152
Slide 23 DIAGNOSIS OF CIRRHOSIS – CAT SCAN This slide shows typical computed tomography findings in compensated cirrhosis. The contour of the liver is irregular, there is obvious splenomegaly and the presence of collaterals indicates portal hypertension and secures the diagnosis of cirrhosis.
Slide 41 DIAGNOSTIC ALGORITHM Diagnostic algorithm to investigate the presence of cirrhosis in patients with chronic liver disease.
Slide 44 MECHANISMS OF PORTAL HYPERTENSION In fluid mechanics, Ohm’s law states that pressure (P) is dependent upon flow (F) and resistance to flow (R). Therefore, portal hypertension can result from an increase in portal venous inflow, an increase in resistance to portal flow or an increase in both flow and resistance.
Slide 47 THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW The normal liver can withstand significant increases in flow, without resulting in increases in portal pressure. The normal portal venous system is a low-pressure system and vessels draining the intraabdominal organs, such as the coronary vein, drain into it.
Slide 48 ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE The deposition of fibrous tissue and the formation of nodules, disrupts the architecture of the liver, leading to an increased resistance to flow and to portal hypertension. Vessels that normally drain into the portal system, such as the coronary vein, reverse their flow and become porto-systemic collaterals. Additionally, with portal hypertension, the spleen increases in size and sequesters platelets and other formed blood cells leading to hypersplenism.
Slide 65 AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION The initial mechanism in the development of portal hypertension in cirrhosis is an increase in vascular resistance to portal flow mostly due to a distorted sinusoidal architecture. However, a subsequent increase in portal venous inflow secondary to splanchnic vasodilatation, maintains the portal hypertensive state.
Slide 82 VARICES INCREASE IN DIAMETER PROGRESSIVELY Both development of varices and growth of small varices occurs at a rate of 7-8% per year. Although there are no identified clinical predictors for the development of varices, factors associated with variceal growth are Child B/C cirrhosis, alcoholic etiology and presence of red wale marks on initial endoscopy. Merli et al., J Hepatol 2003; 38: 266
Slide 97 PROGNOSTIC INDICATORS OF FIRST VARICEAL HEMORRHAGE In a prospective study, the presence of the following clinical features was associated with a high probability of developing variceal hemorrhage: large variceal size, Child B/C and the presence of red wale markings on varices. North Italian Endoscopic Club. N Engl J Med 1988; 319: 983
Slide 138 TREATMENT OF ACUTE VARICEAL HEMORRHAGE Treatment of acute variceal hemorrhage includes general and specific therapies. General management includes establishing intravenous access and fluid resuscitation. Vigorous fluid resuscitation and transfusion to hemoglobin levels >8 g/dL should be avoided as this could precipitate early variceal rebleeding. Prophylactic antibiotic therapy should be instituted promptly in any cirrhotic patient with gastrointestinal hemorrhage. Specific therapy includes pharmacological therapy, endoscopic therapy and shunt therapy.
Slide 144 ENDOSCOPIC VARICEAL BAND LIGATION Endoscopic variceal ligation consists of the placement of rubber rings on variceal columns with the objective of interrupting blood flow and subsequently developing necrosis of mucosa and submucosa and replacement of varices by scar tissue. Endoscopic therapy is a local therapy that has no effect on the pathophysiologic mechanisms that lead to portal hypertension and variceal rupture. Even though it achieves variceal obliteration, varices will eventually recur. Bleeding is controlled in 90% of cases of acute variceal hemorrhage with a rebleeding rate of 30%. Meta-analysis of trials comparing ligation with sclerotherapy has shown that ligation is associated with lower rebleeding rates, lower number of sessions to achieve variceal obliteration and lower mortality. Complications of endoscopic therapy are related mainly to the development of esophageal ulceration and strictures, significantly more frequent after sclerotherapy than after ligation. Laine and Cook. Ann Intern Med 1995; 123:280
Slide 147 THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT Portal hypertension can be corrected by creating a communication between the hypertensive portal system and low-pressure systemic veins, bypassing the liver, i.e., the site of increased resistance. This communication can be created surgically or by the transjugular placement of an intrahepatic stent that connects a branch of the portal vein with a branch of an hepatic vein, a procedure designated transjugular intrahepatic porto-systemic shunt (TIPS). TIPS is performed by advancing a catheter introduced through the jugular vein into a hepatic vein and into a main branch of the portal vein. An expandable stent is then introduced connecting hepatic and portal systems, and blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein. The procedure is highly effective in correcting portal hypertension but can be associated with complications related to diversion of blood flow away from the liver, namely portal-systemic encephalopathy and liver failure.
Slide 240 MANAGEMENT OF UNCOMPLICATED ASCITES Sodium (salt) restriction is effective in only 10-20% of patients with cirrhotic ascites. Those with mild to moderate ascites and those with adequate natriuresis are more likely to respond to sodium restriction alone. Diuretic therapy is the mainstay of management of uncomplicated ascites. Spironolactone is more effective than loop diuretics such as furosemide and therefore therapy of ascites should be spironolactone-based. A progressive diuretic schedule (spironolactone followed by furosemide) requires adjustment less frequently than a combination schedule (spironolactone + furosemide from the outset) and may be preferable, particularly in the outpatient setting.
Slide 242 MANAGEMENT OF UNCOMPLICATED ASCITES: DIURETIC THERAPY Spironolactone should be started at 100 mg/day (once a day in the morning). The dose should be adjusted every 3-4 days to a maximal effective dose of 400 mg/d. If weight loss is inadequate or if hyperkalemia develops, furosemide can be added at an escalated dose from 40 to 160 mg/day. The weight loss goal is 1 kg in the first week and 2 kg/week subsequently. However, diuretics should be reduced if rate of weight loss is more than 0.5 kg/day (or 1 kg/day in patients with peripheral edema). The common side effects of diuretic therapy include electrolyte abnormalities, renal dysfunction, encephalopathy, and painful gynecomastia (with spironolactone).
Slide 276 EARLY DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS (SBP) A high index of suspicion and early diagnosis are key in the management of SBP. A diagnostic paracentesis should be performed in any patient that presents with any symptom (abdominal pain) or sign (fever, abdominal tenderness) of SBP. Since encephalopathy and/or renal dysfunction may be the only evidence of bacterial infection in a cirrhotic patients, diagnostic paracentesis (and blood cultures) should also be performed in this setting. Since SBP is often asymptomatic and is often community-acquired, a diagnostic paracentesis should be performed promptly in any cirrhotic patient admitted to the hospital, regardless of cause for admission. The diagnosis of SBP is established with an ascitic fluid polymorphonuclear count (PMN) greater than 250/mm 3 . Rimola A, et al., J Hepatol 2000; 32: 142
Slide 287 TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS (SBP) Appropriate empiric antibiotic therapy is based on the administration of a safe antibiotic that will cover the most likely causative pathogens and should be initiated as soon as the diagnosis of SBP is established (ascites PMN count >250/mm3). Based on controlled and uncontrolled trials, the recommended antibiotics are third-generation cephalosporins (cefotaxime and ceftriaxone have been the most utilized) or amoxicillin-clavulanic acid, administered intravenously. In patients with uncomplicated SBP, oral ofloxacin has been shown to be as useful as intravenous cefotaxime, however the use of quinolones depends on the local prevalence of quinolone-resistant organisms. Aminoglycosides, however, should be avoided as they are associated with high incidence of renal toxicity in cirrhotic patients. The minimal duration of therapy should be at least 5 days although, in clinical trials, the median duration of therapy needed for a reduction in ascites PMN below 250/mm 3 is 7 days. A repeat diagnostic paracentesis should be performed 2 days after starting antibiotics and at this time ascites PMNs should have decreased by >25% from baseline. Lack of response should prompt further investigations to rule out secondary peritonitis. Rimola A, et al., J Hepatol 2000; 32: 142
Slide 345 HEPATIC ENCEPHALOPATHY Hepatic encephalopathy is defined as the neuropsychiatric manifestations of cirrhosis of the liver.
Slide 348 TYPE C HEPATIC ENCEPHALOPATHY IS THE ENCEPHALOPATHY OF CIRRHOSIS In cirrhosis, hepatic encephalopathy results from a combination of portosystemic shunting and failure to metabolize neurotoxic substances. Astrocytes are the only cells in the brain that can metabolize ammonia and, in hepatic encephalopathy, changes in the astrocytes are seen (Alzheimer’s type II astrocytosis).
Slide 352 STAGES OF HEPATIC ENCEPHALOPATHY These clinical stages of hepatic encephalopathy depend on the mental state and neurological signs.
Slide 353 STAGES OF HEPATIC ENCEPHALOPATHY Mental stages progress from confusion through drowsiness and somnolence to coma.
Slide 351 HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS. The diagnosis of hepatic encephalopathy is based on history and physical exam findings. Ammonia levels are unreliable, and there is a poor correlation between the stage of encephalopathy and blood level of ammonia. Therefore, measurements of ammonia are not necessary. Psychometric tests such as the number connection test and the EEG are typically used in research studies and not for clinical diagnosis.
Slide 362 HEPATIC ENCEPHALOPATHY PRECIPITANTS Precipitating factors for hepatic encephalopathy include a high protein load, gastrointestinal bleeding or constipation, as well as infection and overdiuresis (leading to azotemia and hypokalemia). Narcotics and sedatives by directly depressing brain function further contribute to hepatic encephalopathy. A commonly seen cause of chronic encephalopathy is the placement of the transjugular intrahepatic porto-systemic shunt (TIPS).
Slide 350 PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY This slide demonstrates how ammonia bypasses the liver, either through porto-systemic collaterals or through a created shunt (transjugular intrahepatic porto-systemic shunt) and ultimately reaches the brain.
Slide 354 ASTERIXIS IS THE HALLMARK IN THE DIAGNOSIS OF HEPATIC ENCEPHALOPATHY This slide shows typical features of asterixis. Asterixis is best noted with the outstretched arm attempting to dorsiflex the hand with the fingers extended. The initial movement is a “scissors” movement of the fingers. Subsequently, there is a downward drift of the hand with incomplete recovery motion, followed by sudden palmar flexion. The hand then returns to the initial position by dorsiflexion.
Slide 357 NUMBER CONNECTION TEST This slide shows a number connection test (left panel). In the NCT, which measures cognitive motor abilities, patients must connect numbers from 1 to 25 printed on paper as quickly as possible. The test score is the time required to complete the test, including the time needed to correct any errors. NCT is influenced by age and educational level. Construction apraxia is noted in the panel on the right, in which a patient with encephalopathy is unable to draw a five-pointed star.
Slide 361 TREATMENT OF HEPATIC ENCEPHALOPATHY Treatment of hepatic encephalopathy involves 1) identifying and treating the precipitating factor, and 2) using lactulose adjusted to produce 2-3 bowel movements per day. Protein restriction is carried out typically when patients have stage 4 hepatic encephalopathy, but may not be necessary. Long-term protein restriction is not required. A vegetable protein diet is better tolerated than an animal protein diet.
Slide 363 ACTIONS OF LACTULOSE Lactulose acts by several mechanisms. The acidic pH decreases urease-producing bacteria which produce ammonia. The proton H+ produced combines with NH 3 to give NH 4 , which is non-absorbable, and results in ammonia excretion in stool. The cathartic effect of lactulose is also helpful. It is important to note that data supporting the benefit of lactulose in hepatic encephalopathy are lacking.
Slide 365 HEPATIC ENCEPHALOPATHY – TREATMENT SUMMARY Hepatic encephalopathy can be treated with agents aimed at decreasing ammonia production in the gut. This strategy includes lactulose or non-absorbable antibiotics such as neomycin, metronidazole, or rifaximin. Change in dietary protein from an animal source to a vegetable source may also be beneficial. L-ornithine L-aspartate and benzoate may increase ammonia fixation in the liver. In patients who have a large portosystemic shunt in the absence of liver disease, occlusion of the shunt may be carried out.
